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Utskriftsdato (11.12.2019)

Hodgkin's lymphoma

There are two main groups of Hodgkin's lymphoma (HL):

  • classical 
  • nodular lymphocyte-rich

Treatment of nodular lymphocyte-rich HL and classic HL differ to some extent. 

Almost 90% of patients are cured of HL. It is the combination of chemotherapies which has markedly improved the survival. Corticosteroids such as prednisolone are also used in many treatment schedules.

Previously, mostly radiation therapy was given for localized disease, however, this caused many long term side effects. Today, regimens are used in which chemotherapy are combined with smaller radiation fields and lower dosages. For stage III/IV HL, chemotherapy regimens are given.

Incidence

Hodgkin lymphoma is rare and represents 0.5% of all new cancer cases in the United States. Hodgkin lymphoma is more common among young adults and among men than women and the average age at diagnosis is 39 years. In 2017, it is estimated to be 8,260 new cases of Hodgkin lymphoma in the United States.

 

Age-specific incidence of Hodgkin's Lymphoma, 2010–2014.

Source: National Cancer Institute. Bethesda, MD, USA

 

 

Incidence of Hodgkin's lymphoma, 1975–2014.

Source: National Cancer Institute. Bethesda, MD, USA

Etiology of Hodgkin's lymphoma

In most cases, the etiology of lymphoma is unknown, but research shows some possible risk factors.

Risk factors

  • Microbes (viruses, bacteria)  
    • The Epstein-Barr virus (EBV) is incorporated into the genome in subgroups of HL, but does not necessarily cause the disease.
  • Impaired immune system
    • HIV infection
    • Patients receiving immunosuppressive treatment, including organ transplantation patients
    • Rare genetic diseases
  • Solvents, dyes, and pesticides. Studies have shown a higher frequency of NHL in people exposed to these substances.

Despite accumulation of lymphoma in families, it has not been possible to find a specific genetic disposition.

Staging of Hodgkin's lymphoma

The Ann Arbor staging system (1971) is used in a modified form, and is used by all hospitals in the Nordic countries. Primary extranodal lymphoma is a separate group and is abbreviated with Pe and staged by analogy to Musshofs suggestion from 1975. Primary extranodal Hodgkin's is extremely rare.  

Nodal lymphomas

Stage I: Disease in the lymph node region (spleen, thymus, and Waldeyer's ring are considered as nodal sites).

Stage II: Disease in two or more lymph node regions on the same side as the diaphragm, or one or more lymph node regions on the same side of the diaphragm with infiltration of adjacent extralymphatic organ/tissue (IIE).

Stage II1: Involvement of two neighboring regions which would naturally be included into one radiation field (this term is not in use for HL). 

 

Stage III: Disease in the lymph node region on both sides of the diaphragm or one or more lymph node regions on both sides of the diaphragm with infiltration of extralymphatic organ/tissue (IIIE).

Stage IV: Diffuse or disseminated disease in one or more extralymphatic organs/tissues with or without involvement of lymph nodes.  

 

Primary extranodal lymphoma

Pe I: Primary involvment of extranodal organ/tissue.

Pe IIE: Primary involvement of extranodal organ/tissue with invasion of other organ/tissue. 

Pe II1: Primary involvement of extranodal organ with spreading to regional lymph nodes.

Pe II1E: Primary involvement of extranodal organ with spreading to regional lymph nodes and with invasion of other organ/tissue. 

Pe II2: Primary involvement of extranodal organ with spreading to lymph nodes outside regional lymph nodes, but on the same side of the diaphragm. 

Pe II2E: Primary involvement of extranodal organ with spreading to lymph nodes outside regional lymph nodes, but on the same side as the diaphragm, as well as invasion of other extranodal organ/tissue. Primary extranodal lesions or lymphoma extension to extranodal lesions are seen more often with aggressive lymphomas (about 40%) than for indolent lymphomas (around 25%).

 

 

 

 

Information additional to Ann Arbor

Extranodal growth

Marked with suffix E. Localized involvement of tissue/organ in close proximity to involved lymph nodes such that direct growth - per continuitatem - is assumed.

Bulky disease

Marked with suffix X (diameter ³ 10 cm).

None/with general symptoms

Marked with suffix A/B.

Spreading-organ
(Stage IV)

Marked with first letter of the organ, for example: Stage IV L/H where L stands for lungs and H stands for liver.

Size of lymph nodes

Lymph nodes in thorax/abdomen/pelvis with smallest transversal diameter at minimum > 1.0 cm are considered pathologically enlarged. 

 

Distribution of Hodgkin's lymphoma stages
Stage Hodgkin's lymphoma
I 21%
II 33%
III 23%
IV 23%

(Norwegian national guidelines for diagnostics and treatment of malignant lymphoma, 2010) 

Subgroup A or B

Patients are classified in subgroups A or B. Subgroup A indicates the patient has not had general symptoms. Subgroup B (B symptoms) have one or more of the following general symptoms: 

  • Unexplained weight loss of more than 10% of body weight within the last 6 months.
  • Unexplained persistent or recurrent fever with temperature over 38°C in the last month
  • Repeated serious night sweats in the last month. These patients must often change bed linens multiple times per night. 

General health status

General health status is an important prognostic factor in line with staging and B symptoms.

WHO performance status is used and is staged accordingly:

  • 0: Able to carry out all normal activities without restrictions.
  • 1: Restricted in physicaly strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. 
  • 2: Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours.
  • 3: Capable of only limited self-care, confined to bed or chair 50% or more of waking hours. 
  • 4: Completely disabled. Cannot carry out any self-care.

Symptoms of Hodgkin's lymphoma

There are three common symptoms associated with lymphoma:

  • night sweats - defined based on wet bed linens that must be changed multiple times in the last month
  • fever - unexplained raise in temperature over 38°C for at least one week
  • weight loss - unexplained weight reduction of more than 10% of body weight during the last 6 months

If one or more of these symptoms are present, it is denoted as a "B symptom". B symptoms occur in less than 40% of patients with HL.

Other symptoms may be:

  • itchy skin 
  • repeated infections 
  • bleeding tendency

Findings

  • Enlarged lymph nodes on the neck, axilla, or groin.
  • Abdominal distension. Lymphoma manifestation can block intestinal passage, which can lead to nausea, vomiting, and pain in the abdomen. 
  • Urine blockage by compression of kidneys and urinary tracts. Symptoms of this may be voiding difficulties, low urine production, fatigue, poor appetite, nausea, or swelling of hands and feet. 
  • Back pain, which may progress to be assosiated with symptoms of spinal cord or nerve compression.
  • Lymphoma in the mediastinum may lead to compression of airways resulting in dyspnea and coughing.
  • Pressure on the superior vena cava may lead to expanded neck veins, swelling of the neck, bulging eyes, and cyanosis in certain cases.

Findings vary based on localization of tumor.  

Differential diagnoses of Hodgkin's lymphoma

  • Carcinoma metastasis, including metastasis from testicular cancer
  • Extragonadal germinal cell-tumors
  • Thymoma
  • Adenomas, for example in the thyroid
  • Infections with enlarged lymph nodes (mononucleosis and throat infection)
  • Sarcoidosis
  • Lateral neck cysts   

If there is bone marrow involvement, there are gradual transitions between certain subgroups of malignant lymphomas (small lymphocytic lymphoma, lymphoblastic lymphoma, Burkitt's lymphoma) and leukemias with equivalent cell types. 

Prognosis of Hodgkin's lymphoma

For Hodgkin lymphoma, 16.2% are diagnosed at the local stage and the 5-year survival for localized Hodgkin lymphoma is 91.5%. The number of Hodgkin lymphoma deaths is highest among people aged 75-84. Death rates have been falling on average 3.7% each year over 2004-2014.

In the United States, the 5-year relative survival rate of patients with Hodgkin lymphoma during the diagnosis period 2007-2013, was 86.4%.

In 2014, there were an estimated 204,065 people living with Hodgkin lymphoma in the United States.

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References on Hodgkin's lymphoma

Epidemiology/pathogenesis/etiology

Jaffe ES, Harris NL, Stein H and Vardiman JW. Tumours of Haematopoietic and lymphoid Tissue. Pathology and Genetics. WHO classification of tumours. IARC press. Lyon 2001.

Ekstrom-Smedby K. Epidemiology and etiology of non-Hodgkin lymphoma – a review. Acta Oncol 2006 45: 258-271

Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD

Staging

Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non- Hodgkins lymphoma. J Clin Oncol 1999; 19: 1244?53.

Lister TA, Crowther D, Sutcliffe SB et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkins disease: Cotswolds meeting. J Clin Oncol 1989; 7: 1630-6.

Survival and prognostic factors

Foss Abrahamsen A, Hannisdal E, Nome O et al. Clinical stage I and II Hodgkins disease: Long-term results of therapy without laparatomy. Experience at one institution. Ann Oncol 1996; 7: 145-150.

Hasenclever D, Diehl V. A prognostic score for advanced Hodgkins disease. International Prognostic Factors Project on Advanced Hodgkin?s Disease. N Engl J Med. 1998; 339: 1506-14.

Cancer in Norway 2013, Cancer Registry of Norway, Institute of Population-based Research. Oslo, Norway

The International non-Hodgkins lymphoma prognostic factor project. A predictive model for aggressive non- Hodgkins lymphoma N Engl J Med 1993; 329: 987-94.

Solal Séligny P, Roy P, Colombat P et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258-65.

Histology, immunhistochemistry, and genetic testing

Den norske patologforenings lymfomkode-utvalg: Forslag til Norsk SNOMED for lymfomer, oktober 2001.

Jaffe ES, Harris NL, Stein H and Vardiman JW. Tumours of Haematopoietic and lymphoid Tissue. Pathology and Genetics. WHO classification of tumours. IARC press. Lyon 2001.

Treatment of Hodgkin's lymphoma

Aleman BM, Raemaekers JM, Tirelli U, et al. (European Organization for Research and Treatment of Cancer Lymphoma Group). Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med. 2003 348:2396-406.

Diehl V, Franklin J, Hasenclever D et al. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkins lymphoma: interim report from a trial of the German Hodgkins Lymphoma Study Group. J Clin Oncol 1998; 16: 3810-21.

Foss Abrahamsen A, Hannisdal E, Nome O et al. Clinical stage I and II Hodgkins disease: Long-term results of therapy without laparotomy. Experience at one institution. Ann Oncol 1996; 7: 145-150.

Foss Abrahamsen A, Hannisdal E, Nome O al. Prognostic variables and results of salvage treatment in Hodgkin?s disease. Ann Oncol 1996; 35: 67-72.

Foss Abrahamsen J, Andersen A, Nome O et al. Long- term risk of second malignancy after treatment of Hodgkins disease: the influence of treatment, age and follow- up time. Ann Oncol 2002; 13(11): 1786-91.

Sankila R, Garwicz S, Olsen JH et al. Risk of subsequent malignant neoplasms among 1641 Hodgkins disease patients diagnosed in childhood and adolescence: A population-based cohort study in the five Nordic countries. J Clin Oncol 1996; 14: 1442-6.

Schellog G. The balance between cure and late effects in childhood Hodgkins lymphoma: The experience of the German-Austrian Study-Group since 1978. Ann Oncol 1996; 7 (Suppl 4): 67-72.

Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin disease. N Engl J Med 2003; 348: 2386-95

Travis LB, Hill D, Dores GM et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin’s lymphoma. J Natl Cancer Inst 2005; 97: 1428-37

Diagnostics of Hodgkin's lymphoma

Positive developments in diagnosis of malignant lymphoma have taken place in the last 10-15 years. New advancements in immunology and cytogenetics/DNA technology, especially use of immunophenotyping in diagnostics has facilitated better classification and certainty of diagnoses in some cases.  

Examinations

  • Evaluate the rate of growth of the disease and of any possible spontaneous remission. 
  • General status emphasizing findings of nodal tumor and hepato/splenomegaly. Findings may be drawn, with measurements, on a body contour for later comparison during treatment.
  • Record whether there have been B symptoms (weightloss, fever, pathological night sweats) or other general symptoms.  
  • Blood status with differential count of leukocytes, possibly blood smear, creatinine, urea, electrolytes, liver function tests, ESR, albumin, total protein, serum protein electrophoresis, serum iron, TIBC, beta-2 microglobulin, serological evaluation for CMV, HIV, hepatitis B/C, EBV.   
  • Urine tests (stix analysis and/or microscopy), protein electrophoresis.
  • Chest X-ray is taken routinely for all lymphoma types.

CT and ultrasound

  • Abdominal/pelvis CT are standard examinations for lymphoma evaluation.
  • Neck CT for clinical neck tumoror in the ear-nose-throat area where histology shows Hodgkin's lymphoma with diaphragm involvement. 
  • Thoracic/axillary CT. Consider supplementation with MRI or ultrasound with suspicion of involvementof chest wall or pericardium. 
  • Ultrasound of liver, spleen, paraaortal space is done in addition for all patiens with Hodgkin's lymphoma, especially in case of ambiguous findings on abdominal CT. 

Histopathological examinations

The WHO classification system uses a multiparametric approach to lymphoma classification involving a morphological examination, immunophenotype examination, molecular genetic, cytogenetic, and sometimes virological and clinical data combined. This combined evaluation creates the diagnostic foundation for the lymphoma type, or more specifically, the lymphoma entity.

  • A clonality examination either with immunophenotyping or molecular genetic examination is necessary to diagnose post-transplantation lymphoproliferative disease. 
  • Confirmation of Epstein-Barr virus is necessary to diagnose extranodal NK/T-cell lymphoma (nasal type).
  • Clinical information regarding mediastinal localization is necessary to diagnose mediastinal (thymic) large cell B-cell lymphoma.

Since it is not known in advance which pieces of information and parameters will create the basis for the diagnosis, the tissue must be sent by a standardized procedure to the pathologist together with relevant clinical information.

Relevant clinical information to be included for pathologist

  • Tissue type 
  • Purpose of the examination: diagnostic test, follow-up, suspicion of hematological disease
  • Disease localization: lymph node, extranodal, splenomegaly, hepatomegaly, leukemia
  • Disease debut
  • Short disease history: organ transplantation, HIV or Hepatitis C virus infection, long-term drug therapy such as methotrexate or diphenylhydantoin
  • The pathologist should always be informed of the risk of infection with hepatitis, mycobacteria, or HIV.

Bone marrow aspiration/biopsy

The cells in the blood and lymph system originate from stem cells in bone marrow. For lymphoma, a bone marrow examination is performed.

Blood and bone marrow smear

A smear can provide supplementary information to a bone marrow biopsy since the morphological evaluation of small cell lymphomas is more exact. For instanse diagnosing large granular T-lymphocyte leukemia is more difficult with a bone marrow biopsy alone.

Flow cytometric examination

A flow cytometric examination has two significant advantages:

  • Multiparametric immunophenotyping gives a more exact immunophenotype of cells. This is important if identification of co-expression of markers in the same cell population is wanted. A typical example of this is confirmation of restriction for immunoglobulin light chain expression in B-cell neoplasias.
  • The technique is also more sensitive for the identification of small tumor populations.

It is strongly recommended that the person responsible for the flow cytometry evaluates the morphology of the received material before it is analyzed, or has the morphology evaluated by a qualified person near at hand. In this way the panel of markers to be evaluated in flow cytometri can be narrowed an tailored to the relevant differential diagnosis. This will greatly increase the benefit of the examination.

Fine needle aspiration

Fine needle aspiration/biopsy will without question provide the quickest result/diagnosis.

Cytogenetic examination

This is not part of the routine examination for most cases of malignant lymphomas, but should be performed if there is suspicion of lymphoblastic lymphoma or Burkitt's lymphoma. Many types of malignant lymphoma are characterized by specific chromosomal abberations, and confirmation of these can clarify an otherwise difficult diagnosis.

PET-CTexamination

We emphasize that PET should be used primarily for patients where the result will have consequences for treatment. Newer studies for both aggressive non-Hodgkin lymphoma and Hodgkin's lymphoma show that PET performed after 2-4 chemotherapy cycles is a good method for monitoring the effect of the therapy and that patients not having a negative PET scan have a greater chance for progression or recurrence. It is still not well documented, however, that changing of treatment based on an early positive PET examination will improve the patient's prognosis, even if this appears probable. A possible consequence of a positive PET after 2-4 cycles is changing to another regimen and in some cases this may be followed by harvesting of stem cells and allowing the patient to undergo an autologous stem cell translant.

It is expected that use of PET/CT for lymphoma will increase significantly in coming years. PET examinations cost about 16,000 NOK each.

Heart, lung, and kidney function examinations

Patients undergoing chemotherapy and/or radiotherapy should have the function of organs at risk tested before treatment starts. Possible situations where organ function testing is appropriate are:

  • Lung function tests before full ABVD chemotherapy (bleomycin is toxic to the lungs in high doses)
  • Heart function examination (MUGA scintigraphy or echo examination) in elderly patients before CHOP chemotherapy (doxorubicin is cardiotoxic in high doses)
  • Renography with glomular filtration rate before radiation therapy to the retroperitoneum where parts of the kidneys are included in the field of radiation.

Explorative laparotomy

Explorative laparotomy is performed if the disease evaluation is ambiguous, and where clarification of this will provide significant therapeutic consequences.

Endoscopy

Endoscopy is performed for involvement of Waldeyer's ring and primary extranodal disease with positive or suspicion of gastrointestinal involvement. Upper endoscopy should in addition be carried out for symptomatic patiens with mantle cell lymphoma and marginal zone lymphomas regardless of localization and stage.

ENT examination

This is performed if there is involvement of lymph nodes on the neck and ear/nose/throat area.

Dental treatment

Patients who will be given radiation therapy to the oral cavity or chemotherapy that is expected to cause serious bone marrow suppression should be examined by a dentist for treating possible sites of infection. Patients are simultaneously instructed and given advice on oral hygiene.

Sperm banking

Men who will have chemotherapy or radiotherapy under the diaphragm must be informed of the possibility of sperm banking.

Ovarian tissue banking

Ovarian tissue banking is still considered experimental. Only a few children are born worldwide after reimplantation of ovarian tissue. An entire ovary or pieces of an ovary is removed and frozen. After freezing and thawing, sections of subcapsular ovarian tissue is implanted in the remaining ovary, skin, or freely in the abdominal cavity for later hormone stimulation and IVF. The upper age limit is 35 for extraction. Patients appropriate for this procedure are young women who will undergo treatment with a significant chance for infertility such as autologous and allogeneic stem cell transplantation and radiation therapy to the pelvic region and where the ovaries cannot be relocated out of the radiation field by ovariopexy.

Since the procedure itself probably poses an increased risk for premature menopause and infertility, it should not be offered to women who will complete more ordinary chemotherapy.

PROSEDYRER

Bone Marrow Aspiration and Biopsy from Iliac Crest

General

The cells in the blood and lymph system originate from stem cells in the bone marrow. A bone marrow examination is performed to diagnose lymphoma, leukemia, and metastasis to bone marrow. The examination usually includes an aspiration and/or biopsy from the iliac crest. When diagnosing Hodgkin's lymphoma, an aspirate and biopsy are taken from both sides. Sometimes, aspiration from the sternum is appropriate. In special cases, the aspiration is performed with the help of image guidance in cooperation with the nuclear medicine department. 

A bone marrow examination involves:

  • Smear for primary examination, otherwise for special indications
  • Imprint of biopsy - the biopsy is placed on the slide glass and rolled out. This can be done if there are problems with the aspirate.  
  • Peripheral blood smear is taken if there is suspicion of leukemization (malignant cells in the blood circulation)

An expanded examination may include

  • Flow cytometry immunphenotyping (marker testing)
  • Cytogenetics (chromosome testing)
  • Other molecular testing (For example PCR: polymerase chain reaction, FISH: fluorescence in situ hybridization) 
  • Special examinations associated with studies

The examination is usually performed under local anesthesia. General anesthesia is reserved for children and/or very anxious patients.

Indications

  • To diagnose lymphoma patients
  • Diagnosis of lymphoma infiltration of bone marrow
  • Diagnosis of hematological diseases
  • To check the effect of radiation/chemotherapy on bone marrow if there are problems with long-term cytopenia
  • To diagnose metastatic tumors in bone marrow

Goal

  • To diagnose or exclude disease involvement in the bone marrow

The only contraindication for carrying out a bone marrow biopsy is serious hemophilia. This must be performed in cooperation with a hemophilia clinic.

In case of warfarin treatment, the INR should be ≤ 3.

NSAIDs/ASA need not be discontinued. One should be aware of possible thrombocytopenia.

Equipment

  • Surgical drape
  • Steri strips  
  • Scalpel head
  • Cannulas: blue, pink, and long green
  • Syringes 1 x 10 ml and 2 x 5 ml
  • Local anesthesia
  • Aspiration cannula: short or long as needed. Short is used on the sternum. 
  • Biopsy needle
  • Gloves
  • Sterile care kit
  • Sterile swabs
  • Broad-spectrum antiseptic
  • Pen for marking
  • Straw to mark the puncture point
  • Methanol-stable pen for marking slide
  • 8 slides marked with the patient's initials date of birth if smear is required. Three of them should be marked with the patient's full surname and birth year.
  • Equipment for drawing blood 
  • Fast-acting anticoagulant

Preparation

  • The patient should be sufficiently informed about why the test is being taken and how it will be carried out
  • The examination is carried out by a doctor and usually takes 20-30 minutes.
  • The patient should lie comfortably on the opposite side of the point of puncture.
  • Place a drape under the point of puncture to catch anything which might spill.
  • Patients to be given general anesthesia shall have premedication.

Implementation

This is an aseptic procedure.

Finding the level for puncture

  • Locate the upper iliac crest with access to the posterior iliac spine. 
  • Find the midline by the spinous process.
  • Feel the iliac crest between fingers with the left hand. On an average body frame, the location for sample taking will be about 8 cm caudal to the iliac crest and about 5 cm lateral to the midline of the spinous process.
  • Mark with pen.
  • The point of puncture is marked (for example with a straw).
  • Wash with colored chlorhexidine 5 mg/ml.

Local anesthesia

Correct injection of local anesthesia is crucial for the patient's experience of the procedure.

  • Inject 5–10 ml Xylocain® 10 mg/ml with adrenaline to reduce bleeding in the area.
  • Inject a minimal amount intracutaneously.
  • The patient will feel when the needle apex meets the periosteum. 
  • Rotate the syringe 180° to distribute the local anesthesia in the area.
  • Allow the anesthesia to work before expanding the area by angling the cannula in four directions.
  • To keep the cannula from simply turning in the same area, the cannula should be pulled back slightly each time before changing directions.

Bone marrow aspiration

  • Make a small incision with the scalpel before the biopsy to avoid unnecessary trauma of the skin. The incision will heal better.
  • Insert the cannula toward the posterior iliac spine. Find the middle of the crest and rotate the cannula with careful pressure as it perforates the cortex.
  • When the cannula reaches the spongy bone, the resistance will be significantly less.
  • Some patients experience pain when the cortex is perforated.
  • Remove the mandrin.
  • Attach a 5 ml syringe to the aspiration cannula.
  • Quickly aspirate 0.2–2 ml of marrow for a normal bone marrow smear.
  • Plug the aspiration cannula.

Making the smear

  • Hold the syringe with the cannula pointing down. The bone marrow plugs contain lipids and will then rise.
  • Place 3 small and 7 larger smears on the slides.
  • Redraw up a small amount of the blood on the smears by tilting the slide and aspirate the blood which collects below the smear. This must be done before the smear coagulates.
  • Prepare some regular smears and some with pressure applied.
  • The smears should be dried in air using a fan before fixation and staining.

Aspiration for flow cytometry

  • Aspirate in 0.5 ml Monoparin 1000 IE/ml in a 5 ml syringe to prevent coagulation of the aspirate.
  • Some connect a new aspiration cannula and others use the same cannula.
  • Aspirate 4–5 ml of bone marrow in the syringe containing Monoparin.
  • Carefully pull out the aspiration cannula.
  • Carefully inject the aspirate into a 10 ml specimen container.
  • Compress with swabs.

Punch biopsy

The punch biopsy is carried out as a continuation of the procedure. A cylinder of the bone is removed by drilling a core sample. 

  • Use a biopsy cannula.
  • Enter via the aspiration incision.
  • Insert the biopsy cannula toward the posterior crest. Find the middle of the crest to avoid starting the biopsy-taking on the edge of the iliac crest.
  • Rotate the cannula with steady pressure until it fastens in the hip bone. Avoid sliding into an unanesthesized area.
  • When the cannula is fastened in the to the hip bone, retrieve the mandrin. Turn the cannula so that it points toward the anterior superior iliac spine and has a slope of about 15°.
  • Ask the patient if they experience any pain during the procedure. Pain may indicate that the cannula is pointing in an unfavorable direction. 
  • If it starts to hurt, the insertion must stop. If the cannula is inserted far enough in (2–3 cm), the procedure can be concluded. If the cannula is not inserted far enough, attempt to alter its direction. If the patient still experiences pain, the cannula should be retrieved. A new biopsy attempt can be made with a new puncture next to the initial one. 
  • Insert the "withdrawal spoon" in the cannula.
  • Rotate the biopsy cannula 2–3 rotations in both directions to "loosen" the biopsy.
  • Retrieve the biopsy cannula with the "withdrawal spoon." 
  • Compress the wound well.
  • Carefully take out the spoon with the biopsy.
  • Put the biopsy in saline. 
  • Wash away any blood from the patient. Do not use alcohol since this will fixate the blood. Use sterile swabs and NaCl or cold water.
  • Close the incision with strips. Do not use using sutures to avoid a separate consultation for removal. Sutures increase the risk of infection.
  • Apply an adhesive bandage. 
  • The patient may return to the ward or home after the procedure. 

Follow-up

  • The risk of complications is minimal.
  • For anticoagulation/thrombocytopenia, observe for local bleeding, compression.
  • The bandage should be kept clean and dry for 4–5 days - use a shower bandage.
  • The strips can be removed after 7 days.
  • No other restrictions or observations.
Bone marrow aspiration and biopsy from iliac crestBone marrow aspiration and biopsy from iliac crestBone marrow aspiration and biopsy from iliac crestBone marrow aspiration and biopsy from iliac crest
Bone marrow aspiration and biopsy from iliac crestBone marrow aspiration and biopsy from iliac crestBone marrow aspiration and biopsy from iliac crestBone marrow aspiration and biopsy from iliac crest

Fine needle biopsy, non-aspiration technique

General

Fine needle biopsy is a simple and cost-effective method causing little discomfort for the patient.

It can be used for palpable tumors in patients with cancer or where possible spreading can be confirmed or excluded. It can also be used on patients without a previous cancer diagnosis, either to achieve a diagnosis or to determine further relevant examinations. This method gives the quickest result/diagnosis.

Indications

  • Fine needle biopsy is performed on palpable surface nodes

Goal

  • To obtain a specimen which provides a basis for making a diagnosis.

Equipment

  • 1 x 20 ml syringe filled with air
  • Cannulas, size depending on lesion
  • Colorless chlorhexidine, 1 mg/ml
  • Gloves
  • 3–4 slides
  • 3–4 cover glasses
  • RPMI-medium
  • Labels to mark slides and RPMI-glass
  • Staining solutions (haemacolor)
  • Water for rinsing
  • 6 tubs for staining/rinsing
  • Gauze pads
  • Bandage
  • Fan or hairdryer for drying specimens
  • Microscope, 10X or 20X objective
  • Examination table

Preparation

Explain to the patient precisely what will happen and why.

Implementation

The patient should sit or lie on the examination table - whatever gives the best result. 

  • Wash the area for puncture with colorless chlorhexidine 1 mg/ml.
  • Allow the skin to dry.
  • Palpate the node/tumor.
  • Find the best position for puncturing.
  • Fix the lymph node/tumor between your fingers.
  • Puncture quickly through the skin with the cannula.
  • Move the cannula back and forth into the node in different directions (approximately 2–3 movements/second).
  • When (after 3–4 seconds) the material is visible in the upper part of the cannula passage, the cannula is retrieved.
  • Put a pressure on the point of puncture if needed.
  • Connect the cannula to the syringe filled with air.
  • Carefully spray the specimen from the cannula onto the slide.
  • If the suspicion of lymphoma or tumor is difficult to confirm, repuncture and put some material in the RPMI medium from a new puncture (for flow cytometry/molecular examination etc. Which type of examination is determined after microscopic examination.)
  • Smear the specimen on the slide.
  • Dry the specimen under a fan or hairdryer.
  • Staining: fixation fluid with methanol + haemacolour + rinsing in water  
    • 5 dips in fixation fluid. Allow the solution to drip off on paper. 
    • 3 dips in staining solution 1.
    • 6 dips in staining solution 2. Allow the solution to drip off onto paper.
    • Rinse in two tubs with clean water.
  • Examine the specimen under the microscope with a 10X or 20X objective.

 

 

Observations

  • After the puncture, slight bleeding may occur.
  • Other complications are very rare.
Fine needle biopsy, non-aspiration techniqueFine needle biopsy, non-aspiration techniqueFine needle biopsy, non-aspiration techniqueFine needle biopsy, non-aspiration technique
Fine needle biopsy, non-aspiration techniqueFine needle biopsy, non-aspiration techniqueFine needle biopsy, non-aspiration technique

Positron Emission Tomography (PET)

General

Positron Emission Tomography (PET) is a nuclear medical examination method. PET is a well-documented, well-established and very useful tool in oncological imaging.

Indications

Oncological imaging for:

  • Staging the primary diagnosis and recurrence
  • Evaluating the effect of aggressive chemotherapy treatment
  • Evaluating the effect of completed treatment, including differentiating scar tissue from viable residue tissue
  • Suspicion of recurrence (for example, increased level of tumor marker in the blood)

Goal

  • To provide concrete diagnostic information that will provide a basis for the choice of the best possible treatment.

Definitions

PET has a very high sensitivity and can register absorption of radiopharmaceutical agents in extremely low concentrations. Since the central atoms in biochemical compounds (carbon, oxygen, nitrogen) all have positron-emitting isotopes that can be produced in small hospital cyclotrons, it is possible to mark a number of central molecules such as oxygen, water, amino acids, various metabolites, hormones, and neurotransmitters.

For clinical PET, dextrose is usually used where a hydroxide group is replaced by 18F (18-flourine), a compound that is called 18F-FDG (flourine-18 labeled deoxyglucose). 18F-FDG has a high affinity for cells with increased metabolism, for example cancer cells. The substance is transported into the cells and phosphorylates glucose to 18F-FDG-phosphate, but no further break-down occurs. Because cell membranes are impermeable to phosphorylated deoxyglucose, an intracellular accumulation of the substance occurs.

Limitations

  • Small tumors ( < 0,5 cm) and tumors with low to moderate absorption can escape detection.
  • Inflammatory conditions will produce increased absorption.
  • For patients with diabetes (especially those requiring insulin) and non-fasting patients, high muscular absorption will reduce the sensitivity for tumor detection.
  • Some tumor types have low FDG absorption (for example, prostate and bronchoalveolar carcinoma).

Sources of error

  • Infections and inflammatory conditions (including post-operative changes) will result in increased absorption.
  • Normally, the intestine can have a high absorption.
  • Myocardium often displays high absorption, also in fasting patients.
  • 18 F-FDG is excreted through the kidneys and FDG in the urinary tract can be misinterpreted.
  •  Absorption in brown fat tissue can be misinterpreted as a tumor if PET is not compared with CT. PET/CT combined in the same apparatus gives better specificity than PET alone.

Equipment

  • PET/CT-scanner  
  • Radio-pharmaceutical agent: 18F-FDG is formed by radiating a heavier natural variant of oxygen with protons. This occurs in a cyclotron. Fluorine-18 (18F) is produced at the hospital cyclotron located at Rikshospitalet .

Preparation

Patient preparation depends on the clinical diagnosis.

  • Fast for at least 6 hours before the examination in order to increase the absorption of 18F-FDG. But the patient should drink plenty (2-4 glasses per hour. Water, tea, or coffee without sugar or cream/milk added can be substituted for water.
  • Measurement of s-glucose is performed before injection of 18F-FDG.
  • After intravenous injection of 18F-FDG, it is very important that the patient lies relaxed in a quiet room without talking and avoiding all forms of stimuli, in order to avoid non-specific absorption of 18F-FDG in the muscles.
  • Tranquilizers and painkillers are often administered prior to the injection.
  • The patient should be warm and comfortable prior to the injection in order to prevent absorption in the brown fat, which may affect the interpretation.

There will be other precautions for neurological and cardiological diagnoses.

Implementation

  • The patient must lie completely still while the images are being taken.
  • A whole-body examination takes approximately 25 minutes.
  • For PET, tissue absorption is displayed by positron-emitting, radiopharmaceutical preparations.

Registration of emission

  • The positron is considered a positively charged electron.
  • When the positron leaves the radioactive core, it will travel up to a few millimeters before it collides and fuses with an electron and is transformed into energy; this is called annihilation.
  • The mass of the positron and the electron is transformed into energy in the form of two photons, each of 511 keV, which are emitted in diametrically opposing directions (180°).
  • A ring detector around the patient will catch the photons.
  • The two photons will encounter the ring detector at the same time (coincident detection), and because they have moved in exactly opposite directions, the detection will precisely localize the radiation focus (for example, a lymph node with tumor tissue).
  • A modern PET-camera with ring detector can map the entire body in 20 minutes.
  • The PET-scanners have integrated CT, so that the information from PET is accurately localized anatomically.

Examples of findings

  • Anal cancer: Anal tumor and metastasis in lymph node
  • Hodgkin's lymphoma (HL): HL with involvement of: soft tissue in the larynx , vertebra L4 ,  os pubis L  and femur
  • Cancer of the rectum: Adenocarsinom in rektosigmoideum liver metastases
  • Intracranial tumors: Astrocytoma grade II/III, left parietal lobe  high-grade glioblastoma, right frontal lobe 
  • Lung cancer: Lung tumor  lung cancer with lymph node spread
  • Sarcoma: Soft tissue sarcoma in the left thorax
  • Cancer in the esophagus: Tumor in the distal esophagus
  • Colon cancer: Metastasis-suspect lesion in adrenal gland

Follow-Up

  • At the end of the examination, the radioactivity is small, but the patient should keep a distance (about 3 meters) from children and pregnant ladies the day of the scan.
  • The result will normally be available the following day.
Postitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
Postitron emission (PET) with <sup>18</sup>F-FDGPositron emissions tomografi (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) <sup>18</sup>F-FDG
Positron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomography (PET) <sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
Postitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDGPostitron emission (PET) with <sup>18</sup>F-FDG
Positron emmissions tomography (PET) with<sup>18</sup>F-FDGPositron emission tomography (PET) with <sup>18</sup>F-FDGPositron emission tomografi (PET) with <sup>18</sup>F-FDG

Treatment of Hodgkin's lymphoma

It is important that treatment follows the recommended intervals. If these intervals cannot he upheld, for example due to neutropenia, bone marrow stimulating growth factor (G-CSF) can stimulate the bone marrow to reach an acceptable level before each planned course of chemotherapy. 

Surgery is rarely indicated for Hodgkin's lymphoma.

Curing the disease is still possible after recurrence, and in some cases, after later recurrences. The prognosis of patients with recurrence is better if the relapse develops late after completion of the primary treatment. If recurrence occurs outside the radiation field where radiotherapy was the only primary treatment modality, the prognosis is almost as good as at the time of diagnosis. It is important that the role of radiation therapy in treatment of recurrence is evaluated before chemotherapy begins.

Responsibility for treatment of Hodgkin's lymphoma is centralized to the university hospitals.

 

Surgery of Hodgkin's lymphoma

Surgical biopsies are the preferred specimen for the histopathological diagnosis of all lymphomas, and this is especially true for Hodgkin’s lymphoma (refer to sections on diagnostics). Otherwise, surgery is rarely indicated for Hodgkin's lymphoma.

The following surgical procedures are sometimes performed:

  • Explorative laparotomy
  • Splenectomy

Explorative laparotomy

Explorative laparotomy is performed if other diagnostic examinations do not clarify the disease status in the abdomen, and where clarification of this would lead to significant therapeutic consequences. Explorative laparotomy, or possibly laparoscopy, for obtaining an adequate biopsy is also performed if a diagnosis cannot be made by another method, for example ultrasound-guided biopsy. 

Splenectomy

In one of three patients with Hodgkin's lymphoma, the spleen is involved. Splenectomy was performed previously for confirmation of this. Newer imaging modalities especially use of ultrasound and modern use of chemotherapy has rendered this procedure unnecessary today. 

In some cases, a splenectomy may be perfomed at the end of treatment to evaluate the disease status.

 

PROSEDYRER

Splenectomy

General

Splenectomy was previously carried out to determine whether there was involvement of the spleen in patients with lymphoma. Newer image diagnostics, especially use of ultrasound has rendered this procedure unnecessary, and chemotherapy is given instead. If the spleen is involved at the start of treatment, a splenectomy may still be considered in some cases after chemotherapy. This is done to evaluate the presence of residual disease. This procedure is also a good alternative to local radiotherapy.

For splenic marginal B-cell lymphoma, splenectomy is usually indicated as the first treatment choice. 

Splenectomy may also in some cases be carried out to relieve symptoms of splenomegaly and hypersplenism.

Indications

  • Splenic marginal zone B-cell lymphoma
  • Other primary splenic lymphoma
  • Other lymphoma with spleen involvement

Goal

  • Clarify residual disease
  • Cure the disease 
  • Palliative

Equipment

Tray for laparoscopy or laparotomy.

Preparation

  • The procedure is performed under general anesthesia.
  • Antibiotic and thrombosis prophylaxis are given.

Implementation

The spleen can be removed laparoscopically or transabdominally by open surgery.

  • The phrenicocolic ligament is devided to gain access to the spleen from behind. 
  • The spleen is mobilized from behind. 
  • The spleen is freed from the stomach by deviding the gastrolienial ligament with the arteria and vena gastrica breves. 
  • The hilum is identified. The arteria and vena lienalis are cut and sutureligated close to the spleen to avoid injury to the pancreas. 
  • Hemostasis is performed.
  • A drain is installed if necessary.

Follow-up

Complications

  • Local infection
  • Septicaemia
  • Bleeding
  • Thrombosis

Drug therapy of Hodgkin's lymphoma

The treatment of classic Hodgkin's lymphoma and nodular lymphocyte-rich Hodgkin's lymphoma are somewhat different. 

Classic Hodgkin's lymphoma

The disease frequently presents in stage I or II above the diaphragm. Patients without risk factors have until the late 90ies been given radiation therapy alone (mainly mantle field irradiation). Patients with risk factors have been given combined chemotherapy and the same radiation fields as patients without risk factors.

The large fields that have been used in the treatment of HL in previous decades may to a large degree explain the high incidence of secondary cancer, cardiovascular diseases and some other late effects in survivors after HL.

Today state of the art therapy for HL internationally combines 2-6 chemotherapy courses with smaller radiation fields for stages I and II.

Treatment for stage III and IV is based on chemotherapy, in some cases supplemented with a smaller radiation field.

Early stage classic Hodgkin's lymphoma (stages IA and IIA)

For localized classic Hodgkin's lymphoma in stages IA or IIA, the treatment program developed by the Nordic Lymphoma Group (1999) is followed. Two (patients without risk factors) to four courses (patients with risk factors) of the ABVD regimen are given in addition to modified involved field radiation therapy 20 Gy (patients without risk factors) or 29.75 Gy (patients with risk factors). The number of courses are determined based on the extent of risk factors, which are given below on the flow chart in the nordic protocol.

Supradiaphragmatic disease

Without risk factors

With risk factors (at least 1)

Non-bulky disease

Bulky disease

< 3 lymph node regions involved

2 non-neighboring regions

ESR < 50

³ 3 lymph node regions involved
 

ESR ³ 50

Chemotherapy, 2 courses ABVD + modified involved field
radiotherapy, 20 Gy

Chemotherapy, 4 courses ABVD + modified involved field
radiotherapy, 29.75 Gy

 

Infradiaphragmatic disease   

Without risk factors

With risk factors (at least 1)

Non-bulky disease

Central/pelvic localization

Lymph nodes in the groin alone (stage IA)

IIA

ESR < 50

Lymph nodes in the groin (stage IA) and ESR ³ 50

 

Bulky disease

Chemotherapy, 2 courses ABVD + modified involved field
radiotherapy, 20 Gy

Chemotherapy, 4 courses ABVD + modified involved field
radiotherapy, 29.75 Gy

Advanced classic Hodgkin's lymphoma (stages IIB – IV)

For advanced classic Hodgkin's lymphoma in stages IIB - IV, combination chemotherapy is given and is sometimes supplemented with radiation therapy to 29.75 Gy to areas considered at risk for later relapse (intital bulky sites, residual masses). Until recently, the ABVD regiment has been the gold standard for treating patients with advanced Hodgkin's lymphoma in many countries. Based on results from a three-armed randomized phase III study directed by the German Hodgkin group where COPP/ABVD, BEACOPP standard, and BEACOPP dose-escalated is compared, Norway has changed the treatment scheme somewhat. This applies to patients with advanced disease and poor prognosis (four or more risk factors according to IPS). These patients are given 2 courses of dose-escalated BEACOPP followed by 6 courses of standard BEACOPP.

Nodular lymphocyte-rich Hodgkin's lymphoma

First line treatment is almost always given with the intent to cure patients with nodular lymphocyte-rich Hodgkin's lymphoma.

In 2011, the treatment for early stage disease (I-IIA) was modified to be identical to the algorithm presented above for classical Hodgkin lymphoma. For advanced stages (IIB-IV) 6-8 courses o ABVD is recommended, and Rituximab is added to day 1 of each course. In the rare case of high risk patients with an IPS over 4 or higher, BEACOPP may be warranted, and again one may consider to add Rituximab.

Chemotherapy for patients over 60 years of age 

The prognosis for Hodgkin's lymphoma is more serious after 60 years of age. The reason for this may be that many elderly patients were previously given the LVPP regimen which gave unacceptable hematological toxicity for this age group. ABVD, which has been the standard in recent years is better tolerated. Still, the treatment program for elderly patients is different from that for younger patients with a more cautious and individualized plan depending on health status and other complicating diseases.

The CHOP regimen has been tested thoroughly on elderly patients with non-Hodgkin's lymphoma and has been used for patients over 60 years with Hodgkin's lymphoma. For localized disease, radiotherapy alone in certain cases is recommended, depending on the condition of the patient and disease localization.

PROSEDYRER

Lymfom HMAS

General

High-dose treatment with stem cell support (HDT with SCS) is intensive chemotherapy treatment used to kill cells in bone marrow. It is sometimes combined with total body irradiation to remove all cancer cells. The treatment causes life-threatening loss of blood-producing stem cells. Stem cells must therefore be harvested from the patient's blood/bone marrow before starting treatment. The stem cells are then transferred back to the patient after the high-dose treatment.

Indications

Standard treatment

  • Recurrence of non-Hodgkin lymphoma of cell types B or T, or where complete remission using first-line treatment is not achieved
  • Lymphoblastic lymphoma in first remission as an alternative to maintenance treatment with chemotherapy with conventional doses. 
  • Recurrence of Burkitt's lymphoma
  • Recurrence of B- and T-cell lymphoblastic lymphoma and in patients not previously undergoing HDT with SCS as primary treatment and where an allogeneic transplantation is not appropriate
  • Certain patients with recurrence of follicular lymphoma
  • Hodgkin's lymphoma with recurrence within two years after start of primary treatment including combination chemotherapy, with no response to primary treatment, other and later recurrences.
  • Certain patients with recurrence of transformed non-Hodgkin B-cell lymphoma.
  • Mantle cell lymphomas and peripheral T-cell lymphomas in first remission. 
  • Multiple myeloma: patients < 65 years of biological age.

Goal

  • Cure the disease
  • Prolong survival for patients with multiple myeloma

Background

In 1987 HDT with SCS was called autologous bone marrow transplantation (ABMT). Cells were given that were harvested from the patient's bone marrow. In 1994, the harvesting of stem cells from peripheral blood was started.

Preparation

To exclude active malignant disease, infections, or organ dysfunction which may complicate HDT with SCS, the following examinations are performed before the procedure:
  • X-ray of lungs
  • Ultrasound of stomach, liver, and spleen if CT is not already performed
  • Teeth status with X-ray of the teeth/teeth roots and sinuses
  • Gynecological examination
  • Blood status
    • Hb, leukocytes with differential count, thrombocytes, reticulocytes
    • Albumin, magnesium, phophorus, amylase, CRP, TIBC, s-iron, CK, s-bilirubin, blood sugar
    • Virus antigen HSV, VZV (varicella zoster virus), CMV (cytomegalovirus), EBV (Epstein Barr virus), hepatitis B and C, HIV
    • Virus antigen CMV-PCR (cytomegalovirus polymerase chain reaction)
  • In patients above 60 years:
    • EKG
    • MUGA scan
    • Heart and lung evaluation

Implementation

Mobilization of stem cells to peripheral blood

Stem cells are the precursors of leucocytes, thrombocytes, and hemoglobin. Normally, only small amounts of these stem cells circulate in peripheral blood. In order to harvest stem cells to HDT with SCS from peripheral blood, the stem cells must be mobilized from bone marrow and out into peripheral blood.

  • The patient is given mobilizing chemotherapy depending on the disease. This is usually the same treatment the patient was given as pretreatment.
  • A few days after the mobilizing treatment, growth factor G-CSF is given
  • Due to the extensive production of stem cells in the bone marrow which is initiated by the growth factor, some patients will experience pain in the back, hips, and legs. Some experience influenza-like symptoms.

Harvesting of stem cells

  • Give the total daily dose of growth factor in the morning. 
  • Determine blood cell count
    • Differential counts including leukocytes and CD 34 positive cells (indicate whether stem cells are sufficient in the peripheral blood simultaneously). When CD 34 and reticulocytes are high enough, stem cell harvesting is initiated.
  • A two-lumen veinous catheter is installed by means of ultrasound-guidance.
  • The patient should use the toilet before harvesting starts to avoid disconnection from the machine during harvest.
  • The patient is given two effervescent tablets of Calcium-Sandoz® before connection to prevent calcium reduction.
  • The patient is connected to the harvest machine: one channel of the catheter is connected to the machine leading the blood from the patient into the machine (outlet). The other channel of the catheter is connected to the tube with carries the return blood from the machine to the patient (inlet). In the machine, the blood is centrifuged and the stem cells will remain in a small bag in the apparatus. 
  • Harvesting takes about 5 hours.
  • CD 34 cells harvested from the blood are counted; 2.0 x 106 cells are required per kilogram of body weight.
  • If a sufficient amount of cells is not harvested, the procedure is repeated the following day. In some cases, it is necessary to harvest three times.
  • The cells are preserved and frozen.

In the event a sufficient amount of stem cells is not harvested from the blood, it may be necessary to harvest stem cells from bone marrow.  Alternatively, plerixafor, a ligand blocking the function of the chemokine receptor CXCR4, thereby releasing CD34+ cells from the bone marrow, may be used in combination with G-CSF.

Chemotherapy

  • The appropriate chemotherapy for high-dose treatment (HDT with SCS) is BEAM- (malignant lymphoma), VIP (testicle cancer) or HD-BUM (Ewing's sarcoma).
  • After two days, the stem cells are reinfused back into the patient

Reinfusion of peripheral stem cells

Side effects of reinfusion

  • A foul taste in mouth from the preservative, DMSO, used for freezing of cells. There is also a distinguished smell which is noticeable by others around the patient the first 24 hours after.
  • Chills or feeling of heat in the head
  • Allergic reaction (very rare)
  • Microembolisms in the lungs (very rare)

Infusion procedure

  • Aspirate 1 ml of adrenalin and 2 ml of diazepam 
  • O2 and suction should be available
  • Warm water bottles and extra dyne should be available 
  • Administer ondansetron
  • The patient is connected to an ECG scope.
  • The patient's stem cells are thawn carefully in a water bath at the department. The stem cells are reinfused through the patient's central vein access, most often a Groshong catheter. 
  • All stem cells harvested are infused. A minimum of 4.0 x 106 cells per kg body weight  May vary from 4.0 x 106. The amount may vary from 90-360 ml.
  • Blood pressure, pulse, and oxygen saturation in the blood are measured during the reinfusion every five minutes. After reinfusion, every 30 minutes for 1 hour or according the doctor's directions.
  • If everything is stable, the patient is disconnected from the scope.

Aplasia phase

Observe for

  • Infections (temperature measurement)
  • Bleeding
  • Diarrhea

After about 7-10 days, the new stem cells start to mature. Lymphoma patients are routinely isolated the day after the reinfusion (low granulocytes). For Ewing's sarcoma patients, multiple days may go by before isolation is necessary because their fall in granulocytes is delayed.

The patient is allowed to leave the isolation after 5pm accompanied by a nurse. After about 10-14 days, the neutrophil granulocytes are  at a level where isolation can be brought to an end (≥ 0.3x109).

  • Almost all patients have infections during the first week after reinfusion of stem cells. Antibiotic treatment starts at the first repeated temperature measurement above 38.5°C or 38.0°C or at other suspicion of infection. The patient may have a fungal or possibly viral infection.
  • Use of growth factor after reinfusion is, in principle, unnecessary. It may be applied in special protocols, or when especially long-lasting leukopenia is expected. 
  • Most patients will develop stomatitis, starting most often one week after concluded treatment. They can have mucositis both in the mouth and down into the esophagus. It may be necessary to give morphine intravenously on a pump.
  • As a direct side effect, many patients experience diarrhea.
  • Bleeding can occur and presents itself as petechiae, most often on the legs or from the nose. More rarely, bleeding occurs in the esophagus and stomach.

Follow-up

Follow-up schedule

  • The patient should be evaluated at a University hospital after 3, 6, 9, and 12 months the first year.
  • Further follow-up occurs at a local hospital every 4-6 months for 5 years. Some protocols require longer follow-up.

Rehabilitation phase

Infection risk/fever

The first weeks after high-dosage treatment, the patient must avoid infection, as much as possible. For fever over 38.5°, a doctor or local hospital should be contacted.

Medications

The patient should continue with Bactrim® every Saturday and Sunday: 2 tablets x 2 until 30 days after the reinfusion. The tablets prevent a special type of lung infection (pneumocystic carinii). Some patients develop an allergy to Bactrim® .

The patient should continue with Geavir® every day: 1 tablet of 200 mg x 3 for 30 days. Geavir® is an anti-viral medication. Some patients have developed herpes zoster after discontinuing Geavir®.

Fatigue/lethargy

Most patients will feel tired and lack of energy for a period after high-dosage treatment (weeks, months, possibly years).

Hair loss

Hair will usually regrow within 6 months. This applies to both body hair and hair on the head.

Hormone disturbances

Most women will stop menstruating and start menopause which may include hot flashes and vaginal dryness. Many therefore need hormone treatment which is evaluated at the three month follow-up. It is highly probable that most patients are sterile after this treatment. The likelihood is greatest for men.

Sexuality

Men may experience loss in libido and in some cases impotence. This is often temporary.Both women and men experience reduced sexual desire for a period. This is often physical and/or psychological. Women may experience problems with vaginal dryness.

Diarrhea

The patient has probably experienced diarrhea during the treatment. For some, the diarrhea lasts or is reoccurring. Diarrhea leads to loss of fluid and salts.

Mouth hygiene

Some patients experience tooth decay due to reduced saliva production, vomiting, and poor mouth hygiene.

Heart/Lung/Kidney problems

High-dosage treatment is a great strain to the body's organs. Some may develop heart problems appearing as rhythm disturbances or heart failure. Reduced lung capacity, lung or kidney failure can also develop . These problems apply to few and are dependent on what types of chemotherapy are used before and during the high-dosage treatment. They also depend on whether the patient has had radiation treatment to  these areas. Smoking is very strongly discouraged as it increases the risk for heart and lung problems.

Muscle/bone/leg cramps

Some patients describe muscle and bone pain. This occurs to varying degrees and is caused by reduced blood circulation or low level of magnesium in the blood.

Reduced production of thyroxin

This occurs in some, especially those irradiated to the neck area. During routine follow-up, thyroxin level in the blood is monitored. Some require a supplement of this hormone.

Lumbar Puncture for Diagnostics and Intrathecal Administration of Chemotherapy

General

Indications

  • A diagnostic tool for suspicion of disease in the brain or meninges.
  • Intrathecal chemotherapy treatment, either as prophylaxis or for treatment of disease.

Goal 

  • Diagnose disease in spinal fluid.
  • Treat or prevent disease and/or CNS affection.

If possible, a lumbar puncture should be avoided in cases of:

  • Thrombocyte values < 30,000 (give thrombocyte transfusion first).
  • For INR values > 1.8. Give Octaplas® or Konakion® first, but weigh this with risk of raised anticoagulation. The effect of Konakion® appears first the day after administration. 
  • Heparin combined with an antiplatelet agent such as Albyl-E®, Plavix®, Tielid®, ReoPro®, Aggrastat®. Confer with an hematologist.
  • Disseminated intravascular coagulation.
  • In cases where a patient is undergoing fibrinolytic treatment or where similar treatment concluded less than 2 days prior.
  • Hemophilia C – confer with an hematologist.
  • Full heparinization.

Equipment

  • Sterile care kit
  • Lumbar needle
  • Introducer needle
  • Bandages
  • Sterile gloves
  • Broad-spectrum antiseptic
  • Local anesthetic
  • 2 ml syringe with cannula
  • Two sterile 10 ml specimen containers (more as needed) if samples of spinal fluid are taken.
  • Drape

Preparation

  • Inform the patient about why and how the examination will be carried out.
  • Examine the patient with ophthalmoscopy before the lumbar puncture if there is a suspicion of increased intracranial pressure.
  • Check the chemotherapy immediately before puncture.

Implementation

  • The patient lies on their side in full flexion or sits on the edge of a bed bending forward. In this position, the ligamenta flava is accessible. 
  • Help the patient to remain in this postion during the entire procedure.
  • Wash the area with chlorhexidine.
  • Draw a line between the highest points of the hip bones. This line crosses the spine right over L4.
  • Mark the area with a pen.
  • As needed, administer local anesthetic.
  • To avoid dura leakage, use a thin needle (25 G, or 0.5 mm or thinner).
  • Insert the lumbar needle between L3 and L4 (or L4 and L5). Precise identification of the injection point is difficult.
  • The needle is inserted at the midline, or sideways, and angled horizontally and sagittally, enough to go through the ligamenta flava or very close to the midline.
  • Reasonable constant resistance is noticed from the tissue until meeting the ligamenta flava, which gives greater resistance. 
  • When the needle enters the epidural space, there is less resistance (like a small "give") . The distance between the skin and the dura mater is usually 40–50 mm.
  • Push carefully through the dura-arachnoid mater.
  • Carefully pull out the mandrin and check if spinal fluid comes out. This should be performed sterile such that it can be repeated if positioning is uncertain.
  • The drop rate of spinal fluid coming out rarely surpasses 1 drop/second.
  • The first drops can drop freely as they might contain blood from the puncture.
  • After the desired amount of spinal fluid is tapped for a specimen, chemotherapy can be injected.
  • The needle is removed and a bandage is applied.
  • The patient is helped back to the supine position.

Cell counting and testing for protein and glucose

  • 1 tube (without additive) with minimum of 20 drops (1 ml) marked "spinal fluid for glucose, protein, and cells" 
  • 1 tube with minimum of 60 drops (3 ml) for cytology and flow cytometry

Follow-up

The patient should lie flat with their upper body lowered 20° for 2 hours after intrathecal chemotherapy is administered. Thereafter, the patient should lie flat to avoid a headache.

For headache

  • Lie flat until the headache goes away.
  • Drink a copious amount of fluid.
  • Paracetamol for pain (unless contraindicated).
  • Up to 500 mg caffeine in 1000 ml fluid over 4 hours.
  • If headache lasts more than 2–4 days and is associated with tight dura leakage with epidural "blood patch" then contact an anesthesiologist
Lumbar puncture

Sun Exposure under Drug Therapy

General

Correct information about the possibility of sunbathing may affect patients health and quality of life.

Precautions in connection with sunbathing should be followed under medical cancer treatment and for 2-3 weeks after end of treatment.

Drug cancer treatment includes chemotherapy, antibodies and other drugs used in cancer treatment.

Indication

Sun exposure in connection with drug cancer treatment.

Goal

Prevent sun damage of the skin during and after cancer drug treatment.

Definitions

Photosensitivity

Increased sensitivity to ultraviolet light have been associated with certain drugs used in cancer treatment. Photosensitivity reactions can be expressed in various ways. They can be phototoxic, which is by far the most common, or photoallergic (8,14). Druginduced photosensitivity is mainly caused by wavelengths in the UVA range, but UVB rays may also be involved (8).

Phototoxicity

A phototoxic reaction is reminiscent of a reinforced sunburn, with redness, edema, pain and increased sensitivity in sun-exposed areas of the skin. This is caused by a photochemical reaction of a photosensitive drug and irradiation of sunlight on the skin, which leads to skin cell death. In severe cases, blistering can occur (14). Symptoms may appear immediately or as a delayed inflammatory reaction (3). Higher doses of medication will give an increased risk of skin reaction (14). Healing of skin area will often lead to a hyperpigmentation that can last from weeks to months before they might disappear (8). Although the incidence of drug-induced photosensitivity is unknown, phototoxic reactions is possibly more common than is diagnosed or reported.

Photoallergy

An immunological reaction usually occurring 24-72 hours after sun exposure. The reaction degenerates as an itchy, eczema-like eruptions. In acute cases, one can see rash liquids. The prevalence of eczema is usually limited to sun-exposed skin, but can in severe cases spread to larger areas of the body. Unlike a phototoxic reaction, photoallergy is less dependent on the dose of the causative drug (8).

Photoinstability

Some drugs can be degraded when exposed to light. This can happen both before administration and when the drug is circulating in the body. This degradation can cause redness/rash and edema of the skin. This applies especially for dacarbazine (9). It is unknown whether the effect of the drug is affected and it is therefore recommended that one avoids direct sunlight as long as the drug is active in the body.

PPE ( palmoplantar erythrodysesthesia = Acral erythema )

PPE is also called hand-foot syndrom. The condition starts with altered skin sensation that develops into burning pain, swelling and redness of palm of the hands and soles of the feet. The symptoms can also occur in other parts of the body that is subjected to pressure, for example under tight clothing. In severe cases large blisters and ulceration can develop. The pain can be so severe that daily activities is limited.

PPE is often seen with liposomal doxorubicin (Caelyx®) and high dose cytarabine, but may in principle occur with any anthracyclines, taxanes and fluorouracil (5- FU® ) (9,14) .

Acne-like rash

Pimple-like eruptions in skin areas with a lot of sebaceous glands such as the face, scalp, chest and neck. In contrast to common acne, the liquid-filled blisters does not contain any bacteria (9,10,15).

Hyperpigmentation

Hyperpigmentation is a common side effect in patients receiving chemotherapy, especially alkylating drugs and antibiotics with cytostatic effect. The area that has increased pigmentation may be localized or diffusely distributed. It can occur in the skin, mucous membranes, hair and nails. Pigment changes can be normalized upon discontinuation of the drug, but it may also persist.

Fluorouracil is one of the most common drugs which can provide hyperpigmentation. Others are; metotrexate, busulfan, doxorubicin liposomal, Hydroksyurea®, procarbazine, bleomycin, cyclophosphamide, doxorubicin , ifosfamide, tegafur, mitoxantrone, daunorubicin, fluorouracil, cisplatin, carmustine, thiotepa, docetaxel, vinorelbine, vincristine, imatinib and combination regimens (14).

An increased pigmentation in sun-exposed areas with the use of methotrexate, fluorouracil and capecitabine is described (16,17,18). Beyond that there is little evidence in the literature  that hyperpigmentation aggravates by sun exposure.

Radiation Recall Dermatitis (RRD)/Photo Toxic recall reaction

Flares of an inflammatory skin reaction in an area of ​​previous radiation damaged skin resulting from sunburn or external radiation. RRD can occur from months to years after the initial radiation damage.

Drugs that can provide RRD are; bleomycin, capecitabine, cyclophosphamide, dactinomycin, cytarabine, daunorubicin, docetaxel, doxorubicin liposomal, doxorubicin, etoposide, fluorouracil, gemcitabine, Hydroksyurea® , idarubicin, lomustine, melphalan, methotrexate, paclitaxel, tamoxifen and vinblastine (14). EGFR inhibitors (cetuximab , gefitinib and erlotinib) may also cause other skin reactions that may be exacerbated by sun exposure (9,10,19).

Preparation

The patient is given written and verbal information by the medical responsible doctor and nurse at the start of the drug cancer treatment, and it is repeated as necessary.

Implementation

General Precautions

Prevention and protection:
  • Limit sun exposure during the first days after the cure.
  • Observe skin daily to detect any skin reactions early.
  • Avoid getting sunburned.
  • View extra care between 12.00-15.00 (2).
  • Wear protective clothing and headgear (2,3,4,5,6).
  • Wide-brimmed hats protect better than caps (2.4).
  • Please note that the window glass does not protect against UVA rays (7).
  • Use sunscreen; to protect against UVA and UVB rays, a minimum SPF 15 (3,4,6,8) is applied several times daily.
  • Use mild skin care products without perfumes.

In case of an eruption, sun exposure (including solarium) should be avoided until the skin is healed. Adverse skin reactions can be alleviated with moist and cooling compresses. Mild cortisone salves can also be highly effective. For very severe cases, systemic cortisone might be necessary (3,6,7,9).

When a photosensitive reaction occurs, it is important to consider what other medications the patient is receiving which can also trigger such reactions. For example, steroids, some antibiotics, diuretics and NSAIDs.

Medicaments that most commonly cause skin reactions

Medicament Common reactions Remedial action
Dakarbazin (DTIC)


Phototoxic/photoinstability
See general precautions
Redness in skin, tingling of the scalp and general unwellness
Avoid sunlight completely the day of the treatment (9)
Methotrexate
Phototoxic

See general precautions
Acne-like rash
Avoid direct sun exposure, heat and humidity (9,10). Avoid soap, alcohol based skin products (9). Use moisturizing products and oil bath (4,9,10).
Palmoplantar erythrodysesthesia = Acral erythema (PPE)

Preventive: Pyridoxin (vitamine B6) (2,6,9)

Avoid sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths

(2, 9)

Fluorouracil (5-FU®)

 

Phototoxic See general precautions
Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2,6,9)

Avoid sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths   (2, 9)

Radiation recall
Treatment as with phototoxic

Kapecitabin (Xeloda®)

 

Phototoxic See general precautions
Palmoplantar erythrodysesthesia = Acral erythema (PPE)

Preventive: Pyridoxin (vitamin B6) (2, 6, 9). Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths (2, 9)

Vinblastin

 

Phototoxic
See general precautions
Radiation recall Treatment as with phototoxic
Doxorubicin liposomal (Caelyx®)
Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths (2, 9)

Tegafur

 

Phototoxic
See general precautions
Palmoplantar erythrodysesthesia = Acral erythema (PPE) Preventive: Pyridoxin (vitamin B6) (2, 6, 9)

Avoidance of sunlight, heat, pressure against the skin and tight clothing can according to some studies have an effect (11,12,13). Use moisturizer.

Treatment/relief: Cortisone salves, cortisone tablets, cold compress, cold baths    (2, 9)

EGFR-hemmere

(Cetuximab, panitumab, erlotinib, gefitinib, lapatinib, vandetanib)

Phototoxic
See general precautions
Acne-like rash
Avoid direct sun exposure, heat and humidity (9,10). Avoid soap, alcohol based skin products (9). Use moisturizing products and oil bath(4, 9, 10).

Beyond the medications listed in the table the literature gives som evidence that these substances may cause phototoxic skin reactions :

  • paclitaxel (Taxol®)
  • docetaxel (Taxotere®)
  • hydroxycarbamide ( Hydroksyurea® )
  • imatinib ( Glivec® ) and Dapson® and that paclitaxel can provide radiation recall .

References


  1. LOV-1999-07-02-63 Pasientrettighetsloven - pasrl. Lov om pasientrettigheter.
  2. Polovich M, White JM, Kelleher LO. Chemotherapy and biotherapy guidelines: recommendations for practice. Pittsburgh, PA: Oncology Nursing Society; 2005.
  3. González E, González S. Drug photosensitivity, idiopathic photodermatoses,and sunscreens. J Am Acad Dermatol 1996;35:871-85;quiz 886-7.
  4. Liffrig, JR. Phototrauma prevention. Wilderness Environ Med 2001;12:195-200.
  5. Tan E. Skin toxicity of chemotherapy drugs [created 2007, last updated  2010 Mar 5]. Hentet 1. desember 2010 fra: http://dermnetnz.org/reactions/chemotherapy-toxicity.html
  6. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseases induced by exogenous agents. J Am Acad Dermatol 1995;33:551-73.
  7. Payne, AS & Bernandin, RM. Sunburn [topic last updated 2010 Oct 06]. I: BMJ Best Practice. Hentet 23. november 2010 fra http://bestpractice.bmj.com
  8. Zhang AY, Elmets CA. Drug-induced photosensitivity [updated 2010 Jan 15]. Hentet 1. desember 2010 fra: http://emedicine.medscape.com/article/1049648-overview
  9. Ulrich J, Hartmann JT, Dörr W, Ugurel S. Skin toxicity of anti-cancer therapy. J Dtsch Dermatol Ges 2008;6:959-77.
  10. Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC.Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006;55:657-70
  11. Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212-6.
  12. Mangili G, Petrone M, Gentile C, De Marzi P, Viganò R, Rabaiotti E. Prevention strategies in palmar-plantar erythrodysesthesia onset: the role of regional cooling. Gynecol Oncol 2008;108:332-5.
  13. Tanyi JL, Smith JA, Ramos L, Parker CL, Munsell MF, Wolf JK. Predisposingrisk factors for palmar-plantar erythrodysesthesia when using liposomal doxorubicin to treat recurrent ovarian cancer. Gynecol Oncol 2009;114:219-24.
  14. Payne AS, Savarese DMF. Cutaneous complications of conventional chemotherapy agents. I: UpToDate [version 18.2 2010]. Hentet 1. desember 2010 fra: http://www.uptodate.com
  15. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol 2008;58:545-70.
  16. RELIS Sør. Hyperpigmentering av cytostatika og forverring av sollys. I: RELIS database 2010, Spm.nr 4736. Hentet 1. desember fra: http://relis.arnett.no/Utredning_Ekstern.aspx?Relis=2&S=4736
  17. Hendrix JD Jr, Greer KE. Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol 1992;31:458-66.
  18. Schmid-Wendtner MH, Wendtner CM, Volkenandt M, Heinemann V. Clinical picture: leopard-like vitiligo with capecitabine. Lancet 2001;358(9293):1575.
  19. Segaert S, Tabernero J, Chosidow O, Dirschka T, Elsner J, Mancini L, et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges 2005;3:599-606.

Preparation of Chemotherapy, Spills, and Cleaning a LAF Bench

General

Preparation of chemotherapy outside of a pharmacy

At Oslo University Hospital, the pharmacy primarily prepares chemotherapy for each patient. If it is necessary to dilute/mix the medicine at the department, then this should occur in a designated room with a LAF bench (laminar airflow bench). Many chemotherapy drugs are carcinogenic and teratogenic, and it is extremely important for health personnel to follow directions for preparation of of these medications. At Oslo University Hospital, all chemotherapy should be prepared and administered by a nurse who has completed a cytostatic treatment course at Oslo University Hospital, or by nurses who are certified cancer nurses from Oslo University College.

Pregnant women and employees under physician orders not to temporarily or permanently work with chemotherapy drugs, should not handle or be exposed to these chemicals. Nursing mothers may handle chemotherapy drugs as long as they follow the general guidelines for chemotherapy handling. For each work place, there should be written guidelines for handling of chemotherapy drugs and for first aid for spills and maintenance of fume hoods etc..

Designated room with LAF-bench to dilute/mix chemotherapy

  • The ventilation should be separate from the main ventilation and fumes should be vented to the outside and if necessary, filtered.
  • The room should be well illuminated for visual control of the fluid.
  • The LAF bench should be a workbench having sterile, filtered air from the ceiling with defined speed and an approved fume hood. The bench should be routinely tested and approved.

Goal

  • To protect nurses and surroundings from exposure to cytotoxic chemicals and to preserve the sterility of the drug.

Handling of chemotherapy spills

Chemotherapy drugs are a heterogeneous group of drugs in which many are known mutagens, teratogens and/or carcinogens. Allergic reactions have also been reported. Studies show that there is a health risk during exposure of chemotherapy drugs and there are guidelines for minimizing exposure of health personnel to these chemicals. Workers in daily contact with these drugs will be more at risk due to the increasing use of chemotherapy. Chemotherapy spills refers to spills during preparation and leakage from infusion bags.

Goal

  • To ensure that spills of chemotherapy drugs or waste materials that contain these chemicals are handled in a safe way to protect health and safety.

Cleaning of LAF-bench

The Norwegian Work Authority recommends that each workplace should have written guidelines for handling chemotherapy drugs, first aid for spills, and maintenance of fume hoods etc. A LAF-bench (laminar airflow bench) is a bench protecting workers from the drug being prepared and also protects from microbiological organisms. Those who carry out cleaning should have training and knowledge of the risk for exposure to chemotherapy drugs.

Goal

  • Maintain a clean LAF bench
  • Avoid contamination and preserve the sterility of the drug 
  • Protect people and surroundings from exposure

Source

Applicable directives and guidelines (www.lovdata.no)

  • Warn against exposure to chemicals at the workplace (Kjemikalieforskriften §24), mandated by The Norwegian Labour Inspection Agency from 5 May 2001, last edition from 26 April 2005.
  • Guidance for chemical directives attachment VII Cytostatica from September 2003 (www.arbeidstilsynet.no).

Equipment

  Preparation of chemotherapy in a hospital

  • 2 pairs of gloves: vinyl gloves inside and sterile, powder-free latex gloves outside
  • Protective coat with long arms/plastic apron
  • Arm protectors
  • LAF bench
  • Dilution fluid
  • Syringes and cannulas
  • Sterile compresses
  • Disposable cloths
  • 70% ethanol
  • Absorbent benchcoat with plastic underside for the work bench
  • If a LAF bench is not used, use a protective mask with aerosol filter and protective goggles.

Handling of chemotherapy spills

Spill kit includes:

  • 2 pairs of nitrile gloves, long
  • 2 pairs of latex gloves, long
  • 2 pairs of shoe covers
  • Plastic coat\apron
  • 1 mask
  • 2 diapers
  • 1 bed absorbent bed sheet
  • 2 plastic bags with zippers (30 x 40 cm)
  • 4 thin, white plastic bags (60 x 90 cm)
  • Absorbant material   
  • 8 disposable wash cloths

Washing of LAF-bench

  • Plastic apron
  • Arm protectors
  • Gloves: either double vinyl gloves or special gloves
  • Disposable cloths
  • 70% ethanol
  • Bucket and soapy water
  • Waste container with plastic bag for chemotherapy waste (biohazardous waste)

 

 

Preparation

Preparation of chemotherapy outside of the pharmacy

For preparation of chemotherapy drugs, use gloves and a protective lab coat with long arms or tight-fitting cuffs.   Use two pairs of gloves where the inner pair is vinyl or other latex-free material. The outer glove should be sterile and of latex or other material which is impenetrable.  The gloves are recommended to be changed every half hour for preparation of chemotherapy drugs, and right away with spills.

  • Start the LAF-bench a minimum of 30 minutes before use.
  • Wash hands
  • Put on the inner gloves
  • Disinfect the work surface with 70% ethanol
  • Cover the work surface with a benchcoat. This should not cover the vent; otherwise, the bench will not function properly.
  • Read the dilution directions and find the necessary equipment and medications as described.
  • Choice of dilution system/fluids
    • A transfer cannula should be used in preference to a syringe where possible to maintain a closed system as much as possible.
    • If a syringe is used: use a syringe with Luer lock connection. These have a better connection between the syringe and the cannula.
  • Check the expiration on the drug packaging and infusion fluid.
  • Check that the drug in liquid form does not contain particles or visible solids.
  • Check that the packaging does not have any cracks or leakages.
  • Perform necessary calculations, date, and sign the work form.
  • Obtain another nurse to double check: right patient, work form, drug, dosage, fluid type and volume, as well as calculations.  All checks should be against the original ordination. The person doing the check should sign and date it.
  • Set out necessary equipment on the LAF-bench or where the work will take place. The equipment should be placed in the corner within the ventilation of the LAF-bench.  Remove the outer packaging of the sterile gloves and lay the gloves on the bench.
  • Put on the protective clothing (coat/apron and arm protectors)
  • Put on the sterile gloves in the bench
  • Disinfect the rubber membrane on the infusion bag and hood windows as well as the ampules.
  • Make sure the protective glass on the LAF-bench is pulled down to the correct work level as recommended by the manufacturer of the bench.

Handling of chemotherapy spills

All, except the workers who clean the spill, should leave the room.  Preferably, two people should help each other to remove the spill.  This way, one can ensure that proper precautions are taken.

At Oslo University Hospital, a packet is available from the pharmacy for chemotherapy spills.

Washing of LAF-bench

  • The LAF-bench should be operating under cleaning.
  • The sash should be down, as under normal working conditions.
  • Use a plastic apron, arm protectors, and gloves.

 

 

Implementation

Preparation of chemotherapy drugs outside of a pharmacy

Aseptic procedure

  •   To avoid turbulence of the sterile, laminar air stream:
    • Work at least 15 cm inside the perforation with steady movements
    • Avoid hands or other objects from coming between the airflow and the medicine.
  • Make only one medicine at a time.
  • A full syringe or finished bag should be labeled for the next preparation.  The label should be labeled with the patients name, birthdate, drug and dosage, preparation date, expiration, and the name of the person who prepared and checked the medicine.
  • Avoid spills and aerosol formation
    • Use a dry, sterile compress around neck of the ampule when it is broken.
    • When the cannula is removed from the syringe, hold a sterile compress around the barrel neck to catch any spills.
    • Hold the syringe/ampule such that the opening is directed away from the face.
    • For solid substances, solvent should be added along the glass wall to avoid whirling of particles.
    • With positive/negative pressure in the hood glass: apply a filter cannula first to reduce pressure.
    • With use of adapter: place adapter first in the infusion bag and connect to the hood glass with medicine.
    • When the air is removed from the syringe, place the cannula cap on the cannula again while the syringe is held vertically with the cannula upright. A sterile compress should be held around the opening between the cannula and the syringe to collect spillage.
    • Clean up spills at once
  • After each addition, the contents of the infusion container should be mixed well by inverting and repeating 5-6 times.
  • Infusion fluid which has been added to should be marked satisfactorily.
  • The finished solution should be scrutinized for solid or foreign particles. All solid should be dissolved.
  • If visible changes occur under the mixing procedure, the physician should be contacted and the fluid should not be used. Store the infusion fluid and packaging of the added drug and contact the pharmacy (chemist) for further clarification.
  • All used equipment should be rolled up in the benchcoat (alternatively, all used equipment can be placed in a plastic bag which can be tied or closed with zipper) and disposed of in box with plastic bag for chemotherapy waste/biohazardous waste.
  • LAF-bench should be stopped at least 30 minutes after use.

Multiple additions

  • Addition of multiple drugs for chemotherapy solutions should be avoided. If it is still appropriate, there should be clear documentation of the mixture.
  • Different chemotherapies can mix if their mixing properties are documented (and checked with pharmacist).

Handling of chemotherapy spills

  • Use two pairs of disposable latex\nitrile gloves, plastic coat, mask, shoe covers (used with floor spills) and protective goggles.
  • Lay the smallest diaper in the middle of the spilled fluid. Then, place the absorbent bed sheet over the diaper and the rest of the fluid. Use more diapers and absorbent material if necessary.
  • Dispose of used diapers, absorbent material, bed sheets, and gloves is appropriate waste container, which can be closed.
  • Use new gloves and wash thereafter with soapy water and disposable wash cloths a minimum of three times. Use a new cloth before each wash. Used cloths should not be put back in the wash solution.  Used cloths and gloves should be disposed in the appropriate waste containers (in plastic bags which can be closed).
  • The plastic bags with used equipment should be disposed of in the appropriate containers which are properly labeled.

Washing of LAF-bench

  • Other than a cannula bucket, nothing should be stored in the bench after the last preparation.
  • Washing with 70% ethanol is sufficient if there are no visible spills.
  • For visible spills, wash the bench with soapy water and spray afterwards with 70% ethanol (see procedure under). Soapy water is the most effective for removing chemotherapy spills.

Routine washing

  • Washing should be done every 1-4 weeks depending on frequency of use.
  • Spills and dust pose risks for washing.
  • It is important that any remaining solution of chemotherapy is not spread under washing.
  • Use disposable cloths.
  • To avoid contamination of washing water, the washing hand should not be dipped in the water.
  • Wash with slow movements and use a new cloth as needed.
  • Cloths that have been in contact with the bench should not be put back in the washing water and should be discarded in proper waste container.
  • Wash first the walls from top to bottom with soapy water (the cleanest to the most contaminated) – place the cloth on a squeegee for hard-to-reach areas.
  • The filter in the ceiling of the bench should not be washed.
  • Wash the work surface in the bench – wash from back to forward (from the cleanest to the most contaminated).
  • Raise the work surface.
  • Wash the work surface on the underside, especially the closest, perforated part.
  • Then wash the underside bottom of the work surface.
  • Wash thereafter all surfaces (not the ceiling) with 70% ethanol.
  • Remove protective clothing.
  • Discard all protective clothing for one-time use and washcloths in the appropriate waste container.
  • Wash hands.
  • Replace the cannula bucket.
  • There should be a record for bench washing; the employee who washes should sign and date the record.

Follow-up

Aerosol formation with spraying or squirting can occur:
  • when a syringe is used and cannula is retracted for transfer
  • when an ampule is broken
  • when air is removed to measure volume
  • with a leak in a syringe or IV catheter
  • with waste handling

First aid if contact with chemotherapy drugs

  • Skin: Rinse well with water for 15 minutes. Wash contacted area with regular soap.
  • Eyes: Rinse well with water, or use spray bottle with NaCl 9 mg/ml (at least 20-30 minutes of continual rinsing).
  • Contact a doctor.

Radiation therapy of Hodgkin's lymphoma

Radiation therapy is undergoing final approval and will soon be available.

Radiation therapy for Hodgkin's lymphoma is based on experience performed with large fields toward multiple lymph node stations (extended field) such as the mantle and inverted Y fields. Previously, about 40 Gy was given to each field.  Today, these fields are rarely used, but many patients who have received these treatments are still alive. Radiation therapy of lymphatic regions in the head/neck, supraclavicular, infraclavicular, mediastinal, and axilla regions, as well as combinations of these, are based on experience with the mantle field. Also, irradiation of paraaortal, iliacal, and inguinal/femoral lymph nodes can be considered parts of the inverted Y field. Large fields represent modifications of the mantle field and inverted Y and are used occasionally. 

Long term follow-up of patients cured by these large fields of radiation has shown that this treatment is associated with significant morbidity and mortality. Research results from the last 1 0–15 years have shown that large fields are not longer necessary, and that the radiation dosage can be reduced if treatment is combined with chemotherapy. This development in treatment of Hodgkin's lymphoma has determined many of today's treatment principles and the role of radiation therapy. 

 

Localized disease stage I-IIA

Since 1999, Norway has followed the Nordic protocol for confined disease. Guidelines for radiation therapy for this protocol require using the 'involved field' where a margin of 2 cm is added to the original tumor volume cranio-caudally and this is defined as CTV. Internal target volume (ITV) then involves a margin of about 2–3 cm in the cranio-caudal direction depending on localization and assumed internal movements equivalent to 3-4 cm to the field limit. As a general rule, the CTV includes the entire involved lymph node region in the transversal plane of the levels irradiated, such as all lymph node regions on one side of the neck or mediastinum and lung hilus in full breadth. Lateral margins for ITV in the mediastinum/hilum area should be up to 0.5 cm into healthy lung tissue equivalent to 1.5-2 cm from the mediastinum/hilum to the field limit. If the breadth of the mediastinum/hilum increases before start of therapy, CTV is defined as mediastinal contour/hilum contour only after chemotherapy and not as the original tumor (balloon effect). If the field limits are tuned directly on the simulator, the margins used are equivalent to ITV+1–1.5 cm for set-up margin and penumbra. 

Dosage is the standard 2 Gy x 10 for patients without risk factors and 1.75 Gy x 17 for patients with risk factors (after 4 ABVD cycles). CT-based dosage-planned radiation therapy is used for curative treatment. The greatest advantage of this is the possibility to quality-assure therapy and document strain on healthy organs.    

Stage IIB and III-IV A/B

Randomized studies and metaanalyses have been carried out to investigate the benefit of radiation therapy in patients who have completed full chemotherapy equivalent to 6–8 ABVD cycles. As a general rule, there is no indication for radiation therapy if the patient is in complete radiological remission after chemotherapy or if residual tumor is unchanged over time. Radiation therapy of areas with initial bulky tumor, especially patients with large mediastinal tumors should not be given radiation therapy if there is complete response to chemotherapy. 

For residual tumor after radiation therapy it is more difficult to establish general guidelines. Biopsy of residual changes should be used liberally if possible. With a positive biopsy, irradiation of the area with 29,75–35 Gy is considered. The alternative is to start second line high-dose chemotherapy with subsequent autologous stem cell support. Newer studies indicate that PET may be helpful to differentiate residual fibrosis from active tumor tissue.  

CT-based dosage-planned radiation therapy is used mainly for curative treatment. CTV after full chemotherapy is defined as the residual changes including a margin of 1 cm. ITV is defined with margins including assumed internal movement of CTV. The field limit then involve a margin of 2-3 cm to visible residual tumor. It is reasonable to modify field limits where there are unacceptably large volumes or risk organs involved.  

Children and adolescents (up to and including 18)

Children and adolescents are treated from the special protocol (GPOH-HD 95), or studies in which radiation therapy is given to most patients after chemotherapy despite complete response. The new protocol EuroNet-PHL1 for classical Hodgkin's lymphoma was activated in 2007 and will be open until 2013. In this study, PET-CT will be used to reduce the number of patients treated with radiation therapy without reducing the cure rate of the entire patient group.  

PROSEDYRER

Radiation therapy to axillary region for malignant lymphoma

General

Indications

Radiation therapy to the axilla is given for many types of lymphoma.

Curative radiation therapy

  • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
  • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy.
  • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma. 
  • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.  
  • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given.
  • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered. 
  • For indolent lymphomas with localized disease (stadium I-II1), radiation therapy alone is given to the involved area with margin (involved field).

Palliative radiation therapy

  • As palliative radiation therapy, the method is based on guidelines for the curative plan with individual modifications. 

     

Definitions

Target Volume

 

 

 

Target volume definitions from ICRU
(International Commission on Radiation Units and Measurements)

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/identifiable area of malignant growth.

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume containing GTV and subclinical microscopic malignant disease.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

Planning contour: Beams-Eye-View projection of PTV.

IM (= Inner margin) and SM (= Setup margin)

IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

Field limit

The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

Definition of margins

The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

Target volume for radiotherapy

GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

GTV + 1 cm in the transversal plane

CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

ITV CTV if internal movement is negligent (CNS, ENH and others)

CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

CTV + 2–3 cm in mesentary and stomach

CTV + up to 0.5 cm transversal retroperitoneally

PTV

Not routinely defined

Field limits

Are set to 1 cm outside ITV for set-up margin and penumbra

Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

Involved node

The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

Involved field

The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning, etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

Extended field

This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

Preparation

  • For direct contouring on the simulator, the axillary field is aligned with the overarm abduced to 90º.
  • For CT dosage-planned treatment, the arms are immobilized over the head in a wing board or slightly along the upper body. The reproduceability of the position may be a problem with slightly abduced arms. A 5-point mask with immobilization of the shoulder area may improve stability. With skin folds, skin reactions may be more problematic with doses up to 40 Gy. A side field cannot be given toward the neck if the arms are immobilized over the head with a wing board.
  • In women, the breasts should be moved out of the field, for example by taping to the medial side. 
  • Palpable findings and possible scarring or skin changes are marked with marking thread.

Implementation

Coventional simulation

  • For direct simulation, an isolated axillary field is limited to 1–2 cm cranially and 1–2 cm medially at the intersection of the clavicula and the lateral limit of the lungs.
  • To include lymph nodes of the thoracic wall, the medial thoracic wall is included and one lung border of 1–1.5 cm.
  • Laterally, the limit goes from the humerus to include parts of the axilla. Depending on the localization of the tumor and the patient's anatomy, the limit runs caudally to the nipple. 
  • Cranial and lateral parts of the head of the humerus are blocked out as in a mantle field. 
  • The field limits are modified for adequate margins to the tumor, which should be 3-4 cm from the original tumor in the direction of lymph drainage for indolent lymphomas irradiated to cure the disease, confined stages of Hodgkin's lymphoma after 2–4 ABVD cycles, and confined stages of aggressive lymphomas after 3–6 CHOP-based cycles or equivalent. To achieve such margins, the infraclavicular and supraclavicular fossae on the same side will usually be included. In the transversal plane, 2 cm to the field limit is sufficient, but the region is always in full breadth in the levels included in the field. 
  • For residual lesions after full chemotherapy and in most cases after palliative treatments, a margin of 2 cm to the field limit in all directions is adequate.

CT dose plan, axillary region 

CT-based simulation

  • For contouring of the axilla with CT, it is important to be aware that standard immobilization does not allow 90º abduction of the shoulder. Therefore, the best method for immobilization in relation to the planned target volume should be determined prior (see under preparation). 
  • Contouring of target volume in the axilla is difficult since a strictly anatomical model using CT slices often gives disproportionately large fields of both the lungs and sometimes breasts. A possible solution to this problem is to first identify the desired field limits in the coronal plane with the CT dosage planning program in relation to the guidelines that apply for direct simulation and which are based on modeling of the mantle field.  
  • An ITV can then be generated by subtracting the margin from the set-up variation and penumbra (1–1.2 cm). If necessary, this ITV can be modified for the situation. 
  • Further, it is often difficult to achieve a completely optimal dose distribution in the medial parts of the axilla due to large variations of cross measurements in the axilla and due to the percent of lung in the field. The benefit of optimal dosing in the ITV must be assessed against possible warm areas in, for example, the breast. 

In practice, isolated axilla fields are rare, and the region is often treatment together with supporting supra- and infraclavicular regions.

Fractionation  

Standard fractionation and total dosage for curative treatment is described below. These are also normative for palliative treatment, but must be modified for each patient.  
  • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
  • Hodgkin's lymphoma: 1.75 Gy x 17.
  • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
  • For aggressive non-Hodgkin lymphoma: 2 Gy x 20.

Follow-up

Risk organs

Skin 

  • Soreness in the skin folds of the axilla may occur. 

Lungs

  • Subacute radiation pneumonitis during the first months after treatment may occur. Irradiated areas of the the lungs will often develop fibrosis over time. 

Secondary cancer

For patients receiving mantle field irradiation for Hodgkin's lymphoma, there risk for secondary cancer increases significantly, especially for organs given full therapeutic doses. Breast cancer, lung cancer, thyroid cancer, sarcomas, skin cancer, and melanoma are some of the most common. 

Secondary cancer represents the most significant cause for increased mortality of patients cured of Hodgkin's lymphoma by radiation therapy. For younger women with mantle field irradiation under 35 years, a yearly mammogram is recommended starting about 8 years after irradiation. 

For patients with other lymphoma entities, there are no set follow-up routines for smaller radiation fields and early diagnosis of other cancer forms. 

The patient should be discouraged from smoking.

Radiotherapy of axilla region for malignant melanomaRadiotherapy of the axillary field for malignant lymphoma

Radiotherapy of parotid gland and submandibula for malignant lymphoma

General

Indications

Indolent lymphomas are often present in the salivary glands usually in the form of marginal lesion lymphoma. These lymphomas with underlying Sjøgrens syndrome. Locoregional confined disease is common. Aggressive lymphomas are also observed, but Hodgkin's lymphoma in salivary glands is very rare. 

Curative radiation therapy

  • For localized indolent lymphomas (stage PeI-PeII1), radiation therapy alone is given with the intention of curing the disease. 

  • For localized lymphomas with aggressive histologies (stadium PeI-PeII1), radiation therapy is given as part of curative treatment after chemotherapy (3-6 CHOP-based cycles or equivalent).

  • For residual tumor from aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidated radiotherapy to the residual tumor with margin is considered. 

Palliative radiation therapy

  • For palliative radiation therapy, guidelines are usually the same as for curative therapy but are adapted individually. 

Definitions

Target Volume

Target volume definitions from ICRU
(International Commission on Radiation Units and Measurements)

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/identifiable area of malignant growth.

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume containing GTV and subclinical microscopic malignant disease.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

Planning contour: Beams-Eye-View projection of PTV.

IM (= Inner margin) and SM (= Setup margin)

IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

Field limit

The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

Definition of margins

The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

Target volume for radiotherapy

GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

GTV + 1 cm in the transversal plane

CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

ITV CTV if internal movement is negligent (CNS, ENH and others)

CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

CTV + 2–3 cm in mesentary and stomach

CTV + up to 0.5 cm transversal retroperitoneally

PTV

Not routinely defined

Field limits

Are set to 1 cm outside ITV for set-up margin and penumbra

Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

Involved node

The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

Involved field

The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning, etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

Extended field

This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.


Preparation

Patients must be evaluated by a dentist and treated if necessary before immobilization and start of treatment. 

The patient is immobilized with a mask.

Implementation

The dosage for this radiation therapy should be planned using CT.

CT-based simulation 

  • With isolated involvement of non-Hodgkin lymphoma in salivary gland on one side, CTV is defined as the macrotumor (original tumor before chemotherapy for aggressive lymphomas) with 1 cm margin.

  • For visible tumor growth outside the salivary gland, this is included in the area with 1 cm margin in CTV.

  • The remaining healthy part of the involved salivary gland is also included in CTV. The parotid gland may extend quite deep into the pharynx.

  • In stage Pell1, the involved areas of the neck with 2 cm margin to CTV in the caudal direction are included. For bilateral involvement, the contouring is done equivalent to the contralateral side.

  • In stage PeI of indolent lymphoma, contouring of draining ipsilateral lymph nodes in the upper neck (submandibular, submental, and occipital as well as upper neck region) is considered. 

  • The node region of the neck is included in its entirety in the tranversal plane in slices included in CTV. CTV is chosen such that the field limit on the neck does not involve the spine.

  • Contouring of neck lymph nodes including submandibular and submental nodes can be done according to guidelines developed for CT diagnostics. These appear to include occipital nodes somewhat poorly, and it is important to include these.

  • For unilateral involvement of parotid gland, a field set-up with diagonal wedge field makes it possible to spare the contralateral parotid gland. Isocentric technique with half-beam blocks circumvents joining problems/junctioning issues of anteroposterior irradiation to the neck and supraclavicular fossa. Electron irradiation from the side to the parotid gland is also a possibility. Unilateral involvement of the submandibular gland is likely most effectively covered best with anteroposterior irradiation with sufficient stretching of the neck.

    CT dose plan, parotid gland and submandibula

    Fractionation

    Standard fractionation and total dose for curative treatment is given below. These are also normative for palliative treatment, but should be modified on an individual basis.

    • For curative treatment of indolent NHL: 2 Gy x 15
    • For aggressive NHL: 2 Gy x 20.

     

Follow-up

Risk organs

Salivary glands (especially parotid gland)

Delayed dry mouth should be expected if both parotid glands are irradiated.

Teeth

Defects should be repaired before treatment start to prevent later osteoradionecrosis. Caution should be used with dental treatment after irradiation. 

Eyes and lens

With modern treatment, the doses for these organs should be under the tolerance levels.

Chiasma

With modern treatment, the doses for these organs should be under the tolerance levels. 

Pituitary gland 

With modern treatment, the doses for these organs should be under the tolerance levels.

Radiation therapy of the neck region and supraclavicular fossa for malignant lymphoma

General

Indications

In the Ann Arbor classification system, the neck with the ipsilateral and supraclavicular fossae are one region. In radiation therapy, it is in many cases natural to separate the upper neck region, lower neck region, and supraclavicular fossa on each side from each other. Thus, for example, when treating Waldeyers ring and no involved lymph nodes, it is correct to include the upper neck region with submental, submandibular, and occipital nodes to have an adequate margin in the caudal direction.  When treating the mediastinum, it is important to include the supraclavicular fossa bilaterally to have adequate margins to the tumor to be irradiated. Also, sometimes the supraclavicular fossa and infraclavicular fossa on the same side must be included when the axilla is irradiated. 

Curative radiation therapy

  • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
  • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy.
  • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma. 
  • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.  
  • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given.
  • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered. 
  • For indolent lymphomas with localized disease (stadium I-II1), radiation therapy alone is given to the involved area with margin (involved field).

Palliative radiation therapy

As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

     

     

     

    Kapitteloverskrift mangler!

    Target Volume

     

    Target volume definitions from ICRU
    (International Commission on Radiation Units and Measurements)

    GTV (= Gross Tumor Volume)

    Tumor volume

    Palpable or visible/identifiable area of malignant growth.

    CTV (= Clinical Target Volume)

    Clinical target volume

    Tissue volume containing GTV and subclinical microscopic malignant disease.

    ITV (= Internal Target Volume)

    Target volume

    Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

    PTV (= Planning Target Volume)

    Planning volume

    Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

    Planning contour: Beams-Eye-View projection of PTV.

    IM (= Inner margin) and SM (= Setup margin)

    IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

    Field limit

    The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

    Definition of margins

    The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

    Target volume for radiotherapy

    GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

    Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

    CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

    GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

    GTV + 1 cm in the transversal plane

    CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

    CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

    ITV CTV if internal movement is negligent (CNS, ENH and others)

    CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

    CTV + 2–3 cm in mesentary and stomach

    CTV + up to 0.5 cm transversal retroperitoneally

    PTV

    Not routinely defined

    Field limits

    Are set to 1 cm outside ITV for set-up margin and penumbra

    Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

    Involved node

    The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

    Involved field

    The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

    Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

    For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

    Extended field

    This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

    Preparation

    For radiation therapy to the upper parts of the neck where the upper and/or lower jaw is involved, the patient must be evaluated by a dentist. Any dental treatment must be finished before immobilization and treatment start.

    Patients are immobilized with a mask (3-pint or 5-point mask) with the jaw adequately extended. A slight extension of the neck as for a mantle field is normally sufficient.

    Implementation

    Conventional simulation

    For direct simulation, the neck field can be considered a slice of an earlier mantle field.  

    • The standard upper and lower limit for a full neck field is 1–2 cm cranially for the mandibular angle (with adequate extension of the jaw, also covers submental, submandibular, and occipital nodes) and 1 cm below and along the clavicle. Craniocaudally, the field limit should be modified to have a 3–4 cm margin to the initial tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 2 cm to residual tumor after full chemotherapy for advanced disease. Thus, it is often unnecessary to irradiate the full length of the neck. 
    • If it is necessary to reach higher up on the neck, for example to cover enlarged lymph nodes in the mandibular angle, large parts of the oral cavity and back of the head will be included. In such cases, a connection to the side field by isocentric technique and half-beam block is considered.  
    • If there is involvement of the supraclavicular fossa, an adequate margin in the caudal direction is necessary to include the upper mediastinum and/or infraclavicular fossa. 
    • The lateral limit is in the air (for upper and lower neck field) or 0.5 cm medial to the acromioclavicular joint, which covers the entire supraclavicular fossa.
    • The medial border should be at least 2 cm from the tumor and should cover the entire neck region on the side to be irradiated. For unilateral irradiation, the field limit should not involve the spinal cord, to simplify later junction of new fields. If there is disease near the midline, the field limit should have pedicles on the contralateral side of the spinal column.  
    • For localized indolent lymphomas in stage I-II1, the nearest uninvolved area should be considered to be included, and thus extending the margin to the field limit beyond the 3-4 cm stated above.

    CT-based simulation

    • For CT dose-planned treatment of localized lymphomas, GTV is defined as visible tumor (or original tumor before chemotherapy).   
    • In the craniocaudal direction, there should be a 2 cm margin from the visible/original tumor to CTV (for curative treatment of localized indolent lymphomas or limited chemotherapy for early stages of HL and aggressive NHL). For residual tumor after full chemotherapy for advanved disease, there should be at least a 1 cm margin to CTV craniocaudally. 
    • There should be a 1 cm margin to CTV in the transversal plan, and CTV should normally include the entire involved lymph node region in the transversal plane.
    • Inclusion of the nearest uninvolved nodal area can be considered for indolent lymphomas in stage I-II1. This must then be contoured in the CTV.  
    • For CT dosage-planned treatment, in may be helpful to look at Dahanca's web information for contouring of neck lymph nodes. These suggestions for contouring should only be used as guidance, since it appears that the occipital and nuchal regions are somewhat poorly defined. An additional limitation is the fact that lymphomas do not follow metastatic patterns for carcinomas in the ENT area and that for lymphomas, all neck lymph nodes are irradiated either unilaterally or bilaterally at a given slice level. Since doses rarely surpass 40 Gy, risk organs such as the spine do not pose as a large limitation on treatment. A practical and more simple alternative is to draw the neck on one or both sides as one CTV including all anatomical structures.
    • An alternative is to first define the desired field limits in the coronal slice on the CT dose planning program according to guidelines that apply for direct simulation. An ITV can then be generated by subtracting the margin for set-up variation and penumbra (1-1.2 cm). This ITV can, if necessary, be modified for individual circumstances.  
    • Contouring should be done such that field limits follow geometric shapes as mentioned under conventional simulations, and should not lie in the spinal cord especially. A field is given with anteroposterior direction possibly with segments. To treat higher up on the neck, a side field or possibly diagonal wedge field can be considered. Isocentric technique with half-beam block usually causes junctioning issues.   

    CT dose plan, neck region and supraclavicular fossa

    CT dose plan, axilla region

    Fractionation

    Standard fractionation and total dose for curative treatment is given below. These are also normative for palliative treatment, but should be modified on an individual basis. 

    • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
    • Otherwise for Hodgkin's lymphoma: 1,75 Gy x 17.
    • Curative treatment of indolent NHL: 2 Gy x 15
    • Aggressive NHL: 2 Gy x 20.  

    Follow-up

    Risk organs

    Skin

    A certain degree of acute dermatitis may occur, and temporary hair loss (facial and neck hair) can be expected.

    Mucosa

    Varying degrees of acute mucositis can be expected. Even at doses of 30 Gy, some patients will develop significant yet temporary problems. 

    Teeth

    Defects should be repaired before treatment start to prevent later osteoradionecrosis. Caution should be used with dental treatment after irradiation.

    Blood vessels on the neck

    Reports show there is an increase in risk for later cerebrovascular disease after irradiation of the neck.

    Thyroid gland

    About half of patients irradiated to the entire thyroid gland develop hypothyroidism within years. Annual follow-up is necessary. Thyroid cancer may occur years after irradiation.

    Spinal cord 

    Normal radiation doses for lymphoma are under the tolerance level for serious spinal injury. Unintended warm areas of the spine must be avoided.  

    Radiation therapy of neck region and suprclavicular fossa for malignant lymphomaRadiation therapy of neck region and supraclavicular fossa for malignant lymphomaRadiation therapy of the neck region and supraclavicular fossa for malignant lymphomaRadiation therapy of the neck region and supraclavicular fossa for malignant lymphoma
    Radiation therapy of neck region and supraclavicular fossa for malignant lymphomaRadiation therapy of the neck region and supraclavicular fossa for malignant lymphoma

    Total skin electron radiation therapy for malignant lymphoma

    General

    Irradiating the entire skin with electrons is used to treat certain malignant lymphomas that spread in large areas of the skin. Most patients appropriate for this treatment have mycosis fungoides. Oslo University Hospital has established a treatment arrangement for this demanding treatment form.   

    Indications

    • Mycosis fungoides
    • Other non-Hodgkin cutaneous lymphomas with diffuse spreading 

    Kapitteloverskrift mangler!

    Target Volume

     

    Target volume definitions from ICRU
    (International Commission on Radiation Units and Measurements)

    GTV (= Gross Tumor Volume)

    Tumor volume

    Palpable or visible/identifiable area of malignant growth.

    CTV (= Clinical Target Volume)

    Clinical target volume

    Tissue volume containing GTV and subclinical microscopic malignant disease.

    ITV (= Internal Target Volume)

    Target volume

    Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

    PTV (= Planning Target Volume)

    Planning volume

    Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

    Planning contour: Beams-Eye-View projection of PTV.

    IM (= Inner margin) and SM (= Setup margin)

    IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

    Field limit

    The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

    Definition of margins

    The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

    Target volume for radiotherapy

    GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

    Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

    CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

    GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

    GTV + 1 cm in the transversal plane

    CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

    CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

    ITV CTV if internal movement is negligent (CNS, ENH and others)

    CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

    CTV + 2–3 cm in mesentary and stomach

    CTV + up to 0.5 cm transversal retroperitoneally

    PTV

    Not routinely defined

    Field limits

    Are set to 1 cm outside ITV for set-up margin and penumbra

    Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

    Involved node

    The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

    Involved field

    The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

    Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

    For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

    Extended field

    This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

    Preparation

    • If the disease has not spread to the scalp, fingers and toes, it is sensible to consider shielding these areas with customized lead shields. 

    • Use of supplementary fields toward the vertex, pelvic floor, and soles of the feet should be determined before starting treatment. 

    • An eye shield of lead is molded in wax or gold-plated mesh blocks. These are placed under the eyelids for each treatment, which requires use of eyedrops and local anesthetic. If the skin around the eyes will also be shielded, customized lead shields are taped to the skin. 

    • In men, the testicles will receive a relevant amount of the skin dose, therefore sperm banking should be considered before radiation therapy. 
    • Contacting a dermatologist for supplementary skin care during treatment may be beneficial. 

    Implementation

    Simulation

    • An electron field is used which is at a significant distance from the source to the patient, and the fields are angles with nearly horizontal rays diagonal from below and above. The fields will then add to each other to give a relatively even dose distribution for the entire length of the patient. The field angled from below gives primarily the dose to the upper body, while the field angled from below gives the dose primarily to the lower body.
    • By rotating the patient on a stool during irradiation, the dose will be evenly distributed to the skin. Irradiation should start at different points under rotation every day.
    • The patient should stand centered on a stool with their feet apart and supporting with one hand (or both if necessary) using the support device from the ceiling. The patient alternates between fractions by holding the right or left hand up. The other hand is held 10-15 cm away from the body.
    • The field will not cover the pelvic floor, sole of the feet, and crown. An additional field to these areas may be necessary. These areas are usually treated with an electron field with 2 Gy per fraction in the last part of treatment. To achieve adequate skin coverage, a bolus is necessary for these fields.
    • Any plaque or tumorous lesions requiring treatment with greater doses in depth than the skin should be evaluated for a local supplementary field with higher electron energies.

    Fractionation

    The target dose of 1.2 Gy per fraction is given as five fractions per week. It is recommended to give 30–36 Gy measured as the dose in the surface of the skin, which is in compliance with international recommendations. The electron energy from the source (6MeV) is lower in the surface of the skin to the patient with depth dose curves following. Eighty percent isodose is at a depth of 4 mm. Because large amounts of the dose are given as tangential irradiation, the dose maximum is in the surface of the skin contrary to skin irradiation with electrons perpendicular to the surface.

    Follow-up

    Risk organs

    Skin, nails, hair

    The nearest obligate side effects are:

    • Erythema of the skin
    • Edema of the hands and feet which may last for some time after treatment. 
    • Halt of nail growth. Loss of nails is uncommon. 
    • Reversible complete alopecia
    • Sores on the hands and feet may occur and sometimes with superinfection. 

    Eyes and lenses

    Sore eyes possibly with superinfection may occur. Eye shields prevent cataracts.

    Total Body Irradiation

    General

    Total Body Irradiation (TBI) is variation of radiation therapy where the entire body is the target volume. The treatment is a challenge geometrically, dosimetrically, and logistically.

    Malignant diseases originating from myeloid and lymphoid cells may be appropriate for TBI for two reasons. The neoplastic cells are usually relatively sensitive to radiation and must generally be considered a systemic disease. 

    The doses administered for TBI are very limited mainly due to acute toxicity of bone marrow and lungs, but this is usually surmounted by subsequent transplantation of hematopoietic stem cells. This limits the use of TBI considerably.

    The treatment arrangement requires a high degree of cooperation from the patient. TBI in children requiring general anesthesia consitutes a special problem.

    Indications

    • TBI is used today mainly as a step in conditioning of hematopoietic stem cell tranplantation for myeloid and lymphoid neoplasias and related conditions. For autologous or syngeneic stem cell transplantation, the antitumor effect of radiation therapy is the intended effect, usually together with chemotherapy. Irradiation given in adequate doses for an allogeneic stem cell transplantation will also suppress the patients immune system such that the danger of rejection (host versus graft reaction, graft rejection) of the allogeneic stem cells is reduced. For a traditional stem cell transplant, doses higher that 9 Gy are given. Considering the danger of radiation pneumonitis, traditionally the most serious side effect of acute toxicity from TBI, it has been shown that fractionated treatment with 1.2-2 Gy per fraction given 1-2 times daily is preferred over single fractions above 9 Gy, and the total dose for fractionated treatment can be increased.  The dose rate varies between 0.05–0.1 Gy/min (low dose rate) to 0.5–0.7 Gy/min (high dose rate) and also plays an important radiobiological role. The most common conditioning regimen utilizing TBI at Oslo University Hospital consists of 13 Gy with fractionation in 1.3 Gy x 10 with two fractions daily at a low dose rate followed by cyclophosphamide 3 g/m2 daily for two subsequent days (total 6 g/m2).

       

    • TBI has a possible place in conditioning of allogenic stem cell transplantation with reduced conditioning (mini-allo transplantation). Here, TBI is given in lower doses, usually in one fraction but doses far under 8 Gy. The purpose of TBI for a mini-allo is mainly to suppress the patient's remaining healthy immune system to prevent rejection of the allogeneic stem cells. The most commonly used regimen containing TBI at Oslo University Hospital is the Seattle regimen where TBI is given in one fraction of 2 Gy together with fludarabine. 

       

    • Use of TBI as part of conditioning before a stem cell transplantation must be a considered individually. The most common indications for TBI today are part of conditioning for allogeneic stem cell transplantation for certain patients with acute leukemias, myelodysplastic syndrome and anaplastic anemia. TBI is used rarely today for autologous stem cell transplantations where conditioning regimens consisting of chemotherapy alone are mostly used. 

       

    • Low-dose TBI (less than 2 Gy) given as a single fraction or in fractions of 0.05–0.15 Gy/fraction given in 2–5 fractions per week have previously been used without hematopoietic stem cell support, especially for chronic lymphatic leukemia and indolent lymphomas. Bone marrow suppression, especially thrombocytopenia, is considerable. This from of treatment is not used in Norway today.

    Definitions

    The following definition is partly based on StrålevernRapport 2003:13, which is referring to ICRU50 and 62 as well as NACP.

     

    Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)

     

    GTV (Gross tumor volume)

    Gross palpable or visible/identifiable area of malignant growth.

     

    CTV (Clinical target volume)

    Macroscopic tumor volume including any remaining tumor tissue.

     

    ITV (Internal Target Volume)

    Volume containing CTV and internal margin to allow for internal movements and changes to CTV.

     

    PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
    OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.

    PRV (Planning organ-at-risk volume)

     

    Geometric volume containing risk volume with set-up margin.
    TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
    IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
    CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

     

    Field Limits

    The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

    Definition of margins

    For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.

     

    Target volume for radiation therapy
    GTV Current tumor for indolent NHL stage I/II1, original tumor(before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA

    Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV

     

    CTV GTV + 2 cm craniocaudal for limited disease/short chemotherapy

    GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy

    GTV + 1cm in transverse plane

    CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).

    CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.

     

    ITV CTV if internal movement can be ignored (CNS, ENT)

    CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum

    CTV + 2–3 cm in mesentery

    CTV + 0-0.5 cm transverse retroperitoneally

     

    PTV

    Not routinely defined

     

    Field limits ITV + Setup margin and penumbra (1.2 cm)

    The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)

     

    Involved node

    The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.

     

    Involved field

    Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extension to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.

    Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate.

    For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.

    Extended field

    This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.

    Preparation

    Before treatment, planning around the stem cell transplantation must be finalized. 

    • The indication for hematopoietic stem cell transplant must be determined by a team with experience in this treatment. The general health status of the team and complicating comborbidity must also be evaluated by the team.
    • Stem cells must be available and ready for use by harvesting from the patient or a donor.
    • Days before radiation therapy starts, plans must be made for admission, transport to and from treatment, days for chemotherapy, and planned stem cell reinfusion, as well as necessary follow-up during the aplasia period. 
    • Due to the complexity of the procedure, morbidity and mortality, adequate information for the patient and loved ones from the oncologist responsible for treatment is very important. 
    • A close dialog between the hematologist and oncologist is also very important.

    Implementation

    Conventional simulation

    TBI is complicated in both theory and practice. This is a very simplified summary of the how it is implemented.

    In order to to have room for the entire body in one radiation field, the distance from the source to the skin must be increased, which can be achieved by setting the source to irradiate horizontally such that it is as far as possible from the wall in the bunker. The patient can be positioned 3-4 m away in the other end of the bunker in the desired position. The patiet can lie, stand, or sit in the fetal position depending on the distance allowed by the source whether irradiating with opposing anteroposterior field, lateral field, or a combination. 

    At Oslo University Hospital, the patient lies down sometimes with slightly angled legs in a bed. Half-way through each fraction, the bed is turned 180 degrees. The patient is also changed for every other fraction between laying supine and laterally. The arms are positioned such that they compensate for 'missing' soft tissue in the lungs in the fractions where the lungs are not shielded. The lungs are shielded for fractions 3, 7, of 10 and the patient keeps their arms away from the anterior planes of the lungs during these fractions. Oslo University Hospital uses a moulded mat of VacFix® to give the best possible reproducible lateral position. To achieve full coverage of the skin, a device must be used that functions as a bolus (blanket of tissue-equivalent bolus) or, as at Oslo University Hospital, a shield of plexiglass in a suitable position between the patient and the source generating scatter electrons.   

    Simulation of TBI is done 1-2 weeks before treatment in a procedure known as a test shot or test fraction. The entire procedure can take up to 1.5 hours. 

     

    • A VacFix® is made to stabilize the patient in the lateral position and is used for the fractions where the lungs are to be blocked out (fraction 3 and 7 of 10).
    • The patient will then complete a simulated treatment with a low dose (<0.1 Gy) with a series of dosimeters placed at relevant measuring points on the body.
    • X-ray images are taken of the patient in the lateral position in the VacFix® for contouring of lung blocks. 
    • The treating doctor will draw the lung blocks on the X-ray image. These are drawn analogous to the lung blocks for a mantle field. Blocks follow the lower border of the fourth rib cranially, laterally 0.5–1 cm into the lung tissue, caudally turning 0.5–1 cm above the diaphragm, and medially 1–1.5 cm from the mediastinum/hilum into the lung tissue. The hilar contours are most visible on the right side. On the left side, the contours are drawn equivalent so that part of the lung in front of the heart and parts of the stomach are under the block. 

       

    Treatment

    • During treatment, the patient is admitted to the hospital at the latest the day before treatment. The patient should begin with antiemetic treatment (ondansetron 8 mg x 2 or equivalent) and fluids before the first fraction the evening before starting treatment. A serotonin antagonist is supplemented during treatment with other treatment, if necessary. 
    • Fluids and nausea treatment is constant during TBI treatment. Standard treatment for adults is 2 L NaCl 0.9 % and 2 L glucose 5 %, alternating with 40 mmol KCl per 1000 ml fluid.
    • During this treatment, the patient will start serious bone marrow aplasia and should be handled both at the ward and treatment unit as extra susceptible to infection.  
    • The radiation bunker is washed before each afternoon fraction, and the device the patient is in contact with is washed with alcohol before treatment. The patient will be the last patient of the afternoon and the first patient the following morning.  
    • Additional protection for infection may be necessary such as isolation for neutropenia and the danger of infection upon contact. 
    • For fractions 3 and 7, the treating doctor will check and approve the positioning of the lung blocks. 

     

    Follow-up

    Side effects of TBI must be considered in accompany with other elements of conditioning (chemotherapy) and the type of stem cell donor. For an allogeneic stem cell transplant and a mini-allo transplant, toxicity is more significant and more complex, especially due to graft versus host complications. 

    The most significant acute side effects:

    Nausea and vomiting 

    Affect most patients, also after the first fraction. Antiemetic prophylaxis before the first fraction, preferably the evening before, is recommended.

    Radiation-induced mucositis 

    Affects most patients and can be serious. Opiates may be necessary for pain treatment. Diarrhea may be a consequence of radiation-induced intestinal mucosa changes. 

    Hair and nail growth

    Radiation therapy together with chemotherapy will cause reversible alopecia. Nail growth will stop and new nails may grow in replacement. 

     

    Bone marrow

    Fall of white blood cells will increase the risk of infections necessitating isolation of the patient during the aplasia period. Together with chemotherapy and immunosuppressive treatment, TBI may cause serious infections. Fall in platelets may lead to bleeding and require transfusions. Fall in red blood cells will cause anemia-related symptoms and require transfusions.

    The most significant long-term side effects: 

    Lung toxicity

    For certain regimens of TBI at Oslo University Hospital, dosing to the lungs is relatively low, but together with chemotherapy, injections and GVH, lung toxicity may occur. 

    Fertility

    Both women/girls and men/boys, the risk for sterility is considered very high with TBI with a total dose of 13 Gy, but this is not obligate for all patients. The risk depends most likely on multiple circumstances such as age, sex, total dose, and collective amount of chemotherapy.

    Endocrine disturbances

    Despite low doses, endocrine function should be monitored after TBI especially in children and adolescents.

    Growth disturbances

    Doses to the bone are low, but together with endocrine disturbances, growth disturbances may occur in children and adolescents.  

     

    Secondary cancer

    The risk for a new malignant disease increases partly due to chemotherapy and radiation therapy, and partly due to necessary immunosuppressive treatment for allogeneic transplantations.

    Lung block (1)Lung block (2)Lung block (3)Lung block (4)

    Cutaneous radiotherapy for malignant lymphoma

    General

    Primary cutaneous lymphomas (PCL) and skin involvement occur as part of generalized lymphomas originating from other parts than the skin. PCL is defined as lymphomas assumed to arise in skin and which primarily manifest only in skin. 

    Of PCL arising from T cells (ca. 70 % off PCL), mycosis fungoides dominates followed by cutaneous large cell anaplastic CD30+ T-cell lymphoma, lymphomatoid papulous and peripheral T cell lymphomas. Treatment of PCL arising from T cells is summarized elsewhere. Of PCL arising from B cells (ca. 30 % of PCL), marginal zone lymphomas and DLBCL are the most common. The histological profile correlates poorer with the clinical profile than for other lymphomas. Large cell anaplastic T cell lymphoma and subgroups of DLBCL isolated in skin have relatively good prognosis. The skin area of the primary localization is significant for the prognosis since DLBCL, leg type, has a poorer prognosis tham PCL of type DLBCL.  

    Indications

    • For MF, radiation therapy is often part of multiple local measures. Depending on the size of the area and danger of delayed cosmetic disfiguring in the skin, fractionation in 2 Gy x 15 or 3 Gy x 8 is often chosen. Internationally, fractionation down to 2 Gy x 4 is also recommended for single lesions. For generalized disease in the skin that is not treatable by other local measures, total skin electron irradiation is an option.
    • CD30+ ALCL is often localized to one or more areas in the skin, and is often suitable for local radiation therapy as 30–40 Gy in fractions of 2 Gy, as recommended in the literature. With more extensive skin involvement, the disease is considered generalized (stage IV) and treated with chemotherapy. Radiation therapy is given to any residual lesions as 2 Gy x 20. 
    • CD30- ALCL and PTL have -even with primary involvement in skin- a poorer prognosis and are treated with chemotherapy such as aggressive T cell lymphomas, followed sometimes by radiation therapy. For localized involvement (stage PeI), 3 CHOP-based cycles are given followed by radiation therapy as 2 Gy x 20, or only radiation therapy alone. With more advanced skin involvement, the disease is considered generalized (stage IV), and is treated with 6–8 courses and radiation therapy is given to any residual lesions as 2 Gy x 20. 
    • Indolent PCL of B celle origin (marginal zone lymphoma, folicular lymphoma) with localized disease (stage PeI) or few areas of involvement in skin is treated radiation therapy alone as 2 Gy x 15. For advanced disease in skin (stage IV), treatment can be postponed or possibly given to symptomatic or cosmetically disfigured areas. Systemic treatment is used only if local treatment does not provide adequate control of symptoms.  
    • For aggressive PCL of B cell origin (DLBCL), radiation therapy is given at the end of chemotherapy according to the stage-adapted arrangement. With local involvement (stage PeI), 3 CHOP-based cycles are given along with radiation therapy as 2 Gy x 20. For extensive skin involvement (stage IV) 6-8 cycles is given, possibly followed by radiation therapy to remaining residual lesions. 

    Definitions

    Target Volume

     

    Target volume definitions from ICRU
    (International Commission on Radiation Units and Measurements)

    GTV (= Gross Tumor Volume)

    Tumor volume

    Palpable or visible/identifiable area of malignant growth.

    CTV (= Clinical Target Volume)

    Clinical target volume

    Tissue volume containing GTV and subclinical microscopic malignant disease.

    ITV (= Internal Target Volume)

    Target volume

    Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

    PTV (= Planning Target Volume)

    Planning volume

    Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

    Planning contour: Beams-Eye-View projection of PTV.

    IM (= Inner margin) and SM (= Setup margin)

    IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

    Field limit

    The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

    Definition of margins

    The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

    Target volume for radiotherapy

    GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

    Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

    CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

    GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

    GTV + 1 cm in the transversal plane

    CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

    CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

    ITV CTV if internal movement is negligent (CNS, ENH and others)

    CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

    CTV + 2–3 cm in mesentary and stomach

    CTV + up to 0.5 cm transversal retroperitoneally

    PTV

    Not routinely defined

    Field limits

    Are set to 1 cm outside ITV for set-up margin and penumbra

    Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

    Involved node

    The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

    Involved field

    The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

    Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

    For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

    Extended field

    This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

    Preparation

    Preparation and examinations prior to treatment will depend on which area and size of the skin to be irradiated and depth of the chosen treatment. The need for immobilization depends also on individual circumstances.

    Implementation

    Conventional simulation

    Local skin areas are usually treated with electrons where energy and use of bolus is customized for each patient. The field border on the skin should be 2 cm from visible tumor. X-rays (photons with 50–150 keV) are considered for very superficial lesions up to 2-3 mm, but compared to electrons, have a longer tail on the depth dose curve, and therefore give larger doses to deeper structures. For curved surfaces, electrons may be difficult to use, and irradiation with photons and use of bolus may be more simple, for example, on parts of an extremity.  

    With extensive involvment of the skin on a foot or leg, irradiation in a water bath is an option. This treatment provides good dose coverage in the skin around the entire foot and leg. This treatment causes significant dermatitis with desquamation and edema in large areas in most patients after a short time.

    Fractionation

    Fractionation and total dose for indolent lymphomas is normally 2 Gy x 15 or 3 Gy x 8, and for aggressive lymphomas, 2 Gy x 20. For palliation of advanced mycosis fungoides, 2 Gy 4 is also used.

    Follow-up

    Risk organs will depend on the area treated, field size, and range of depth for the chosen treatment.

    Skin

    A certain degree of acute dermatitis in healthy skin within the radiation field can be expected. 

    Cutaneous lymphoma (3)Cutaneous lymphoma

    Radiation therapy for iliacal region for malignant lymphoma

    General

    Indications

    The iliacal regions cover lymph nodes along the iliacal vessels from the aortic bifurcature to the inguinal ligament. Radiation therapy to the iliacal region is given in many situations. 

    The iliacal regions is normally irradiated either together with the paraortic and inguinal fields (dog leg field) or together with the inguinal/femoral region. 

    Curative radiation therapy

    • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
    • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy.
    • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma. 
    • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.  
    • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given.
    • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered. 
    • For indolent lymphomas with localized disease (stadium I-II1), radiation therapy alone is given to the involved area with margin (involved field).

    Palliative radiation therapy

    • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

         

         

      Definitions

      Target Volume

       

      Target volume definitions from ICRU
      (International Commission on Radiation Units and Measurements)

      GTV (= Gross Tumor Volume)

      Tumor volume

      Palpable or visible/identifiable area of malignant growth.

      CTV (= Clinical Target Volume)

      Clinical target volume

      Tissue volume containing GTV and subclinical microscopic malignant disease.

      ITV (= Internal Target Volume)

      Target volume

      Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

      PTV (= Planning Target Volume)

      Planning volume

      Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

      Planning contour: Beams-Eye-View projection of PTV.

      IM (= Inner margin) and SM (= Setup margin)

      IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

      Field limit

      The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

      Definition of margins

      The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

      Target volume for radiotherapy

      GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

      Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

      CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

      GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

      GTV + 1 cm in the transversal plane

      CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

      CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

      ITV CTV if internal movement is negligent (CNS, ENH and others)

      CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

      CTV + 2–3 cm in mesentary and stomach

      CTV + up to 0.5 cm transversal retroperitoneally

      PTV

      Not routinely defined

      Field limits

      Are set to 1 cm outside ITV for set-up margin and penumbra

      Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

      Involved node

      The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

      Involved field

      The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

      Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

      For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

      Extended field

      This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

      Preparation

      Radiation therapy to the iliacal region is considered part of an inverted Y field.

      • Sperm banking for men and possibly freezing of ovarian tissue or operative elevating or fixing of the ovaries (ovariopexy) in girls/women is considered. 
      • The patient lies supine with their arms by their side.
      • In male patients, there must be adequate space between the legs for placement of a gonadal shield (scrotum cup, lead belt and/ or gonadal shield). For irradiation of the iliacal region on one side (and dog leg field or L field), a lead belt is used where the scrotum is over on the contralateral side and shielded with a lead shield. For bilateral irradiation, a scrotum cup is used in addition to a lead shield. 
      • For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should be considered. Ovariopexy is the surgical relocation of the ovaries out of the small pelvis to the midline behind the uterus. Surgical clips should indicate where the ovaries are located. Only then is it possible to exclude the ovaries from the target volume. The ovaries can be shielded additionally from diffuse radiation by using a gonadal shield attached to the treatment table.
      • If there is uncertainty of kidney function and the location of the kidneys relative to the fields, GFR with renography should be performed before simulation. 
      • To localize the kidneys during simulation, intravenous urography is performed. Evaluation of the amount of kidney included in the field that will necessitate changes to the fields after, for example 18–20 Gy can then be done.
      • The need for marking the biopsy scar/palpable findings with marking thread should be considered. 

      Implementation

      Conventional simulation

      • For direct simulation, the standard upper border is the upper edge of L5.
      • The lower border is at the ingional ligament.
      • The lateral borders standardly run from a point 1 cm lateral to the transverse processes on L5 to the lateral edge of the acetabulum thereby covering the terminal line with up to a 2 cm margin.
      • The medial border for unilateral irradiation runs from a point 1 cm lateral to the contralateral transverse processes on L5 and parallel to the lateral border ending in middle of the obturator foramen.
      • Depending on the craniocaudal extent of the tumor, the field border should have a 3–4 cm margin to the initial tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 2 cm margin to the residual tumor after full chemotherapy for advanced disease.
      • The border from the tumor to the field border in the transversal plane should be 2 cm.
      • For bilateral irradiation, the field border is equivalent on both sides. Placement of blocks in the midline of the pelvis is considered to shield the intestines, bladder, and gonads.
      • For simulation of the field to the iliacal and inguinal region, Oslo University Hospital has traditionally given the field from the front below the inguinal ligament where the lymph nodes lie deeper. A flat filter was previously used for this. A standard procedure has been developed for unilateral and inguinal irradiation that achieves the same result using the half-beam block technique. 

      CT-based simulation

      • The actual or orginal tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) defines GTV.
      • CTV is generated by the margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy). A 1 cm margin to CTV in the transversal plane, and CTV are contoured such that the entire nodal region is included in the levels irradiated.
      • CTV is set similar to ITV.
      • An alternative is to first define the desired field borders in the coronal slice on the CT dose plan program according to the guidelines that apply for direct simulation. An ITV can then be generated by subracting the margin from the set-up variation and penumbra (1–1,2 cm). This ITV can, if necessary, be modified for the situation.

      CT dose plan, iliacal region  

      CT dose plan, modified inverted Y-field

      Gonadal shielding

      • Gonads present in the primary field, but not within the target volume, must be shielded by blocks in the filter holder or by using a multileaf collimator. At Oslo University Hospital HF, lead blocks have traditionally been used rendering 10 half value layers. The standard blocks used previously for the scrotum (in men) and bladder bladder (both women and men) are no longer used. The leaves from the multileaf collimator can be enhanced by using and extra lead layer to give the same effect.   

      • For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should be considered. Ovariopexy is the surgical relocation of the ovaries out of the small pelvis to the midline behind the uterus. Surgical clips should indicate where the ovaries are located. Only then is it possible to exclude the ovaries from the target volume.

      • In addition to shielding, it is important to consider use of close shielding against diffuse radiation, which mainly occurs in the filter holder and multileaf collimator. This applies to both the gonads that lie inthe primary field but are shielded with blocks or multileaf collimator and for gonads that lie outside but near the primary field. At Oslo University Hospital today, a lead belt is used to pull the scrotum away from the field for unilateral irradiation in the pelvic region, as well as a gonadal shield attached to the treatment table. For symmetric irradiation in the pelvic region, a scrotum cup is used (5 mm of lead under and on the side of the scrotum) with a 3 cm lead block on top. The ovaries are shielded from diffuse spreading if they are in the primary field or near it with a gonadal shield attached to the treatment table.   

      Fractionation

      Standard fractionation and total dose for curative treatment is given below. These are also guidelines for palliative treatment, but must be modified individually.

      • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10 (note that iliacal involvement itself is a risk factor)
      • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
      • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
      • For aggressive NHL: 2 Gy x 20.

      Follow-up

      Risk organs

      Intestines

      In some patients, nausea, diarrhea and rectal symptoms in the form of pain and bleeding can occur.

      Bladder

      Radiation-induced cystitis may occur.

      Gonads

      The dose to the gonads should be as small as possible to preserve fertility. Reliable birth control during treatment is necessary, and is recommended until a year has passed after treatment. 

      Femur head and femur neck

      Osteoporosis of the femur head and femur neck may occur after radiation therapy and increases the chance of fracture.   

      Radiation therapy of the infraclavicular region for malignant lymphoma

      General

      The infraclavicular region is a specific region in the Ann Arbor classification, but is rarely involved alone. The region is almost never treated alone with radiation; it is usually treated together with the axillary and supraclavicular region.

      Curative radiation therapy

      • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
      • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy.
      • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma. 
      • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.  
      • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given.
      • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered. 
      • For indolent lymphomas with localized disease (stadium I-II1), radiation therapy alone is given to the involved area with margin (involved field).

      Palliative radiation therapy

      As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

         

         

         

         

        Definitions

        Target Volume

         

        Target volume definitions from ICRU
        (International Commission on Radiation Units and Measurements)

        GTV (= Gross Tumor Volume)

        Tumor volume

        Palpable or visible/identifiable area of malignant growth.

        CTV (= Clinical Target Volume)

        Clinical target volume

        Tissue volume containing GTV and subclinical microscopic malignant disease.

        ITV (= Internal Target Volume)

        Target volume

        Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

        PTV (= Planning Target Volume)

        Planning volume

        Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

        Planning contour: Beams-Eye-View projection of PTV.

        IM (= Inner margin) and SM (= Setup margin)

        IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

        Field limit

        The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

        Definition of margins

        The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

        Target volume for radiotherapy

        GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

        Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

        CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

        GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

        GTV + 1 cm in the transversal plane

        CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

        CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

        ITV CTV if internal movement is negligent (CNS, ENH and others)

        CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

        CTV + 2–3 cm in mesentary and stomach

        CTV + up to 0.5 cm transversal retroperitoneally

        PTV

        Not routinely defined

        Field limits

        Are set to 1 cm outside ITV for set-up margin and penumbra

        Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

        Involved node

        The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

        Involved field

        The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

        Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

        For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

        Extended field

        This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

        Preparation

        Since the infraclavicular region is often treated together with the axilla and supraclavicular region, the method is usually similar to the axillary field.

        • For direct alignment on the simulator, the axillary field is aligned with the overarm abduced to 90º.
        • For CT dosage-planned treatment, the arms are immobilized over the head in a wing board or slightly along the upper body. The reproduceability of the position may be a problem with slightly abduced arms. A 5-point mask with immobilization of the shoulder area may improve stability. With skin folds, skin reactions may be more problematic with doses up to 40 Gy. A side field cannot be given toward the neck if the arms are immobilized over the head with a wing board, and contouring ofthe infraclavicular region may be more uncertain since the claviclel and soft tissue will change the position.
        • In women, the breasts should be moved out of the field. 
        • Palpable findings and possible scarring or skin changes are marked with marking thread.

          

        Implementation

        Conventional simulation

        Since the infraclavicular region is usually treated together with the axilla and supraclavicular region, the same method applies.

        For direct simulation, the field to the infraclavicular region together with the axilla and supraclavicular area runs cranially below the neck and medially at the pedicles on the same side of the spine. 

        • To include lymph nodes on the thoracic wall, the thoracic wall is included medially and an edge of the lung of 1 cm. This line follows the lower edge of the fourth rib in toward the medial border. 
        • Laterally, the border runs from the humerus and includes the lateral parts of the axilla.
        • Caudally, the border runs by the breast, depending on the location of the tumor and the patient's anatomy.  
        • Cranially and laterally, the head of the humerus is blocked out as in the mantle field.
        • The field limits are modified to have an adequate margin to the tumor. The field border should have a 3–4 cm margin to the initial tumor volume in the direction of lymph drainage (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 2 cm margin to residual tumor after full chemotherapy for advanced disease. In the transversal plane, there should always be a 2 cm minimum to the field border, but the region is usually included in full standard width in the levels included in the field.  
        • Parts of the mediastinum, for example the upper mediastinum, are sometimes included.

        CT dose plan, neck region and supraclavicular fossa

        CT dose plan, axillary region

        CT-based simulation

        • For contouring of the axilla with CT, it is important to be aware that standard immobilization does not allow 90º abduction of the shoulder. Therefore, the best method for immobilization in relation to the planned target volume should be determined prior (see under preparation). 
        • Contouring of target volume in the axilla is difficult since a strictly anatomical model using CT slices often gives disproportionately large fields of both the lungs and sometimes breasts.
        • A possible solution to this problem is to first identify the desired field borders in the coronal slive with the CT dosage planning program in relation to the guidelines that apply for direct simulation and which are based on modeling of the mantle field.  An ITV can then be generated by subtracting the margin from the set-up variation and penumbra (1–1.2 cm). If necessary, this ITV can be modified for the situation. 
        • Further, it is often difficult to achieve a completely optimal dose distribution in the medial parts of the axilla due to large variations of cross measurements in the axilla and due to the percent of lung in the field. The benefit of optimal dosing in the ITV must be assessed against possible warm areas in, for example, the breast. 
         

        Fractionation  

        Standard fractionation and total dosage for curative treatment is described below. These are also normative for palliative treatment, but must be modified for each patient.  

        • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
        • Hodgkin's lymphoma: 1.75 Gy x 17.
        • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
        • For aggressive non-Hodgkin lymphoma: 2 Gy x 20.

        Follow-up

        Risk organs

        Skin 

        • Soreness in the skin folds of the axilla may occur. 

        Lungs

        • Subacute radiation pneumonitis during the first months after treatment may occur. Irradiated areas of the the lungs will often develop fibrosis over time. 

        Secondary cancer

        For patients receiving mantle field irradiation for Hodgkin's lymphoma, there risk for secondary cancer increases significantly, especially for organs given full therapeutic doses. Breast cancer, lung cancer, thyroid cancer, sarcomas, skin cancer, and melanoma are some of the most common. 

        Secondary cancer represents the most significant cause for increased mortality of patients cured of Hodgkin's lymphoma by radiation therapy. For younger women with mantle field irradiation under 35 years, a yearly mammogram is recommended starting about 8 years after irradiation. 

        For patients with other lymphoma entities, there are no set follow-up routines for smaller radiation fields and early diagnosis of other cancer forms. 

        The patient should be discouraged from smoking.

        Radiation therapy for the infraclavicular region for malignant lymphoma

        Radiation therapy for the inguinal and femoral region for malignant lymphoma

        General

        Indications

        Lymph nodes by the inguinal ligament and upper thigh are defined by the Ann Arbor classification systen as one region. Lymphoma involvement occurs in the femoral region with relative variation compared to caudal spreading. 

        Radiation therapy to the inguinal/femoral region is given in many instances, often together with the iliacal region or as a dog-leg field. 

        Curative radiation therapy

        • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
        • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy.
        • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma. 
        • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.  
        • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given.
        • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered. 
        • For indolent lymphomas with localized disease (stadium I-II1), radiation therapy alone is given to the involved area with margin (involved field).

        Palliative radiation therapy

        • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

             

             

             

           

          Definitions

          Target Volume

           

          Target volume definitions from ICRU
          (International Commission on Radiation Units and Measurements)

          GTV (= Gross Tumor Volume)

          Tumor volume

          Palpable or visible/identifiable area of malignant growth.

          CTV (= Clinical Target Volume)

          Clinical target volume

          Tissue volume containing GTV and subclinical microscopic malignant disease.

          ITV (= Internal Target Volume)

          Target volume

          Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

          PTV (= Planning Target Volume)

          Planning volume

          Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

          Planning contour: Beams-Eye-View projection of PTV.

          IM (= Inner margin) and SM (= Setup margin)

          IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

          Field limit

          The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

          Definition of margins

          The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

          Target volume for radiotherapy

          GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

          Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

          CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

          GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

          GTV + 1 cm in the transversal plane

          CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

          CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

          ITV CTV if internal movement is negligent (CNS, ENH and others)

          CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

          CTV + 2–3 cm in mesentary and stomach

          CTV + up to 0.5 cm transversal retroperitoneally

          PTV

          Not routinely defined

          Field limits

          Are set to 1 cm outside ITV for set-up margin and penumbra

          Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

          Involved node

          The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

          Involved field

          The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

          Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

          For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

          Extended field

          This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

          Preparation

          Radiation therapy to the inguinal and femoral region is considered part of an inverted Y field.

          • Sperm banking for men and possibly freezing of ovarian tissue or operative elevating or fixing of the ovaries (ovariopexy) in girls/women is considered. 
          • The patient lies supine with their arms by their side.
          • In male patients, there must be adequate space between the legs for placement of a gonadal shield (scrotum cup, lead belt and/ or gonadal shield). For irradiation of the iliacal region on one side (and dog leg field or L field), a lead belt is used where the scrotum is over on the contralateral side and shielded with a lead shield. For bilateral irradiation, a scrotum cup is used in addition to a lead shield. 
          • For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should be considered. Ovariopexy is the surgical relocation of the ovaries out of the small pelvis to the midline behind the uterus. Surgical clips should indicate where the ovaries are located. Only then is it possible to exclude the ovaries from the target volume. The ovaries can be shielded additionally from diffuse radiation by using a gonadal shield attached to the treatment table.
          • If there is uncertainty of kidney function and the location of the kidneys relative to the fields, GFR with renography should be performed before simulation. 
          • To localize the kidneys during simulation, intravenous urography is performed. Evaluation of the amount of kidney included in the field that will necessitate changes to the fields after, for example 18–20 Gy can then be done.
          • The need for marking the biopsy scar/palpable findings with marking thread should be considered. 
           

          Implementation

          Conventional simulation

          • A standard inguinal and femoral field has a cranial border at minimum 2 cm above the inguinal ligament. The caudal border is below the fossa ovalis, which by X-ray is almost equivalent to the lower border distal to the small trochanter.  
          • The lateral border standardly runs from the lateral border of the acetabulum. The medial border is such that the skin border medial to the thigh is spared, which is about 2-3 cm lateral to the symphysus.
          • Depending on the craniocaudal extent of the tumor, the field border should have a 3–4 cm margin to the initial tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 2 cm margin to the residual tumor after full chemotherapy for advanced disease. 
          • The border from the tumor to the field border in the transversal plane should be 2 cm. 
          • An isolated inguinal/femoral field may possibly be irradiated from the front in one field, and electron radiation may also be considered. This may give a smaller dose to the femur head. 
          • Since the distal iliacal region is often included, the half-beam block technique can be used which allows one front field in the bottom area and through irradiation in the upper area. At Oslo University Hospital, a standard procedure for unilateral and inguinal irradiation has been created for this purpose.

          CT-based simulation

          • The actual or orginal tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) defines GTV.
          • CTV is generated by the margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy). A 1 cm margin to CTV in the transversal plane, and CTV are contoured such that the entire nodal region is included in the levels irradiated.
          • CTV is set similar to ITV.
          • An alternative is to first define the desired field borders in the coronal slice on the CT dose plan program according to the guidelines that apply for direct simulation. An ITV can then be generated by subracting the margin from the set-up variation and penumbra (1–1.2 cm). This ITV can, if necessary, be modified for the situation. 

          CT dose plan, inguinal and femoral region 

          Gonadal shielding

          • Gonads present in the primary field, but not within the target volume, must be shielded by blocks in the filter holder or by using a multileaf collimator. At Oslo University Hospital HF, lead blocks have traditionally been used rendering 10 half value layers. The standard blocks used previously for the scrotum (in men) and bladder bladder (both women and men) are no longer used. The leaves from the multileaf collimator can be enhanced by using and extra lead layer to give the same effect.   

          • For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should be considered. Ovariopexy is the surgical relocation of the ovaries out of the small pelvis to the midline behind the uterus. Surgical clips should indicate where the ovaries are located. Only then is it possible to exclude the ovaries from the target volume. 

          • In addition to shielding, it is important to consider use of close shielding against diffuse radiation, which mainly occurs in the filter holder and multileaf collimator. This applies to both the gonads that lie in the primary field but are shielded with blocks or multileaf collimator and for gonads that lie outside but near the primary field. At Oslo University Hospital today, a lead belt is used to pull the scrotum away from the field for unilateral irradiation in the pelvic region, as well as a gonadal shield attached to the treatment table. For symmetric irradiation in the pelvic region, a scrotum cup is used (5 mm of lead under and on the side of the scrotum) with a 3 cm lead block on top. The ovaries are shielded from diffuse spreading if they are in the primary field or near it with a gonadal shield attached to the treatment table.    

          Fractionation

          Standard fractionation and total dose for curative treatment is given below. These are also guidelines for palliative treatment, but must be modified individually.  

          • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10 (note that iliacal involvement itself is a risk factor)
          • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
          • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
          • For aggressive NHL: 2 Gy x 20.

          Follow-up

          Risk organs

          Intestines

          In some patients, nausea, diarrhea and rectal symptoms in the form of pain and bleeding can occur.

          Bladder

          Radiation-induced cystitis may occur.

          Gonads

          The dose to the gonads should be as small as possible to preserve fertility. Reliable birth control during treatment is necessary, and is recommended until a year has passed after treatment. 

          Femur head and femur neck

          Osteoporosis of the femur head and femur neck may occur after radiation therapy and increases the chance of fracture.

          Radiation therapy of the inguinal and femoral region for malignant lymphomaRadiation therapy of inguinal and femoral region for malignant lymphoma.

          Radiation therapy with mantle field for malignant lymphoma

          General

          A standard mantle field includes all lymph node stations over the diaphragm. The mantle field originated as extended field treatment of supradiaphragmal spreading of Hodgkin's lymphoma.  

          The standard mantle field is rarely used today, but many long-term survivors of HL have received this treatment. Many examples of involved field radiation therapy to the diaphragm can be considered a section of the mantle field. Further, fields with sizes close to a mantle field are also considered involved field irradiation in some situations today. It is therefore advantageous to know the principles for modeling a mantle field as for the inverted Y field.

          • High mantle field includes treatment of the upper cervical lymph nodes (preaurciular and possibly retroauricular lymph nodes) and Waldeyer's ring including the tonsil field.
          • Low mantle field includes the submental, submandibular, and nuchal lymph nodes as the upper stations. The upper field border was at the level of the point of the chin and the bottom of the posterior skull.
          • Minimantle was the expression for fields where the mediastinum could be excluded. 

          Definitions

          The following definition is partly based on StrålevernRapport 2003:13, which is referring to ICRU50 and 62 as well as NACP.

           

          Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)

          GTV (Gross tumor volume)

          Gross palpable or visible/identifiable area of malignant growth.

          CTV (Clinical target volume)

          Macroscopic tumor volume including any remaining tumor tissue.

          ITV (Internal Target Volume)

          Volume containing CTV and internal margin to allow for internal movements and changes to CTV.

          PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
          OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.

          PRV (Planning organ-at-risk volume)

          Geometric volume containing risk volume with set-up margin.
          TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
          IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
          CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

           

          Field Limits

          The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

          Definition of margins

          For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.

           

          Target volume for radiation therapy
          GTV Current tumor for indolent NHL stage I/II1, original tumor(before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA

          Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV

          CTV GTV + 2 cm craniocaudal for limited disease/short chemotherapy

          GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy

          GTV + 1cm in transverse plane

          CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).

          CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.

          ITV CTV if internal movement can be ignored (CNS, ENT)

          CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum

          CTV + 2–3 cm in mesentery

          CTV + 0-0.5 cm transverse retroperitoneally

          PTV

          Not routinely defined

          Field limits ITV + Setup margin and penumbra (1.2 cm)

          The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)

          Involved node

          The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.

           

          Involved field

          Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extention to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.

          Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate.

          For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.

          Extended field

          This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.

          Preparation

          • Patients must be evaluated by a dentist and treated if necessary before immobilization and start of treatment. 
          • The patient is immobilized supine on a VacFix® and with a mask. It is important the patient has their chin stretched sufficiently (5° extension of the mandible). The arms should be abduced to 90° when irradiating the axilla. The arms should be rotated upward for a low mantle field and downward when the tonsil field is joined.
          • In women, the breasts should be moved out of the field with lung blocks. 
          • It should be considered to mark papable lymph nodes or biopsy scars with lead thread to locate again on simulation film. 
          • Fields resembling mantle fields may be suitable for CT dose-planned treatment. Immobilization of the arms abduced to 90° is not possible on CT machines. Immobilization of the arms can be done over the head with with a wing board, or the arms slightly abduced along the upper body. The reproduceability of the position may be a problem with slightly abduced arms. A 5-point mask with immobilization of the shoulder area may improve stability. With skin folds, skin reactions may be more problematic with doses up to 40 Gy. A side field cannot be given toward the neck if the arms are immobilized over the head with a wing board.

          Implementation

          Conventional simulation

          Low mantle field

          • A large field (up to 50 x 50 cm) is modeled with a cranial border of 1 cm above the jaw angle, which with an adequate chin stretch, represents a line from the point of the chin, under the ear canal and to the bottom of the posterior skull.  If there is visible tumor in this area, a higher field border should be considered (more of the oral cavity and posterior skull is included).  the alternative is a field border caudal to the palpable tumor that joins the tonsil field (side field to periauricular lymph nodes and Waldeyer's ring) outside the macrotumor. 
          • The caudal field limit is by Th10/11.
          • If there will be a joining of the tonsil field or later paraaortal field/inverted Y field, the field limits must be placed to facilitate movement of joinings, but should be go through macroscopically involved areas.  This must be planned before simulations and a physicist must be consulted. 
          • Field borders on the sides must be outside the thoracic wall and include part of the humerus so that lateral parts of the axillar are well included.
          • Placement of blocks must be defined.
          • It is standard to place a larynx block over the larynx in the front field and a medulla block over the cervical spine in the rear field. A larynx block and medullablock should be exluded for cervical tumors near the midline. 
          • Lung blocks, humerus blocks, and axilla blocks are use in both fields. Lung blocks are drawn around 0.5-1  within the thoracic walls laterally, follow the underside of rib 4 (to cover infraclavicular regions) and should follow the contour of the upper mediastinum and hilum with 1.5–2 cm margin in the lung parenchym. The blocks do not follow the shadows of the heart on the left side, but instead turn in under the hilum, such that the left stomach and lung in the front and back of the heart are shielded. 
          • Humerus blocks are drawn from the center of the humerus head and half of the humerus shaft within the radiation field. This allows for irradiation of the lateral and apical parts of the axilla. 
          • Soft tissue and lung caudal to the axilla are shielded with an axillary block, typically at the level of the breast. 
          • Contouring of blocks may vary depending on the extent of the tumor, for example tumor invasion of the anterior thoracic will necessitate inclusion of larger parts of the thoracic.  
          • For many patients, it is necessary to block out large parts of the lower mediastinum during the entire or parts of treatment to reduce the dose to the heart and heart valve level.

          CT dose plan, neck region and supraclavicular fossa

          CT dose plan, axilla region 

          Tonsil field for high mantle field 

          • The tonsil fields, which include large parts of Waldeyer's ring and also known at the periauricular field, are modelled on a simulator as opposing fields toward periauricular lymph nodes and large parts of Waldeyer's ring. When treating the high mantle field, the mantle field is given concomitantly with side fields in this region. The mantle field is standardly set such that the crosspoints of the anterior and posterior fields lie in the frontal plan through the ear canal. When irradiation toward the tonsil field, the side fields lie partly or completely in front of this frontal plane. 
          • Modeling of borders for the tonsil field standardly runs in the middle of the sphenoidal sinus for the upper border (sella turcica with pituitary and eyes), anterior border behind the teeth in the upper and lower jaw and lower border joined with the upper border of the mantle field. The posterior border is normally in front of the outer ear canal, but may lie behind the ear canal in some cases.
          • With joinings toward the tonsil field, a joining is placed based on a standard developed with a physicist. The lower border of the tonsil field with joining should not go into the macro tumor, and with high cervical lymphadenopathy this must be moved caudally compared to the standard high mantle field. The side fields must then include the submandibular and occipital nodes.
          • With joinings farther down the neck toward an extended side field, the joining must also be planned during simulation. 
          • It is today seldom to join the entire mantle field with the tonsil field, or large side fields to Waldeyer's ring and upper cervical lymph nodes. The total field size usually allows for use of the isocentric technique with half-beam block, which avoids problems with field junctions.The side fields with Waldeyer's ring as well as periauricular, submandibular, and occipital lymph nodes are irradiated cranial to the central beam from side to side. The neck and other caudal regions are irradiated with anteroposterior beams caudal to the central beam.

          CT-based simulation

          The mantle field cannot be directly transferred to CT based simulation because CT machines do not support 90° abduction of the shoulder joint. Involved field irradiation the size of a modified mantle field may then be the case, and it may be possible to use CT for planning.

          • The actual or orginal tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) defines GTV.
          • CTV is generated by the margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy). A 1 cm margin to CTV in the transversal plane, and CTV are contoured such that the entire nodal region is included in the levels irradiated.
          • Contouring of Waldeyer's ring, neck lymph nodes, axilla, infraclavicular regions and mediastinum is described in their respective chapters.
          • The margin to ITV in the transversal plane in the mediastinum is up to 1 cm in the craniocaudal direction and up to 0.5 cm in the transversal plane. On the neck and in the axilla, there is no margin for internal movement.
          • An alternative is to first define the desired field borders in the coronal slice on the CT dose plan program according to the guidelines that apply for direct simulation. An ITV can then be generated by subracting the margin from the set-up variation and penumbra (1–1.2 cm). This ITV can, if necessary, be modified for the situation. 

          Fractionation

          Standard fractionation and total dose for curative treatment is given below. These are also normative for palliative treatment, but should be modified on an individual basis. 

          • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
          • Otherwise for Hodgkin's lymphoma: 1,75 Gy x 17.
          • Curative treatment of indolent NHL: 2 Gy x 15
          • Aggressive NHL: 2 Gy x 20.  

          Follow-up

          Risk organs

          Mucosa 

          Acute mucosa toxicity such as mucositis in the mouth, pharynx, and esophagus during treatment and closely following occurs in most patients and some have significant problems. 

          Skin and hair

          Reversible alopecia to irradiated areas of the posterior skull and the jaw including beard growth should be expected. Skin and axilla soreness of skin folds may also occur. 

          Bone marrow

          Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment.

          Lense, eyes, chiasma, pituitary

          Fields to the periauricular lymph nodes and Waldeyer's ring may give a small dose to these organs, which is usually under the dose tolerance. It is important to avoid unintended hotspots to these organs.  

          Teeth should be evaulated and treated before treatment to prevent later osteoradionecrosis. Caution should be used for dental treatment after irradiation of the jaw region.  

          Salivary glands 

          Dry mouth can be expected with fields including both parotid glands. If this can be avoided, problems are often moderate in the long run.

          Thyroid gland

          At least half of lymphoma patients with irradiation to the neck develop hypothyroidism within years. Lifetime follow-up of thyroid status is indicated. Thyroid cancer can occur years after radiation therapy.

          Cerebrovascular disease

          After radiation therapy to neck vessels, there is a known increased risk for cerebrovascular complications.  

          Lungs

          Subacute radiation pneumonitis during the first months after treatment may occur. Irradiated areas of the lungs will often develop fibrosis over time.

          Heart

          Patients have increased cardiovascular mobidity after irradiation which includes the heart valve area and/or parts of the myocardium. Valve problems, coronary heart disease, heart failure, and constrictive pericarditis are the most common side effects. These side effects are especially common in patients previously irradiated with a mantle field for Hodgkin's lymphoma. Guidelines in Norway recommend yearly follow-up with a general practicioner starting 10 years after treatment focusing on reduction of other risk factors (smoking, obesity, hypercholesterolemia, high blood pressure, physical inactivity) and early evaluation of symptoms or changes that my imply heart disease. Patients should be strongly discouraged from smoking.

          Secondary cancer

          For patients treated with mantle field irradiation for Hodgkin's lymphoma, there is a significant risk for secondary cancer, especially in organs receiving full therapeutic doses. Breast cancer, lung cancer, thyroid cancer, sarcomas, and skin cancer/melanoma are the most common forms. Secondary cancer is a significant cause of death of patients cured for Hodkin's lymphoma by radiation therapy. For younger women treated with mantle field irradiation in ages under 35, it is recommended to have yearly mammography screening starting 8 years after radiation therapy was given. For other cancer forms, there are no defined follow-up routines. Patients should be strongly discouraged from smoking.

          Radiation therapy with mantle field for malignant lymphoma.

          Radiation therapy for the liver for malignant lymphoma

          General

          Indications

          The liver is often involved with lymphoma as part of advanced disease and usually with multiple lesions or diffuse spreading in the liver. This applies to both Hodgkin's lymphoma and all forms of non-Hodgkins lymphoma. In most cases, patients will be candidates for chemotherapy primarily for advanced disease and only isolated residual lesions are suitable for radiation therapy. Primary extranodal involvement in the liver with only localized focal lymphoma spreading to the liver is very rare, and even then should it be considered whether to treat as advanced disease. 

          Since the tolerance for ionizing radiation for the entire liver is likely slightly under 30 Gy (TD5/5 for liver failure), irradiation of the entire organ is difficult if it is desired to give doses the same as for malignant lymphomas. Irradiation of up to 1/3 of the liver is, however, possible with doses up to 50 Gy.

          Curative radiation therapy

          • Isolated residual lesions after chemotherapy for the respective lymphoma may be appropriate for consolidative radiation therapy. 
          • Primary extranodal involvement in the liver with focal lymphoma spreading (stage PeI) is very rare. In such a case, treatment for advanced disease with chemotherapy and radiation therapy should still be considered only for possible residual lesions. 

          Palliative radiation therapy

          • For palliative radiation therapy, the method usually follows the same guidelines as for curative therapy with individual modifications.
          • Smaller doses to the entire liver are considered for local symptoms such as liver involvemet and capsule pain. 

          Definitions

          Target Volume

           

          Target volume definitions from ICRU
          (International Commission on Radiation Units and Measurements)

          GTV (= Gross Tumor Volume)

          Tumor volume

          Palpable or visible/identifiable area of malignant growth.

          CTV (= Clinical Target Volume)

          Clinical target volume

          Tissue volume containing GTV and subclinical microscopic malignant disease.

          ITV (= Internal Target Volume)

          Target volume

          Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

          PTV (= Planning Target Volume)

          Planning volume

          Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

          Planning contour: Beams-Eye-View projection of PTV.

          IM (= Inner margin) and SM (= Setup margin)

          IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

          Field limit

          The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

          Definition of margins

          The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

          Target volume for radiotherapy

          GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

          Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

          CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

          GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

          GTV + 1 cm in the transversal plane

          CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

          CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

          ITV CTV if internal movement is negligent (CNS, ENH and others)

          CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

          CTV + 2–3 cm in mesentary and stomach

          CTV + up to 0.5 cm transversal retroperitoneally

          PTV

          Not routinely defined

          Field limits

          Are set to 1 cm outside ITV for set-up margin and penumbra

          Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

          Involved node

          The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

          Involved field

          The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

          Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

          For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

          Extended field

          This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

          Preparation

          • Liver function should be evaluated before treatment based on the planned treatment and irradiated volume.
          • One or both kidneys will usually be partly or completely involved during treatment, and evaluation of kidney function for total and each side separately with GFR and renography may be done before treatment. 

          Implementation

          Conventional simulation

          Direct contouring on the simulator may be appropriate for a palliative situation to initiate treatment quickly. 

          • X-ray, palpation findings, or ultrasound with margining of liver borders in the abdominal cavity may be advantageous to determine field borders.

          • Since the liver moves during respiration, a good margin in all phases of respiration is necessary.

          CT-based simulation

          Treatment is done using CT dose planning for curative treatment of residual lesions. 

          • The residual lesion after chemotherapy is GTV and CTV is generated with 1 cm margin.

          • Since the liver moves during respiration, a minimum of 1-2 cm margin to ITV is favorable in the craniocaudal direction while 1 cm is sufficient in the transversal plane. 

          Fractionation

          Standard fractionation and total dose for curative treatment is given below. 

          • For HL: 1.75 Gy x 17
          • For indolent NHL: 2 Gy x 15
          • For aggressive NHL: 2 Gy x 20
          • For palliative treatment, fractionation and total dose must be adapted for each patient. Caution should be used if there is suspicion of extramedullary hematopoiesis in the liver.  

          Follow-up

          Risk organs

          Liver

          Liver testing should be evaluated during and in the first weeks after treatment.

          Stomach and intestines

          If parts of the stomach or intestines are included in the fields, nausea can be expected and prophylaxis should be given before the first fraction. Dyspepsia, diarrhea, and pain may be signs of mucositis in the stomach and intestines. Ulcerations and peforation may occur.

          Bone marrow 

          With extramedullary hematopoiesis in the liver, radiation therapy is considered to cause significant decline in counts during and in the weeks after treatment. Regular examination is necessary during this time. Caution should be used with fraction size, number of fractions per week, and total dose in such cases.  Kidneys

          Depending on the dose, renal function may be reduced. Renal hypertonia may occur later on. 

          Radiation therapy for lung for malignant lymphoma

          General

          Indications

          With advanced lymphoma, the lungs are often involved and usually with multiple lesions. This applies to both Hodgkin's lymphoma and all forms of Non-Hodgkin lymphoma. In most cases, these patients will be candidates for primary chemotherapy as for advanced disease. With residual lesions, radiation therapy is considered in some cases. Since the tolerance for ionizing radiation for the entire lung is slightly below 18–20 Gy (TD5/5 for lung failure), irradiation of the entire organ is often difficult if it is desired to give doses the same as for malignant lymphoma. Therefore, consolidative radiaion therapy is given only under special circumstances to the entire lung or both with lower fractions and total doses than otherwise for lymphomas. Primary extranodal involvement of the lungs with only one localized focal lymphoma manifestation (considered stage PeI) is very rare, and even then it must be considered whether such cases should be treated as advanced disease and whether surgery should be chosen as local treatment in a curative plan.  

          Curative radiation therapy

          • Residual lesions after chemotherapy each lymphoma where the clinical profile indicates that the chemotherapy effect should be consolidated in the lungs. This may apply to, for example, patients with recurrence of aggressive lymphomas or Hodgkin's lymphoma who are treated to cure the disease, and where lung manifestations (possibly together with mediastinal recurrence manifestations) dominate the clinical profile.
          • Patients under 18 years with Hodgkin's lymphoma with lung involvement will have radiation therapy for the lungs in primary treatment based on guidelines from protocol GPOH-HD-95 (selected patients only).   
          • Primært ekstranodal affeksjon i lungen med lokalisert fokal lymfomutbredelse (tenkt stadiumPeI) er svært sjelden. Dersom slikt forekommer, må en likevel vurdere om slike tilfeller bør behandles som utbredt sykdom med egnet kjemoterapi og om kirurgi skal velges som lokalbehandling i et kurativt opplegg.

          Palliative radiation therapy

          • Palliative radiation therapy of entire or both lungs is almost never indicated. 

          Definitions

          Target Volume

           

          Target volume definitions from ICRU
          (International Commission on Radiation Units and Measurements)

          GTV (= Gross Tumor Volume)

          Tumor volume

          Palpable or visible/identifiable area of malignant growth.

          CTV (= Clinical Target Volume)

          Clinical target volume

          Tissue volume containing GTV and subclinical microscopic malignant disease.

          ITV (= Internal Target Volume)

          Target volume

          Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

          PTV (= Planning Target Volume)

          Planning volume

          Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

          Planning contour: Beams-Eye-View projection of PTV.

          IM (= Inner margin) and SM (= Setup margin)

          IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

          Field limit

          The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

          Definition of margins

          The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

          Target volume for radiotherapy

          GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

          Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

          CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

          GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

          GTV + 1 cm in the transversal plane

          CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

          CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

          ITV CTV if internal movement is negligent (CNS, ENH and others)

          CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

          CTV + 2–3 cm in mesentary and stomach

          CTV + up to 0.5 cm transversal retroperitoneally

          PTV

          Not routinely defined

          Field limits

          Are set to 1 cm outside ITV for set-up margin and penumbra

          Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

          Involved node

          The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

          Involved field

          The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

          Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

          For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

          Extended field

          This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

          Preparation

          • Consider whether lung function must be evaluated before radiation therapy begins. Regardless, this may be advantageous for further follow-up.
          • For conventional simulation, the patient lies in a position similar to the mantle field, with their arms abduced to 90°. Or, their arms and legs are along their sides but sufficiently away from their upper body. 
          • For CT-based planning, the patient lies with their arms and legs along their sides but as far away from their upper body as possible. Immobilization in a wing board is a possible alternative. 

          Implementation

          Conventional simulation  

          • A large field is modeled such that the field borders cover all parts of the lung(s) for both normal expiration and inspiration. There should be an adequate margin to lung tissue to cover set-up variation and penumbra, or a minimum of 1.5–2 cm.
          • The posterior sinus is identified by side images from the simulator. The upper spleen and liver are always included in the radiation field. 
          • For unilateral lung irradiation without the mediastinum, the field border should be on the same side of the medulla in the soft tissue of the mediastinum. In children, irradiation of the thoracal column should be symmetric to avoid growth imbalances.   

          CT-based simulation

          Lung irradiation can also be done by CT planning.

          • Both lungs and the entire medistinum are drawnn on the inside of the thoracic wall as a CTV. 
          • To take into account respiration movements, there must be a 1 cm margin to ITV in the transversal plane and 1-2 cm margin craniocaudally (ITV1).
          • Any structures in the mediastinum to be treated simultaneously with another fraction are defined as a separate ITV (ITV2).
          • Any fractionated doses larger than the what the lungs receive must be given as a concomitant boost. Dosing to ITV1 is then, for example 1.2 Gy x 10 and to ITV2 1.75 Gy x 17, where 0.55 Gy is given to ITV2 as concomitant boost at the first 10 fractions, and ITV2 alone is given 1.75 Gy at the last 7 fractions.
          • The field set-up should be checked by illumination on the simulator to make sure the lungs are included both during inspiration and expiration as for conventional simulation. 

           CT dose plan, lung  

          Fractionation

          The total dose to whole or parts of the lung should not exceed 15 – 18 Gy. The regular dose/fraction in later years given by Oslo University Hospital has been, depending on previous chemotherapy/high dose treatment, 12 or 15 Gy in 1.2–1.5 Gy fractions.

          Usually, bilateral lung irradiation is given together with irradiation of the mediastinum. The mediastinum should be given 1.75– 2 Gy per fraction and a higher total dose of 30–40 Gy. This is achieved by using a lung filter which allows a full fractionated dose of 1.75–2 Gy to the mediastinum, but reduces the dose to the lungs to 1.2 –1.5 Gy at each fraction, or, by giving mediastinal irradiation as a concomitant boost after the fraction to the lungs is given. The mediastinum must often be given multiple fractions after lung irradiation is concluded. When calculating the lung doses, the lung correction factor must be used. 

          Follow-up

          Risk organ

          Lung

          It is possible to develop acute and subacute pneumonitis during and in the months following treatment, as well as chronic lung function disturbances. A chest X-ray should be taken after treatment is finished and for pulmonary symptoms during and in the months following treatment. A thoracic CT is more sensitive in showing radiation-reactive changes. Radiation-induced pneumonitis is treated with steroids in cooperation with a lung specialist.

          Lung fibrosis and lung failure can occur in the long-term.

          Radiation therapy for the mediastinum and hilum of lung for malignant lymphoma

          General

          In the Ann Arbor system the mediastinum is one region and is separated fromthe hilar lymph nodes on each side.

          For radiation therapy, it is common to view the mediastinum as:

          • the upper region above the carina.
          • the middle region around the carina which includes tracheobronchial and bronchopulmonary lymph nodes (lung hilum on both sides). 
          • lymph nodes immediately subcarinal and at the base of the heart.
          • Posterior/lower region with lymph nodes below the carina behind the heart along the esophagus, descending aorta, thoracic column, and in the carciophrenic angles.  

          Lymphoma involvement in the mediastinum occurs normally as large conglomerate tumors in close proximity to the heart. In addiion to involvment in the middle and posterior mediastinum, there is often paracardial involvement along and and in the pericardium ventrally, ventrolaterally on the right or left side and in the cardiophrenic angles. Lymphoma involvement near the heart is often a challenge for planning radiation therapy. 

          Indications

          Curative radiation therapy

          • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent). The initial tumor volume before chemotherapy is critical for field modeling, but it is important to take into account tumor reduction after chemotherapy where the lung was pushed to the side, but not infiltrated by lymphoma before chemotherapy (the balloon effect).  
          • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy. Isolated involvment of NLPHL in the mediastinum is rare.
          • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma.
          • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.
          • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given. The initial tumor volume before chemotherapy is critical for field modeling, but it is important to take into account tumor reduction after chemotherapy where the lung was pushed to the side, but not infiltrated by lymphoma before chemotherapy (the balloon effect). With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered.
          • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered.
          • Mediastinal tumors from lymphoblastic lymphomas/ALL, Burkitt's lymphoma and primary mediastinal B cell lymphomas are always considered for radiation therapy, even after intensive chemotherapy. This is usually done by irradiating the original tumor volume in the craniocaudal direction, but with consideration for the balloon effect in the transversal plane.
          • For indolent lymphomas with localized disease (stadium I-II1), radiation therapy alone is given to the involved area with margin (involved field).

           

           

          Palliative radiation therapy

          • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

               

               

               

               

               

               

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            • If large parts of the lungs or heart are included inthe radiation field, lung and heart function should be evaluated before treatment.
            • Immobilization of patients for radiation therapy for the mediastinum depends on which other regions will also be treated and whether treatment will be planned by CT.
            • If parts of the neck will also be irradiated, a 3-point or 5-point mask is preferably used.
            • For simultaneous irradiation of the axilla, patient is immobilized with the arm abduced to 90º for conventional simulation. For CT planning, a wing board or 5-point mask is used with the arms slightly abduced along the upper body.
            • In women, the breasts should be moved out of the field.
            • Palpable findings and possible scarring or skin changes are marked with marking thread.

             

            Implementation

            Conventional simulation

            For direct simulation, the craniocaudal layout of the radiation field should be individualized, such that the extent of the tumor (initial or after chemotherapy) is included with the correct margin to the field border in the craniocaudal direction. Depending on the extent of the tumor in the craniocaudal direction, the field border should have a 3-4 cm margin to the initial tumor volume (for curative treatment for localized indolent lymphomas or limited chemotherapy for early stages of HL and aggressive NHL) or 2-3 cm margin to the residual tumor after full chemotherapy for advanced disease.  

            If the upper mediastinum is included in the radiation field, it is sometimes necessary to include the supraclavicular fossa bilaterally to achieve an adequate margin to the macro tumor. 

            Even after limited chemotherapy, the actual tumor volume after chemotherapy always defines the margin to the lungs, not the initial volume (balloon effect). The mediastinum is always irradiated in full width in the levels included, and if the hilum level is included, the tracheobronchial and brochopulmonary lymph nodes are also included. This means that the field borders are laterally 1.5 cm out to lung tissue and follow the hilar contours on the simulator image (see mantle field). If the extent of the tumor lies on one side of the heart or in the cardiophrenic angle on one side, modeling should take this into account to spare as much of the heart as possible. If tumor has spread in the thoracic wall, which is included in the initial tumor volume to be irradiated, the field width must be modified, or joined with an electron field (increased lung irradiation).

            CT-based simulation

            • The actual or original tumor volume (for curative treatment for localized indolent lymphomas or after limited chemotherapy for early stages of HL and agressive NHL) defines GTV.
            • CTV is generated with margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy). A 1 cm margin to CTV in the transversal plane, and CTV is drawn such that the entire node region is included in the areas to be irradiated. If there is not infiltration into the lungs or bone, CTV is limited with similar anatomical barriers. 
            • If the hilum of the lung is in the CT slice where CTV is drawn, the hilar regions should also be included in CTV. The reason for this is that border recurrences in the hilar areas are difficult to retreat. It is important to be aware that larger parts of the hilum appear on CT compared to X-ray, and liberal modeling of the hilar regions may result in a much better mediastinal field. 
            • ITV is generated with margin to CTV up to 1 cm craniocaudally and up to 0.5 cm in the transversal plane out to healthy lung.
            • An alternative is to first define the desired field borders in the coronal slice on the CT planning program according to the guidelines that apply for direct simulation. An ITV can then be generated by subtracting the margin from the set-up variation and penumbra (1–1.2 cm). This ITV can be modified if necessary for the situation. 
            • When evaluating the field set-up and dose plan, it is important to check the final fields in the beams eye view since they are often disproportionately large.   
            • The standard field layout is from behind and front, since this avoids sharing the dose with large volumes of healthy tissue. 
            • Moulded lung blocks give smaller doses to the lungs than leaves from multileaf collimators with standard leaf widths of 0.5-1 cm. Moulded blocks may be necessary when the axillas are included in the radiation field. 
            • When evaluating dose-volume histograms, the cumulative dose to the heart is often small, but the critical structures at the valve level/outlet of the coronary arteries often receive a full therapeutic dose. Because of this, irradiation of partial volumes of the heart and tolerance are of limited benefit in terms of heart disease.
            • In cases of paracardial lymphoma where standard anteroposterior rays give large doses to the whole heart, may represent a challenge. Individualized modification of modeling is necessary where as much of the heart is held outside ITV. Even if the distance to the field border from the tumor should be 2 cm, parts of the left stomach can usually be held out of the fields of radiation. These patients are usually also candidates for more advanced field layouts and may possibly benefit from IMRT.  

            CT dose plan, mediastinum and lung hilum  

            CT dose plan, neck region and supraclavicular fossa  

            CT dose plan, axillary region  

            Fractionation

            Standard fractionation and total dosage for curative treatment is described below. These are also normative for palliative treatment, but must be modified for each patient.

            • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
            • Hodgkin's lymphoma: 1.75 Gy x 17.
            • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
            • For aggressive non-Hodgkin lymphoma: 2 Gy x 20.
            • For residual lesions after CHOP-based chemotherapy with higher doses of anthracyclines, other intensive chemotherapy and HMAS (for example Hodgkin's lymphoma, primary mediastinal B cell lymphomas, lymphoblast lymphomas/ALL or Burkitt's lymphoma), lower doses than those mentioned above are considered sufficient in some cases. 

            Follow-up

            Organs at risk

            Mucosa

            Acute mucosa toxicity such as mucositis in the esophagus during treatment and closely following occurs in most patients and some have significant problems.

            Bone marrow

            Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment.

            Thyroid gland

            At least half of lymphoma patients with irradiation to the neck develop hypothyroidism within years. Lifetime follow-up of thyroid status is indicated. Thyroid cancer can occur years after radiation therapy.

            Lung

            Subacute radiation pneumonitis during the first months after treatment may occur. Irradiated areas of the lungs will often develop fibrosis over time.

            Heart

            Patients have increased cardiovascular mobidity after irradiation which includes the heart valve area and/or parts of the myocardium. Valve problems, coronary heart disease, heart failure, and constrictive pericarditis are the most common side effects. These side effects are especially common in patients previously irradiated with a mantle field for Hodgkin's lymphoma. Guidelines in Norway recommend yearly follow-up with a general practicioner starting 10 years after treatment focusing on reduction of other risk factors (smoking, obesity, hypercholesterolemia, high blood pressure, physical inactivity) and early evaluation of symptoms or changes that my imply heart disease. Patients should be strongly discouraged from smoking.

            Secondary cancer

            For patients treated with mantle field irradiation for Hodgkin's lymphoma, there is a significant risk for secondary cancer, especially in organs receiving full therapeutic doses. Breast cancer, lung cancer, thyroid cancer, sarcomas, and skin cancer/melanoma are the most common forms. Secondary cancer is a significant cause of death of patients cured for Hodkin's lymphoma by radiation therapy. For younger women treated with mantle field irradiation in ages under 35, it is recommended to have yearly mammography screening starting 8 years after radiation therapy was given. For other cancer forms, there are no defined follow-up routines. Patients should be strongly discouraged from smoking.

            Mediastinum and hilum of lung

            Radiation therapy for mesenterial lymph nodes for malignant lymphoma

            General

            Indications

            Mesenterial lymph nodes are a separate lymph node region in the Ann Arbor system. The region is large, and characteristically lesions in this area have much internal movement.  

            Curative radiation therapy

            • Limited stages of Hodgkin's lymphoma (stage IA/IIA) with mesenterial involvement is rare, and central infradiaphragmal disease itself is a risk factor. According to guidelines, these patients are given 4 ABVD cycles followed by consolidative radiation therapy to the involved field, but this is based on the premise that involved areas can be included in a reasonable field with adequate margin. If this is not the case, for example due to large tumor masses, the position of the kidneys etc., chemotherapy for advanced disease should be given, and radiation therapy considered for residual lesions.  
            • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy. This is based on the premise that involved areas can be included in a reasonable field with adeqate margin. If this is not the case, for example due to large tumor masses, the position of the kidneys etc., chemotherapy for advanced disease should be given, and radiation therapy considered for residual lesions.
            • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma.
            • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.  
            • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy is given after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field). This is based on the premise that involved areas can be included in a reasonable field with adeqate margin. If this is not the case, for example due to large tumor masses, the position of the kidneys etc., chemotherapy for advanced disease should be given, and radiation therapy considered for residual lesions.
            • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered.
            • For indolent lymphomas with localized disease (stage I-II1), radiation therapy alone is given to the involved area with margin (involved field). This is based on the premise that involved areas can be included in a reasonable field with adeqate margin. If this is not the case, for example due to large tumor masses, the position of the kidneys etc., chemotherapy for advanced disease should be given, and radiation therapy considered for residual lesions.

            Palliative radiation therapy

            • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

               

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            • The patient lies supine with their arms by their side.
            • Sperm banking for men and possibly freezing of ovarian tissue or operative elevating or fixing of the ovaries (ovariopexy) in girls/women is considered.
            • Gonadal shielding may be necessary. In male patients, there must be sufficient spread between the legs to place a shield (gonadal block or lead belt).
            • If there is uncertainty of the patient's kidney function, GFR with renography should be done before simulation. 
            • To localize the kidneys during simulation, intravenous urography is performed. Evaluation of the amount of kidney included in the field that will necessitate changes to the fields after, for example 18–20 Gy can then be done.
            • The need for marking the biopsy scar/palpable findings with marking thread should be considered.

            Implementation

            Conventional simulation 

            Direct simulation of fields to mesentary and other abdominal lymphoma manifestations should only by done for palliative treatment with a relatively short goal for symptoms relief. Much movement oflesions in the mesentary must be expected as well as a low accuracy by X-ray on the simulator.   

            For direct simulation, the field borders are placed with adequate margins to the tumor to include microscopic growth in the tumor border zone (1 cm),  penumbra and set-up variation (minimum 1–1.2 cm) and assumed internal movement. In addition, there is uncertainty because during palpation or X-ray, tumor borders can almost never be defined with certainty. One must depend on information from radiological diagnostics which is transferred to the simulator image (for example the relation of the tumor to bone structures).  

            The fields are often large. 

            CT-basert simulering

            Treatment should be done based on CT-guided dose planning.

            • The actual or orginal tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) defines GTV.
            • CTV is generated with a 1 cm margin in all directions, but is limited to the contact surfaces where infiltration is not expected such as bone structures. 
            • A 2-3 cm margin is made for internal movement for ITV. ITV should, again, be limited. For example, if the movement in toward the retroperitoneal structures such as the kidney and spine is significantly less that in the peritoneal cavity. 
            • Standard field set-up is with anteroposterior beams, but in many cases, the extent of the tumor in the kidney region, side differences in kidney function etc. necessitate other field set-up with better shielding of healthy renal tissue, for example a diagonal field or side field.  

            CT dose plan, mesenterial lymph nodes 

            CT dose plan, paraaortal region 

            Gonadal shielding

            • Gonads present in the primary field, but not within the target volume, must be shielded by blocks in the filter holder or by using a multileaf collimator. At Oslo University Hospital HF, lead blocks have traditionally been used rendering 10 half value layers. The standard blocks used previously for the scrotum (in men) and bladder bladder (both women and men) are no longer used. The leaves from the multileaf collimator can be enhanced by using and extra lead layer to give the same effect.   

            • For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should be considered. Ovariopexy is the surgical relocation of the ovaries out of the small pelvis to the midline behind the uterus. Surgical clips should indicate where the ovaries are located. Only then is it possible to exclude the ovaries from the target volume. 

            • In addition to shielding, it is important to consider use of close shielding against diffuse radiation, which mainly occurs in the filter holder and multileaf collimator. This applies to both the gonads that lie in the primary field but are shielded with blocks or multileaf collimator and for gonads that lie outside but near the primary field. At Oslo University Hospital today, a lead belt is used to pull the scrotum away from the field for unilateral irradiation in the pelvic region, as well as a gonadal shield attached to the treatment table. For symmetric irradiation in the pelvic region, a scrotum cup is used (5 mm of lead under and on the side of the scrotum) with a 3 cm lead block on top. The ovaries are shielded from diffuse spreading if they are in the primary field or near it with a gonadal shield attached to the treatment table.

            Fractionation

            Standard fractionation and total dose for curative treatment is given below. These are also guidelines for palliative treatment, but must be modified individually. 

            • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
            • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
            • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
            • For aggressive NHL: 2 Gy x 20.
            • For large abdominal fields where doses to the kidneys are limited, fractionation into 1.2 Gy x 15-16 or 1.5 Gy x 12-13 may be considered.

            Follow-up

            Organs at risk

            Organs at risk depend on the localization of the tumor in the abdomen and the size of the radiation fields.

            Stomach and intestines

            Nausea can be expected in most patients undergoing this treatment. Nausea prophylaxis should be started before the first fraction. Dyspepsia, diarrhea, and pain may be a sign of mucositis in the stomach and intestines. Ulcerations and perforation can also occur. 

            Urinary tracts

            Cases of radiation-induced cystitis can occur. Depending on the dose to the kidneys, kidney function may be reduced and renal hypertonia may occur in the long run.

            Bone marrow 

            Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment. Regular follow-up may be necessary during this time. 

            Fertility 

            Great emphasis should be placed on reducing the dose to the gonads to preserve fertility. Reliable birth control during treatment is necessary and is recommended for one year after treatment. 

            Secondary cancer

            Irradiation under the diaphragm is associated with increased risk for later cancer in organs within or near the fields of radiation.

            Radiation therapy for the spleen for malignant lymphoma

            General

            Indications

            The spleen and lymph nodes along the splenic vessels and by the hilum of the spleen are considered one lymphatic region in the Ann Arbor system. Lymph node involvement in the spleen usually occurs as part of the general disease. With local treatment for lymphoma in the spleen, a splenectomy is an alternative that must be considered on an individual basis.    

            Curative radiation therapy

            • Residual tumor in the speen after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent) or aggressive lymphomas (6–8 CHOP-based cycles or equivalent) may be a circumstance for consolidative radiation therapy to the whole spleen. Alternatives may be a splenectomy, or with a negative biopsy, observation only. 
            • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma.
            • Localized stages of Hodgkin's lymphoma (stage IA/IIA) with spleen involvement, based on severity, are considered for consolidative radiation therapy to the involved field after 2–4 ABVD cycles or equivalent. Chemotherapy as for advanced disease may be considered an alternative, but radiation therapy is given only to residual lesions after a splenectomy. 
            • Localized stages of aggressive lymphomas (stage I/PeI-II1/PeII1), based on severity, are given consolidative radiation therapy after CHOP-based chemotherapy or equivalent to the initial tumor volume before chemotherapy. In both of these cases, the lymph nodes along the splenic vessels are included, and if necessary, the upper retroperitoneal lymph nodes as well to achieve adequate margins to the primary tumor area.  
            • Indolent lymphomas with localized spleen involvement almost never occur, and are primarily evaluated for splenectomy. 

            Palliative radiation therapy

            • Palliative radiation therapy to the spleen for lymphoma or myeloproliferative disease is an alternative. The indications for this may be, for example, splenomegaly with abdominal discomfort or hypersplenism. Radiation therapy may also be an alternative for patients not expected to tolerate a splenectomy. 
            • It is important to evaluate the degree of extramedullary hematopoiesis in the spleen in these patients, since radiation therapy in many cases can lead to serious pancytopenia, especially if the spleen contributes signficantly to the hematopoiesis. 

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            • The patient should be given a pneumococcal vaccine at least 2 weeks before starting radiation therapy for the spleen, which is the same as for a splenectomy. 
            • The left kidney will always be partly or comletely involved in treatment and evaluation of kidney function (total and each side) and kidney position is done before simulation/dose planning, especially if the dose is over 20 Gy. 
            • Ultrasound before direct simulation to mark the position of the spleen on the abdominal wall during normal inspiration and expiration is advantageous. 
            • The patient lies supine.

            Implementation

            Conventional simulation

            • For conventional simulation, it is sometimes possible to use palpation findings as a guideline for field modeling, or view the spleen as a soft tissue shadow on X-ray images. 

            • Ultrasound to mark the position of the spleen on the abdominal wall during normal inspiration and expiration may be advantageous. 

            • The spleen lies under the left diaphragmatic arch and follows this cranially and laterally. The medial and caudal borders of the spleen may vary. Craniocaudally, consideration for movement of the diaphragm should be taken, and the field border should therefore be up to 2 cm above the diaphragm in the lung. 

              The movement of the diaphragm is checked by X-ray. 

            • Lymph nodes of the hilum of the spleen and along the splenic vessels are often included. 

            • The stem of the spleen with vessels often project over the upper third of the left kidney and in toward the upper paraaortal region.  

            • The field border should have a minimum 2 cm margin to the spleen contour. With involvement of the hilum of the spleen, a there must also be a margin along this in toward the upper paraaortal region. 

            CT-based simulation

            • Visible tumor in the spleen is defined as GTV together with any visible changes in the hilum of the spleen and along the splenic vessels. 

            • CTV is generated with a 1 cm margin. The entire spleen is always included in CTV. The hilum of the spleen and lymph nodes along the splenic vessels and in toward the upper paraaortal region are aslo included if this indicated.  

            • There should be a margin of 1 cm (minimum) in the craniocaudal direction to ITV (diaphragm movement) and 0.5–1 cm in the transversal plane.

            • The pasient should be viewed on the simulator to check that the field borders are sufficient, and especially that the cranial borders are over the diaphragm with adequate margins in all phases of respiration.  

            CT dose plan, spleen

            Fractionation

            Standard fractionation and total dose for curative treatment is given below.

            • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
            • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
            • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
            • For aggressive NHL: 2 Gy x 20.
            For palliative therapy, the fractioned dose and dose and total dose should be individualized. 
            • Many patients without extramedullary hepatopoiesis in the spleen will tolerate fractions of 1.2–1.5 Gy given 4-5 times per week up to 20–30 Gy. Field reduction may be possible as the spleen reduces in size. 
            • If there is suspicion of extramedullary hematopoiesis in the spleen, fractioned doses of 0.2–0.5 Gy given 3 times per week may be advantageous, at least initially. The patient's general status and counts are evaluated regularly during treatment. The total dose and field reduction is evaluated during treatment, and total doses of 1–10 Gy may be adequate treatment for most. 

            Follow-up

            Organs at risk 

            Stomach and intestines

            Nausea can be expected in most patients undergoing this treatment. Nausea prophylaxis should be started before the first fraction. Dyspepsia, diarrhea, and pain may be a sign of mucositis in the stomach and intestines. Ulcerations and perforation can also occur.

            Bone marrow 

            Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment. Regular follow-up may be necessary during this time.

            Kidney 

            Depending on the dose received by the kidneys, a reduction in kidney function and renal hypertonia may occur in the long run.

            Radiation therapy for the nose and sinuses for malignant lymphoma

            General

            Indications

            Lymphomas in this area are often aggressive lymphomas such as DLBCL, NK/T cell lymphomas, and Burkitt's lymphoma. NK/T cell lymphomas as a group are rare, but have a predilection for this localization. Tumors often have a locally aggressive growth pattern with infiltration of bone in surrounding structures (eye, skull with possible intracranial growth, oral cavity, skin). As for aggressive lymphomas in general, they are normally treated with chemotherapy initially according to histology, stage, and risk profile. Aggressive lymphomas in this localization lead to a higher risk for CNS manifestations and CNS-directed treatment/prophylaxis is often indicated. 

            Curative radiation therapy

            • Radiation therapy is given as consolidative after chemotherapy regardless of histology and should always be considered if there is involvement of bone and/or there is residual tumor after chemotherapy.

            Palliative radiation therapy

            • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

               

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            • The patient must be evaluated by a dentist and any dental treatment must be finished before treatment is started.
            • If one or both eyes are involved, it must be evaluated whether there is disease that may limit the dose to one or both eyes.
            • The patient must be immobilized with a mask.

            Implementation

            CT-based simulation

            The treatment is planned using CT.

            • Visible tumor is defined as GTV. If initially there is locally advanved growth, with bone destruction, the initial tumor volume before chemotherapy is used in areas with bone involvement.
            • CTV is generated with 1 cm margin to GTV.
            • Avoid hot areas in organs at risk such as the eyes, optic chiasma, or pituitary with complicated field layout.

            CT dose plan, nose and sinuses

            Fractionation

            Standard fractionation and total dose for curative treatment is given below. These doses are also guidelines for palliative treatment, but should be modified for individual circumstances.

            • For Hodgkin's lymphoma: 1.75 Gy x 17
            • For aggressive Non-Hodgkins lymphoma: 2 Gy x 20

            Follow-up

            Organs at risk

            Mucosa 

            Acute mucosal toxicity such as mucositis in the nose, mouth, and larynx during treatment and shortly after occurs in most patients, some are considerably affected.

            Skin and hair

            Reversible alopecia in irradiated areas of the head and jaw (beard growth) should be expected. 

            Lense, eyes, optic chiasma, pituitary gland

            Fields to the ear-nose-throat region will contribute a small dose that normally lies under the tolerance dose for these organs. It is important to avoid unintended hot spots in these organs.

            Teeth

            Defects should be repaired before treatment start to prevent later osteoradionecrosis. Caution should be used with dental treatment after irradiation. 

            Salivary glands

            Lasting dry mouth should be expected if the field includes both parotid glands. If this can be avoided, problems are often reduced moderately.

            Blood vessels in the neck 

            After irradiating blood vessels in the neck, there is a small increased risk for cerebrovascular complications.

            Radiation therapy with inverted-Y field for malignant lymphoma

            General

            Indications

            A standard inverted-Y field covers all paraaortal, iliacal, and inguinal lymph nodes as well as upper femoral nodes. The inverted-Y field originated from the extended field for treating Hodgkin's lymphoma with infradiaphragmal spreading. 

            The standard inverted-Y field is seldom used today. Many examples of involved field radiotherapy under the diaphragm are considered parts of an inverted Y field. Fields the size of an inverted-Y field are also considered involved field irradiation in some instances. Like the mantle field, it is therefore advantageous to know the principles of modeling an inverted-Y field.

            Curative radiotherapy

            • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
            • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy.
            • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma.
            • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.
            • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given.
            • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the

            Palliative radiotherapy

            • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

               

            Definitions

            The following definition is partly based on StrålevernRapport 2003:13, which is referring to ICRU50 and 62 as well as NACP.

             

            Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)

            GTV (Gross tumor volume)

            Gross palpable or visible/identifiable area of malignant growth.

            CTV (Clinical target volume)

            Macroscopic tumor volume including any remaining tumor tissue.

            ITV (Internal Target Volume)

            Volume containing CTV and internal margin to allow for internal movements and changes to CTV.

            PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
            OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.

            PRV (Planning organ-at-risk volume)

            Geometric volume containing risk volume with set-up margin.
            TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
            IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
            CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

             

            Field Limits

            The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.

             

            Target volume for radiation therapy
            GTV Current tumor for indolent NHL stage I/II1, original tumor(before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal for limited disease/short chemotherapy

            GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy

            GTV + 1cm in transverse plane

            CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.

            ITV CTV if internal movement can be ignored (CNS, ENT)

            CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum

            CTV + 2–3 cm in mesentery

            CTV + 0-0.5 cm transverse retroperitoneally

            PTV

            Not routinely defined

            Field limits ITV + Setup margin and penumbra (1.2 cm)

            The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)

            Involved node

            The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.

             

            Involved field

            Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extention to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.

            Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate.

            For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.

            Extended field

            This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.

            Preparation

            • Sperm banking for men and possibly freezing of ovarian tissue should be assessed before treatment starts.
            • Evaluate the need for ovariopexy in girls/women of fertile age before simulation. 
            • The patient lies supine with their arms along their side. The doctor ensures the patient is immobilized on the simulator. For men, there must be a sufficient spread between the legs for gonadal shielding.
            • If there is uncertainty of kidney function and the location of the kidneys relative to the fields, GFR with renography should be performed before simulation.
            • To localize the kidneys during simulation, intravenous urography is performed. Evaluation of the amount of kidney included in the field that will necessitate changes to the fields after, for example 18–20 Gy can then be done.
            • The need for marking the biopsy scar/palpable findings with marking thread should be considered.

            Implementation

            Conventional simulation

            • A large rectangular field is modeled with the upper field border at Th10/11. The lower field border runs below the groin with adequate margin to palpable findings. If the femoral lymph node regions will also be included, the caudal field border can be on the thigh. The field ends laterally at the greatest width of the groin, which is standardly the lateral border of the acetabulum.   
            • Blocks are placed over the primary field in the shape of an inverted-Y. A block is placed parallel with the lower thoracal and lumbar spine down to L4 to shield the kidneys and intestines. The standard field width which covers the transverse processes bilaterally with a 0.5-1 cm margin gives a typical width of 8-10 cm. From the lower edge of L4, a block is drawn diagonally to the acetabulums lateral border. From the acetabulum, the field border continues vertically down. 
            • A block is placed in the midline of the pelvis to shield the bladder, rectum, and genitals. A standard block template was previously used for this, which was a lead block placed in a filter holder in the lower part of the field to shield the testicles in men, and a rectangular displaceable part that could be extended cranially to block the bladder for men and women. Today, a multileaf collimator with additional block material (together 10 half value layers) is a more appropriate alternative (see below).
            • At Oslo University Hospital, a filter was previously used in large parts of the frontal field with diagonal lines in the lower edge. The lower edge of this filter (flat filter) would lie caudal to the inguinal ligament and the diagonal sides of the lower edge had a standard angle of 20º, which produced a line from the symphysus up to the lateral edge of the acetabulum on both sides. Below the filter border, the target volume was covered only by the frontal field (for example with 2 Gy per fraction). Above the filter border, the frontal field gave half a dose (1 Gy). This was done to avoid irradiation of the hip area (which only receives a dose from the lower part of the frontal field) and thereby reducing the dose to the head of the femur. A flat filter is no longer used today. For irradiation of the inguinal and iliacal region on one side, a simplified procedure has been developed for direct simulation, where the flat filter is replaced by the half-beam block technique. 
            • If the patient was previously irradiated with a mantle field, the lower border of the mantle field should have been reconstructed in the actual position. The joining was calculated and it was routine to place a 20 mm medulla block in the posterior field. 
            • The Y field usually covers both groin areas, but more recently, it is more common that only parts of this large area are covered, for example the paraaortal regions down to the bifurcature of the large vessels, paraaortal region with one side of the pelvis and goin (L field or dog leg field) or only lymph nodes in the groin on one side possibly with the distal iliac region. Sometimes the spleen is included with the target volume. These fields are considered modifications of the same inverted Y field. 

            Gonadal shielding for inverted-Y field

            • Gonads present in the primary field, but not within the target volume, must be shielded by blocks in the filter holder or by using a multileaf collimator. At Oslo University Hospital HF, lead blocks have traditionally been used rendering 10 half value layers. The standard blocks used previously for the scrotum (in men) and bladder bladder (both women and men) are no longer used. The leaves from the multileaf collimator can be enhanced by using and extra lead layer to give the same effect.
            • For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should be considered. Ovariopexy is the surgical relocation of the ovaries out of the small pelvis to the midline behind the uterus. Surgical clips should indicate where the ovaries are located. Only then is it possible to exclude the ovaries from the target volume.
            • In addition to shielding, it is important to consider use of close shielding against diffuse radiation, which mainly occurs in the filter holder and multileaf collimator. This applies to both the gonads that lie in the primary field but are shielded with blocks or multileaf collimator and for gonads that lie outside but near the primary field. At Oslo University Hospital today, a lead belt is used to pull the scrotum away from the field for unilateral irradiation in the pelvic region, as well as a gonadal shield attached to the treatment table. For symmetric irradiation in the pelvic region, a scrotum cup is used (5 mm of lead under and on the side of the scrotum) with a 4 cm lead block on top. The ovaries are shielded from diffuse spreading if they are in the primary field or near it with a gonadal shield attached to the treatment table.

            CT-based simulation

            • The actual or orginal tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) defines GTV.
            • CTV is generated by the margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy).  A 1 cm margin to CTV in the transversal plane and CTV are contoured such that the entire nodal region is included in the levels irradiated. When treating the original tumor volume, one should consider drawing in the actual tumor volume in the transversal plane where the original tumor volume has pushed healthy organs to the side and then moved back to their original place after chemotherapy (balloon effect). 
            • Margin to ITV in the transversal plane is 0–0.5 cm.
            • An alternative is to first define the desired field borders in the coronal slice on the CT dose plan program according to the guidelines that apply for direct simulation. An ITV can then be generated by subracting the margin from the set-up variation and penumbra (1–1.2 cm). This ITV can, if necessary, be modified for the situation.

            CT dose plan, inverted-Y field 

            Fractionation

            Standard fractionation and total dose for curative treatment is given below. These are also guidelines for palliative treatment, but must be modified individually.

            • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
            • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
            • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
            • For aggressive NHL: 2 Gy x 20.

            Follow-up

            Organs at risk 

            Stomach and intestines 

            Nausea can be expected in most patients undergoing this treatment. Nausea prophylaxis should be started before the first fraction. Dyspepsia, diarrhea, and pain may be a sign of mucositis in the stomach and intestines. Ulcerations and perforation can also occur.

            Bladder

            Radiation-induced cystitis may occur.

            Bone marrow 

            Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment. Regular follow-up may be necessary during this time.

            Fertility

            Great emphasis should be placed on reducing the dose to the gonads to preserve fertility. Reliable birth control during treatment is necessary and is recommended for one year after treatment.

            Kidney 

            Depending on the dose received by the kidneys, a reduction in kidney function and renal hypertonia may occur in the long run.

            Head and neck of the femur

            Osteoporosis of the head and neck of the femur may occur after irradiation, which increases the risk of fracture. 

            Secondary cancer

            Like the mantle field, there is an increased risk for other cancer forms, especially for organs within the radiation field receiving a full therapeutic dose. 

            Radiation therapy of eye for malignant lymphoma

            General

            Malignant lymphomas in the eye originate from the eyelid, lacrimal gland, conjunctiva, or retroorbital structures. Histologically, these are often MALT lymphomas with histologies resembling marginal zone lymphoma. 

            Indications

            Curative radiotherapy

            • Marginal zone lymphomas are often localized lymphomas in stage PeI, and are candidates for curative radiation therapy alone.  
            • Aggressive lymphomas (DLBCL, Burkitt's lymphoma, NK/T cell lymphoma) occur usually as more advanved disease in the ENT area with invasion into the eye. For these types, consolidative radiation therapy after chemotherapy is often given. Depending on the degree that bone structures are involved, tumor volume before chemotherapy may be decisive for field modeling.
            • Intraocular lymphomas are usually histologically DLBCL, occuring as part of PCNSL and treated as such. If radiotherapy is given as part of multimodal therapy, the eye should be included and usually bilaterally. 

            Palliative radiotherapy

            • For palliative radiotherapy, the method will follow guidelines for curative radiotherapy with individual modifications. 

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            • Isolated fields toward the eye normally to not involve the teeth in the upper jaw. If treatment becomes expanded at some point, and the teeth in the upper jaw are infiltrated, dental treatment must be finished before immobilization and treatment start. 
            • If there is relevant eye disease limiting the dose to one or both eyes, the patient should be evaluated by an opthomologist. 
            • The patient is immobilized in a mask.

            Implementation

            Conventional simulation

            With isolated skin involvement on the eyelid, local irradiation with electrons or X-rays is considered. An eye shield inside the eyelid is used to spare the lense and retina. 

            CT-based simulation

            • For deep-lying lesions, CT dose-planned treatment with photons is used.  
            • For marginal zone lymphoma in stage PeI, the entire eye within the ocular cavity is considered CTV and ITV. This is to avoid recurrence and the need to retreat in the same area. For stage PeI, local node stations are not drawn in as CTV. Bolus is considered for lesions near the skin surface. 
            • For consolidative treatment after chemotherapy for aggressive lymphomas, the initial tumor volume with areas for bone involvment is usually the appropriate GTV, and CTV is generated with 1 cm margin. 
            • Avoid hotspots in surrounding organs at risk such as the optic chiasma and pituitary gland. 
            • For marginal zone lymphomas in paired organs, recurrence or new lymphoma sometimes occurs in the contralateral organ. This is particularly the case with marginal zone lymphoma of the eye. This should be considered when choosing field set-up, and dosing to healthy tissue on the contralateral side of the head should be avoided. Two diagonal wedge fields from the front are normally adequate. 

            CT dose plan, eye

            Fractionation

            Standard fractionation and total dose for curative therapy is given below. These are also guidelines for palliative treatment, but should be modified individually. 

            • For curative treatment of indolent NHL: 2 Gy x 15
            • For aggressive NHL: 2 Gy x 20

            Follow-up

            Organs at risk 

            Optim chiasma and pituitary gland

            The radiation doses for lymphoma treatment is under the tolerance limit for these structures, but hot areas should be avoided in these organs. 

            Eyes and lenses

            Cataract in the irradiated eye should be expected within years after treatment if the lense cannot be shielded. The radiation dose for lymphoma treatment is under the tolerance limit for the retina and optic nerve. The contralateral eye should be shielded as much as possible.

            Salivary glands

            The parotid gland is, in most cases, not included in the high-dose area, even on the side of the irradiated eye. The contralateral parotid gland should be spared as much as possible to avoid dry mouth. 

            Radiation therapy for the paraaortic region for malignant lymphoma

            General

            Indications

            Paraaortic, paracaval, and interaorticaval lymph nodes from the diaphragm to the aortic bifurcature are covered by one paraaortic field. Radition therapy to the paraaortal region is given in many circumstances.

            Curative radiotherapy

            • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
            • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy.
            • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma.
            • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.
            • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given.
            • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the involved area with margin (involved field).

            Palliative radiotherapy

            • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            The paraaortal field is considered part of an inverted Y field. 

            • Sperm banking for men and possibly freezing of ovarian tissue should be assessed before treatment starts. 
            • Evaluate the need for ovariopexy in girls/women of fertile age before simulation. 
            • The patient lies supine with their arms by their side. The doctor will ensure the patient is immobilized on the simulator. In male patients, there should be sufficient spread between the legs for placement of gonadal shielding.    
            • If there is uncertainty of the patient's kidney function, GFR with renography should be done before simulation.
            • To localize the kidneys during simulation, intravenous urography is performed. Evaluation of the amount of kidney included in the field that will necessitate changes to the fields after, for example 18–20 Gy can then be done.
            • The need for marking the biopsy scar/palpable findings with marking thread should be considered.

            Implementation

            Conventional simulation

            • For modeling of the paraortal field by direct simulation, the upper field border is usually located at Th10/11 and the lower border is at the bottom edge of L4 or L5. Craniocaudally, the field limit should then have a minimum of 3-4 cm margin to the initial tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 2 cm margin to residual tumor after full chemotherapy of advanced disease.  
            • Standard field width is such that the transverse processes are within the field with about a 1 cm margin giving field width of 8-10 cm. Lateral field limits must be individualized depending on the extent of the tumor, localization of the kidneys, kidney function, and total dose. Tumor spreading in the transversal plane with a 2 cm margin defines the field breadth. For early stages of lymphoma after short systemic treatment where reduction of the tumor may lead to a better margin to the kidney and intestines after chemotherapy (balloon effect), the residual tumor can usually be used as basis for the field width.  
            • As for other regions, the paraaortal region is irradiated in the entire width of the levels where indicated. 
            • If a mediastinal field has previously been given and a joining is necessary, the field and joining must be calculated by a physicist. Consider using a medulla block, such as a block in the posterior field over the nearest 2-3 cm of medulla to the joining.
            • Areas of recurrence between the paraortal field and earlier mediastinal field should be avoided since they may be difficult to retreat.

            CT based simulation

            • The actual or orginal tumor volume (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) defines GTV.
            • CTV is generated by the margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy). A 1 cm margin to CTV in the transversal plane and CTV are contoured such that the entire nodal region is included in the levels irradiated.
            • Margin to ITV in the transversal plane is 0–0.5 cm.
            • An alternative is to first define the desired field borders in the coronal slice on the CT planning program according to the guidelines that apply for direct simulation. An ITV can then be generated by subtracting the margin from the set-up variation and penumbra (1–1.2 cm). This ITV can be modified if necessary for the situation.
            • Standard field set-up is with an anteroposterior beam, but in many situations tumor spreading to the kidney region, side differences in kidney function etc. necessitates other field field set-up with better shielding of healthy kidney tissue, for example a diagonal field or side field.
            • If a mediastinal field has previously been given and a joining is necessary, the field and joining must be calculated by a physicist. Consider using a medulla block, such as a block in the posterior field over the nearest 2-3 cm of medulla to the joining. 
            • Areas of recurrence between the paraortal field and earlier mediastinal field should be avoided since they may be difficult to retreat.

            CT dose plan, paraaortal field

            Gonadal shielding

            • Gonads present in the primary field, but not within the target volume, must be shielded by blocks in the filter holder or by using a multileaf collimator. At Oslo University Hospital HF, lead blocks have traditionally been used rendering 10 half value layers. The standard blocks used previously for the scrotum (in men) and bladder bladder (both women and men) are no longer used. The leaves from the multileaf collimator can be enhanced by using and extra lead layer to give the same effect.
            • For girls and women of fertile age, shielding of the ovaries and/or ovariopexy should be considered. Ovariopexy is the surgical relocation of the ovaries out of the small pelvis to the midline behind the uterus. Surgical clips should indicate where the ovaries are located. Only then is it possible to exclude the ovaries from the target volume.
            • In addition to shielding, it is important to consider use of close shielding against diffuse radiation, which mainly occurs in the filter holder and multileaf collimator. This applies to both the gonads that lie in the primary field but are shielded with blocks or multileaf collimator and for gonads that lie outside but near the primary field. At Oslo University Hospital today, a lead belt is used to pull the scrotum away from the field for unilateral irradiation in the pelvic region, as well as a gonadal shield attached to the treatment table. For symmetric irradiation in the pelvic region, a scrotum cup is used (5 mm of lead under and on the side of the scrotum) with a 4 cm lead block on top. The ovaries are shielded from diffuse spreading if they are in the primary field or near it with a gonadal shield attached to the treatment table.

            Fractionation

            Standard fractionation and total dose for curative treatment is given below. These are also guidelines for palliative treatment, but must be modified individually.

            • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
            • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
            • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
            • For aggressive NHL: 2 Gy x 20.

            Follow-up

            Organs at risk

            Stomach and intestines

            Nausea can be expected in most patients undergoing this treatment. Nausea prophylaxis should be started before the first fraction. Dyspepsia, diarrhea, and pain may be a sign of mucositis in the stomach and intestines. Ulcerations and perforation can also occur.

            Bone marrow 

            Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment. Regular follow-up may be necessary during this time. 

            Gonads

            The dose to the gonads should be as small as possible to preserve fertility. Reliable birth control during treatment is necessary, and is recommended until a year has passed after treatment.

            Kidney 

            Depending on the dose received by the kidneys, a reduction in kidney function and renal hypertonia may occur in the long run.

            Radiation therapy for the scrotum and testicles for malignant lymphoma

            General

            Indications

            Lymphoma occuring in the testicles is often aggressive and dominated by diffuse giant cell B cell lymphoma, Burkitt's lymphoma, or lymphoblastic lymphoma/ALL. Diffuse giant cell B cell lymphomas occur most commonly in elderly patients. Lymphoma is often localized to both testicles, even if only one testicle appears to be involved clinically and/or radiologically. 

            If tumor in the testicle is the patient's primary symtom, an orchiectomy is usually performed for diagnostic purposes. If the testicles are involved as part of generalized lymphoma or leukemia, this is usually not the case. 

             

            Treatment of lymphoma in the testicles follows the given guidelines for the respective histological entity. 

            Curative radiation treatment

            • With giant cell B cell lymphoma, recurrence is not uncommon in the remaining testicle - even after orchiectomy and adequate chemotherapy. Irradiation of the scrotum/remaining testicle may also be important for prophylaxis of later CNS progression. 
            • With lymphoblastic lymphoma /ALL and Burkitt's lymphoma with testicular involvement, it has been discussed whether radiation therapy to the scrotum is a valuable supplement to systemic chemotherapy with the assumption that the blood-testes barrier can reduce the effect of chemotherapy in the testicles. In the absence of sufficient data in this area however, this is evaluated on an individual basis. 

             

            Palliative radiation treatment

            • For palliative radiation therapy, the method usually follows the same guidelines as for curative therapy with individual modifications. 

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            • The patient lies supine with his legs spread. Leg supports may be considered. 
            • The room should be warm and the patient relaxed. The patient should be touched with warm hands.
            • The penis is immobilized out of the radiation beam, for example on the lower abdomen.

            Implementation

            Conventional simulation

            • If the anatomy of the patient allows, treatment is given with the scrotum laying on a "bench".
            • The scrotum and testicles are wrapped in bolus material since the scrotal skin is thin and otherwise would not achieve full coverage of the testicles. 
            • The entire scrotum should be included in the target volume and the cranial border for the field should extend to the root of the penis to ensure that the testicles are within the field also during retraction of the funicle.
            • Photons or electrons can be given based on depth from the front, but the entire depth of the scrotum must be given a full dose. With use of electrons, 90% of the isodose behind the target volume should lie in the bolus material under the scrotum. 
            • Alternatives to this set-up may be necessary if the scrotal skin is not mobile elastic enough. Electrons can then be considered, for example, at a sufficient depth diagonal from the front toward the scrotum/perineum using a bolus.  

            Fractionation

            • For DLBC, 2 Gy x 20 is routinely used.
            • For consolidative treatment of testicular involvement with Burkitt's lymphoma, ALL or lymphoblastic disease after or during intense chemotherapy protocols, it is more difficult to indicate a sure fractionation and total dose. It is recommended to give a minimum of 24–26 Gy in the literature and higher some places. Oslo University Hospital has most commonly used 2 Gy x 15.

            Follow-up

            Organs at risk

            Skin

            Acute dermatitis in the scrotal skin may occur since there are many skin folds and the skin is exposed to moisture during fractions. 

            Mucosa 

            In the urethra and rectum, mucositis may occur with dysuria and rectal symptoms.

            Testicles

            Irradiation of the testicles in the mentioned doses will cause permanent sterility. Reliable birth control is still recommended during treatment and the first year after. Testosterone production may decline many years after treatment and should be evaluated regularly. 

            Radiation therapy for bone with malignant lymphoma

            General

            Indications

            Malignant lymphomas originating in the bone are rare, except for solitary plasmacytoma. If localized malignant lymphomas in the bone are present, there is often uncertainty whether they should be staged as PeI and treated accordingly or be considered cases of primary generalized disease. Bone involvement occurs most often as part of generalized disease of all histological subgroups of Hodgkin's and Non-Hodgkin lymphoma. Bone involvement can also occur as a local extension of lymphoma in the legs, for example from extranodal lymphomas in the nose/sinuses and from retroperitoneal nodal tumors with spinal invasion.

            Myeloma is usually associated with bone involvement, and most patients are candidates for radiotherapy during the course of the disease.

            Curative radiation therapy

            • Histology and stage determine whether treatment can be curative. 
            • For isolated unifocal bone involvement of indolent lymphomas or solitary plasmacytoma, radiotherapy alone can be given with a curative intention. 
            • For isolated bone involvement, bone involvement as part of generalized disease, or extension to legs from surrounding structures of Hodgkin's or aggressive non-Hodgkin lymphoma, it is indicated to irradiate after curative chemotherapy, but only if there is one or maximum two areas of bone involvement. If radiation therapy is given, it is to be given to the entire area with initial bone involvment even if the tumor has responded well to chemotherapy. With more than two areas of bone involvement, spreading to the bone is considered generalized and radiotherapy to all lesions is not sensible.

            Palliative radiation therapy

            • According to regular palliative guidelines, it is appropriate to irradiate bone involvement in danger of fracture, pain, or compression of the spinal cord and other neurogenic tissue.

            Definitions

            Target Volume

             

            Target volume definitions from ICRU
            (International Commission on Radiation Units and Measurements)

            GTV (= Gross Tumor Volume)

            Tumor volume

            Palpable or visible/identifiable area of malignant growth.

            CTV (= Clinical Target Volume)

            Clinical target volume

            Tissue volume containing GTV and subclinical microscopic malignant disease.

            ITV (= Internal Target Volume)

            Target volume

            Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

            PTV (= Planning Target Volume)

            Planning volume

            Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

            Planning contour: Beams-Eye-View projection of PTV.

            IM (= Inner margin) and SM (= Setup margin)

            IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

            Field limit

            The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

            Target volume for radiotherapy

            GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

            GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

            GTV + 1 cm in the transversal plane

            CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

            ITV CTV if internal movement is negligent (CNS, ENH and others)

            CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

            CTV + 2–3 cm in mesentary and stomach

            CTV + up to 0.5 cm transversal retroperitoneally

            PTV

            Not routinely defined

            Field limits

            Are set to 1 cm outside ITV for set-up margin and penumbra

            Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

            Involved node

            The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

            Involved field

            The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

            Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

            For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

            Extended field

            This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.

            Preparation

            Preparation for radiotherapy and immobilization depends on the area to be treated with radiation.

            Implementation

            Conventional simulation

            • Modeling the field on the simulator should give a minimum 2 cm margin from visible tumor to the field border. The original tumor before chemotherapy determines the shape of the field regardless.

            • The fields should follow regular geometric guidelines so that later joinings and retreatment is as easy as possible.

              For example, the field limits are always placed in the intervertebral spaces and the entire body of vertebra with transverse processes and spinous processes are included.

              Likewise, the long bones are irradiated in full width with good margin lengthwise in the marrow cavity and in soft tissue outside the bones.

            • When irradiating extremities, it is important to be aware of the degree of uncertainty in modeling from one fraction to the next. Also, when treating the extremities, a border of healthy soft tissue should be excluded to prevent development of lymphedema.

            CT-based simulation

            • For modeling on CT, visible tumor (the original tumor in legs for consolidative treatment after chemotherapy) is GTV.

            • CTV is generated with a 1 cm margin to GTV.

            • Bone structures usually have little internal movement except for the ribs and sternum which move during respiration. For the sternum, margins should be 1–1.5 craniocaudally and 0.5–1 cm transversally evaluated from CTV to ITV.

            • The finished fields should follow the geometric guidelines given above such that later joinings and retreatment is as easy as possible.

              For example, the field limits are always placed in the intervertebral spaces and the entire body of vertebra with transverse processes and spinous processes are included.

              Likewise, the long bones are irradiated in full width with good margin lengthwise in the marrow cavity and in soft tissue outside the bones.

            • A possible solution to this is to first define the desired field borders in the coronal slice on the CT dose plan program according to the guidelines that apply for direct simulation. An ITV can then be generated by subtracting the margin for the set-up variation and penumbra (1–1.2 cm). This ITV can if necessary be modified for individual situations.

            CT dose plan, bone

            Fractionation

            Standard fractionation and total dose for curative treatment is given below.

            • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
            • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17.
            • For localized indolent lymphomas: 2 Gy x 15
            • For solitary plasmacytomas: 2 Gy x 20
            • For aggressive non-Hodgkin lymphomas: 2 Gy x 20.

            For a palliative indication, doses of 3 Gy x 10 (fracture danger, weight-bearing bone structures, compression of neurogenic tissue), 4 Gy x 5 or 8 Gy x 1 (pain as indication) are considered.

            Follow-up

            Organs at risk depend on the area with bone pathology. Remember to consider use of gonadal shielding when treating near testicles or ovaries. 
            Humerus

            Radiation therapy for Waldeyer's ring with malignant lymphoma

            General

            Next to the gastrointestinal tract, Waldeyer's ring is is a common localization for extranodal lymphomas. Even though Waldeyer's ring is anatomically not lymph node region, it is considered a region for staging of malignant lymphomas according to the Ann Arbor classification. 

             

            Lymphomas in this region are generally DLBCL, but follicular lymphomas also occur relatively often. 

            The most common localization is the palatine tonsil followed by the nasopharynx and base of the tongue. Hodgkin's lymphoma rarely occurs in Waldeyer's ring. 

            Curative radiation therapy

            • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given. 
            • For residual tumor of aggressive lymphomas after full chemotherapy (6–8 CHOP-based cycles or equivalent), consolidative radiation therapy to the residual tumor with margin is considered. 
            • For indolent lymphomas with localized disease (stage I–II1), radiation therapy alone to the involved area with margin is given (involved field).  
            • Ved lokaliserte stadier av klassisk Hodgkin lymfom (stadium IA/IIA) gis strålebehandling mot opprinnelig tumoraffisert område med margin (”involved field”) etter kjemoterapi (ABVD eller tilsvarende).
            • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent).
            • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma.
            • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered. 

            Palliative radiation therapy

            • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

               

             

            Definitions

            Target Volume

             

             

            Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)

            GTV (Gross tumor volume)

            Gross palpable or visible/identifiable area of malignant growth.

            CTV (Clinical target volume)

            Macroscopic tumor volume including any remaining tumor tissue.

            ITV (Internal Target Volume)

            Volume containing CTV and internal margin to allow for internal movements and changes to CTV.

            PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
            OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.

            PRV (Planning organ-at-risk volume)

            Geometric volume containing risk volume with set-up margin.
            TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
            IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
            CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

            Field Limits

            The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.

             

             

             

            Target volume for radiation therapy
            GTV Current tumor for indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal for limited disease/short chemotherapy

            GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy

            GTV + 1cm in transverse plane

            CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.

            ITV CTV if internal movement can be ignored (CNS, ENT)

            CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum

            CTV + 2–3 cm in mesentery

            CTV + 0-0.5 cm transverse retroperitoneally

            PTV

            Not routinely defined

            Field limits ITV + Setup margin and penumbra (1.2 cm)

            The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)

             

             

            Involved node

            The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.

             

            Involved field

            Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extention to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.

            Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate.

            For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.

            Extended field

            This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.

             

             

            Preparation

          • The patient must be evaluated by a dentist and any dental treatment must be finished before treatment is started.
          • The patient must be immobilized with a mask while the neck is slightly extended as for the mantle field.
          • Implementation

            CT-based simulation

            Dose planning with CT is standard for this treatment.

            • The actual (for curative treatment of localized indolent lymphomas or residual tumor after full chemotherapy for advanved disease) or original tumor volume (for curative treatment after limited chemotherapy for early stages of HL and aggressive NHL) defines GTV.
            • CTV is generated by the margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy). There is a 1 cm margin to CTV in the transversal plane.
            • Previously, the entire Waldeyer's ring was included in CTV the same as all the nodal regions of the neck or axillary groin or equivalent. Waldeyer's ring was then included in CTV from the base of the skull to the lingual tonsils on the base of the tongue and down to os hyoid. Drawing of Waldeyer's ring as CTV follows the mucosa from the lower edge of the base of the skull/sphenoid sinus and forward to the choanae and back to the spine where the retropharyngeal nodes are included. The area of the openining of the eustachian tube is outlined. the platinar tonsils and root of the tongue are included down to os hyoid. Submental, submandibular, and occipital were included in CTV. 
            • For localized stages of Hodgkin's lymphomas or aggressive lymphomas after stage-adapted chemotherapy, it is considered necessary to irradiate the originally involved area of Waldeyer's ring with margin (GTV with margin 1–2 cm to CTV) after chemotherapyy.
            • For localized indolent lymphomas in Waldeyer's ring (Stage I–III), where curative radiotherapy is given, all of Waldeyer's ring is treated (see above) with involved lymph node areas and possibly with the next draining uninvolved lymph node station. Lymph nodes are treated unilaterally on the neck. With lymph node involvement near the midline in Waldeyer's ring they may be treated bilaterally. 
            • Drawing (contouring?) of neck lymph nodes including retropharyngeal, submandibular, and submental nodes is done according to guidelines developed for CT diagnostics. These guidelines appear to cover occipital nodes less effectively, which should be included.
            • Isocentric irradiation with halvblender technique allows irradiation from side to side toward Waldeyer's ring, submandibular, submental, and occipital lymph nodes on the upper neck and anteroposterior beam to the lower part of the neck/supraclavicular region. For unilateral irradiation of parts of Waldeyer's ring, it is often sensible to give a diagonal wedge field to spare the salivary glands of the uninvolved side. 

            CT dose plan, Waldeyer's ring

            Fractionation

            Standard fractionation and total dose for curative treatment is given below. These are also guidelines for palliative treatment, but must be modified individually.

            • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
            • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
            • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
            • For aggressive NHL: 2 Gy x 20.

            Follow-up

            Organs at risk

            Mucosa 

            Acute mucositis in the mouth, pharynx, and esophagus, during treatment and shortly after occurs in most patients and may cause some patients significant problems.

            Skin and nails

            Reversible alopecia of irradiated areas of the back of the head and jaw (beard growth) should be expected. 

            Lense, eyes, optic chiasma, pituitary gland

            Fields toward Waldeyer's ring will contribute a dose or radiation to these organs, which is normally under the tolerance dose. It is important to avoid hotspots in these organs.

            Teeth

            Defects should be evaluated before treatment to prevent later osteoradionecrosis. Caution should be used with dental treatment after irradiation of the jaw region. 

            Salivary glands 

            Lasting dry mouth should be expected with fields including both parotid glands. If this can be avoided, problems are often moderate in the long run.

            Blood vessels in the neck

            After irradiation of blood vessels in the neck, there is a slight increase in risk for cerebrovascular complications.

            Radiation therapy for the entire CNS axis

            General

            Lymphomas primarily occur in the CNS or involve the CNS as part of a generalized disease.

            Radiation treatment of intracerebral, intraspinal, or meningeal/cerebrospinal fluid lymphoma manifestations may be appropriate as one or more treatment alternatives. This treatment is often part of a multimodal approach in combination with systemic and intrathecal/intraventricular chemotherapy.   

            Radiation treatment can be given to the entire CNS axis (brain, spinal cord, and cerebrospinal fluid space down to the S1/2 level, sometimes including both eyes and optical nerves) or only the brain with surrounding fluid space. Due to the diffuse growth and tendency for meningeal involvement of lymphomas, whole brain radiation is almost always indicated. Radiation of only parts of the brain or a boost to parts of the brain is normally not recommended.

            Treatment is administered together or at the end of CNS-directed chemotherapy/intrathecal chemotherapy.

            Indication

            • Total CNS axis (whole brain with spinal cord and dural sac) is most often irradiated as part of protocols for acute lymphoblastic leukemia, where it is included as part of CNS prophylaxis or treatment for a manifest CNS disease.  

             

            In some patients with lymphoma in the CNS, radiation to the entire neuro axis is also used.

            Curative radiation therapy

            Radiation treatment of of the entire CNS axis can be administered as a segment of curative treatment for:

             

            • Treatment/prophylaxis of CNS manifestations of lymphoblastic/acute lymphoblastic leukemia and Burkitt's lymphoma 
            • Treatment/prophylaxis of CNS manifestations for acute lymphoblastic leukemia and Burkitt's lymphoma. For treatment/prophylaxis of a CNS disease as part of treatment to cure acute lymphoblastic leukemia, radiation treatment may be included. It is often combined with CNS-directed chemotherapy/intrathecal treatment.  It may be appropriate (but not obligatory) to give radiation to the spinal cord simultaneously.
            • Treatment/prophylaxis of CNS manifestation from other malignant lymphomas - In other malignant lymphomas where the CNS is involved, radiation treatment to the brain is considered individually as part of a treatment plan to cure the disease. In the case of meningeal spreading or findings in the spinal cord, it may be appropriate to combine with radiation treatment of the spinal cord.

            Palliative radiation therapy

            • Radiation of the total CNS axis is resource-consuming treatment with side effects. This treatment form is therefore not suited for palliative treatment in all patients with generalized lymphoma in the CNS. For palliative radiation treatment, the method for the radiation therapy itself follows the same guidelines as for curative treatment with individual modifications.

            Definitions

            Target Volume

             

             

            Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)
            GTV (Gross tumor volume) Gross palpable or visible/identifiable area of malignant growth.
            CTV (Clinical target volume) Macroscopic tumor volume including any remaining tumor tissue.
            ITV (Internal Target Volume) Volume containing CTV and internal margin to allow for internal movements and changes to CTV.
            PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
            OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.
            PRV (Planning organ-at-risk volume) Geometric volume containing risk volume with set-up margin.
            TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
            IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
            CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

            Field Limits

            The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

            Definition of margins

            For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.

             

            Target volume for radiation therapy
            GTV Current tumor for indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA

            Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV

            CTV GTV + 2 cm craniocaudal for limited disease/short chemotherapy

            GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy

            GTV + 1cm in transverse plane

            CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).

            CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.

            ITV CTV if internal movement can be ignored (CNS, ENT)

            CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum

            CTV + 2–3 cm in mesentery

            CTV + 0-0.5 cm transverse retroperitoneally

            PTV Not routinely defined
            Field limits ITV + Setup margin and penumbra (1.2 cm)

            The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)

            Involved node

            The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.

            Involved field

            Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extention to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.

            Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate.

            For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.

            Extended field

            This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.

            Preparation

            • Patient is immobilized in the prone position with the help of VacFix® with head support for the prone position and mask.  
            • The patient should lie as comfortable as possible with the shoulders as far down as possible. 
            • There should be a certain hyperextension of the neck to give the smallest possible dose to the mouth.
            • The spinal column should be as straight as possible. 
            • Sedation is usually necessary to carry out fixation, simulation, and treatment in children.

            Implementation

            Conventional simulation

            Modeling of the field to the brain and spinal cord can be done with conventional simulation, but CT-based planning is recommended.

            • The whole brain is irradiated from side to side down to the caudal border of C3 or C4 (depending on shoulder position, see other chapter). It is very important to be precise with adjustment of the field borders in relation to the base of the skull as for total brain irradiation.
            • At the caudal edge of C3 or C4, a juncture is made with the upper dorsal medulla field. The juncture must be planned with a physicist. 
            • Depending on the height of the patient, 1 or 2 medulla fields are given from behind. If there are two fields, there is also a juncture between these in the thoracic column. The juncture is calculated by a physicist and juncture movement must be planned during the simulation.
            • The lower border for the medulla fields must be below the end of the dural sac which is typically at the level of S2.
            • The lateral borders are lateral to the vertebral bodies with 1 cm margins to cover the dural sac where it follows the nerve roots out of the intevertebral foramen in addition to tuning uncertainty and penumbra.  
            • The medulla fields are dosed by depth where the depth is calculated from the dorsal skin surface to the dorsal aspect of the vertebral bodies/ventral limit of the spinal cord. Due to curvature of the vertebral column, the depth will vary according to the level of the vertebral column. It may be very difficult to identify the structures of the vertebrae on the coronal fluoroscopic simulator images. Differences in depth are compensated by filters of varying thickness.  

            CT-based simulation 

            Dose planning with CT is recommended for radiation to the entire CNS axis. CT uptake saves time for the patient compared to conventional simulation and is therefore considered patient-friendly. Dose planning is also more simple. 

            • A CT scan is taken after immobilization in VacFix® in the prone position with a mask. 
            • The whole brain and spinal canal limited to S2 at minimum toward the legs is modeled as CTV.
            • It is very important to include the extensions of the subarachnoid space, along the cranial nerves at the base of the skull and the dural extensions along the nerve roots in the intevertebral foramina, are well covered.
            • If the whole brain is to have more fractions than the spinal cord, the whole brain down to C3 or C4 must be modeled as a separate CTV for planning these fractions.
            • Check the field limits of the set-up cover the base of the skull well and the lateral limits for the medulla fields are 1 cm outside the vertebral bodies.
            • It may be beneficial to place the isocenter for the upper medulla field relatively high to obtain a geometric, and relatively clean juncture of the lateral fields toward the brain. Moving junctures can then be avoided between the brain and upper medulla field. 
            • Movement of junctures between the medulla fields is performed routinely.

            CT dose plan    

            Fractionation

            Fractionation and total dose depend on multiple factors, among others, the type of lymphoma and which protocol is followed.

            For a curative treatment plan, the following are indicated:

            • For lymphoblastic leukemia/ALL, treatment is administered according to study protocols, for example NOPHO in children, preferably 2 Gy x 9-12 to the whole brain and 2 gy x 6-9 to the spinal cord.
            • For other lymphomas and for palliative treatment, fractionation is determined individually.

            Follow-up

            Organs at risk

            Brain 

            There is a risk of short-term nerve toxicity such as dizziness, nausea, headache and long-term neuropsychiatric changes. Antiemetic treatment should be considered before starting treatment. Long-term neuropsychiatric changes may depend on multiple factors such as age, and if chemotherapy is administered simultaneously (especially high-dose MTX). Those at the highest risk are patients over 60 years who receive whole brain irradiation after high-dose MTX.    

            Blood and bone marrow

            Large amounts of bone marrow is included in the radiation field for the CNS axis. Counts with differential counts must be taken during and for a time after treatment.  

            Lens of the eye

            A dose of over 4-6 Gy must often be accepted to obtain sufficient coverage to structures near the lamina cribrosa. This may pose a risk for cataract development in some patients.  

            Pituitary gland

            The dosages used are often lower than the tolerance dose for adults, however, endocrine function should be followed long after treatment in children.

            Growth inhibition

            The entire spinal column is irradiated. Even if the doses are small, some growth inhibition may occur.

            Gonads

            Total CNS axis is irradiated as part of intensive treatment protocols, which collectively has a negative influence on fertility. The dose to the testicles should be minimized as much as possible by shielding. The ovaries in girls and women at a fertile age will be very close to the spinal cord fields and are difficult to shield.

            Whole brain radiation therapy

            General

            Indications

            Lymphomas primarily occur in the CNS or affect the CNS as part of a generalized disease.

            Radiation treatment of intracerebral, intraspinal, or meningeal/cerebrospinal fluid lymphoma manifestations may be appropriate as one or more treatment alternatives. This treatment is often part of a multimodal approach in combination with systemic and intrathecal/intraventricular chemotherapy.   

            Radiation treatment can be given to the entire CNS axis (brain, spinal cord, and cerebrospinal fluid space down to the S1/2 level, sometimes including both eye sockets and optical nerves) or only the brain with surrounding liquor space. Due to the diffuse growth and tendency for meningeal involvement of lymphomas, whole brain radiation is almost always indicated. Radiation of only parts of the brain or a boost to parts of the brain is normally not recommended.

            Radiation therapy to cure the disease 

            Radiation therapy to the whole brain can be given as a part of multimodal curative treatment in:

            • Primary CNS lymphomas (PCNSL) - In younger patients (< 60 years), radiation to the brain is often included in treatments where CNS-directed chemotherapy is followed by radiation therapy. The role that radiation therapy plays, as well as the total dosage and fractioning , is uncertain. At the Oslo University Hospital, we use the protocol from Memorial Sloan Kettering Cancer Center. In older patients, a combination with chemotherapy often causes significant neurotoxicity, therefore radiation therapy is used with caution and preferably reserved for patients who do not achieve effect from chemotherapy, or for recurrence of the disease. For a multi-modal treatment arrangement for PCNSL, it is generally not recommended to administer radiation treatment to the spinal cord, even if lumbar puncture has shown more generalized meningeal spreading of tumor cells. If the eye ball is not known to be involved, it is not included in the radiation field. A new nordic protocol for PCNSL is under planning where radiation is not used as the primary treatment, for both older or younger patients. 
            • Treatment/prophylaxis of CNS manifestations for acute lymphoblastic leukemia and Burkitt's lymphoma - For treatment/prophylaxis of a CNS disease as part of treatment to cure acute lymphoblastic leukemia, radiation treatment may be included. It is often combined with CNS-directed chemotherapy/intrathecal treatment. It may be appropriate (but not obligatory) to give radiation to the spinal cord simultaneously.
            • Treatment/prophylaxis of CNS manifestation from several other malignant lymphomas: In other malignant lymphomas where the CNS is involved, radiation treatment to the brain is considered individually as part of the treatment plan to cure the disease. If there is meningeal spreading or findings in the spinal cord, it may be appropriate to add radiation treatment to the spinal cord.

            Palliative radiation therapy

            • For palliative radiation therapy, the method generally follows the same guidelines as for curative treatment, with individual adjustments.

            In younger patients (< 60 years), radiation to the brain is often included in treatments where CNS-directed chemotherapy is followed by radiation therapy. The role that radiation therapy plays, as well as the total dosage and fractioning, is uncertain. 

            The curative schedule after chemotherapy with hyperfractionated treatment may have possible advantages. At Oslo University Hospital (Radiumhospitalet), the treatment schedule from MSKCC is used. In elderly patients, a combination of chemotherapy of this kind often causes significant neurotoxicity, and radiation therapy should be used with caution, preferably reserved for patients with poor response to chemotherapy or with recurrence.  

            For multimodal treatment for PCNSL, radiation therapy is normally not given to the spinal cord, even if lumbar puncture has shown more generalized meningeal scattering of tumor cells. If there is no known involvement of the bulb of the eye, the eye is not included in the radiation field. A new Nordic protocol for PCNSL is planned where radiation therapy will not be used during primary treatment, either for elderly or younger patients.  

            For treatment/prophylaxis for CNS disease as part of the curative treatment arrangement for ALL/lymphoblastic disease, lower doses are preferably used (18–24 Gy in 1.8–2 Gy per fraction), often in combination with CNS-directed chemotherapy/intrathecal treatment. Simultaneous radiotherapy to the spinal cord is often given (but not obligatory). 

            For other malignant lymphomas with CNS involvement, radiotherapy to the brain is considered, either as part of a curative or palliative plan. In cases of meningeal scattering of tumor cells or findings in the spinal cord, radiation therapy of the spinal cord may also be given.

              Definitions

              Target Volume

               

               

               

              Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)

               

              GTV (Gross tumor volume)

              Gross palpable or visible/identifiable area of malignant growth.

               

              CTV (Clinical target volume)

              Macroscopic tumor volume including any remaining tumor tissue.

               

              ITV (Internal Target Volume)

              Volume containing CTV and internal margin to allow for internal movements and changes to CTV.

               

              PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
              OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.

              PRV (Planning organ-at-risk volume)

               

              Geometric volume containing risk volume with set-up margin.
              TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
              IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
              CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

              Field Limits 

              The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

              Definition of margins

              For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.

               

              Target volume for radiation therapy
              GTV Current tumor for indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA

              Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV

               

              CTV GTV + 2 cm craniocaudal for limited disease/short chemotherapy

              GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy

              GTV + 1cm in transverse plane

              CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).

              CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.

               

              ITV CTV if internal movement can be ignored (CNS, ENT)

              CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum

              CTV + 2–3 cm in mesentery

              CTV + 0-0.5 cm transverse retroperitoneally

               

              PTV

              Not routinely defined

               

              Field limits ITV + Setup margin and penumbra (1.2 cm)

              The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)

               

              Involved node

              The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.   

              Involved field

              Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extension to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.   

              Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate. 

              For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.  

              Extended field

              This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.

               

               

              Preparation

              • For radiation therapy to the whole brain without the spinal cord, the patient lies supine and is immobilized with a mask. 
              • There should be slight flexion of the neck. 
              • The position of the lenses can be marked with a piece of lead at the lateral edge of the orbita.
              • If fields are to be joined toward the spinal cord, the patient must be immobilized as described in the procedure for the total CNS axis.

              Implementation

              Conventional simulation

              • Cranial and lateral limits are outside the patient in the air.
              • For modeling of the caudal borders on the simulator, it is important to include the base of the skull with branches of the cranial nerves as these are covered by the meninges to an extent (be especially aware of the lamina cribrosa). Usually, the brain stem is included farther down than for solid tumors. At the same time, the lenses should be blocked and the eyes as much as possible. For curative treatment, it must sometimes be accepted that tolerance doses for lenses are exceeded. 
              • Field shaping from side to side including eye blocks will obtain a  "German helmet" configuration and reaches farther down the cervical column with good margins to the spinal canal (for example to discs C2/C3 or C3/C4 level).
              • Orbital cavities can be included if there is known lymphoma involvement of the eye ball or optic nerves. 

              CT-based simulation

              • For treatment which is planned with CT, the entire brain is modeled including the outer liquor space as CTV. For practical purposes, the inside of the bone in the cranium and the spinal canal is the limit.
              • Be very precise when contouring the skull. The dura sacs which follow the nerve roots in the different foramens must be included in the CTV. CTV includes also the upper cervical column such that the field limits later remain at levels with for example C3 or C4.   
              • The orbital cavities may be included in CTV if there is known lymphoma in the eye ball or optic nerves.
              • Field shaping will be two opposing lateral fields. Field shaping should be checked with regards to skeletal structures at the base of the skull before approval just to ensure good coverage of the lamina cribrosa and other foramens in the cranial nerves.  

              CT dosage plan

              Fractionation

              Fractionation and total dose depend on multiple factors, among others, the type of lymphoma and the protocol is followed. For a treatment plan intended to cure the disease the following is recommended:  

              For PCNSL, Oslo University Hospital follow the protocol from  MSKCC, which is 1.80 Gy x 25 for patients under 60 years subsequent to 5 courses of high-dose MTX, if the patient is not in complete remission. For involvement of the eye, these are included with 1.8 Gy x 20. If the patient is in complete remission, 1.2 Gy x 30 is given with 2 fractions daily. Patients over 60 are not routinely given radiation therapy.

              For lymphoblastic leukemia/ALL, treatment is administered according to study protocols, for example NOPHO in children, preferably 2 Gy x 9-12.

              For other lymphomas, fractionation is determined individually.

              For palliative treatment, 3 Gy x 10 is most often used.

              Follow-up

              Organs at risk

              Brain 

              There is a risk of short-term nerve toxicity causing dizziness, nausea, headache and long-term neuropsychiatric changes. Antiemetic treatment should be considered before starting treatment. Long-term neuropsychiatric changes may depend on multiple factors such as age and if chemotherapy is administered simultaneously (especially high-dose MTX). Those at the highest risk are patients over 60 years who receive whole brain radiation after high-dose MTX.   

              Lens of the eye

              A dose over 4-6 Gy must often be accepted to obtain adequate coverage to structures near the lamina cribrosa. This may pose a risk for cataract development in some patients.  

              Pituitary gland

              The dosages used are often lower than the tolerance dose for adults, however, endocrine function should be followed long after treatment in children. 

              Radiation therapy for the stomach for malignant lymphoma

              General

              Indications

              In addition to Waldeyer's ring, the stomach is a common extranodal localization for malignant lymphomas. Among indolent lymphomas, marginal zone lymphomas dominate, other entities are more rare. For patients with marginal zone lymphomas with infection of H. pylori, triple treatment is considered standard treatment in Norway as long as guidelines are followed for diagnostics, treatment, and follow-up. Aggressive stomach lymphomas constitute most mantel cell lymphomas, diffuse giant cell lymphomas and Burkitt's lymphoma. Serious bleeding and/or massive invasion to serosa with danger of perforation are considered for a stomach resection or gastrectomy as a primary measure after consultation between oncologist and surgeon. 

              Curative radiation therapy

              • Patients with marginal zone lymphoma stage PeI
                • Without H. pylori infection
                • Patients who cannot or do not wish to follow the recommended follow-up schedule for eradicative treatment. 
                • Unfavorable cytogenetic aberrations or a thickened stomach wall are also possible grounds for primary radiation therapy. 
              • Patients with marginal zone lymphoma also in regional lymph nodes (stage Pe II1)
              • Patients without effect of or with local recurrence after eradicative treatment.
              • Other forms of indolent stomach lymphomas in stages Pe l and Pe ll1
              • If primary surgery is completed for indolent stomach lymphoma and the surgery is radical, no additional treatment is given for stage PeI. If there is residual lymphoma in the stomach or involvement of regional lymph nodes (stadium Pe II1), supplementary radiotherapy is given to residual areas and regional lymph nodes. 
              • Aggressive lymphomas in the stomach are treated from protocols for their respective histology. Diffuse giant cell B cell lymphoma stages Pe I-Pe II are treated as desribed for DLBCL stage I/II. Three to six CHOP-based cycles followed by radiation therapy with 2 Gy x 20 (40 Gy) are given. Stages Pe II2- IV are treated as advanced disease of DLBCL and supplementary radiotherapy is considered for any residual lesions. Mantel cell lymphomas are treated analagous to DLBCL with suitable chemotherapy followed by radiotherapy, or are considered for inclusion of ongoing protocols. Burkitt's lymphoma is treated from the GMALL-NHL-2002 protocol where radiotherapy to the stomach may be appropriate after chemotherapy.

              Palliative radiation therapy 

              • For palliative radiotion therapy, the method normally follows the same guidelines as the curative plan with individual modifications.

              Definitions

              Target Volume

               

              Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)

              GTV (Gross tumor volume)

              Gross palpable or visible/identifiable area of malignant growth.

              CTV (Clinical target volume)

              Macroscopic tumor volume including any remaining tumor tissue.

              ITV (Internal Target Volume)

              Volume containing CTV and internal margin to allow for internal movements and changes to CTV.

              PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
              OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.

              PRV (Planning organ-at-risk volume)

              Geometric volume containing risk volume with set-up margin.
              TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
              IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
              CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

              Field Limits

              The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.

              Definition of margins

              For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.

               

               

               

              Target volume for radiation therapy
              GTV Current tumor for indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA

              Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV

              CTV GTV + 2 cm craniocaudal for limited disease/short chemotherapy

              GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy

              GTV + 1cm in transverse plane

              CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).

              CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.

              ITV CTV if internal movement can be ignored (CNS, ENT)

              CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum

              CTV + 2–3 cm in mesentery

              CTV + 0-0.5 cm transverse retroperitoneally

              PTV

              Not routinely defined

              Field limits ITV + Setup margin and penumbra (1.2 cm)

              The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)

               

               

              Involved node

              The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.

               

              Involved field

              Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extention to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.

              Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate.

              For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.

              Extended field

              This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.

               

               

              Preparation

              • GFR with renography should be completed before treatment planning to evaluate kidney funciton. 
              • Large parts of the sleen are often within the radiation field. Immunization against Streptococcal pneumona is considered.
              • It may be necessary to give a small amount of oral contrast fluid (water alone may function well) for CT uptake for better visualization of the stomach. 
              • Other standards may exist for stomach content and CT uptake to achieve a reproduceable size of the stomach. At Oslo University Hospital, we recommend the patient is fasts for early morning CT. The patient is given a small glass of water as oral contast agent before CT. The patient must fast for each treatment, and we try to schedule treatment in the morning before breakfast.

              Implementation

              CT-based simulation

              Radiation therapy of the stomach and regional lymph nodes should be done with the help of CT. 

              • The patient lies supine.
              • Standards should exist for the patient for CT uptake with a reproducible stomach size for simulation and treatment (see above).
              • Any visible tumors/lymph node manifestations represent GTV. Any endoscopic findings may also be of help to define visible tumor. 
              • CTV is generated with a 1 cm margin to GTV.  Regardless, the entire stomach or any residual areas after surgery are included in CTV. For stage PeI, uninvolved draining lymph nodes assumed to lie along the curvature minor and major, hilum of the spleen, by the celiac trunk and subpyloric lymph nodes areas are included, or contoured on a separate CTV. For stage PeII1, where the nearest draining lymph nodes are involved, it should be considered whether the secondary lymph nodes stations are included in CTV. 
              • The stomach is a mobile organ and should have good margins to ITV (1–2 cm), especially in craniocaudal extensivenss.
              • A multiple field technique will usually be the result, usually as anteroposterior and lateral opposing fields. In this way, the dose to the left kidney can be reduced compared to purely anteroposterior technique. 

              CT dose plan, stomach

              Fractionation

              Standard fractionation and total dose for curative treatment is given below. These are also guidelines for palliative treatment, but must be modified individually.

              • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
              • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17
              • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
              • For aggressive NHL: 2 Gy x 20.

               

              Follow-up

              Organs at risk

              Stomach and intestines 

              Nausea can be expected in most patients undergoing this treatment. Nausea prophylaxis should be started before the first fraction. Dyspepsia, diarrhea, and pain may be a sign of mucositis in the stomach and intestines. Ulcerations and perforation can also occur.

              Bone marrow 

              Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment. Regular follow-up may be necessary during this time.

              Gonadal organs

              The dose to the gonads should be as small as possible to preserve fertility. Reliable birth control during treatment is necessary, and is recommended until a year has passed after treatment.

              Kidney 

              Depending on the dose received by the kidneys, a reduction in kidney function and renal hypertonia may occur in the long run.

              Complication treatment of Hodgkin's lymphoma

              Both chemotherapy and radiation therapy cause varying degrees of side effects. It is usually necessary to provide supportive care to achieve the full effect of treatment and/or relieve problems related to treatment experienced by the patient.

              Chemotherapy may cause

              • Varying degrees of nausea. Adequate prophylaxis and treatment is critical. Read more
              • Change in bone marrow function, especially granulocytopoiesis. This may in some cases lead to the need for stimulation of bone marrow to complete treatment. Read more
              • Tumor lysis syndrome occurs most frequently after chemotherapy in patients with relatively large tumor masses and high cell proliferation. Read more
              • Febrile neutropenia arises from a reduced immune system. Fever is often the only symptom. Read more
              • Infertility Read more

              Radiation therapy may cause

              • Nausea, which is intensified with chemotherapy. It is normal for patients to lose 5-6 kg from poor appetite during treatment. Read more

              PROSEDYRER

              Smoking cessation in connection with cancer treatment

              General

              In patients treated with surgery, radiation and/or chemotherapy, the treatment efficacy may be affected by smoking. Smoking has an impact on both metabolism and pharmacokinetics.

              Smoking may inhibit wound healing after surgery and increase the probability of surgical site infections. Because smokers generally have more mucus in the airways and are less able to remove it, they also may have a increased risk of serious lung complications during anesthesia. However, it is disputed whether or not it is beneficial to quit smoking directly prior to surgery and this should be considered in each case individually. (28,30-33). Smokers are more prone to stagnation of bronchial secretion than non-smokers and rapid postoperative extubation is important. 

              Patients who continue smoking during radiation therapy have a lower risk of complete respons, development of secondary cancer, increased toxicity and several other side effects compared to non-smokers and smokers that quit before treatment. Continued smoking during radiation therapy is also associated with oral mucositis, impaired ability to taste, dry mouth, reduced voice quality, weight loss, cachexia, fatigue, pneumonia, bone-and soft tissue necrosis.

              Tobacco may have an effect the metabolism and the mechanisms of chemotherapy and in this way may make the treatment less effective. Smokers undergoing chemotherapy may also experience a weakened immune system, increased rates of infection, exacerbation of common side effects, weight loss, cachexia, fatigue and cardiac or pulmonary toxicity. Some findings suggest that it may also apply to monoclonal antibodies.

              Cancer patients who quit smoking before chemo- and radiation therapy get a total symptom burden equal to that of non-smokers, but those who continue to smoke state a higher symptom burden. Targeted measures in smoking cessation may increase quality of life and lead to less treatment interruptions.

              A lot of patients wonder if there is any point to quit smoking after receiving a cancer diagnosis. tudies show that continued smoking is associated with increased treatment-related toxicity, increased risk of second primary cancers, reduced quality of life, reduced treatment effect and reduced survival in patients with cancer. This applies to both cancer diagnoses where smoking is a known causal factor, as with lung- and head and neck cancers and in cases where smoking has no known correlation with the diagnosis. Studies conducted on smoking and cancer diagnoses such as breast cancer, prostate cancer, colorectal cancer, esophageal cancer, cervical and ovarian cancer as well as leukemia and lymphoma cancers show that to continuation of smoking after a proven cancer diagnosis is associated with increased risk of mortality.

              Studies support that quitting smoking improves cancer, and emphasizing the potential importance of targeted smoking cessation in cancerpatients during and after treatment. The link between tobacco and impact on cancer and cancer treatment is a complex matter.

              Regarding the significance of the various components much is still unkown. When it comes to tobacco use in cancer treatment research is primarily done on the link between cigarette smoking and efficacy of cancer treatment. Nevertheless, it cannot be excluded that using other smokeless tobacco products such as snuff and chewing tobacco, may also impact the cancer treatment. According to international guidelines all tobacco use should be stopped during cancer treatment.


              Benefits of smoking cessation and risks of continued smoking in patients with cancer
              Quitting smoking results in the following benefits: Continued smoking results in a risk of :
              • improved treatment results.
              • less side effects
              • fewer infections
              • improved respiration and circulation
              • increased survival
              • reduced efficacy of treatment.
              • postoperative complications and longer recovery.
              • cardiovascular and respiratory complications.
              • recurrence of cancer, and secondary cancer.
              • shortened life expectancy.

               

              Indication

              Weaning of nicotine in connection to cancer treatment. 

              Goal

              Healthcare providers should convey evidence-based information to patients about how smoking affects cancer treatment, the risk of side effects and prognosis and also provide guidance and relevant treatment for smoking cessation.

              Preparation

              Patients require clear, formalized and fact-based guidance and continuous follow-up. Many patients want encouragement for smoking cessation early in the disease. Being hospitalized is a good opportunity because patients have access to support and help to reduce nicotine withdrawal symptoms and discomfort.

              A patient recently diagnosed with cancer is often motivated to quit smoking and also receptive to conversations about how to do this. Motivation or willingness to quit often changes during the treatment, and use of tobacco and motivation should therefore be discussed at every consultation.

              Clarifying the patient´s smoking habit is important. The time of day the patient lights their first cigarette says something about the degree of addiction. Making the patient aware of the situations in which he or she smokes most; at work, at home or in social settings, can help break unwanted patterns of behavior.

              Implementation

              The best and most direct approach to motivate the patient is telling that tobacco use will decrease the effectiveness of treatment and the most important thing the patient can do himself is to stop using tobacco.

              • Speak directly to the patient about how tobacco use may decrease the effectiveness of treatment.
              • Discuss smoking cessation with the patient at each visit.
              • Clarify any misunderstandings about the risks of tobacco use. Point out the importance of quitting.

              Sometimes there may be misunderstandings about what kind of health risk smoking during and after cancer treatment may entail.

              Advice to those who are not ready for smoking cessation
              The smokers statement The response of health care professionals
              Justifications
              The damage from smoking is already done.
              Some damage is done, but continued smoking will still damage your health and reduce the effects of treatment. Quitting smoking is more important now than ever.
              This response tells the patient that it is not too late to quit smoking, and the effect of treatment will be positive.

              I have reduced smoking.
              That is great, and now you need to focus on quitting completely. What do you think keeps you from quitting altogether?
              This response tells the patient the importance of quitting completely, as the benefits of quitting at baseline are documented.
              This is not a good time to quit smoking.
              The benefits of quitting are greatest now, before treatment begins. What is needed to make you feel ready to quit smoking?
               
              This response make the patient aware of the fact that quitting smoking optimizes the cancer treatment.

              Health professionals must assist the patient identifying realistic expectations and goals for smoking cessation. For some, it may feel easier to scale down the number of cigarettes than to quit completely. The patient should know that every puff affects their health, and that the total health benefits can only be achieved through smoking cessation. For patients unable to stop completely, a gradual reduction may be a step in the right direction.

              The probability of success for smoking cessation significantly increases for those who receive professional help in combination with nicotine replacement therapy (NRT) or non-nicotine based products. For the best possible effect of NRT the patient needs professional guidance to find the right product and dosage. For some patients combining two products or receiving a higher dosage than recommended will give the best effect. Sometimes the product must be replaced during the treatment.

              Treatment with nicotine replacement therapy

              Topical products are patches (Nicorette®, Nicotinell®), chewing gum (Nicorette®, Nicotinell®), lozenges (Nicorette®, Nicotinell®), inhalator (Nicorette®) or a combination of these. These products contain nicotine and therefore reduce the withdrawal symptoms experienced after smoking cessation.

              • Patch: Nicorette® 5 mg,10 mg and 15 mg/16 hours up to 6 months or Nicotinell® 7 mg,14 mg og 21 mg/24 hours up to 3 months.
              • Chewing gum: Nicorette®/Nicotinell® 2 mg and 4 mg, 8-12 pcs/day up to 12 months.
              • Lozenges: Nicorette® 2 mg and 4 mg, typically 8-12 pcs/day, maximum respectively 15 pcs/day up to 9 months or Nicotinell® 1 mg and 2 mg, typically 8-12 pcs/day, maximum is respectively
                25 and 15 pcs/day up to 12 months.
              • Inhalator: Nicorette® 10 mg/dosage container, 4-12 pcs/day up to 6 months.

              Combination therapy means combining patches with chewing gum, lozenges or an inhalator.

              • Nicorette® patch15 mg/16h and Nicorette chewing gum 2 mg. 5-6 chewing gums daily. Maximum 24 pcs/day
              • Nicorette® patch 15 mg/16h and Nicorette® inhalator 10 mg: 4-5 dosage-container daily. Maximum 8 pcs/day

              Nicotine replacement therapy increases the chance of smoking cessation by 50 to 70% after six months. Two products used in combination increase the chance of smoking cessation compared to the use of only one product.

              Side effects

              • Headache, dizziness, nausea, flatulence and hiccup.
              • Irritation in the mouth and esophagus using chewing gum/ lozenges/inhalator
              • Skin irritations while using patches.

              Precautions

              • Precaution in acute cardiovascular disease, peripheral arterial disease, cerebrovascular disease, hyperthyroidism, diabetes mellitus, kidney- and liver failure and peptic ulcers.
              • Should not be used during pregnancy, unless the potential benefit outweighs the potential risk.
              • The products should not be used during breastfeeding.

              Treatment with non-nicotine medications

              Bupropion (Zyban®) is a selective reuptake inhibitor of dopamine and norepinephrine. The mechanism behind why the ability to refrain from smoking increases by using bupropin is unknown. A should be set for smoking cessation for the second week of treatment.

              Bupropion increases the chance of smoking cessation after 6 months by nearly 70%.

              Side effects

              • Dry mouth, nausea, insomnia, hypersensitivity reactions and seizures (convulsions)

              Precautions

              • Contraindicated in people with disease that can cause convulsions,  people with substance abuse or other circumstances lowering the seizure threshold.
              • Depression, which in rare cases includes suicidal thoughts and – behavior including  suicide attempt.
              • Safety and efficacy have not been established for people under 18 years.
              • Should not be used during pregnancy.

              Varenicline (Champix®) is a partial agonist by a subtype of nicotinic receptors. It has both agonistic activity with lower intrinsic efficacy than nicotine and antagonistic activity in the presence of nicotine.

              A date for smoking cessation should be set. Treatment should start 1-2 weeks, or up to 35 days, before that date. The starting dose is 0,5 mg one time daily on days 1-3, then 0,5 mg two times daily on days 4-7, then 1 mg two times daily on day 8 and until the end of treatment. The treatment should last for 12 weeks.

              Side effects

              • Nausea, sleep disturbances, headache, constipation, flatulence and vomiting

              Precations

              • Links have been reported between the use of varenicline and an increased risk of cardiovascular events, suicidal thoughts, depression and aggressive and erratic behavior
              • Safety and efficacy have not been established for people under 18 years of age
              • Should not be used during pregnancy

              Follow-up

              If the patient experiences a relapse, it is important to inform them that this is completely normal, and encourage them to continue. If the most common measures do not work,
              consideration should be given both to increase the NRP and to provide closer follow-up by health care providers.

              Guidance in smoking cessation is described in the literature as brief and clear advice and then further follow-up with a telephone helpline offering treatment for addiction and behavior change/issues. It is not necessary for the patient to have decided to quit smoking in order to be referred to a quitline. If the patient agrees to receive a call from quitline, he or she will be followed up by a supervisor. Supervisors are bound by confidentiality, are up-to-date professionally and offer free follow-up counseling calls for up to a year.

              References

              1. Gritz E, Fingeret M, Vidrine D. Tobacco control in the oncology setting. American Society of Clinical Oncology, eds Cancer Prevention An ASCO Curriculum Alexandria, VA: American Society of Clinical Oncology. 2007.
              2. ASCO ASoCO. Tobacco Cessation Guide for Oncology providers,. 2012 (02.12.2014).
              3. Zevallos JP, Mallen MJ, Lam CY, Karam-Hage M, Blalock J, Wetter DW, et al. Complications of radiotherapy in laryngopharyngeal cancer: Effects of a prospective smoking cessation program. Cancer. 2009;115(19):4636-44.
              4. Obedian E, Fischer DB, Haffty BG. Second malignancies after treatment of early-stage breast cancer: Lumpectomy and radiation therapy versus mastectomy. Journal of Clinical Oncology. 2000;18(12):2406-12.
              5. Park SM, Lim MK, Jung KW, Shin SA, Yoo K-Y, Yun YH, et al. Prediagnosis smoking, obesity, insulin resistance, and second primary cancer risk in male cancer survivors: National Health Insurance Corporation Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(30):4835.
              6. Van Den Belt-Dusebout AW, De Wit R, Gietema JA, Horenblas S, Louwman MWJ, Ribot JG, et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. Journal of Clinical Oncology. 2007;25(28):4370-8.
              7. Warren GW, Kasza KA, Reid ME, Cummings KM, Marshall JR. Smoking at diagnosis and survival in cancer patients. International Journal of Cancer. 2013;132(2):401-10.
              8. Hooning MJ, Botma A, Aleman BMP, Baaijens MHA, Bartelink H, Klijn JGM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. Journal of the National Cancer Institute. 2007;99(5):365-75.
              9. Li CI, Daling JR, Porter PL, Tang M-TC, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor–positive invasive breast cancer. Journal of Clinical Oncology. 2009;27(32):5312-8.
              10. Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. Smoking and prostate cancer survival and recurrence. JAMA - Journal of the American Medical Association. 2011;305(24):2548-55.
              11. Joshu CE, Mondul AM, Meinhold CL, Humphreys EB, Han M, Walsh PC, et al. Cigarette smoking and prostate cancer recurrence after prostatectomy. Journal of the National Cancer Institute. 2011;103(10):835-8.
              12. Phipps AI, Baron J, Newcomb PA. Prediagnostic smoking history, alcohol consumption, and colorectal cancer survival: The Seattle Colon Cancer Family Registry. Cancer. 2011;117(21):4948-57.
              13. Kountourakis P, Correa AM, Hofstetter WL, Lee JH, Bhutani MS, Rice DC, et al. Combined modality therapy of cT2N0M0 esophageal cancer. Cancer. 2011;117(5):925-30.
              14. Waggoner SE, Darcy KM, Fuhrman B, Parham G, Lucci J, Monk BJ, et al. Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: A Gynecologic Oncology Group study. Gynecol Oncol. 2006;103(3):853-8.
              15. Schlumbrecht MP, Sun CC, Wong KN, Broaddus RR, Gershenson DM, Bodurka DC. Clinicodemographic factors influencing outcomes in patients with low-grade serous ovarian carcinoma. 2011. p. 3741-9.
              16. Nagle CM, Bain CJ, Webb PM. Cigarette smoking and survival after ovarian cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2557-60.
              17. Ehlers SL, Gastineau DA, Patten CA, Decker PA, Rausch SM, Cerhan JR, et al. The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia. Bone Marrow Transplant. 2011;46(2):285-90.
              18. Talamini R, Polesel J, Spina M, Chimienti E, Serraino D, Zucchetto A, et al. The impact of tobacco smoking and alcohol drinking on survival of patients with non-Hodgkin lymphoma. International Journal of Cancer. 2008;122(7):1624-9.
              19. Toll B, Brandon T, Gritz E, Warren G, Herbst R. AACR Subcommittee on Tobacco and Cancer. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Clin Cancer Res. 2013;19:1941-8.
              20. Arntzen A, Sandvold B. Hvordan veilede om røykeslutt? Sykepleien Forskning. 2010;5(3):182-90.
              21. Dresler CM. Is it more important to quit smoking than which chemotherapy is used? 2003. p. 119-24.
              22. Hsu CCT, Kwan GNC, Chawla A, Mitina N, Christie D. Smoking habits of radiotherapy patients: Did the diagnosis of cancer make an impact and is there an opportunity to intervene? J Med Imag Radiat Oncol. 2011;55(5):526-31.
              23. Richards J. Words as Therapy: Smoking Cessation. The journal of family practice. 1992;34(6):687-92.
              24. Cooley ME, Lundin R, Murray L. Smoking cessation interventions in cancer care: opportunities for oncology nurses and nurse scientists. Annual review of nursing research. 2009;27:243.
              25. Mazza R, Lina M, Boffi R, Invernizzi G, De Marco C, Pierotti M. Taking care of smoker cancer patients: a review and some recommendations. Annals of Oncology. 2010;21(7):1404-9.
              26. Waller LL, Weaver KE, Petty WJ, Miller AA. Effects of continued tobacco use during treatment of lung cancer. 2010. p. 1569-75.
              27. Peppone LJ, Mustian KM, Morrow GR, Dozier AM, Ossip DJ, Janelsins MC, et al. The Effect of Cigarette Smoking on Cancer Treatment-Related Side Effects. Oncologist. 2011;16(12):1784-92.
              28. Kuri M, Nakagawa M, Tanaka H, Hasuo S, Kishi Y. Determination of the duration of preoperative smoking cessation to improve wound healing after head and neck surgery. Anesthesiology. 2005;102(5):892.
              29. Krueger JK, Rohrich RJ, Mustoe TA. Clearing the smoke: The scientific rationale for tobacco abstention with plastic surgery. 2001. p. 1074-5.
              30. Nakagawa M, Tanaka H, Tsukuma H, Kishi Y. Relationship between the duration of the preoperative smoke-free period and the incidence of postoperative pulmonary complications after pulmonary surgery. Chest. 2001;120(3):705-10.
              31. Barrera R, Shi W, Amar D, Thaler HT, Gabovich N, Bains MS, et al. Smoking and timing of cessation: Impact on pulmonary complications after thoracotomy. Chest. 2005;127(6):1977-83.
              32. Mason DP, Subramanian S, Nowicki ER, Grab JD, Murthy SC, Rice TW, et al. Impact of Smoking Cessation Before Resection of Lung Cancer: A Society of Thoracic Surgeons General Thoracic Surgery Database Study. Annals of Thoracic Surgery. 2009;88(2):362-71.
              33. Gajdos C, Hawn MT, Campagna EJ, Henderson WG, Singh JA, Houston T. Adverse Effects of Smoking on Postoperative Outcomes in Cancer Patients. Ann Surg Oncol. 2012;19(5):1430-8.
              34. Alsadius D, Hedelin M, Johansson KA, Pettersson N, Wilderang U, Lundstedt D, et al. Tobacco smoking and long-lasting symptoms from the bowel and the anal-sphincter region after radiotherapy for prostate cancer. Radiother Oncol. 2011;101(3):495-501.
              35. Chen AM, Chen LM, Vaughan A, Sreeraman R, Farwell DG, Luu Q, et al. Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. International Journal of Radiation Oncology Biology Physics. 2011;79(2):414-9.
              36. Eifel PJ, Jhingran A, Bodurka DC, Levenback C, Thames H. Correlation of smoking history and other patient characteristics with major complications of pelvic radiation therapy for cervical cancer. Journal of Clinical Oncology. 2002;20(17):3651-7.
              37. Bjarnason GA, MacKenzie RG, Nabid A, Hodson ID, El-Sayed S, Grimard L, et al. Comparison of Toxicity Associated With Early Morning Versus Late Afternoon Radiotherapy in Patients With Head-and-Neck Cancer: A Prospective Randomized Trial of the National Cancer Institute of Canada Clinical Trials Group (HN3). International Journal of Radiation Oncology Biology Physics. 2009;73(1):166-72.
              38. Browman GP, Wong G, Hodson I, Sathya J, Russell R, McAlpine L, et al. Influence of Cigarette Smoking on the Efficacy of Radiation Therapy in Head and Neck Cancer. The New England Journal of Medicine. 1993;328(3):159-63.
              39. Browman GP, Mohide EA, Willan A, Hodson I, Wong G, Grimard L, et al. Association between smoking during radiotherapy and prognosis in head and neck cancer: A follow-up study. Head Neck-J Sci Spec Head Neck. 2002;24(12):1031-7.
              40. Travis LB, Gospodarowicz M, Curtis RE, Clarke EA, Andersson M, Glimelius B, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. Journal of the National Cancer Institute. 2002;94(3):182-92.
              41. Ford MB, Sigurdson AJ, Petrulis ES, Ng CS, Kemp B, Cooksley C, et al. Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer. 2003;98(7):1457-64.
              42. Dresler CM, Gritz ER. Smoking, smoking cessation and the oncologist. 2001. p. 315-23.
              43. Balduyck B, Nia PS, Cogen A, Dockx Y, Lauwers P, Hendriks J, et al. The effect of smoking cessation on quality of life after lung cancer surgery. Eur J Cardiothorac Surg. 2011;40(6):1432-8.
              44. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clinical Cancer Research. 2006;12(7 I):2166-71.
              45. Helsedirektoratet. Forberedelse til røykeslutt 2011. Available from: http://helsedirektoratet.no/publikasjoner/forberedelser-til-roykeslutt/Publikasjoner/forberedelse-til-roeykeslutt.pdf   
              46. Brunnhuber K, Cummings KM, Feit S, Sherman S, Woodcock J. Putting evidence into practice: Smoking cessation: BMJ Publishing Group; 2007.
              47. Helsedirektoratet. Røyketelefonen 2013 [updated 12.12.201102.12.2014]. Available from: http://www.helsedirektoratet.no/folkehelse/tobakk/snus-og-roykeslutt/royketelefonen/Sider/default.aspx.
              48. Legemiddelverk S. Legemidler A-Å 2013 [02.12.2014]. Available from: http://www.legemiddelverket.no/Legemiddelsoek/Sider/Legemidler_A-AA.aspx.
              49. Hughes JR, Stead LF, Lancaster T, Rev CDS. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews: Reviews 2007. 2014 (1).
              50. Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2012;11(11).
              51. Cahill K, Stead LF, Lancaster T, Polonio IB. Nicotine receptor partial agonists for smoking cessation. Sao Paulo Med J. 2012;130(5):346-7

              Nutrition during Cancer Treatment

              General

              Monitoring the patient's nutritional status is an important part of cancer treatment. The goal is to identify malnutrition as early as possible in order to initiate treatment as quickly as possible.

              Measures include diet according to symptoms and the nutritional condition. The patient should be offered nutrition-rich food, snacks, nutritional drinks, tube feeding and intravenous nutrition.

              Because cancer treatment breaks down both cancer cells and normal cells, the body requires an adequate supply of nourishment to increase growth of new cells. 

              In cancer patients, the sensation of hunger is not always present to the necessary degree. In these cases, it is important to take actions to improve the nutritional status of the patient. The nutritional condition is easiest followed by monitoring body weight over time.

              Indication

              • Cancer treatment (chemotherapy, radiation, surgery).

              Goal

              • Maintain nutritional status in order for the patient to have the best possible conditions for implementing treatment.

              Definitions

              Subjective Global Assessment (SGA)

              Subjective Global Assessment (SGA) is a scheme for classifying the patient's nutritional status.

              Other tables that are frequently used are Malnutrition Universal Screening Tool (MUST), Mini Nutritional Assessment (MNA) and Nutrition Risk Score (NRS). In principle, these schemes are prepared in the same way as SGA, but they are not validated for patients with cancer.

              Weight loss is one of the most important signs of change in nutritional status. A weight loss of more than 15% over the past 6 months or more than 5% over the last month is a significant and serious weight loss. If the weight loss occurs in combination with low BMI (body mass index) (< 20 kg/m2 for adults) and/or a food intake of less than 60% of the calculated requirement over the past 10 days, the patient will be malnourished or be at nutritional risk.

              Calculation of nutrition and fluid requirements

              • Ambulatory patients:  30-35 kcal/kg/day
              • Bed-ridden patients:  25-30 kcal/kg/day
              • Elderly above 70 years:  Recommended amount is reduced by 10%
              • Fluid requirement:  30-35 ml/kg/day

              Nutritionally enriched diet / enrichment of food and beverages

              Nutritional beverages may be used as a meal in itself or between meals. Nutritional drinks can be a more valuable snack than "normal" food, because it is often easier for the patient to drink than to eat. It has been shown that if nutritional drinks are introduced as snacks, it does not affect the energy intake during the main meals.

              There are a number of ready-made nutritional drinks on the market. Some of the products are of nutritionally complete. They contain carbohydrates, protein and fat and are supplemented with all the necessary vitamins, minerals and trace minerals and possibly fiber. Some of these products can be used as the sole source of nutrition. The energy content varies from 85-200 kcal/100 ml and some products have a high protein content. Other nutritional drinks are supplement drinks adjusted to individual needs such as allergies, intolerance and special conditions associated with illnesses.

              The products are also adapted to age, and the dose is determined individually by a clinical dietician/doctor.

              Many patients prefer homemade nutritional drinks based on full fat milk, cream, ice cream, fruit and possibly flavor supplements. These are free of additives and have a fresher taste. The energy and protein content is close to the commercial products and at the same time they are more sensibly priced.

              Tube feeding

              Tube feeding is preferable to total parenteral nutrition (TPN) when the digestive system is working. Nutrition supply to the intestine is more physiological. It protects against bacterial growth, maintains the intestine's mucous membrane structure and function, and promotes motility. Tube feeding involves less risk of metabolic complications.

              Tube feeding is used in the event of

              • insufficient food intake (less than 60% of energy requirements) over the past 5-7 days despite oral intake
              • weight loss >2 % over the past week, >5 % over the past month or >10% over the past 6 months
              • danger of weight loss due to planned treatment
              • low albumin values (under 35 g/l, lower limit for normal area)
              • stenosis with feeding obstacles in pharynx/gullet

              Tube feeding must not be used for the following conditions.

              • Paralysis or ileus of the alimentary tract
              • Short bowel syndrome
              • Serious diarrhea
              • Serious acute pancreatitis
              • Obstruction of the intestine
              • Serious fluid problems

              Tube feeding solutions

              The tube feeding solution must be nutritionally complete because they shall be used as the sole source of nourishment. The most frequently used are standard (1 kcal/ml), fiber-containing (1 kcal/ml) or energy-rich (1.5 kcal/ml). There are also tube feeding solutions which are adapted to patients with digestion and absorption problems, patients with diabetes or lactose allergy, and intensive care patients.

              Tube feeding solutions, which are adapted to cancer patients are energy-rich (1.5 kcal/ml). They contain extra omega-3 fatty acids, rich in MCT acid and enriched with extra vitamins and minerals. Recommended dosage is 500 ml/day.

              Parenteral nutrition

              Parenteral nutrition should only be used if food by mouth or tube feeding cannot be maintained. Parenteral nutrition can also be used as a supplement to tube feeding or ordinary food. 

              Precautions must be taken for kidney failure, heart failure, lung failure, large fluid and electrolyte loss, diabetes mellitus and liver failure.

              Preparation

              The patient is classified as well-nourished, somewhat malnourished or seriously malnourished on the basis of information about weight development, food intake, symptoms and physical functioning. This classification has been shown to correlate well with more objective measurements of nutritional status and morbidity, mortality and quality of life.

              Actions include individual adjustment of diet according to symptoms and nutritional status.

              Tube feeding

              The end of the tube is often inserted into the stomach. In the event of poor gastric function, total gastrectomy or pancreatic resection, the feeding tube should be inserted in the duodenum or jejunum. The position of the feeding tube is vital for the choice of feeding-tube solution and mode of administration.

              The most common solution is to insert the tube nasogastrically, but it can also be done through the abdominal wall (PEG).

              Parenteral nutrition

              It is preferable to use intravenous or parenteral nutrition as a supplement to oral/tube feeding instead of only TPN (total parenteral nutrition).

              • Central veins must be used for TPN with high osmolality.
              • Peripheral veins can be used for short-term parenteral nutrition. In this case, a large vein on the forearm is used and a small needle. Nutrition is then given as more diluted solutions.

              Implementation

              All patients are weighed regularly (1–2 times each week). This is a prerequisite to being able to register changes in the nutritional status.

              Varied and healthy food contributes to the growth of new cells and enhances the immune system.

              • Fruit, berries and vegetables are rich in vitamins, minerals, antioxidants and fiber, which contribute to enhances the immune system and contributes to keeping the digestive system working.
              • Fish, shellfish, poultry, meat, eggs, cheese, milk, beans and nuts are rich in proteins, which are the building blocks of new cells.
              • Bread, rice, pasta, porridge and breakfast cereals supplement the diet with proteins, carbohydrates, fiber, vitamins and minerals.
              • Oil, margarine, butter, mayonnaise products, nuts, cream, heavy cream, desserts etc. are fat and energy rich products, which are important to maintain the energy intake at a satisfactory level.
              • Cancer patients also have a requirement for plenty of fluid, especially during treatment, to discharge waste.

              Often, the patients must have an individually adjusted diet. In the event of lack of appetite, it is generally more important that you eat (enough food) than what you eat (the right food). It is beneficial to have small portions and for the food to be as abundant in energy as possible. These patients will often have a need for 6–8 small meals everyday to obtain their energy requirements.

              Enrichment of food and drink is done in order to increase the energy content of the food product without increasing the volume. Full-fat products such as full-fat milk, cream, butter, heavy cream, mayonnaise, sugar, honey, eggs and cheese etc. are primarily used. Enrichment powders from pharmacies may also be used. Some powders are nutritionally complete, i.e. they contain everything the body requires in terms of energy and nutrients, while others only contain pure energy (carbohydrates, fat and/or protein). 

              Tube feeding

              Tube feeding is given continuously with a low drop rate or by interval/bolus administration (individually adapted meals with high drop rate).

              When the patient's energy and fluid requirements are fulfilled, it will be decided whether the patient will be given bolus or continuous supply at night, in order to increase mobilization during the day. However, this requires that the patient does not have diarrhea, nausea or other complaints associated with the supply of nutrition.

              For a running feeding tube:

              • Every 4-8 hours, it should be aspirated in order to monitor the gastric emptying. This applies especially to immobile and weak patients.
              • Weekly or more often, the nutrition program/fluid balance, evaluation, edema control, blood tests (albumin, K, Mg, P, blood glucose) should be monitored weekly or more often.
              • Every 4-6 weeks, the tube should be changed. Alternate the uses of nostrils avoid irritation in the nose through prolonged feeding.

              Experience shows that the use of infusion pumps causes fewer side effects and ensures correct volume and rate.

              Bolus supply

              Initiation of tube feeding with bolus supply is only recommended

              • if the patient been taking any food until the last 24 hours
              • if the patient is taking some food and requires tube feeding for additional nourishment

              It is recommended to use pumps for bolus supply for the first 1–2 days.

              Continuous supply

              If the patient cannot tolerate bolus supply (vomiting, abdominal discomfort, nausea, diarrhea), reverting to continuous supply should be considered.

              Tube feeding should always be administered continuously to very malnourished patients or if the tube end is located distally to the pylorus.

              Parenteral nutrition

              If the patient has a satisfactory nourishment status, begin with 100% of the requirement. If the patient is seriously malnourished, start with 80 % of the requirement and increase slowly to 100% over the course of three days.

              The patient must be monitored closely in relation to

              • electrolytes (potassium, phosphate and magnesium).
              • infusion rate.
              • twenty-four hour urine sample and fluid balance should be calculated daily.
              • glucose in the blood and urine, and electrolyte in the blood should be examined daily at the start.
              • liver tests, kidney function tests and triglycerides should be taken examined at least once every week.

              For TPN treatment longer than 1 month, vitamins and trace elements should be examined.

              Follow-up

              The patient's nutrition status should be monitored at follow-up visits after the end of treatment.

              Treatment of Nausea Induced by Chemotherapy

              General

              The majorities of chemotherapy drugs are emetic to varying degrees and may cause nausea and vomiting. Today, there are efficient antiemetic drugs that can significantly reduce the side effects.

              Other factors that can aggravate or prolong the presence of nausea and vomiting are: pain, anxiety, electrolyte disturbances, constipation, dyspepsia, and ulcers.

              There is a distinction between acute nausea, which occurs within the first 24 hours, and late nausea, which occurs later than 24 hours after the treatment.

              Acute nausea can be effectively treated with 5HT3-antagonists (ondansetron, tropisetron, palonosetron), and possibly combined with steroids. Dopamine antagonists (metoklopramid, metopimazine) also have some effect on acute nausea. If this treatment is not effective, it may be improved with aprepitant.

              If standard prophylaxis and treatment of nausea is not satisfactory, other nausea regimens should be tried.

              Indication

              • Nausea induced by chemotherapy drugs.

              Goal

              • Prevention and treatment of nausea and vomiting.

              Definitions

              Chemotherapies according to emetic potential

              High emetogenicity   

              Group 1

              Moderate emetogenicity   

               Group 2

              Low/minimal emetogenicity

              Group 3

              All cisplatin-containing regimens (CiFu, GemCis, BEP, TIP, VIP, PV, AP, EDP, DHAP, ECX, weekly dose cisplatin, and others) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosfamide, vincristine, prokarbazine, prednisolone)
              Doxorubicin/epirubicine weekly dose
              Doxorubicin/ifosfamide Bendamustine
              Docetaxel
              FEC-60 og FEC-100
              (fluorouracil, epirubicin, cyklophosfamide)
              Carboplatin
              ENAP (etoposide, mitoxsantrone, cytarabine, prednisolone)
              ABVD (doxorubicin, bleomycin, vinblastine, dakarbazine Carboplatin/pemetrexed
              FLv (fluorouracil)
              FOLFIRINOX
              Carboplatin/vinorelbine
              FuMi (fluorouracil, mitomycin)

              CHOP (cyclophosfamide, doxorubicin, vincristine, prednisolone)
              Gemcitabine

              CHOEP (cyclophosfamide, doxorubicin, vincristine, etoposide, prednisolone)
              Methotrexate weekly dose
                 Dakarbazine
              Navelbine
                    ECO/ACO (epirubicin/doxorubicin, cyclophosfamide, vincristine)
              Paclitaxel
                     EOX (epirubicin, oxaliplatin, capecitabine)
              Pemetrexed
                    EPOCH-F (etoposide, prednisolone, vincristine, cyclofosfamide, doxorubicin, fludarabine)

                  EPOCH-F (etoposide, prednisolone, vincristine, cyclophosfamide, doxorubicin, fludarabine)
               
                  FLIRI (fluorouracil, irinotecan)
               
                  FLOX (fluorouracil, oxaliplatin)    
                 Gemcitabine/carboplatin      
                 HD-Cytarabine
                 
                  HD-Methotrexate    
                IGEV (ifosfamide, gemcitabine, vinorelbine)
                
                 IME (ifosfamide, methotreksate, etoposide)  
                 Irinotecan  
                 Streptozocin  
                 Vorphase (cyclophosfamide)
               

              References

              1. Lehne G, Melien Ø, Bjordal K, Aas N, Mella O. Kvalme og oppkast ved cytostatikabehandling i: Dahl O, Christoffersen T, Kvaløy S, Baksaas. Cytostatic Medication cancer treatment. 7. edition. Oslo. Department of Pharmacotherapeutics and The Norwegian Cancer Society, 2009, p 119-130.

              Preparation

              Nausea regimens are selected according to the emetogenicity of the relevant drugs.

              • Inform about the risk for and treatment of nausea. 
              • In the event of anxiety or conditional nausea, give tranquilizers if necessary.

              Implementation

              • Start with an optimal antiemetic regimen starting with the first cycle of chemotherapy in order to counteract the amplification of the nausea that often occurs with a new treatment.
              • Start the oral antiemetic regimen 1-2 hours before chemotherapy and approx. 15-30 minutes before an intravenous injection.
              • If the patient is already nauseous, the medication should be administered parenterally or rectally.

              Antiemetic regimens

              Mildly emetic chemotherapy

              • Metoclopramide 10 mg is given intravenously before treatment with cytostatic agents.
              • Metoclopramide 10 mg is given orally uptil 3 times.

              Moderately emetic chemotherapy

              Ondansetron 8 mg orally 2 x daily. In the event of nausea before treatment, give ondansetron intravenously. If this has little effect, try ondansetron 8 mg x 3 or change to a 5HT3-antagonist, for example, tropisetron 5 mg orally/intravenously or palonosetron 250 µg intravenously.

              Highly emetic chemotherapy, or if other treatment does not help

              For highly emetic chemotherapy drugs, or if other treatment is not adequate, a 5HT3-antagonist can be given orally or intravenously. It should be combined with dexamethasone 8-16 mg intravenously ½-1 hour before treatment, and further, 8 mg x 2 intravenously or orally on the first day.

              In addition, dopamine antagonists may be given, for example, metoclopramide 10 mg x 3.

              In some cases, traditional nausea treatment is not sufficient. In this case, the patient can be treated with aprepitant. Aprepitant is used for highly emetic regimens and for patients where the usual antiemetic treatment has failed during moderate emetogenic treatment. Aprepitant is given orally 1 hour before chemotherapy and is combined with dexamethasone and 5HT3-antagonists:  125 mg capsules orally on day 1, then 80 mg orally on days 2-5, depending on the duration of the treatment. Aprepitant can enhance the effect of taxane and etoposide, as well as vinorelbine, and can reduce the effect of warfarin.

              The regimen is repeated daily if highly emetic treatment is given over a number of days.

              Delayed nausea

              Aprepitant in combination with dexamethasone and 5HT3-antagonists is preferable if there is a high risk of delayed nausea and vomiting. This is offered especially to patients who have previously experienced delayed nausea.

              Conditional nausea

              In the event of conditional nausea, diazepam or other tranquilizers may be considered. Diversion or desensitization can be tried in more serious cases.

              Follow-up

              Ondansetron can have a constipating effect. Use of a laxative for several days should be considered.

              Bone marrow stimulation with G-CSF for lymphoma

              General

              G-CSF (granulocyte colony-stimulating factor) is a hematopoetic growth factor. Human G-CSF is a glycoprotein which regulates production and liberation of neutrophile granulocytes from bone marrow.  

              For bone marrow stimulation with G-CSF, the drugs Neupogen® and Neulasta® are injected subcutaneously. Neulasta® and Neupogen® are available in prefilled syringes. Neupogen® is given once daily during aplasia. Neulasta® has a protracted effect and is given only one day after chemotherapy (i.e. day 2-4).

              The patients may administer the injection themselves at home if they are instructed and comfortable doing so.  

               

              Indications

              • Mobilization of stem cells to peripheral blood for autologous stem cell harvesting, usually a dosage of 10 µg/kg/day.
              • For high-dose chemotherapy with autologous stem cell support (HMAS), where bone marrow is used as the stem cell source. 
              • Primary prophylaxis to maintain dose intensity for curative chemotherapy with documentation that this is not possible without G-CSF (for example CHO(E)P-14, dose-escalated BEACOPP).
              • Secondary prophylaxis for curative chemotherapy where the patient after previous chemotherapy developed neutropenic fever. 
              • Secondary prophylaxis to maintain dose intensity for curative chemotherapy where experience has shown that the patient developed neutropenia that would have led to neutropenia leading to dose reduction or postponement of therapy (for example CHOP-21, ABVD, standard BEACOPP)
              • Lasting neutropenic fever in a critically ill patient, for example serious pneumonia, hypotension, serious sepsis, or fungal infection. 

              Preparation

            • Adequate information to the patient
            • Instruction in subcutaneous injection for patients giving self-injections.
            • Implementation

              • The Neupogen® dose is 5 µg/kg/day. For patients over 80 kg, 480 µg x 1 s.c. Otherwise, 300 µg x 1 s.c. (in protocol studies, dosage may be different). Neulasta® has a standard dosage of 6 mg s.c. (used only one day after chemotherapy).

              • G-CSF is used from 2–5 days after neutrophile > 5 x 109/l or > 1 x 109/l for three days.
              • Use of G-CSF for mobilization of stem cells to peripheral blood before autologous stem cell harvesting is usually given as 10 µg/kg/day distributed as two doses per day (morning and evening).
              • Before stem cell harvesting the entire dose is given in the morning.

              Follow-up

              • It is very important that the patient is informed of the risk for infections associated with low neutrophil counts.
              • Patients at risk for low leukocyte values must be given information about precautions for rising temperature. The patient should immediately contact a doctor if the temperature rises above 38.5 °C, or 38.0 °C measured over two hours.  
              • G-CSF may cause influenza-like symptoms as well as pain in large bone marrow-producing bones. The need for pain medication must be weighed against the fever-reducing effect. 
              • Some patients have required opiates for pain during treatment with growth factor. 

              Transfusions

              General

              Transfusions of blood components are often necessary for the patient to complete the planned cancer treatment.

              Blood transfusions are appropriate for low hemoglobin (Hb) and thrombocyte transfusions for low thrombocytes (trc) which also poses a risk for serious bleeding.

              Normal values

              • Hemoglobin 13.4–17 g/dl
              • Platelets 145–348 109/l

              Indications

              Blood transfusion

              Assessment for a blood transfusion based on:

              • Hb/hct
              • symptoms/sign/function level
              • underlying disease (heart/lung, serious infection)
              • expected development of anemia (marrow function, current bleeding)
              • acute blood loss > 15% of total blood volume
              • Hb < 8.0 g/dl and symptom causing chronic anemia
              • Hb < 8.0 g/dl and reduced bone marrow production without sign of regeneration
              • Hb < 8.0 g/dl in perioperative period
              • Hb < 7.0 g/dl in patients without symptoms of other disease
              • Hb < 10.0 and receiving radiation therapy

              Platelet transfusion

              The patient is assessed for thrombocyte transfusion based on:

              • clinical status (bleeding, bleeding tendency, or fever/infection)
              • ongoing bleeding and thrombocytopenia < 50x19/l
              • degree of thrombocytopenia and cause of thrombocytopenia (reduced production or increased consumption)

              Prophylactic platelet transfusion

              • For values < 10x109/l secondary to previous chemotherapy
              • Before invasive procedures
              • For spinal puncture and installation of central vein catheter, thrombocytes should be 30x109/l and 
              • Puncture biopsies (liver/kidney/tumor) > 40x109/l
              • For major surgeries, thrombocytes should be > 50x109/l. After surgery, thrombocytes should be monitored and transfusion repeated, if necessary.

              Remember clinical evaluations: possible bleeding, other risk factors for bleeding, diagnosis, treatment, prognosis.

              Goal

              • Complete the planned treatment
              • Ensure hemostasis 
              • Ensure adequate oxygen transport to peripheral tissue.
              • Maintain intravascular fluid volume for adequate circulations of vital organs

              Definitions

              Blood

              For a blood transfusion for anemia, SAGMAN erythrocytes are used. One unit is obtained from 450 ml blood. Most of the plasma is removed and replaced with 100 ml SAGMAN solution (Saltwater-Adenine-Glucose-Mannitol). Hematocrit is about 0.60%.

              Platelets

              One unit contains 240-300 x 109 platelets and is prepared from blood donors with type O and A. In acute situations, the receiver's blood group is of minor importance.
              Two kinds of platelet products are available:
              • Apheresis platelets produced from thrombophereses from one donor
              • Buffcoat platelets produced from buffy coat from 4 donors

              All cellular blood products should be leukocyte filtered. Leukocyte filtration is done to remove antigen-presenting and virus-bearing cells. 99.99% of leukocytes in the unit are removed.

              Radiation

              Blood and thrombocytes are irradiated to a minimum of 25 Gy in the blood bank to eliminate T-lymphocytes.

              This is done for:

              • Bone marrow transplant or stem cell transplant (1 month before or 3 months after HMAS until 1 year after allogeneic stem cell transplant)
              • For use of HLA-compatible platelet concentrations
              • For all transfusions from relatives
              • For use of fresh blood
              • For use of fludarabine

              Preparation

              Blood tests

              Before the first blood transfusion, the following blood tests are performed:
              • Virus antigens
                • HCV
                • HBV
                • HIV
              Every three days, and as needed, pre-transfusion tests are taken.

              Compatibility

              Erythrocyte concentration—Rh(D) negative products can usually be given to everyone while Rh(D) positive can only be given to Rh(D) positive receivers.

              Thrombocyte concentration—Rh(D) negative girls and women in fertile ages who obtain Rh(D) positive thrombocyte products should be given a prophylaxis for Rh immunization. Boys/men and women who are over the fertile age may obtain thrombocytes regardless of Rh(D) type.

              Implementation

              Blood components should never be given together with other medications.
              • Premedication if the patient has reacted to previous transfusions.
              • Secure venous access
              • The blood product is checked to ensure the correct unit is given to the correct patient.
              • Use blood set with filter
              • Give SAGMAN over 1 hour and thrombocytes 20-30 minutes per unit.
              • Rinse the set with NaCl 9 mg/ml at the end of the infusion
              • Store the blood product bag for one day before discarding

              Observations

              The patient should be observed during the transfusion with emphasis on reactions. Most serious transfusion reactions occur within the first 20 minutes.

              Symptoms of transfusion reaction:
              • chills
              • fever
              • feeling of heat in the face
              • breathing difficulty
              • itching
              • nervousness
              • fall in blood pressure
              • shock
              Suspect/manifest blood transfusion reaction:
              • Stop transfusion immediately
              • Start treatment if necessary (intravenous fluid, adrenalin, steroids, oxygen, respirator)
              • Check blood bag and compatibility form. The residue should be sent to the blood bank.

              Follow-up

              Hemoglobin and thrombocytes are checked.

              If poor effect of platelet transfusion, platelet value should be checked after approximately one hour. The value should have increased by approximately 30x109/l or more after a standard dose.

              If the increase is drastically less, the cause may be:
              • Abnormally high consumption. This is an indication for more frequent transfusions.
              • Antigens against HLA or platelet-specific antigens. The patient must be examined in cooperation with the blood bank to find compatible donors.

              Prevention of Tumor Lysis Syndrome

              General

              Tumor lysis syndrome is a life-threatening complication in cancers where rapid cell loss is caused when treatment is initiated.

              In tumor lysis syndrome, there is a rapid decrease of cells in a matter of hours/days causing depletion of intracellular substances into extracellular space. This causes an increased serum concentration of calcium, phosphate, magnesium, urine substances, and uric acid.  

              Uric acid can lead to precipitation of uric acid crystals in the renal tubules and lead to reduction of renal function. Renal failure is worsened by the binding of phosphate ions with calcium ions creating calcium phosphate crystals which also precipitate in the tubules. When calcium phosphate is > 8-10 mmol/l, the risk of precipitation of crystals in the kidneys and other tissue, increases.  

              Hyperkalemia from release of intracellular potassium is the greatest acute threat to the patient. Levels > 7 mmol/l increases the risk for cardiac arrhythmia and cardiac arrest. 

              Tumor lysis syndrome is observed in association with the first course of chemotherapy, start of radiation therapy, or steroid treatment.

              Patients who are disposed for developing tymor lysis syndrome have:

              • a relatively large tumor mass with high cell proliferation
              • elevated leukocyte count (leukemized blood profile)
              • elevated LDH
              • elevated uric acid
              • reduced renal function 

              The patient`s well being is often already influenced by the disease. Therefore, the degree of electrolyte disturbance contributes to complicating the patient's progress. 

              The prognosis is good with adequate prophylaxis and timely treatment.

              Indication

              • Acute leukemia, lymphoblastic lymphoma, Burkitt's lymphoma (often observed)
              • Other aggressive B- and T-cell lymphomas and indolent lymphomas with massive leukemization treated with monoclonal antibodies (less frequent) 
              • Solid tumors such as small cell lung cancer, medulloblastoma, testical cancer, and advanced breast cancer (rare) 

              Goal

              • Prevention of tumor lysis syndrome

              Definitions

              Tymor lysis is the disintegration of tumor cells, either spontaneously or due to different forms of tumor-directed treatment.

              Preparation

              • Sufficient information about the risk of developing tumor lysis syndrome.
              • Start prophylaxis for tumor lysis syndrome as soon as possible, preferably 1-2 days after starting chemotherapy. 

              Implementation

              Forced hydration is important.

              • Intravenous fluid for adults: 3000-8000 ml NaCl/24 hours. For children, 3000-5000 Salidex® ml/m2/day, depending on the amount of expected tumor disintegration.   
              • Administer allopurinol tablets.
              • If uric acid and creatinine values are higher than expected, rasburicase is administered intravenously, which degrades uric acid rapidly, instead of allopurinol. 
              • Ensure control of fluid accounting.
              • Observe that the hourly diuresis is over 250 ml/hour for adults. Furosemide 20 mg can be given for normal renal function for every 1000 ml of fluid administered. For reduced renal function, it may be necessary to give significantly higher doses. For children, furosemide is administered for insufficient diuresis. Hourly diuresis should be 100-250 ml/hour. 
              • Alkalization of urine is somewhat controversial, but of importance if uric acid is elevated and before and during administration of high dose methotrexate i.v.: for adults, sodium bicarbonate tablets (1-2 g x 3-5 per day) are administered. If there is a significant risk for tumor lysis, or if the patient cannot take tablets, NaHCO3 is administered intravenously (about 160 mmol/24 hours). Dosing depends on the acid-base status. For children, 40 mmol NaHCO3  per 1000 ml is added and possibly KCl additions to the hydration fluid, based on blood test results.
              • Monitoring urine should occur with pH measurements every 4 hours. The pH should be > 7.0.
              • Weighing the patient twice daily is also a method of assessing the fluid balance. 
              • Administer electrolyte supplements as needed.

              When the risk of developing tumor lysis is significant after starting treatment, values for Na, K, Cl, Ca, Mg, P, creatinine, uric acid and urine substances in the blood should be checked 2 or more times daily.  

              For fully developed tumor lysis syndrome, it may be necessary to repeat tests 3-5 times a day. For greater electrolyte disturbances, a venous acid-base status should also be taken.

              For large electrolyte disturbances such as hyperkalemia > 7mmol/l and/or serious hypocalcemia and weakened renal function, the patient should be transferred to the intensive division. A nephrologist should be contacted for emergency help in case of dialysis.

              Follow-up Care

              Tumor lysis tests are checked 2-4 times in the first days after starting treatment. If the patient has not developed tumor lysis syndrome in the next 2-4 days, the patient may continue the work-up/cancer treatment or possibly return home.

              Febrile Neutropenia

              General

              Febrile neutropenia occurs in compromised immune systems due to a low number of leukocytes, especially granulocytes. Patients with a declining number of granulocytes after chemotherapy, can during bacterial sepsis, quickly develop extensive neutropenia and become critically ill. Febrile neutropenia can be a life-threatening condition.

              A patient with neutropenia and simultaneous fever or clinical suspicion of systemic infection should be treated as quickly as possible with broad spectrum antibiotics including gram-negative and gram-positive coverage as soon as the required microbiological samples are taken.

              The clinical situation is most critical in patients who have not yet started antibiotic treatment. When broad-spectrum antibiotic treatment is started, monitoring the fever may be permitted.

              Fever is often the only symptom. Some have septicemia without fever. One should therefore also be aware of other symptoms such as lethargia, diarrhea, or visible sign of infection. The local clinical symptoms and signs (redness, pain, temperature increase, swelling (boil), and reduced organ function) are most often very much reduced or completely absent during neutropenia.

              Indications

              • A patient with neutropenia and simultaneously fever or clinical suspicion of systemic infection

              Goals

              • Avoid septicemia.
              • The patient is able follow the planned scheme of treatment.

              Definitions

              Fever is defined as:

              • a single (rectal) temperature ≥ 38.5 °C or
              • temperature ≥ 38 °C for more than 2 hours or
              • temperature ≥ 38 °C measured three times during 24 hours

              There is a known increase of infections when neutrophil < 1.0 x 109/l.  The infection risk increases with degree and duration of neutropenia. The neutropenia is considered severe when granulocytes are ≤ 0.5 x 109/l.

              Preparation

              The following diagnostic tests should be performed:

              • Adequate microbiologic tests: blood culture x 2-3, throat/nasopharynx, urine, catheter opening any surgical incisions. All blood cultures should be taken simultaneously to avoid losing valuable time.
              • Blood culture and other microbiological samples should be taken before antibiotic treatment is started
              • Blood tests with differential count of leukocytes, thrombocytes, Hb, CRP, SR, creatinine
              • X-ray of chest

              Information

              Before initiation of chemotherapy, the patient should be extensively informed, both verbally and in writing, of febrile neutropenia and  its consequences.

              A patient who can develop febrile neutropenia should obtain a written statement of the condition to present to other treatment providers.

              Use of an isolated or private room

              Patients with neutrophil granulocytes ≤ 0.3 x 109/l should have a private room if possible. Guidelines for protective isolation should be followed. Thorough washing of hands is especially important.

               

              Implementation

              • Treatment is started as soon as possible.  Treatment may be postponed a maximum of 30 minutes to complete microbiological testing.
              • Start septicemia treatment for fever if neutropenia is expected, regardless of granulocyte value.

              Antibiotic regimen

              • Benzylpenicillin sodium 5 mg IE x 4 tobramycin or gentamicin 5-10 mg/kg x1
              • Tazocin® 4 g x 3
              • Cefotaxime® 1 g x 4 if aminoglycoside should be avoided
              • Ceftazidim® 1 g x 4  with suspicion of pseudomonas infection
              • Meronem ® 0.5 g x 4 usually 2nd or 3rd choice

              When using aminoglycoside, the first dose should be high. Keep in mind the following:

              • age
              • sex
              • kidney function
              • fat index   

              Otherwise, the dose should be decided from concentration of aminoglycoside determined after the second day and thereafter monitored 2x per week. 

              Serum concentration of tobramycin and gentamycin

              For single dose in 24 hours

              • Trough concentration (0-test = 24 hour test) < 0.5 mg/l
              • Top concentration (30 minute after infusion is completed) > 12 mg/l

              For multiple doses in 24 hours

              • Trough concentration < 2 mg/l, top concentration (30 minutes after the infusion is completed) preferably > 8-10 mg/l 
              • Avoid aminoglycoside :
                • If kidney function is reduced. Avoid aminoglycoside if cisplatin is used. If cisplatin has been previously used, many patients will have subclinically reduced kidney function. If necessary, use aminoglycoside for a short period and monitor kidney function closely.
                • If carboplatin is used, determine glomerulus filtration rate (GFR) for each new treatment. Penicillin/aminoglycoside can be used if GFR is stable (has not declined more than 15% if initial value is in the normal range)
                • With sarcoma: Protocols with very high doses methotrexate and ifosfamid (> 5 g/m2) should be used in sarcoma treatment. It is not abnormal for these patients to have an increase in creatinine.
                • with massive ascites
                • with suspicion of or documented myeloma kidney (myelomatosis)
                • If aminoglycoside has been used in the past two weeks
              • Suspicion of staphylococcus aureus as a cause of infection (relatively rare)
                • Give penicillinase-stable penicillin, cloxacillin, or dicloxacillin, possibly clindamycin instead of ordinary penicillin. Yellow staphylococci are also killed by cefotaxime and by merop
              • Gram-positive cocci in multiple blood cultures and if the patient has clinical signs of infection
                • Use vancomycin 500 mg x 4 until resistance determination is available
              • Poor patient condition and suspicion of gram-negative septicaemia
                • Use “double gram-negative” with for example ceftazidim or tobramycin
                • Other preparations with good effects against most gram-negative bacteria are meropenem and ciprofloxacin
              • Suspicion of anaerobic infection
                • Use an anaerobic drug: Metronidazol 500 mg x 3, clindamycin 600 mg x 4, piperacillin/tazobactam 2g x 4 or meronem 500 mg x 4.  This especially applies if there is suspicion of anaerobic infection under the diaphragm such as gallbladder, intestines, perforation, abscess.
                • penicillin is often adequate for anaerobic infections above the diaphragm.

              With continuing clinical signs of infection, adjust the antibiotic treatment according to resistance determination in blood culture. Maintain gram-negative coverage.

              Systemic fungal treatment

              By persistent fever after multiple days with broad spectrum antibiotic treatment, one should consider empirical treatment of possible candida-sepsis, for example with fluconazole 600 mg the first 24 hours, and thereafter 400 mg x 1.

              If candida is documented without adequate response to fluconazole, a fungicide drug should be used, for example amphotericin B.

              If suspected infection with Aspergillus apply voriconazole, amphotericin B or caspofungin.

              Follow-up

              Observe for symptoms of a new infection.

              Sperm Banking

              General

              Sperm banking services may apply to patients having a disease or undergoing treatment which reduces or eradicates the patient's fertility. The decision for storage is made by the doctor in charge of the patient in cooperation with the chief physician at the andrology laboratory.

              Stored sperm can only be used for assisted fertilization by the patient's spouse or partner in a stable relationship (duration more than 2 years).

              The offer for freezing and storing sperm does not guarantee treatment with assisted fertilization. The decision for this is made by the treating doctor according to guidelines and laws for assisted fertilization.

              The patient may store up to three samples. The samples should be taken with a few days in between and the patient should not have ejaculated for two days prior to sample collection.

              Indications

              • Cancer treatment rendering a man infertile.

              Goal

              • The possibility of having children after treatment is concluded.

              Equipment

              • A urine sample container.
              • A room for the patient to be undisturbed.

              Preparation

              • Inform the patient verbally and in writing.
              • Conform to rules and guidelines.
              • A blood test for HIV and hepatitis to rule out infectious sperm.

              Imlementation

              • The sperm sample is collected via masturbation and is collected directly into a urine sample container. A condom should not be used as this contains spermicide.
              • The sample should be allowed to cool and should be delivered to the andrology laboratory in less than one hour after ejaculation.

              Follow-Up

              • The sperm sample is held in under quarantine until HIV and hepatitis results are available.
              • The sperm can be stored for 10 years and possibly longer if the patient desires.
              • After filling 55 years or death the sperm is destroyed.

              Ovarian Tissue Freezing

              General

              Presently, ovarian tissue freezing is still in a trial stage. Optimal indication, clinical efficacy, and technical conditions for freezing tissue are still being explored and changing. 

              The treatment is authorized by law in the regulation for biotechnology § 2–17 in Norway. The Womens' Clinic at Oslo University Hospital located at Rikshospitalet performs ovarian tissue freezing for Norway.  

              Thawing and reintroduction of tissue, and possibly in vitro fertilization, are possible techniques for reestablishing fertility after full remission of cancer. On a world basis, only a minority of births have been documented after reintroduction of ovarian tissue. Until now, it has not been relevant to reintroduce ovarian tissue for women in Norway who have stored tissue at Oslo University Hospital. Due to the experimental nature of the method, the patient must be well informed of the uncertainty surrounding the technique and the need for further method development.

              Indications

              The indication for ovarian tissue freezing is gonadotoxic treatment including chemotherapy and radiation therapy which lead to a high probability (> 50%) of sterility. The treating oncologist makes the final decision for the procedure.

              Ovarian tissue freezing provides women who are treated for cancer the possibility of maintaining their fertility.

              Examples of diagnoses where ovarian tissue freezing may be relevant:

              • Cancer in pediatric and adolescent years:
                • leukemia
                • lymphoma
                • sarcoma
              • Cancer in women of reproductive age:
                • breast cancer
                • leukemia
                • lymphoma
              • Benign hematological diseases, for example thalassemia or major aplastic anemia. Freezing of ovarian tissue is rarely indicated in other benign diseases.

              Theoretically, there is no lower age limit for removing ovarian tissue, but an individual assessment must be done in each case.

              Contraindications

              • Age > 35 years
              • HIV infection, hepatitis B, hepatitis C or syphilis
              • Conditions which exclude a laparoscopic ovariectomy
              • Treatment which prevents future pregnancy such as a hysterectomy or life-long treatment where pregnancy is contraindicated.
              • Ovarial reserve is already lost due to, for example, previous chemotherapy or induction treatment. Previously completed chemotherapy with preserved ovarial reserve is not a contraindication.
              • Disseminated systemic cancer is a relative contraindication. Risk of micrometastases in frozen tissue makes reintroduction of tissue in these cases inappropriate. In vitro fertilization of egg cells is a technique apparently several years into the future. These patients should therefore be well under 35 years. 

              Goal

              • Maintain fertility in females £ 35 years undergoing treatment that will eradicate or strongly reduce fertility.

              Background

              Radiation and chemotherapy are gonadotoxic which can lead to ovarian failure and infertility by inducing apoptosis and/or DNA damage in egg cells and surrounding cells.

              Depending on the type of cancer and regimen for chemotherapy and radiation therapy, the treatment can lead to ovarian failure and infertility. The age of the female is significant. Young girls and women maintain menstruation and reproduction ability to a larger degree than women over 30 years, however they also become menopausal earlier than expected.   

              Preparation

              Oncologist at the treating institution

              • Consider oncological indications and contraindications regarding the procedure
              • Inform the patient about the option
              • Contact the department for childlessness and assisted fertilization

              Physician at the department for childlessness and assisted fertilization

              • Assess the patients situation according to the requirements of the biotechnology laws and regulations, surgical risk, ovarian reserve, and planned treatment course.

              • Obtain written consent for freezing of tissue.
              • Decide the day for the operation.

              Implementation

              • The procedure is carried out under general anesthesia.
              • An entire ovary or biopsies from the ovaries are retrieved by laparoscopy.
              • After preparation in the laboratory, the tissue is frozen and stored at -196 °C.

              Follow-up care

              Storage of preserved ovarian tissue

              The preserved ovarian tissue can only be stored as long as it is required by the donor and as long as it is considered medically justifiable after individual assessment. The tissue should be destroyed when the woman dies. 

              The option to freeze and store ovarian tissue does not provide an automatic right for future reintroduction of tissue or other form of treatment. The decision is made by the treating doctor according to guidelines set by biotechnology laws and other relevant regulations.

              Erythropoitin (EPO) for anemia

              General

              Anemia with hemoglobin < 11.0 mg/l is normal during chemotherapy. This will often lead to prominent fatigue. Anemia can be treated symptomatically with transfusion of erythrocytes, or bone marrow can be stimulated with erythropoitin (EPO).

              Patients with chemotherapy-induced anemia will usually have sufficient iron storage, but some may need iron supplementation. 

              Anemia should normally not cause postponement of treatment. It is quickly corrected by an erythrocyte transfusion – and treatment may then be started.

              Indication

              • Patients with chemotherapy-induced anemia

              Contraindications

              • Hypersensitivity to darbepoetin alfa, r-HuEPO or any of the additional ingredients.
              • Poorly-controlled hypertension
              • Reduced liver function (raised s-bilirubin). EPO is most likely eliminated via the liver. There is presently no toxicity data on patients with reduced liver function.
              • Some studies indicate a detrimental effect on patient survival by the use of EPO in cancer patients, and this treatment should be avoided for anemia in cancer patient for whom there is a curative goal with the treatment.

               

              Goal

              • Reach hemoglobin level of 12–13 g/l

              Preparation

              • Survey blood status
              • Evaluate iron status

              Implementation

              • EPO is given in a dosage of 40,000 IE subcutaneously once daily
              • With use of Aranesp®, one dose of 500 μg subcutaneously is given every third week
              • For hemoglobin of 12 g/l, the dose is reduced by 25–50%, for example 300 μg every third week
              • For hemoglobin of 14 g/l, treatment is stopped until it has fallen to under 12 g/l where treatment is resumed with a 50% dose (for example, 300 μg or lower every third week). Repeated dosage reductions may be necessary. 
              • If the increase in hemoglobin rises above 2 g/dl (1.3 mmol/l) within 4 weeks, the dose should be reduced by 25–50%.

              Assurance of efficient erythropoesis

              • Low s-iron and high ferritin implies iron deficiency. It is then recommended to give iron supplementation, for example slow-release iron tablets 100 mg x 2 daily for the first 4 weeks then once daily. If still no effect from this treatment, immediate action should be taken to find the cause.
              • Lack of iron, folic acid, or vitamin B12 reduces the effect of erythropoietin-stimulating drugs and should therefore be treated.
              • In the case of functional iron deficiency, iron storage is not released as needed and iron must be taken parenterally. Functional iron deficiency is characterized by normal or raised ferritin and normal serum iron/TIBC. 
              • Simultaneous infections, inflammatory or traumatic episodes, hidden blood loss, severe aluminum toxicity, or underlying hematological disease or bone marrow fibrosis can also impair erythropoietin response.
              • Reticulocyte count should be monitored as part of the evaluation.
              • If typical causes for no response have been excluded and the patient has reticulocytopenia, a bone marrow examination should be considered. If bone marrow assessment implies erythroaplasia (Pure Red Cell Aplasia – PRCA), testing with anti-erythropoietin antibodies should be done.

              Follow-up

              Follow-up of hemoglobin under EPO treatment is necessary because overstimulation can lead to polycytemia.

              Movement and strict bed rest for threatening spinal cord lesion

              General

              Approximately 5% of the patients with advanced malignancies develop symptoms of threatening spinal cord lesion. The condition is most frequently in patients with cancer originating from lungs, prostate or breast, but is also seen in other types of cancer where bone metastases may occur.

              Symptoms

              • Pain in the back, possibly in the neck
              • Changes in existing pain (increased intensity, changed character, radiance of pain)
              • Pain that worsens with exertion (for example cough, sneeze or going to the toilet)
              • Walking difficulties and inability to control the extremities
              • Paralysis of the legs and-/or arms
              • Loss of sensation
              • Urinary problems and/or defecation problems

              The stability in columna

              • Ambulatory patients without neurological deficits do not need strict bed rest.
              • For other patients, it may be appropriate to have strict bed rest until the stability of columna is assessed. The need of strict bed rest is assessed by a physician based on the risk of increased neurological deficits and the degree of pain. When columna is considered stable enough (usually clarified 2 to 4 days after the initiation of radiotherapy), gradually mobilization until pain threshold should quickly get started. Increasing pain or neurological deficits should be observed during mobilization.
              • For strict bed rest, the head end of the bed can be elevated up to 30 ° C.
              • If flat bed rest causes increased pain, the head end of the bed should be raised until pain reduction.

              Indication

              • Threatening spinal cord lesion caused by tumor/metastases.

              Goal

              • Limit spinal cord damage so that  functions may be maintained.

              Preparation

              The patient and their family should receive proper information and guidance regarding to disease, treatment and restrictions. For advanced disease, small chance of getting better and short life expectancy, quality of life rather than strict restrictions should be emphasized.

              The patient should, if he/she wishes, be involved in decisions regarding to treatment and further training.

              Implementation

              Use of cervical collar and corset

              • Lack of documentation of the effect of using cervical collar and corset, require the patient's wishes to be taken into account in assessing whether this should be used.
              • Cervical collar may be relevant for spinal cord lesions in the cervical level of the spinal cord. Some patients find this pain relieving. A neurologist/neurosurgeon will decide whether there is a need for cervical collar.
              • A corset are generally not used preoperatively, but if prescribed by a surgeon, it may be used postoperatively.
              • The corset must be adjusted by a prosthetist or physiotherapist.
              • The corset is put on in either supine position, sitting position or in standing position, initially by competent personnel. The patient is instructed to put on the corset unassisted.

              Bed rest and positioning

              • The patient should be referred for physical therapy at an early stage. To avoid accumulation of mucus in the lungs, the physiotherapist should give instructions in appropriate breathing exercises, consider use of mini-pep and need for chest physiotherapy.
              • Patients who need strict bed rest must have electrically controlled bed with a pressure relieving mattress.

              Movement in bed

              • The patients must be instructed in how to move to lateral position in bed using logrolling. Logrolling involves moving to lateral position without rotation or flexion/extension in columna. The healthcare staff are performing the movement to lateral position by rolling the patient while their hands are securely placed over the patient's hips and back/shoulder.
              • If the patient has mobility in the legs, he/she may, using bent knees and hips and feet down in the mattress as well as arms straight up in the air as levers, roll over to lateral position.
              • When the patient needs to be moved higher up in bed, the bed should be tilted a bit backward, the patient is lifted calmly with the sheet close to the body by means of the draw sheet and two persons.
              • Slingbar is not recommended for cervical or thoracic lesions.

              Activity during bed rest

              • By instructions from a physiotherapist, nurses can assist the patient to do appropriate activity and exercises. Passive exercises when paresis or paralysis is present, otherwise active exercises.
              • Activity that causes pain must be interrupted.
              • Individually customized movements of upper and lower extremities, passive or active, are carried out in a supine position with a low strain on columna.
              • A footboard made of compact foam at the end of the bed is an aid to prevent the patient from sliding down in the bed and provides a resistant surface against which the patient can push for a good venous-/muscle pump.
              • Strength training of arms by static resistance to the mattress and without movement of the columna, is recommended. Light hand weights for arm exercises are only considered when the affection is in the lumbar level.
              • The need for contracture prophylaxis is considered, and if there is a drop foot a footboard should be customized.
              • Instructions in self-training will be given, preferably also as a written program as well.

              Thrombosis prophylaxis

              • Bedridden patients should have compression stockings in thigh/- possibly knee length, unless contraindicated.
              • Patients at high risk of venous thrombosis should also have subcutaneous thrombosis prophylaxis with low molecular weight heparin.
              • The duration of thrombosis prophylactic treatment is considered individually based on current risk factors, general health condition and mobilization of the patient.

              Pressure relief and prevention of pressure ulcers

              • Patients who must have strict bed rest is particularly prone to pressure ulcers.
              • Prevention of pressure ulcers must be followed in relation to risk assessment, assessment of the patient's skin, skin care, nutrition, pressure relieving underlay, change of position in bed/chair and mobilization.
              • For patients with/having strict bed rest, change of positions in bed must be in accordance with the restrictions.

              Bladder function

              • An assessment of  the bladder function is done at arrival. An accuracate anamnesis is obtained: Last urination, episodes of incontinence, frequency, painful urination and abdominal pain.
              • Evaluate the  bladder function at least once a day for any changes.
              • If incontinence, insert a permanent catheter.
              • If it turns out to be permanent muscle tone, evaluate eventually intermittent catheterization or insertion of suprapubis catheter.
              • Bedpan/urinal bottle should be easily accessible at strict bed rest. When using bed pan, loggrolling is required.

              Gastrointestinal function

              • An assessment of  the gastrointestinal function is done at arrival.
              • An accuracate anamnesis is obtained: Last bowel movements, frequency, consistency, nausea/vomiting, abdominal pain and previous ailments.
              • Evaluate the gastrointestinal function evaluated at least once a day.

              Pain relief

              • Spinal cord compression can cause severe pain that may be difficult to treat. If so, contact the pain -/palliative team.

              Mobilization

              • The patient and the healthcare staff collaborate to find the right level of activity.
              • Go gradually from an increased angle on the bed`s back rest to sitting position, to sitting position on the bedside and then to standing position. The back rest is gradually raised to about 45 ° and the bed´s leg-rest is angled and the patient can try this sitting position, further to 60 °. By worsening of pain and/or neurological outcomes, the patient is returned to the previous position for reconsideration. If the increase of the back-rest is unproblematic, the patient can further be mobilized to the bedside.
              • The first time the patient is moved to sitting position on the bedside, this is preferably done by a physiotherapist together with a nurse by rolling over to lateral position (logrolling). The patient sits up assisted by two persons, one at the upper body and one supporting the legs over the edge of the bed.
              • When affection in the cervical region only, the patient can be mobilized up to a sitting position by raising the head of the bed and bring the legs over the bedside. The patient is allowed to sit for a little while, blood pressure and pain are evaluated.
              • Exercises to increase circulation and good breathing exercises are recommended. Balance in a sitting position is considered.
              • When the patient is moved to standing position, custom walking aids must be used (pulpit walker or forearm walker). To ensure safe mobilization the first time, assistance of two persons are recommanded.
              • For lasting paresis, a high-back reclining wheelchair with leg rests should be customized.
              • The need of other aids, like transfer slide board, drop foot brace, grasping forceps and similar equipment, should be considered.
              • Instruction in self-training should be given, preferably after a written program in standing exercise and walking exercice with support.
              • Gradually, the patient can sit  for short periods of time, using a good armchair with a high seat and good backrest.

              Follow-up Care

              • Patients with a long life expectancy should be considered for further training at a suitable institution.
              • Patients with a short expected life expectancy are usually not recommended for stay at rehabilitation institutions.

              The website www.physiotherapyexercises.com is recommended for obtaining exercises.

              Intravenous Extravasation of Cytotoxic Drugs

              General

              Intravenous extravasation occurs when there is an accidental leak of intravenous cytotoxic fluid (chemotherapy drug) from the vein to surrounding tissue.  

              If chemotherapy is given in a peripheral vein, a large vein should be used, which is preferably in the underarm. Before the infusion begins, the vein should be checked for leaks by injecting NaCl 9 mg/ml or glucose 50 mg/ml. Backflow should also be checked. The patient must be informed that pain or burning in the area is not normal and they must inform the doctor.

              Cytotoxic chemotherapy drugs should always be given through a central vein catheter to reduce the risk of intravenous extravasation.

              Risk factors for intravenous extravasation:

              • Small veins (infants and children)
              • Brittle veins (elderly patients)
              • Reduced physical health (cancer patients)
              • Sclerosizing veins
              • Rolling veins
              • Poor circulation (if the needle is placed in an arm with edema)
              • Obstructed vena cava (raised venous pressure may cause leakage)
              • Conditions such as diabetes and radiation damage
              • Obesity

              Chemotherapeutic drugs are separated into three groups according to the degree of toxicity:

              • Non-cytotoxic/irritating
              • Tissue irritant
              • Cytotoxic

              Cytotoxic drugs can cause blisters or ulcerations leading to skin necrosis if extravasation occurs. If intravenous extravasation is left untreated, it can lead to permanent tissue damage, necrosis, scar formation around ligaments, nerves and joints, infections, abscesses, contractures, and in the worst case, amputation.

              Indication

              • Intravenous extravasation of cytotoxic drugs. 

              Goal

              • Limit damage of tissue from intravenous extravasation.

              Definitions

              Non-cytotoxic drugs or non-irritants

              Non-cytotoxic/non-irritant drugs normally do not cause skin necrosis.

              Irritants

              Drugs that are tissue irritants can cause pain in and around the injection site and along the vein. They can also cause inflammation. Some tissue irritating drugs cause ulceration if a large amount leak extravasally.

              Cytotoxic drugs

              Cytotoxic drugs are categorized into subgroups according to the mode of damage. This categorization is important for the choice of treatment.

              DNA-binding

              DNA binders absorb locally into the cells, bind to DNA, and cause cell death. After cell death, the drug molecule can be liberated from the dead cell and start killing healthy cells. This group is divided into these subgroups:  

              • Anthracycline
              • Alkylating drugs
              • Other

              For doxorubicin and mitomycin, progrediating tissue damage has been reported over weeks, and in some cases, months after intravenous extravasal injection.

              Non DNA-binding

              This group of medications can lead to cell death through other mechanisms than DNA binding drugs. This group is divided into:

              • Vinca alkaloids
              • Taxanes

               

              Chemotherapy cytotoxicity (1)
              Cytotoxic, necrosis

              Irritant, can cause flaking or inflammation

              Non-cytotoxic or non-irritant
              Amsacrine Cisplatin Aldesleukin
              Decarbazine Doxorubicin liposomal Alemtuzumab
              Dactinomycin Estramustine** Asparaginase
              Docetaxel**** Etoposide Bleomycin
              Doxorubicin* Floxuridine Bevacizumab
              Epirubicin* Florouracil Bortezomib
              Daunorubicin* Irinotecan Cetuximab
              Idarubicin* Carboplatin Cyclophosphamide**
              Irinotecan Carmustin** Cytarabine
              Kloremtin** Oxaliplatin Fludarabine
              Mitoguazon Pemetrexed Gemcitabine
              Mitomycin-C Ralitrexed Ibritumomab tiuxetan
              Mitoxanthrone Temoporfin Ifosfamide**
              Paclitaxel**** Teniposide Interferon
              Plicamycin Topotecan Cladribine
              Streptozocin Methylene blue***** Clofarabine
              Verteporphin   Melfalan**
              Vinblastine***   Methotrexate
              Vindesine***   Rituximab 
              Vincristine***   Tiotepa**
              Vinorelbine***   Trastuzumab

               * = Anthracycline

              ** = Alkylating agents

              *** = Vinca alkaloids

              **** = Taxanes

              *****= Methylene blue is not a chemotherapy drug, but is used for ifosfamide-induced encephalopathy, and is therefore included on the list.  

              All chemotherapy drugs can damage tissue in high concentrations.

              References

               

              1. Allwood M, Stanley A WP. The Cytotoxics Handbook. Ed. 4th ed. 2002. 2001
              2. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726

              Preparation

              Identification of an extravasal injection

              • A burning, stinging pain or other acute change of the puncture site.
              • Local redness or inflammation of the skin around the puncture site.
              • The infusion rate slows/stops.
              • Swelling of the puncture site.

              Extravasation has probably also occurred if blood cannot be aspirated, resistance is felt on the plunger when a syringe is used, and/or there is no current if the drug is infused. 

               

              Implementation

              Flow chart for treatment of intravenous extravasation of cytotoxic drugs:

              Emergency response:

              • Stop the infusion immediately.
              • Allow the needle to remain and aspirate with as much water as possible. Avoid applying direct pressure on the area of extravasation.  
              • The volume, type, and time of extravasation should be recorded.
              • A doctor/plastic surgeon should be called for to examine the patient.
              • The damaged area and skin manifestations should be marked/photographed.
              • The affected area should be kept elevated.
              • The remaining chemotherapy should not be discarded.
              • The patient should be informed about what is happening and what must be done. 
              • The needle is removed while aspirating.
              • Pain medication is administered if necessary.

              Based on which medication has leaked extravasally, the doctor or plastic surgeon will decide whether conservative treatment or primary surgery is necessary.

              Conservative treatment

              Conservative treatment consists of two different treatment strategies to limit the damage by extravasation: localize/neutralize and spread/dilute (2).

              Localize and neutralize:

              • Place an ice pack on the area for 15-20 minutes, at least 4 times daily for multiple days. A coldpack is used to limit spreading of the drug. Studies have indicated that there is reduced cellular uptake of drugs at lower temperatures (2).
              • The drug that has leaked extravasally is neutralized by a specific drug if the instructions are followed.
              • The affected area of the body should be kept elevated.

              Spread and dilute (applies to vincristine, vinorelbine, vindesine, and vinblastine):

              • Warm compresses are placed on the area for 15–20 minutes, at least 4 times daily, for multiple days.
              • To dilute the drug that has leaked extravasally, many subcutaneous injections are given with hyaluronidase diluted with sterile water.

              If the patient has lasting pain or blisters, surgical treatment should be considered by excising the area with direct sutures, skin transplant, or flap reconstruction.

              Another type of reconstruction may be necessary at a later time. 

              Treatment 

              Dexrazoxan (Savene®)

              Dexrazoxan is an EDTA analong used to treat extravasation of anthracycline (doxorubicin, daunorubicin, epirubicin, idarubicin). The mechanism of action is not fully understood, but it is believed that it may work through two mechanisms. By chelating iron, the formation of the iron-doxorubicin complex and  iron-mediated hydroxy radicals are hindered, which cause oxidative damage to cell membranes and proteins. Another possible mechanism is inhibition of topoisomerase II (3).

              Treatment lasts for 3 days. In all cases of extravasation of anthracycline, this treatment should be assessed by an oncologist and surgeon/plastic surgeon.

              • The first infusion should start as soon as possible and within 6 hours after extravasation. 
              • On the following two days, the infusions should occur at the same time as the previous infusion (+/- 3 hours).
              • If possible, the infusion should be placed in a vein where there is no extravasation.
              • An ice pack or cooling element used on the area must be removed at least 15 minutes before the infusion starts to ensure sufficient blood circulation.

              Cost

              A package costs about NOK 100,000.-. If the expiration date runs out, the drug is replaced by the pharmaceutical company free of cost.

              Dimethylsulfoxide (DMSO)

              DMSO (70–90% solution) quenches free radicals and prevents formation of sores. The solution can be used after extravasation of cytotoxic drugs (anthracycline, mitomycin C, doxorubicin, idarubicin, epirubicin andactinomycin D) together with cooling of the area when other treatment methods cannot be used (5, 6). DMSO cannot be used in combination with dexrazoxan (3, 4).

              • An area twice as big as the affixed area is treated with the solution every 8 hours for one week.(6)

              Hyaluronidase

              Hyaluronidase is an enzyme that breaks down hyaluronic acid found in connective tissue. This leads to permeability and increased diffusion of the drug that is leaking extravasally, and is used only to spread the drug out into the tissue (spread and dilute).  

              • Hyaluronidase is administered subcutaneously or intradermally in 5-10 locations on the border of the area where the drug has leaked extravasally (7).

              Surgical treatment

              "Wash-out"

              The washing out technique can be used with chemotherapy drugs when tissue damage is likely. When used with anthracycline, it is important that this is performed before the chemotherapy drug goes intracellularly.

              In most cases, this is a very successful method if it is performed within 6 hours after the extravasation.

              • The patient receives regional anesthesia.
              • Multiple small incisions must be made to ensure sifficient access to the damaged subcutaneous tissue.
              • With an infiltration needle, which is usually used for liposuction, isotonic NaCl is flushed through the tissue and drains through the incisions.
              • The infiltrated fluid is then carefully removed by suction through a small needle used for liposuction.
              • The procedure is repeated until 300-500 ml fluid is used.

              References

              1. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
              2. Hasinoff BB. Dexrazoxane use in the prevention of anthracycline extravasation injury. Future Oncol 2008; 2006: 1–15.
              3. Statens legemiddelverk. Preparatomtale. 2008
              4. Langstein HN, Duman H, Seeling D, Butler CF, Evens GR. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plastic Surg 2002; 49: 369–74. 
              5. Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: A prospective clinical study. J Clin Oncol 1995; 13: 2851–5.
              6. Clinical Pharmacology© 2008 database. Hyaluronidase. 2008.

              Follow-Up

              For conservative treatment 

              The damaged tissue should be observed for multiple weeks (with mitomycin at least 13 weeks) since necrosis can occur after months.

              For emergency surgical treatment

              Patients treated by a plastic surgeon should receive follow-up care by the surgeon until the wound has healed.

               

              Intravenous extravasation of cytotoxic drugs.Intravenous extravasation of cytotoxic drugs.Extravasation of tissue toxic chemotherapy

              Follow-up care after treatment of Hodgkin's lymphoma

              Follow-up examinations

              All follow-up visits should include a clinical history and clinical examination with special attention to lymph node status and examination of the heart, lungs, and abdomen. Areas originally involved by lymphoma and irradiated organs/areas should be focused on for recurrence and side effects after treatment. Blood tests should be performed at each follow-up visit and should include hematological tests with differential counts of leukocytes, SR, LDH, TSH, and free T4 in patients who have been irradiated to the neck and/or upper mediastinum, liver and kidney function tests (especially after irradiation to the kidney regions or other nephrotoxic therapy).

              Follow-up with chest imaging should be done with X-ray or CT, but MRI should be considered if frequent follow-up is necessary, especially in children and adolescents to reduce radiation exposure.

              Follow-up of the abdomen and pelvis for slim patients should be done with imaging using ultrasound of the liver, spleen, and retroperitoneum instead of CT. Multiple CT scans give a significant amount of radiation over time, therefore MRI as an alternative to CT should be considered. MRI should be considered routine for children and adolescents.

              The follow-up schedules given below are only guidelines and apply as long as the patient is in remission. For curative treatment of Hodgkin and non-Hodgkin's lymphoma, response is evaluated at least once during chemotherapy as well as after chemotherapy and additional radiation therapy. For palliative chemotherapy, the follow-up schedule is customized, likewise for untreated patients under observation.

              The goal of treatment is to cure the disease after first-line therapy and also, for most patients, after recurrence therapy. Blood examination should include the tests mentioned above. A clinical examination should be peformed at all follow-up visits.

              • The first follow-up visit is 1–2 months after completed therapy to evaluate whether the patient is in full remission. The examination should include imaging and bone marrow examination if findings were present before treatment.
              • The first two years after completing treatment will involve follow-up visits every 3 months. Only a chest X-ray is performed after three months. X-ray or chest CT or ultrasound of the abdomen/pelvis is taken after 6, 12, and 24 months. Chest X-ray is taken only at follow-up visits where CT is not performed.  
              • 3 years: Follow-up visit every 4 months. Chest X-ray after 28 and 32 months, X-ray or chest CT and CT or ultrasound of abdomen/pelvis after 36 months. 
              • 3–5 years: biannual follow-up visits with chest X-ray and annual imaging  (ultrasound or CT) of the abdomen/pelvis. 
              • Further annual checks should be carried out with the patient's primary care doctor with guidelines for what the visits should include, for example, thyroid function tests (TSH and free T4) in patients who have received radiation therapy to the neck.
              • For certain patients, especially those who have completed radiation therapy, it is recommended the patient is examined after 10 years with a heart and lung function examination and mammography where appropriate.

              Follow-up after high-dose treatment with autologous stem cell support (HDT with SCS)

              For recurrence after HDT with SCS, there is rarely a curative treatment option except for rare localized recurrences which can be controlled by radiotherapy. Many patients with recurrence after such treatment for Hodgkin's can, however, live long (many years) with a good quality of life after the recurrence is confirmed. Complications and side effects after completed treatments must be confirmed and registered. Physiotherapy for symptoms from muscle and bone is often of help. Psychological problems can occur long after treatment is finished. Some patients must be rehabilitated to less heavy or demanding jobs.  

              Upon discharge after HDT with SCS, the patient is informed of the applicable vaccination program. Full reimmunization (three doses) of tetanus, diphtheria, and whooping cough are recommended after 12 months.   

              The intervals between visits are the same as those given for different lymphoma types.

              What patients often struggle with

              • Fatigue. This patient group may struggle with fatigue long after treatment is over. This may last for months, maybe years.  Many Hodgkin's patients are relatively young and are in education when they receive the diagnosis. It has been shown that many struggle with resuming their studies later due to difficulties in consentrating and memory problems. Some needs to restart their education. It is importantto evaluate the degree of fatigue in patients treated for lymphoma. Many patients have experienced that there is too little discussion and not enough knowledge shared. It is also important to exclude depression since treatment is very different.
              • Fertility, which is an increasing problem with age and amount/type of treatment. For those who have utilized sperm banking, assisted fertilization may be necessary.
              • Psychological and socioeconomic problems. Many patients benefit from counseling with a social worker or psychiatric nurse. 
              • Dry mouth, tooth decay, and gum diseases are often present after irradiation to the oral cavity. With sufficient documentation from a dentist stating dental care is required as a result of irradiation, the patient can apply for reimbursement from the national health service. 
              • Hypothyroidism after irradiation to the neck is observed in > 50% of patients long after follow-up. 
              • Myalgias and strain injuries are sometimes observed after irradiation to the muscles. These patients often benefit from physiotherapy in the form of heat, massage, and exercises.  

              PROSEDYRER

              Fatigue before, during, and after Cancer Treatment

              General

              There are many reasons why cancer patients feel fatigued. In many patients, the causes are synergistic. Cancer patients are often very sick during treatment periods and may experience extreme fatigue during intensive chemotherapy. It is also very important to be aware that fatigue is a symptom of many other medical conditions, both physical and psychological, which also affects cancer patients. Some known causes of fatigue associated with cancer and cancer treatment are: 

              • Cancer itself
              • An operation
              • Current or recently concluded chemotherapy
              • Current or recently finished radiation therapy
              • Severe anemia
              • Other symptoms such as pain and nausea 
              • Fever or infection
              • Too little fluid or food intake
              • Reduced lung function
              • Changes in sleep
              • Worries, anxiety, stress, or depression

              For some of these conditions, such as infections, there is medical treatment available. Fatigue that occurs after an operation or during chemotherapy and radiation therapy will, for most, gradually disappear when strength is regained. If a patient was feeling healthy after treatment and all of the sudden experiences fatigue, they should contact their doctor. If a patient feels fatigue and at the same time feels stressed, worried, or down, they may be reluctant to speak to their doctor or health personnel about it. It is still recommended to talk about these problems. Talking about it may be therapeutic, and provides room for discussing measures with a qualified person with experience with patients that have the same problems. For cured patients experiencing chronic fatigue, it may be difficult to pinpoint a specific cause. Many of these patients experience improvement by changing their lifestyle to a lower tempo than before the diagnosis.

              Definition

              Everyone knows what it feels like to be tired, fatigued, or lethargic when sick. This feeling is the most common side effect of cancer and cancer treatment. A symptom is a condition or state that something is not right in the body. Other frequent symptoms associated with cancer and cancer treatment are reduced appetite and nausea. Most patients who experience fatigue associated with cancer say that the feeling does not improve with rest, and many describe a lack of energy or exhaustion.  

              If fatigue arises during chemotherapy or radiation therapy, most patients experience that it will gradually go away when treatment is over and their strength is regained. This type of fatigue is considered acute. Improvement may take time depending on the intensity of treatment. Some patients experience that fatigue lasts for months, or even years. This is considered chronic fatigue. The ability to carry out daily activities, a lack of humor, health-related worries, a reduced capacity to carry out work functions, or less energy for family, can also accompany chronic fatigue. Most patients will find it difficult to be told by their doctor that they are considered healthy, while their friends and family expect them to be normal again, despite having a lack of energy and ability to perform activities they want to.  

              For many, feeling fatigued is often accompanied by having difficulty concentrating, poor memory, and an increased need for sleep. Most patients will need more sleep than before they became sick. For many, sleep is not restful, and it may take time to "get going" in the morning. Many also experience that they quickly become drained of strength if they exert themselves, and that it takes a long time before regaining strength after exertion. Exertion in this context can mean both physically and mentally such as working on a task that requires concentration.

              Preparation

              Fatigue can occur in all phases of cancer illness. Some patients feel it before the diagnosis, and almost all patients experience fatigue during radiation therapy or chemotherapy. A minority of patients experience long term fatigue after cancer treatment is over and the disease is cured. Patients who cannot be cured will almost always feel tired, worn-out, and exhausted. The degree of fatigue in these patients varies depending on the cancer type, spreading, and other symptoms of the disease.

              The patient should be given necessary information on both causes of fatigue and measures he/she can take.

              Implementation

              General measures that can reduce feeling tired and fatigued

              Following suggestions are meant as general advice that may not necessarily apply to everyone in all situations. This advice is based on results from studies, experiences from cancer patients, and recommendations from experts. Each patient should assess what works for them. It is recommended to express concerns and seek advice for what measures you can take and what you should avoid.

              General advice
              • Try to live as "normal" as possible.
              • Try to plan your day to include time to rest.
              • Take many small breaks during the day instead of a few long ones.
              • Rest after strenuous activity.
              • Plan your daily activities and do those that are most important for you.
              • Set realistic goals for yourself and try to be happy with those you accomplish.
              • Try to recognize activities that make you especially tired/fatigued and limit them, or spread them out over longer intervals. 
              • Try to accept that you do not have the energy to do the things you could previously.
              • Assess what is important for you to do yourself and what you can allow others to do.
              • Assume you will be tired after something strenuous even if you experience the activity as positive.

              Physical activity and exercise

              Exercise and physical activity that is appropriate for you will reduce the feeling of fatigue. Regular exercise is the most effective measure against chronic fatigue in cancer patients. Nevertheless, both too much and too little exercise can worsen fatigue, therefore, it is important to find a level (frequency and intensity) that suits you. You should never exercise so intensely that you must stop a session or exercise period because you are exhausted. Remember that daily form varies for everyone and adjust your exercise routine accordingly. Make long-term goals (months) and gradually increase activity, and carefully for a period. 

              • Activities such as walking, biking, swimming, dance, and aerobics are recommended.
              • Light exercise periods at regular intervals are better than intense, sporadic periods.
              • Always start with a slow tempo and increase gradually before finishing with a slow tempo again.
              • Always sit down and rest after exercise but try not to lay down and sleep.
              • Physical therapists and sport pedagogs can provide advice on exercises that are right for you. The principles are the same for all exercise, but it should be adjusted for your energy level.  

              Sleep

              Many cancer patients with chronic fatigue have sleep pattern disturbances. It is important to maintain a normal rhythm even if you feel like sleeping during the day.

              • Try to wake up at the same time every day and keep a regular bedtime.
              • Avoid too much activity right before bedtime.
              • Try not to sleep during the day because this will disturb your biological rhythm.
              • But, a short afternoon nap may be energizing!
              • Rest during the day by relaxing in a good chair, but try not to fall asleep.
              • Speak to your doctor about lasting sleep disturbances.

              Nutrition

              Having a reduced appetite or intake of food can also result in a lack of strength and energy. We recommend eating healthy food regularly, and to follow the national guidelines on nutrition. Special diets or supplements do not improve fatigue unless there is a deficiency.

              Work situation

              Some patients do not have the strength to continue working, or they must reduce their hours because of chronic fatigue. Consulting with a social worker may be beneficial for guidance regarding your work situation, your welfare rights, and financial situation. 

              Some adjustments that you and your employer can make:

              • Discuss the possibility for more simple or easier tasks, especially if you have a physically demanding profession.
              • Assess the possibility of reducing your hours.
              • Remember to take regular breaks also at work, if possible.
              • Assess the possibility of flexi-time to work during the hours you have energy, as well as the possibility of working from home.

              Care for children

              Caring for children or adolescents may be very difficult when you are fatigued or lack energy and strength. There are, however, some measures you can take:

              • Explain to your children that you are tired and are not able to do as much as you used to.
              • Discuss what the children can help you with and allow them to take part in household chores.
              • Try to establish permanent household chores for all family members.
              • Try to do activities that suit you that do not require too much energy, and can be performed without too much exertion. 
              • Ask and accept help from others for driving to and from activities, school, etc. if this relieves you.

              Drug therapy

              In Norway, there is currently no specific drug therapy for chronic fatigue associated with cancer. If the fatigue is due to specific conditions, this is of course treated with medication, if possible. Sometimes, such treatments improve the fatigue, but other times they do not. Examples of treatment that often reduce fatigue are treatment for infections and depression. 

              Treatment with medications that stimulate production of red blood cells is not recommended for cancer patients due the the danger of serious side effects.

              Follow-up

              Information about fatigue

              Healthcare workers in cancer care will often have knowledge about fatigue and cancer. Most general care physicians have general experience with fatigue but meet relatively few cancer patients. There is a lot of information available on the internet of varying quality. Below is a list of web adresses and some literature. Be aware that you may find opposing advice because knowledge on treatment especially, is limited.

              Some articles/books:

              • Armes J., m.fl. (2004). Fatigue in cancer. Oxford University Press.
              • Berger A.M., m.fl. (2009). NCCN Clinical Practice Guidelines in Oncology. Cancer-Related Fatigue. www.nccn.org
              • Patarca-Montero R. (2004). Handbook of cancer-related fatigue. Haworth Medical Press

              Lymphedema

              General

              According to etiology, there are two general classifications of lymphedema primary and secondary lymphedema. Primary lymphedema is caused by deficient or faulty development of the lymph system. Secondary lymphedema occur as a complication from trauma or diseases which damage the lymphatic vessels or lymph nodes. The primary cause of lymphedema in the western world, is impaired or disrupted flow of lymph fluid caused by cancer or cancer treatment (secondary lymphedema).

              Lymphedema occurs when the transport capacity of the lymph system is reduced significantly.
              The swelling is caused by an accumulation of fluid (rich in protein) in the tissue, due to reduced drainage of lymph fluid (1,2). The swelling is often chronic. A lymphedema can lead to pain/discomfort and changes in the soft tissues in the affected area (fibrosis) (3,4). Lymphedema occurs most often during the first 2-3 years after cancer treatment (5 6). Without treatment, lymphedema can lead to progressive swelling.

              In some cancer treatment the lymph nodes and fatty tissue are removed, most often in the axilla, pelvis and the groin. This treatment causes damage to the lymphatic wessels and reduces the number of lymph nodes. The subsequent reduced capacity for drainage of lymph fluid in the arm and leg may result in lymphedema.

              Radiation therapy may cause tissue scarring and fibrosis. The combination of surgery and radiation therapy to the axilla additionally increases the risk of developing lymphedema.

              Cancer related lymphedema can also occur due to metastasis in areas where blocking the central lymph vessels in advanced disease.

              Factors which may increase the risk for developing lymphedema are:

              • obesity
              • infection in the area where lymphedema occurs
              • overheating/sunburn
              • trauma of the arm/leg on the operated side

              Indications for treatment

              Lymphedema in the arm/hand, breast, leg, groin, face and neck after treatment of:

              • breast cancer where axillary dissection is performed
              • gynecologic cancer where the lymph nodes in the pelvis or the groin are removed
              • melanoma where the lymph nodes in the axilla or the groin are removed
              • lymphoma and cancer of the head and neck region where lymph nodes in the neck region are removed
              • prostate cancer where the lymph nodes in the pelvis or the groin are removed
              • sarcoma where lymph nodes are removed

              Without treatment the lymphedema can increase in size. This may cause skin changes (fibrosis), increased swelling and therefore more discomfort in the area (3).

              Contraindications

              Absolute
              • acute infections, local or general (erysipelas)
              • arterial insufficiency with risk of necrosis
              • thrombosis and embolism
              Relative

              Untreated cancer disease, heart failure, or kidney failure

              Goal

              • reduce lymphedema
              • relieve tormenting side effects
              • improve function 
              • prevent complications such as skin changes and inflammation in the area (erysipelas)

              References

              1. Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol 2008;52:799-806.
              2. Lawenda BD, Mondry TE, Johnstone PAS. Lymphedema: (Review) A primer on the identification and management of a chronic condition in oncologic treatment. CA Cancer J Clin 2009;59:8-24.
              3. Mortimer PC. The patophysiology of lymphedema. Cancer 1998;83(12 Suppl American): 2798-802.
              4. Erickson VS, Pearson ML, Ganz PA, Adams J, Kahn KL. Review: Arm edema in breast cancer patients. J Natl Cancer Inst 2001;93:96-111.
              5. Nesvold IL, Dahl AA, Løkkevik E, Mengshoel AM, Fosså SD. Arm and shoulder morbidity in breast cancer patients after breast-conserving therapy versus mastectomy. Acta Oncol 2008;47:835-842.
              6. Norman SA, Russel Locario A, Potashnik SL, et al (2009) Lymphedema in breast cancer survivors: incidence, degree, time course, treatment, and symptoms. J Clin Oncol 2009;27:390-397.
              7. Johansen J, Overgaard J, Blichert Toft M, Overgaard M. Treatment morbidity associated with the management of the axilla in breast-conserving therapy. Acta Oncol 2000;39:349-54

              Definitions

              Complete psysical therapy treatment of lymphedema

              Consists of manual lymph drainage, compression therapy, skin care and instruction in exercises and self-treatment (1). The treatment is performed by physical therapists with special expertise.
              The treatment may be extensive at the start. In cases of severe swelling one usually start with manual lymph drainage followed by bandaging of the arm/leg (1).

              Manual Lymph Drainage

              This is a kind of massage which requires guided training to perform optimally. The goal is to encourage the drainage of lymph fluid and thereby reduce the swelling of the tissue (2). It is quite different from other kinds of massage applied within physiotherapy. The anatomical conditions of the lymph system is the basis for manual lymph drainage. These are: the course of the large lymph veins, the borders of different lymphatic functional regions (watershed), natural anastomoses crossing these lines, and the lack of valves in the lymphatic vessels .

              Bandaging

              Bandaging is used mostly at the start of a treatment to reduce swelling. When the swelling is reduced a compression stocking is adjusted.

              Compression stocking

              Clinical experience and research show that compression is the most important treatment. (3;4) Accordingly it is of great importance to adjust a compression stocking for the arm or leg. If there is swelling of the hand, a compression glove might help.
              A compression stocking is used to increase tissue tension. The pressure from the stocking increases absorption of tissue fluid. The stocking provides a graded pressure highest distally and lowest proximally. To adjust the stocking, the circumference of the arm or leg is measured at several defined points. There are several compression classes, but the most commonly used are class 1 and 2. The stocking should provide a constant pressure without causing discomfort. It may take some time to get used to the compression stocking. Some choose to use the stocking occasionally, while others wear it daily.
              A facemask at night is recommended to treat lymphedema in the neck and face region (5). Patiens with lymphedema in the groin can be helped by using a bike pant or a panty. Bandaging, tubigrip or bike pants may benefit if there is swelling of the penis and scrotum .

              Intermittent pressure massage with pulsation

              Treatment is carried out with an electronically powered apparatus which blows air in a double-walled cuff. The cuff, covering the whole arm or leg, has multiple channels and creates a peristaltic pressure wave in proximal direction. The treatment encourages the lymph drainage and thereby reduces the swelling (4).

              References

              1. The diagnosis and treatment of peripheral lymphedema. Consensus document of the International Society of Lymphology Executive Committee. Lymphology 2003;36:84-91.
              2. McNeely ML, Peddle CJ, Yurick JL, Dayes IS, Mackey JR. Conservative and dietary interventions for cancer-related lymphedema: A systematic review and meta-analysis. Cancer 2010.
              3. Badger C, Preston N, Seers K, Mortimer P. Physical therapies for reducing and controlling lymphedema of the limbs. Cochrane Database Syst Rev 2004;CD003141.
              4. Johansson K, Albertsson M, Ingvar C, Ekdahl C. Effects of compression bandaging with or without manual lymph draining treatment in patients with postoperative arm lymphedema. Lymphology 1999;32:103-110.
              5. Deng J, Ridner SH, Murphy BA. Lymphedema in patients with head and neck cancer. 2011;38:1-10.

                                                                                        

              Preparation

              Main points of information

              Information should be given to patients who have received surgery only or combined with radiotherapy with increased risk of getting lymphedema. The patient usually gets information about lymphedema after the surgery. Sufficient information and guidance is important and crucial for both avoiding getting lymphedema and being able to identify lymphedema at the very beginning.

              • The function and purpose of the lymphatic system
              • Causes of lymphedema
              • Symptoms of lymphedema
              • Different treatment options
              • Precaution
              • Complications/side effects caused by the disease and treatment
              • The importance of maintaining mobility in the arm or leg

              Symptoms of lymphedema

              • A feeling of uncomfortable change
              • A feeling of heaviness
              • Bursting pain
              • Changes of consistency (visible or palpable) in the soft tissues
              • Suspicion of increased circumference
              • Swelling may disappear overnight, but usually returns during daytime
              • Some have swelling sporadically

              The dominating symptom is lasting swelling in the involved area. Other symptoms will to a large extent depend on the amount, duration, and localization of the edema.

              Moderate swelling after cancer surgery, can be a reaction which often spontaneously disappears.

              Diagnostics

              Lymphedema is usually measured using a clinical method. There are multiple methods to measure the extent of lymphedema. The gold standard is the water displacement method, which measures and compares the volumes of both arms/legs. But a method of comparing volume by using several circumferential measurements of the arms/legs is often used in research and sometimes in the clinical setting. The most widely used method is measurement of circumference at multiple anatomic points on the arm/leg with comparison with the contralateral arm/leg. A difference in circumference of ≥2cm is often defined as lymphedema. Stemmer sign is also used.

              Implementation

              With development of lymphedema, it is important to take precautionary measures as soon as possible. Treatment with compression is the component which seems to be most effective in reducing the swelling. Manual lymph drainage is often used in combination with bandaging in the first 1-2 weeks of the treatment. This complete decongestive therapy is a composite treatment including multiple techniques which are performed by a specially trained physical therapist.

              The intensive phase

              • Compression treatment – possibly with bandaging and thereafter adjustment of an elastic stocking
              • Manual lymph drainage
              • Circulation and drainage inducing exercises
              • Skin care

              During the intensive phase, the patient is usually treated 5 days a week with continuously bandaging until the desired volume reduction is achieved. This usually takes one to two weeks.

              Bandaging

              After stimulating the lymphatic flow by manual lymph drainage, a compression stocking is used or the whole arm is bandaged for one to two weeks. The bandages should be worn as long as they are not too uncomfortable. Correct bandaging with short, elastic bandages provide the tissue with high pressure under activity and low pressure while resting.

              • An ointment with a low pH (5.5) should be applied to the skin.
              • A light tube gauze should be worn.
              • The padding is then applied.
              • The bandaging starts distally to the lymphedema.
              • The bandages are laid evenly, circularly, and in multiple layers.
              • The pressure should decrease gradually from distal to proximal.
              • The pressure is regulated partially with the bandaging technique and mainly by the number of layers of bandages.

              Compression stocking

              • The stocking may be removed at night.
              • At night an ointment is preferably applied to the skin.
              • With incipient  lymph edema, wear the stocking during activity.
              • In moderate and extensive lymph edema, the stocking is usually worn all day.
              • The stocking should be washed at least every third day.

              A poorly customized stocking may create faulty compression. The most frequent error is that the compression stocking is used after it has lost its elasticity (worn out) and therefore has less effect.

              Manual Lymph Drainage

              The massage strokes should be performed in the direction of the lymphatic drainage with light pressure and with slow motions. The treatment should not be painful.

              Manual lymph drainage has four main movements: standing circles, pumping grip, turning grip, and corkscrew grip.

              Pressure massage with pulsator

              Pulsation is never a first choice for treatment of lymphedema, but could be a measure over time when monitoring has shown that the treatment is effective. At the start, the patient should be informed about possibly complications. Sometimes, an increase in edema is seen proximal to the cuff. Further pulsation treatment should then be postponed until manual lymph drainage and exercises have improved the condition. If the pressure is too high, the lymphatic vessels may be damaged and the amount of interstitial fluid may increase.
              The pressure should be moderate and the patient should experience the treatment as comfortable. It is not the amount of pressure that is important, but uniform rhythmic pressure wave. Tuning of rate and pressure are adjusted for each patient.
              Usually, the treatment should last for twenty minutes at the start increasing gradually to thirty to forty minutes. Can be used daily or when needed. Pulsation treatment may also be performed by the patient at home.

              Skin Care

              Regardless of whether the patient has lymphedema or not, it is important to hinder the occurrence of scratches, sores, and unnecessary skin irritation. Use of gloves is appropriate in some situations. The patient should also be cautious of overheating and sunburn. The main goal of skin care is to prevent infections, because this can trigger an eruption of lymph edema.

              Regular use of bandages and compression stockings dries out the skin. Use of skin care products and cleansers with a low pH (5.5) are recommended. Good skin care keeps the skin soft and supple and maintains the skins natural ability to fight infection.

              Disinfecting ointment and adhesive tape should be used in the event of an ulcer or scratch or if there is danger of infection.

              Maintenance phase

              • Use of elastic stocking and/or glove as needed
              • Skin care
              • Regular exercises to facilitate the muscle-joint pump
              • Possible intermittent pressure massage with pulsator

              The patient obtains some treatment during the maintenance phase and may have treatment by a physical therapist if necessary. In the short term, the treatment is almost always satisfactory. In the long run, the result depends on the patient practicing the measures recommended. The pulsator may usually be borrowed from a health care center.

              Exercises to improve mobility and lymph flow of the shoulder/arm

              Dynamic exercises with a relaxation phase are optimal. "Throwing" movements may feel uncomfortable. Many experience that it is better to walk with poles, but it is important to maintain a loose grip of the pole.

              Correctly adjusted movement exercises:

              • induce circulation without straining the reduced lymphatic system
              • provide adequate joint movements
              • stimulate dynamic change between tension and relaxation, preferably in conjunction with respiration

              Movement therapy in a heated pool may be favorable for some lymphedema patients. Water pressure stimulates lymphatic drainage and simultaneously activates circulation and movement.

               

              Follow-Up

              If necessary, the patient may obtain a referral for physical therapy in their home area for further follow-up. Follow-up and guidance by a physical therapist with the necessary skills is important. Some with serious lymphedema will need frequent treatment for the rest of their life. But others will be able to manage the treatment themselves by adhering to the guidelines that they have learned. Compression with stockings and skincare are often sufficient treatment. So many patients do not need physical therapy as treatment, but rather information and functional guidance.

              Moderate physical activity improves joint movement, circulation, and well-being, as well as stimulation of lymph drainage. Blood pressure should not be measured and vaccinations should not be given in the treated arm. Gloves are recommended for gardening.

              Complications

              Fibrosis of the dermis and epidermis with affects some persons with lymphedema. The skin loses its elasticity and is more easily traumatized than normal skin.

              The immune system is weakened in the edematous area. This may be for multiple reasons, among others, weakened transport of dendritic cells, lymphocytes, and proteins. If the area’s regional lymph nodes are removed, this will also weaken the local immune system.

              In some edema patients, especially secondary lymphedema, a distinctive reaction (erysipelas) may occur in the skin of the affected area. This will usually start acutely with a strong feeling of malaise with high fever, hyperemia with flushing, and increased swelling of the skin. The area of skin involvement is often limited. The symptoms are usually improved after four to six days but it is not uncommon for the edema to deteriorate. The condition should be treated with antibiotics (penicilin) as quickly as possible.

              Lymph edema in the armLymph edema in the arm.Lymph edema in the legLymph edema in the leg
              Lymph edema in the arm.Lymph edema in the arm.