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Utskriftsdato (26.7.2017)

Multiple myeloma

Multiple myeloma is the malignant growth of plasma cells. Plasma cells are B lymphocytes specialized for production of immunoglobulines. It is assumed that the malignant transformation occurs in a cell that has been through maturation in germinal centers of the spleen or a lymph node.

A characteristic of multiple myeloma is the increase of monoclonal plasma cells in the bone marrow, which produce monoclonal gammaglobulin (paraprotein), or sometimes only light or heavy monoclonal chains. 

Plasma cells produce immunoglobulins, each clone their own immunoglobulin. A plasma cell clone which grows uncontrollably can produce large amounts of immunoglobulin. This can be diagnosed using electrophoresis of serum or urine as a peak in the gamma region and is described as the M-component (monoclonal component). The M-component is a relative and indirect indicator of the activity/size of the clone and is important for the diagnosis and evaluation of treatment response.

When myeloma cells proliferate in the bone marrow, they may suppress the production of normal blood cells and lead to low hemoglobin (anemia), reduced immune defense (enhanced susceptibility to infections), or low number of thrombocytes (increased risk of bleeding). They may also affect the balance between bone breakdown and bone build-up and give rise to areas of low bone density (osteolytic lesions) which may lead to fractures. The immunoglobulin produced by the myeloma cells can have various properties. Some of these proteins can give rise to deposits in tissues and lead to organ damage, for instance, influence the renal function.

The disease is progressive and is sometimes diagnosed before symptoms develop. Curative treatment for myelomatous disease is rarely possible, but for the last 10-15 years, several new drugs have been developed, which have currently nearly doubled the survival rate.

Cytokine production in the disease process mutually influences the various bone marrow cells: between malignant plasma cells, stroma cells, osteoblasts, and osteoclasts. This causes expansion of the malignant clone, osteolysis of cortical bone, possibly with subsequent pathological fractures that may cause significant pain.

Simultaneously, the production of normal hematopoetic tissue is suppressed which eventually leads to bone marrow failure with pancytopenia.

Incidence 

Myeloma is more common in men than women and represents 1.8% of all new cancer cases in the United States. Approximately 0.8% of men and women will be diagnosed with myeloma at some point during their lifetime. Myeloma is most frequently diagnosed among people aged 65-74. In 2017, it is estimated to be 30,280 new cases of myeloma in the United States (1).

 

 

Age-specific incidence of multiple myeloma, 2010–2014.

Source: National Cancer Institute. Bethesda, MD, USA

 

 

Incidence of cancer of multiple myeloma, 1975–2014.

Source: National Cancer Institute. Bethesda, MD, USA

Etiology of multiple myeloma

There are no known causes of multiple myeloma.

How a plasma cell is transformed into a myeloma cell is not completely understood, but there are many genetic changes present in a myeloma cell. The genetic changes are either chromosomal (translocations and deletions) or mutations in single genes.Most translocations have breakpoints in the gene region of the heavy chain of the immunoglobulin molecule, which indicates that the changes occur when the B lymphocyte is changing the phenotype from IgM to one of the other immunoglobulin types.The mutations are often in genes that encode proteins important for cell growth, cell differentiation and cell death. These mutations do not occur in the germ cells (sperm cells and ova) and myeloma is therefore not inheritable in the usual meaning of the word. However, there are indications of some overrepresentation of myeloma and related diseases in the closest family. This disposition cannot be tested for. It is possible that all factors giving rise to mutations (for example ionizing radiation) may contribute to the development of myeloma. Several mutations are probably a prerequisite for the development of a plasma cell into a myeloma cell.

Risk Factors

The risk for MGUS (monoclonal gammopathy of undetermined sigificance) progrediating to active multiple myeloma is about 1% annually.

The only known risk factor for developing multiple myeloma is the serum M-protein level. The risk percentage in a period of 10 years approaches the same M-protein level measured in g/l (for example 20 g/l poses a risk equivalent to 20%).

Histology of multiple myeloma

Photomicrograph of bone marrow from patient with multiple myeloma.
Click to enlarge image.

 

Plasma cells from patients with myeloma are usually immature in appearance with centrally located nuclei, distinct nucleoli, and perinuclear vacuolization. There are also often multinucleated plasma cells.

Immunohistochemical analysis can verify monoclonality.

The plasma cells produce monoclonal IgG or IgA that can be detected through a characteristic serum protein electrophoresis pattern. Eighty percent of the patients have a complete monoclonal Ig in the serum and most of them simultaneously produce light chains something that may cause so-called Bence-Jones proteinuria.

Types

Asymptomatic multiple myeloma

In asymptomatic multiple myeloma, the M-component is >30 g/l and/or plasma cells in bone marrow aspirate >10% without organ involvment related to myelomatosis or the presence of any specific biomarkers.

(Symptomatic) Multiple myeloma

In multiple myeloma, there is M-component in serum or urine (without volume requirement), >10% monoclonal plasma cells in bone marrow aspirate or biopsy. In addition, there must be presence of organ injury related to multiple myeloma or any other selected criteria indicating the high risk of symptom development within a short period of time.

Solitary medullary plasmacytoma

In solitary plasmacytoma, there is solitary bone destruction, with or without tumor, consisting of monoclonal plasma cells without other sign of multiple myeloma.

Plasma cell leukemia

Multiple myeloma where >20% of leukocytes in peripheral blood represent plasma cells or >2 x 109/L  of the bloodcells are plasma cells.

Non-secretory  myelomatosis

In about 1% of the multiple myeloma patients, there is no detectable monoclonal Ig. this is called (real) non-secretory myelomatosis. Immunofluorescence or immunohistochemical analysis of the bone marrow will then almost always demonstrate intracellular monoclonal Ig.

Light chain disease

In 20% of multiple myeloma patients, only light chain is produced. These light chains can most often be measured in serum (FLC) and in urine (urinary electrophoresis).This type of myelomatosis is named “light chain disease”.

These light chains are toxic to the kidneys, therefore, many patients with this disease are referred to the hospital because of renal insufficiency. Patients referred to the hospital with renal insufficiency of unknown cause should be evaluated to exclude myelomatosis with measurements of light chains as described above (FLC and U-elfo).

AL - amyloidosis

There is a type of amyloidosis associated with monoclonal plasma cell proliferative disease, AL-amyloidosis. The amyloid forming protein in this amyloid fibrils is larger or smaller N-terminal fragments of monoclonal light chain IG. These proteins are deposited in the tissue and affect organs. In this disease, there is often found a monoclonal component, either by serum protein electrophoresis, urine protein electrophoresis or by free light chains. Clone plasma cells are found in the bone marrow, although the amount may be low. The same plasma cell clone may also cause myelomatosis, and the patients may therefore have both of these conditions at the same time as part of the same disease. This patient group has a somewhat better prognosis than myelomatosis, but the spread is greater. Patients with affection of the heart have a worse prognosis.

Staging of multiple myeloma

International Staging
Stage                                     Criteria Median Survival
I s-ß2m (ß2-microglobulin) <3,5 mg/l and serum albumin > 35 g/l 62 months
II neither I or III 45 months
III s-ß2m > 5,5 mg/l 29 months

Metastatic patterns for multiple myeloma

Thoracic X-ray of tumor with soft tissue component. Click to enlarge image.

Most commonly, myeloma cells spread in the bone marrow of the bones creating multiple small tumors. Hence, the disease is called "multiple myeloma" in English literature.  

In some cases, one localized tumor forms in a single bone, known as a plasmocytoma.  

In rare cases, the disease is also found outside the bone marrow in soft tissue or other organs. In advanced multiple myeloma, the disease can spread to the blood system known as "leukemization" and is then called plasma cell leukemia. The disease may also debut as plasma cell leukemia.

Symptoms of multiple myeloma

The symptoms are caused by the localization of myeloma cells in bone marrow and the effect of the M-component (paraprotein).

  • Symptoms of bone disease are, for example, lasting inexplicable back pain
  • Reduced kidney function
  • Anemia, more rarely leukopenia and thrombocytopenia
  • Hypercalcemia due to osteolysis
  • Repeated or lasting bacterial infections due to reduced immune system
  • Hyperviscosity
  • Symptoms which indicate compression of the spinal cord/nerveroots 
  • Sign of amyloidosis, for example large tongue, carpal tunnel syndrome, kidney and/or heart failure
  • Prolonged elevated blood sedimentation rate as a coincidental finding.
MRI of patient with myeloma in spine. Click to enlarge image. MRI of patient with destruction and collapse of vertebra. Click to enlarge image. X-ray of patient with pathological fracture in humerus. Click to enlarge image.

 

Differential diagnoses of multiple myeloma

Differential diagnostics are intended to differentiate multiple myeloma from other malignant diseases with bone marrow involvement, chronic inflammation conditions, and lymphoproliferative diseases.

MGUS

A M-component with < 30 g/l and < 10 % plasma cells in bone marrow biopsy which is not accompanied by symptoms, biomarkers or sign of multiple myloma or other B-lymphoproliferative disease is called MGUS (monoclonal gammopathy of undetermined significance).

The differentiation between MGUS and asymptomatic multiple myloma is based on the size of the M-component and amount of plasma cells in the bone marrow. However, there is no indication for treatment until (symptomatic) multiple myeloma is present.

MGUS is never accompanied by osteolytic lesions or anemia. A low concentration of M-component in an elderly person without symptoms should not be of concern if the patient does not have clinical symptoms. MGUS is relatively common (up to 2% in people over 50 and 3% in people over 70). Thus, most persons having M-protein in their serum have MGUS and not cancer of the bone marrow.

Other conditions where the M-protein may be present are:

  • AL-amyloidosis
  • Solitary plasmacytoma
  • B-cell non-Hodgkin lymphoma (including Waldenstrom macroglobulinemia)
  • Chronic lymphatic leukemia
  • Autoimmune disease such as SLE

Prognosis of multiple myeloma

The prognosis depends on whether the malignant melanoma is localized, regional, or metastatic at the time of diagnosis. For multiple myeloma, 5.0% are diagnosed at the local stage and the 5-year survival for localized multiple myeloma is 71%. The overall 5-year survival rate for patients with multiple myeloma during the period 2007-2013 was 49.6%.

The number of deaths is highest among people aged 75-84. Death rates have been falling on average 0.7% each year over 2005-2014.

In 2014, there were an estimated 118,539 people living with myeloma in the United States and in 2017 there are an estimated 12,590 people will die of this disease (1).

In most cases, multiple myeloma is still an incurable disease. The prognosis is very heterogenous. The median survival time was 3-5 years before the appearance of newer drugs (bortezomib, thalidomide, lenalidomide). There are many indications that patients now survive significantly longer from the time of diagnosis.

Factors associated with poor prognosis are:

  • High serum level of ß2 microglobulin and C-reactive protein as well as low albumin values at the time of diagnosis
  • Atypical plasma cell morphology and high proliferative activity
  • Deletions/monosomy in chromosome 13 and 17, non-hypoploidy, and specially balanced translocations such as t(4;14), t(14;16)

 

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References on multiple myeloma

  1. 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
  2. The Norwegian Hematology Group. Guidelines on the diagnosis and management of multiple myeloma 2005 [Online]. 2005 [retrieved 2007 September 3], available from: http://www.nordic-myeloma.org/pdf/uk_nmsg_guidelines_2005.pdf

Diagnostics of multiple myeloma

The following conditions should be investigated with regard to multiple myeloma:

  • Bone pain, anemia, and high SR
  • Recent kidney failure or hypercalcemia

Examinations performed when multiple myeloma is a possible diagnosis:

  • Blood tests: Hb, white blood cell differential count,thrombocytes, albumin, magnesium, ionized calcium, creatinine, urea, ß-2 microglobulin, proBNP, troponin T, ALP, INR, IgG, IgA, IgM, free light chains (kappa/lambda ratio).
  • Serum protein electrophoresis (Urine electrophoresis is only necessary if there is no detection of pathological FLC ratio or monoclonal component  by serum protein electrophoresis)
  • Bone marrow examinations: Aspirate smear and FISH. Biopsy.
  • Low-dose CT scan of skeleton. This means low-dose CT from knees to at least vertex.

Multiple myeloma is usually confirmed by the presence of monoclonal protein (M protein/paraprotein) in serum or urine and/or findings on X-ray, as well as increased number of plasma cells in the bone marrow.

Excluding other conditions with monoclonal immunoglobulin in serum, with or without increased number of plasma cells in bone marrow and primary amyloidosis, is sometimes difficult. The condition often requires observation and repeated examinations for a final diagnosis. It is also important to remember that most organ manifestations may have other causes and association with the plasma cell clone must be probable.

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

Treatment of multiple myeloma

Multiple myeloma is mainly treated with drugs.

Treatment of asymptomatic multiple myeloma has not been documented to extend survival. The treatment indication is primarily when the patient has clinical symptoms such as bone metastasis or sign of organ involvement such as anemia, increased tendency for infection, bone marrow failure, kidney failure, and hypercalcemia, or the presence of biomarkers as pathological light chain ratio (> 100),  very large number of plasma cells (>60%) or more than one lesion at MRI scan.

The goal of the treatment is:

  • improve quality of life
  • prolong survival 

High-dose chemotherapy with autologous stem cell support (HDT with SCS) can prolong survival in younger patients. In some cases, an allogeneic stem cell transplantation may be appropriate.

Allogeneic stem cell transplantation has curative potential and can provide a very long remission in those with a suitable donor. However, the risk of fatal or troublesome side effects is so substantial that the treatment is rarely used. Allogeneic stem cell transplant with reduced pre-treatment is under evaluation in multiple studies and is so far not established in the primary treatment.   

Patients who cannot be offered high-dose treatment are given chemotherapy to improve quality of life and prolong survival

Surgery

Surgery is seldom indicated for multiple myeloma.

Vertebroplasty, a procedure for injecting bone cement into painful, fractured vertebrael bodies,is applicable in selected patients.

Drug therapy

Treatment > 65- 70 years

Melphalan-Prednisolone-Bortezomib MPV

Melphalan-Prednisolone (MP) with the addition of bortezomib (Velcade®) is documented as better treatment than Melphalan-Prednisolone ( MP- which previously was the standard treatment). Other drug combinations have not been tested against MPV. MPV is in Norway, and also in Europe, the most established and used first-line treatment for patients not relevant for high-dose therapy with stem cell transplantation.

Lenalidomide-dexamethasone (LenDex)

Lenalidomide-dexamethasone (LenDex) is approved as first-line treatment since 2015 after being better documented than MPT (MP-thalidomid) in a clinical multisenter study. There are only indirect data on which patients who should have MPV and which ones who should have LenDex. But especially patients with renal failure, high risk cytogenetics or other signs of aggressive disease will often be prioritized for MPV (however, caution in the usage of melphalan). Elderly patients that are more fragile may be relevant to LenDex. Both MP and MPT have previously been standard first-line treatment. Currently, there are no natural situations where these will be the first choice.

Treatment of patients <65 years

Standard treatment for patients <65-70 years of biological age with adequate general condition and good organ functions is HMAS (High-dose melphalan with autologous stem cell support). Treatment-related mortality is 1-2%. 

The availability of new medications such as thalidomide, bortezomib, and lenalidomide treatment give better response before HMAS and prolonged time to progression after HMAS. The induction treatment before HMAS is 4 cycles with combinations of chemotherapy and corticosteroids. Two regimes are in use  in Norway today. One is a combination of cyclophosphamide, bortezomib (Velcade®) and dexamethasone, called VCD. The other is a combination of bortezomib, thalidomide and dexamethasone, so-called VTD.

Conditioning with melphalan alone, without total-body radiation, is recommended. The dosage is usually 200 mg/m2, but the dosage should be reduced in elderly and patients with kidney failure.

HMAS may prolong survival in younger patients and in certain cases it may be appropriate to treat with allogeneic stem cell transplantation. Allogeneic stem cell transplantation has curative potential and can provide a very long remission in those with a suitable donor.  However, the risk of fatal or troublesome side effects is so substantial that the treatment is rarely used. Allogeneic stem cell transplant with reduced pre-treatment is under evaluation in multiple studies and is so far not established in the primary treatment. The treatment is  not applicable in the first-line treatment.

Patients who cannot be offered high-dose treatment are given chemotherapy to improve quality of life and prolong survival.

Treatment of solitary tumor

A small amount of patients have a solitary tumor of monoclonal plasma cells (localized disease/plasmacytoma) either in bone or extramedullary. Some of these patients can be cured with radiation and/or surgery. However, these patients must be monitored carefully for possible development of multiple myeloma.

Treatment for patients with relapse and/or refractory illness

In younger patients where HMAS may be performed, high-dose melphalan gives the best prognosis. Replacing medication in the induction therapy increases the chance of better response, but are not better documented in clinical trials. If possible, the treatment should be included in a treatment study.

Today there are many alternative drugs and drug combinations for use in relapse of myeloma. So-called «novel drugs» include anything but alkylating agents and corticosteroids.

The drugs can be divided into the following groups :

  • Alkylating agents: Melphalan, cyclophosphamide, bendamustine
  • IMiDs (Immunomodulatory Drugs): Thalidomide, Lenalidomide, Pomalidomide
  • Protease inhibitors (PIs): Bortezomib, Carfilzomib®, Ixazomib
  • Antibodies: Daratumumab, Elotuzumab
  • HDAC inhibitors: Panobinostat.
  • Corticosteroids: Dexamethasone (Prednisolone is not used in case of relapse).

A lot of considerations must be considered when choosing a combination for the treatment of relapse, and there are many different opinions about this. If good tolerance and good bone marrow function are expected, the patient will most probably benefit from triplet therapy.  That is, Dexamethasone® plus two drugs from different groups mentioned above. The best documented regimen is carfilzomib-lenalidomide-Dexamethasone. Carfilzomib is provisionally used on registration exemption.

In most cases, a novel drug should be included. it is reasonable  to change the drug group in case of relapse. That is, if the previous treatment was based on an imide, it is reasonable to base the next one on a protease inhibitor, and vice versa. HDAC inhibitors and antibodies are currently unavailable outside clinical trials.

Side effects that have occurred must be considered when choosing medication. Both bortezomib and thalidomide may cause neuropathy, and most (with the exception of thalidomide) may cause bone marrow suppression.

Other considerations may also be relevant in the assessment, such as the patient's wishes and practical implication.

PROSEDYRER

Lymfom HMAS

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

Radiation therapy is administered for incomplete spinal cord lesions, incomplete fractures in weight-bearing bones or as palliative treatment.

Complication treatment

Cancer treatment causes side effects to varying degrees.

It is usually necessary to provide supportive care in order for the patient to complete and gain the full effect of planned treatment.

Supportive care can also be provided to reduce side effects and improve the patient's quality of life during and after treatment.

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

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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.

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.

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.

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.

Bone Marrow Stimulation with G-CSF

General

Bone marrow stimulation with G-CSF (Neupogen®, Granocyte®) is only recommended for febrile neutropenia which does not respond to antibiotic treatment, severe neutropenia (granulocytes < 0.5 x 109 /L for more than 1 week), and in cases where it is necessary to administer curative treatment with sufficient dosage intensity.

Indications 

  • To maintain dosage intensity for curative treatment; when a reduction in dosage will significantly reduce the chance of cure.
  • As prophylaxis for treatments associated with a high risk for febrile neutropenia (> 40 %)
  • Febrile neutropenia that does not respond quickly to antibiotic treatment
  • Long-lasting neutropenia

Goal

  • Maintain treatment intensity

Preparation

The patient should be adequately informed about the treatment.

Implementation

  • The dosage of Neupogen® is 5 µg/kg daily. The treatment is initiated, at the earliest, 48 hours after the treatment is completed. The treatment continues for 10 days.
  • The dosage of Neulasta® is 6 mg subcutaneously administered 24 hours after chemotherapy is completed. The neutrophil cells are counted on day 15.
  • The subsequent course is started on day 21, if the neutrophil count is 0.5 or higher, and the patient has not had febrile neutropenia.
  • It is important not to postpone the treatment if the neutrophil count is 0.5 or higher. The neutrophil count will compulsory decline after ending Neupogen® stimulation. Low values at the start of treatment should not be alarming if the values during hospitalization have been high enough to avoid febrile neutropenia.
  • Stimulation late in the cycle should only be performed for long-lasting, severe neutropenia. At least 48 hours should pass after completed stimulation treatment before the next chemotherapy course  is started. In these cases, it is always important to check that the doses are correct and to recalculate GFR etc. Continuation of chemotherapy will either require a drastic dosage reduction or secondary prophylaxis with G-CSF.

 

Follow-up Care

It is of utmost importance that the patient is informed of the risk of infections associated with a low neutrophil count.

Patients at risk for developing  very low values, must be  informed to take their temperature if they feel unwell or  febrile. In case of  a temperature above 38 °C they should contact their doctor immediately.

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.

Follow-up care after treatment of multiple myeloma

Follow-up occurs usually at the hospital the patient belongs to. 

The goal of the follow-up is to identify new symptoms early and provide the patient with the best possible quality of life and as long lifespan as possible. The M-component is followed. A rising M-component is an sign of progression.

Follow-up care will focus on:

  • Anemia
  • Infections
  • Renal failure 
  • Hypercalcemia
  • Osteolytic lesions
  • Pain and fractures

Anemia

Some patients have anemia at the time of diagnosis. This does not always improve during treatment of the underlying disease. For anemia symptoms, transfusions or possibly erythropoietin injections are appropriate.

Infections

Patients generally have a reduced concentration of normal immunoglobulines which is often treated with corticosteroids and, in periods, may have severe neutropenia from chemotherapy. These patients are therefore more prone to infection and must be treated with antibiotics as soon as possible if symptoms and signs of infection develop.

Certain patients with recurring infections may benefit from substitution treatment with gammaglobulin. Indications for this type of treatment should be identified by a specialist. Some medications also increase the risk of viral infections such as herpes zoster.

Renal failure

Renal failure is observed in about 30% of patients, and in most patients, the kidneys are affected by the disease.

Serious renal failure requiring dialysis or other life-saving treatment occurs in 3–12%.

The pathogenesis for renal failure is multifactorial. One cause is the amount of light chain components of immunoglobulin leading to proximal tubular damage. Patients with Bence Jones myeloma (light chains only) are especially prone to this complication.

Other factors are dehydration, hypercalcemia, elevated uric acid, infections, and nephrotoxic medications.

More rare causes are amyloidosis, light chain precipitates, or plasma cell infiltration.

Prevention of renal failure

  • Renal function should be maintained by adequate fluid intake. 
  • The patient should obtain thorough information about the importance of monitoring renal function.
  • Patients should be careful in use of nephrotoxic medications including aminoglycosides, RAS-inhibitors and NSAIDs.

Hypercalcemia

Destruction of bone tissue associated with tumor growth can lead to elevated calcium levels in the blood.

Hypercalcemia, symptomatic or asymptomatic, occurs in up to 30% of multiple myeloma patients and usually when the disease is active (new or progressing). Quick diagnosis and treatment are very important. Symptoms which may indicate hypercalcemia are nausea/vomiting, constipation, thirst, polyuria, depression, and coma.

The threshold for further diagnostics must be low.

Recommendations for hypercalcemia
Grade Treatment
Mild hypercalcemia (calcium level 2.6–2.9 mmol/l) Oral rehydration
Moderate to severe hypercalcemia (³ 2.9 mmol/l) Intravenous rehydration, possibly furosemide

If the patient is not already receiving bisphosphonates, treatment should be initiated.

If the patient is taking bisphosphonates, starting a more potent medication or increasing the dosage may be appropriate.

Additional treatment may be necessary in patients with refractory disease.

Osteolytic lesions

All patients with myeloma benefit from and should have bisphosphonate treatment. This is given once a month and helps prevent development of new lesions. In Norway, this treatment is usually given for 2 years.

Osteonecrosis of the jaw is a feared side effect which can occur after long-term bisphosphonate treatment (most often > 2 years). To avoid this, it is important that patients are carefully examined by a dentist before starting this type of treatment. A dentist must approve start-up of the treatment.

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