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Utskriftsdato (12.12.2017)

Leukemia

Leukemia is characterized by an increase of abnormal leukocytes in bone marrow. The disease can develop when immature blood cells, which have the ability to regenerate and have a growth advantage compared to normal cells, generate a leukemic clone. Hereditary or acquired deficiency of immunological surveillance can contribute to establishing a leukemic clone. Some leukemic cells can grow without the growth factors which normal cells need to multiply, and many leukemia cells react more poorly to feed-back signals which normally inhibit growth and division of cells. A leukemic clone does not grow more explosively than normal cells, but has a greater tendency to continue replicating and lesser tendency to differentiate and be destroyed. A leukemic clone will gradually take over the bone marrow, and in most cases, spread to the blood.

Leukemia is separated into acute and chronic forms based on the degree of maturity of the characteristic cells.

Acute leukemia

Acute leukemia is divided into two main groups:

  • Acute myeloid leukemia (AML) – clonal expansion of immature myeloid cells (granulocytes, monocytes, erythrocytes, and/or megakaryocytes)
  • Acute lymphoblastic leukemia (ALL) – clonal expansion of immature lymphatic cells

Of adult patients diagnosed with acute leukemia, 80% have acute myeloid leukemia and 20% have acute lymphoblastic leukemia.

Chronic leukemia

Chronic leukemia is divided into two main groups:

  • Chronic myeloid leukemia (CML) – clonal expansion in one or more of the hematopoetic cell rows in bone marrow and also often in the spleen, with mature differentiation of the cells. The disease is progressive and without adequate treatment will often develop into acute leukemia after 4-6 years.  
  • Chronic lymphocytic leukemia (CLL) – clonal expansion of lymphocytes with mature phenotype. The disease is heterogenous with a variable disease course, from being an indolent illness without need for treatment or shortening of life to an agressive disease with a fatal ending after 2-4 years. A small group of patients have more rare subgroups, for example hairy cell leukemia or prolymphocyte leukemia.  

Incidence

Although leukemia is among the most common childhood cancers, it most often occurs in older adults. Leukemia is slightly more common in men than women and represents 3.6% of all new cancer cases in the United States. Approximately 1.5% of men and women will be diagnosed with leukemia at some point during their lifetime. Leukemia is most frequently diagnosed among people aged 65-74. In 2017, it is estimated to be 40,710 new cases of leukemia in the United States (5).

 

Age-specific incidence of leukemia, 2010–2014.

Source: National Cancer Institute. Bethesda, MD, USA

 

 

Incidence of cancer of leukemia, 1975–2014.

Source: National Cancer Institute. Bethesda, MD, USA

 

Etiology of leukemia

In almost all cases, the etiology is unknown.

Risk Factors 

Acute leukemia

Chronic exposure to certain chemicals (for example benzene) can increase the risk of developing leukemia and myelodysplastic syndrome (MDS). The same applies to long-term treatment with alkylating substances and ionizing radiation. However, very few patients have been exposed to these exogenous factors. 

There are indications that mutations in cellular oncogenes, tumor suppressor genes, and transcription factors may be carcinogenic.  

Chronic leukemia

Chronic myeloid leukemia is characterized by the presence of the fusion protein bcr-abl. This occurs by the oncogene abl on chromosome 9 moving to the gene area bcr on chromosome 22 t(9;22). This is how the Philadelphia chromosome is created which has a shortened long arm on chromosome 22. See animation:

For chronic lymphatic leukemia, sex (men:women is 2:1) and genetic factors appear to predispose for the disease. 

First degree relatives of patients with chronic lymphatic leukemia have a more than 3 times greater chance to develop chronic lymphatic leukemia or other lymphoid malignancy compared to the rest of the population. For chronic lymphatic leukemia, familial disposition is the only well-documented risk factor. It is not unlikely that the disease presents itself earlier and in a more serious form in successive generations.

The disease is very rare in East Asians and the incidence is as low among East Asians living in western countries. 

Certain retroviruses can trigger the disease in animals which may indicate that certain viral infections may influence leukemia in humans. Some rare cases of T-cell leukemia are associated with infection of a human retrovirus (HTLV I).

Staging of leukemia

Acute leukemia

Two classification systems are used: WHO and FAB. The FAB classification is still the most utilized system. 

Both systems are based on morphological examinations of blood and bone marrow smears.

Photomicrograph of MCG-stained bone marrow from patient with acute myloid leukemia, M3. Click to enlarge the image.

Whichever superior diagnostic technique is applied, there are patients who require a combination of cytochemical, immunological, cytogenetic, and special molecular genetic examinations to achieve the correct diagnosis and prognosis. Such examinations are therefore part of the WHO classification. This classification will eventually replace the FAB classification.

The criteria for making the diagnosis of acute myeloid leukemia is reduced from 30% blasts in the FAB classification to 20% in the WHO classification.

Division of AML according to FAB criteria
M0 – undifferentiated leukemia
M1 – without sign of maturity
M2 – with sign of maturity
M3 – hypergranular promyelocyte leukemia
M4 – myelomonocyte leukemia
M5 – monoblast leukemia
M6 – erythro leukemia
M7 – megakaryoblast leukemia
Division of ALL according to FAB criteria
L1 – cytoplasma-deficient, small blasts
L2 – more heterogenous with emphasis on cytoplasma richness and size
L3 – B-cell blasts with basophile vacuolized cytoplasma 

Chronic leukemia

Photomicrograph of MCG-stained peripheral blood smear from patient with chronic myeloid leukemia. Click to enlarge the image.

Disease progression of chronic myeloid leukemia is separated into three phases.  

Chronic phase

Untreated     

Treated

< 15 % blast cells in blood or bone marrow

< 30 % – the sum of blast cells and promyelocytes in blood or bone marrow

< 20 % basophile granulocytes in peripheral blood

Thrombocyte count > 100 x 109/l

Normal or close to normal blood values without immature granulocytes in the blood

Accelerated phase
Blast count between 15–29 % in blood or bone marrow

≥ 30 %, the sum of blast cells and promyelocytes in blood or blood marrow.

≥ 20 % basophile granulocytes in blood

Thrombocyte count < 100 x 109/l, which cannot be explained by treatment  

Often also increasing splenomegaly

new chromosome changes in Ph+ clone

Blast phase
Characterized by >30 % of the cells in blood or bone marrow are blasts

Patients have symptoms of acute leukemia.

Extramedullary illness 

The accelerated phase is usually a short transition phase between the chronic phase and blast phase.

Chronic lymphatic leukemia is characterized by accumulation of small, mature-appearing lymphcytes in blood, bone marrow, and organs. It is common to separate patients into prognostic groups at the time of diagnosis.

Stage division of CLL according to Binet
Criteria Stage
  A B C
Number of involved lymph node regions 0–2 3–5 0–5
Hemoglobin (g/dl) >10 >10 <10
Thrombocytes (109/l) >100 >100 <100
Survival (years) >10 5 2.6

Metastatic patterns of leukemia

Leukemias are disseminated diseases originating in the bone marrow. In principle, leukemic blasts can be found all over the body. The most common places where spreading is found outside the bone marrow are spinal fluid, (CNS leukemia) liver, spleen, lymph nodes, and testicles.

When the lymph nodes in the mediastinum are involved (occurs especially in T-cell leukemia), mediastinal tumors can occur with potential life-threatening compression of respiratory tracts and large veins.

For acute myeloid leukemia, in rare cases, extramedullary tumors (myelosarcoma) are present with or without apparent bone marrow affection. These patients are still treated for acute myeloid leukemia.

Symptoms of leukemia

Acute leukemia

Acute leukemia starts with development of symptoms within a few days to weeks, sometimes months.

The symptoms are often due to bone marrow failure:

  • anemia symptoms
  • infections due to granulocytopenia 
  • tendency for bleeding due to thrombocytopenia 
  • disturbance of coagulation system

In addition, the patient often has B symptoms:  

  • weight loss 
  • recurring fever
  • night sweats 

For the clinical examination of patients with acute lymphatic leukemia and acute myeloid leukemia M4 (myelomonocyte leukemia), there are often enlarged lymph nodes and hepatosplenomegaly. Leukemic infiltrates in gums are not uncommon with acute myeloid leukemia M4.

Some patients have petechia and sometimes ecchymoses. Patients with serious neutropenia (granulocytes under 0.5 x 109/l) can sometimes develop life-threatening systemic bacterial infections already before the diagnosis is made.

A rare subgroup of acute myeloid leukemia, hypergranular promyelocyte leukemia (M3), is clinically characterized by a great propensity to develop decompensated disseminated intravascular coagulation (DIC) with a large risk for bleeding and thrombosis.

Chronic leukemia

Chronic leukemia is more insidious in its debut.

For chronic myeloid leukemia, there is often moderate or prominent splenomegaly, but rarely or never lymph node tumors.

For chronic lymphatic leukemia, there is often moderate local or generalized lymph node tumors and light to moderate splenomegaly.

Differential diagnoses of leukemia

Infections

Mononucleosis is sometimes mistaken for acute leukemia.

Severe aplastic anemia

Acute leukemia sometimes starts as severe bone marrow failure with leukopenia. Serious aplastic anemia must be excluded in these cases. A bone marrow examination, sometimes marrow biopsy, will provide the correct diagnosis.

Myelodysplastic syndromes

Differentiation from myelodysplastic syndromes (MDS) is important. This disease group is heterogenous with a tendency for transition to acute leukemia in some cases. These patients often have bone marrow failure to some degree and generally do not benefit from intense chemotherapy since the effect on MDS is much poorer than on acute leukemia.

Lymphblastic lymphoma

Differentiation between acute lymphatic leukemia and lymphoblastic lymphoma with bone marrow infiltration is difficult and may be somewhat artificial. There is evidence to support that the malignant cell population is of the same type, but that the disease primarily starts in lymph nodes or bone marrow.

Thrombocytosis

Chronic myeloid leukemia can in some cases be confused with essential thrombocytosis. A finding of the Philadelphia chromosome and BCR-ABL will clarify this.

Myelomonocyte leukemia

The Philadelphia chromosome-positive myeloid leukemia can morphologically resemble other myelo-proliferative diseases, for example, chronic myelomonocyte leukemia (CMML), and in rare cases, reactive granulocytosis from infectious diseases.  

Chronic lympho-proliferative illness

Even when specimens of blood and bone marrow are successfully prepared, it is not always simple to achieve a definite diagnosis when bone marrow and/or blood is dominated by homogeneous mononuclear cells with a relatively mature appearance. For both the prognosis and treatment, it is very important to differentiate the subgroups of chronic lympho-proliferative diseases.  

Lasting clonal B cell lymphocytosis will, in more than 90% of cases, appear to be chronic lymphatic leukemia.

Non-Hodgkins lymphomas with leukemization and bone marrow infiltration are sometimes confused with chronic lymphatic leukemia. Immunophenotyping of the leukemic cells or a lymph node biopsy will provide diagnostic and prognostic clarification and influence the choice of treatment.  

Prognosis of leukemia

People with leukemia have many treatment options, and treatment for leukemia can often control the disease and its symptoms. The overall 5-year survival rate for patients with leukemai during the period 2007-2013 was 60.6%.

Death rates from leukemia are higher among the elderly and the percent of leukemia deaths is highest among people aged 75-84. Death rates have been falling on average 1.0% each year over 2004-2013.

In 2014, there were an estimated 387,728 people living with leukemia in the United States and in 2017 there are an estimated 24,500 people will die of this disease (2).

References on leukemia

  1. Nasjonalt handlingsprogram med retningslinjer for diagnostikk, behandling og oppfølging av pasienter med maligne blodsykdommer (2013), Helsedirektoratet (National guidelines for diagnostic, treatment and follow-up care of leukemia, Norwegian Directorate of Health)
  2. 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
  3. Baccarani M et al: European Leukemia Net recommendations for the management of chronic myeloid leukemia

Diagnostics of leukemia

Acute leukemia starts relatively acutely with development of symptoms within a few days to weeks, sometimes months. Untreated, the disease usually has a stormy course and the patient may die of infection or bleeding in a few weeks or months.

Chronic leukemia has a more insidious initial phase than acute leukemia and is often discovered coincidentally during a routine check or examination and treated for other illnesses. 

Examinations

  • Determine clinical growth rate of the disease
  • General status emphasizing pathological node tumors and hepato/splenomegaly 
  • Record whether there have been B symptoms (weight loss, fever, pathological night sweats) or other general symptoms
  • Urine stix
  • Pulmonary X-ray is taken routinely for all types of leukemia

The cornerstone of the diagnosis is the morphological test using May Grünwald/Giemsa-stained blood and bone marrow smear (possibly supplemented with a bone marrow biopsy).

Supplementary examinations such as cytochemical changes and immunophenotyping are necessary in cases of doubt where an exact diagnosis is decisive for specific treatment. If the treatment is aggressive and potentially offers a cure, a correct diagnosis is decisive for the future of the patient.

A cytochemical examination of bone marrow cells and to an increasing degree molecular genetic testing, are important for assessment of the patient's prognosis and choice of treatment. 

For suspicion of acute leukemia in a patient under 60–70 years, the regional hospital should be contacted immediately for transferal of the patient, for immediate medical work-up, and to start treatment. 

Diagnostics for:

PROSEDYRER

Diagnosing Acute Myeloid Leukemia

General

Acute myeloid leukemia is divided into 7 subgroups (M0-M7). The group division is based on the morphological examination after the FAB-classification of blood and bone marrow smears and can be supported by immunophenotyping, cytogenetic, and molecular genetic testing, as well as combinations of these techniques. This is done in the WHO staging which is increasingly applied also in Norway.

It is important to obtain a diagnosis and determine which subgroup the patient belongs to. The more rare subgroup, M3 (acute hypergranular promyelocyte leukemia), is especially important to identify as it is often accompanied by non-compensated disseminated intravascular coagulation (DIC). This type of leukemia requires special treatment which must be started immediately when there is a well-founded suspicion of this diagnosis. With correct treatment the prognosis is far better than for the other subgroups.

The type of chromosome changes in leukemia cells at the time of diagnosis may be of importance for treating patients, especially those under 60 years. Patients are divided according to low and high risk criteria.

Indication

  • Suspicion of acute myeloid leukemia 

Goal

  • Confirm the diagnosis
  • Identify risk group for disease progression
  • Cure the disease

Norsk selskap for hematologi. Akutt myelogen leukemi, handlingsprogram [Online]. Februar 2007 [hentet 15. april 2007]; tilgjengelig fra: URL: http://www.legeforeningen.no/asset/15380/1/15380_1.doc

Examinations

Bone marrow aspiration

A bone marrow aspiration is necessary to diagnose acute myeloid leukemia.

Examinations performed on the aspirate:

  • Microscopy, MGG staining and possible cytochemical staining
  • Immunophenotyping (flow cytometry)
  • Cytogenetics with directed testing using FISH or molecular genetic techniques
  • Vital freezing of leukemia cells and/or RNA/DNA extraction for later molecular genetic analyses should be done, if possible.

Biopsy of the iliac crest is not obligatory unless the aspirate is inadequate. The biopsy can in some cases provide additional valuable information. 

Blood tests

General:

ABO typing, hemoglobin, leukocytes with differential counting, thrombocytes, blood smear, LD, albumin, creatinine, Na, K, Ca, phosphate, urate, glucose, CRP, bilirubin, AFOS, ASAT, ALAT, LDH, CMV.

Special testing:

  • HLA typing – taken if there is a need for HLA compatible blood components
  • Lysozyme – in case of raised lysozyme it is probable the patient has acute myeloid leukemia
  • FLT3 analysis (PCR) – a prognostic factor which indicates high risk of recurrence

Lumbar puncture

A lumbar puncture is performed when there is a clinical suspicion of CNS leukemia. Patients with M4-M5 with high LPK (leukocyte particle concentration) have an increased risk for spreading to the central nervous system.

A cytological examination of the aspirate is performed and possibly with immunophenotyping, cell counting and measurement of spinal protein. In case of elevated cell count, cytospin with MGG staining is performed.

Interpretations of findings in spinal fluid can be difficult as there may be contamination with blast containing blood during the spinal puncture.

Familial evaluation

In cases where an allogeneic stem cell transplant is considered, HLA typing of siblings and parents is done when remission is achieved. In a clinical situation, this means all patients under 60 who reach complete remission.

It is important to emphasize that this does not necessarily mean that there will be indication for allogeneic stem cell transplantation in all cases. This will depend on a number of prognostic factors, comorbidity and the course of the disease during and after the induction therapy.

Definitions

May-Grünwald/Giemsa staining

In order to differentiate between cell structures, the May-Grünwald/Giemsa stain is used (MGG stain). This staining method works by a chemical reaction between stain substances and the biochemical components of the cell. The stain substances are neutral salts which ionize in water and react with oppositely charged ions in the cell. MGG staining is the basis for the FAB classification. 

Alpha-naphthyl acetatesterase staining

In many cases of MGG stained of bone marrow specimens, and even easier in peripheral blood, there may be indications of myelomonocytic leukemia (FAB classification M4-M5). In certain cases, these immature cells will have an abundance of cytoplasm, but no apparent clover leaf-cuts in nuclei, making the FAB classification ambiguous (either M1-M2 or M4-M5). In these cases, the alpha-naphthyl acetatesterase stain is useful, which is positive in myelomonocytic leukemia and monocytic leukemia and negative for other types.

Diaminobenzidine peroxidase staining

Of the cytochemical examinations, diaminobenzidine peroxidase (DAB stain) is the most useful supplement to MGG staining. Some acute myeloid leukemia, as when using the MGG stain, have under 5% promyelocytes and will have more than 5% granulated, immature/blast-resembling cells when using this stain. 

Lysozymes in serum

The lysozymes are produced by cells in the granulocytic series and predominantly the monocytic series. The enzyme is not produced by cells in the lymphocytic series. If a patient with acute leukemia has a raised serum lysozyme, it is probable the patient has acute myeloid leukemia and acute lymphatic leukemia is very unlikely. If the serum lysozyme is more than 4 times over the normal limit, this indicates M4 or M5.

Flow cytometry immunophenotyping

Immunologically, the disease is defined by expression of two or more of the following myelomonocytic markers: myeloperoxidase (MPO), CD13, CD33, CD65 and/or CD117. MPO is considered to be the most specific myeloid marker. An attempt at correlating immunophenotype with subtypes with regard to the FAB classification has been made, but there are only 3 subtypes which are clearly defined by their immunophenotype: M0, M6 and M7.

Cytogenetic and molecular genetic testing

Using genetic technology methods, for example FISH analysis, (fluorescent in situ hybridization) or PCR (polymerase chain reactions), details are revealed of gene material which change places, lacks or changes of chromosomes, and the significance this has for differentiation and growth of leukemia cells. This has an increasing significance for treatment since the methods are very sensitive for the presence of characteristic gene material from leukemia cells. An example of this is testing for internal tandem duplication (FLT3 gene) which is an unfavourable prognostic sign. 

FLT3 is a tyrosine kinase receptor which has a large impact on hematopoetic cell proliferation. In 18-30% of all adult patients, an internal tandem duplication (ITD) is observed of FLT3-ITD, which is considered to cause an increase of tyrosine phosphorylation leading to leukemia development.

The FLT3 mutations occur most often in acute myloid leukemia with normal karyotype and high blast value in the blood. There is agreement that FLT3-ITD is associated with high recurrence risk in younger patients. The FLT3 gene is also observed in M3,but here without indicating a poorer prognosis.

Another example is nucleophosmin1 mutation (NPM1-mutation). In patients with normal cytogenetics and absence of FL3T-ITD the presence of such mutations is associated with better than average prognosis.

Gene technology methods are increasing the understanding of leukomogenesis and thus contributing to development of new treatment principles. Testing for the APL/retinol alpha receptor, the translocation with DNA-hybridization techniques in M3, is an example of this. For this type of leukemia, very good results are achieved by treatment with retinol, which causes differentiation and apoptosis of leukemia cells.

More than half of the patients with acute leukemia have non-random (clonal) chromosome changes. That is, the same change in two or more mitoses from bone marrow cells. Certain cytogenetic changes are associated with special morphological changes.

Great emphasis is put on the results of such examinations during the risk consideration regarding transplantation of allogeneic stem cells in the first remission.

Implementation

The most important morphological finding during microscopy of newly discovered leukemia is evidence of Auer rods in cytoplasm of leukemia cells. The finding is characteristic for acute myeloid leukemia but is only found in 30% of patients.  

Typical findings in acute myeloid leukemia

Immature M1 / sign of maturition M2  / hypergranular promyelocyte M3

  • Auer rods (the minority of patients have Auer rods in leukemia cells)
    • In M3, many large Auer rods are often observed. These patients often have disseminated coagulation (DIC). The promyelocytes are often the most heavily granulated.
  • ≥ 5% promyelocytes
  • Peroxidase positive
  • Possibly immunophenotype, but this is usually unnecessary 

M3 is important to recognize since early initiation of treatment may lead to a relatively good prognosis in this subgroup.

In some patients with FAB type M2, the translocation t(8;21) is present. For M3, most of the translocations found are at t(15;17). Patients with these cytogenetic changes have a relatively good prognosis.

Myelomonocyte M4 / monoblast M5

  • Auer rods (minority of patients with AML have Auer rods in leukemia cells)
  • a-naphthylacetatesterase positive
  • Raised lysozyme
  • Possibly immunophenotype, but this is usually unecessary

Inversion of chromosome 16 is observed in myelomonocyte leukemia (M4) with abnormal eosinophils in bone marrow. These patients have a relatively good prognosis.

Erythro M6

Characteristic findings of bone marrow are >30% blasts of non-erythroid cells > 50 % erythropoiesis, most often dyserythropoiesis.

If there is suspicion of erythrocyte leukemia (M6), it is important to be certain the patient does not have megablastic anemia as a result of a B12 or folic acid deficiency or dyserythropoietic anemia.

Undifferentiated M0 / megakaryoblastic M7

  • Immunophenotype

To settle for a diagnosis for acute M0 and M7, it is necessary to carry out immunophenotyping with flow cytometry and/or immunohistochemistry.

Follow-up

As soon as the diagnosis is made, treatment is initiated.

Prognosis grouping

Low risk

Low risk patients have a favorable chromosome abnormality such as Inv(16), t(8;21) and t(15;17). An allogeneic stem cell transplantation is usually not appropriate for these patients in their first remission. NPMI mutation with normal cytogenetics and absence of FLT3ITD.

High risk

An unfavorable deviation may be an indication to start searching for unrelated stem cell donors early in the disease course, if the patient does not have a familial donor.

High risk criteria for AML
Late remission > 1 induction course
Multiple cytogenetic defects > 5
Cytogenetic abnormality Inv (3), t(3;3), -5, -7, part 5, part 7, t(9;22),
Secondary AML Earlier chemotherapy and/or myelodysplastic syndrome
Internal duplication of FLT3 gene  

All others are considered standard risk.

In all patients where there is a reason to start intensive inductive treatment, the cytogenetic examination of bone marrow cells should be done at the time of diagnosis before start of treatment. This result is decisive for prognosis grouping which is central for the possible indication for an allogeneic stem cell transplantation (STC) early in the disease course. 

In patients over 60 years, the result may be a guide for the intensity of the treatment which must be given when remission is achieved after induction treatment. Older patients with a cytogenetic abnormality indicating a poor prognosis hardly benefit from additional intense consolidation treatment, which causes bothersome or life-threatening complications, and little to no improvement in long-term prognosis. It is important not to over-treat the patient.  

Results from cytogenetic examinations must be available when the patient is ready for consolidation treatment after induction treatment.

Acute myeloid leukemiaAcute myeloid leukemiaAcute myeloid leukemia

Diagnosing Acute Lymphoblastic Leukemia

General

Acute lymphoblastic leukemia (ALL) often grows rapidly, and quickly accomplished examinations with treatment starting after 1-2 days may be significant to save a patient with a large tumor mass.

For the choice of treatment, it is critical to have a comprehensive morphological, immunological, and cytogenetic characterization of the tumor cells.

ALL is separated into 3 subgroups (L1-L3). The grouping is based on the morphological examination after the FAB classification of blood and bone marrow smears and is supported by immunophenotyping, cytogenetic, and molecular genetic examinations as well as combinations of these techniques. WHO staging is increasingly applied also in Norway. 

ALL and lymphoblastic lymphoma have many similarities. Both diseases originate from rapid proliferating cells with blast morphology. Conditions with more than 25% lymphoblasts in bone marrow are considered acute lymphoblastic leukemia. If the bone marrow criteria is met, the condition is leukemia even with mediastinal tumors or other lymph node tumor.

Burkitt's lymphoma/leukemia (L3) originates from more mature B lymphocytes and requires special treatment. The treatment is determined by the type of tumor cells and not whether the disease manifests itself as leukemia or lymphoma. 

Indication

  • Suspicion of acute lymphoblastic leukemia

Goal

  • Confirm the diagnosis 
  • Identify risk group for disease progression
  • Cure the disease

 

 

 

 

 

 

 

 

Norsk selskap for hemtaologi. Handlingsprogram for diagnostikk og behandling av akutt lymfoblastisk leukemi/lymfoblastisk lymfom og burkitt lymfom leukemi hos voksne [Online]. Mars 2006 [hentet 15. april 2007]; tilgjengelig fra: URL:http://www.legeforeningen.no/asset/33493/1/33493_1.doc

Definitions

May-Grünwald/Giemsa staining

In order to differentiate between cell structures, the May-Grünwald/Giemsa stain is used (MGG stain). This staining method works by a chemical reaction between stain substances and the biochemical components of the cell. The stain substances are neutral salts which ionize in water and react with ions in the cell. MGG staining is the basis for the FAB classification. 

There are no other special examinations as useful as microscopy of MGG-stained blood and bone marrow smears to differentiate between different types of leukemia.

Flow cytometry immunophenotyping

Flow cytometry immunophenotyping is necessary to clarify the origin of the leukemic clone and for adequate characterization of leukemic cells included for later use for MRD diagnostics.

Cytogenetic and molecular genetic examinations

Using genetic technology methods, for example FISH analysis, (fluorescent in situ hybridization) or PCR (polymerase chain reactions), details are revealed of gene material which change places, lacks or changes of chromosomes, and the significance this has for differentiation and growth of leukemia cells. This has an increasing significance for treatment since the methods are very sensitive for the presence of characteristic gene material from leukemia cells. The most important example of this is evidence of BCR-ABL. PCR will identify BCR-ABL regardless of where the gene is located in the genome, and is today the most sensitive method for finding the fusion gene.

The presence of this fusion gene indicates a poor prognosis using normal chemotherapy. The Philadelphia chromosome (which is a shortened chromosome 22) occurs due to a translocation between chromosome 9 and 22, where the fusion gene BCR-ABL is created .

Examinations

Bone marrow aspiration

A bone marrow aspiration or bone marrow biopsy if it is difficult to aspirate representative bone marrow, is necessary to diagnose ALL. A biopsy can in some cases also provide additional valuable information.

Examinations performed on the aspirate:

  • Microscopy, MGG staining, and possible cytochemical staining
  • Immunophenotyping (flow cytometry)
  • Cytogenetics with directed testing using FISH or molecular genetic techniques
  • If possible, a cell suspension which is frozen locally for later supplementary examinations.
  • RNA/DNA extraction for later molecular genetic analyses should be done, if possible.

In all patients, the bone marrow aspirate and blood are sent to PCR for BCR-ABL.

Blood tests

General:

ABO typing, hemoglobin, leukocytes with differential counting, thrombocytes, blood smear, LD, albumin, creatinine, Na, K, Ca, phosphate, urea, glucose, CRP, CMV.

Special testing:

  • Blood tests at the start of treatment with emphasis on development of tumor lysis syndrome: urate, Ca, Mg, K+, phosphate, creatinine, and liver tests.  
  • HLA typing – taken if there is a need for HLA compatible blood components

Lumbar puncture

A lumbar puncture is performed when there is a clinical suspicion of CNS leukemia or for the first intraspinal prophylaxis treatment. 

Examinations performed on the aspirate:

  • Cell count - for an increase in cell count, cytospin with MGG staining is performed
  • Spinal protein

In some cases, a cytological examination of the spinal fluid is done and possibly with immunophenotyping.

Interpretations of findings in spinal fluid may be difficult when there are blasts in blood due to the risk of contamination by puncture bleeding.

Familial evaluation

In cases where an allogeneic stem cell transplant is considered, HLA typing of siblings and parents is done when remission is achieved. This means all patients under 60 who reach complete remission.

 

Findings

Acute lymphoblastic leukemia is divided into early B-cell population (about 80%), T-cell (about 10-15%), and B-cell with surface immunoglobulin (< 5 %).

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia, have a poorer prognosis, and represent more than 20% of adult cases.

About 95% of all types of acute lymphoblastic leukemia (except for B-cell) have elevated terminal deoxylnucleotidyl transferase (TdT) . If this marker is negative, the diagnosis of acute lymphoblastic leukemia is doubtful.

Acute B-lymphoblastic leukemia / B-lymphoblastic lymphoma, L1  or L2

  • Originates from precursor B-cells
  • Defined by lymphoblastic morphology L1 or L2
    • L1 – blasts with very little cytoplasm (< 15 of nucleus area), and less than 5% promyelocytes, negative diaminobenzidine peroxidase (DAB staining)
    • L2 – less than 5% promyelocytes, more cytoplasm than L1
  • Immunophenotype like immature B-cells

Acute T-lymphoblastic leukemia / T-lymphoblastic lymphoma, L1  or L2

  • Originates from precursor T-cells 
  • Defined by lymphoblastic morphology L1 or L2
    • L1 – blasts with very little cytoplasm (< 15 of nucleas area), and less than 5% promyelocytes, negative diaminobenzidine peroxidase (DAB staining).  
    • L2 – less than 5% promyelocytes, more cytoplasm than L1
  • Immunophenotype like immature T cells
  • CD1a is negative for Pro tT and mature T-ALL, positive for cortical T-ALL

Burkitt's leukemia/ lymphoma L3

  • Orginates from more "mature" B-cells 
  • Defined by lymphoblastic morphology (deep basophilic cytoplasm, vacuoles, FAB L3)
  • Immunophenotype like mature B-cells
  • Characteristic karyotype
  • These leukemia cells usually have three translocations: t(8;14), t(2;8), and t(8;22).

Follow-up

As soon as the diagnosis is made, treatment is initiated.

Prognostic factors

High-risk for acute B-lymphoblastic leukemia:

  • Philadelphia chromosome/bcr-abl/t(9;22)(q34;q11)
  • t(4;11)(q21;q23) and other 11q23 anomalies
  • massively hypodiploid karyotype
  • complex karyotype, that is > 5 discrepancy
  • leukocytes in blood > 30 x 109/l
  • ≥ 5 % blasts in bone marrow smear 4 weeks after starting treatment
  • positive MRD-status 12 months after time of diagnosis

High-risk for T-cell illness:

  • ≥ 5 % blasts in bone marrow smear 4 weeks after starting treatment
  • pro T-ALL
  • mature T-ALL
  • positive MRD status 12 months after time of diagnosis

All others are considered standard risk.

Minimal residual disease (MRD)

In younger patients (< 60), it is recommended to try to define the leukemia-specific marker with immunophenotyping or molecular genetic method at the time of diagnosis and follow the MRD level during treatment when the clone-specific marker can be defined. If, as in the case of high-risk leukemia, a decision to use allogeneic stem cell transplant as primary consolidation treatment has been made, or this is clearly inappropriate (age > 60), the MRD determination has no practical consequences and can be left out.

It is recommended that the MRD is determined in the bone marrow aspirate at the concluded consolidation treatment (before starting maintenance treatment) and 12 months after the time of diagnosis, if clone-specific markers are successfully defined at the time of the diagnosis. Examinations should be avoided in the aplasia phase since the chance for an unsuccessful test is the greatest.

In order for the MRD analysis to be emphasized, the sensitivity of the analysis must be at least 10-4. Ideally, the analysis should be carried out on two clone-specific markers. If the results are difficult to interpret, the analysis should be repeated.

  • With positive MRD-status (> 10–4) after concluded induction (about week 16) an allogeneic stem cell transplantation should be considered. Alternatively, the MRD level is followed with a new test after 1 month. Increasing MRD (1 log unit or more) indicates a high risk for recurrence.
  • With positive MRD-status (> 10–4) after 12 months, an allogeneic stem cell transplantation is considered. For transition from previous negative to positive status which is not due to variation in test sensitivity, supplementary reinduction treatment is considered. Contact the Section for Blood Diseases for planning further treatment.

It is currently recommended that all patients complete full maintenance treatment even if MRD is negative in week 16 and 12 months. Rapid decline of MRD (negative in week 2 and week 16) indicates good prognosis.

Knowledge of the use of MRD is under rapid development.

Acute lymphatic leukemiaAcute lymphatic leukemiaAcute lymphatic leukemiaAcute lymphatic leukemia

Diagnosing Chronic Myeloid Leukemia

General

Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disease which is distinguished by an increased number of mature and immature granulocytes in peripheral blood, bone marrow, with increased granulocytopoiesis and splenomegaly.

The disease is defined by the presence of the BCR-ABL fusion gene. This anomaly is probably necessary and sufficient for the development of chronic myeloid leukemia.

Indication

  • Suspicion of chronic myeloid leukemia

Goal

  • Confirm the diagnosis
  • Identify risk group for disease progression
  • Choose the correct treatment and follow-up care

Background

By definition, the BCR-ABL fusion gene is always present in chronic myeloid leukemia.

In over 95% of cases, the BCR-ABL chimera gene is present on chromosome 22, t(9;22)(q34,q11)  . The resulting chromosome 9 achieves an elongation of the long arm, which is not apparent when looking at the chromosomes during cell division under a microscope (karyotyping, cytogenetic examination). In contrast, the resulting chromosome 22 becomes conspicuously shortened in its long arm. This may be seen during cytogenetic examination.

The short chromosome 22 received the name Philadelphia chromosome (Ph) after the location of its discovery.

In chronic myeloid leukemia without visible Ph, the BCR-ABL gene is often created by translocations involving more chromosomes than chromosome 9 and 22. In these cases, the karyotype changed in a way that a typical Ph is not recognized. Polymerase chain reaction analyses (PCR) will catch the presence of BCR-ABL regardless of where the gene is located in the genome. This is the most sensitive method for finding the fusion gene.

In rare cases, clinical and laboratory findings may be consistent with chronic myeloid leukemia without finding Ph or BCR-ABL. These cases are classified as atypical chronic myeloid leukemia and represent another disease entity.

The Philadelphia chromosome is not only found in chronic myeloid leukemia. It is also present in about 20% of adults and 2–5% of children with acute lymphatic leukemia.

The ABL gene always splits between exon 1 and exon 2 from the rest of chromosome 9, while the BCR gene can break in multiple places from chromosome 22. The consequence is that in different patients, there can be different lengths of the fusion gene and thereby the fusion protein. The normal fusion protein of chronic myeloid leukemia is 210 kD (p210). Chronic myeloid leukemia can sometimes have a benign course and is then often associated with a longer form, p230. Ph+ acute lympatic leukemia, which is an aggressive disease, is often found in a shorter form, p190.

The ABL protein is a tyrosine kinase enzyme, which when transcribed from chromosome 9, is under "strict control" by the N-terminus which has a self-inhibiting effect on the tyrosine kinase activity. When the gene moves to chromosome 22, the N-terminus of the protein is derived from the BCR gene. This does not have a self-inhibiting effect on the tyrosine kinase activity. Consequently, there is uninhibited tyrosine kinase activity. Phosphorylation of tyrosine is an important mechanism for intracellular signaling and we know that the tyrokinase BCR-ABL affects many signal pathways which are important for cell division, cell differentiation, ahesion, apoptosis, and transcription regulation. 

It is striking that the p190 BCR-ABL gene, often found in acute lymphatic leukemia, has a higher tyrosine activity than p210 BCR-ABL, which is most common in chronic myloid leukemia. The gene p230 BCR-ABL has the lowest tyrosine activity and is associated with a less aggressive clinical course. It appears the degree of tyrosine kinase activity is of importance for the aggressiveness of the disease.

Examinations

Many CML patients are diagnosed before they develop symptoms during health checks or routine blood tests. Leukocytosis and an enlarged spleen cause suspicion of the disease.

Patient history and clinical examinations

Survey general leukemia symptoms and hyperviscosity symptoms which can occur in chronic myeloid leukemia.

Blood tests

  • Hb
  • Leukocytes with differentiation
  • Thrombocytes
  • S-LD
  • Uric acid
  • Liver tests
  • Renal function tests
  • BCR-ABL mutation analysis

Blood smear

  • Morphological assessment

Bone marrow aspirate/biopsy

  • Morphological assessment
  • Cytogenetic examination 

Findings

Typical findings are leukocytosis and the clinical examination often uncovers splenomegaly.

Usually, the neutrophile granulocytes and myelocytes in peripheral blood are > 50 x 109/l (blood resembles bone marrow) . The thrombocyte value may be elevated, normal, or low and anemia is present. 

Basophilia is very common. The bone marrow is abundant with cells and is dominated by granulocytopoeisis which completely matures in the chronic phase.

The diagnosis is confirmed by the presence of the Philadelphia chromosome in the cytogenetic analysis of bone marrow/peripheral blood and detection of BCR-ABL from PCR analysis in peripheral blood.

Follow-up

As soon as the diagnosis is confirmed, treatment is started.

Prognostic factors

Risk assessments tied to the expected disease outcome, treatment, and probability for reaching the treatment goal with the treatment alternatives, is central to handling of the patient.

The disease phase, age, thrombocyte count, spleen size, and number of blasts in peripheral blood are risk factors forming the basis for separating patients into the following prognosis groups:

  • high risk of progression
  • intermediary risk for progression
  • low risk for progression

Individual treatment plans should be made. Good objective information and patient involvement in decisions where uncertainty is the greatest is very important.

Cytogenetic changes such as deletions on the derivative chromosome 9 and other cytogenetic changes in the Ph+ clone are negative prognostic indicators. This data is important for what strategy is chosen at the time of diagnosis and for sub-optimal response to treatment.

Monitoring the disease

Chronic myeloid leukemia and its treatment effect can be monitored on three levels:

Hematological response

  • Leukocytes < 10 x 109/l
  • Thrombocytes < 450 x 109/l
  • < 5 % myelocytes in blood
  • No blasts or promyelocytes in blood
  • < 20 % basophile granulocytes in blood
  • No extramedullary manifestations

Cytogenetic response

  • Complete cytogenetic response (CCyR) – 0 % Ph+
  • Partial cytogentic reponse (PCYR) – 1-35 % Ph+
  • Major cytogenetic response (MCyR) – PCyR + CCyR (0-35 % Ph+)
  • Minor cytogenetic response – 36-65 % Ph+
  • Minimal cytogenetic response – 66-95 % Ph+

Cytogenetic response and the amount of bone marrow cells which are Ph+ are examined by freezing mitogen-stimulated cells in metaphase. At least 20 metaphases (cell divisions) should be examined.

Molecular response

  • Complete – BCR-ABL transcript not detectable  
  • Major – BCR-ABL transcript ≤ 0,1%

PCR techniques measure BCR-ABL in the blood as a percent of the total ABL transcript. One hundred percent is the average of BCR-ABL transcript divided by the total ABL transcript x 100 in a reference population on 30 newly diagnosed CML patients. A result of 0.1% equals a 1000 fold reduction (3 log) of the transcript amount in relation to the reference population's average value and is expressed as "major molecular response." The concept "complete molecular response" in practice means the level is below the method's level of detection, which is usually reached by a 4-5 fold reduction of the BCR-ABL transcript.  

The degree of cytogenetic and molecular response at a given point in time has shown to be a very good surrogate marker for progression-free survival.

Chronic myeloid leukemiaChronic myeloid leukemia Chronic myeloid leukemia

Diagnosing Chronic Lymphocytic Leukemia

General

Chronic lymphocytic leukemia has an insidious debut. Suspicion of the disease occurs in patients who have lasting lymphocytosis, possibly combined with anemia, thrombocytopenia, enlarged lymph nodes and/or a B-symptom. The patient often does not have symptoms at the time of diagnosis and the disease is discovered coincidentally by examination for other reasons.

Three out of five patients are asymptomatic when the diagnosis is made. 

The disease is characterized by an elevation of small, mature-appearing lymphocytes in blood, bone marrow, and lymphoid organs.

Previously, it was common to use the expression chronic lymphocytic leukemia in patients who presented with lasting lymphocytosis with mature-appearing lymphocytes. In the majority of cases, this fits with how we use the description also today, however, with the introduction of new diagnostic methods, such as immunophenotyping and karyotyping, it is evident that leukemic forms of non-Hodgkin's lymphoma are an important differential diagnostic group. It is essential to differentiate between leukemia of B-cell and T-cell types.

Indication

  • Suspicion of chronic lymphocytic leukemia 

Goal

  • Confirm the diagnosis
  • Prognostic assessment
  • Assess whether there is indication for treatment 

 

 

 

 

 

 

 

Norsk selskap for hematologi. Handlingsprogram for kronisk lymfatisk leukemi [Online] 2005 [hentet 15. april 2007]; tilgjengelig fra: URL: http://www.legeforeningen.no/index.gan?id=84611

Background

In chronic lymphatic leukemia there is almost always a presence of clonal proliferation of B-lymphocytes with a characteristic immunophenotype CD5+C19+CD20+CD23+. The physiological parallel to the malignant cells is a small population of CD5+ B-lymphocytes localized in the mantel zone of secondary lymph node follicles. CD5+ B-lymphocytes belong to their own B-cell line. They dominate early in the oncogenesis and are known for secretion of natural auto-antibodies.

Cytogenetic anomalies

IgVH gene

Whether the IgVH gene has undergone somatic hypermutation or not, chronic lymphatic leukemia is separated into two disease groups: mutated and unmutated, which have very different prognoses. In patients with an unmutated IgVH gene, the median survival is 8–9 years, while it appears the survival for patients with a mutated IgVH gene is no different from an age-adapted normal population. The median survival is > 24 years.

Translocation

A series of cytogenetic anomalies have been described, but none of these are specific for chronic lymphatic leukemia. They are also not primary events in the disease development, but appear later in the disease course. They do not have a diagnostic value like the translocations t(14;18)(q32;q21) and t(11;14)(q13;q32) appearing in follicular lymphoma and mantel cell lymphoma respectfully, however, these cytogenetic anomalies still have a great prognostic value. 

Deletions

The most common cytogenetic anomalies are del 6q, del 13q, del 11q, del 17p, and trisomi 12, and are evident in 80% of patients using fluorescence in situ hybridization (FISH).

Median survival for the different deletions:

  • del 17p - median survival is 30 months 
  • del 11q - median survival is 68 months

These cytogentic anomalies are associated with poor prognosis and often poor and/or short-lasting effect of chemotherapy.

  • del 13q - median survival has not been reached in published studies, but 60% survive after 192 months

This karyotype is associated with a good prognosis.

Conventional chemotherapy is dependent on functioning signal pathways for apoptosis in the tumor cells to be effective. However, for del 17p in particular, this is not the case. The p53 signal pathway, which is a central signal pathway for apoptosis, is defective.

Expression of CD 38 and ZAP-70 (zeta-associated protein) was introduced as a possible surrogate marker for the unmutated IgVH gene, but none of the markers show full correlation to VH mutation status. They both appear to contribute with independent prognostic information.

Examinations

The clinical examination should include:

Status

  • Lymph node palpation
  • Liver and spleen palpation
  • Height and weight

Blood tests

General:

ABO typing, hemoglobin, leukocytes with differential counting, thrombocytes, blood smear, LD, albumin, creatinine, Na, K, Ca, phosphate, urate, glucose, CRP.

  • Protein electrophoresis of serum/plasma and quantification of Ig
  • Direct antiglobulin test (DAT). DAT should be repeated in all patients with anemia and before starting treatment.
  • Reticulocytes – determination of reticulocytes should be done in all patients with anemia before starting treatment.
  • Biochemical kidney and liver parameters. Determination of these parameters including urate should be done at the time of diagnosis and treatment start (at minimum).

Flow cytometry of blood or bone marrow

Immunophenotyping of lymphocytes in blood (or bone marrow) should be performed in all patients and at least in all who need treatment/before start of treatment. Additionally, immunophenotyping may be performed in patients with mild lymphocytosis to confirm the diagnosis and in patients with atypical morphology to exclude leukemized forms of other chronic lymphoproliferative diseases.

Bone marrow examination

Examinations of bone marrow are not required to diagnose the leukemia, but are considered necessary before starting treatment. This is partly because the examination contributes to clarifying the cause of cytopenia and partly because the bone marrow examination is necessary to evaluate the response to treatment. The examination may also contribute to diagnostic information in atypical lymphocyte morphology or low CLL score.  

 

Findings

A definite diagnosis requires at a minimum: lymphocytosis, characteristic morphology of blood smear using light microscopy, and characteristic immunophenotype.

Close to 80% of the patients have a lymph node tumor when the diagnosis is made and about half of the patients have splenomegaly. It is very common to find leukemic organ infiltration in almost all organs during autopsy, but this is rarely the cause of clinical symptoms.  

The diagnosis requires evidence of lasting lymphocytosis ( > 5 x 109/l). When the diagnosis is made, the lymphocyte value is most often > 40 x 109/l and sometimes > 100 x 109/l. The leukemic cells resemble normal lymphocytes and are 1.5–2 times larger than erythrocytes. They have very sparse basophilic cytoplasm and most often have a round-oval nucleus with condensed chromatin without a distinct nucleolus.

Diagnostic criteria for chronic lymphocytic leukemia

Lymphocytosis

The diagnosis requires lasting (> 6 months) lymphocytosis > 5 x 109/l. Patients with clonal B-cell lymphocytosis between 3 and 5 x 109/l and morphology consistent with chronic lymphocytic leukemia may develop clinical symptoms. For lymphocytosis < 10 x 109/l, detection of monoclonal lymphocyte population with characteristic immunophenotype is necessary to make the diagnosis. 

Lymphocyte morphology

In typical lymphocytic leukemia, >90% of the cells are small or medium lymphocytes with condensed chromatin (like pine tree bark), diffuse or no nucleolus, and with very sparse cytoplasm (high nuclei/cytoplasm ratio). In 15% of patients, the morphology is atypical due to the high number of prolymphocytes (>10%, but <55 %) or low nucleus/cytoplasma ratio).

Immunophenotype

CD19, CD20, CD23, CD5, k or l light chains. CD5 expression cannot be detected in 5–10% of cases and membrane-bound Ig cannot be found in an equivalent amount of cases.

 

CLL Score
                        Expression
Marker CLL (score) Other leukemia/NHL score
mIg Weak/negative (1) Moderate/strong (0)
CD5 Positive (1)        Negative (0)
CD23 Positive (1) Negative (0)
CD79b or CD22 Weak/negative (1) Moderate/strong (0)
FMC7 Negative (1) Positive (0)

Score 4–5 in about 90% of cases with chronic lymphocytic leukemia, score 0–1 in about 90% of cases of the other leukemia and about 75% of cases with leukemized NHL. The remaining have a score of 2.

Bone marrow aspirate

More than 30% lymphocytes in a smear with not too few cells (not obligatory).

The diagnosis is confirmed by evidence of monoclonal population of B-cells with characteristic immunophenotype and morphology in blood.

About 15% of patients have anemia, normocytic and normochromic, at the debut of the disease. In 20%, a positive direct antiglobulin test can be detected (DAT+) at some point during the disease course due to the production of IgG auto-antibodies in non-neoplastic B lymphocytes. Only 8% of patients develop autoimmune hemolytic anemia.

Thrombocytopenia is observed in almost all patients with advanced illness, which is due to reduced thrombopoiesis. Also, immune-mediated thrombocytopenia occurs due to thrombocyte-specific auto-antibodies at any time during the course of the disease.

Hypogammaglobulinemia is detected early in the disease course in at least half of patients and in about 5% of the patients, a monoclonal gammopathy can be detected, usually of the IgM type. The paraprotein has the same specificity as that which is detected on the surface of the leukemic cells.  

Bone marrow is always infiltrated by leukemic cells, but the growth pattern varies.

Follow-up

Staging and some laboratory parameters provide a certain amount of prognostic information, but are not a suitable basis for estimating the prognosis at the time of diagnosis.  

Prognostic Factors

Parameter Median survival (years)

Infiltration of bone marrow:

 
diffuse  3-5
sporadic  10

Lymphocytosis:

 
< 50 x 109/l  6
> 50 x 109/l  3-4

Doubling time:

 
> 12 months  10
< 12 months  5

Prolymphocytes in blood:

 
< 5 % prolymphocytes  6
> 5 % prolymphocytes  3-4

In the last 10 years, the knowledge of the biology of disease has increased significantly, and with the help of this knowledge, the conditions are much better for communicating the patient's prognosis at the time of diagnosis.  

Patients who do not need treatment are routinely checked (frequency is adapted individually).

At follow-up visits, anamnesis is emphasized and the clinical examination should focus on lymphoid organs, and laboratory parameters such as hemoglobulin, leukocytes with differential count, and thrombocytes.

Chronic lymphatic leukemiaChronic lymphatic leukemia

Immunophenotyping with flow cytometry

General

Flow cytometry immunophenotyping is an important link in the evaluation and treatment assessment of lymphoma and leukemia. The test provides a quick and quantitative analysis of a cell population, cell line origin, stage of differentiation, maturition, and biological activity.   

Flow cytometry immunophenotying is a method for measuring physical and chemical properties of cells and particles in a stream of fluid. Within immunology, flow cytometry is more commonly used, since it can be used to classify different blood cells. DNA measurements are also used. Evaluation of results requires special knowledge and expertise.

Indications

  • Suspicion of lymphoma
  • Suspicion of leukemia
  • Response evaluation of treatment for lymphoma or leukemia

Goal

  • Confirm or exclude malignant disease
  • Be a contributing factor for determining which treatment plan the patient should follow. 
  • Diagnose disease recurrence

Definitions

Flow cytometry

The cells are in a suspension, which are led individually through a nozzle where they are illuminated with a laser. The fluorochromes (substances which fluoresce) are excited by the laser and emit light. This emitted light is transmitted by a lens and filter system to a detector which amplifies and translates the electrical pulses to numerical values.

Knowledge of how the cells spread light after illumination in the flow cytometer allows us to differentiate the cells from each other. Multiple parameters are measured simultaneously: unique fluorescence as well as degree and direction of light spreading. Low angle (FSC) and wide angle (SSC) light spreading indicate the size and complexity of the cell.

The computer stores data of DNA content for every cell passing the laser, so that diagrams are made which provide a precise overview over the number of cells with a certain amount of DNA. In this way, it is possible to see how many cells are found in different phases of the cell cycle.

Immunophenotyping

Blood contains many cell types with different functions. These cells originate from multi-potent stem cells from bone marrow. Classification of leukemia and lymphomas are determined to a large extent by the antigen expression of the cell surface.  

The cells are labeled with fluorochromes attached to monoclonal antibodies which are targeted for antigens on cell surfaces or in cytoplasm. By utilizing fluorescent monoclonal antibodies against the surface antigens, it is possible to identify immunophenotypes expressed on leukemic cells but not on normal cells.

Minimal Residual Disease (MRD)

Flow cytometry is a sensitive method used to identify one leukemic cell among 10,000 normal cells. It is used for surveillance of treatment effect when the risk for recurrence of leukemia is under assessment. If the blast cells are under 5%, the disease is considered to be in morphological remission. 

Due to chemotherapy-resistant blast cells which remain in very small amounts in bone marrow, some patients will have recurrence of the disease. The probability of this is associated with the number of blast cells during and after treatment.

These blast cells are called MRD. Patients having an MRD level < 0.01% after treatment have a better prognosis than those with a level of ≥ 0.01 %. Flow cytometry is a useful examination for assessing the risk for recurrence of the disease.

Cancer cells usually have an abnormally high DNA content. Having information about this is of prognostic importance. It appears that tumors and leukemia cells with abnormal DNA content have a poorer prognostic impact than normal DNA content.

DNA flow cytometry

DNA flow cytometry can be used to measure DNA of cell nuclei, which has a prognostic value.

Preparation

An aspirate is taken of: 

  • peripheral blood
  • bone marrow 
  • cell suspension from lymph nodes

Implementation

  • A smear of the test material is made and stained for a microscopic examination.
  • The specimen is washed with physiological saline to remove plasma proteins which can interfere with antibody-antigen binding.  

From the microscopy assessment, clinical information and patient history, it is determined which combinations of antibodies will be used for staining in each case.

  • The red blood cells are hemolysed leaving a concentrate consisting of only white blood cells.
  • The specimen is analyzed by the flow cytometer.
  • The raw data are analyzed using dedicated software.

Follow-up

  • The result from the analysis is assessed by the treating doctor.
  • The result is available after a few hours up to a few days, depending on the complexity of the analysis.

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

Lumbar Puncture for Diagnostics and Intrathecal Administration of Chemotherapy

General

Indications

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

Goal 

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

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

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

Equipment

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

Preparation

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

Implementation

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

Cell counting and testing for protein and glucose

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

Follow-up

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

For headache

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

Treatment of leukemia

Leukemia is treated primarily with drug therapy.

Radiation therapy is administered for acute leukemia if there is metastasis to the central nervous system, and in some cases for allogenic stem cell transplantation treatment with myeloablative and non-myeloablative pre-treatment.

Infertility

The question of whether patients can have children after intense chemotherapy treatment is of great significance for younger patients and their partners. The question of freezing sperm should be discussed with the patient and offered if medically justifiable.  

Freezing ovarial tissue for patient with leukemia is today experimental. There is a risk that the ovarian tissue is infiltrated with leukemia cells, and today there is no methodology for safe fertilization.

Surgery of leukemia

Surgery is rarely used for treating leukemia.

Drug therapy of leukemia

Acute leukemias

Treatment of acute leukemia is principally chemotherapy to reduce or, optimally, to remove all leukemic clones.

Treatment for:

Chronic leukemias

For chronic myeloid leukemia, there is consensus that newly diagnosed patients in most situations should be given imatinib as the first choice of treatment. The observation time is limited for tyrosine kinase inhibitors, and treatment with an allogeneic stem cell transplantation is documented to cure the disease. New second-generation tyrosine kinase inhibitors are already registered and third-generation tyrosine kinase inhibitors are under development. Transplantation methods are also under development and new data from clinical studies are accumulating quickly. Algorithms for treatment and reponse evaluation are under continual change. 

It is recommended that treatment of CML patients is done in cooperation with a university hospital.

In chronic lymphoblastic leukemia, there is no clear evidence that disease-directed treatment can prolong survival. Drug therapy is given to reduce symptoms.  

Treatment for:

Allogeneic stem cell transplantation

Up to 70% of adult patients below 40 years with acute myeloid leukemia, who are in their first remission with chemotherapy, can be cured by an allogeneic stem cell transplantation from an HLA-identical sibling donor after bone marrow eradication treatment. The transplantation is used as consolidation treatment instead of regular chemotherapy. But in patients aged over 40, the results are somewhat poorer.  

For leukemia in more advanced phases, (accelerated phase of chronic myeloid leukemia, other remission or start of recurrence of acute leukemia) the possibility for curing the disease is less (< 40 %). If the disease is more advanced, the chance of curing the disease is under 10–15%.

Fatal complications occur in larger groups in at least 20–30%, usually within a few months, and increase with age and more advanced illnesses. They are more frequent with unrelated donors than for identical tissue types from sibling donors.

For acute lymphoblastic leukemia among adults, 5 year recurrence-free survival is achieved in up to 35% with modern chemotherapy. The results are better in younger patients compared to older patients. At most treatment centers, a first remission is treated by an allogeneic stem cell transplantation only in high risk patients. Adults cannot be cured with chemotherapy alone after recurrence of acute leukemia. However, with bone marrow eradicating treatment and allogeneic stem cell transplantations with HLA-identical stem cells, the disease is cured in 20-30%.

Differences between non-myeloablative and myloablative allogeneic stem cell transplant

During non-myeloablative stem cell transplantations, serious bone marrow depression, mucosal damage, and other organ toxicity following conditioning are usually avoided. In return, the patient receives a powerful immunosuppressive treatment. It is therefore necessary to be as aware of opportunistic infections as for a myeloablative transplant, but it will often develop later in the disease course.

Futhermore, the disease course for graft-versus-host disease (GVHD) will be different since acute GVHD often occurs also after 100 days, during or after a gradual reduction of immunosuppression. Treatment may be necessary.  

GVHD often occurs when the patient converts from mixed to full chimera status of T-cells.

PROSEDYRER

Treatment of Acute Myeloid Leukemia

General

Acute myeloid leukemia is treated with chemotherapy which reduces, or optimally, eradicates the leukemic clone. The stipulation for achieving long-term survival or curing the disease is that the patient must reach complete hematological remission (CHR).

CHR is defined as < 5% blasts in normal cellular bone marrow combined with normalized cell count in the blood. In practice, this is only achievable after infusion of chemotherapy with such a high dose intensity that the treatment is life-threatening. Chemotherapy will heavily affect normal hematopoiesis causing bone marrow aplasia with serious neutropenia, thrombocytopenia, and anemia, in periods from one to multiple weeks.

The patient's age is an indicator for what can reasonably be achieved. Induction treatment is appropriate for patients below about 60 years, while patients between 60-70 years can be treated to cure the disease only in certain cases. Patients older than 70 years will in the majority of cases, benefit most from good palliative treatment. An exception is patients with acute hypergranular promyelocyte leukemia (M3).

Curative treatment should take place at the hematology section of a regional hospital or a well-equipped central hospital with a designated section for blood diseases. There should be sufficient resources of blood banking and competent on-call personnel. If necessary, there should be cooperation with a regional hospital.

Indication

  • Acute myeloid leukemia

Goal

  • Control the disease, possibly cytogenetically and molecularly. 
  • Cure the disease.

Treatment Plan

Experience shows that certain patient groups will not benefit from the most intensive chemotherapy schedules. In these cases, the treatment is "watchful waiting" or less potent chemotherapy. This applies to:

  • Patients over 70 years, or patients under 70 with reduced health condition not due to leukemia, or other serious illness in addition to leukemia.
  • Older patients with certain forms of acute leukemia which, from experience, are refractory to intensive chemotherapy combinations. These types are the terminal acute leukemia occurring during treatment for other diseases, for example, polycythemia vera, myelofibrosis, aplastic anemia, myelodysplastic syndrom (MDS), and after treatment of Hodgkin's or non-Hodgkin's lymphoma or multiple myeloma.

With these exceptions, combinations of chemotherapy are given to all patients with acute myeloid leukemia, but treatment is adapted for age, health status, and comorbidity.

Treatment program

Cytarabine (cytosine arabinoside) is included in all chemotherapy combinations administered to induce remission of acute myeloid leukemia.

 

Treatment plan for acute myeloid leukemia < 60 years
Medication Administration method

Treatment 1A

 
Daunorubicin 50 mg/m2 day 1, 2, 3 intravenous infusion
Cytosine arabinoside 200 mg/m2 day 1–7 intravenous infusion over 24 hours
Treatment 1B is administered if there is no marrow aplasia and < 5% blasts in marrow smear 14 days after start

Treatment 1B

 
Daunorubicin 50 mg/m2 dag 1, 2 intravenous infusion
Cytosine arabinoside 200 mg/m2 day 1–5 intravenous infusion over 24 hours
Consolidation treatment: Treatment 2–5 assumed CHR after treatment 1A, possibly 1A + 1B

Treatment 2-5

 
Cytosine arabinoside 3 g/m2 x 2 days 1,3, 5 intravenous infusion over 3 hours

For FAB subgroup M3, a modified regimen is given in addition to the vitamin A derivative, tretinoin (ATRA).

Cytarabine combined with idarubicin is about as effective as daunorubicin in an equipotent dose, in terms of bringing the patient into remission.

Complete hematological remission

Remission criteria:

  • B-neutrophile > 1 x 109/l
  • Thrombocytes > 100 x 109/l
  • no need for blood transfusion
  • < 5% blasts in normal cellular bone marrow smear
  • absence of extramedullary leukemia

All patients under 60 years and their siblings, parents, and sometimes children, should have their tissue typed after remission is reached. All patients who have reached complete hematological remission (CHR), must have additional treatment (consolidation treatment (treatment 2-5)), otherwise there will be recurrence of the disease, almost without exception. This treatment regimen causes complete hematological remission (CHR) in about 80% of patients, and 4 year survival of 40-45%. Four year recurrence-free survival in patients with t(8;21) and Inv(16) is 70–80 %. Patients with cytogenetic anomalies and a high risk for recurrence have about 20% chance of recurrence-free survival.

Patients with a family donor are offered allogeneic stem cell transplant treatment in the first CHR except for patients with favorable prognostic signs. Critical weight is put on  the cytogenetic deviations of the leukemia cells at the time of diagnosis. In some patients with high risk criteria, who do not have a family donor, it is possible to search for an unrelated donor.

In patients who are in complete or partly hematological remission, blood values and bone marrow must always be checked before starting a new course. It is important to be aware that patients undergoing combination treatment rarely have normal blood and bone marrow function even if they are in complete hemotological remission. These blood and bone marrow changes are therefore not a sign of leukemia, but rather a result of the treatment.

Patients over 60 years

High-dose consolidation treatment or allogeneic stem cell transplantion treatment with myloablative pre-treatment are not appropriate for patients over 60 years due to the high risk of toxicity and death related to treatment. All patients must be assessed individually. An alternative is to administer 2-4 courses with combinations of amsacrine, etoposide, mitoxantron, and cytarabine, which are adapted for patient response and possible observed toxic damage. Other regimens are also used. It has not been shown whether any specific regimen is clearly the best. 

Refractory disease and recurrence during treatment

These patients have a poor prognosis and should receive palliative treatment with transfusions, antibiotics for infections, and chemotherapy combinations to control the disease. Patients who have suitable family donors and are not transplanted in the first remission are candidates for an allogeneic stem cell transplantation at the start of remission, and should therefore be followed carefully. A transplantation at the start of recurrence, from a donor who is not a biological relative, is not feasible for practical reasons. 

Preparation

  • Inform the patient about the disease, treatment, and side effects.
  • Evaluate familial donor relations.
  • Insertion of central vein catheter.

Implementation

High-dose cytarabine is standard treatment for patients < 60 years and is administered as four repeated courses with 4 week intervals.

Alternative treatment protocols including high dose treatment with autologous stem cell support have not, so far, been shown to give better results.

Follow-up

Intensive chemotherapy treatment leads to significant granulocytopenia and thrombocytopenia. Therefore, frequent blood tests are necessary.

While the patient is hospitalized and receives aggressive combination treatment, and between later courses, hemoglobin, rod and segmental nucleated granulocyte counts, as well as platelets, should be checked at least twice a week after a course of chemotherapy until bone marrow regeneration.

Consolidation treatment also causes bone marrow aplasia for 1–2(3) weeks. There is a certain risk for serious CNS toxicity from high doses of cytarabine, which is not given to patients over 60 years. Caution must also be taken for patients with liver and kidney involvement.

Side effects

During the intensive treatment period, the patient will, in periods from weeks to months, require hospitalization as a result of the treatment due to infections, the need for transfusions, and/or organ failure.

Chemotherapy of this intensity unfortunately leads to death in some patients, due to sepsis or other complications during the first months of treatment. This applies especially to elderly patients.

Liberal use of thrombocyte concentrates in combination with optimal doses of antimicrobial and antifungal agents is a prerequisite for safe treatment.  

Nutrition

Nutritional problems occur, more or less, among patients receiving this treatment. This is due to nausea, vomiting, mucositis, diarrhea, dry mouth, pain, constipation, and changes in smell and taste senses. Many will require intravenous nutrition. Good nutritional guidance is important.  

Mucositis

Mucositis, both in the mouth and other mucosa, often occurs when blood values are at their lowest. The intensity of the soreness is individual. Sore mucosa in the mouth is not only an entrance for bacteria, but can also be painful. Prophylactic mouth hygiene should be given during the entire treatment. 

Nausea

Nausea improves 1-2 days after a treatment. Some patients have lasting problems often of multifactorial etiology.  

Hair loss

Hair loss will occur 2-3 weeks after starting chemotherapy.

Recurrence after treatment is finished

For recurrence of the disease, the possibility for reaching new remission with the original induction regimen is about 30-50% better the longer it has been since the conclusion of treatment. Therefore, if recurrence occurs more than 12 months after concluded treatment, it is usually recommended to try the original induction regimen first.  

Recurrence during the first year after treatment will rarely reach remission with the original induction regimen, and the prognosis is poor. Treatment is planned individually.

If patients under 60 years reach a new CHR, an allogeneic stem cell transplantation is an option if a familial donor is available. A transplant from an unrelated donor may also be appropriate.

Treatment of Acute Lymphoblastic Leukemia

General

The principle for treating acute lymphoblastic leukemia is to give chemotherapy which reduces or optimally, eradicates the leukemic clone.

About half of the patients fall into an age group where chemotherapy is expected to be beneficial or eradicate the disease. The patient's age is an indicator for what is reasonable to expect. The condition for achieving long-term survival or curing the disease is to reach complete hematological remission (CHR), which is defined as < 5% blasts in normocellular bone marrow combined with a nearly normalized cell count in the blood.  

In practice, this is only achievable after infusion of chemotherapy with such a high dose intensity that the treatment is life-threatening. Chemotherapy will heavily affect normal hematopoiesis causing bone marrow aplasia with serious neutropenia, thrombocytopenia, and anemia, in periods from one to multiple weeks.

The most intensive treatment regimens are relevant for patients under about 60 years, while patients between 60-70 years can be treated with an intensive induction protocol to cure the disease only in certain cases. Patients older than 70 years will in most cases, achieve the best benefit from good palliative treatment. An exception is patients with acute hypergranular promyelocyte leukemia (M3).

Diagnostics and treatment to cure the disease should occur at a hematology section of a regional hospital or a well-equipped central hospital with a designated section for blood diseases. They should have sufficient resources of blood banking and competent on-call personnel. If necessary, there should be cooperation with a regional hospital.

Indication

  • Acute lymphoblastic leukemia 

Goals

  • Hematological, cytogenetic, and molecular control of the disease.
  • Cure the disease. 

Norsk selskap for hematologi. Handlingsprogram for diagnostikk og behandling av akutt lymfoblastisk leukemi/lymfoblastisk lymfom og burkitt lymfom leukemi hos voksne [Online]. Mars 2006 [hentet 15. april 2007]; tilgjengelig fra: URL:http://www.legeforeningen.no/asset/33493/1/33493_1.doc

Treatment Plan

Treatment is based on the Hammersmith 82 regimen, which in recent updates provides successful results for total survival. For rare variants of the disease, documentation of this regimen is uncertain, therefore other alternatives are available.

Patients with acute lymphoblastic leukemia are usually not candidates for an allogeneic stem cell transplantation in the first remission because results from chemotherapy are usually good. The most important exception is for patients with detected Philadelphia chromosome and/or BCR-ABL fusion transcription in the leukemia cells. For these patients, an imatinib regimen and allogeneic stem cell transplantation are recommended in the first remission. There are also other prognostic factors.

Surveillance of minimal residual disease (MRD) in bone marrow is recommended in patients < 60 years where an allogeneic stem cell transplantation may be appropriate, but where the indication is uncertain based on traditional risk factors.

Hammersmith 82

Treatment for acute lymphoblastic leukemia consists of an induction phase of 16 weeks followed by maintenance treatment for three years.

Induction treatment

  • Vincristine 2 mg intravenously day 1 for weeks 1–5
  • Doxorubicin 30 mg/m2 intravenously day 1 weeks 2, 3 and 4
  • Asparginase 10000 µg/m2 intravenously every other day in weeks 2 and 3
  • Metotrexate intrathecal 15 mg day 1 in weeks 3, 5, 7, 10, 12, 14 and 16
  • Cyclophosphamide 750 mg/ m2 intravenously day 1 in weeks 3 and 5
  • Prednisolone 40 mg/m2 orally daily in weeks 1–4, gradually reducing until discontinuation in week 5
  • DTC:
    • Daunorubicin 50 mg/m2 intravenously days 1, 3 and 5 in week 7
    • Cytosar 200 mg/ m2/ 24 hours, on days 1–5 in week 7
    • Thioguanin 150 mg/m2 orally on days 1–5 in week 7
  • Metotrexate 1500 mg/m2 intravenously with calcium folinate in weeks 10 and 12
  • Mercaptopurine 35 mg/m2 orally daily in weeks 10–16

An examination of bone marrow is performed in week 4-5 before starting DTC and with the MRD examination in week 16. Modification of dosage intensity is often necessary due to serious side effects.

Maintenance treatment (x 13)

  • Dexamethazone 6 mg/m2 orally daily in weeks 1–3
  • Vincristine 2 mg intravenously day 1 weeks 1–3
  • Doxorubicin 30 mg/m2 intravenously day 1 in week 2
  • Cyclophosphamide 600 mg/m2 intravenously day 1 in week 3
  • Methotrexate 15 mg/m2 orally daily for 3–5 days in week 4
  • Mercaptopurin 70 mg/m2 orally daily in weeks 5–8
  • Methotrexate 15 mg/m2 for 3–5 days in week 8
  • Mercaptopurine 80 mg/m2 orally daily in weeks 9–11
  • Methotrexate 15 mg/m2, 3–5 days in week 12 

In the first two maintenance cycles, monthly intrathecal methotrexate (15 mg) is administered for a total of 13 intrathecal injections.

Vincristine can often not be given in full because of polyneuropathy.

During maintenance treatment, moderate bone marrow suppression is striven for (neutrophiles and granulocytes are held between 0.5–1.5 x 109/l.

During the last three maintenance cycles, doxorubicin is replaced with cytarabine to avoid too high accumulation of anthracycline dosage.

If infections due to treatment occur as a result of bone marrow suppression, the treatment intensity should be reduced. 

Treatment of elderly patients (~60+)

Older patients with acute lymphoblastic leukemia usually suffer more from side effects than benefit from the most intense chemotherapies. The goal of treatment is palliative for most of these patients.

If assessing whether it is possible to complete intensive chemotherapy: normal ALL-protocol (Hammersmith) can be used as a framework with reduction of dosage and shortening. Stop vincristine if there is neuropathy. Asparaginase can be omitted in some. High-dose methotrexate is not tolerated well in elderly; maximum dosage is 500 mg/m2.

When remission is reached after induction, direct transition to simplified maintenance (6 mercaptopurine + methotrexate (if possible)) should be considered, without consolidation.

Patients over 60 often do not tolerate intense chemotherapy well, but may benefit from taking imatinib for a period, for Ph+ (BCR-ABL+) acute lymphoblastic leukemia.

The OPAL or VAD regimen is used by some as a palliative induction regimen for acute lymphoblastic leukemia in elderly patients with reduced function status.

Acute lymphoblastic leukemia in the central nervous system

For blasts in spinal fluid, intrathecal methotrexate is administered (15 mg twice per week) until the spinal fluid is free of blasts. Thereafter, weekly four times, for example.

The CNS prophylaxis is resumed according to protocol if the response has been successful.

Systemic treatment is continued according to protocol.

At least 8 intrathecal injections should be administered with not more than a 1 month interval after the spinal fluid is free of blasts.

If the brain is involved, CNS radiation of 24 Gy may be considered when remission is reached.

In a palliative situation, cytarabine with depot properties can be considered to reduce the number of injections.

Preparation

  • Provide information about the disease, treatment, and side effects.
  • Evaluate family donor situation.
  • Insert central vein catheter.

Implementation

Acute pre and pro B-lymphoblastic leukemia

Approximate age 18–60 years:

  • normal ALL-protocol (Hammersmith 82).

Acute T-lymphoblastic leukemia

Approximate age 18–60 years:

  • normal ALL-protocol (Hammersmith 82), alternatively hyper CVAD

The documentation of the effect of Hammersmith 82 is somewhat less here than in pre and pro B-ALL, and the alternatives are equally relevant.    

Bukitt’s lymphoma/leukemia

GMALL B-ALL/NHL 2002 with rituximab.

In the special case of Burkitt’s lymphoma/leukemia, there is often a very quick treatment response and therefore a high risk for developing Tumor Lysis syndrome.

Ph+ (BCR-ABL+) acute lymphoblastic leukemia

Hyper CVAD combined with imatinib, with an allogeneic stem cell transplantation as soon as possible in the first complete remission. If treatment is chosen, imatinib can be used in elderly patients either alone or combined with steroids as an induction for palliative indication.

Follow-up

Intensive chemotherapy treatment leads to significant granulocytopenia and thrombocytopenia. Therefore, frequent blood tests are necessary.

While the patient is hospitalized and receives aggressive combination treatment, and between later courses, hemoglobin, rod and segmental nucleated granulocyte counts, as well as platelets, should be checked at least twice a week after a course of chemotherapy until bone marrow regeneration.

Side effects

During the intensive treatment period, the patient will, in periods from weeks to months, require hospitalization as a result of the treatment due to infections, the need for transfusions, and/or organ failure. Large amounts of antibiotics and blood products are used.

Liberal use of thrombocyte concentrates in combination with optimal doses of antimicrobial and antifungal agents is a prerequisite for safe treatment. Chemotherapy of this intensity unfortunately leads to death in some patients, due to sepsis or other complications during the first months of treatment. This applies especially to older patients.

Nutrition

Nutritional problems occur, more or less, among patients receiving this treatment. This is due to nausea, vomiting, mucositis, diarrhea, dry mouth, pain, constipation, and changes in smell and taste senses. Many will require intravenous nutrition. Good nutritional guidance is important.  

Pain

Vincristine can cause neuromuscular manifestations. This often starts with sensory disturbances and paresthesia. Neuritis pain and serious delayed motor disturbances can occur with continued treatment. The neuromuscular side effects are muscle weakness, muscle atrophy, disappearance of deep delayed reflexes, bone pain, and difficulty walking which is sometimes significant, jaw pain, painful swallowing, and constipation. Vincristine can also lead to ptosis. The side effects are usually completely or partly reversible, but can last longer for some.

Mucositis

Mucositis, both in the mouth and other mucosa, often occurs when blood values are at their lowest. The intensity of the soreness is individual. Sore mucosa in the mouth is not only an entrance for bacteria, but can also be painful. Prophylactic mouth hygiene should be performed during the entire treatment. 

Nausea

Nausea improves 1–2 days after a treatment. Different chemotherapy agents cause nausea to varying degrees. The most emetic drugs are doxorubicin, daunorubicin, and cyclophosphamide.

Gastritis

Due to large doses of steroids, the patient is at risk for gastritis/gastric ulcer. Hydrogen blockers or proton-pump inhibitors are used routinely as prophylaxis during high dose steroid medication.  

Change in appearance/alopecia

Hair loss, often in tufts, will occur 2–3 weeks after starting chemotherapy. The patient will often develop an appearance resembling Cushing's disease from the use of steroids.

Change in self-image

This treatment is often a great burden for the patient, both physically and psychologically. This may alter the patient’s self-image.

Criteria for remission

Complete remission is defined as:

  • Hb > 10 g/dl
  • Granulocytes > 1.5 x 109/l
  • Thrombocytes > 100 x 109/l
  • No blasts in peripheral blood, spinal fluid, and absence of previously affected extramedullary localizations.
  • The bone marrow should have tri-linear hematopoiesis and blast cells < 5 %

Recurrence

Recurrence from earlier complete remission is diagnosed when blast cells with typical appearance and immunophenotype constitute 5% or more in bone marrow or are detected spinal fluid or other extramedullary localizations.

Other treatment alternatives:

  • Autologous stem cell support (HMAS) in first remission
  • For acute T-lymphoblastic leukemia with standard risk, HMAS can be assessed as an alternative to maintenance treatment.
  • Allogeneic stem cell transplantation

Treatment of Chronic Myeloid Leukemia

General

Chronic myeloid leukemia often starts with an indolent chronic phase which, before treatment with imatinib was introduced, progressed in 4–6 years via an accelerated phase to acute leukemia.

In the accelerated phase, the number of blasts and basophilic granulocytes increase in peripheral blood. The symptoms also increase in parallel and the condition is then more difficult to treat. This phase can last up to one year and then evolve into the blast phase (transformation). The disease profile is then acute leukemia where the immunophenotype can be lymphoblastic or myeloblastic. The prognosis is poor in these cases.

The tyrosine kinase inhibitor imatinib is the most effective medication for treatment of chronic myeloid leukemia. An allogeneic stem cell transplantation (myeloablative/non-myeloablative) is the only treatment method which, with assurance, can cure the disease.

Treatment with hydroxy urea (HU) gives longer survival than busulfan. Treatment with interferon-a gives approximately 6 months average extended survival compared to hydroxyl urea (HU) if administered at the disease debut.

Indication

  • Chronic myeloid leukemia

Goal

  • Control the disease on hematological, cytogenetic, and molecular levels.
  • Maintain good quality of life.

Background

Allogeneic stem cell transplantation

Using a family donor, about 70% of patients who receive transplantations (myeloablative/non-myeloablative) in the first chronic phase can be cured. With an unrelated donor, about 50% can be cured. The mortality associated with transplantations is, however, relatively high. This is the main objection against choosing this method as first line treatment. 

Based on registry data, chances of survival and transplantation-related mortality can be estimated using the following independent risk factors:

  • disease phase
  • age
  • tissue compatibility between donor and patient
  • sex of the donor (female donor to male patient is unfavorable)
  • time from the diagnosis

In rare cases of chronic myeloid leukemia where there is a risk for disease progression and relatively low risk for transplantation complications, an allogeneic stem cell transplantation may be appropriate as first line treatment.

It is recommended that all CML patients are initially assessed as a potential candidate for a transplant, and that familial donor status is surveyed at the time of diagnosis (HLA typing), even if imatinib should be first line treatment.  

Imatinib

Imatinib mesylate is an aminopyrimidine which shows relatively high specificity for inhibitation of BCR-ABL tyrosine kinase. It acheives this by competitively binding to the ATP receptor site on the BCR-ABL molecule.

Imatinib was registered in the EU in 2002 as first line treatment for newly diagnosed chronic myeloid leukemia in the chronic, accelerated, or blast phase.

Inhibition of BCR-ABL, in contrast to chemotherapy and interferon, directly attacks the disease pathogenesis, and is targeted therapy based on molecular biological knowledge. It is therefore also of great theoretical significance. 

Imatinib does not kill leukemic stem cells and therefore does not eradicate the disease. Imatinib treatment is therefore in most cases, life-long treatment.

Imatinib resistance

About 20% of chronic myeloid leukemia patients will either not tolerate imatinib, not respond with the desired effect (primary resistance), or the response will disappear (secondary resistance). These patients require alternative treatment. The high number of complete cytogenetic responses (CCyR) in the chronic phase of imatinib treatment has required more sensitive molecular monitoring with quantitative PCR techniques to evaluate the degree of response and early detection of loss of response.

Primary resistance

Primary resistance may have multiple causes such as amplification of the BCR-ABL gene, constitutive activation of kinases farther down the signal pathways such as "SRC activation," loss of p53 or clonal evolution with other genetic changes. 

Secondary resistance

In secondary resistance, it is known that in 50% of cases, there are point mutations which cause amino acid replacements in or at the imatinib binding site in the BCR-ABL molecule. These can either directly interfere with imatinib binding or cause conformational changes resulting in imatinib being unable to bind.  

Some resistance mutations are treated by increasing the dosage to change the conditions for competition between ATP (adenosine triphosphate) and the medication. Other cases cannot be treated by an increase in dosage. There is also evidence that some mutations receive a great growth advantage since imatinib inhibits all unmutated CML cells. In these rare cases, imatinib treatment induces disease progression.

Most resistance mutations are present in CML subclones already at the time of diagnosis. Others are selected during treatment. Not all mutations are of clinical significance.

Secondary resistance is rare if imatinib is started at the time of diagnosis, but more frequent if the patient is in a late chronic phase when starting the treatment. It is therefore probably important to start imatinib treatment early.

Second generation BCR-ABL inhibitors

Based on BCR-ABL and imatinib's three-dimensional structure, other second-generation tyrosine kinase inbibitors have been constructed which are not as dependent on known mutations to be effective. The first two are already registered (dasatinib and nilotinib) for use in imatinib resistance/intolerance. These drugs are also not effective on all mutations, for example the T315I mutation.

New tyrosine kinase inhibitors are in trial.

 

 

Preparation

  • Provide information about the disease, treatment, and side effects.
  • Risk stratification.
  • Evaluate sibling donor situation.
  • Consider treatment alternatives.

Implementation

Multiple substances can inhibit the tyrosine kinase BCR-ABL, however, the inhibitor which is best explored is imatinib. Today, imatinib is the only tyrosine kinase inhibitor approved for first line treatment.

Imatinib treatment

Chronic phase

Imatinib is primary treatment for adult patients with Ph+ and/or BCR-ABL positive chronic myeloid leukemia.

The recommended dosage in the chronic phase is 400 mg/day.

If the patient is in a chronic phase and is still treated with hydroxy urea or interferon, without complete cytogenetic response, they should usually change to imatinib.

Accelerated phase

If the disease starts with an accelerated phase, a higher dosage of imatinib is given (600–800 mg/day). Patients who are < 55–60 years with a stem cell donor are appropriate for an allogeneic stem cell transplantation in this phase.  

Blast phase

If the disease starts with a blast phase, the condition will most often be perceived as acute leukemia and treated accordingly. If BCR-ABL is detected or Ph+, it should be considered whether imatinib should be added or the dosage increased to 600-800 mg/day.

Development of blast crisis during imatinib treatment represents therapy failure. Dosage increase to 800 mg of a second-generation tyrosine kinase inhibitor possibly combined with conventional induction treatment for acute leukemia should be considered depending on the ABL mutation status and immunophenotype.

It is important to differentiate between the myeloid and lymphoid blast phase by utilizing microscopy supplemented with cytochemistry and immunophenotyping. The myeloid blast phase is more common than the lymphoid. 

All treatment other than a stem cell transplantation has a short time limit and if the patient can be made fit for a transplantation, this should be the goal of the treatment.

An allogeneic stem cell transplantation in the blast phase is not included in the Norwegian stem cell program because international results are very poor. The patient must have reached a chronic phase for the transplantation to be considered since there is still a large risk of recurrence.

Poor response to imatinib or progression

For all forms of poor response or progression, an allogeneic stem cell transplantation is appropriate for patients < 55–60 years. Alternatively, second-generation tyrosine kinase inhibitors may be tried. Treatment should be discussed with a regional hospital. Liberal referral use is recommended for consideration by the Norwegian group for allogeneic stem cell transplantations. 

Interferon

Treatment with interferon (IFN) as monotherapy or combined with cytarabine extends survival by an average of 18 months. Today, this treatment is relevant in cases of intolerance to tyrosine kinase inhibitors or resistance in patients who are not suited for an allogeneic stem cell transplantation. For low risk of progression at the time of diagnosis or complete cytogenetic reponse to INF, 10 year survival is reported to be 70%. However, the problem is that few reach complete cytogenetic response with interferon treatment. Different combinations of imatinib and IFN and/or cytarabine are under evaluation in clinical studies. Interferon is the preferred treatment if it is necessary to treat the disease during pregnancy.

Hydroxyurea and busulfan

Hydroxyurea (HU) has replaced busulfan because it is more effective and easier to manage. HU can be chosen at diagnosis if there is a need for rapid reduction of leukocyte count with later transition to imatinib. Use of HU may also be indicated for elderly patients and patients with a weakened health status, as well as for palliative treatment with failing tyrosine kinase inhibitor treatment in patients who are not appropriate for a transplantation, interferon treatment, or clinical trial. The treatment goal is to bring the patient to a stable chronic phase. Busulfan is still relevant for a few patients where other therapies are not suitable.

Follow-up

Side effects

Imatinib

The side effects from imatinib treatment have so far been mild.

The most common side effects are:

  • hematological toxicity, anemia, neutropenia, and thrombocytopenia
  • rise of transaminases  
  • peripheral edemas
  • rash

Data beyond 8 year treatment is not available. However, there has been discussion of a possible influence on calcium and phosphate metabolism, worsening of heart failure, and development of urothelial malignancies.

Hydroxy urea

Common side effects from high doses: 

  • hematological toxicity
  • nausea/vomiting
  • diarrhea

Allergic rash, aphthous ulcers, and skin ulcerations occur. Macrocytosis and megaloblastic marrow is common.

Monitoring and treatment

Because not all patients tolerate or have consistently good effect of imatinib, and there exist alternative treatment regimens for some patients, careful monitoring is required. Based on present experience, definite achievements can be expected at certain time intervals. The treatment goals provide a basis for stratifying patients into optimal responders, sub-optimal responders and non-responders. These definitions may change over time as more experience is accumulated.

Today, hematological, cytogenetic, and molecular reponses are monitored:  

  • cytogenetics is performed twice a year on patients who have reached complete cytogenetic response, thereafter annually to catch possible changes, and clonal evolution
  • molecular monitoring is performed every 3 months
  • mutation analysis is performed if response is lost

Consensus at the current time in Europe is that the following response must be present for the patient not be categorized as a non-responder:

  • 3 months – at least one complete hematological response
  • 6 months – at least one cytogenetic response (< 95 % Ph+)
  • 12 months – at least partial cytogenetic response (< 35 % Ph+)
  • 18 months – at least one complete cytogenetic response (0 % Ph+)

Sub-optimal responses are also defined at these given points in time indicating critical evaluation of the treatment. Presence of unfavorable prognostic markers such as a high risk for progression at the time of diagnosis, detected deletions on derivative chromosome 9 and/or cytogenetic changes int he Ph+ clone are also emphasized in the response assessment.  

If these are acceptable goals which should prompt change in treatment at the given point in time, they should be considered in connection with the patient's total situation and the available treatment alternatives. 

Fertility

Imatinib is considered a teratogen and should not be taken during conception or pregnancy.

Allogenic stem cell tranplantation with conventional conditioning usually causes permanent infertility. In these cases, sperm banking should be addressed at the time of diagnosis before the patient starts drug therapy.

Hydroxy urea probably does not cause permanent reduction of gonadal function but is assumed to be a teratogen.

In cases where the disease is diagnosed in connection with pregnancy, frequent follow-up with a hematologist and obstetrician is required throughout the pregnancy.

Treatment of Chronic Lymphocytic Leukemia

General

For chronic lymphocytic leukemia, there is no clear evidence that disease-directed treatment has a life-prolonging effect. The treatment can, however contribute to extending remission and symptom-free periods. This means that treatment is initiated when the disease causes symptoms.  

Indication

The most common indications for anti-leukemic treatment of chronic lymphatic leukemia:

  • bone marrow failure equivalent to Binet's stage C
  • general symptoms such as weight loss and night sweats
  • large symptom-causing tumor
  • troublesome lymph node tumor
  • rapidly progressive lymphocytosis (lymphocyte doubling time < 6 months)
  • autoimmune hemolytic anemia and/or immune-mediated thrombocytopenia, which does not respond to high doses of steroids or is recurring after reduction of treatment intensity.

Goals

  • For the patient to be symptom-free as long as possible.
  • To maintain good quality of life for the patient.

 

 

 

 

 

 

 

Norsk selskap for hematologi. Handlingsprogram for kronisk lymfatisk leukemi [Online] 2005 [hentet 15. april 2007]; tilgjengelig fra: URL: http://www.legeforeningen.no/index.gan?id=84611

Background

Currently, many doctors will recommend that prognostic parameters are surveyed before starting treatment. Some will emphasize these results in choosing treatment, but at present it is unknown whether a risk-adapted treatment strategy is advantageous.

An exception for this may be if del17p exists at the start of treatment. Because these patients are often chemo-refractory, there may be reason to consider alemtuzumab (anti CD52 antibody) as primary treatment. It has not been shown by clinical studies that such an approach to primary treatment provides a gain in survival time.

Chlorambucil monotherapy, fludarabine monotherapy, and fludarabine/cyclophosphamide combination treatment are alternative first line treatments.  

 

Treatment responses to treatment alternatives
Treatment  Complete response Partial response No response/progression
Chlorambucil  8 % 64 % 28 %
Fludarabine 15 % 66 % 19 %
Fludarabine/
cyclophosphamide
39 % 55 %  6 %
Fludarabine/
cyclophosphamide/
rituximab
52 % 43 %  5 %

 

It appears that combination treatment is the most effective as it leads to more responses, more complete responses, and longer disease-free survival than the two other treatment alternatives. However, the total survival is the same for all four treatment alternatives. This is because second line treatment and possible later treatment are also successful, especially in those primarily treated with chlorambucil.

Corticosteroids have traditionally been used in combination with alkylating chemotherapy drugs, such as chlorambucil, for chronic lymphocytic leukemia and other lympho-proliferative diseases. Corticosteroids in addition to chlorambucil do not give a higher response rate, longer remission time, or longer progression-free survival than chlorambucil alone. 

Corticosteroids are not appropriate for treatment of chronic lympocytic leukemia unless there is a special indication for it. Prednisone/prednisolone is indicated for autoimmune hemolytic anemia and immune-mediated thrombocytopenia. It has also been common to initially recommend corticosteroids for treatment of patients with significant anemia, thrombocytopenia, or granulocytopenia, as a result of bone marrow failure (1 mg/kg/day for 2–3 weeks before starting chemotherapy). However, this treatment is not well documented.

Allogeneic stem cell transplant

An allogeneic stem cell transplantation may be a treatment alternative for younger patients, especially patients who are refractory to conventional treatment. The benefits of an allogeneic stem cell transplantation for acute lymphocytic leukemia are not yet clear.

Preparation

  • Provide information about the disease, treatment, and side effects.
  • Evaluate familial donor situation.
  • Consider treatment alternatives.

Implementation

Treatment recommendations

Chlorambucil (6–8 courses)

  • Continual: 0.08–0.12 mg/kg
  • Intermittently:  
    •  10 mg/m2 for 10 days, every 28 days
    •  30 mg/m2 in 4 doses, 1 day every 14 days  
    •  15 mg/m2 for 4 days, every 28 days
  • High continually: 10 mg/m2 until response or toxicity

Fludarabine (6–8 courses) 

  • 40 mg/m2 for 5 days, every 28 days

Fludarabine/ Cyclophosphamide (6–8 courses) 

  • 40 mg/m2 for 3 days, every 28 days
  • 250 mg/m2 for 3 days, every 28 days
  • Possible addition of rituximab recommended as 375 mg/m2 at first course and 500 mg/m2 for subsequent courses.

Treatment for recurrence

There are no clear recommendations regarding treatment for recurrence after first line treatment. If the need for further treatment appears after 2 years or more, there are good chances that first line treatment can achieve a new response. No response or early recurrence indicates that alternative treatment regimens should be tried. 

For chlorambucil resistance, the next obvious choice is a fludarabin treatment regimen. If fludarabin monotherapy was used as first line treatment, an alternative is combination treatment supplemented with monoclonal antibody (rituximab (anti-CD20 antibody) or alemtuzumab). Newer clinical studies indicate that fludarabin resistance is associated with very poor prognosis and experimental treatment including allogeneic stem cell transplantation should be considered for these patients. 

At present, an allogeneic stem cell transplantation should only take place within evaluable clinical studies.

Splenectomy

Certain patients have significant splenomegaly and lymphocyte infiltration in the bone marrow with relatively moderate lymphocytosis in the blood. In these patients, the spleen can cause troublesome local symptoms or cause anemia and thrombocytopenia due to hypersplenism. In these situations, a splenectomy is a good treatment alternative. A splenectomy may also be worth trying with immune hemolysis or thrombocytopenia which responds poorly to adequate steroid doses.

Infections

Patients with chronic lymphocytic leukemia often have an increased tendency for infections which may be due to granulocytopenia or, more frequently, hypogammaglobulinemia. In these patients with serious infection complications, which are reasonable to believe are secondary to gammaglobulinemia (infections with capsule-covered bacteria), there is a documented effect from prophylaxis substitution treatment with gammaglobulin. It is important to be aware that many patients have significant hypogammaglobulinemia without infection tendencies. In these patients, there is no indication for substitution treatment.

Follow-up

After treatment is finished, a formalized evaluation of the treatment response should be performed based on NCI criteria. As a minimum, this involves a complete clinical examination with emphasis on lymph nodes, the liver, and spleen.

Determination of hemoglobin, leukocytes, granulocytes, lymphocytes, and thrombocytes in blood should be done a few weeks after concluded treatment. Additionally, a bone marrow examination should be performed, preferably with both aspirate and biopsy.

Response criteria (NCI)
Criterion Complete response Partial response Progressive disease
Symptoms None               None  
Lymph nodes Nodes > 50% reduction > 50% increase or new manifestations
Liver/spleen Not palpable > 50% reduction > 50% increase or new manifestations
Hemoglobin > 11 g/dl

> 11 g/dl or 50% improvement

 
Granulocytes > 1,5 x 109/l > 1,5 x 109/l or 50 % improvement  
Lymfocytes < 4 x 109/l > 50% reduction

> 50 % increase

Thrombocytes > 100 X 109/l >100 x 109/l or 50% improvement  
BM-aspirate < 30 % lymfocytes    
BM-biopsy No infiltrates Nodular infiltrates  

Some doctors will also include a CT of the abdomen and thorax in this type of response evaluation, but outside of clinical studies, the clinical benefit to be obtained from these procedures is doubtful.

Thereafter, the patient is checked at regular intervals (individually adapted) with patient history, clinical examination, and certain laboratory parameters as mentioned above.

The indication for re-treating will usually be the same as for primary treatment.

Transformation to aggressive B-cell lymphoma (Richter's syndrome)

Some patients with chronic lymphocytic leukemia over years exhibit an increasing number of promyelocytes with declining treatment response. This is not actually a transformation, but a more rapid selection of clones over time which is less sensitive to treatment. Richter's syndrome occurs in 3-5% of patients with chronic lymphatic leukemia. The disease profile is characterized by rapid growth of one or more lymph nodes accompanied by systemic manifestations such as fever and/or weight loss. A histological examination of the affected lymph node is similar to that of large-cell B-cell lymphoma.

Treatment of chronic lymphocytic leukemia

Allogeneic stem cell transplantation with myeloablative conditioning

General

An allogeneic stem cell transplantation with myeloablative conditioning facilitates maximization of treatment with chemotherapy, perhaps in combination with total body radiation. The treatment involves removal of the patient's bone marrow and replacing it with new bone marrow from a donor with compatible tissue. Additionally, an immunological effect is often achieved directed toward the remaining leukemia cells. Hematopoetic stem cells are transferred from an individual who is normally tissue-identical but genetically different from the patient. 

The patient should not have a serious, complicated disease and there must be an appropriate donor. Using a family donor, a transplantation with myeloablative conditioning is appropriate for patients under 60 years. Unrelated, HLA-identical donors are suitable for certain patients below 55-60 years. It is important to take into consideration the patient's biological age. If it is possible to choose between multiple donors, it is preferred that the donor is of the same sex as the patient. If possible, a CMV negative donor is preferred if the patient is CMV negative.   

The treatment can cure otherwise incurable blood diseases, but its intensity is associated with many side effects. There is also a risk of fatal complications.

Indications

  • Acute myeloid leukemia (AML)
    • After recurrence, in the beginning of the first recurrence or in later, preferably second remission.
    • In the first remission for patients who do not have a low risk for recurrence, if the patient is under 60 years and there is a family donor. 
    • Patients under 55-60 years with high risk for recurrence with unrelated suitable donor, in the first remission.  
  • Acute lymphoblastic leukemia (ALL)
    • In the first remission with high risk criteria and for new remission after first recurrence. 
  • Chronic myeloid leukemia leukemia (CML)
    • In the chronic phase with poor or no response of tyrosine kinase inhibitors or in accelerated phase.
  • Multiple myeloma 
  • Younger patients with good response to primary treatment and with a suitable family donor. At the present time, the indication is debated.
  • Other 
  • Serious aplastic anemia, myelodysplastic syndrome, primary myelofibrosis, chronic myelomonocyte leukemia, and other rare diseases. 

 Goal

  • Cure the disease

Background

Donor

A blood related donor is preferred and currently, a blood related donor with up to one incompatible HLA (human leukocyte antigen) can be used. 

If the patient does not have a blood related donor, it is considered whether an unrelated donor with HLA, A, B, C, DR and DQ identity can be used. Despite serological techniques, unrelated donors may still have small differences in their HLA molecules which are of significance for GVHD and rejection reactions, therefore genomic typing is performed.

In younger patients, a stem cell transplantation for acute and chronic myeloid leukemia with marrow from an unrelated HLA genetically identical donor has given almost the same results as using stem cells from blood related donors.

The upper age limit for patients accepting stem cells from unrelated donors is somewhat lower than for patients who have a blood related donor because the risk for complications is greater and increases with age.

If it is not possible to find a living donor for the patient, searching for cord blood as a source of stem cells may be an altenative.

Stem cell harvesting

Hematopoietic stem cells are harvested by extracting bone marrow from the donor's hip bone or by mobilizing hematopoietic stem cells from bone marrow to blood. Mobilization can be done with the help of hematopoietic growth factors, most often granulocyte colony stimulating factor (G-CSF) given subcutaneously. The growth factors most likely influence adhesion molecules on the stem cells and bone marrow stroma allowing the stem cells to release into the blood stream. Because of this technique, it has become common to refer to stem cell transplantations instead of bone marrow transplantations as it reflects both methods of harvesting stem cells.   

Harvesting from bone marrow

For extraction of stem cells from bone marrow, the tissue-compatible donor is given general anesthesia and lies in the prone position. Bone marrow is aspirated by repeated punctures of the hip bone. The procedure lasts 1 hour on average. The aspirated bone marrow with the stem cells is transferred to blood pouches with heparin. From the donor, 2 x 108 per/kg body weight of nuclei-containing cells are transferred to the recipient.  

Harvesting from blood

Harvesting stem cells from blood does not require anesthesia, but the procedure can be time-consuming. The stem cells are harvested from a peripheral vein with the help of leukapheresis machines.

Each leukapheresis requires many hours. It is necessary to have 1-3 leukaphereses and a minimum of  2 x 106 CD34 of positive cells per/kg body weight of the recipient.

There are indications that the use of stem cells from blood can lead to quicker hematopoietic reconstitution than stem cells from bone marrow. 

Preparation

The application for a transplantation is submitted to the Allogeneic Stem Cell Group of Norway. As a minimum, the application must include a short disease history including  information about the time of remission, treatment given, precise diagnosis and evidence for it. It is also necessary to provide cytogenetic and molecular genetic data. Information about complications from treatment, general health status, organ function, and whether the patient has a blood-related donor should also be included.

Examinations before transplantation

In addition to the different blood tests and bone marrow tests, there are a series of examinations which all patients must complete before a stem cell transpIantation:

  • Lung function tests
  • Dental examination
  • Sperm examination/examination from gynecological clinic
  • Eye examination 
  • X-ray examination of heart and lungs, possibly other organs 

Sperm banking/ovarian tissue

It is important to offer sperm banking to men, if it is possible, before starting chemotherapy for a serious illness. It is realistic to assume the patient will be sterile after the transplantation.

Banking ovarian tissue is technically possible, but at current, use of this tissue is experimental.

Information

The patient and their family should receive thorough information about treatment, complications, and circumstances which should be in order before the treatment.

The patient will also be offered to speak to another patient who has completed a stem cell transplantation.

Preparation for stem cell transplant

Before starting conditioning, there are measures which must be taken to prevent and treat complications of chemotherapy and GVHD

Intravenous access

All patients must have a central vein catheter. If it is necessary to perform plasma replacement due to ABO incompatibility, the patient will need a two-way dialysis catheter. 

Hemotherapy

All blood products given during the time frame from one month before the transplantation to at least 12 hours after must be radiated to prevent proliferation of possibly included T-lymphocytes in the immunosuppressed patient, causing GVHD. Irradiation is necessary despite always using leukocyte-filtered blood products.  

All patients should receive blood products which are filtered for leukocytes. This ensures that the products are functional with CMV-negative patients and are used on both anti CMV-positive and negative patients.

Antibiotic prophylaxis

Three weeks before the transplantation, an antibiotic prophylaxis with trimetoprim-sulfa is started. This prophylaxis is taken until 4 days before the transplantation but is resumed with a stable graft. This treatment continues for 6 months from the transplantation day in patients without chronic GVHD, given the granulocyte count stays over 0.5 x 109/l. Patients requiring steroid treatment and/or who have chronic GVHD should continue with a pneumocystic pervecii prophylaxis for 6 months.

Valacyclovir is administered the day before the transplantation until 28 days after, if the patient is positive for herpes simplex and/or varicella zoster virus serology. The dosage is reduced if serum creatinine >150 mmol/l.

The mouth and throat are inspected daily for candida. For positive clinical findings, a nystatin mixture is given or amphotericin chewable tablets.

GVHD prophylaxis

Cyclosporin and methotrexate are given routinely to prevent acute and chronic GVHD. Other regimens are also used.

Prevention of CNS recurrence

For acute lymphoblastic leukemia, 2 intrathecal methotrexate injections are administered as part of pre-treatment.

Implementation

Conditioning

Bone marrow eradication treatment

For malignant blood diseases, a high-dose combination of busulfan and cylcophosphamide is given during the last 8 days before the transplant. Busulfan is given for 4 days and cyclophosphamide is given for 2 days. Patients who are not able to take busulfan orally will receive an intravenous preparation. In patients who have had CNS recurrence of acute leukemia, total CNS radiation may be appropriate before the other medications are given.

In special cases, it is recommended to administer fractioned total-body radiation and cyclophosphamide.

Prevention of hemorrhagic cystitis

Byproducts of chemotherapy drugs cause sores and inflammation of bladder mucosa causing bleeding. To prevent this, the following is administered:

  • forced hydration – starting before the first dose of busulfan (or cyclophosphamide for total-body radiation) with continual intravenous infusion and measurement of diuresis. Hydration is stopped approximately 20 hours after the last infusion of cyclophosphamide
  • mesna – uroprotector given intravenously for prevention of urinary toxicity in connection with administration of cyclophosphamide

Nausea prophylaxis and treatment

Metoclopramide is always given before busulfan and ondansetron is given before cyclophosphamide. Other medications are used in cases where this regimen is insufficient.

Infusion of stem cells

The stem cells are transferred to the recipient via intravenous infusion, as in a normal blood transfusion, or during support (as for HMAS) if the stem cells have been frozen .

The stem cells migrate to the recipient's bone marrow where they establish with the help of adhesion molecules and proliferate in a complicated, and far from fully clarified, interaction between cytokines, growth factors, and other cellular interactions. 

After 2-4 weeks, the granulocytes will start to appear in the patient's peripheral blood. Effective platelet production usually starts somewhat later.  

For ABO incompatibility between the donor and recipient, serious hemolysis may occur. Therefore, antibodies must be removed either by plasmapheresis, if the recipient has antibodies in a high titer against the donor erythrocytes, or by removing the plasma from the donor marrow if the donor has a high titer against the recipient. Sometimes erythrocytes must be removed from the stem cell product.

Follow-up

During the first weeks after a stem cell transplantation, the patient is very susceptible to infections, especially bacterial. The patient will remain in protected isolation with positive pressure ventilation and filtered air from the fifth day after the transplantation (granulocyte count  < 0.2 x 10 9/l). The patient may come out of isolation when the granulocyte count is stable (> 0.2 x 109/l) for at least 3 consecutive days, sometimes longer.

During the period the patient is in isolation, the patient, family and health personnel must follow their respective routines to reduce the risk of infection. Certain routines are performed daily until the new marrow starts to function. The purpose of following these routines is to prevent complications and ensure that possible complications are discovered early.

Daily routines:

  • blood tests
  • rectal temperature, pulse, and blood pressure
  • weight measurement 
  • fluid balance
  • inspection of mouth, throat, and skin

For complications, it is important that treatment is initiated as soon as possible.

Platelet and erythrocyte transfusions

Transfusions of thrombocytes and erythrocytes are necessary in the weeks after the transplantation to maintain platelets and Hb at safe levels.  

ABO-incompatible donor

During a stem cell transplantation with an ABO-incompatible donor, erythrocytes of type O are given subsequent to the transplantation until the erythrocytes in the patient have changed to the donor's blood type.

Nutrition

Chemotherapy generally causes nausea and vomiting. Medications can also influence sense of taste and reduce appetite for days or weeks. Most patients also experience mucositis with considerable pain after intensive chemotherapy.   

The patient's nutritional status is monitored and the need for parenteral nutrition (TPN) is considered individually. Almost all patients need TPN for a period after conditioning and in the aplasia phase. 

Mucositis

Mucositis, both in the mouth and other mucosa and intestines, often occurs when blood values are at their lowest. The intensity of the soreness is individual. Sore mucosa in the mouth is not only an entrance for bacteria, but can also be painful. Prophylactic oral hygiene should be performed during the entire treatment. Painful mucositis may necessitate treatment with analgesics, often opiates.

For painful rectal mucosa, ointment should be liberally applied. After each toilet visit, soft toilet paper dampened with peanut oil and subsequent abundant ointment should be used. A bath with green soap will soothe the pain.

Diarrhea

Patients who have received intensive chemotherapy, and/or total body irradiation, usually experience diarrhea. This is due to temporary damage of the intestinal mucosa from the treatment. Diarrhea can be expected to last during, and a few weeks after the treatment. 

GVHD can also cause intensive diarrhea. This type of diarrhea can occur a few weeks after the transplantation, about the time when the transplantation is expected to take, but also later on.

Intensive and broad spectrum antibiotic treatment in the aplasia phase will cause changes in the intestinal flora with diarrhea. Patients are also susceptible to infection from food. 

Nutritional status is generally controlled by administering total parenteral nutrition with fluid, electrolyte, and protein substitution.

Complications

Some complications should be expected after the transplant. Complications are sometimes serious and life-threatening, and in the worst case, fatal.

Infections

Due to large doses of busulfan and cyclophosphamide, the patient will have a serious immune defect and granulocytopenia during the first few days after taking the medication. 

For serious granulocytopenia, normal signs of infection will often not be present because the patient will not create pus. In the aplasia phase, bacterial infections are almost always primary, which can quickly become very serious. The only sign of infection is often fever, which must be taken very seriously for these types of patients. 

A reliable microbiological diagnosis is obtained relatively rarely. In cases where there is bacterial growth, the treatment is adjusted according to the resistance pattern.

If the patient becomes afebrile from the antibiotic treatment, the treatment should continue for at least 3 days or until the granulocyte count is over 0.2 x 109/l.

Both GVHD prophylaxis and GVHD requiring treatment with steroids or another immunosuppressant, increase immune deficiency. Even after the patient has received sufficient granulocytes, the immune system is still impaired, with a significant risk for infections. 

Important opportunistic microbes which can cause life-threatening infections are:

  • cytomegalovirus (CMV)
  • fungus (candida og aspergillus)
  • pneumocystic jerovecii
  • various bacteria

The patient must therefore be monitored by checking for the CMV antigen or PCR. Only leukocyte-filtered products can be used. These products rarely or never transfer CMV infections. 

One should be aware of new lung infiltrates, especially in patients with chronic GVHD. It is important to try to obtain diagnostic material. The threshold for doing bronchoscopy with broncial rinsing is low.

Fungal infection

In patients who are in the aplastic phase receiving antibiotics for 5-7 days without being afebrile, or who have a new rise in temperature despite adequate antibiotic treatment, a systemic or invasive fungal infection must be considered, especially if another infection cannot be detected in a blood culture. Empirical treatment must be considered with antimycotics in a sufficient dose, often intravenously must be considered.

Pneumonia/respiratory infection

Focal infiltrates are most often due to either a bacterial or fungal infection. It is important to be aware that patients without granulocytes rarely develop obvious infiltrates. An X-ray of the lungs is often negative in the aplasia phase. HR-CT is a much more sensitive examination. Infiltrates may become visible when the granulocytes return after the cytopenia phase, with a radiologically aggravation. This may be in spite of adequate treatment and clinical improvement. It is therefore very important with close clinical observation.

Interstitial pneumonia

Interstitial pneumonia is a lung infection with numerous small areas of infection. The condition is a feared complication in stem cell transplanted patients. Interstitial pneumonia can occur both before and many months after the engraftment. The mortality is high. The condition may be due is due to infections sensitive to treatment. 

  • CMV infection
  • Pneumocystic jerovecii (observed rarely during trimetoprim-sulfa prophylaxis)

It is therefore very important to initiate the correct treatment. Patients with interstitial pneumonia can quickly become dependent on a respirator and must be followed closely with a pulse oxymeter and by monitoration of arterial blood gases.  

CMV infection

A CMV infection is not uncommon after an allogeneic stem cell transplantation and is often due to reactivation of a virus in sero-positive patients. Acute GVHD and treatment of this increases the risk. 

The manifestations can vary from asymptomatic virus production via thrombocytopenia and leukopenia, to unexplained fever, hepatitis or gastrointestinal symptoms with life-threatening interstitial pneumonia. 

CMV pneumonitis typically occurs 40-60 days after the transplantation but can also occur later on. The fear of CMV pneumonitis is one of the reasons leukocyte-filtered products are used for allogeneic stem cell transplantations.

Detection of a CMV infection (positive pp65 or CMV-PCR) will usually lead to starting treatment with ganciclovir. The dose is reduced for reduced renal function. For granulocytes under 0.7 x 109/l, foscarnet is given instead. pp65 or CMV-PCR should be monitored at least once a week during the treatment.

Hepatic veno-occlusive disease

This condition is due to chemotherapy and/or total body irradiation. An obstruction of sinusoidal blood flow is due to damaged terminal hepatic vessels and sublobular veins. The condition is rare and is often observed 3-4 weeks after the transplant. 

The elevation of transaminase at the time of the transplantation causes an increased risk for hepatic veno-occlusive disease. The first sign is often gradual weight increase and increased need for platelet infusion. The patient may have intense abdominal pain, especially in the epigastrium and right hypochondrium, elevated bilirubin, and transaminase, with enlarged liver and soreness. Ascites may appear with weight gain, encephalopathy, and coagulopathy. At a later stage, the patient may develop hepatorenal syndrome.    

The treatment is expectative and symptomatic. The patient must be followed clinically very closely with monitoration of fluid and electrolyte balance. The prognosis is poor for serious involvement.

Thrombotic microangiopathy

These conditions occur rarely, but are potentially serious complications which affect about 5% of patients. The pathogenesis is only partly known, but endothelial damage is a central factor.

  • Microangiopathic hemolytic anemia (MAHA)
  • Hemolytic-uremic syndrome (HUS)
  • Thrombotic thrombocytopenic purpura (TTP)

 Symptoms are:

  • serious hemolysis 
  • renal failure
  • thrombocytopenia
  • neurological manifestations due to reduced circulation in capillaries

The benefit of therapeutic measures is controversial. Cyclosporin A is replaced with mycopholate or tacrolimus. A problem is that tracrolimus can also cause thrombocytopenia. It is also possible, but seldom effective, to perform plasma exchange.

Acute GVHD

Graft-versus-host disease is a condition where T-lymphocytes from the donor attack cells and tissue of the patient.

Bone marrow failure

Bone marrow failure refers to lasting anemia, leukopenia, and thrombocytopenia. Causes for bone marrow failure may be: 

  • rejection of bone marrow
  • delayed engraftment
  • infection (CMV among others)
  • bone marrow-toxic medications
  • GVHD

Megakaryocyte function is restored often lastly restored after the stem cell transplantation. Thrombocytopenia may also be due to enhanced consumption of platelets from infection, GVHD, and immunizing. 

In addition to reduced marrow function, anemia may be due to bleeding and/or hemolysis. For ABO incompatibility, a significant delay of adequate erythropoiesis is often observed (up to one year).

Long-term anorexia

Anorexia may be due to infection, GVHD, renal dysfunction, or medications. If the patient in addition has problems with swallowing, esophagitis, gastritis, or an ulcer may be the cause. The nutritional status should be maintained intravenously, as needed, which itself may cause anorexia in some patients.  

Hemorrhagic cystitis

Hemorrhagic cystitis is primarily due to high doses of cyclophosphamide, however, high doses of busulfan also play a role. Despite prophylactic measures with forced hydration and mesna, some patients still develop hematuria/dysuria/pollakisuria. The symptoms generally appear during or in the first three days after a cyclophosphamide infusion. Some patients can also develop hemorrhagic cystitis later on, possibly as a manifestation of GVHD, but also from a viral infection (CMV, adenovirus, BK virus).

The treatment is to continue or resume forced hydration/diuresis. Analgesics or antiviral treatment is started if necessary. 

Recurrence after allogeneic stem cell transplantation

For recurrence after a transplantation for CML, it has been shown that an infusion of T-lymphocytes from the donor causes complete remission in about 70% of patients who recur to a chronic phase. This GVL (graft-versus-leukemia) effect is more poorly documented in recurrence after transplantation for acute leukemia.

Further follow-up

Allogeneic Stem Cell Transplant with Non-Myeloablative Conditioning

General

An allogeneic stem cell transplantation with non-myeloablative conditioning is currently an option which is still experimental. The method and indication is therefore under constant change.

Conditions:

  • Patient is not appropriate for a conventional allogeneic stem cell transplantation (age, complicated illness, < 70 years).
  • The disease is potentially curable with an allogeneic stem cell transplantation.
  • No CNS involvement from the disease. 
  • Left ventricle ejection fraction ≥ 40 %.
  • No serious disturbances in lung function (need for oxygen supply, DLCO < 30 %, FEV1 < 30%).
  • No serious disturbances of biochemical liver parameters, that is:
    • bilirubin more than 2 fold above the normal limit 
    • ASAT and ALAT more than 4 fold above the normal limit
  • Karnofsky score greater than or equal to 50%.
  • Blood pressure 150/90 with standard hypertension medication.
  • Renal function almost normal.

The principle for this type of treatment is to utilize the anti-tumor effect from the donor's T-lymphocytes (and NK cells). The mechanism for this effect is unclear and the frequency of response varies from disease to disease. The method consists of a conditioning regimen which is strongly immunosuppressive, but not myeloablative, to achieve a mixed and subsequent full T-cell chimerism. When the result is successful, the autologous tumor cells are destroyed by the allogeneic lymphocytes. 

Indications

  • Patients with an HLA-identical relative donor or 10/10 identical unrelated donor, who are not suitable for conventional allogeneic stem cell transplantation. Preferably within diagnosis-specific clinical protocols. Must be reported to EBMT.

Possible diagnoses: 

  • Mantel cell- and follicular lymphoma with recurrence after HMAS and chemosensitive disease
  • Chronic lymphocytic leukemia after unsuccessful chemotherapy, including fludarabine
  • Chronic myeloid leukemia with unsuccessful cytogenetic response to optimal drug therapy
  • Multiple myeloma after HMAS
  • AML in research protocol - patients with potential family donor

Goal

  • Cure the disease.

Background

Donor

A blood related donor is preferred and currently, a blood related donor with up to one HLA (human leukocyte antigen) mismatch may be used. 

If the patient does not have a blood related donor, it may in some cases be considered whether an unrelated donor with HLA, A, B, C, DR and DQ identity can be used. Despite serological techniques, unrelated donors may still have small differences in their HLA molecules which are of significance for GVHD and rejection reactions, therefore genomic typing is performed.  

Stem cell harvesting

Hematopoietic stem cells are harvested by extracting bone marrow from the donor's hip bone or by mobilizing hematopoietic stem cells from bone marrow to blood. Mobilization can be done with the help of hematopoietic growth factors, most often granulocyte colony stimulating factor (G-CSF) given subcutaneously. The growth factors most likely influence adhesion molecules on the stem cells and bone marrow stroma allowing the stem cells to release into the blood stream. Because of this technique, it has become common to refer to stem cell transplantations instead of bone marrow transplantations as it reflects both methods of harvesting stem cells.

Harvesting from bone marrow

For extraction of stem cells from bone marrow, the tissue-compatible donor is given general anesthesia and lies in the prone position. Bone marrow is aspirated by repeated punctures of the hip bone. The procedure lasts 1 hour on average. The aspirated bone marrow with the stem cells is transferred to blood pouches with heparin. From the donor, 2 x 108 per/kg body weight of nuclei-containing cells are transferred to the recipient.

Harvesting from blood

Harvesting stem cells from blood does not require anesthesia, but the procedure can be time-consuming. The stem cells are harvested from a peripheral vein with the help of leukapheresis machines.

Each leukapheresis requires many hours. It is necessary to have 1-3 leukaphereses and a minimum of 2 x 106 CD34 of positive cells per/kg body weight of the recipient.

There are indications that the use of stem cells from blood can lead to quicker hematopoietic reconstitution than stem cells from bone marrow.

Preparation

The application for a transplant is submitted to the Allogeneic Stem Cell Group of Norway with copy to the lymphoma group at the Oslo University Hospital, the Radium Hospital. As a minimum, the application must include a short disease history including  information about the time of remission, treatment given, precise diagnosis and evidence for it. It is also necessary to provide the results from cytogenetic and molecular genetic data. Information about complications from treatment, general health status, organ function, and if the patient has a blood-related donor should also be included.

Examination before transplantation

In addition to the different blood tests and bone marrow tests, there are a series of examinations which all patients must complete before a stem cell transplantation:

  • Lung function tests
  • Dental examination
  • Sperm examination/examination from gynecological clinic
  • Eye examination 
  • X-ray examination of heart and lungs, possibly other organs

Infertility

It is unknown how this treatment affects fertility in men and women. It is important to offer sperm banking to men, if it is possible.

Banking ovarian tissue is technically possible, but at the present time, this is experimental.

Information

The patient and their family should receive thorough information about treatment, complications, and circumstances which should be in order before the treatment.

Preparation for stem cell transplantation

Before starting conditioning, there are measures which must be taken to prevent and treat complications of chemotherapy and GVHD

Intravenous access

All patients must have a central vein catheter. If it is necessary to perform plasma replacement due to ABO incompatibility, the patient will need a two-way dialysis catheter. 

Hemotherapy

All blood products given during the time frame from one month before the transplant, to at least 12 hours after, must be radiated to hinder proliferation of any included T-lymphocytes in the immunosuppressed patient, causing GVHD. Radiation is necessary despite always using leukocyte-filtered blood products.  

All patients should receive blood products which are filtered for leukocytes. This ensures that the products are functional with CMV-negative patients and are used on both anti CMV-positive and negative patients.

Immunosuppression

Cyclosporin is started before the transplant and administered orally, or intravenously if the patient is not able to take tablets. Other immunosuppressive drugs (tacrolimus, mycophenolate mofetil, alemtuzumab, sirolimus) are also used.

Antibiotic prophylaxis

  • Pneumocystic jerovecii prophylaxis—trimetoprim sulfa as for myeloablative transplants
  • Fungal prophylaxis—fluconazole daily from the 3rd day before the transplant and for 75 days after
  • Herpes zoster virus (HZV)/varicella zoster virus (VZV) prophylaxis:
    • for serum negative donor and recipient, prophylaxis is unecessary 
    • for HSV and/or positive recipient or negative recipient/positive donor, valacyclovir is given for a minimum of 4 weeks 
    • for VZV positive donor and/or recipient, valacyclovir is given until day 360.
  • Cytomegalovirus (CMV)—follow the same routines as for a myeloablative transplantation

Implementation

Conditioning regimens

Flu/2 Gy TBI (Seattle Protocol)

  • Flubarabine is administered intravenously on days 4, 3, and 2 before the transplantation.
  • On the day of the transplantation, the patient undergoes total body irradiation with 2 Gy.

Fludarabine/cyclophosphamide (Modified NCI protocol)

  • Fludarabine and cyclophosphamide are administered intravenously on days 6, 5, 4, 3 before the transplantation.
  • Day 2 before the transplantation, the immunosuppressant sirolimus is given.

For successful conditioning regimens, support treatment in the form of a 5 HT3  receptor antagonist or metoclopramid is given to prevent nausea, which is usually moderate.

In addition, the patient should have at least 3 liters of fluid per day during conditioning, either orally or intravenously. Allopurinol is given to prevent uric acid nephropathy.

Radiation treatment given in conjunction with the Seattle protocol often causes nausea which is treated with ondansetron. Other conditioning regimens are also used.

Infusion of stem cells

The stem cells are supplied to the recipient by intravenous infusion, as in a normal blood transfusion or as a boost.  

The stem cells migrate to the recipient's bone marrow where they establish with the help of adhesion molecules and proliferate in a complicated, and far from fully clarified, interaction between cytokines, growth factors, and other cellular interactions.   

For ABO incompatibility between the donor and recipient, serious hemolysis may occur. Therefore, antibodies must be removed either by plasmapheresis, if the recipient has antibodies in a high titer against the donor erythrocytes, or by removing the plasma from the donor marrow if the donor has a high titer against the recipient.


 

Follow-up

Hospitalization is not always necessary. If hospitalization is necessary, the patient should have a private room and is monitored with the same tests as a patient in myeloablative conditioning. Patients who are under outpatient care should be seen every other day for the first weeks, and should be instructed to contact an emergency doctor immediately if their temperature is > 38°C and/or increasing malaise. The unit should have a low threshold for admitting the patient for a clinical evaluation.

Bone marrow suppression should be expected between days 7 and 21, but seldom to a serious degree. The cyclosporin concentration should be measured daily for the first 2–3 weeks, otherwise, tests for cyclosporin concentration and other tests are taken Monday, Wednesday, and Friday for ordinary transplantations. 

On days 28, 56 and 84 after the transplantation, tests are taken for chimerism studies.

The remission status is assessed every 3 months with blood and bone marrow tests as for a myeloablative stem cell transplant. This may be supplemented with cytogenetics, flow cytometry, and/or PCR tests. For extramedullary disease optimal image analysis is taken which is usually CT.

Complications

Some complications should be expected after the transplant. Complications are sometimes serious and life-threatening, and in the worst case, fatal.

Infections

Due to large doses of busulfan and cyclophosphamide, the patient will have a serious immune defect and granulocytopenia during the first few days after taking the medication.

For serious granulocytopenia, normal signs of infection will often not be present because the patient will not create pus. In the aplasia phase, bacterial infections are almost always primary, which can quickly become very serious. The only sign of infection is often fever, which must be taken very seriously for these types of patients.

A reliable microbiological diagnosis is obtained relatively rarely. In cases where there is bacterial growth, the treatment is adjusted according to the resistance pattern.

If the patient becomes afebrile from the antibiotic treatment, the treatment should continue for at least 3 days or until the granulocyte count is over 0.2 x 109/l.

Both GVHD prophylaxis and GVHD requiring treatment with steroids or another immunosupressant, increase immune deficiency. Even after the patient has received sufficient granulocytes, the immune system is still impaired, with a significant risk for infections.

Important opportunistic microbes which can cause life-threatening infections are:

  • cytomegalovirus (CMV)
  • fungus (candida og aspergillus)
  • pneumocystic jerovecii
  • bacteria, such as pneumococcus, influenza hemofilus

The patient must therefore be monitored by checking for the CMV antigen or PCR. Only leukocyte-filtered products can be used. These products rarely or never transfer CMV infections.

One should be aware of new lung infiltrates, especially in patients with chronic GVHD. It is important to try to obtain diagnostic material. The threshold for doing bronchoscopy with broncial rinsing is low.

Fungal infection

In patients who are in the aplastic phase receiving antibiotics for 5-7 days without being afebrile, or who have a new rise in temperature despite adequate antibiotic treatment, a systemic or invasive fungal infection must be considered, especially if another infection cannot be detected in a blood culture. Empirical treatment must be considered with antimycotics in a sufficient dose, often intravenously must be considered.

Pneumonia/respiratory infection

Focal infiltrates are most often due to either a bacterial or fungal infection. It is important to be aware that patients without granulocytes rarely develop obvious infiltrates. An X-ray of the lungs is often negative in the aplasia phase. HR-CT is a much more sensitive examination. Infiltrates may become visuble when the granulocytes return after the cytopenia phase, with a radiologically aggravation. This may be in spite of adequate treatment and clinical improvement. It is therefore very important with close clinical observation.

Interstitial pneumonia

Interstitial pneumonia is a lung infection with numerous small areas of infection. The condition is a feared complication in stem cell transplanted patients. Interstitial pneumonia can occur both before and many months after the engraftment. The mortality is high. The condition may be due is due to infections sensitive to treatment.

  • CMV infection
  • Pneumocystic jerovecii (observed rarely during trimetoprim-sulfa prophylaxis)

It is therefore very important to initiate the correct treatment. Patients with interstitial pneumonia can quickly become dependent on a respirator and must be followed closely with a pulse oxymeter and by monitoration of arterial blood gases.

CMV infection

A CMV infection is not uncommon after an allogeneic stem cell transplantation and is often due to reactivation of a virus in sero-positive patients. Acute GVHD and treatment of this increases the risk.

The manifestations can vary from asymptomatic virus production via thrombocytopenia and leukopenia, to unexplained fever, hepatitis or gastrointestinal symptoms with life-threatening interstitial pneumonia.

CMV pneumonitis typically occurs 40-60 days after the transplantation but can also occur later on. The fear of CMV pneumonitis is one of the reasons leukocyte-filtered products are used for allogeneic stem cell transplantations.

Detection of a CMV infection (positive pp65 or CMV-PCR) will usually lead to starting treatment with ganciclovir. The dose is reduced for reduced renal function. For granulocytes under 0.7 x 109/l, foscarnet is given instead. pp65 or CMV-PCR should be monitored at least once a week during the treatment.

Thrombotic microangiopathy

These conditions occur rarely, but are potentially serious complications which affect about 5% of patients. The pathogenesis is only partly known, but endothelial damage is a central factor.

  • Microangiopathic hemolytic anemia (MAHA)
  • Hemolytic-uremic syndrome (HUS)
  • Thrombotic thrombocytopenic purpura (TTP)

Symptoms are:

  • serious hemolysis
  • renal failure
  • thrombocytopenia
  • neurological manifestations due to reduced circulation in capillaries

The benefit of therapeutic measures is controversial. Cyclosporin A is replaced with mycopholate or tacrolimus. A problem is that tracrolimus can also cause thrombocytopenia. It is also possible, but seldom effective, to perform plasma exchange.

Acute GVHD

Graft-versus-host disease is a condition where T-lymphocytes from the donor attack cells and tissue of the patient.

Bone marrow failure

Bone marrow failure refers to lasting anemia, leukopenia, and thrombocytopenia. Causes for bone marrow failure may be:

  • rejection of bone marrow
  • delayed engraftment
  • infection (CMV among others)
  • bone marrow-toxic medications
  • GVHD

Megakaryocyte function is restored often lastly restored after the stem cell transplantation. Thrombocytopenia may also be due to enhanced consumption of platelets from infection, GVHD, and immunizing.

In addition to reduced marrow function, anemia may be due to bleeding and/or hemolysis. For ABO incompatibility, a significant delay of adequate erythropoiesis is often observed (up to one year).

Long-term anorexia

Anorexia may be due to infection, GVHD, renal dysfunction, or medications. If the patient in addition has problems with swallowing, esophagitis, gastritis, or an ulcer may be the cause. The nutritional status should be maintained intravenously, as needed, which itself may cause anorexia in some patients.

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


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  13. Tanyi JL, Smith JA, Ramos L, Parker CL, Munsell MF, Wolf JK. Predisposingrisk factors for palmar-plantar erythrodysesthesia when using liposomal doxorubicin to treat recurrent ovarian cancer. Gynecol Oncol 2009;114:219-24.
  14. Payne AS, Savarese DMF. Cutaneous complications of conventional chemotherapy agents. I: UpToDate [version 18.2 2010]. Hentet 1. desember 2010 fra: http://www.uptodate.com
  15. Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: an update. J Am Acad Dermatol 2008;58:545-70.
  16. RELIS Sør. Hyperpigmentering av cytostatika og forverring av sollys. I: RELIS database 2010, Spm.nr 4736. Hentet 1. desember fra: http://relis.arnett.no/Utredning_Ekstern.aspx?Relis=2&S=4736
  17. Hendrix JD Jr, Greer KE. Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol 1992;31:458-66.
  18. Schmid-Wendtner MH, Wendtner CM, Volkenandt M, Heinemann V. Clinical picture: leopard-like vitiligo with capecitabine. Lancet 2001;358(9293):1575.
  19. Segaert S, Tabernero J, Chosidow O, Dirschka T, Elsner J, Mancini L, et al. The management of skin reactions in cancer patients receiving epidermal growth factor receptor targeted therapies. J Dtsch Dermatol Ges 2005;3:599-606.

Preparation of Chemotherapy, Spills, and Cleaning a LAF Bench

General

Preparation of chemotherapy outside of a pharmacy

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

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

Designated room with LAF-bench to dilute/mix chemotherapy

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

Goal

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

Handling of chemotherapy spills

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

Goal

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

Cleaning of LAF-bench

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

Goal

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

Source

Applicable directives and guidelines (www.lovdata.no)

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

Equipment

  Preparation of chemotherapy in a hospital

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

Handling of chemotherapy spills

Spill kit includes:

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

Washing of LAF-bench

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

 

 

Preparation

Preparation of chemotherapy outside of the pharmacy

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

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

Handling of chemotherapy spills

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

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

Washing of LAF-bench

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

 

 

Implementation

Preparation of chemotherapy drugs outside of a pharmacy

Aseptic procedure

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

Multiple additions

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

Handling of chemotherapy spills

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

Washing of LAF-bench

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

Routine washing

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

Follow-up

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

First aid if contact with chemotherapy drugs

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

Radiation therapy of leukemia

Tumor cells from most forms of leukemia are relatively sensitive to radiation. However, radiation therapy still has a limited scope in treatment of leukemia, mainly due to the generalized growth of the disease.  

Radiation may be a supplementary treatment for different types of leukemia. Treatment protocols for leukemia often include detailed indications for radiation therapy. There are guidelines for what patients and which organs are recommended for radiation therapy, definitions for target volume and risk organs, fractioning and total dose. Use of radiation is so protocol-dependent that general recommendations cannot be given. 

Total brain or total CNS axis (brain with spinal cord and cerebrospinal fluid space) are the most common areas appropriate for radiation treatment with the goal of curing the disease. Radiation in these areas can be given as prophylaxis against or treatment for manifest CNS affection.

Patients with acute lymphocytic leukemia of testicles or with a large mediastinal tumor may also be appropriate for consolidating radiation treatment to these areas.

Radiation of the entire body (total body irradiation, TBI) may be part of the conditioning regimen before an allogeneic or autologous stem cell transplantation.

Radiation therapy to most regions may be appropriate as palliative treatment in situations where local progression of leukemia dominates the clinical picture.

PROSEDYRER

Whole brain radiation therapy

General

Indications

Lymphomas primarily occur in the CNS or affect the CNS as part of a generalized disease.

Radiation treatment of intracerebral, intraspinal, or meningeal/cerebrospinal fluid lymphoma manifestations may be appropriate as one or more treatment alternatives. This treatment is often part of a multimodal approach in combination with systemic and intrathecal/intraventricular chemotherapy.   

Radiation treatment can be given to the entire CNS axis (brain, spinal cord, and cerebrospinal fluid space down to the S1/2 level, sometimes including both eye sockets and optical nerves) or only the brain with surrounding liquor space. Due to the diffuse growth and tendency for meningeal involvement of lymphomas, whole brain radiation is almost always indicated. Radiation of only parts of the brain or a boost to parts of the brain is normally not recommended.

Radiation therapy to cure the disease 

Radiation therapy to the whole brain can be given as a part of multimodal curative treatment in:

  • Primary CNS lymphomas (PCNSL) - In younger patients (< 60 years), radiation to the brain is often included in treatments where CNS-directed chemotherapy is followed by radiation therapy. The role that radiation therapy plays, as well as the total dosage and fractioning , is uncertain. At the Oslo University Hospital, we use the protocol from Memorial Sloan Kettering Cancer Center. In older patients, a combination with chemotherapy often causes significant neurotoxicity, therefore radiation therapy is used with caution and preferably reserved for patients who do not achieve effect from chemotherapy, or for recurrence of the disease. For a multi-modal treatment arrangement for PCNSL, it is generally not recommended to administer radiation treatment to the spinal cord, even if lumbar puncture has shown more generalized meningeal spreading of tumor cells. If the eye ball is not known to be involved, it is not included in the radiation field. A new nordic protocol for PCNSL is under planning where radiation is not used as the primary treatment, for both older or younger patients. 
  • Treatment/prophylaxis of CNS manifestations for acute lymphoblastic leukemia and Burkitt's lymphoma - For treatment/prophylaxis of a CNS disease as part of treatment to cure acute lymphoblastic leukemia, radiation treatment may be included. It is often combined with CNS-directed chemotherapy/intrathecal treatment. It may be appropriate (but not obligatory) to give radiation to the spinal cord simultaneously.
  • Treatment/prophylaxis of CNS manifestation from several other malignant lymphomas: In other malignant lymphomas where the CNS is involved, radiation treatment to the brain is considered individually as part of the treatment plan to cure the disease. If there is meningeal spreading or findings in the spinal cord, it may be appropriate to add radiation treatment to the spinal cord.

Palliative radiation therapy

  • For palliative radiation therapy, the method generally follows the same guidelines as for curative treatment, with individual adjustments.

In younger patients (< 60 years), radiation to the brain is often included in treatments where CNS-directed chemotherapy is followed by radiation therapy. The role that radiation therapy plays, as well as the total dosage and fractioning, is uncertain. 

The curative schedule after chemotherapy with hyperfractionated treatment may have possible advantages. At Oslo University Hospital (Radiumhospitalet), the treatment schedule from MSKCC is used. In elderly patients, a combination of chemotherapy of this kind often causes significant neurotoxicity, and radiation therapy should be used with caution, preferably reserved for patients with poor response to chemotherapy or with recurrence.  

For multimodal treatment for PCNSL, radiation therapy is normally not given to the spinal cord, even if lumbar puncture has shown more generalized meningeal scattering of tumor cells. If there is no known involvement of the bulb of the eye, the eye is not included in the radiation field. A new Nordic protocol for PCNSL is planned where radiation therapy will not be used during primary treatment, either for elderly or younger patients.  

For treatment/prophylaxis for CNS disease as part of the curative treatment arrangement for ALL/lymphoblastic disease, lower doses are preferably used (18–24 Gy in 1.8–2 Gy per fraction), often in combination with CNS-directed chemotherapy/intrathecal treatment. Simultaneous radiotherapy to the spinal cord is often given (but not obligatory). 

For other malignant lymphomas with CNS involvement, radiotherapy to the brain is considered, either as part of a curative or palliative plan. In cases of meningeal scattering of tumor cells or findings in the spinal cord, radiation therapy of the spinal cord may also be given.

    Definitions

    Target Volume

     

     

     

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

     

    GTV (Gross tumor volume)

    Gross palpable or visible/identifiable area of malignant growth.

     

    CTV (Clinical target volume)

    Macroscopic tumor volume including any remaining tumor tissue.

     

    ITV (Internal Target Volume)

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

     

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

    PRV (Planning organ-at-risk volume)

     

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

    Field Limits 

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

    Definition of margins

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

     

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

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

     

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

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

    GTV + 1cm in transverse plane

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

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

     

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

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

    CTV + 2–3 cm in mesentery

    CTV + 0-0.5 cm transverse retroperitoneally

     

    PTV

    Not routinely defined

     

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

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

     

    Involved node

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

    Involved field

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

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

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

    Extended field

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

     

     

    Preparation

    • For radiation therapy to the whole brain without the spinal cord, the patient lies supine and is immobilized with a mask. 
    • There should be slight flexion of the neck. 
    • The position of the lenses can be marked with a piece of lead at the lateral edge of the orbita.
    • If fields are to be joined toward the spinal cord, the patient must be immobilized as described in the procedure for the total CNS axis.

    Implementation

    Conventional simulation

    • Cranial and lateral limits are outside the patient in the air.
    • For modeling of the caudal borders on the simulator, it is important to include the base of the skull with branches of the cranial nerves as these are covered by the meninges to an extent (be especially aware of the lamina cribrosa). Usually, the brain stem is included farther down than for solid tumors. At the same time, the lenses should be blocked and the eyes as much as possible. For curative treatment, it must sometimes be accepted that tolerance doses for lenses are exceeded. 
    • Field shaping from side to side including eye blocks will obtain a  "German helmet" configuration and reaches farther down the cervical column with good margins to the spinal canal (for example to discs C2/C3 or C3/C4 level).
    • Orbital cavities can be included if there is known lymphoma involvement of the eye ball or optic nerves. 

    CT-based simulation

    • For treatment which is planned with CT, the entire brain is modeled including the outer liquor space as CTV. For practical purposes, the inside of the bone in the cranium and the spinal canal is the limit.
    • Be very precise when contouring the skull. The dura sacs which follow the nerve roots in the different foramens must be included in the CTV. CTV includes also the upper cervical column such that the field limits later remain at levels with for example C3 or C4.   
    • The orbital cavities may be included in CTV if there is known lymphoma in the eye ball or optic nerves.
    • Field shaping will be two opposing lateral fields. Field shaping should be checked with regards to skeletal structures at the base of the skull before approval just to ensure good coverage of the lamina cribrosa and other foramens in the cranial nerves.  

    CT dosage plan

    Fractionation

    Fractionation and total dose depend on multiple factors, among others, the type of lymphoma and the protocol is followed. For a treatment plan intended to cure the disease the following is recommended:  

    For PCNSL, Oslo University Hospital follow the protocol from  MSKCC, which is 1.80 Gy x 25 for patients under 60 years subsequent to 5 courses of high-dose MTX, if the patient is not in complete remission. For involvement of the eye, these are included with 1.8 Gy x 20. If the patient is in complete remission, 1.2 Gy x 30 is given with 2 fractions daily. Patients over 60 are not routinely given radiation therapy.

    For lymphoblastic leukemia/ALL, treatment is administered according to study protocols, for example NOPHO in children, preferably 2 Gy x 9-12.

    For other lymphomas, fractionation is determined individually.

    For palliative treatment, 3 Gy x 10 is most often used.

    Follow-up

    Organs at risk

    Brain 

    There is a risk of short-term nerve toxicity causing dizziness, nausea, headache and long-term neuropsychiatric changes. Antiemetic treatment should be considered before starting treatment. Long-term neuropsychiatric changes may depend on multiple factors such as age and if chemotherapy is administered simultaneously (especially high-dose MTX). Those at the highest risk are patients over 60 years who receive whole brain radiation after high-dose MTX.   

    Lens of the eye

    A dose over 4-6 Gy must often be accepted to obtain adequate coverage to structures near the lamina cribrosa. This may pose a risk for cataract development in some patients.  

    Pituitary gland

    The dosages used are often lower than the tolerance dose for adults, however, endocrine function should be followed long after treatment in children. 

    Radiation therapy for the entire CNS axis

    General

    Lymphomas primarily occur in the CNS or involve the CNS as part of a generalized disease.

    Radiation treatment of intracerebral, intraspinal, or meningeal/cerebrospinal fluid lymphoma manifestations may be appropriate as one or more treatment alternatives. This treatment is often part of a multimodal approach in combination with systemic and intrathecal/intraventricular chemotherapy.   

    Radiation treatment can be given to the entire CNS axis (brain, spinal cord, and cerebrospinal fluid space down to the S1/2 level, sometimes including both eyes and optical nerves) or only the brain with surrounding fluid space. Due to the diffuse growth and tendency for meningeal involvement of lymphomas, whole brain radiation is almost always indicated. Radiation of only parts of the brain or a boost to parts of the brain is normally not recommended.

    Treatment is administered together or at the end of CNS-directed chemotherapy/intrathecal chemotherapy.

    Indication

    • Total CNS axis (whole brain with spinal cord and dural sac) is most often irradiated as part of protocols for acute lymphoblastic leukemia, where it is included as part of CNS prophylaxis or treatment for a manifest CNS disease.  

     

    In some patients with lymphoma in the CNS, radiation to the entire neuro axis is also used.

    Curative radiation therapy

    Radiation treatment of of the entire CNS axis can be administered as a segment of curative treatment for:

     

    • Treatment/prophylaxis of CNS manifestations of lymphoblastic/acute lymphoblastic leukemia and Burkitt's lymphoma 
    • Treatment/prophylaxis of CNS manifestations for acute lymphoblastic leukemia and Burkitt's lymphoma. For treatment/prophylaxis of a CNS disease as part of treatment to cure acute lymphoblastic leukemia, radiation treatment may be included. It is often combined with CNS-directed chemotherapy/intrathecal treatment.  It may be appropriate (but not obligatory) to give radiation to the spinal cord simultaneously.
    • Treatment/prophylaxis of CNS manifestation from other malignant lymphomas - In other malignant lymphomas where the CNS is involved, radiation treatment to the brain is considered individually as part of a treatment plan to cure the disease. In the case of meningeal spreading or findings in the spinal cord, it may be appropriate to combine with radiation treatment of the spinal cord.

    Palliative radiation therapy

    • Radiation of the total CNS axis is resource-consuming treatment with side effects. This treatment form is therefore not suited for palliative treatment in all patients with generalized lymphoma in the CNS. For palliative radiation treatment, the method for the radiation therapy itself follows the same guidelines as for curative treatment with individual modifications.

    Definitions

    Target Volume

     

     

    Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)
    GTV (Gross tumor volume) Gross palpable or visible/identifiable area of malignant growth.
    CTV (Clinical target volume) Macroscopic tumor volume including any remaining tumor tissue.
    ITV (Internal Target Volume) Volume containing CTV and internal margin to allow for internal movements and changes to CTV.
    PTV (Planning Target Volume) Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
    OAR (Organ-at-Risk) Normal tissue senstive to radiation that may significantly affect planning and/or dose.
    PRV (Planning organ-at-risk volume) Geometric volume containing risk volume with set-up margin.
    TV (Treated Volume) Volume within an isodose surface considered sufficient based on the treatment intention.
    IV (Irradiated Volume) Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
    CI (Conformity Index) Relationship between the planning target volume and treated volume (PTV/TV).

    Field Limits

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

    Definition of margins

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

     

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

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

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

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

    GTV + 1cm in transverse plane

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

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

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

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

    CTV + 2–3 cm in mesentery

    CTV + 0-0.5 cm transverse retroperitoneally

    PTV Not routinely defined
    Field limits ITV + Setup margin and penumbra (1.2 cm)

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

    Involved node

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

    Involved field

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

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

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

    Extended field

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

    Preparation

    • Patient is immobilized in the prone position with the help of VacFix® with head support for the prone position and mask.  
    • The patient should lie as comfortable as possible with the shoulders as far down as possible. 
    • There should be a certain hyperextension of the neck to give the smallest possible dose to the mouth.
    • The spinal column should be as straight as possible. 
    • Sedation is usually necessary to carry out fixation, simulation, and treatment in children.

    Implementation

    Conventional simulation

    Modeling of the field to the brain and spinal cord can be done with conventional simulation, but CT-based planning is recommended.

    • The whole brain is irradiated from side to side down to the caudal border of C3 or C4 (depending on shoulder position, see other chapter). It is very important to be precise with adjustment of the field borders in relation to the base of the skull as for total brain irradiation.
    • At the caudal edge of C3 or C4, a juncture is made with the upper dorsal medulla field. The juncture must be planned with a physicist. 
    • Depending on the height of the patient, 1 or 2 medulla fields are given from behind. If there are two fields, there is also a juncture between these in the thoracic column. The juncture is calculated by a physicist and juncture movement must be planned during the simulation.
    • The lower border for the medulla fields must be below the end of the dural sac which is typically at the level of S2.
    • The lateral borders are lateral to the vertebral bodies with 1 cm margins to cover the dural sac where it follows the nerve roots out of the intevertebral foramen in addition to tuning uncertainty and penumbra.  
    • The medulla fields are dosed by depth where the depth is calculated from the dorsal skin surface to the dorsal aspect of the vertebral bodies/ventral limit of the spinal cord. Due to curvature of the vertebral column, the depth will vary according to the level of the vertebral column. It may be very difficult to identify the structures of the vertebrae on the coronal fluoroscopic simulator images. Differences in depth are compensated by filters of varying thickness.  

    CT-based simulation 

    Dose planning with CT is recommended for radiation to the entire CNS axis. CT uptake saves time for the patient compared to conventional simulation and is therefore considered patient-friendly. Dose planning is also more simple. 

    • A CT scan is taken after immobilization in VacFix® in the prone position with a mask. 
    • The whole brain and spinal canal limited to S2 at minimum toward the legs is modeled as CTV.
    • It is very important to include the extensions of the subarachnoid space, along the cranial nerves at the base of the skull and the dural extensions along the nerve roots in the intevertebral foramina, are well covered.
    • If the whole brain is to have more fractions than the spinal cord, the whole brain down to C3 or C4 must be modeled as a separate CTV for planning these fractions.
    • Check the field limits of the set-up cover the base of the skull well and the lateral limits for the medulla fields are 1 cm outside the vertebral bodies.
    • It may be beneficial to place the isocenter for the upper medulla field relatively high to obtain a geometric, and relatively clean juncture of the lateral fields toward the brain. Moving junctures can then be avoided between the brain and upper medulla field. 
    • Movement of junctures between the medulla fields is performed routinely.

    CT dose plan    

    Fractionation

    Fractionation and total dose depend on multiple factors, among others, the type of lymphoma and which protocol is followed.

    For a curative treatment plan, the following are indicated:

    • For lymphoblastic leukemia/ALL, treatment is administered according to study protocols, for example NOPHO in children, preferably 2 Gy x 9-12 to the whole brain and 2 gy x 6-9 to the spinal cord.
    • For other lymphomas and for palliative treatment, fractionation is determined individually.

    Follow-up

    Organs at risk

    Brain 

    There is a risk of short-term nerve toxicity such as dizziness, nausea, headache and long-term neuropsychiatric changes. Antiemetic treatment should be considered before starting treatment. Long-term neuropsychiatric changes may depend on multiple factors such as age, and if chemotherapy is administered simultaneously (especially high-dose MTX). Those at the highest risk are patients over 60 years who receive whole brain irradiation after high-dose MTX.    

    Blood and bone marrow

    Large amounts of bone marrow is included in the radiation field for the CNS axis. Counts with differential counts must be taken during and for a time after treatment.  

    Lens of the eye

    A dose of over 4-6 Gy must often be accepted to obtain sufficient coverage to structures near the lamina cribrosa. This may pose a risk for cataract development in some patients.  

    Pituitary gland

    The dosages used are often lower than the tolerance dose for adults, however, endocrine function should be followed long after treatment in children.

    Growth inhibition

    The entire spinal column is irradiated. Even if the doses are small, some growth inhibition may occur.

    Gonads

    Total CNS axis is irradiated as part of intensive treatment protocols, which collectively has a negative influence on fertility. The dose to the testicles should be minimized as much as possible by shielding. The ovaries in girls and women at a fertile age will be very close to the spinal cord fields and are difficult to shield.

    Total Body Irradiation

    General

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

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

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

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

    Indications

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

       

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

       

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

       

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

    Definitions

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

     

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

     

    GTV (Gross tumor volume)

    Gross palpable or visible/identifiable area of malignant growth.

     

    CTV (Clinical target volume)

    Macroscopic tumor volume including any remaining tumor tissue.

     

    ITV (Internal Target Volume)

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

     

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

    PRV (Planning organ-at-risk volume)

     

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

     

    Field Limits

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

    Definition of margins

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

     

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

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

     

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

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

    GTV + 1cm in transverse plane

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

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

     

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

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

    CTV + 2–3 cm in mesentery

    CTV + 0-0.5 cm transverse retroperitoneally

     

    PTV

    Not routinely defined

     

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

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

     

    Involved node

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

     

    Involved field

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

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

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

    Extended field

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

    Preparation

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

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

    Implementation

    Conventional simulation

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

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

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

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

     

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

       

    Treatment

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

     

    Follow-up

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

    The most significant acute side effects:

    Nausea and vomiting 

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

    Radiation-induced mucositis 

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

    Hair and nail growth

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

     

    Bone marrow

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

    The most significant long-term side effects: 

    Lung toxicity

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

    Fertility

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

    Endocrine disturbances

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

    Growth disturbances

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

     

    Secondary cancer

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

    Complication treatment of leukemia

    Cancer treatment causes side effects to varying degrees.

    It may be necessary to provide supportive care in order for the patient to complete and obtain 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

    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.

    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.

    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.

    Bone marrow stimulation with G-CSF for lymphoma

    General

    G-CSF (granulocyte colony-stimulating factor) is a hematopoetic growth factor. Human G-CSF is a glycoprotein which regulates production and liberation of neutrophile granulocytes from bone marrow.  

    For bone marrow stimulation with G-CSF, the drugs Neupogen® and Neulasta® are injected subcutaneously. Neulasta® and Neupogen® are available in prefilled syringes. Neupogen® is given once daily during aplasia. Neulasta® has a protracted effect and is given only one day after chemotherapy (i.e. day 2-4).

    The patients may administer the injection themselves at home if they are instructed and comfortable doing so.  

     

    Indications

    • Mobilization of stem cells to peripheral blood for autologous stem cell harvesting, usually a dosage of 10 µg/kg/day.
    • For high-dose chemotherapy with autologous stem cell support (HMAS), where bone marrow is used as the stem cell source. 
    • Primary prophylaxis to maintain dose intensity for curative chemotherapy with documentation that this is not possible without G-CSF (for example CHO(E)P-14, dose-escalated BEACOPP).
    • Secondary prophylaxis for curative chemotherapy where the patient after previous chemotherapy developed neutropenic fever. 
    • Secondary prophylaxis to maintain dose intensity for curative chemotherapy where experience has shown that the patient developed neutropenia that would have led to neutropenia leading to dose reduction or postponement of therapy (for example CHOP-21, ABVD, standard BEACOPP)
    • Lasting neutropenic fever in a critically ill patient, for example serious pneumonia, hypotension, serious sepsis, or fungal infection. 

    Preparation

  • Adequate information to the patient
  • Instruction in subcutaneous injection for patients giving self-injections.
  • Implementation

    • The Neupogen® dose is 5 µg/kg/day. For patients over 80 kg, 480 µg x 1 s.c. Otherwise, 300 µg x 1 s.c. (in protocol studies, dosage may be different). Neulasta® has a standard dosage of 6 mg s.c. (used only one day after chemotherapy).

    • G-CSF is used from 2–5 days after neutrophile > 5 x 109/l or > 1 x 109/l for three days.
    • Use of G-CSF for mobilization of stem cells to peripheral blood before autologous stem cell harvesting is usually given as 10 µg/kg/day distributed as two doses per day (morning and evening).
    • Before stem cell harvesting the entire dose is given in the morning.

    Follow-up

    • It is very important that the patient is informed of the risk for infections associated with low neutrophil counts.
    • Patients at risk for low leukocyte values must be given information about precautions for rising temperature. The patient should immediately contact a doctor if the temperature rises above 38.5 °C, or 38.0 °C measured over two hours.  
    • G-CSF may cause influenza-like symptoms as well as pain in large bone marrow-producing bones. The need for pain medication must be weighed against the fever-reducing effect. 
    • Some patients have required opiates for pain during treatment with growth factor. 

    Prevention of Tumor Lysis Syndrome

    General

    Tumor lysis syndrome is a life-threatening complication in cancers where rapid cell loss is caused when treatment is initiated.

    In tumor lysis syndrome, there is a rapid decrease of cells in a matter of hours/days causing depletion of intracellular substances into extracellular space. This causes an increased serum concentration of calcium, phosphate, magnesium, urine substances, and uric acid.  

    Uric acid can lead to precipitation of uric acid crystals in the renal tubules and lead to reduction of renal function. Renal failure is worsened by the binding of phosphate ions with calcium ions creating calcium phosphate crystals which also precipitate in the tubules. When calcium phosphate is > 8-10 mmol/l, the risk of precipitation of crystals in the kidneys and other tissue, increases.  

    Hyperkalemia from release of intracellular potassium is the greatest acute threat to the patient. Levels > 7 mmol/l increases the risk for cardiac arrhythmia and cardiac arrest. 

    Tumor lysis syndrome is observed in association with the first course of chemotherapy, start of radiation therapy, or steroid treatment.

    Patients who are disposed for developing tymor lysis syndrome have:

    • a relatively large tumor mass with high cell proliferation
    • elevated leukocyte count (leukemized blood profile)
    • elevated LDH
    • elevated uric acid
    • reduced renal function 

    The patient`s well being is often already influenced by the disease. Therefore, the degree of electrolyte disturbance contributes to complicating the patient's progress. 

    The prognosis is good with adequate prophylaxis and timely treatment.

    Indication

    • Acute leukemia, lymphoblastic lymphoma, Burkitt's lymphoma (often observed)
    • Other aggressive B- and T-cell lymphomas and indolent lymphomas with massive leukemization treated with monoclonal antibodies (less frequent) 
    • Solid tumors such as small cell lung cancer, medulloblastoma, testical cancer, and advanced breast cancer (rare) 

    Goal

    • Prevention of tumor lysis syndrome

    Definitions

    Tymor lysis is the disintegration of tumor cells, either spontaneously or due to different forms of tumor-directed treatment.

    Preparation

    • Sufficient information about the risk of developing tumor lysis syndrome.
    • Start prophylaxis for tumor lysis syndrome as soon as possible, preferably 1-2 days after starting chemotherapy. 

    Implementation

    Forced hydration is important.

    • Intravenous fluid for adults: 3000-8000 ml NaCl/24 hours. For children, 3000-5000 Salidex® ml/m2/day, depending on the amount of expected tumor disintegration.   
    • Administer allopurinol tablets.
    • If uric acid and creatinine values are higher than expected, rasburicase is administered intravenously, which degrades uric acid rapidly, instead of allopurinol. 
    • Ensure control of fluid accounting.
    • Observe that the hourly diuresis is over 250 ml/hour for adults. Furosemide 20 mg can be given for normal renal function for every 1000 ml of fluid administered. For reduced renal function, it may be necessary to give significantly higher doses. For children, furosemide is administered for insufficient diuresis. Hourly diuresis should be 100-250 ml/hour. 
    • Alkalization of urine is somewhat controversial, but of importance if uric acid is elevated and before and during administration of high dose methotrexate i.v.: for adults, sodium bicarbonate tablets (1-2 g x 3-5 per day) are administered. If there is a significant risk for tumor lysis, or if the patient cannot take tablets, NaHCO3 is administered intravenously (about 160 mmol/24 hours). Dosing depends on the acid-base status. For children, 40 mmol NaHCO3  per 1000 ml is added and possibly KCl additions to the hydration fluid, based on blood test results.
    • Monitoring urine should occur with pH measurements every 4 hours. The pH should be > 7.0.
    • Weighing the patient twice daily is also a method of assessing the fluid balance. 
    • Administer electrolyte supplements as needed.

    When the risk of developing tumor lysis is significant after starting treatment, values for Na, K, Cl, Ca, Mg, P, creatinine, uric acid and urine substances in the blood should be checked 2 or more times daily.  

    For fully developed tumor lysis syndrome, it may be necessary to repeat tests 3-5 times a day. For greater electrolyte disturbances, a venous acid-base status should also be taken.

    For large electrolyte disturbances such as hyperkalemia > 7mmol/l and/or serious hypocalcemia and weakened renal function, the patient should be transferred to the intensive division. A nephrologist should be contacted for emergency help in case of dialysis.

    Follow-up Care

    Tumor lysis tests are checked 2-4 times in the first days after starting treatment. If the patient has not developed tumor lysis syndrome in the next 2-4 days, the patient may continue the work-up/cancer treatment or possibly return home.

    Sperm Banking

    General

    Sperm banking services may apply to patients having a disease or undergoing treatment which reduces or eradicates the patient's fertility. The decision for storage is made by the doctor in charge of the patient in cooperation with the chief physician at the andrology laboratory.

    Stored sperm can only be used for assisted fertilization by the patient's spouse or partner in a stable relationship (duration more than 2 years).

    The offer for freezing and storing sperm does not guarantee treatment with assisted fertilization. The decision for this is made by the treating doctor according to guidelines and laws for assisted fertilization.

    The patient may store up to three samples. The samples should be taken with a few days in between and the patient should not have ejaculated for two days prior to sample collection.

    Indications

    • Cancer treatment rendering a man infertile.

    Goal

    • The possibility of having children after treatment is concluded.

    Equipment

    • A urine sample container.
    • A room for the patient to be undisturbed.

    Preparation

    • Inform the patient verbally and in writing.
    • Conform to rules and guidelines.
    • A blood test for HIV and hepatitis to rule out infectious sperm.

    Imlementation

    • The sperm sample is collected via masturbation and is collected directly into a urine sample container. A condom should not be used as this contains spermicide.
    • The sample should be allowed to cool and should be delivered to the andrology laboratory in less than one hour after ejaculation.

    Follow-Up

    • The sperm sample is held in under quarantine until HIV and hepatitis results are available.
    • The sperm can be stored for 10 years and possibly longer if the patient desires.
    • After filling 55 years or death the sperm is destroyed.

    Intravenous Extravasation of Cytotoxic Drugs

    General

    Intravenous extravasation occurs when there is an accidental leak of intravenous cytotoxic fluid (chemotherapy drug) from the vein to surrounding tissue.  

    If chemotherapy is given in a peripheral vein, a large vein should be used, which is preferably in the underarm. Before the infusion begins, the vein should be checked for leaks by injecting NaCl 9 mg/ml or glucose 50 mg/ml. Backflow should also be checked. The patient must be informed that pain or burning in the area is not normal and they must inform the doctor.

    Cytotoxic chemotherapy drugs should always be given through a central vein catheter to reduce the risk of intravenous extravasation.

    Risk factors for intravenous extravasation:

    • Small veins (infants and children)
    • Brittle veins (elderly patients)
    • Reduced physical health (cancer patients)
    • Sclerosizing veins
    • Rolling veins
    • Poor circulation (if the needle is placed in an arm with edema)
    • Obstructed vena cava (raised venous pressure may cause leakage)
    • Conditions such as diabetes and radiation damage
    • Obesity

    Chemotherapeutic drugs are separated into three groups according to the degree of toxicity:

    • Non-cytotoxic/irritating
    • Tissue irritant
    • Cytotoxic

    Cytotoxic drugs can cause blisters or ulcerations leading to skin necrosis if extravasation occurs. If intravenous extravasation is left untreated, it can lead to permanent tissue damage, necrosis, scar formation around ligaments, nerves and joints, infections, abscesses, contractures, and in the worst case, amputation.

    Indication

    • Intravenous extravasation of cytotoxic drugs. 

    Goal

    • Limit damage of tissue from intravenous extravasation.

    Definitions

    Non-cytotoxic drugs or non-irritants

    Non-cytotoxic/non-irritant drugs normally do not cause skin necrosis.

    Irritants

    Drugs that are tissue irritants can cause pain in and around the injection site and along the vein. They can also cause inflammation. Some tissue irritating drugs cause ulceration if a large amount leak extravasally.

    Cytotoxic drugs

    Cytotoxic drugs are categorized into subgroups according to the mode of damage. This categorization is important for the choice of treatment.

    DNA-binding

    DNA binders absorb locally into the cells, bind to DNA, and cause cell death. After cell death, the drug molecule can be liberated from the dead cell and start killing healthy cells. This group is divided into these subgroups:  

    • Anthracycline
    • Alkylating drugs
    • Other

    For doxorubicin and mitomycin, progrediating tissue damage has been reported over weeks, and in some cases, months after intravenous extravasal injection.

    Non DNA-binding

    This group of medications can lead to cell death through other mechanisms than DNA binding drugs. This group is divided into:

    • Vinca alkaloids
    • Taxanes

     

    Chemotherapy cytotoxicity (1)
    Cytotoxic, necrosis

    Irritant, can cause flaking or inflammation

    Non-cytotoxic or non-irritant
    Amsacrine Cisplatin Aldesleukin
    Decarbazine Doxorubicin liposomal Alemtuzumab
    Dactinomycin Estramustine** Asparaginase
    Docetaxel**** Etoposide Bleomycin
    Doxorubicin* Floxuridine Bevacizumab
    Epirubicin* Florouracil Bortezomib
    Daunorubicin* Irinotecan Cetuximab
    Idarubicin* Carboplatin Cyclophosphamide**
    Irinotecan Carmustin** Cytarabine
    Kloremtin** Oxaliplatin Fludarabine
    Mitoguazon Pemetrexed Gemcitabine
    Mitomycin-C Ralitrexed Ibritumomab tiuxetan
    Mitoxanthrone Temoporfin Ifosfamide**
    Paclitaxel**** Teniposide Interferon
    Plicamycin Topotecan Cladribine
    Streptozocin Methylene blue***** Clofarabine
    Verteporphin   Melfalan**
    Vinblastine***   Methotrexate
    Vindesine***   Rituximab 
    Vincristine***   Tiotepa**
    Vinorelbine***   Trastuzumab

     * = Anthracycline

    ** = Alkylating agents

    *** = Vinca alkaloids

    **** = Taxanes

    *****= Methylene blue is not a chemotherapy drug, but is used for ifosfamide-induced encephalopathy, and is therefore included on the list.  

    All chemotherapy drugs can damage tissue in high concentrations.

    References

     

    1. Allwood M, Stanley A WP. The Cytotoxics Handbook. Ed. 4th ed. 2002. 2001
    2. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726

    Preparation

    Identification of an extravasal injection

    • A burning, stinging pain or other acute change of the puncture site.
    • Local redness or inflammation of the skin around the puncture site.
    • The infusion rate slows/stops.
    • Swelling of the puncture site.

    Extravasation has probably also occurred if blood cannot be aspirated, resistance is felt on the plunger when a syringe is used, and/or there is no current if the drug is infused. 

     

    Implementation

    Flow chart for treatment of intravenous extravasation of cytotoxic drugs:

    Emergency response:

    • Stop the infusion immediately.
    • Allow the needle to remain and aspirate with as much water as possible. Avoid applying direct pressure on the area of extravasation.  
    • The volume, type, and time of extravasation should be recorded.
    • A doctor/plastic surgeon should be called for to examine the patient.
    • The damaged area and skin manifestations should be marked/photographed.
    • The affected area should be kept elevated.
    • The remaining chemotherapy should not be discarded.
    • The patient should be informed about what is happening and what must be done. 
    • The needle is removed while aspirating.
    • Pain medication is administered if necessary.

    Based on which medication has leaked extravasally, the doctor or plastic surgeon will decide whether conservative treatment or primary surgery is necessary.

    Conservative treatment

    Conservative treatment consists of two different treatment strategies to limit the damage by extravasation: localize/neutralize and spread/dilute (2).

    Localize and neutralize:

    • Place an ice pack on the area for 15-20 minutes, at least 4 times daily for multiple days. A coldpack is used to limit spreading of the drug. Studies have indicated that there is reduced cellular uptake of drugs at lower temperatures (2).
    • The drug that has leaked extravasally is neutralized by a specific drug if the instructions are followed.
    • The affected area of the body should be kept elevated.

    Spread and dilute (applies to vincristine, vinorelbine, vindesine, and vinblastine):

    • Warm compresses are placed on the area for 15–20 minutes, at least 4 times daily, for multiple days.
    • To dilute the drug that has leaked extravasally, many subcutaneous injections are given with hyaluronidase diluted with sterile water.

    If the patient has lasting pain or blisters, surgical treatment should be considered by excising the area with direct sutures, skin transplant, or flap reconstruction.

    Another type of reconstruction may be necessary at a later time. 

    Treatment 

    Dexrazoxan (Savene®)

    Dexrazoxan is an EDTA analong used to treat extravasation of anthracycline (doxorubicin, daunorubicin, epirubicin, idarubicin). The mechanism of action is not fully understood, but it is believed that it may work through two mechanisms. By chelating iron, the formation of the iron-doxorubicin complex and  iron-mediated hydroxy radicals are hindered, which cause oxidative damage to cell membranes and proteins. Another possible mechanism is inhibition of topoisomerase II (3).

    Treatment lasts for 3 days. In all cases of extravasation of anthracycline, this treatment should be assessed by an oncologist and surgeon/plastic surgeon.

    • The first infusion should start as soon as possible and within 6 hours after extravasation. 
    • On the following two days, the infusions should occur at the same time as the previous infusion (+/- 3 hours).
    • If possible, the infusion should be placed in a vein where there is no extravasation.
    • An ice pack or cooling element used on the area must be removed at least 15 minutes before the infusion starts to ensure sufficient blood circulation.

    Cost

    A package costs about NOK 100,000.-. If the expiration date runs out, the drug is replaced by the pharmaceutical company free of cost.

    Dimethylsulfoxide (DMSO)

    DMSO (70–90% solution) quenches free radicals and prevents formation of sores. The solution can be used after extravasation of cytotoxic drugs (anthracycline, mitomycin C, doxorubicin, idarubicin, epirubicin andactinomycin D) together with cooling of the area when other treatment methods cannot be used (5, 6). DMSO cannot be used in combination with dexrazoxan (3, 4).

    • An area twice as big as the affixed area is treated with the solution every 8 hours for one week.(6)

    Hyaluronidase

    Hyaluronidase is an enzyme that breaks down hyaluronic acid found in connective tissue. This leads to permeability and increased diffusion of the drug that is leaking extravasally, and is used only to spread the drug out into the tissue (spread and dilute).  

    • Hyaluronidase is administered subcutaneously or intradermally in 5-10 locations on the border of the area where the drug has leaked extravasally (7).

    Surgical treatment

    "Wash-out"

    The washing out technique can be used with chemotherapy drugs when tissue damage is likely. When used with anthracycline, it is important that this is performed before the chemotherapy drug goes intracellularly.

    In most cases, this is a very successful method if it is performed within 6 hours after the extravasation.

    • The patient receives regional anesthesia.
    • Multiple small incisions must be made to ensure sifficient access to the damaged subcutaneous tissue.
    • With an infiltration needle, which is usually used for liposuction, isotonic NaCl is flushed through the tissue and drains through the incisions.
    • The infiltrated fluid is then carefully removed by suction through a small needle used for liposuction.
    • The procedure is repeated until 300-500 ml fluid is used.

    References

    1. Ekstravasation Guidelines Implementeringsværktøj [Online] 2007 [hentet 10. mars 2009]; Tilgjengelig fra URL: http://www.cancerworld.org/CancerWorld/getStaticModFile.aspx?id=2726
    2. Hasinoff BB. Dexrazoxane use in the prevention of anthracycline extravasation injury. Future Oncol 2008; 2006: 1–15.
    3. Statens legemiddelverk. Preparatomtale. 2008
    4. Langstein HN, Duman H, Seeling D, Butler CF, Evens GR. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plastic Surg 2002; 49: 369–74. 
    5. Bertelli G, Gozza A, Forno GB, Vidili MG, Silvestro S, Venturini M et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: A prospective clinical study. J Clin Oncol 1995; 13: 2851–5.
    6. Clinical Pharmacology© 2008 database. Hyaluronidase. 2008.

    Follow-Up

    For conservative treatment 

    The damaged tissue should be observed for multiple weeks (with mitomycin at least 13 weeks) since necrosis can occur after months.

    For emergency surgical treatment

    Patients treated by a plastic surgeon should receive follow-up care by the surgeon until the wound has healed.

     

    Intravenous extravasation of cytotoxic drugs.Intravenous extravasation of cytotoxic drugs.Extravasation of tissue toxic chemotherapy

    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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    Follow-up care after treatment of leukemia

    The follow-up arrangements are only guidelines and apply as long as the patient is in remission. For treatment that is potentially curative, the response is monitored multiple times during and after chemotherapy.

    For palliative chemotherapy as well as for untreated patients under observation, the follow-up arrangement must be individualized.

    All follow-up visits should include a medical history and clinical examination.

    Blood testing is carried out at all visits and should include hematological tests with differential counts of leukocytes, blood smear, SR, LDH, and possibly liver and kidney function tests (especially after nephrotoxic therapy) and bone marrow smear.

    The follow-up can be transferred to a local hospital according to guidelines from the specialist division, but it is very important that doctors at the local hospital have the competence and interest for this patient group. It is important to detect recurrence early in patients who are suitable for an allogeneic stem cell transplantation. It is also very important to be aware of the long-term side effects after treatment in this relatively young patient group. 

    Complications

    Fatigue

    This patient group may be troubled by fatigue long after treatment is over. It may take months or sometimes years before returning back to a normal energy level. Some leukemia patients are relatively young and are students when they receive the diagnosis. Some may have problems resuming their studies due to difficulties concentrating and memory problems. 

    Fertility

    Fertility challenges are an increasing problem with increasing age and depend on the amount/type of treatment. For those who have completed sperm banking, it may be necessary to use assisted fertilization. Some younger patients will be able to conceive normally, but this is very uncommon after a myeloablative stem cell transplantation.

    Psychological and socioeconomic problems 

    Some patients benefit from speaking to a social worker or psychiatric nurse. 

    PROSEDYRER

    Follow-up for patients after allogeneic stem cell transplantation

    General

    An allogeneic stem cell transplantation is an intensive and demanding treatment for the patient.

    Until the patient is discharged from the hospital, the focus of the patient and the treating health personnel is on the patient to survive the treatment. When the patient returns home, they often expect they will normalize along with their environment. However, many patients experience resuming their the normal daily life as diffucult after treatment. There are many causes for this, for example complications, GVHD, or fatigue. Many transplanted patients experience less energy during the day which may affect the entire family.

    Close follow-up of stem cell transplanted patients is a central part of the treatment scheme.

    Indication

    • Allogeneic stem cell transplantation

    Goal

    • The patient is able to cope with their changed life situation.
    • The local health clinic has knowledge about follow-up and expected complications.
    • The patient feels secure and taken care of.

    Background

    An allogeneic stem cell transplantation is a treatment form which is only offered to patients with diseases having a primarily poor prognosis. That is, their expected survival time is limited with other treatment forms. 

    The treatment involves using chemotherapy and possibly radiation to remove immune cells from the bone marrow of the patient and replacing them with new bone marrow from the donor. The treatment is so intense that it is associated with life-threatening complications including death.

    Preparation

    Before the transplantation, the patient will receive thorough information from a:

    • doctor 
    • nurse

    The patient and family may also establish contact with a:

    • transplantation coordinator
    • social worker
    • dietician 
    • physical therapist
    • hospital priest

    The patient will also be offered to talk to another patient who has previously undergone a stem cell transplantation.

    If the patient has children, it is very important the school/health personnel are contacted and informed about the treatment and precautions which must be taken in connection with the treatment.

    Procedure

    Work-up and treatment occurs at the section for blood diseases at Oslo University Hosptial and for some patient groups in collaboration with the Norwegian Radium Hospital.

    The stay has 3 phases:

    • Examinations before the transplantation takes 2–3 days and usually occur 1-2 months before the transplantation. 
    • Bed rest associated with the transplantation is generally 4-8 weeks with myeloablative conditioning, sometimes much shorter for non-myeloablative. 
    • When isolation is no longer necessary, the patient is moved to another room at the department. The patient is then discharged but must stay at the patient hotel or other place in the Oslo region, or at home if the patient lives in the vicinity of the hospital. For the first period after the patient is discharged, the patient will have follow-up visits 2–3 times per week at the outpatient clinic.  
    • Later follow-up occurs in close dialog with the patient's regional health clinic or local hospital. 

    Implementation

    During the first weeks after the patient is discharged, the patient will have an outpatient consultation with both a doctor and nurse.

    At the consultation, the following are focused upon:

    • nutritional status
    • blood tests
    • need for transfusions
    • physical, psychological, and social rehabilitation
    • infection status
    • acute GVHD

    An important part of the blood testing in the first 6-12 months is to follow the level of ciclosporin and CMV-PCR. Most patients can stop taking ciclosporin 1 year after the transplant. 

    If the patient has newly diagnosed or a recurrence of GVHD, it may be necessary to increase the dose of ciclosporin, possibly in combination with steroids or other immunosuppressant.

    After returning home, follow-up visits are divided between the regional and local hospitals.

    The vein catheter is removed when there is no longer a need for transfusions and the patient is able to take sufficient amounts of per oral fluid and solid food, which is usually after 3 months.

    Further follow-up

    The patient will complete comprehensive testing of blood and body function after 3, 6, 9, and 12 months. At these visits, the patient will also be offered to speak to a nurse. The nurse will convey information to relevant cooperation partners, for instance a social worker, psychologist, the school, and the Cancer Registry.

    Women receive regular follow-up by a gynecologist with emphasis on hormone treatment and development of chronic GVHD. Eye and lung examinations are also performed at some visits.

    Thereafter, the patient is seen annually for 5 years.

    Bone marrow function and the immune system during the first 3 months

    The immune system of a transplanted patient needs at least 12 months before it functions normally, provided the patient does not have chronic GVHD. The patient will therefore be more susceptible to infections than normal and runs a certain risk for bleeding if the thrombocyte count is considerably reduced. The problem decreases gradually, but it is very important that signs of infection or bleeding are taken seriously.

    Patients receiving steroid treatment for GVHD will have a reduced immune system long after the transplantation. It is therefore especially important that this patient group is taken seriously when contacting a doctor with suspicion of infection. If adequate treatment is not started immediately, there is a risk of sepsis with serious infections.

    Precautions the patient should follow for the first 3 months:

    • avoid contact with people who are obviously infected with a cold or have a known contagious illness
    • avoid contact with children with pediatric illnesses or people who have been in contact with pediatric illnesses
    • visitors should wash their hands
    • avoid contact with household animals
    • follow food restrictions to avoid growth of microorganisms

    Normal household cleaning is sufficient.

    It is recommended that the patient uses a face mask for the first 3 months after the transplant if staying at the hospital or when in close contact with many people. When outside in fresh air, it is not necessary to use a face mask. The patient should avoid public transportation, the cinema, theater, and places with large amounts of people, in the first three months after the transplant.

    Children

    Children should be taken out of day care/preschool about 14 days before the patient returns home. Children should not be allowed to attend day care/preschool in the first period after the patient returns home due to the risk of infection.

    Psychological

    Being seriously ill over a long period of time is a great psychological burden. Treatment and consequences of treatment may be very straining in periods for both the patient and family. Often, the patient will feel depressed after returning home and it may take a significant amount of time before resuming normal activity. The patient and family must adjust their expectations for life.

    It is important that the patient and their family allow time to process their experiences from the transplant and illness period. Some will benefit from psychological care or other therapy.  

    Sexual relations

    Long-term illness and treatment is challenging for relationships. The interaction between partners may have changed and it may be difficult to return to the state before the illness. Physical changes in both men and women may also influence sexual relations.

    Even if the possibility of pregnancy is small after treatment, prevention is recommended for the first year. After the first year, there are no special precautions.

    Back to work/school/studies

    The time at which to resume work/school/studies depends on how quickly the patient recuperates after the transplantation. In most cases, it is recommended that the patient does not start working until 6 months after the stem cell transplantation. It is also important that the patient does not return to work before he/she feels ready. We recommend that the patient discusses this with their closest contacts, health personnel and/or other professionals. The patient should also plan with their employer before resuming work.

    Follow-up

    The patient should contact their doctor if they have the following symptoms:

    • rash
    • fever
    • sudden and lasting cough
    • shortness of breath
    • unexpected bleeding
    • sudden diarrhea, significant constipation, abdominal pain, nausea
    • mouth soreness, significant sore throat, or problems swallowing
    • pain associated with urination or bowel movements
    • acute headache
    • pain limited to an area in the face/body
    • contact with possible infectious illness

    Delayed reactions after stem cell transplantation (after 1 year)

    Chronic GVHD

    About 30% develop GVHD, 1/3 are new cases, 1/3 are recurrence of acute GVHD, 1/3 are lasting acute GVHD. GVHD occurs more frequently with unrelated donors.

    Infections

    The patient should be revaccinated according to the standard vaccination program after 1 year. The patient should not be inoculated with live vaccine.

    Infections in the form of Herpes zoster, CMV and encapsulated bacteria are rare, but occur if the patient has chronic GVHD.

    For confirmed hypogammaglobulinemia and recurrence of serious infections, gammaglobulin substitution may be necessary.  

    Lung complications

    Moderate to serious restrictive loss of function in about 20%, especially in patients with chronic GVHD.

    Lung complications with obstructive failure, obliterating bronchiolitis in < 5 %, is observed especially in patients with chronic GVHD. The most important treatment is early infection therapy. Effect of increased immunosuppression is uncertain and this type of treatment requires increased attention with regard to infections.  

    Hemosiderosis

    Hemosiderosis is caused by numerous erythrocyte transfusions and may cause long-term organ damage. Blood-letting is therefore performed with ferritin > 500, from about 6 months after the transplantation, if the patient will tolerate it. Blood is drawn until ferritin is at a stable level within the normal reference area.

    Hypothyroidism

    About 15% will become hypothyroid (preferable monitored after TBI).

    Gonadal function, growth and development

    All stem cell transplanted women will have a follow-up program at the women's clinic.

    Almost all women remain in amenorrhea and half will develop menopausal symptoms.

    Almost all stem cell transplanted men develop gonad failure with azospermia. Restitution of gonad function after multiple years has been observed in some cases.

    Possible pregnancy

    The risk for fetal injury at birth and the first years after birth do not appear to have increased. Long-term observations indicate that the risk of fetal injury is not great.

    Cataract

    Cataracts occur in most long-term survivors after total body irradiation. The frequency after busulfan and cyclophosphamide is still uncertain, but is not uncommon.

    Leukemia recurrence

    Very rare after 2-3 years, but can occur even after > 6 years.

    Secondary neoplasia

    • Cumulative risk after 15 years, 6% with out total body irradiation, 20% with total body irradiation.
    • Lymphoid neoplasms in donor cells occur in rare cases and are often associated with EBV. This usually occurs within a year after a transplantation and especially in patients who have received T-cell filtered marrow with HLA-incompatibility and who are treated for steroid-refractory acute GVHD.
    • Basal cell and squamous cell carcinoma
    • Leukemia in donor cells < 1%

    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