Myelosuppression
Quick Facts
- Myelosuppression in patients receiving chemotherapy for CRC may manifest as neutropenia, thrombocytopenia, or anemia
- Irinotecan has induced severe myelosuppression, particularly when used with fluorouracil in bolus form versus as a continuous infusion
- Using scales to accurately grade myelosuppression, reducing dose when necessary, and administering agents to treat neutropenia can help improve patient outcome
Background
Myelosuppression is a common effect of most chemotherapy agents, and oncology nurses are experienced in its assessment and management.1 In general, myelosuppression related to chemotherapy for CRC may manifest as any of the following:
- Neutropenia
- Thrombocytopenia
- Anemia
Different agents and forms of administration used to treat CRC may show different hematologic toxicities. Examples of these variations are as follows:
- Fluorouracil (5-FU): myelosuppression (more common with bolus than with continuous infusion)2
- Oxaliplatin: neutropenia, thrombocytopenia1,3,4
- Irinotecan: neutropenia, febrile neutropenia (more common with bolus 5-FU regimens such as IFL [irinotecan, 5-FU, and leucovorin] and FOLFIRI)5,6
- Capecitabine: myelosuppression, including anemia (neutropenia and thrombocytopenia in approximately 20% of patients, anemia in 14%)6
- Bevacizumab: none commonly reported (incidence increases when given in combination chemotherapy)7
- Cetuximab: none commonly reported (incidence increases when given with irinotecan)8
Irinotecan has induced severe myelosuppression, and use of a colony-stimulating factor (CSF) should be considered. Elderly patients (> 65) who (1) have received previous radiation therapy in the pelvic or abdominal region, (2) have a performance status of 2 or higher, or (3) are homozygous for the UGT1A1*28 allele should be assessed with caution before treatment with irinotecan.9,10
Neutropenia Management
Neutropenia is usually managed by monitoring blood counts. The counts must be adequate at the start of the treatment cycle, and the administration of growth factors, such as granulocyte colony-stimulating factor (G-CSF) for neutropenia should occur after chemotherapy.11,12
Classification and Grading
In general, neutropenia is classified as mild, moderate, or severe:
- Neutropenia: ANC (absolute neutrophil count) < 2,000 cells/mm3
- Mild neutropenia: ANC 1,000 to 1,500 cells/mm3
- Moderate neutropenia: ANC 500 to 1,000 cells/mm3
- Severe neutropenia: ANC < 500 cells/mm3
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.02 grading scale for febrile neutropenia is as follows13
Grade
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1
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-
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2
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-
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3
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Present
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4
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Life-threatening consequences; urgent intervention indicated
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5
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Death
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Treatment
There are two preparations of G-CSF for the treatment of neutropenia: filgrastim (Neupogen®) and pegfilgrastim (Neulasta®). These agents differ in dosing and timing of administration but have similar side effects; the most common complaint is of bone pain after the injection(s).14
ONS recently released guidelines for infection prevention with specific information on neutropenia. These guidelines, called “Putting Evidence into Practice” (PEP), may be accessed at http://www.ons.org/Research/PEP/Infectionwww.ons.org/Research/PEP/Infection
Additionally, the National Comprehensive Cancer Network (NCCN) has a practice guideline for the use of growth factors and the prevention and treatment of cancer-related infections in patients with cancer. Users are required to register on the NCCN website to gain access to Guidelines. Following registration, the guidelines are available without charge. The NCCN website URL is http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf.
Febrile neutropenia may require growth factors and antibiotic therapy, and some patients may need to be hospitalized; concomitant diarrhea and neutropenia must be recognized and treated promptly to avoid serious patient outcomes, including death. In some patients, dose adjustments of chemotherapy may be necessary for future treatment.15
Thrombocytopenia Management
Thrombocytopenia (defined as a platelet count < 100,000/mcL) is usually followed by monitoring of blood counts, and platelet transfusion may be necessary in patients who have platelet counts < 10,000 to 20,000 mcL or are symptomatic.
Clinical signs of thrombocytopenia include1
- Bruising
- Petechiae
- Purpura
- Blood in stool, urine, or vomitus
- Bleeding from body orifices
Careful assessment and care of patients with thrombocytopenia are necessary. Oncology nurses should minimize trauma to the patient, including avoidance of intramuscular injections, monitoring medications known to affect platelet count, and applying adequate pressure to areas of blood draws or intravenous procedures.
Assessment and Dosages in Managing Neutropenia and Thrombocytopenia
Although neutropenia and thrombocytopenia are common side effects of many chemotherapy agents, they may be managed by oncology nurses who perform comprehensive assessments of their patients undergoing treatment. Utilization of scales to accurately grade and identify the different aspects of myelosuppression, reducing dose when necessary, and administering agents to treat neutropenia can help improve patient outcome.12
Dose Adjustment Table for Agents Used for Thrombocytopenia and Neutropenia in the Treatment of CRC
Oxaliplatin, 5-FU3
Grade 4 neutropenia
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Reduce dose to 75 mg/m2and reduce 5-FU by 20% (300-mg/m2bolus and 500-mg/m222-h infusion)
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Grade 3/4 thrombocytopenia
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Reduce dose to 65 mg/m2and reduce 5-FU by 20% (300-mg/m2bolus and 500-mg/m222-h infusion)
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Irinotecan, 5-FU, Leucovorin10
Grade of Neutropenia
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Cycle of Therapy
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Grade 0
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Maintain dose level
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Grade 1
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Maintain dose level
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Grade 2
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1 dose level
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Grade 3
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Omit dose until grade = 2 is reached, then 1 dose level
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Grade 4
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Omit dose until grade = 2 is reached, then 2 dose levels
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Anemia Management
Anemia can occur with the chemotherapy agents used in the treatment of CRC and are reported with capecitabine, oxaliplatin, and irinotecan in clinical studies.
In patients with cancer, the erythropoietin response is inadequate and the stimulus for red blood cell (RBC) production is insufficient. Additionally, although the normal life span of a circulating RBC is 120 days, cancer patients suffering from anemia may have an RBC life span of only 60 or 90 days.1
Anemia may be classified by a variety of toxicity scales. However, scales often do not link patients’ symptoms with their well-being. Sample scales are the National Cancer Institute (NCI), World Health Organization (WHO), and Eastern Cooperative Oncology Group (ECOG).16
Grade
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NCI/ECOG
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WHO
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0
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Within normal limits (WNL)
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> 11 g/dL
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1 (mild)
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10 g/dL–normal
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9.5–10.9 g/dL
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2 (moderate)
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8–10 g/dL
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8–9.4 g/dL
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3 (serious)
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6.5–7.9 g/dL
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6.5–7.9 g/dL
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4 (life-threatening)
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< 6.5 g/dL
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< 6.5 g/dL
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Patients who have moderate to severe anemia may experience the following symptoms17:
- Fatigue
- Dyspnea at exertion or rest
- Chest discomfort
- Cognitive impairment
Fatigue is one of the most frequently reported symptoms in patients who have chemotherapy-induced anemia; one large study of 379 patients with cancer found that 76% of all cancer patients reported experiencing fatigue at least a few days a month, and 88% of the respondents felt that fatigue caused a change in their daily routine; 30% had fatigue daily.18
Blood transfusion may be appropriate for patients with anemia, based on each individual’s symptoms and laboratory data.
Erythropoietin-stimulating agents (ESA) may be given to selected patients with anemia if needed. Two medications are available to treat anemia: epoetin alfa (Procrit®) and darbepoetin alfa (Aranesp®). Although both agents are indicated for the treatment of anemia, the dose and timing of administration differ. The side effects of ESAs are similar and include hypertension, headache, arthralgia, diarrhea, and nausea. Blood counts should be monitored to ensure that hemoglobin levels do not rise inappropriately.19 Based on recent data, changes have been made to the labeling for both ESAs. These changes include the addition of a black box warning stating that ESAs have been found to shorten overall survival and/or time to tumor progression in certain patient populations (breast, non-small cell lung, head and neck, lymphoid, and cervical cancers) when dosed to a hgb of >12 g/dl. The lowest dose possible should be used to minimize these risks, and therapy should be discontinued following the completion of a chemotherapy course.20,21 Current joint guidelines from the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) recommendations are to use an ESA as the hgb approaches or falls below 10 g/dl, and to avoid use of these products in patients with cancer who are not receiving chemotherapy.22-23
References
- Polovich M, Whitford, JM, &, Olsen, M., et al, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, Pa: Oncology Nursing Society; 2009:121-145.
- Nicum S, Midgley R, Kerr DJ. Chemotherapy for colorectal cancer. J R Soc Med. 2000;93:416-419.
- Eloxatin prescribing information. Available at: http://www.eloxatin.com/hcp/default.aspx Accessed January 27, 2010.
- Viale PH, Fung A, Zitella, L. Advanced colorectal cancer: current treatment and nursing management with economic considerations. Clin J Oncol Nurs. 2005;9:541-552.
- Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342.
- Fischer DS, Knobf MT, Durivage HJ, Beaulieu NJ. The Cancer Chemotherapy Handbook. 6th ed. Philadelphia, Pa: Mosby-Yearbook; 2003.
- Avastin prescribing information. Neutropenia and infection. Available at: http://www.gene.com/gene/products/information/oncology/avastin/insert.jsp#warnings. Accessed January 27, 2010.
- Erbitux prescribing information. Table 5: incidence of adverse events. Available at: http://packageinserts.bms.com/pi/pi_erbitux.pdf. Accessed January 27, 2010.
- Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR Study. J Clin Oncol. 2004;22:229-237.
- Camptosar: dosing and administration. Pfizer Web site. Available at: https://www.pfizeroncology.com/sites/pop/pages/camptosar.aspx Accessed January 27, 2010.
- National Comprehensive Cancer Network (NCCN). Myeloid growth factors and Prevention and treatment of cancer-related infections v.1.2010. Available with free registration at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#supportive. Accessed January 27, 2010.
- Wilkes G. New therapeutic options in colon cancer: focus on oxaliplatin. Clin J Oncol Nurs. 2002;6:131-137.
- National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.02. Available at:http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf. Page 3. Accessed January 27, 2010.
- Neupogen (filgrastim). Available at: http://www.neupogen.com/pdf/Neupogen_PI.pdf. Accessed January 27, 2010.
- Benson A, Ajani A, Catalano RB, et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918-2926.
- Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst. 1999;91:1616-1634.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Cancer- and Chemotherapy-Induced Anemia v.2.2010. Available with free registration at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#supportive. Accessed January 27, 2010.
- Curt GA, Breitbart W, Cella D, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the fatigue coalition. Oncologist. 2000;5:353-360.
- Miller CB, Jones RJ, Piantadosi S, et al. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990;322:1689-1692.
- Procrit prescribing information. New safety information. Available at: http://www.procrit.com/impor_safe.html. Accessed January 27, 2010.
- Aranesp prescribing information. Important safety information. Available at: http://www.aranesp.com/#boxed_warning. Accessed January 27, 2010.
- Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008;111:25–41.
- Rizzo JD, Somerfield MR, Hagerty KL, et al. Erratum for Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008;111:25-41; Blood, 2008;111:3909.
Key Definitions
Anemia—a condition in which the blood is deficient in red blood cells, in hemoglobin, or in total volume. According to the World Health Organization definition, anemia in women is generally considered to be a hemoglobin <12.0gm/dl; in men, a hemoglobin <13.0gm/dl.
Arthralgia—joint pain
Colony-stimulating factor (CSF)—a man-made protein very similar to naturally produced proteins in the body that predominantly signal the production of white blood cells
Erythropoietin—a hormone made by the kidney that stimulates the bone marrow to release reticulocytes that mature into red blood cells
Erythropoietin-stimulating agents (ESA)—engineered biologically using recombinant DNA technology that stimulate the erythropoietic process
Febrile neutropenia—dangerously low level of neutrophils (usually less than 500 cells/mm3) accompanied by fever; a condition that indicates that the patient may have a potentially life-threatening infection
Homozygous—containing two copies of the same allele--an organism that has two identical alleles for a particular trait
Myelosuppression—suppression of the bone marrow's production of blood cells and platelets
Neutropenia—a deficiency of white blood cells (leucopenia) in which the decrease in white blood cells is chiefly in the neutrophils
Thrombocytopenia—decrease in the number of blood platelets
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