Canadian Supportive Care Recommendations for the Management of Neutropenia in Patients with Cancer
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PRACTICEKOUROUKIS et al. GUIDELINE SERIES Canadian supportive care recommendations for the management of neutropenia in patients with cancer C.T. Kouroukis MD MSc,* S. Chia MD,† S. Verma MD,‡ D. Robson MD,‡ C. Desbiens MD,§ C. Cripps MD,|| and # J. Mikhael MD MEd ABSTRACT therapy regimens in a wider spectrum of cancer pa- tients, often resulting in increases in hematologic tox- Hematologic toxicities of cancer chemotherapy are icities. Also, as the population ages and demographics common and often limit the ability to provide treat- shift, greater numbers of older adults, some with sig- ment in a timely and dose-intensive manner. These nificant comorbidities, are being considered for che- limitations may be of utmost importance in the adju- motherapy that may result in significant toxicity. vant and curative intent settings. Hematologic toxici- Agents to attenuate hematologic toxicities have ties may result in febrile neutropenia, infections, been in widespread use, particularly in primary and fatigue, and bleeding, all of which may lead to addi- secondary prevention of the neutropenia and febrile tional complications and prolonged hospitalization. neutropenia (FN) associated with chemotherapy and The older cancer patient and patients with significant stem-cell transplantation (SCT). In cancer patients, FN comorbidities may be at highest risk of neutropenic has been shown to have a significant impact on pa- complications. Colony-stimulating factors (CSFs) such tient outcomes and on the health care system 1. The as filgrastim and pegfilgrastim can effectively attenu- potential benefits of colony-stimulating factors (CSFs) ate most of the neutropenic consequences of chemo- such as granulocyte colony–stimulating factor (G-CSF) therapy, improve the ability to continue chemotherapy must be measured against their cost and potential on the planned schedule, and minimize the risk of fe- toxicities. brile neutropenia and infectious morbidity and mor- The consensus statement presented here was pre- tality. The present consensus statement reviews the use pared to summarize, from the Canadian perspective, of CSFs in the management of neutropenia in patients current guidelines on the use of CSFs, taking into ac- with cancer and sets out specific recommendations count the available evidence and recently updated in- based on published international guidelines tailored to ternational guidelines 2–4. The present paper reviews the specifics of the Canadian practice landscape. We the updated guidelines, recommendations for primary review existing international guidelines, the indications and secondary prophylaxis, and the use of growth fac- for primary and secondary prophylaxis, the importance tors in leukemia, SCT, and radiotherapy. In addition, of maintaining dose intensity, and the use of CSFs in disease-specific recommendations are made for breast leukemia, stem-cell transplantation, and radiotherapy. cancer, lymphoma, lung cancer, and gastrointestinal Specific disease-related recommendations are provided cancer. Finally, the latest safety information regard- related to breast cancer, non-Hodgkin lymphoma, lung ing the use of growth factors is discussed. cancer, and gastrointestinal cancer. Finally, CSF dosing and schedules, duration of therapy, and associated acute 2. SUMMARY OF EXISTING GUIDELINES and potential chronic toxicities are examined. The American Society of Clinical Oncology (ASCO), KEY WORDS the European Organization for Research and Treat- ment of Cancer (EORTC), and the National Compre- Canadian recommendations, neutropenia, febrile neu- hensive Cancer Network (NCCN) have all published tropenia, supportive care, colony-stimulating factors, guidelines for the use of CSFs in patients with can- chemotherapy-induced neutropenia, safety cer 2–4 (Table I). The 2005 ASCO guidelines were updated 2 from 1. INTRODUCTION the 2000 version; their evidence base included MEDLINE and Cochrane Library searches up to and Advances in cancer treatment have led to the devel- including September 2005. The ASCO guidelines en- opment and administration of more-complex chemo- dorse the importance of preventing FN as a clinical 9 Copyright © 2008 Multimed Inc. CURRENT ONCOLOGY—VOLUME 15, NUMBER 1 PRACTICE GUIDELINE SERIES TABLE I Current guidelines for primary prophylaxis with granulocyte colony–stimulating factor (G-CSF) 2–4 Neutropenic event risk ASCO 2006 2 EORTC 2006 3 NCCN 2006 4 Moderate to high Use G-CSF (~20%) Use G-CSF (≥20%) Use G-CSF (>20%) Intermediate Recommend G-CSF (<20%) Consider G-CSF (10%–20%) Consider G-CSF (10%–20%) Low Not specified G-CSF not recommended (<10%) G-CSF not recommended for most patients (<10%) Risk factor assessment +++ +++ ++ ASCO = American Society of Clinical Oncology; EORTC = European Organization for Research and Treatment of Cancer; NCCN = National Comprehensive Cancer Network. outcome, regardless of other factors, particularly receiving curative or adjuvant treatment and treat- when the FN rate associated with treatment is at least ment to prolong survival or to improve quality of life. 20% and no other equally efficacious regimen that For patients being treated with regimens associated would not require CSFs is available. Primary prophy- with a 10%–20% risk of FN, consideration should be laxis with CSFs is recommended for FN prevention in given to using a CSF in high-risk patients, but CSFs patients at higher risk based on age, medical history, should not be used in low-risk patients (those with a disease characteristics, and myelotoxicity of the che- less-than-10% risk of FN), unless a specific patient is motherapy regimen. Dose-dense chemotherapy re- at significant risk of serious consequences of FN and quiring CSFs is recommended only when clearly that patient is being treated with curative or adjuvant supported by the available evidence or as part of a intent. clinical trial. Prophylactic CSF is suggested for older Filgrastim (Neupogen: Amgen, Thousand Oaks, patients (65 years of age or older) with aggressive- CA, U.S.A.), pegfilgrastim (Neulasta: Amgen), and histology lymphoma treated with curative intent. Sec- ancestim (Stemgen: Amgen) are the only CSFs ap- ondary prophylaxis is recommended for patients who proved for use in Canada. experience a neutropenic complication associated with an earlier chemotherapy cycle and in whom a 3. GUIDELINES FOR PROPHYLAXIS reduced dose in a subsequent cycle could compro- mise disease-free survival (DFS), overall survival (OS), 3.1 Primary Prophylaxis or another treatment outcome. In 2006, EORTC published its guidelines for the Updated international guidelines 2,3 have suggested use of CSFs in patients with cancer and chemotherapy- broadening the indication for CSF use for primary pro- induced neutropenia. Those guidelines were based phylaxis in patients with solid tumours and hemato- on literature published from 1996 through Septem- logic malignancies alike. The upfront use of G-CSFs is ber 2005 3. In 2003, the EORTC Cancer in the Elderly suggested with the use of dose-dense chemotherapy Task Force had published guidelines regarding the in some patients with breast cancer 6 and hematologic use of CSFs in elderly patients with cancer 5. The EORTC malignancies 7. Figure 1 shows a combined EORTC and guidelines recommend prophylactic CSFs when the FN ASCO algorithm (combined interpretation of the 2006 rate of the proposed treatment is 20% or more. In the G-CSF guidelines of ASCO 2 and EORTC 3) for primary case of regimens with FN rates of between 10% and G-CSF prophylaxis. 20%, the decision to use CSFs should be based on Based on the ASCO and EORTC updates, the thresh- patient-related risk factors, such as older age (over old to recommend primary prophylaxis with G-CSFs 65 years of age), advanced stage of disease, previ- was reduced from a 40% to a 20% risk of FN. The ous FN episodes, and lack of antibiotic prophylaxis. initial estimate of 40% had been calculated from a As do the ASCO guidelines, the EORTC guidelines rec- pharmacoeconomic study 8 based on the results of a ommend CSFs when a reduction in chemotherapy is randomized study using G-CSF in patients with small- associated with poorer prognosis and when dose- cell lung cancer (SCLC) 9. The pharmacoeconomic dense regimens associated with a clinical and sur- analysis indicated that prophylactic use of G-CSFs was vival benefit are being used. cost-effective when the FN rate was at least 40%. The The updated NCCN guidelines for the management current lower value of 20% risk was arrived at using of chemotherapy-induced neutropenia 4 are based on clinical rather than economic evaluation. Addition- a panel review of available evidence. The NCCN guide- ally, more recent studies have indicated that G-CSFs lines recommend routine CSF use to reduce the risk of can dramatically reduce the FN rate even in patients FN, the risk of hospitalization, and the use of intrave- with a baseline FN risk of about 20% 10,11. nous antibiotics in patients treated with a regimen The evaluation of neutropenia risk has been sum- associated with a 20% risk of FN (category 1 evi- marized for several types of chemotherapy regimens dence). That recommendation encompasses patients (see the EORTC guidelines’ Table 4 or the ASCO guide- 10 CURRENT ONCOLOGY—VOLUME 15, NUMBER 1 KOUROUKIS et al. FIGURE 1 Combined European Organization for Research and Treatment of Cancer 3 and American Society of Clinical Oncology 2 algorithm for primary prophylaxis with granulocyte colony–stimulating factor (G-CSF). FN = febrile neutropenia; NHL = non-Hodgkin lymphoma. lines’ Table 1 for a complete list). Although the rel- evaluations from other jurisdictions may not be ap- evant data were taken from clinical trials, it is impor- plicable to Canadian practice 14. The ASCO recommen- tant to realize that the risk of FN in practice could be dations emphasize that the decision to use G-CSFs to substantially higher, particularly if patients are older prevent FN should be based on clinical data rather or have comorbidities that may render them ineligible than on economics, looking at evidence of reduction for most clinical trials and increase their risk of com- in infection-related endpoints. plications 1,5.