Neutropenic complications remain the main dose-limiting toxicity of cancer chemotherapy treatment and are associated with considerable morbidity, mortality, and costs.1 Although patients who have experienced a prior neutropenic event are at increased risk of subsequent events, several studies have shown that the risk of the initial neutropenic event is greatest in the first cycle, when most patients are receiving full-dose chemotherapy.2-4 Recombinant white blood cell growth factors or colony-stimulating factors have been demonstrated to reduce the risk and consequences of neutropenic complications and enable safe delivery of myelosuppressive chemotherapy at full dose on schedule in multiple randomized controlled trials.5
ASCO published its first clinical practice guideline on the use of hematopoietic colony-stimulating factors in 1994. These guidelines have been updated periodically, including in 1996, 1997, 2000, and 2006.6 In the interim, several additional guidelines on the use of colony-stimulating factors were updated.7,8
In July 2015, another guideline update based on a comprehensive and systematic review of the medical literature since 2005 was published in the Journal of Clinical Oncology.9 A complete summary of the recommendations appears in this issue of The ASCO Post. These recommendations include a restatement of previous recommendations as well as several important modifications and additions to the previous guidelines based on several additional clinical trials and newly introduced agents. The recommendations are applicable to patients with a broad range of adult and pediatric malignancies including solid tumors and lymphoma.
Restatement of Previous Recommendations
Recommendations with little or no modification based on the updated review include primary prophylaxis, starting shortly after completion of the initial and subsequent cycles of chemotherapy in patients with an approximately ≥ 20% risk of febrile neutropenia based on treatment-, disease-, and patient-specific risk factors for febrile neutropenia, as well as in patients receiving dose-dense chemotherapy regimens. This recommendation is supported by well-designed clinical trials. Although evidence has shown that colony-stimulating factor prophylaxis may reduce early treatment-related as well as long-term mortality, this recommendation was based on the reduction in risk of febrile neutropenia as a clinically meaningful outcome in patients receiving cancer chemotherapy.5,10
While encouraging the further development and validation of risk prediction models, the guidelines updated a list of recognized patient risk factors for the development of febrile neutropenia, as well as those predictive of a poor clinical outcome resulting from febrile neutropenia or infection.9,11,12 Specifically, the update panel recommended the use of prophylactic colony-stimulating factors in patients aged ≥ 65 years receiving potentially curative chemotherapy for diffuse aggressive non-Hodgkin lymphoma (NHL), especially in the presence of comorbidities.13,14 Secondary prophylaxis in subsequent cycles is again recommended in patients who experience febrile neutropenia in a prior cycle of the same chemotherapy when a reduction in dose, delay in treatment, or an alternative less-myelosuppressive regimen might adversely impact important patient outcomes.
The panel again recommended against the routine use of colony-stimulating factors in patients with afebrile neutropenia, as well as in most patients with existing febrile neutropenia receiving antibiotics, unless there is high risk for infectious complications. The use of colony-stimulating factors continues to be recommended for peripheral blood cell mobilization, as well as to support patients undergoing stem cell transplantation.
The panel presented similar recommendations for appropriate use of these agents in pediatric patients with cancer but specifically recommended against their use in children with nonrelapsed acute lymphoblastic leukemia or acute myeloid leukemia. The guidelines do not address the use of colony-stimulating factors in adults with acute myeloid leukemia or myelodysplastic syndromes. On the basis of formal consensus, use of the colony-stimulating factors is recommended in patients exposed to potentially lethal doses of total-body radiation.9
Modifications or Additions
At the same time, the updated white blood cell growth factor guidelines have modified or added to previous guideline recommendations. After a review of the limited and conflicting available evidence, the panel concluded that the value of dose-dense regimens with colony-stimulating factor support has been demonstrated in patients receiving adjuvant systemic chemotherapy for early-stage breast cancer but not in patients with NHL, and, therefore, cannot be routinely recommended in the latter.15,16 However, evidence supporting colony-stimulating factor support of patients receiving high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin for urothelial cancer was considered sufficient for recommendation.17
Finally, although the data are rapidly evolving and variable, the panel concluded that filgrastim, pegfilgrastim, tbo-filgrastim, and filgrastim-sndz could all be used for the prevention of treatment-related febrile neutropenia. The panel concluded that in addition to filgrastim and pegfilgrastim, newly introduced agents, either through a conventional approval mechanism (tbo-filgrastim) or through a new approval process for biosimilars (filgrastim-sndz), can be used to reduce the risk of febrile neutropenia.
Limited data have suggested that pegfilgrastim may be more effective than filgrastim in reducing the risk of febrile neutropenia.18,19 The choice of agent will depend upon clinical experience, patient convenience, and cost. The panel reiterated recommendations for administration of the colony-stimulating factors to start within 1 to 3 days after administration of chemotherapy.9 ■
Disclosure: Dr. Lyman is a member of the ASCO Guideline Panel on the Use of White Blood Cell Growth Factors and principal investigator on a research grant to the Fred Hutchinson Cancer Research Center from Amgen.
References
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