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Letter to the Editor |
reply |
aSection of Hematology/Oncology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; bCenter for Oncology Research and Treatment, PA, Dallas, Texas, USA; cUnion State Bank Cancer Center, Nyack Hospital, Nyack, New York, USA; dSt. Louis Cancer & Breast Institute, St. Louis, Missouri, USA; eAlvin & Lois Lapidus Cancer Institute, Baltimore, Maryland, USA; fAmgen Inc., Thousand Oaks, California, USA
Correspondence: Howard Ozer, M.D., Ph.D., Section of Hematology-Oncology, University of Oklahoma Health Science Center, P.O. Box 26901, Williams Pavilion, Room WP2080, Oklahoma City, Oklahoma 73190, USA. Telephone: 405-271-4022; Fax: 405-271-3020; e-mail: howard-ozer{at}ouhsc.edu
Received July 31, 2007; accepted for publication October 24, 2007.
Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
Febrile neutropenia (FN) is a serious medical condition contributing to morbidity, mortality, and increased costs in cancer patients [1–9]. Pegfilgrastim and filgrastim are indicated to decrease the incidence of infection, as manifested by FN, in patients receiving myelosuppressive anticancer drugs associated with a clinically significant FN incidence. This indication has remained constant since the initial U.S. Food and Drug Administration approval.
The threshold for colony-stimulating factor (CSF) primary prophylaxis was initially set at 40% by the American Society for Clinical Oncology (ASCO) guidelines based solely on economic criteria [10]. Patients treated on regimens that had FN rates <40% were thus less likely to receive CSF prophylaxis. The intent of this trial was to determine whether a lower threshold would provide a clinical benefit to patients participating in the study. Indeed, both the package insert and the ASCO and National Comprehensive Cancer Network (NCCN) guidelines now recommend that patients receive primary prophylaxis when treated with chemotherapy regimens with an FN risk of approximately 20% across all cycles and <20% when patients have specific risk factors for FN [10–12].
Further, the assumption that patients in our study had "good performance status and few comorbidities" is incorrect. Our protocol allowed patients not ordinarily considered for enrollment in clinical trials because of comorbid illness or inadequate performance status. These patients have a higher risk for developing complications with chemotherapy and may potentially benefit most from pegfilgrastim use.
The FN rate of the Awareness of Neutropenia in Chemotherapy (ANC) Study Group Registry was unknown at the time of this study's initiation, because the registry and our study were designed to run concurrently for subsequent comparative value. The primary endpoint of our protocol, neutropenia-related hospitalizations (a highly correlative, but conservative measure of FN), was expected to be between 2% and 10% with CSF prophylaxis depending on the patient's tumor type.
Our clinical trial received institutional review board review and approval from all investigational sites and patients gave written informed consent before enrolling into this study. Bone pain is a known side effect for pegfilgrastim and other CSFs; however, in the placebo-controlled pivotal study, most reports of bone pain were mild or moderate in severity and transient, and only 1% and 2% of patients in the placebo and pegfilgrastim groups, respectively, reported severe bone pain.
The theoretical concern that pegfilgrastim could act as a growth factor for a tumor type cannot be excluded [13–15]. However, long-term survival was not shown to be adversely impacted for patients receiving G-CSFs in two well-controlled studies [16–18]. Similarly, a higher risk of acute myeloid leukemia and/or myelodysplastic syndrome was not identified when G-CSF was administered to healthy donors donating peripheral blood stem cells (n >100,000) [19].
The trial cost was provided by Amgen Inc., with pegfilgrastim reimbursed by patients and their insurers. The current ASCO guidelines endorse clinical research as a platform to provide evidence-based medical decisions: "clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment is needed" [10].
The cost of pegfilgrastim used in our trial is in line with that of other drugs studied in oncology trials. In fact, most trials are performed today using this model unless a drug is being tested in a nonapproved indication. For example, in the Hudis et al. [16] trial cited above testing dose-dense chemotherapy, filgrastim was used in the dose-dense arms and was supported by patients or third-party sources. The total cost of filgrastim in that study for 988 patients was $11,373,856.00 (assuming $2,878 per cycle for four cycles; http://www.drugstore.com). The drug cost in clinical trials can be substantial and, according to the criteria above, should be fully reimbursed by third-party carriers.
As indicated above, the FN rate of the ANC Study Group Registry was unknown at the time of this study's initiation because the registry and our study were run concurrently. The pegfilgrastim package insert and updated ASCO and NCCN guidelines recommend that patients receive primary prophylaxis when they are treated with chemotherapy regimens that have an FN risk of approximately 20% across cycles and <20% when patients have specific risk factors for FN [10–12].
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