Original StudyA Randomized, Placebo-Controlled Phase II Study Evaluating the Reduction of Neutropenia and Febrile Neutropenia in Patients With Colorectal Cancer Receiving Pegfilgrastim With Every-2-Week Chemotherapy
Introduction
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related death in the United States.1 Over the past decade, numerous studies have indicated that combining 5-fluorouracil (5-FU)/leucovorin (LV) with irinotecan and/or oxaliplatin can prolong survival in patients with advanced CRC. A common toxicity of these combination regimens is neutropenia.2, 3 Neutropenia increases the risk for infection presenting as febrile neutropenia (FN), which can lead to chemotherapy dose reductions and delays, hospitalizations, and death.4, 5 The rate of grade 3/4 neutropenia in patients with advanced CRC has been reported to be 42% in patients receiving an every-2-week regimen of FOLFOX (5-FU/LV/oxaliplatin),2 46% in patients receiving a every-2-week regimen of FOLFIRI (5-FU/LV/irinotecan),3 and over 50% in patients receiving an every-2-week regimen of FOIL (5-FU/LV/oxaliplatin/irinotecan).6
Pegfilgrastim, a granulocyte colony-stimulating factor (G-CSF), is approved in the United States to decrease the risk of infections in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy associated with a significant incidence of FN.7 The pegfilgrastim labeling information recommends that pegfilgrastim not be administered in the period between 14 days before and 24 hours after chemotherapy administration.7 For every-2-week regimens incorporating infusional 5-FU, an 11-day interval would exist between administration of pegfilgrastim and the next cycle of chemotherapy. To date, limited data exist regarding this schedule of pegfilgrastim administration. Previous pharmacokinetic data have shown, however, that pegfilgrastim levels generally reach subtherapeutic levels (with recovery of absolute neutrophil counts) by day 12 after administration, suggesting that pegfilgrastim administration with every-2-week chemotherapy was possible.8, 9
This randomized, placebo-controlled phase II study was designed to evaluate whether prophylactic pegfilgrastim administered with first- or second-line chemotherapy was feasible and reduced the incidence of grade 3/4 neutropenia and neutropenia-related complications in patients receiving 14-day oxaliplatin- or irinotecan-containing 5-FU–based chemotherapy regimens for advanced or metastatic CRC.
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Patients
Eligible patients (≥ 18 years of age) had locally advanced or metastatic colorectal adenocarcinoma not curable by surgery and not amenable to curative radiation therapy; life expectancy of ≥ 12 weeks; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematopoietic, liver, and kidney functions. Patients could have received adjuvant chemotherapy and up to 1 previous chemotherapy regimen for metastatic disease, provided that 30 days had elapsed since the last dose of
Results
This randomized, placebo-controlled phase II study was conducted at 54 sites in the United States between February 2003 and March 2008. The study protocol was reviewed and approved by the institutional review board at each study site, and written informed consent was obtained from each patient before enrollment.
Discussion
This study demonstrated that pegfilgrastim administered on day 4 of an every-2-week CRC chemotherapy regimen significantly reduced the incidence of grade 3/4 neutropenia (P < .001). Although the incidence of FN was relatively low with these regimens, pegfilgrastim-treated patients had significantly less grade 3/4 FN compared with placebo-treated patients (2% vs. 8%; OR, 0.27; 95% CI, 0.07-1.00; P = .04). Pegfilgrastim use also reduced chemotherapy dose delays and dose reductions due to
Conclusion
The results from this study support the feasibility of using pegfilgrastim with every-2-week chemotherapy regimens in patients with CRC and support the efficacy of pegfilgrastim in preventing neutropenia across regimens and tumor types. Further evaluation of pegfilgrastim may be warranted in patients with CRC who are at a high risk for complications or who are candidates for potentially curative surgery following chemotherapy administration.
Acknowledgments
We extend our appreciation to Linda Runft, PhD, and Brian McGuire at Amgen, who provided writing assistance for this manuscript. Funding and investigational product for this study were supplied by Amgen (Thousand Oaks, CA).
Disclosures
Dr. Heim owns Amgen stock. Dr. Swan has received standard per-patient funding from Amgen. Dr. Dreiling is an employee of Amgen and owns Amgen stock. May Mo is an employee of Amgen and owns Amgen stock. Dr. Malik has received research funding from Amgen, has served as a consultant or been on an advisory or research panel for Amgen, ImClone Systems Incorporated, Novartis Pharmaceuticals Corporation, Pfizer Inc., and Roche Pharmaceuticals, and has participated on a Speaker's Bureau for Roche
References (16)
- et al.
Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial
Lancet
(2000) - et al.
Low incidence of neutropenic events in patients with lymphoma receiving first-cycle pegfilgrastim with chemotherapy: results from a prospective community-based study
Clin Lymphoma Myeloma
(2007) - et al.
Cancer statistics, 2007
CA Cancer J Clin
(2007) - et al.
Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer
J Clin Oncol
(2000) Optimizing the management of chemotherapy-induced neutropenia
Clin Adv Hematol Oncol
(2003)- et al.
Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review
J Clin Oncol
(2007) - et al.
Biweekly chemotherapy with oxaliplatin, irinotecan, infusional fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer
J Clin Oncol
(2002) - Amgen Inc. Neulasta® (pegfilgrastim). Prescribing Information;...
Cited by (56)
A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pegfilgrastim in Patients Receiving First-Line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for Locally Advanced or Metastatic Colorectal Cancer: Final Results of the Pegfilgrastim and Anti-VEGF Evaluation Study (PAVES)
2017, Clinical Colorectal CancerCitation Excerpt :The present phase III trial was designed after publication of data from a phase II trial of patients with advanced CRC receiving FOLFOX4, FOLFIRI, or FOIL4 (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) that had shown an incidence of grade 3/4 FN of 8.5%, with pegfilgrastim reducing the rate to 2.4% (P = .04). The incidence of grade 3/4 neutropenia in that study was 43%, with pegfilgrastim reducing the rate to 13% (P < .001).4 The addition of bevacizumab to the FOLFOX4 and FOLFIRI regimens in PAVES was expected to further increase the FN risk and hence fall into the intermediate-to-high FN risk category as described in the NCCN guidelines.14
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Portions of this study have been previously presented as posters at scientific meetings including: The 9th World Congress of Gastrointestinal Cancer; June 27-30, 2007; Barcelona, Spain. The Multinational Association of Supportive Care in Cancer International Symposium; June 27-30, 2007; St. Gallen, Switzerland. The American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2009; Orlando, Florida.