Original Study
A 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

https://doi.org/10.3816/CCC.2010.n.013Get rights and content

Abstract

Background

Adding irinotecan and/or oxaliplatin to every-2-week 5-fluorouracil (5-FU)/leucovorin (LV) prolongs survival in patients with colorectal cancer (CRC) but increases neutropenia frequency. Pegfilgrastim is indicated to decrease infection as manifested by febrile neutropenia (FN) in patients receiving chemotherapy at > 14-day intervals. This randomized, placebo-controlled phase II study examined pegfilgrastim efficacy and safety in patients with CRC receiving every-2-week chemotherapy.

Patients and Methods

Patients with CRC were randomized 1:1 to pegfilgrastim 6 mg or placebo administered per-cycle on day 4. Randomization was stratified by chemotherapy regimen (patients received every-2-week FOLFOX4 [5-FU/LV/oxaliplatin], FOLFIRI [5-FU/LV/irinotecan], or FOIL [5-FU/LV/oxaliplatin/irinotecan] at physician discretion). The primary endpoint was incidence of grade 3/4 neutropenia. Secondary endpoints included incidence of grade 3/4 FN and adverse events. After 4 cycles of study treatment, progression-free survival (PFS) and overall survival (OS) were followed for ≤ 2 years in long-term follow-up.

Results

Of 241 eligible patients analyzed, 118 were in the placebo and 123 in the pegfilgrastim group. In the treatment period, the odds ratio for grade 3/4 neutropenia for pegfilgrastim versus placebo was 0.19 (95% CI, 0.10-0.37; P < .001); grade 3/4 FN incidence was also significantly lower in pegfilgrastim-treated patients (2%) compared with placebo-treated patients (8%; P = .04). Pegfilgrastim was well tolerated, with leukocyte counts remaining stable during cycles 2-4. In long-term follow-up, both treatment groups had similar PFS and OS.

Conclusion

Pegfilgrastim was well tolerated in patients with CRC receiving every-2-week chemotherapy and significantly reduced neutropenia and FN compared with placebo, though FN was uncommon in both treatment groups. Results suggest that pegfilgrastim administration is feasible in CRC patients receiving 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.

Section snippets

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

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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.

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