Originally published as JCO Early Release 10.1200/JCO.2009.21.9220 on May 4 2009

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Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer

From the National Surgical Adjuvant Breast and Bowel Project; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh; Allegheny General Hospital, Pittsburgh, PA; University of Florida, Gainesville, FL; Helen F. Graham Cancer Center, Newark, DE; University of North Carolina, Chapel Hill; Southeast Cancer Control Consortium – Community Clinical Oncology Program, Goldsboro, NC; Atlanta Cancer Care, Atlanta, GA; Kaiser Permanente, Northern California, Vallejo, CA; Florida Cancer Specialists, Sarasota, FL; Kaiser Permanente, Colorado, Denver, CO; and All Ireland Clinical Oncology Research Group, Dublin, Ireland.

Corresponding author: Carmen J. Allegra, MD, University of Florida, Division of Hematology and Oncology, Medical Science Bldg, N-503, 1600 SW Archer Rd, Box 100277, Gainesville, FL 32610; e-mail: Carmen.Allegra{at}medicine.ufl.edu.

Purpose The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy.

Patients and Methods Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group).

Results Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment.

Conclusion Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.

Supported by Public Health Service Grants No. U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974 from the National Cancer Institute, Department of Health and Human Services.

Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

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