NE Oncology Issue – June 2007

Meenakshi Kashyap

Bevacizumab is effective in combination with XELOX or FOLFOX-4


Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that inhibits the vascular endothelial growth factor (VEGF), an angiogenesis factor secreted by tumour cells to bring about new blood vessel formation. Cancer Care Ontario guidelines recommend the addition of bevacizumab to improve overall survival as first-line therapy in patients with advanced colorectal cancer receiving 5-fluorouracil (5-FU)–based chemotherapy, and as second-line therapy for patients who did not receive bevacizumab as part of their initial treatment.2

The NO169663 trial was initially started as a randomized phase III study to compare the efficacy of XELOX (cape-citabine and oxaliplatin) versus FOLFOX-4 (5-fluorouracil, leucovorin, and oxaliplatin). The protocol was amended to include bevacizumab in a partially blinded 2 x 2 factorial design to determine the following objectives:

  • Non-inferiority of XELOX versus FOLFOX-4
  • Superiority of bevacizumab in combination with chemotherapy (XELOX and FOLFOX-4) versus chemo-therapy alone for progression-free survival (PFS)

Study design

  • The study was a double-blind study with regard to bevacizumab and placebo administration (Table 1).
  • Patients with criteria such as ECOG PS ≤1, number of unidentified measurable lesions ≥1, no prior systemic therapy for advanced mCRC, and no prior treatment with oxaliplatin or bevacizumab were enrolled in the study. If patients had undergone prior adjuvant therapy, they should not have progressed during or within six months of completion.
  • Patients were randomized to XELOX ± bevacizumab or FOLFOX-4 ± bevacizumab.
    • XELOX + bevacizumab or placebo, for 21-day cycle
      • Bevacizumab (or placebo) 7.5 mg/kg day 1
      • Oxaliplatin 130 mg/m2 day 1
      • Capecitabine 1,000 mg/m2 twice daily days 1–14
    • FOLFOX-4 + bevacizumab or placebo, for 14-day cycle
      • Bevacizumab (or placebo) 5 mg/kg day 1
      • Oxaliplatin 85 mg/m2 day 1
      • Folinic acid 200 mg/m2 days 1, 2
      • Fluorouracil 400 mg/m2 bolus days 1, 2
      • followed by 600 mg/m2 over 22 h
  • Primary endpoint was progression-free survival.
  • Secondary endpoints were overall survival, response rate assessed according to RECIST, and safety evaluated using NCI CTC v3.0.

Key findings

  • There was a significant prolongation of PFS in the bevacizumab + oxaliplatin–based chemotherapy arm (HR = 0.83 [97.5% CI: 0.072–0.95]; p = 0.0023) and a trend toward prolonged overall survival (OS).
  • A higher proportion of discontinuation of therapy because of adverse events (AEs) occurred in the bevacizumab-containing arms versus the placebo-containing arms (31% versus 21%).
  • Most treatment discontinuations, however, were due to chemotherapy rather than bevacizumab-related events.
  • Most common reasons for treatment discontinuation were neurotoxicity, GI events, general disorders, and hematological events.
  • Incidence of grade 3 or 4 events with and without bevacizumab are summarized in Table 2.

Key conclusions

  • There was significant improvement in PFS with the addition of bevacizumab to front-line oxaliplatin-based chemotherapy.
  • Analysis of ‘on treatment’ PFS versus ‘general’ PFS suggests that continuation of bevacizumab until disease progression may be necessary to optimize the effect of bevacizumab on PFS.
  • The observed OS difference did not reach statistical significance (p = 0.077).

References: 1. Canadian Cancer Statistics, 2007. 2. Welch S, Kocha W, Rumble RB, et al. The role of bevacizumab (AvastinTM) combined with chemotherapy in the treatment of patients with advanced colorectal cancer: a clinical practice guideline evidence-based series #2–25: Section 1. Cancer Care Ontario, 2005. 3. Saltz L, Clarke S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX-4: updated efficacy results from XELOX-1/NO16966, a randomized phase III trial in first-line metastatic colorectal cancer. Program and abstracts of the 43rd American Society of Clinical Oncology Annual Meeting; June 1–5, 2007; Chicago, Illinois; Abstract 4028.

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Vera Hirsh, MD, FRCPC
Chief of the Hematology-Oncology Service, Santa Cabrini Hospital
Associate Professor, Medicine and Oncology, McGill University
Associate Physician, Oncology Service, at the Royal Victoria, Montreal General, and Montreal Chest Hospitals
With a current practice in both hematology and oncology, Dr. Vera Hirsh is an associate professor of medicine and oncology at McGill University. Her research at the Quebec Pulmonary Unit focuses on the treatment of lung cancer, and she continues to chair ongoing international chemotherapy trials. Dr. Hirsh chaired the Quebec Lung Cancer Committee to establish guidelines for the treatment of lung cancer. In addition, she has published abstracts, articles, and book chapters. Dr. Hirsh is a member of advisory boards for many pharmaceutical companies and the Medical Oncology Standing Committee of RTOG.

Christine Cripps, MD, FRCPC
Medical Oncologist, Director,
Continuing Medical Education,
Ottawa Hospital Regional Cancer Centre
Dr. Christine Cripps is a medical oncologist and director of the Continuing Medical Education Department at the Ottawa Hospital Regional Cancer Centre. She also holds a position of Associate Professor, Medicine at the University of Ottawa. A keen teacher, Dr. Cripps’ main areas of interest include gastrointestinal cancer and head and neck cancer. She also enjoys cycling, skiing, and sailing when time permits.

Stephen K. L. Chia, MD, FRCPC
Assistant Professor of Medicine Department of Medicine
University of British Columbia
British Columbia Cancer Agency
Dr. Chia is a staff oncologist with the British Columbia Cancer Agency (BCCA), Vancouver, Canada. He also serves as physician coordinator for both the breast cancer and head and neck cancer clinical trials at the BCCA – Vancouver Cancer Centre. He is an active researcher in phase I-III trials in breast cancer, head and neck cancer and investigational new drugs. He is currently carrying out studies in breast cancer with grant funded research from the National Cancer Institute of Canada, Canadian Breast Cancer Alliance and Canadian Breast Cancer Foundation – British Columbia/Yukon Chapter. Dr. Chia is an active member of the British Columbia Breast Tumor Group, Breast Cancer Systemic Policy Group and Head and Neck Tumor Group.

José Chang, MD, FRCPC
Head of Medical Oncology, RS
McLaughlin Durham Regional Cancer Centre, Oshawa
Dr. José Chang is the principal investigator and site representative for the National Cancer Institute of Canada Clinical Trials Group, and is an examiner for the Medical Council of Canada. His research interests lie in the areas of breast cancer, melanoma, lymphoma, and quality of life during chemotherapy. Dr Chang has presented at major oncology meetings of the American Society of Clinical Oncology, San Antonio Breast Cancer Symposia, and European Breast Cancer Conference. A member of the editorial board of the journal Current Oncology, Dr. Chang has published in journals such as the Journal of Clinical Oncology, European Journal of Cancer, and Canadian Medical Association Journal.