Elsevier

The Lancet Oncology

Volume 13, Issue 12, December 2012, Pages 1225-1233
The Lancet Oncology

Articles
Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial

https://doi.org/10.1016/S1470-2045(12)70509-0Get rights and content

Summary

Background

Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma.

Methods

Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 400 mg/m2 bolus plus 600 mg/m2 22-h continuous infusion on day 1; leucovorin 200 mg/m2 plus fluorouracil 400 mg/m2 bolus plus 600 mg/m2 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m2 on day 1 every 2 weeks plus oral capecitabine 1000 mg/m2 twice daily on days 1–15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4–8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918.

Findings

Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab–FOLFOX4, and 952 to receive bevacizumab–XELOX. After a median follow-up of 48 months (range 0–66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab–FOLFOX4 group, and 253 (27%) in the bevacizumab–XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98–1·39; p=0·07), and for bevacizumab–XELOX versus FOLFOX4 was 1·07 (0·90–1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·27 (1·03–1·57; p=0·02), and for bevacizumab–XELOX versus FOLFOX4 was 1·15 (0·93–1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3–5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab–XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab–FOLFOX4: 297 [26%]; bevacizumab–XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab–FOLFOX4, and five receiving bevacizumab–XELOX.

Interpretation

Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer.

Funding

Genentech, Roche, and Chugai.

Introduction

The prognosis of colorectal cancer is dependent on disease stage. The rate of 5-year survival is more than 60% in individuals with lymph node involvement, but less than 5% in those with distant metastases.1, 2, 3, 4, 5, 6, 7 As metastatic disease is generally incurable, the concept of adjuvant chemotherapy was developed to allow patients with high-risk primary colon tumours the best chance of cure.

The survival benefits of adjuvant therapy in patients with resected, node-positive colon cancer were established in the 1990s.8, 9, 10 A 6-month course of bolus fluorouracil and leucovorin emerged as the standard of care;9, 10 it was later superseded in trials by infusional fluorouracil and leucovorin regimens, which had an improved safety profile.2, 11 Further changes to adjuvant treatment have since been made after the finding that adding oxaliplatin to fluoropyrimidines reduces the relative risk of recurrence by 20–23%.4, 12, 13

VEGF is a crucial regulator of normal and pathological angiogenesis.14 VEGF inhibition with bevacizumab, a humanised anti-VEGF monoclonal antibody, has direct antivascular effects in human tumours,15 improving outcomes when given with chemotherapy in patients with metastatic colorectal cancer.16, 17, 18

National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 investigated the efficacy of bevacizumab plus adjuvant oxaliplatin-based chemotherapy in patients in the USA with stage II/III colon cancer.19 Adding bevacizumab did not increase disease-free survival (DFS) significantly after a median follow-up of 3 years (hazard ratio [HR] 0·89, 95% CI 0·76–1·04; p=0·15). However, a significant, but transient, effect was seen in the experimental group during bevacizumab exposure and at up to 3 months after completion of bevacizumab.

This article reports the primary efficacy findings from the AVANT trial (BO17920). This study was designed to show the superiority of bevacizumab added to oxaliplatin in combination with fluorouracil and leucovorin (FOLFOX4) or capecitabine (XELOX) compared with FOLFOX4 in terms of DFS in patients who had undergone surgery with curative intent for stage III colon carcinoma.

Section snippets

Study design and patients

AVANT was a prospective, multicentre, randomised, parallel, three-arm, phase 3 trial. The results of several phase 3 trials have shown that FOLFOX and XELOX are equivalent in the setting of metastatic colorectal cancer.16, 17, 18 As a result, rather than using a 2×2 factorial trial design, which would have required an equivalency hypothesis between the arms making the trial inefficient in terms of patient number, we used a parallel three-arm design. This study was done in accordance with the

Results

From Dec 20, 2004, to June 8, 2007, 3451 patients from 330 centres in 34 countries worldwide were randomly assigned to receive FOLFOX4 (n=1151), bevacizumab–FOLFOX4 (n=1155) or bevacizumab–XELOX (n=1145; figure 1). Of the 3451 patients enrolled, 2867 (83%) had stage III disease (FOLFOX4, n=955; bevacizumab–FOLFOX4, n=960; bevacizumab–XELOX, n=952). Baseline demographic and clinical characteristics were balanced between groups (table 1).

Median duration of oxaliplatin treatment was 5·3 months

Discussion

AVANT did not show a significant DFS improvement after a minimum of 3 years' follow-up with the addition of bevacizumab to either FOLFOX4 or XELOX in patients with resected stage III disease. After a minimum of 5 years' follow-up, overall survival data, unlike those from NSABP C-08,19 suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy (numerically more relapses and deaths due to disease progression were seen in both bevacizumab groups).

Bevacizumab

References (37)

  • Efficacy of adjuvant fluorouracil and folinic acid in colon cancer

    Lancet

    (1995)
  • N Wolmark et al.

    Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04

    J Clin Oncol

    (1999)
  • T André et al.

    Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial

    J Clin Oncol

    (2003)
  • JP Kuebler et al.

    Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07

    J Clin Oncol

    (2007)
  • DG Haller et al.

    Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer

    J Clin Oncol

    (2011)
  • N Ferrara et al.

    The biology of vascular endothelial growth factor

    Endocr Rev

    (1997)
  • CG Willett et al.

    Direct evidence that the VEGF specific antibody bevacizumab has antivascular effects in human rectal cancer

    Nat Med

    (2004)
  • H Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
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