ArticlesBevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial
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1990s.8, 9, 10 A 6-month course of bolus fluorouracil and leucovorin emerged as the standard of care;9, 10 it was later superseded in trials by infusional fluorouracil and leucovorin regimens, which had an improved safety profile.2, 11 Further changes to adjuvant treatment have since been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.
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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
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