Elsevier

The Lancet Oncology

Volume 14, Issue 11, October 2013, Pages 1077-1085
The Lancet Oncology

Articles
Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial

https://doi.org/10.1016/S1470-2045(13)70154-2Get rights and content

Summary

Background

Elderly patients are often under-represented in clinical trials of metastatic colorectal cancer. We aimed to assess the efficacy and safety of bevacizumab plus capecitabine compared with capecitabine alone in elderly patients with metastatic colorectal cancer.

Methods

For this open-label, randomised phase 3 trial, patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were randomly assigned in a 1:1 ratio via an interactive voice-response system, stratified by performance status and geographical region. Treatment consisted of capecitabine (1000 mg/m2 orally twice a day on days 1–14) alone or with bevacizumab (7·5 mg/kg intravenously on day 1), given every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Efficacy analyses were based on the intention-to-treat population. The primary endpoint was progression-free survival. The trial is registered with ClinicalTrials.gov, number NCT00484939.

Findings

From July 9, 2007, to Dec 14, 2010, 280 patients with a median age of 76 years (range 70–87) were recruited from 40 sites across ten countries. Patients were randomly assigned to receive either bevacizumab plus capecitabine (n=140) or capecitabine only (n=140). Progression-free survival was significantly longer with bevacizumab and capecitabine than with capecitabine alone (median 9·1 months [95% CI 7·3–11·4] vs 5·1 months [4·2–6·3]; hazard ratio 0·53 [0·41–0·69]; p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 53 (40%) patients in the combination group and 30 (22%) in the capecitabine group, and treatment-related serious adverse events in 19 (14%) and 11 (8%) patients. The most common grade 3 or worse adverse events of special interest for bevacizumab or chemotherapy were hand-foot syndrome (21 [16%] vs nine [7%]), diarrhoea (nine [7%] vs nine [7%]), and venous thromboembolic events (11 [8%] vs six [4%]). Treatment-related deaths occurred in five patients in the combination group and four in the capecitabine group. The most common any-grade adverse event of special interest for bevacizumab was haemorrhage (34 [25%] vs nine [7%]).

Interpretation

The combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer.

Funding

F Hoffmann-La Roche.

Introduction

Metastatic colorectal cancer, as with many cancers, is mainly a disease of elderly people. The median age at diagnosis of colorectal cancer is about 69 years, and roughly 61% of patients are diagnosed at age 65 years or older.1 Risks associated with old age should be taken into account when treatment options are considered, since elderly patients are more likely than younger patients to present with age-related decline in organ function and comorbidities at diagnosis.2, 3 Despite the prevalence of colorectal cancer in the elderly population, such patients are often excluded from randomised trials or represent a minority of enrolled patients.4 As a result, additional data about appropriate treatment options for elderly patients are needed.

Bevacizumab, a humanised monoclonal antibody against VEGF-A, improves progression-free and overall survival when added to chemotherapy in first-line and second-line treatment settings and when continued beyond first progression in metastatic colorectal cancer.5, 6, 7, 8 Subgroup and pooled analyses from randomised trials, along with data from large observational cohort studies, have suggested that the survival benefits associated with the use of bevacizumab in first-line treatment are similar in elderly patients and in the general population.4, 9, 10, 11, 12, 13, 14, 15, 16

International guidelines recommend fluorouracil or capecitabine with or without bevacizumab as first-line treatment for patients with metastatic colorectal cancer for whom more intensive treatment is not appropriate.17, 18 Although these recommendations are supported by data from randomised trials of bevacizumab, these studies did not exclusively enrol a defined elderly patient population.19, 20 Results of phase 2 studies21, 22 have suggested the feasibility and potential efficacy of bevacizumab with capecitabine in patients with metastatic colorectal cancer who are aged 70 years and older.

Despite clinical evidence in the general population of patients with metastatic colorectal cancer, the absence of specific data from randomised trials and the perception of increased toxic effects in elderly patients with comorbidities have led to reservations about treating elderly people with bevacizumab plus chemotherapy.23 We aimed to assess the efficacy and safety of bevacizumab in combination with capecitabine in an exclusively elderly patient population with metastatic colorectal cancer.

Section snippets

Study design and participants

AVEX (AVastin in the Elderly with Xeloda) is a randomised, open-label, international, phase 3 trial of capecitabine with or without bevacizumab in elderly patients with metastatic colorectal cancer. Participants were recruited from 40 study sites across ten countries (Austria, Canada, Hungary, Italy, Mexico, Poland, Slovenia, South Korea, Spain, and the UK; appendix). Eligible patients were aged 70 years or older and had histologically or cytologically confirmed carcinoma of the colon, rectum,

Results

280 patients were enrolled between July 9, 2007, and Dec 14, 2010. Efficacy analyses used a clinical cutoff date of Jan 19, 2012, giving median follow-ups of 24·8 months (IQR 15·1–37·7) for the bevacizumab plus capecitabine group and 21·6 months (12·8–31·9) for the capecitabine-only group. Final safety analyses used a cutoff date of March 8, 2013, giving median follow-ups of 34·4 months (23·9–48·5) and 29·2 months (25·5–42·4), respectively. The intention-to-treat population consisted of 280

Discussion

Our results show that the addition of bevacizumab to capecitabine significantly improved progression-free survival in elderly patients with metastatic colorectal cancer (panel), with a safety profile consistent with that reported by other studies of bevacizumab plus capecitabine in metastatic colorectal cancer.

Overall survival did not differ significantly between the treatment groups. However, the study was not sufficiently powered to detect differences in overall survival. The use of

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