Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group

Summary

Background

The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation.

Methods

In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637.

Findings

Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36–57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56–0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups.

Interpretation

Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life.

Funding

Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.

Introduction

The availability of new drugs has improved the prognosis of patients with metastatic colorectal cancer.¹ The addition of bevacizumab, a humanised monoclonal antibody against VEGF, to fluoropyrimidine-containing chemotherapy has resulted in significant benefits in overall or progression-free survival,2, 3, 4, 5, 6 and is deemed a standard first-line treatment option for patients with metastatic colorectal cancer.

Since metastatic disease can be controlled by systemic treatment for a substantial period of time, strategies that reduce time on treatment and associated side-effects without compromising survival are highly desirable. However, questions remain about the optimum use of drugs and duration of treatment. For chemotherapy, making all effective drugs available during the course of disease (ie, sequentially) was shown to be more important than their combined use,⁷ which we and others subsequently confirmed in prospective randomised trials.8, 9 The feasibility of chemotherapy-free intervals has been studied.10, 11, 12, 13, 14 The results from the MRC,¹⁰ COIN,¹¹ and GISCAD¹⁴ trials did not show a clear benefit in terms of survival for continuous versus intermittent chemotherapy, whereas those from OPTIMOX2¹³ were less straightforward. In the OPTIMOX1 trial¹² the intermittent use of oxaliplatin did not compromise survival. The optimum duration of chemotherapy in combination with targeted therapy has not been investigated in a prospective trial. Theoretically, discontinuation of a drug that inhibits the transduction of growth signals could result in tumour regrowth. For chemotherapy plus bevacizumab, this theory is supported by data from the NO16966 trial (FOLFOX/CAPOX with or without bevacizumab),⁴ in which a preplanned subgroup analysis showed inferior survival results for patients in whom treatment was discontinued earlier than 28 days from disease progression or death. The positive outcome of the ML18147 trial¹⁵ (bevacizumab continuation beyond first progression) also supports the value of a continued use of targeted drugs.

In the CAIRO3 trial, we aimed to identify the value of maintenance treatment with capecitabine plus bevacizumab versus observation until disease progression in patients with metastatic colorectal cancer without disease progression after six cycles of capecitabine, oxaliplatin, and bevacizumab.