Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer : The ACHIEVE Phase 3 Randomized Clinical Trial

Key Points

Question

Can a shortened course of adjuvant oxaliplatin-based chemotherapy reduce peripheral sensory neuropathy (PSN) without compromising efficacy in patients with stage III colon cancer?

Findings

In this phase 3 randomized clinical trial of 1313 patients, 3 months of adjuvant therapy significantly reduced the rate of any grade of PSN at 3 years, compared with 6 months of treatment. The incidence of any grade of PSN lasting for 3 years was significantly lower for the chemotherapy drug capecitabine plus oxaliplatin (CAPOX) than for the drug modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6); these treatment outcomes were consistent with those of the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration.

Meaning

A 3-month chemotherapy regimen of CAPOX may be the most appropriate treatment option for colon cancer, particularly in low-risk patients.

Abstract

This phase 3 randomized clinical trial evaluates the outcomes and the incidence of peripheral sensory neuropathy of 3 months vs 6 months of adjuvant oxaliplatin-based chemotherapy for colon cancer.

Abstract

Importance

Oxaliplatin-based chemotherapy is associated with debilitating peripheral sensory neuropathy (PSN) for patients with stage III colon cancer.

Objective

To assess disease-free survival (DFS) and long-lasting PSN in patients treated with 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy.

Design, Setting, and Participants

An open-label, multicenter, phase 3 randomized clinical trial of 1313 Asian patients with stage III colon cancer was conducted investigating the noninferiority of 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. From August 1, 2012, to June 30, 2014, participants were randomized to the 2 treatment groups. Data were analyzed from July 2017 to June 2018.

Interventions

Patients were randomized to receive 3 or 6 months of adjuvant chemotherapy. The choice of chemotherapy regimen, with the drugs modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX), was at the discretion of the treating physician.

Main Outcomes and Measures

The primary outcome was DFS. Secondary end points included the evaluation of PSN for up to 3 years and overall survival.

Results

Of the 1313 patients (651 were women and mean age was 66 [range, 28-85] years) enrolled and randomized, 22 were not treated because 10 were unable to begin treatment within 2 weeks of enrollment, 7 withdrew their consent, and 5 were not treated for various other reasons. Of 1291 patients treated (650 in the 3-month arm and 641 in the 6-month arm), 969 (75%) received the chemotherapy drug CAPOX. The hazard ratio (HR) for DFS of the 3-month arm compared with the 6-month arm was 0.95 (95% CI, 0.76-1.20). Hazard ratios were 1.07 (95% CI, 0.71-1.60) and 0.90 (95% CI, 0.68-1.20) for the drugs mFOLFOX6 and CAPOX, and 0.81 (95% CI, 0.53-1.24) and 1.07 (95% CI, 0.81-1.40) for patients with low-risk disease (TNM classification stages T1-3 and N1) and high-risk disease (stages T4 or N2), respectively. The rates of any grade of PSN lasting for 3 years in the 3-month vs 6-month treatment arms were 9.7% vs 24.3% ( P < .001). Incidence of PSN lasting for 3 years was significantly lower for patients treated with CAPOX than for patients treated with mFOLFOX6 in both the 3-month (7.9% vs 15.7%; P = .04) and 6-month arms (21.0% vs 34.1%; P = .02).

Conclusions and Relevance

The incidence of long-lasting PSN was significantly lower for 3 months than for 6 months of therapy, and significantly lower for treatment with the drug CAPOX than with mFOLFOX6. Since the shortened therapy duration did not compromise outcomes, a 3-month course of CAPOX may be the most appropriate treatment option, particularly for patients with low-risk disease.

Trial Registration

UMIN Clinical Trials Registry: UMIN000008543