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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Yoshino reports research funding from Chugai Pharmaceutical Co, Ltd, Sanofi KK, and Sumitomo Dainippon Pharma Co, Ltd. Dr Yamanaka reports honoraria from Chugai, Takeda, Taiho, Boehringer-Ingelheim, Bayer, and Pfizer; fees for consultancy from Gilead Sciences, Daiichi-Sankyo, Huya Biosciences, and Sysmex; and research funding from Chugai, Takeda, Taiho, Daiichi-Sankyo, Ono, Boehringer-Ingelheim, Bayer, Merck Serono, Astellas, and Eli Lilly. Dr Oki reports speaking fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Bayer Japan, Merck Serono, Eli Lilly, Yakult Honsha, and Takeda Pharmaceutical. Dr Kotaka reports honoraria from Chugai Pharmaceutical, Yakult Honsha, Takeda Pharmaceutical, Taiho Pharmaceutical, and Merck Serono. Dr Nakamura reports honoraria from Chugai, and Yakult. Dr Kato reports speaking fees from Chugai Pharmaceutical Co and Yakult Honsha. Dr Gamoh reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Yakult Honsha, Ono Pharmaceutical, Takeda Pharmaceutical, Daiichi-Sankyo, Nippon Kayaku, and Eli Lilly Japan. Dr Maehara reports speaking fees from Yakult Honsha Co, Ltd, and Chugai Pharmaceutical Co, Ltd; and research funding from Yakult Honsha Co, Ltd, and Chugai Pharmaceutical Co, Ltd. Dr Ohtsu reports honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Chugai, and Taiho; and research funding from Bristol-Myers Squibb. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram Showing Patient Disposition

CAPOX indicates capecitabine plus oxaliplatin; mFOLFOX6, modified fluorouracil, l-leucovorin, and oxaliplatin; mITT, modified intention to treat.

Figure 2.. Overall Disease-Free Survival (DFS) According to Duration of Adjuvant Treatment

HR indicates hazard ratio; No., number of patients.

Figure 3.. Disease-Free Survival (DFS) Rates According to Disease Risk and Regimen Used

Three-year DFS rates in patients with low-risk (A and B) and high-risk (C and D) disease treated with mFOLFOX6 (A and C) or CAPOX (B and D) regimens for 3 or 6 months. CAPOX indicates capecitabine plus oxaliplatin; HR, hazard ratio; mFOLFOX6, modified fluorouracil, l-leucovorin, and oxaliplatin; No., number of patients.