Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant 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

Comparison of Irinotecan and Oxaliplatin as the First-Line Therapies for Metastatic Colorectal Cancer: A Meta-analysis

“…Moreover, a previous report indicated that peripheral sensory neuropathy lasts for a long period and affects QOL after treatment. 47 Thus, physicians should consider QOL during not only the rst-line treatment but also the overall survival time when selecting the regimens.…”

Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1

“…46 In the ACHIEVE trial, at a median follow-up of 3 years, the prevalence all grade neuropathy was 23.3% vs 10%, while grade 3 was only 0.3 vs 0%. 47 In the ACHIEVE trial, it was also observed that the incidence of any grade PSN was lower for patients treated with CAPOX compared with FOLFOX in both the 6 months and 3 months treatment groups. All other studies did NR any LT.…”

“…The 3 months treatment arm received a grade B based on non-inferiority in combination with less toxicity. [46][47][48] T4 versus T1-3 and N2 versus N1 subgroups were prespecified however their combinations in subgroups and its interaction test was not significant, thus these subgroup analyses were post hoc and could not be graded.…”

Adjuvant Therapies in Colon Cancer

“…But patients with diabetes seem to develop neuropathy at lower cumulative dose [26]. Another report suggests that incidence neuropathy may be less XELOX 3-wekely (130 mg/m 2 ) regimen than FOLFOX 2-weekly (85 mg/m 2 ) regimen [27]. Therefore, choice of oxaliplatin in the adjuvant treatment of colon cancer should be based on individual assessment of risk of recurrence and other clinical factors.…”