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

Takayuki Yoshino, Takeharu Yamanaka, Eiji Oki, Masahito Kotaka, Dai Manaka, Tetsuya Eto, Junichi Hasegawa, Akinori Takagane, Masato Nakamura, Takeshi Kato, Yoshinori Munemoto, Shintaro Takeuchi, Hiroyuki Bando, Hiroki Taniguchi, Makio Gamoh, Manabu Shiozawa, Tsunekazu Mizushima, Shigetoyo Saji, Yoshihiko Maehara, Atsushi OhtsuMasaki Mori

Research output: Contribution to journalArticle

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..

Original languageEnglish
Pages (from-to)E1-E8
JournalJAMA Oncology
DOIs
Publication statusAccepted/In press - Jan 1 2019

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oxaliplatin
Phase III Clinical Trials
Peripheral Nervous System Diseases
Adjuvant Chemotherapy
Colonic Neoplasms
Randomized Controlled Trials
Drug Therapy
Disease-Free Survival
Pharmaceutical Preparations
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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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. / Yoshino, Takayuki; Yamanaka, Takeharu; Oki, Eiji; Kotaka, Masahito; Manaka, Dai; Eto, Tetsuya; Hasegawa, Junichi; Takagane, Akinori; Nakamura, Masato; Kato, Takeshi; Munemoto, Yoshinori; Takeuchi, Shintaro; Bando, Hiroyuki; Taniguchi, Hiroki; Gamoh, Makio; Shiozawa, Manabu; Mizushima, Tsunekazu; Saji, Shigetoyo; Maehara, Yoshihiko; Ohtsu, Atsushi; Mori, Masaki.

In: JAMA Oncology, 01.01.2019, p. E1-E8.

Research output: Contribution to journalArticle

Yoshino, T, Yamanaka, T, Oki, E, Kotaka, M, Manaka, D, Eto, T, Hasegawa, J, Takagane, A, Nakamura, M, Kato, T, Munemoto, Y, Takeuchi, S, Bando, H, Taniguchi, H, Gamoh, M, Shiozawa, M, Mizushima, T, Saji, S, Maehara, Y, Ohtsu, A & Mori, M 2019, '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', JAMA Oncology, pp. E1-E8. https://doi.org/10.1001/jamaoncol.2019.2572
Yoshino, Takayuki ; Yamanaka, Takeharu ; Oki, Eiji ; Kotaka, Masahito ; Manaka, Dai ; Eto, Tetsuya ; Hasegawa, Junichi ; Takagane, Akinori ; Nakamura, Masato ; Kato, Takeshi ; Munemoto, Yoshinori ; Takeuchi, Shintaro ; Bando, Hiroyuki ; Taniguchi, Hiroki ; Gamoh, Makio ; Shiozawa, Manabu ; Mizushima, Tsunekazu ; Saji, Shigetoyo ; Maehara, Yoshihiko ; Ohtsu, Atsushi ; Mori, Masaki. / 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. In: JAMA Oncology. 2019 ; pp. E1-E8.
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title = "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..",
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TY - JOUR

T1 - Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer

T2 - The ACHIEVE Phase 3 Randomized Clinical Trial

AU - Yoshino, Takayuki

AU - Yamanaka, Takeharu

AU - Oki, Eiji

AU - Kotaka, Masahito

AU - Manaka, Dai

AU - Eto, Tetsuya

AU - Hasegawa, Junichi

AU - Takagane, Akinori

AU - Nakamura, Masato

AU - Kato, Takeshi

AU - Munemoto, Yoshinori

AU - Takeuchi, Shintaro

AU - Bando, Hiroyuki

AU - Taniguchi, Hiroki

AU - Gamoh, Makio

AU - Shiozawa, Manabu

AU - Mizushima, Tsunekazu

AU - Saji, Shigetoyo

AU - Maehara, Yoshihiko

AU - Ohtsu, Atsushi

AU - Mori, Masaki

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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..

AB - 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..

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