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A randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer

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Abstract

Purpose

Biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) enhances antitumor activity. LV is thus often added to 5-FU-based regimens for the treatment of metastatic colorectal cancer (mCRC). A combination of S-1, oxaliplatin, and LV (SOL) was shown to be feasible, effective, and safe in a previous phase I trial. We therefore conducted a randomized phase II trial to evaluate efficacy and safety of SOL compared with mFOLFOX6.

Methods

Patients with mCRC and no prior chemotherapy were randomly assigned to receive either SOL or mFOLFOX6. SOL consisted of S-1 (40–60 mg bid) plus oral LV (25 mg bid) for 1 week and oxaliplatin (85 mg/m2) on day 1, repeated every 2 weeks.

Results

Among 107 patients enrolled from July 2008 through July 2009, 105 (56 in the SOL group and 49 in the mFOLFOX6 group) were eligible and evaluated. The median progression-free survival was 9.6 months in the SOL group and 6.9 months in the mFOLFOX6 group [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.49–1.40]. The median overall survival was 29.9 and 25.9 months, respectively (HR 0.91, 95 % CI 0.55–1.49). The response rate was 55 % in both groups. Grade 3 or 4 adverse drug reactions were neutropenia (20 % with SOL vs 41 % with mFOLFOX6), sensory neuropathy (20 vs 2.0 %), anorexia (13 vs 7.8 %), fatigue (11 vs 5.9 %), and diarrhea (11 vs 3.9 %).

Conclusions

SOL demonstrated promising efficacy and acceptable toxicity as first-line chemotherapy for mCRC. Further studies of SOL combined with molecular target agents are warranted.

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Acknowledgments

We thank all the patients, their families, the investigators, and the medical staff. We are grateful to Yoshihiko Maehara, Keisuke Aiba, Atsushi Sato for their kind advice as members of the Independent Data and Safety Monitoring Committee and Junji Tanaka, Kohki Yoshikawa, Takayuki Yoshino as members of the Independent Review Committee. We also thank Yuh Sakata for his advice as the medical advisor. Statistical data analysis was performed by Takanori Tanase, Taiho Pharmaceutical Co., Ltd.

Ethical standard

I.H. has reported having an advisory role at Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. KShimada, TOishi, and M.T. have reported having an advisory role at Taiho Pharmaceutical Co., Ltd. KY, H.K., H.O., KShimada, I.H., T.N., KShirao, T.E., T.D., and N.B. have reported receiving honoraria from Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. TOhishi has reported receiving honoraria from Taiho Pharmaceutical Co., Ltd. K.Y., H.K., K. Shimada, I.H., T.N., K. Shirao, T.E., and T.D. have reported receiving research funding from Taiho Pharmaceutical Co., Ltd. and Yakult Honsha Co., Ltd. H.O., T. Otsuji, T.K., T. Ohishi, and N.B. have reported receiving research funding from Taiho Pharmaceutical Co., Ltd. All procedures performed in this study were in accordance with the ethical standards of the institutional review board at each participating center and with the 1964 Declaration of Helsinki and Japanese Good Clinical Practice Guidelines.

Informed consent

Written informed consent was obtained from all individual participants included in this study.

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Corresponding author

Correspondence to Kentaro Yamazaki.

Appendix

Appendix

See Tables 4 and 5.

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Yamazaki, K., Kuwano, H., Ojima, H. et al. A randomized phase II study of combination therapy with S-1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer. Cancer Chemother Pharmacol 75, 569–577 (2015). https://doi.org/10.1007/s00280-015-2676-0

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  • DOI: https://doi.org/10.1007/s00280-015-2676-0

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