A phase II study of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA) in patients with unresectable metastatic colorectal cancer
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Adding leucovorin to fluorouracil is known to improve response rate and overall survival in first-line chemotherapy for metastatic colorectal cancer (mCRC). The present multicenter phase II study evaluated the efficacy and safety of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA).
Patients with unresectable and untreated mCRC received S-1 (40–60 mg bid) plus leucovorin (25 mg bid) orally for 1 week, and oxaliplatin (85 mg/m2) and bevacizumab (5 mg/kg) intravenously on day 1, every 2 weeks. Efficacy endpoints, including the response rate (the primary endpoint) and progression-free survival, were assessed by an independent review committee.
Of the 29 eligible patients, 25 patients (86 %) had a partial response [95 % confidence interval (CI) 68–96 %] and the remaining four patients showed stable disease with a trend toward tumor shrinkage. The median progression-free survival was 15 months (95 % CI 10–26 months). The median overall survival was not reached after a median follow-up time of 34 months. The 3-year survival rate was 54 %. Curative resections of metastatic lesions were performed in eight patients (28 %). Common grade 3 or 4 adverse events were neutropenia (20 %), hypertension (23 %), anorexia (20 %), fatigue (17 %), diarrhea (10 %), and peripheral sensory neuropathy (53 %).
The SOLA therapy showed excellent efficacy and tolerable toxicities except for peripheral sensory neuropathy in patients with mCRC. Since oxaliplatin-induced neuropathy can be alleviated by modifying its administration, SOLA is a promising candidate regimen to be compared with FOLFOX plus bevacizumab in a future phase III trial.
Clinical trial number
KeywordsS-1 Leucovorin Oxaliplatin SOLA Colorectal cancer Bevacizumab
We thank the patients; their families; all the investigators who participated in the study; all of the independent data monitoring committee members (Y. Maehara, K. Aiba, and A. Sato); Y. Sakata as a medical adviser; all of the independent review committee members (J. Tanaka, S. Hironaka, and T. Ushimi); T. Tanase, Taiho Pharmaceutical Co., Ltd for statistical analysis; and M. Hiramatsu, Taiho Pharmaceutical Co., Ltd for his support of this report. This study was funded by Taiho Pharmaceutical Co., Ltd, Tokyo, Japan. Employees of Taiho Pharmaceutical Co., Ltd were involved in the study design and the data collection and analysis. They also provided writing assistance.
Compliance with ethical standards
Conflict of interest
T Nishina has received honoraria from Taiho Pharmaceutical (Taiho), Chugai Pharmaceutical (Chugai), and Yakult Honsha (Yakult) and has received research funding from Taiho. T. Kato has received research funding from Taiho. K. Yamazaki has received honoraria from Taiho, Chugai, and Yakult and has received research funding from Taiho. T. Yoshino has received honoraria from Chugai and has received research funding from Taiho. Y. Miyata has received research funding from Taiho. T. Esaki has received honoraria from Taiho, Chugai, and Yakult and has received research funding from Taiho. T. Moriwaki has received honoraria from Taiho and Chugai and has received research funding from Taiho. N. Boku has received honoraria from Taiho and Yakult and has received research funding from Taiho. I. Hyodo has received honoraria and research funding from Taiho, Chugai and Yakult.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
- 4.Yamada Y, Takahari D, Matsumoto H et al (2013) Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 14:1278–1286CrossRefPubMedGoogle Scholar
- 5.Muro K, Boku N, Shimada Y et al (2010) Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non-inferiority study (FIRIS study). Lancet Oncol 11:853–860CrossRefPubMedGoogle Scholar
- 8.Xu R, Li J, Xu J et al (2013) Phase II study of S-1 plus leucovorin (1 week treatment regimen followed by 1 week rest period) in patients with untreated metastatic colorectal cancer in Japan and China: comparing results of each country and updating overall survival. J Clin Oncol 31 (suppl 4; abstr 528)Google Scholar
- 16.Van Cutsem E, Köhne C-H, Láng I, et al (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29:2011–2019CrossRefPubMedGoogle Scholar
- 17.Sommeijer DW, Shi Q, Meyer JP et al (2013) Prognostic value of early objective tumor response (EOTR) to first-line systemic therapy in metastatic colorectal cancer (mCRC): Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database. J Clin Oncol 31 (suppl; abstr 3520)Google Scholar
- 18.de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2937–2938Google Scholar
- 19.Grothey A, Deschler B, Kroening H et al (2002) Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24 h 5-FU infusion/FA + Oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 21:129a (abstr 512)Google Scholar
- 20.Brienza S, Vignoud J, Itzakhi M et al (1995) Oxaliplatin (LOHP): Global safety in 682 patients (pts). Proc Am Soc Clin Oncol 14:209 (abstr 513)Google Scholar