Cancer Chemotherapy and Pharmacology

, Volume 76, Issue 3, pp 547–553 | Cite as

A phase II study of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA) in patients with unresectable metastatic colorectal cancer

  • Tomohiro NishinaEmail author
  • Takeshi Kato
  • Kentaro Yamazaki
  • Takayuki Yoshino
  • Yoshinori Miyata
  • Taito Esaki
  • Toshikazu Moriwaki
  • Narikazu Boku
  • Ichinosuke Hyodo
Original Article



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



S-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.

Ethical standard

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.

Supplementary material

280_2015_2825_MOESM1_ESM.docx (36 kb)
Supplementary material 1 (DOCX 35 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Tomohiro Nishina
    • 1
    Email author
  • Takeshi Kato
    • 2
  • Kentaro Yamazaki
    • 3
  • Takayuki Yoshino
    • 4
  • Yoshinori Miyata
    • 5
  • Taito Esaki
    • 6
  • Toshikazu Moriwaki
    • 7
  • Narikazu Boku
    • 8
  • Ichinosuke Hyodo
    • 7
  1. 1.Department of Gastrointestinal Medical OncologyNational Hospital Organization Shikoku Cancer CenterMatsuyamaJapan
  2. 2.Department of SurgeryKansai Rosai HospitalAmagasakiJapan
  3. 3.Division of Gastrointestinal Oncology and EndoscopyShizuoka Cancer CenterShunto-gun, ShizuokaJapan
  4. 4.Department of Gastroenterology and Gastrointestinal OncologyNational Cancer Center Hospital EastKashiwaJapan
  5. 5.Department of Medical OncologySaku Central HospitalSakuJapan
  6. 6.Department of Gastrointestinal and Medical OncologyNational Kyushu Cancer CenterFukuokaJapan
  7. 7.Division of Gastroenterology, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  8. 8.Department of Clinical OncologySt. Marianna University School of MedicineKawasakiJapan

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