title: A single-arm phase II trial of combined chemotherapy with S-1, oral leucovorin, and bevacizumab in heavily pre-treated patients with metastatic colorectal cancer.
abstract: BACKGROUND
  The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy.
  
  
  METHODS
  Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR).
  
  
  RESULTS
  A total of 31 patients were enrolled. DCR was 65% [95% confidence interval (CI), 48-100%] and the response rate was 7% (95% CI, 0.7-22%). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95% CI, 2.1-9.3] and 9.9 [95% CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26%) and diarrhea (11%), which were manageable by dose reduction/interruption.
  
  
  CONCLUSIONS
  SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC.
  
  
  BACKGROUND
  This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( ID UMIN000009083 ) on 11 October 2012.
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. kazuhisa.yamaguchi@med.toho-u.ac.jp.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Omori Medical Center, 6-11-1 Omorinishi, Ota-ku, 143-8541, Tokyo, Japan. kazuhisa.yamaguchi@med.toho-u.ac.jp.
authors: Kazuhisa
authors: K
authors: Yamaguchi
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. h.taniguchi@aichi-cc.jp.
authors: Hiroya
authors: H
authors: Taniguchi
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. a.komori@aichi-cc.jp.
authors: Azusa
authors: A
authors: Komori
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. yukiya.narita@aichi-cc.jp.
authors: Yukiya
authors: Y
authors: Narita
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. shntt2@gmail.com.
authors: Sohei
authors: S
authors: Nitta
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. mnomura@aichi-cc.jp.
authors: Motoo
authors: M
authors: Nomura
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. skadowaki@aichi-cc.jp.
authors: Shigenori
authors: S
authors: Kadowaki
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. daisuke.takahari@jfcr.or.jp.
authors: Daisuke
authors: D
authors: Takahari
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. tura@aichi-cc.jp.
authors: Takashi
authors: T
authors: Ura
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. mandoh@aichi-cc.jp.
authors: Masashi
authors: M
authors: Andoh
authors: Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Aichi, Japan. kmuro@aichi-cc.jp.
authors: Kei
authors: K
authors: Muro
authors: Division of Clinical Research Promotion Office, Depertment of Clinical, Research Support Center, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, 411-8777, Shizuoka, Japan. ke.mori@acchr.jp.
authors: Keita
authors: K
authors: Mori
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Omori Medical Center, 6-11-1 Omorinishi, Ota-ku, 143-8541, Tokyo, Japan. igarashi@med.toho-u.ac.jp.
authors: Yoshinori
authors: Y
authors: Igarashi
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D016879:Salvage Therapy / Q000379:methods; D005641:Tegafur / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D000068258:Bevacizumab; D010094:Oxonic Acid; D002955:Leucovorin