title: Phase I study of neoadjuvant chemoradiotherapy with S-1 plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis: -KOGC04-.
abstract: BACKGROUND
  In patients with highly advanced gastric cancer, the recurrence rate remains high and the prognosis disappointing. We previously reported a phase I study of a neoadjuvant chemoradiotherapy of S-1 plus weekly cisplatin. Although adequate safety and efficacy were reported, myelosuppression was frequently observed, leading to treatment delay in several cases. To decrease toxicity and improve efficacy, we planned a phase I study with a modified chemotherapy regimen with biweekly cisplatin.
  
  
  METHODS
  Patients with advanced gastric cancer and lymph node metastasis who were treated by our institution between 2011 and 2012 were eligible for inclusion. The initial chemoradiotherapy schedule consisted of 6 weeks of S-1 orally administered on days 1-15 with an escalating dose of cisplatin administered on days 1 and 15. The starting dose (level 1) of cisplatin was 15 mg/m(2), the second dose (level 2) was 20 mg/m(2), and the third dose (level 3) was 25 mg/m(2). Radiation of 40 Gy was administered in 20 fractions. After initial chemoradiotherapy, one cycle of combination chemotherapy with S-1 plus cisplatin was delivered. The second cycle was 42 days in duration and included S-1 administered on days 1-29 plus biweekly cisplatin administered on days 1, 15, and 29. After neoadjuvant treatment, a curative gastrectomy with extended (D2) lymph node dissection was planned.
  
  
  RESULTS
  Nine patients were enrolled. At level 3, one patient had dose-limiting grade 3 diarrhea. Another patient experienced grade 3 nausea and intended to discontinue the treatment. Overall, because 2 of 3 patients experienced dose-limiting toxicity at level 3, we confirmed level 3 (Cisplatin 25 mg/m(2)) as the maximum tolerated dose and level 2 (Cisplatin 20 mg/m(2)) as the recommended dose (RD). The response rate was 78%, and 8 patients underwent curative gastrectomy. Resected specimens showed a histological response in 6 patients (75%), including one with a pathological complete response.
  
  
  CONCLUSIONS
  In this phase I trial, RD of cisplatin was identified as 20 mg/m(2). Generally, S-1 plus biweekly cisplatin can be given safely with concurrent radiation. We have initiated a multicenter phase II trial to further confirm the efficacy and safety of this approach.
  
  
  BACKGROUND
  UMIN000008941.
authors.forename: Satoru
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. surgeontsune@yahoo.co.jp.
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Takahashi
authors.forename: Junichi
authors.initials: J
authors.lastname: Fukada
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Fukuda
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kawakubo
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saikawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Kawaguchi
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Shigematsu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010094:Oxonic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D011879:Radiotherapy Dosage; D013274:Stomach Neoplasms / Q000473:pathology / Q000628:therapy*; D005641:Tegafur / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002945:Cisplatin