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Phase 2 Trial of Oral S-1 Combined with Low-Dose Cisplatin For ANTICANCER RESEARCH 28 : 2373-2378 (2008) Phase 2 Trial of Oral S-1 Combined with Low- dose Cisplatin for Unresectable Advanced Pancreatic Cancer SHINOMI INA, MASAJI TANI, MANABU KAWAI, SEIKO HIRONO, MOTOKI MIYAZAWA, RYOHEI NISHIOKA, YOICHI FUJITA and HIROKI YAMAUE Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama, Japan Abstract. Objectives: A phase 2 trial of S-1 combined with A new 5- fluorouracil ( 5-FU) pro-drug, S-1, is potentially cisplatin was conducted for unresectable pancreatic cancer. effective for pancreatic cancer because chemosensitivity tests Patients and Methods: S-1 was administered for 28 days have shown that 5-FU inhibits the growth of pancreatic followed by a rest of 14 days. Cisplatin was infused on days cancer cells as well as other gastrointestinal carcinomas (4). 1-5, 8-12, 15-19 and 22-26 of the first course. After the second In addition, the European Study Group for Pancreatic Cancer course, S-1 was administered as maintenance chemotherapy. 1 (ESPAC-1) trial demonstrated that 5-FU in combination Results: Thirty patients were enrolled and the responses with leu covorin improved postoperative survival for resected observed were 0 complete response, 5 partial response, 22 pancreatic cancer (5). Recently, S-1 has been reported to stable disease and 3 progressive disease, with an overall promote a clinical response to pancreatic cancer (6-8). response rate of 17% (95% confidence internal ( CI), 6- Therefore, S-1 may become one of the key drugs for 35%). Toxicity was tolerable, with grade 3 toxicities observed pancreatic cancer. for leukocytopenia (10%), neutropenia (7%), anemia (3%), Cisplatin has been reported to have a 21% overall thrombocytopenia (3%), anorexia (13%), and nausea and response rate with a n MST of 4 months for advanced vomiting (7%). The median survival time (MST) and the 1- pancreatic cancer (9). Cisplatin enhances the antitumor effect year survival rate were 9.0 months (95% CI, 6.0-14.5 months) of 5-FU, inhibiting methionine uptake into tumor cells and and 35.7% (95% CI, 19-55%), respectively . Conclusion: S-1 reducing the methionine pool in the cells (10), which leads with low-dose cisplatin is well tolerated and effective for to increased methionine biosynthesis and the pooling of advanced pancreatic cancer. folate cofactors. Increased 5,10-methylenetetrahydrofolate enhances 5-FU cytotoxicity by increasing the reduction of Gemcitabine (GEM) is the standard chemotherapeutic agent thymidylate synthase to yield the ternary complex, which for unresectable pancreatic cancer and yields significant binds tightly to the 5-FU metabolites fluorodeoxyuridylate, clinical symptomatic control. Nevertheless, the prognosis of thymidylate synthase, and 5,10-methylenetetrahydrofolate pancreatic cancer treated by GEM is still poor, with a median (11). One of the advantages of low-dose cisplatin is the survival time (MST) and 1-year survival rate of 5.7 months avoidance of renal failure and the lack of a requirement for and 18% respectively, and the response rate remains 5.4% hydration of several hours’ duration, which is necessary with (1). Many phase 2 or 3 studies of a combination of GEM high-dose cisplatin. The other merits of low-dose cisplatin with other anticancer agents, including molecular-targeting are a lower incidence of nausea and vomiting than normally drugs, have failed to prolong survival (2, 3). Therefore, it is occurs at higher doses (12). A phase 1 study in gastric necessary to identify new chemotherapeutic regimen s in cancer combining S-1 and low-dose cisplatin has been addition to single-agent GEM in order to improve the performed, and efficacy and safety were demonstrated (12). prognosis of patients with pancreatic cancer. Moreover, this combination has been applied as a neoadjuvant chemotherapy for advanced gastric cancer (13). The therapeutic advantage of low-dose cisplatin and S-1 for gastric cancer might be translated to the treatment of Correspondence to: Hiroki Yamaue, MD, Second Department of pancreatic cancer. Surgery, Wakayama Medical University, School of Medicine, 811-1 A phase 2 trial was conducted using S-1 with low-dose Kimiidera, Wakayama 641-8510, Japan. Tel: +81 73 441 0613, Fax: cisplatin for unresectable pancreatic cancer based on the +81 73 446 6566, e-mail: [email protected] phase 1 trial for gastric cancer to ensure the safety of this Key Words: S-1, cisplatin, advanced pancreatic cancer, phase Ⅱ treatment modality and to evaluate the response rate, survival study. and toxicity. 0250-7005/2008 $2.00+.40 2373 ANTICANCER RESEARCH 28 : 2373-2378 (2008) Patients and Methods Table Ⅰ. Patient characteristics (n=30). No. of patients (%) End-point. The primary end-point of this study was to determine the overall response rate of the combination of S-1 and low-dose Median age (range) 67.5 (44-75 years) cisplatin. The secondary end-points were to evaluate the MST, Gender 1-year survival rate, completion rate, compliance and toxicity. Male 11 (37) Female 19 (63) Patient selection. Patients diagnosed with unresectable pancreatic ECOG PS cancer were enrolled in this trial between January 2003 and April 2007 0 10 (33) in Wakayama Medical University Hospital (WMUH). The eligibility 1 20 (67) criteria included unresectable advanced pancreatic cancer with liver Stage (UICC 6th edition) metastases, peritoneal dissemination, distant metastasis, and/or locally Ⅲ 10 (33) advanced disease based on diagnostic imaging using computed Ⅳ 20 (67) tomography (CT) or histological examinations, an Eastern Cooperative Locally advanced 10 (33) Oncology Group performance status (PS) ≤2, 20-75 years of age, Metastatic 20 (67) without previous anticancer treatments or radiation, life expectancy Prior treatment ≥12 weeks, without jaundice, capable of efficient oral intake of Bypass operation 7 (23) nutrition, and adequate organ function (Hb ≥8.0 g/dl, white blood cells Biliary stenting 5 (17) (WBCs) ≥3,000/μl, neutrophils ≥1,500/μl, platelets ≥100,000/μl, Exploratory laparotom y 4 (13) aspartate aminotransferase (AST) ≤3 times the upper limit of normal, ECOG PS: Eastern Cooperative Oncology Group performance status; alanine aminotransferase (ALT) ≤3 times the upper limit of normal, UICC: International Union Against Cancer. total bilirubin ≤3 times the upper limit of normal, and serum creatinine ≤1.5 mg/dl). Informed consent was obtained from all the patients prior to starting the treatment regimen. This study was approved by the ethical committee at WMUH. April 2007, and 30 patients were registered in this study. Of Study design. S-1 was administered orally according to body surface these, 9 had liver metastasis, 5 had peritoneal dissemination, area (BSA) as follows: BSA <1.25 m 2, 80 mg/day; BSA 1.25 to 1.5 4 had both liver metastasis and peritoneal dissemination, 2 2 2 m , 100 mg/day; BSA ≥1.5 m , 120 mg/day. One course consisted of had distant metastasis to paraaortic lymph nodes and 10 consecutive administration for 28 days followed by a rest of 14 days. patients had locally advanced disease such as invasion to the Low-dose cisplatin was infused at 4 mg/m 2 on days 1-5, 8-12, 15-19 and 22-26 of the first course. After the second course, S-1 at the same celiac and the superior mesenteric artery. dosage alone was administered without cisplatin as maintenance chemotherapy. S-1 was repeated until the occurrence of disease Efficacy and survival. Twenty-two patients (73%) completed progression, unacceptable toxicities, or the patient’s refusal to the first course. The remaining eight patients (27%) continue. If a grade 3 or higher toxicity was observed or the patient experienced grade 3 toxicity and interruption of the course was unable to maintain adequate oral intake, the temporary was required. Two patients restarted the remaining course interruption of the course and a n S-1 dose reduction by 20 mg/day was with a dose reduction because of neutropenia and allowed. This treatment was terminated when grade 3 or 4 toxicity was observed at that dose. When progressive disease was recognized, a cholangitis. The other six patients required treatment different chemotherapeutic regimen was administered if possible. termination because of disease progression (1), unacceptable toxicities (3) and patient refusal (2). One patient died during Evaluation of response and safety. The response was assessed using the first course due to progression of the disease. There were CT scanning in accordance with the Response Evaluation Criteria 17 patients who continued S-1 administration, the average in Solid Tumors (RECIST) criteria (14), and the toxicity was duration was 4.8 courses (0.5-18 courses). assessed in accordance with the National Cancer Institute Common The responses observed were 0 complete response, 5 partial Toxicity Criteria (NCI-CTC) Version 2.0. The overall survival and the MST were analyzed using the Kaplan-Meier method, and the response s, 22 stable disease and 3 progressive disease; the differences were analyzed using the log-rank test. overall response rate, therefore, was 17% (95% confidence The clinical benefit (CB) assessment was conducted as reported interval ( CI), 6-35%). The median time to progression was in prior trials (1, 15). Pain and functional impairment comprised the 4.6 months (95% CI, 2.6-7.9 months). The overall survival primary assessment of CB and were assessed by pain intensity and was 9.0 months (95% CI, 6.0-14.5 months) and the 1-year analgesic consumption, and the Karnofsky performance status, survival rate was 37.0% (95% CI, 19.1-54.9%; Figure 1). respectively. The MST and the 1-year survival rate of the patients with Results locally advanced disease and without distant metastasis were 13.6 months (95% CI, 8.0-30.7 months) and 60% (95% CI, Patient characteristics. The patient characteristics are shown 30-90%), in comparison to 7.0 months (95% CI, 4.9-9.9 in Table I.
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