Japanese Journal of Clinical Oncology Advance Access originally published online on February 12, 2008
Japanese Journal of Clinical Oncology 2008 38(3):227-229; doi:10.1093/jjco/hym178
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© The Author (2008). Published by Oxford University Press. All rights reserved
Randomized Phase III Trial of Adjuvant Chemotherapy with Gemcitabine versus S-1 in Patients with Resected Pancreatic Cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01)
1 Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, Shizuoka
2 Division of Gastrointestinal Oncology, Shizuoka Cancer Center Hospital, Shizuoka
3 Department of Surgical Oncology, Graduate School of Medicine, Hokkaido University, Sapporo
4 Upper Gastric Surgery, National Cancer Institute East Hospital, Chiba, Japan
5 Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
For reprints and all correspondence: Atsuyuki Maeda, Shizuoka Cancer Center Hospital, Division of Hepato-Biliary-Pancreatic Surgery, 1007 Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777 Japan. E-mail: a.maeda{at}scchr.jp
Received October 12, 2007; accepted December 19, 2007
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Abstract |
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A randomized controlled trial has begun in Japan to compare orally administered S-1 with intravenous gemcitabine (GEM) as adjuvant chemotherapy for patients with curatively resected pancreatic cancer. Patients are enrolled within 10 weeks after pancreatectomy to be treated for six months after assignment to either S-1 (80 mg/m2/day for four weeks, repeated similarly every six weeks for a total of four courses) or GEM (1000 mg/m2 on days 1, 8 and 15, repeated similarly every four weeks for a total of six courses). The primary endpoint is overall survival; secondary endpoints include relapse-free survival, incidence of adverse events and health-related quality of life. Each treatment arm includes 180 patients, providing an expected hazard ratio of 0.87 and an upper margin of 1.25 (two-sided alpha-error, 0.05; power, 0.8). Follow-up abdominal computed tomography is repeated every three months during the first two years, then every six months for three years.
Key Words: pancreatic cancer • adjuvant chemotherapy • gemcitabine • S-1 • phase III
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INTRODUCTION |
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In 2005, approximately 23 000 Japanese died of pancreatic cancer which was the fifth leading cause of cancer mortality (1), while with 33 370 deaths in the United States during 2006 (2). Although surgery is the only curative treatment option for this disease, only a small number of patients are in a resectable stage at the time of diagnosis because of the aggressiveness of the disease and absence of disease-specific symptoms. Even after potentially curative surgery, incidence of locoregional or distant recurrence is 80% or higher. Curability by surgery alone, then, appears to be sharply limited.
Gemcitabine (GEM) has been employed widely for patients with unresectable or recurrent pancreatic cancer, since Burris et al. (3) reported results of their phase III study demonstrating monotherapy with GEM achieved significantly more improvement in survival and in antitumor effect than 5-fluorouracil (FU) monotherapy. Recently, Oettle et al. (4) reported significant improvement of disease-free survival associated with marginal overall survival benefit from GEM adjuvant chemotherapy in comparison with post-operative observation in patients with resected pancreatic cancer (CONKO-001).
S-1 is a new oral fluorinated pyrimidine developed in Japan (5). The agent contains tegafur (FT, a prodrug of 5-FU), 5-chloro-2,4-dihydropyrimidine (CHDP) and potassium oxonate (Oxo); aiming to benefit from biochemical modulation of 5-FU. S-1 has shown significant clinical activity in various solid tumors such as gastric cancer, colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Two phase II studies of S-1 for advanced pancreatic cancer showed high response rates and long time to progression, which are anticipated to be better performance than GEM (6, 7). Thus S-1 might be expected to show equivalent or superior efficacy compared with GEM in an adjuvant setting. Moreover, treatment with oral S-1 is more convenient than infusion of GEM. We, therefore, conducted a phase III randomized controlled trial to compare S-1 to GEM as adjuvant chemotherapy for patients with curatively resected pancreatic cancer.
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DIGEST OF THE STUDY PROTOCOL |
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Objective
A randomized phase III trial was designed to elucidate non-inferiority of oral administration of S-1 as adjuvant chemotherapy in comparison with GEM in patients with curatively resected pancreatic cancer. The study protocol was approved by the Institutional Protocol Review Board of Shizuoka Cancer Center (the affiliation of the principal investigator) and other participating institutions.
Study Setting
The study is a multi-institutional prospective randomized controlled trial, with participating institutions including 24 specialized centers as of 30 March 2007.
Study Support
The study is supported by grants from a non-profit foundation: Pharma Valley Center, Shizuoka Organization for Creation Industries, Shizuoka, Japan.
Endpoints
The primary endpoint is overall survival. Secondary endpoints include relapse-free survival, adverse events defined by Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0 and health-related quality of life (HR-QOL) measured according to EuroQol 5 Dimensions (EQ-5D) (8, 9), which includes single-item measures of: mobility, self-care, usual activities, pain/discomfort and anxiety/depression.
Eligibility Criteria
Tumors are staged according to the sixth edition of the tumor-nodes-metastasis (TNM) classification system of the Union International Contre Cancer (UICC).
Inclusion criteria
Prior to entry to the study, patients must fulfill the following inclusion criteria: (i) histologically proven invasive ductal carcinoma of the pancreas; (ii) clinical and surgical findings indicating stage II or lower, or stage III with the resection including celiac artery; (iii) accomplishment of macroscopically curative resection with histologic R0 or R1 residual disease; (iv) peritoneal lavage cytologic examination negative for cancer cells; (v) absence of distant metastases or malignant ascites; (vi) adequate oral intake; (vii) age of 20 or more years; (viii) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (ix) absence of prior chemotherapy or radiotherapy within 3 years; (x) entry within 10 weeks after pancreatectomy; (xi) satisfying the following laboratory data; white blood cells, 
3000/mm3 and 
12 000/mm3; platelet count, 100 000/mm3; hemoglobin, 8.0 g/dL; serum total bilirubin, 2.0 mg/dL; aspartate aminotransferase (AST), 100 IU/L; alanin aminotransferase (ALT), 100 IU/L; creatinine, 1.2 mg/dL and (xii) written informed consent.
Exclusion criteria
Exclusion criteria are as follows: (i) history of treatment with gemcitabine or S-1; (ii) definite recurrent disease before entry; (iii) massive pleural effusion or ascites; (iv) pulmonary fibrosis or interstitial pneumonia; (v) severe diarrhea; (vi) heart disease of New York Heart Association (NYHA) grade III or IV; (vii) history of myocardial infarction within 6 months; (viii) acute inflammation or infection; (ix) uncontrollable diabetes mellitus; (x) blood transfusion within 2 weeks of entry; (xi) other serious medical conditions; (xii) severe mental disorder; (xiii) medical history of allergy or hypersensitivity to any drug; (xiv) synchronous cancers likely to affect survival or adverse events; (xv) pregnancy, breast feeding, or desire of a woman to preserve fertility; (xvi) desire of a man to preserve fertility; (xvii) regular use of frucitocin, fenitoin, or warfarin and (xvi) patients with inappropriateness for this study as judged by primary care physicians.
Registration
Eligible patients within 10 weeks after surgery are registered centrally and assigned randomly to a treatment at non-profit organization, Comprehensive Support Project for Oncological Research (CSPOR), Tokyo, Japan. Randomization is performed by the minimization method. Patients are stratified according to three factors: institution, nodal metastasis status (N0 versus N1), and residual tumor after surgery (R0 versus R1). Patient registration began on 2 April 2007.
Treatment Methods
Enrolled patients are assigned to GEM (arm A) or to S-1 (arm B).
Arm A: GEM (control)
Gemcitabine (1000 mg/m2) is given by intravenous infusion over 30 minutes on days 1, 8 and 15, followed by a 1-week rest. This cycle is repeated for six months or until recurrent disease is confirmed.
Arm B: S-1
S-1 (80 mg/m2/day) is given orally for four weeks, followed by a 2-week rest. This course is repeated four times or until recurrent disease is confirmed. S-1 is given in amounts not exceeding 80 mg/m2/day as two divided doses (after breakfast and dinner), determined according to body surface area (BSA): BSA below 1.25 m2, 80 mg; 1.25 to 1.5 m2, 100 mg and BSA over1.5 m2, 120 mg.
Study Design And Statistical Methods
Statistical analyses are based on the intention-to-treat principle. The hypothesis to be tested is that overall survival of pancreatic cancer after R0 or R1 resection is not significantly worse after adjuvant chemotherapy with S-1 than GEM (10). In this trial, hazard ratio is calculated using a proportional hazard model, with a non-inferiority margin defined in advance as 1.25. On the basis of an estimated overall 3-year survival of 36% with GEM, the anticipated difference in survival between treatment arms would be no >5%. The planned study period includes three years for accrual and two years for follow up. Assuming a 10% loss of follow-up, we calculated that 180 patients were needed in each treatment arm (80% power; two-sided alpha error, 5%). An interim analysis is planned at the time when 180 patients have died or when three years have elapsed after initiation of the study, whichever occurs first.
Decision Criteria
At the beginning of the study, we set up decision criteria to be used after obtaining results of the trial as follows: (i) if the hazard ratio of the S-1 arm is < 0.87, adjuvant chemotherapy with S-1 will be recommended as one of standard adjuvant chemotherapy after pancreatectomy; (ii) if the hazard ratio is between 0.87 and 1.00, S-1 will be offered as an optional choice for adjuvant chemotherapy; (iii) and if the hazard ratio is one or more, S-1 will not be recommended as adjuvant chemotherapy. Occurrence of severe adverse events and health-related quality of life (HR-QOL) are to be considered in the decision.
Registration Of The Protocol
The study protocol was registered to the web site of the University Hospital Medical Information Network (UMIN), Japan (protocol ID UMIN000000655) on 27 March 2007. Details are available at the following address: https://center.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000000791&type=summary&language=E.
Participating Institutions
In north-to-south order, participating centers include: Asahikawa Medical College, Graduate School of Medicine Hokkaido University, Yamagata University School of Medicine, Jichi Medical University, Tochigi Cancer Center, Graduate School of Comprehensive Human Sciences University of Tsukuba, National Cancer Center Hospital East, Chiba Cancer Center, Gunma Prefectural Cancer Center, Saitama Cancer Center, Graduate School of Medicine, Yokohama City University, Kanagawa Cancer Center Hospital, Shizuoka Cancer Center Hospital, Shizuoka General Hospital, Seirei Mikatahara Hospital, Aichi Cancer Center Hospital, Nagoya University Graduate School of Medicine, Fujita Health University, Kasugai Municipal Hospital, Ogaki Municipal Hospital, Toyama Prefectural Central Hospital, Osaka National Hospital, Kure Medical Center, and Kyushu Cancer Center.
Conflict of interest statement
None declared.
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