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A correction has been published: N Engl J Med 2008;358(18):1977.
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Background Advanced gastric cancer can respond to S-1, an oral fluoropyrimidine. We tested S-1 as adjuvant chemotherapy in patients with curatively resected gastric cancer.
Methods Patients in Japan with stage II or III gastric cancer who underwent gastrectomy with extended (D2) lymph-node dissection were randomly assigned to undergo surgery followed by adjuvant therapy with S-1 or to undergo surgery only. In the S-1 group, administration of S-1 was started within 6 weeks after surgery and continued for 1 year. The treatment regimen consisted of 6-week cycles in which, in principle, 80 mg of oral S-1 per square meter of body-surface area per day was given for 4 weeks and no chemotherapy was given for the following 2 weeks. The primary end point was overall survival.
Results We randomly assigned 529 patients to the S-1 group and 530 patients to the surgery-only group between October 2001 and December 2004. The trial was stopped on the recommendation of the independent data and safety monitoring committee, because the first interim analysis, performed 1 year after enrollment was completed, showed that the S-1 group had a higher rate of overall survival than the surgery-only group (P=0.002). Analysis of follow-up data showed that the 3-year overall survival rate was 80.1% in the S-1 group and 70.1% in the surgery-only group. The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% confidence interval, 0.52 to 0.87; P=0.003). Adverse events of grade 3 or grade 4 (defined according to the Common Toxicity Criteria of the National Cancer Institute) that were relatively common in the S-1 group were anorexia (6.0%), nausea (3.7%), and diarrhea (3.1%).
Conclusions S-1 is an effective adjuvant treatment for East Asian patients who have undergone a D2 dissection for locally advanced gastric cancer. (ClinicalTrials.gov number, NCT00152217
[ClinicalTrials.gov]
.)
S-1 (TS-1, Taiho Pharmaceutical) is an orally active combination of tegafur (a prodrug that is converted by cells to fluorouracil), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which degrades fluorouracil), and oteracil (which inhibits the phosphorylation of fluorouracil in the gastrointestinal tract, thereby reducing the gastrointestinal toxic effects of fluorouracil) in a molar ratio of 1:0.4:1.12,13 The rate of response to treatment with S-1 alone exceeded 40% in two late phase 2 trials involving patients with advanced or recurrent gastric cancer.14,15 The pharmacokinetics of the fluorouracil that is derived from S-1 is not influenced by gastrectomy,16 and for this reason, S-1 is suitable for the postoperative adjuvant setting. In a pilot study,17 we examined the feasibility of using S-1 postoperatively in patients with gastric cancer. We report the results of a large-scale trial — the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC) — involving patients with stage II or III gastric cancer who underwent D2 surgery.
Methods
The trial was conducted in accordance with the World Medical Association Declaration of Helsinki and Japanese Good Clinical Practice guidelines. The protocol was approved by the institutional review board of each participating hospital. Written informed consent was obtained from all patients.
All members of the steering committee and the sponsor jointly designed the trial and collected the data, which were held by the independent ACTS-GC Data Center. The data were analyzed by the independent data and safety monitoring committee. All academic members of the steering committee vouch for the validity and completeness of the data and the analysis. All of the authors reviewed and approved the final version of the manuscript before submission.
Eligibility Criteria
The criteria for eligibility were histologically proven gastric cancer of stage II (excluding T1 cases), IIIA, or IIIB; D2 or more extensive lymph-node dissection with R0 surgery (with the result of no residual tumor18); no hepatic, peritoneal, or distant metastasis; no tumor cells in peritoneal fluid on cytologic analysis; an age of 20 to 80 years; no previous treatment for cancer except for the initial gastric resection for the primary lesion; and adequate organ function (a leukocyte count of at least 4000 per cubic millimeter or the lower limit of the normal range; a platelet count of at least 100,000 per cubic millimeter; a total bilirubin level of no more than 1.5 mg per deciliter [25.7 µmol per liter], aspartate aminotransferase and alanine aminotransferase levels no more than 2.5 times the upper limit of the normal range; and a serum creatinine level no greater than the upper limit of the normal range). Stage classification and the evaluation of resected specimens were performed in accordance with the guidelines of the Japanese Gastric Cancer Association.18
Study Design and Treatment
The primary end point was overall survival; secondary end points were relapse-free survival and the degree of safety of S-1. Patients were enrolled, within 6 weeks after surgery, over the telephone or by fax by staff at the ACTS-GC data center. Patients were randomly assigned to either the S-1 group or the surgery-only group, with the assignments made at the ACTS-GC data center by means of the minimization method and according to the cancer stage (II, IIIA, or IIIB). Zelen's adjustment19 was applied to balance the numbers of patients between each group at each participating hospital.
Patients assigned to the S-1 group received two oral doses of 40 mg of S-1 per square meter of body-surface area per day, for 4 weeks, followed by 2 weeks of no chemotherapy. Specifically, during the treatment weeks, patients with a body-surface area of less than 1.25 m2 received 80 mg daily; those with a body-surface area of 1.25 m2 or more but less than 1.5 m2 received 100 mg daily; and those with a body-surface area of 1.5 m2 or more received 120 mg daily. This 6-week cycle was repeated during the first year after surgery. If patients had hematologic toxic effects of grade 3 or grade 4 (highest possible grade) or nonhematologic toxic effects of grade 2, grade 3, or grade 4, their daily dose was reduced, from 120 mg to 100 mg, 100 mg to 80 mg, or 80 mg to 50 mg. The surgery-only group received no anticancer treatment after surgery, unless there was a confirmed relapse.
Patients in both groups were to be followed up for 5 years postoperatively. Adverse events were assessed according to the Common Toxicity Criteria of the National Cancer Institute (version 2.0).
Follow-up
Patients in the S-1 group underwent hematologic tests and assessments of clinical symptoms every 2 weeks. Patients in the surgery-only group underwent similar examinations at least every 3 months. Evaluation for adverse events was performed every 3 months for 1 year after surgery.
The presence of a relapse was determined by means of imaging studies, including ultrasonography, computed tomography (CT), gastrointestinal radiography series, and endoscopy. Patients underwent at least one type of imaging study, usually CT, at 6-month intervals during the first 2 years after surgery and at 1-year intervals thereafter until year 5 after surgery. Case-report forms, which included the results of these tests and evaluations and the survival status of patients, were submitted 1 year, 1.5 years, 2 years, 3 years, 4 years, and 5 years after surgery. Patients, their physicians, endoscopists, and radiologists were aware of the group assignment after surgery, and no placebo was used. However, relapses and other events were evaluated by members of the steering committee, who were unaware of the group assignments.
Statistical Analysis
The results of a previous study conducted in Japan20 served as the basis for determining the required numbers of patients.21 The 5-year overall survival rate in the surgery-only group was assumed to be 70%. We calculated that a total enrollment of 1000 patients was needed for a hazard ratio for death of 0.70 in the S-1 group as compared with the surgery-only group, with the use of the log-rank test, a two-sided alpha of 5%, and a statistical power of 80%, assuming 3 years of recruitment and an additional 5 years of follow-up.
Efficacy was to be evaluated in two interim analyses performed by an independent data and safety monitoring committee 1 year and 3 years after the completion of enrollment. Significance was evaluated with the use of the method of Lan and DeMets22 and the O'Brien–Fleming boundary. Person-years were used to estimate information fractions for use in interim analyses. When calculating information fractions, we assumed that patients who had not completed the study before the interim analysis were continuously observed until the final analysis.
Data for all randomly assigned patients, whether eligible or not, were included in efficacy analyses. Data for eligible patients were also analyzed to evaluate the robustness of the results. Overall survival was defined as the period between randomization and death. All deaths, including those from other diseases, were considered to be events. Relapse-free survival was defined as the period between randomization and the occurrence of an event — relapse or death — whichever came first. Data for patients who had not had an event were censored as of the date of the final observation.
The median time from surgery to randomization was 28 days (range, 7 to 42) in the S-1 group and 28 days (range, 6 to 42) in the surgery-only group. Because the number of days from surgery to randomization varied among patients, we also calculated the overall survival from the date of surgery. In the first interim analysis, overall survival was also measured from the date of surgery. The Kaplan–Meier method was used to estimate the cumulative survival. The primary confirmatory analysis was performed with the use of the stratified log-rank test, with the cancer stage — which was used in the random assignment of patients at enrollment — as a stratification factor. The Cox proportional-hazards model was used to calculate the hazard ratios. All P values calculated in the subgroup analysis were two-sided and were not adjusted for multiple testing. P values of less than 0.05 were considered to indicate statistical significance.
Results
Characteristics of Patients
We enrolled and randomly assigned 1059 patients — 529 to the S-1 group and 530 to the surgery-only group — at 109 centers between October 2001 and December 2004. After randomization, 25 patients (14 in the S-1 group and 11 in the surgery-only group) were found to be ineligible. The reasons for ineligibility were as follows: the absence of cytologic examination of the peritoneal fluid (nine patients), cancers other than gastric cancer (five), previous treatment for gastric cancer (four), laboratory test values at enrollment that did not meet the protocol requirements (four), limited (D1) surgery (one), stage IV cancer (one), and T1 cancer (one). The main analyses were based on data from all randomly assigned patients, including those who were ineligible. The two groups were well balanced with regard to baseline clinical characteristics, surgical procedures, and pathological findings (Table 1).
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The first interim analysis was based on data derived from case-report forms submitted by December 2005, 1 year after enrollment of the last patient. This analysis (median follow-up, 2.0 years) was conducted by the independent data and safety monitoring committee in June 2006. In this interim analysis, both overall survival and relapse-free survival differed between the two groups, both for all randomly assigned patients (overall survival, P=0.002; relapse-free survival, P<0.001) and for all eligible patients (overall survival, P<0.001; relapse-free survival, P<0.001). The significance level of the differences was close to the predetermined threshold for the interim analysis, P=0.001. Given these results, the data and safety monitoring committee recommended discontinuation of the trial and publication of the results based on updated data (from follow-up surveys as of June 30, 2006).
Adverse Events and Treatment Compliance
Data on 517 patients in the S-1 group and 526 in the surgery-only group were analyzed for adverse events. Data from the remaining 12 patients in the S-1 group, who did not receive S-1, and from the remaining 4 patients in the surgery-only group, who requested that their treatment assignment be changed after randomization, were not included in the safety analysis. Adverse events of grade 1, 2, 3, or 4 (defined according to the Common Toxicity Criteria of the National Cancer Institute, version 2.0) — including leukopenia, anemia, thrombocytopenia, elevated total serum bilirubin levels, and nonhematologic toxic effects — were more frequent in the S-1 group than in the surgery-only group. The adverse events of grade 3 or 4 that were more frequent in the S-1 group were anorexia, nausea, diarrhea, leukopenia, anemia, elevated total serum bilirubin level, stomatitis, and rash (Table 2).
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Overall Survival and Relapse-free Survival
On the basis of follow-up data updated on June 30, 2006, the median time from randomization to follow-up was 2.9 years in both the S-1 group and the surgery-only group. Seven patients in the S-1 group and six patients in the surgery-only group were lost to follow-up. A total of 102 patients died in the S-1 group, and 140 patients died in the surgery-only group. The causes of death in the S-1 and surgery-only groups were as follows: relapse (in 96 and 124 patients, respectively), other cancer (1 and 2), a cause other than cancer (4 and 7), and unknown causes (1 and 7). The number of patients who had recurrent metastasis was 133 in the S-1 group and 188 in the surgery-only group.
The hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.68 (95% confidence interval [CI], 0.52 to 0.87; P=0.003). The 3-year overall survival rate was 80.1% in the S-1 group (95% CI, 76.1 to 84.0) and 70.1% in the surgery-only group (95% CI, 65.5 to 74.6) (Figure 1A). The hazard ratio for relapse in the S-1 group, as compared with the surgery-only group, was 0.62 (95% CI, 0.50 to 0.77; P<0.001). The rate of relapse-free survival at 3 years was 72.2% in the S-1 group (95% CI, 67.9 to 76.4) and 59.6% in the surgery-only group (95% CI, 54.9 to 64.3) (Figure 1B). Among eligible patients, the hazard ratio for death in the S-1 group, as compared with the surgery-only group, was 0.66 (95% CI, 0.51 to 0.86; P=0.002). The results for all randomly assigned patients were similar.
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Common sites of first relapse were the peritoneum, hematogenous sites, and lymph nodes (Table 3). Local relapse occurred in 7 patients in the S-1 group (1.3%) and in 15 patients in the surgery-only group (2.8%). Postoperative treatment with S-1 reduced the frequencies of peritoneal and lymph-node relapses. In the surgery-only group, 84 patients (15.8%) had peritoneal relapse, and 46 patients (8.7%) had lymph-node relapse. In the S-1 group, 59 patients (11.2%) had peritoneal relapse, and 27 (5.1%) had lymph-node relapse.
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The overall survival of eligible patients was analyzed according to sex, age, cancer stage (Japanese classification and tumor–node–metastasis [TNM] classification), tumor stage, nodal stage (Japanese classification18 and TNM classification), and histologic type (Figure 2). A total of 25 ineligible patients (14 in the S-1 group and 11 in the surgery-only group), including those who had stage IV disease, were excluded. There was no significant interaction between the treatment group and any of the variables studied.
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Few large-scale trials (those with >500 patients) have compared postoperative adjuvant therapy with surgery alone among patients with gastric cancer. Such large trials have been performed by Nakajima et al. (the JCOG [Japan Clinical Oncology Group] 8801 study),20 Macdonald et al. (the INT-0116 study),7 and Cunningham et al. (the MAGIC trial).8 The JCOG 8801 study in Japan failed to demonstrate therapeutic benefits of adjuvant chemotherapy. The authors suggested that surgery probably resulted in a cure only in patients with T1 tumors, who accounted for nearly one third of all patients in the study, possibly masking differences in overall survival. The INT-0116 study, performed in the United States, showed that adjuvant chemoradiotherapy prolonged overall survival and relapse-free survival. Most patients in the INT-0116 study underwent either D0 or D1 surgery, with only 10% undergoing D2 surgery. The characteristics of patients in the INT-0116 study differed from those in the JCOG 8801 study and those in our trial. An analysis of benefit according to the type of lymph-node dissection showed no effect of adjuvant chemoradiotherapy among patients who underwent D2 surgery. In the MAGIC trial, conducted mainly in the United Kingdom, perioperative and postoperative chemotherapy with epirubicin, cisplatin, and infused fluorouracil significantly prolonged overall survival and relapse-free survival. In that study, D2 surgery was not performed as a standard procedure.
In addition to the JCOG 8801 study, the JCOG 9206-1,23 JCOG 9206-2,24 and National Surgical Adjuvant Study Group for Gastric Cancer (N-SAS-GC)25 studies have evaluated postoperative adjuvant chemotherapy after D2 surgery in Japan. These studies involved only about 200 patients each. Although the results of the N-SAS-GC study showed that adjuvant chemotherapy with uracil–tegafur (an oral fluoropyrimidine prodrug) was effective, confirmatory studies were needed. Because of the high incidence of gastric cancer in Japan, an effective regimen for adjuvant chemotherapy is particularly important there. Our decision to perform this phase 3 trial of S-1 in patients who underwent curative resection was based on the results of previous clinical trials showing that S-1 alone is effective for the treatment of advanced gastric cancer and may therefore be useful as adjuvant chemotherapy.
More than 100 centers located throughout Japan participated in our trial. To ensure a uniform level of surgical quality, the participating centers were selected from among hospitals performing at least 100 operations annually for gastric cancer. All of our patients, except one who received D1 surgery and was therefore ineligible, underwent surgery that was at least D2. The rate of local relapse in the surgery-only group was 2.8% (15 of 530 patients), indicating that surgery alone was satisfactory in terms of local control. In all, 29% of patients underwent splenectomy, whereas 4% underwent pancreatectomy.
After a median follow-up of 2.9 years, the rate of overall survival was higher in the S-1 group than in the surgery-only group. This outcome is consistent with the results of a previous trials conducted in Japan.3,25 Our results are also consistent with those of a meta-analysis showing that the hazard ratio for death among patients who received S-1, as compared with those who did not, ranged from 0.70 to 0.82.1,2,3,4,5,6 In addition, the effectiveness of postoperative adjuvant chemotherapy with S-1 for gastric cancer is consistent with the high response rates among patients with advanced gastric cancer.14,15 Adverse events of grade 3 or grade 4 occurred in less than 5% of patients in the S-1 group, except for anorexia (which occurred in 6% of patients), and compliance with S-1 treatment was good. We therefore believe that S-1 is useful as adjuvant chemotherapy after curative surgery in patients with gastric cancer.
Our results were obtained at a median follow-up of 2.9 years after randomization (median follow-up after surgery, 3.0 years). The survival rate 3 years after surgery was 80.5% in the S-1 group and 70.1% in the surgery-only group. These results were similar to those obtained when survival rates were measured from the date of randomization, with a hazard ratio for death in the S-1 group, as compared with the surgery-only group, of 0.68 (P=0.002). The results may change marginally at the 5-year follow-up. However, the number of events in the surgery-only group has already reached nearly 80% of that initially predicted for 5 years. At the first interim analysis, the predicted probability that overall survival in the S-1 group would be significantly better than that in the surgery-only group at final analysis was estimated to be 99.3%.26
Although it has sometimes been suggested that there may be differences in certain aspects of gastric cancer in Japan and the West, there have been no significant differences identified between Japan and the United Kingdom with regard to possible genetic influences or between Japan and European countries in the distribution of important prognostic factors.27,28,29 Moreover, Italian investigators have reported that pancreas-preserving D2 dissection performed at centers with experience in this procedure can provide a survival benefit.30 If adequate D2 dissection were performed, we believe that treatment outcomes in Western countries would be similar to those in Japan. We acknowledge that the results of our trial may not be valid in countries where D2 surgery is not considered the standard operation.
Supported by a grant from Taiho Pharmaceutical, Tokyo.
Drs. Sakuramoto, Sasako, Yamaguchi, Kinoshita, Fujii, Nashimoto, Nakajima, Imamura, Yamamura, and Kurita report receiving lecture fees from Taiho Pharmaceutical; and Dr. Ohashi, consulting and lecture fees from Taiho Pharmaceutical. No other potential conflict of interest relevant to this article was reported.
We thank Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of an earlier version of this manuscript.
Source Information
From Kitasato University School of Medicine, Sagamihara (S.S.); National Cancer Center Hospital (M.S.), the Cancer Institute Hospital (T.Y., T.N.), Nihon University School of Medicine (M.F.), University of Tokyo (Y.O.), and Tokyo Metropolitan Komagome Hospital (K.A.) — all in Tokyo; National Cancer Center Hospital East, Kashiwa (T.K.); Niigata Cancer Center Hospital, Niigata (A.N.); Sakai City Hospital, Sakai (H.F., H.I.); Osaka City General Hospital, Osaka (M.H.); Aichi Cancer Center Hospital, Nagoya (Y.Y.); and National Hospital Organization Shikoku Cancer Center, Matsuyama (A.K.) — all in Japan.
Address reprint requests to Dr. Sakuramoto at the Department of Surgery, Kitasato University School of Medicine, 2-1-1 Asamizodai, Sagamihara, Kanagawa 228-8520, Japan, or at sakura{at}med.kitasato-u.ac.jp.
References
Members of the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC) group were as follows: Steering Committee: M. Sasako, T. Yamaguchi, T. Kinoshita, M. Fujii, A. Nashimoto, H. Furukawa; Independent Data and Safety Monitoring Committee: K. Yoshino, Y. Ohashi, Y. Maehara, A. Ohtsu; Medical Advisor: T. Nakajima; Statistical Analyst: Y. Ohashi; Principal Investigators (all in Japan): Sapporo Medical University Hospital — K. Yamaguchi; Shinnittetsu Muroran General Hospital — M. Takahashi, Y. Suzuki; Hokkaido University Hospital — S. Okushiba, S. Hirano, H. Manase, T. Shichinohe; Hirosaki University Hospital — H. Kawasaki; Iwate Medical University Hospital — M. Terashima, A. Takagane, H. Fujiwara; Iwate Prefectural Central Hospital — I. Mochizuki; National Hospital Organization Sendai Medical Center — T. Saito; Miyagi Cancer Center — T. Fujiya; Tohoku University Hospital — K. Shiiba, T. Mizoi, T. Kobayashi; Yamagata Prefectural Central Hospital — N. Fukushima; Yamamoto Kumiai General Hospital — K. Aoki; Fukushima Medical University Hospital, Surgery I — M. Gotoh; Fukushima Medical University Hospital, Surgery II — S. Takenoshita; Tsuboi Hospital — N. Koyama, K. Nakayama, N. Sakurazawa; Saiseikai Niigata Daini Hospital — T. Aiba, Y. Sakai; Niigata Cancer Center Hospital — A. Nashimoto; Gunma University Hospital — E. Mochiki, R. Aihara; Gunma Prefectural Cancer Center — T. Fukuda, N. Kawano; Tsuchiura Kyodo General Hospital — S. Hiranuma; Tsukuba University Hospital — K. Ohta, N. Ohkohchi, S. Inagawa; Dokkyo Medical University Hospital — K. Sasaki; Tochigi Cancer Center — T. Inada; Saitama Cancer Center — Y. Tanaka; Dokkyo Medical University Koshigaya Hospital — S. Akao, M. Yamaguchi; Saitama Medical University Hospital — I. Koyama, R. Hirayama, W. Ichikawa; Chiba University Hospital — T. Suzuki, Y. Gunji, Y. Nabeya; National Cancer Center Hospital East — T. Kinoshita; Chiba Rousai Hospital — H. Nose, K. Kusashio; Chiba Cancer Center — N. Takiguchi; International Medical Center of Japan — T. Shimizu; Showa University Toyosu Hospital — K. Kumagai; National Cancer Center Hospital — M. Sasako; Fraternity Memorial Hospital — S. Miyoshi; Tokyo Metropolitan Bokutoh Hospital — S. Inoue; Showa University Hospital — S. Suzuki, Y. Tajima; Tokyo Metropolitan Komagome Hospital — K. Arai, Y. Iwasaki; Mitsui Memorial Hospital — A. Umemura; Cancer Institute Hospital — T. Yamaguchi; Nihon University Itabashi Hospital — M. Fujii, T. Takayama; Tokyo Metropolitan Fuchu Hospital — J. Matsumoto; Showa General Hospital — M. Teruya; Keio Unversity Hospital — T. Kubota, Y. Otani, Y. Saikawa; National Hospital Organization Tokyo Medical Center — K. Kubochi; St Luke's International Hospital — S. Ohigashi; Tokyo Medical and Dental University Hospital — T. Kawano; Kitasato University East Hospital — H. Shimao, S. Sakuramoto; Yokohama City University Medical Center — T. Imada, C. Kunisaki; Yokohama Municipal Citizens' Hospital — M. Takahashi; Kanagawa Cancer Center — M. Sairenji, O. Kobayashi; Yokosuka Kyosai Hospital — H. Hosoi, K. Nagahori; Yokohama Rosai Hospital — M. Ozaki; Saiseikai Yokohamashi Nanbu Hospital — T. Suda, H. Ike; Shizuoka General Hospital — M. Takagi; Fujieda Municipal General Hospital — H. Yokoyama; Showa Inan General Hospital — K. Hayashi; Shinshu University Hospital — A. Sugiyama, N. Koide; Nagano Municipal Hospital — Y. Munakata; Gifu Municipal Hospital — H. Tanemura; Ogaki Municipal Hospital — Y. Kaneoka; Chukyo Hospital — M. Matsuda; Aichi Cancer Center Hospital — Y. Yamamura; National Hospital Organization Nagoya Medical Center — K. Kondo; Aichi Medical University Hospital — T. Nonami; Aichi Cancer Center Aichi Hospital — H. Kojima; Kainan Hospital — A. Harada; Fukui-ken Saiseikai Hospital — Y. Asada; Fukui Red Cross Hospital — H. Yamamoto, F. Tanaka; Toyama Prefectural Central Hospital — M. Kaji; Kyoto Second Red Cross Hospital — A. Takenaka; Kyoto First Red Cross Hospital — H. Kurioka; NTT West Osaka Hospital — M. Kinuta, H. Yano; Osaka City General Hospital — M. Higashino; National Hospital Organization Osaka National Hospital — T. Tsujinaka; Osaka Medical Center for Cancer and Cardiovascular Diseases — M. Hiratsuka, I. Miyashiro; Sakai City Hospital — H. Furukawa, H. Imamura; Kinki University Hospital — A. Tanaka, H. Shigeoka, H. Imamoto; Osaka Red Cross Hospital — T. Kitai, T. Inomoto; Kansai Medical University Takii Hospital — Y. Nakane, K. Nakai; Minoh City Hospital — S. Iijima; Kobe University Hospital — Y. Hamabe, H. Ikuta, T. Kamigaki; Hyogo Cancer Center — S. Fujiwara, Y. Kanbara; Kansai Rosai Hospital — S. Tamura; Hiroshima University Hospital — K. Yoshida; National Hospital Organization Kure Medical Center and Chugoku Cancer Center — M. Koseki; Hiroshima City Asa Hospital — W. Takiyama; Hiroshima Red Cross & Atomic-bomb Survivors Hospital — T. Ishida; Shimane Prefectural Central Hospital — N. Osaki; Tottori University Hospital — S. Tsujitani; Okayama Saiseikai General Hospital — N. Tsutsui; Yamaguchi University Hospital — S. Yoshino; Tokushima University Hospital — M. Nishi, N. Kurita; National Hospital Organization Shikoku Cancer Center — A. Kurita; Matsuyama Red Cross Hospital — T. Matsusaka, T. Nishizaki; National Hospital Organization National Kyushu Cancer Center — T. Okamura, M. Haraguchi, Y. Toh; National Hospital Organization Kyushu Medical Center — K. Ikejiri; Kitakyushu Municipal Medical Center — T. Iwashita; Fukuoka University Chikushi Hospital — K. Futami; Saiseikai Fukuoka General Hospital — T. Kusumoto; Kokura Memorial Hospital — M. Sugano, Y. Arima, A. Tanaka; Social Insurance Tagawa Hospital — T. Tanaka; Saga Prefectural Hospital Koseikan — T. Kusumoto, H. Orita; Sasebo City General Hospital — H. Ishikawa; National Hospital Organization Nagasaki Medical Center — K. Miyashita; Miyazaki Prefectural Miyazaki Hospital — K. Toyoda, T. Shimozono; Oita Prefectural Hospital — T. Kano, T. Ikeda; Saiseikai Kumamoto Hospital — N. Shigaki; Kumamoto Regional Medical Center — Y. Yagi; Japanese Red Cross Kumamoto Hospital — T. Hirata; and National Hospital Organization Kumamoto Medical Center — Y. Haga, H. Matsuzaki, M. Kai, N. Yoshida.
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