Japanese Journal of Clinical Oncology 32:363-364 (2002)
© 2002 Foundation for Promotion of Cancer Research
Randomized Controlled Trial to Evaluate Splenectomy in Total Gastrectomy for Proximal Gastric Carcinoma: Japan Clinical Oncology Group Study JCOG 0110-MF
1 Gastric Surgery Division, National Cancer Center Hospital and 2 Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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A randomized controlled trial has started in Japan to evaluate the role of splenectomy in the surgical management of gastric cancer. Patients with T2 or deeper carcinoma in the proximal third of the stomach are intra-operatively randomized to either splenectomy or spleen preservation. Tumors invading the greater curvature of the stomach or those with apparent nodal involvement in the splenic hilum are excluded. Surgeons in 29 specialized institutions will recruit 500 patients. Endpoints are overall survival, operative morbidity, operative time and blood loss.
Recent European clinical trials of gastrectomy showed that splenectomy is an important risk factor for post-operative morbidity and mortality (1,2). However, Japanese retrospective studies revealed that 20–30% of patients with non-early carcinoma in the proximal stomach have nodal metastasis in the splenic hilum (3) and therefore pancreas-preserving splenectomy (4) is part of the standard operation in specialized centers. There have been no prospective clinical trials to evaluate the role of splenectomy in total gastrectomy for gastric cancer. The Clinical Trial Review Committee of the Japan Clinical Oncology Group (JCOG) approved the following protocol on April 4, 2002, and the study was activated on June 3, 2002.
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PROTOCOL DIGEST OF THE JCOG 0110-MF |
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Purpose
To evaluate the role of splenectomy in potentially curative total gastrectomy for proximal gastric carcinoma in terms of survival benefit and post-operative morbidity.
Study Setting
A multi-institutional (29 specialized centers), randomized controlled trial.
Resources
Health Sciences Research Grants for Medical Frontier Strategy Research and Grants-in-Aid for Cancer Research (Nos 14S-3, 14S-4), from the Ministry of Health, Labor and Welfare, Japan.
Endpoints
Primarily, overall survival. Secondarily, post-operative morbidity, operation time and perioperative blood loss.
Eligibility Criteria
Tumors are staged according to the Japanese Classification of Gastric Carcinoma (5).
Inclusion Criteria
Preoperatively, (1) histologically proven adenocarcinoma, (2) T2 or deeper lesion in the upper third of the stomach without involvement of the greater curvature or esophageal invasion, irrespective of the primary tumor location or existence of multiple foci, (3) no distant metastasis, not linitis plastica (‘Borrmann 4’), not stump carcinoma, no prior treatment for gastric cancer, (4) age 
20 and 
75 years, (5) sufficient organ function and (6) written informed consent. Intra-operatively, (7) T2/T3/T4 and N0/N1/N2, no tumor on the greater curvature, no direct invasion of the pancreas or spleen, negative peritoneal lavage cytology and (8) no apparent nodal metastasis in the splenic hilum or along the splenic artery.
Exclusion Criteria
(1) Liver cirrhosis or portal hypertension, (2) idiopathic thrombocytopenic purpura, (3) severe pulmonary dysfunction, (4) synchronous or metachronous (within 5 years) malignancy.
Randomization
By telephone call to the JCOG Data Center during operation after confirmation of the above criteria. The patients are randomized by the minimization method of balancing the groups according to the T-stage and institution.
Treatment Methods
Splenectomy Group
Pancreas-preserving splenectomy is performed with full mobilization of the distal pancreas and spleen. Lymph nodes along the splenic artery are completely dissected. The splenic artery is usually divided 5–6 cm from its origin.
Spleen Preservation Group
The spleen and the pancreas are not mobilized from the retroperitoneum. The nodes along the splenic artery are dissected. The splenic hilar nodes can be removed in easy cases, but without splenic mobilization.
In both groups, total gastrectomy with D2 lymphadenectomy (except for hilar nodes in Group B) is performed according to the Japanese Classification of Gastric Carcinoma (5). No adjuvant therapy is given until recurrent disease is diagnosed.
Follow-up
Patients are seen by their surgeon every 3 months for 5 years. Blood tests and abdominal computed tomography or ultrasonography are carried out every 6 months. Events of systemic infectious disease including pneumococcal pneumonia are surveyed at each clinic visit.
Study Design and Statistical Methods
This trial is designed to evaluate non-inferiority of splenic preservation to the standard splenectomy in terms of overall survival. If the survival is approximately equivalent, splenic preservation will be the preferred treatment. The hypothesis to be tested is that 5 year survival proportion on spleen preservation is 5% less than that (65–70%) following splenectomy. The planned sample size is 500, 250 cases per arm, with 5 years of follow-up after 5 years of accrual. This will provide a 70% power to reject the null hypothesis when 5 year survival is 3% greater following splenic preservation when compared with splenectomy.
Interim Analysis and Monitoring
Interim analysis is planned to take place once, taking into account multiplicity using Lan and DeMets approach. The Data and Safety Monitoring Committee (DSMC) of the JCOG independently reviews the interim analysis report and will consider stopping the trial early. In-house interim monitoring is performed by the Data Center to ensure data submission, patient eligibility, protocol compliance, safety and on-schedule study progress. The monitoring reports are submitted to and reviewed by, the DSMC every 6 months.
Participating Institutions (from North to South)
Iwate Medical University (Department of Surgery 1), Sendai National Hospital, Miyagi Cancer Center, Yamagata Prefectural Central Hospital, Saitama Cancer Center, National Cancer Center Hospital East, National Cancer Center Hospital, Tokyo Metropolitan Komagome Hospital, International Medical Center of Japan, Cancer Institute Hospital, Tokyo Metropolitan Bokuto Hospital, Kanagawa Cancer Center, Niigata Cancer Center Hospital, Nagaoka Chuo General Hospital, Tsubame Rosai Hospital, Toyama Prefectural Central Hospital, Kanazawa University (Gastroenterologic Surgery), Gifu Municipal Hospital, Aichi Cancer Center, Kinki University (First Department of Surgery), Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka National Hospital, Osaka Medical College (General and Gastroenterological Surgery), Toyonaka Municipal Hospital, Sakai City Hospital, Okayama University, Hiroshima City Hospital, National Shikoku Cancer Center, Kagoshima University
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FOOTNOTES |
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+ . T. Sano, study coordinator; S. Yamamoto, study statistician; M. Sasako, group chair.
For reprints and all correspondence: Takeshi Sano, Gastric Surgery Division, National Cancer Center Hospital. 5–1–1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
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1 Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ. Extended lymph-node dissection for gastric cancer. Dutch Gastric Cancer Group. N Engl J Med 1999;340:908–14.
2 Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, Sydes M, Fayers P. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Cooperative Group. Br J Cancer 1999;79:1522–30.[Web of Science][Medline]
3 Sasako M, McCulloch P, Kinoshita T, Maruyama K. New method to evaluate the therapeutic value of lymph node dissection for gastric cancer. Br J Surg 1995;82:346–51.[Medline]
4 Maruyama K, Sasako M, Kinoshita T, Sano T, Katai H, Okajima K. Pancreas-preserving total gastrectomy for proximal gastric cancer. World J Surg 1995;19:532–6.[Medline]
5 Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma, 2nd English edition. Gastric Cancer 1998;1:8–24.[Medline]
Received July 1, 2002; accepted July 8, 2002
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