Jpn J Clin Oncol 2014;44(1)101– 103 doi:10.1093/jjco/hyt157 Advance Access Publication 27 November 2013
A Randomized Phase III Trial Exploring the Prognostic Value of Extensive Intraoperative Peritoneal Lavage in Addition to Standard Treatment for Resectable Advanced Gastric Cancer: CCOG 1102 Study Kazunari Misawa1,*, Yoshinari Mochizuki2, Norifumi Ohashi3, Takanori Matsui4, Hiroshi Nakayama5, Kenji Tsuboi6, Mitsuru Sakai7, Seiji Ito1, Satoshi Morita8 and Yasuhiro Kodera9 Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, 2Department of Surgery, Komaki Municipal Hospital, Komaki, 3Department of Gastroenterological Surgery, Aichi Medical University, Nagakute, 4 Department of Gastroenterological Surgery, Aichi Cancer Center Aichi Hospital, Okazaki, 5Department of Surgery, Nagoya Medical Center, Nagoya, 6Department of Surgery, Tosei General Hospital, Seto, 7Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, 8Department of Biostatistics and Epidemiology, Graduate School of Medicine, Yokohama City University, Yokohama and 9Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan *For reprints and all correspondence: Kazunari Misawa, Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. E-mail: [email protected] Received May 30, 2013; accepted September 28, 2013
A randomized controlled trial has started in Japan to evaluate the efficacy of extensive intraoperative peritoneal lavage in the treatment of resectable advanced gastric cancer. Patients with T3 or deeper carcinoma of the stomach are intraoperatively randomized to either extensive intraoperative peritoneal lavage þ arm or extensive intraoperative peritoneal lavage2 arm. A total of 300 patients will be accrued from 20 institutions. The primary endpoint is disease-free survival, and secondary end-points are overall survival, peritoneal recurrence-free survival and incidence of adverse events. Key words: gastric cancer – gastrectomy – peritoneal lavage – clinical trial – Phase III
INTRODUCTION Even if curatively resected, patients with T4 stage or serosapositive gastric cancer often suffer from recurrence as peritoneal dissemination, and the prognosis of those patients is extremely poor (1 – 4). Peritoneal recurrence could be caused by cancer cells that had already been shed from the serosal surface at the time of surgery, sometimes detectable by examining the peritoneal washes, or those that were disseminated during surgical procedures. It is important to eliminate the intraperitonealfree cancer cells to prevent peritoneal recurrence. Kuramoto et al. (5) reported the result of a prospective randomized control study to evaluate the efficacy of extensive intraoperative peritoneal lavage followed by intraperitoneal
chemotherapy (EIPL – IPC) in the treatment of advanced gastric cancer with intraperitoneal-free cancer cells without overt peritoneal metastasis (CYþ/P2). In this study, patients with CYþ/P2 status were randomly allocated to three groups: surgery-alone group, surgery plus IPC group and surgery plus EIPL and IPC (EIPL – IPC) group. The overall 5-year survival rate of the patients in the EIPL – IPC group (43.8%) was significantly better than that of the IPC group (4.6%) and the surgery-alone group (0%), and the EIPL – IPC group had a significantly lower incidence of peritoneal recurrence than the other groups. Although the EIPL therapy is easy to perform, safe and inexpensive, it might practically nullify the number of
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ at North Dakota State University on June 7, 2015
1
102
EIPL for resectable advanced gastric cancer
intraperitoneal-free cancer cells. It is expected that the EIPL reduces the incidence of peritoneal recurrence not only among patients with CYþ/P2 status, but also in a population with curatively resected serosa-positive gastric cancer. Based on these findings, we planned a randomized Phase III trial to compare gastrectomy plus EIPL followed by standard adjuvant chemotherapy with gastrectomy and standard adjuvant chemotherapy for macroscopically resectable gastric cancer of T3.
PROTOCOL DIGEST OF THE CCOG 1102
(vii) (viii) (ix) (x)
Age 20– 80 years old. PS (ECOG) of 0 or 1. Adequate organ functions for gastrectomy. Written informed consent from the patient.
Intraoperative inclusion criteria: (xi) Clinically T3(SS), T4a(SE) or T4b(SI). (xii) Clinically H0 and M0. (xiii) No peritoneal dissemination, except for a small number of deposits around the stomach. (xiv) Possible for R0 or R1 surgery due to only CY1. (xv) No need of thoracotomy for resection.
OBJECTIVE
STUDY SETTING The study was a multi-institutional prospective, randomized Phase III trial, where 20 institutions are actively participating as of May 2013.
EXCLUSION CRITERIA (i) Synchronous or metachronous (within 5 years) malignancies other than carcinoma in situ. (ii) Cancer of the remnant stomach. (iii) Uncontrollable hypertension or uncontrollable diabetes mellitus. (iv) Continuous systemic steroid therapy. RANDOMIZATION
Data center services are funded by a non-profit organization, the Chubu Clinical Oncology Group (CCOG), Nagoya, Japan. All treatments have been approved as a general practice within the scope of general medical insurance.
The participants are to call to the CCOG Data Center by telephone during surgery after confirmation of the respectability and other criteria mentioned above. The patients are randomized to either EIPLþ arm or EIPL2 arm. The minimization method is used for randomization, balancing the arms according to the T-stage (T3/T4a/T4b), pre-operative chemotherapy (with/without) and institution.
ENDPOINTS
TREATMENT METHODS
The primary end-point is disease-free survival, and secondary end-points are overall survival, peritoneal recurrence-free survival and incidence of adverse events.
EIPL2ARM
RESOURCES
ELIGIBILITY CRITERIA
Total or distal gastrectomy with D2 lymphadenectomy is performed according to the Japanese gastric cancer treatment guideline (7). Peritoneal lavage is done with ,3 l of physiological saline before the closure of the abdominal wall.
Tumors are staged according to the Japanese Classification of Gastric Carcinoma (6).
EIPL1 ARM
INCLUSION CRITERIA
After total or distal gastrectomy with D2 lymphadenectomy, the peritoneal cavity is extensively rinsed 10 times with 1 l physiological saline at a time, followed by complete aspiration of the fluid. In total, 10 l saline is to be used.
Preoperative inclusion criteria: (i) Histologically proven primary gastric adenocarcinoma. (ii) Clinical T3(SS), T4a(SE) or T4b(SI) according to the Japanese Classification of Gastric Carcinoma, Third English edition (6). (iii) Clinical H0 and M0. (iv) Scheduled for open surgery. (v) Possible for R0 or R1 surgery by distal or total gastrectomy with D2 lymphadenectomy. (vi) Length of esophageal invasion 3 cm and no need of thoracotomy for resection.
FOLLOW-UP Adjuvant chemotherapy with S-1 for 1 year is recommended for patients with curative resection and pathological stage IIB, IIIA, IIIB or IIIC tumors. Patients are seen and assessed with physical examination and analysis of tumor markers every 3 months until the second year and every 6 months until the fifth year. Abdominal and pulmonary computed tomography is carried
Downloaded from http://jjco.oxfordjournals.org/ at North Dakota State University on June 7, 2015
The aim of this study was to demonstrate the superiority in disease-free survival of the addition of EIPL to the standard treatment in patients with T3 carcinoma of the stomach.
Jpn J Clin Oncol 2014;44(1)
out once every 6 months until the third year and once every year until the fifth year. Upper gastrointestinal endoscopy is carried out every year until the third year. When physicians suspect peritoneal recurrences either clinically or from computed tomography findings, they are requested to attempt to confirm the diagnosis with additional imaging examination such as enteroclysis and barium enema. In the event of no significant findings, physicians will need to decide on the diagnosis clinically based on the results of all of examinations and patient’s symptoms.
103
PARTICIPATING INSTITUTIONS Aichi Cancer Center Aichi Hospital, Aichi Cancer Center Hospital, Atsumi Hospital, Chunichi Hospital, Gifu Prefectural Tajimi Hospital, Ichinomiya Municipal Hospital, Kainan Hospital, Komaki Municipal Hospital, Konan Kosei Hospital, Meitetsu Hospital, Nagoya Central Hospital, Nagoya Medical Center, Nagoya Memorial Hospital, Nagoya University Hospital, Nakatsugawa Municipal Hospital, Okazaki Municipal Hospital, Tokai Central Hospital, Tosei General Hospital, Toyohashi Medical Center and Yokkaichi Municipal Hospital.
STUDY DESIGN AND STATISTICAL ANALYSIS
INTERIM ANALYSIS AND MONITORING Two interim analyses are planned: the first at the time when half of the total patients are registered and the second after the completion of registration. The Data and Safety Monitoring Committee will independently review the interim analysis reports and consider whether it is necessary to stop the trial prematurely. In-house interim monitoring will be performed by the Data Center to evaluate and improve the study progress and quality. UMIN CLINICAL TRIALS REGISTRY This trial was registered at the UMIN Clinical Trials Registry as UMIN000005907 (http://www.umin.ac.jp/ctr/index.htm) and was activated on 8 July 2011.
Funding This study was supported, in part, by Chubu Clinical Oncology Group (CCOG).
Conflict of interest statement None declared.
References 1. Nashimoto A, Nakajima T, Furukawa H, et al. Randomized trial of adjuvant chemotherapy with mitomycin, fluorouracil, and cytosine arabinoside followed by oral fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol 2003;21: 2282– 7. 2. Yoo CH, Noh SH, Shin DW, Choi SH, Min JS. Recurrence following curative resection for gastric carcinoma. Br J Surg 2000;87:236– 42. 3. Sasako M, Sano T, Yamamoto S, et al. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med 2008;359:453– 62. 4. Kodera Y, Nakanishi H, Yamamura Y, et al. Prognostic value and clinical implications of disseminated cancer cells in the peritoneal cavity detected by reverse transcriptase-polymerase chain reaction and cytology. Int J Cancer 1998;79:429–33. 5. Kuramoto M, Shimada S, Ikeshima S, et al. Extensive intraoperative peritoneal lavage as a standard prophylactic strategy for peritoneal recurrence in patients with gastric carcinoma. Ann Surg 2009;250:242 –6. 6. Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101– 12. 7. Japanese Gastric Cancer A. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011;14:113– 23.
Downloaded from http://jjco.oxfordjournals.org/ at North Dakota State University on June 7, 2015
This randomized trial is designed to demonstrate that EIPLþ is superior to EIPL2 in terms of disease-free survival. The hypothesis is that the 3-year disease-free survival of EIPLþ arm is greater than that of the control (EIPL2, with estimated 3-year disease-free survival of 55%, which was assumed from the historical data of the similar cohort operated at Aichi Cancer Center Hospital between 2000 and 2004. This cohort consisted of pT3, pT4a and pT4b tumors at the proportion of 36:53:11). To ensure at least 80% power to detect the difference of 15% with a both-sided alpha of 5%, the planned sample size is 300 cases, 150 cases per arm, with 2 years of accrual and 3 years of follow-up. If a statistically significant improvement in 3-year disease-free survival is demonstrated, gastrectomy with EIPL will be the new standard treatment.
A Randomized Phase III Trial Exploring the Prognostic Value of Extensive Intraoperative Peritoneal Lavage in Addition to Standard Treatment for Resectable Advanced Gastric Cancer: CCOG 1102 Study Kazunari Misawa1,*, Yoshinari Mochizuki2, Norifumi Ohashi3, Takanori Matsui4, Hiroshi Nakayama5, Kenji Tsuboi6, Mitsuru Sakai7, Seiji Ito1, Satoshi Morita8 and Yasuhiro Kodera9 Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, 2Department of Surgery, Komaki Municipal Hospital, Komaki, 3Department of Gastroenterological Surgery, Aichi Medical University, Nagakute, 4 Department of Gastroenterological Surgery, Aichi Cancer Center Aichi Hospital, Okazaki, 5Department of Surgery, Nagoya Medical Center, Nagoya, 6Department of Surgery, Tosei General Hospital, Seto, 7Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, 8Department of Biostatistics and Epidemiology, Graduate School of Medicine, Yokohama City University, Yokohama and 9Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan *For reprints and all correspondence: Kazunari Misawa, Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. E-mail: [email protected] Received May 30, 2013; accepted September 28, 2013
A randomized controlled trial has started in Japan to evaluate the efficacy of extensive intraoperative peritoneal lavage in the treatment of resectable advanced gastric cancer. Patients with T3 or deeper carcinoma of the stomach are intraoperatively randomized to either extensive intraoperative peritoneal lavage þ arm or extensive intraoperative peritoneal lavage2 arm. A total of 300 patients will be accrued from 20 institutions. The primary endpoint is disease-free survival, and secondary end-points are overall survival, peritoneal recurrence-free survival and incidence of adverse events. Key words: gastric cancer – gastrectomy – peritoneal lavage – clinical trial – Phase III
INTRODUCTION Even if curatively resected, patients with T4 stage or serosapositive gastric cancer often suffer from recurrence as peritoneal dissemination, and the prognosis of those patients is extremely poor (1 – 4). Peritoneal recurrence could be caused by cancer cells that had already been shed from the serosal surface at the time of surgery, sometimes detectable by examining the peritoneal washes, or those that were disseminated during surgical procedures. It is important to eliminate the intraperitonealfree cancer cells to prevent peritoneal recurrence. Kuramoto et al. (5) reported the result of a prospective randomized control study to evaluate the efficacy of extensive intraoperative peritoneal lavage followed by intraperitoneal
chemotherapy (EIPL – IPC) in the treatment of advanced gastric cancer with intraperitoneal-free cancer cells without overt peritoneal metastasis (CYþ/P2). In this study, patients with CYþ/P2 status were randomly allocated to three groups: surgery-alone group, surgery plus IPC group and surgery plus EIPL and IPC (EIPL – IPC) group. The overall 5-year survival rate of the patients in the EIPL – IPC group (43.8%) was significantly better than that of the IPC group (4.6%) and the surgery-alone group (0%), and the EIPL – IPC group had a significantly lower incidence of peritoneal recurrence than the other groups. Although the EIPL therapy is easy to perform, safe and inexpensive, it might practically nullify the number of
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ at North Dakota State University on June 7, 2015
1
102
EIPL for resectable advanced gastric cancer
intraperitoneal-free cancer cells. It is expected that the EIPL reduces the incidence of peritoneal recurrence not only among patients with CYþ/P2 status, but also in a population with curatively resected serosa-positive gastric cancer. Based on these findings, we planned a randomized Phase III trial to compare gastrectomy plus EIPL followed by standard adjuvant chemotherapy with gastrectomy and standard adjuvant chemotherapy for macroscopically resectable gastric cancer of T3.
PROTOCOL DIGEST OF THE CCOG 1102
(vii) (viii) (ix) (x)
Age 20– 80 years old. PS (ECOG) of 0 or 1. Adequate organ functions for gastrectomy. Written informed consent from the patient.
Intraoperative inclusion criteria: (xi) Clinically T3(SS), T4a(SE) or T4b(SI). (xii) Clinically H0 and M0. (xiii) No peritoneal dissemination, except for a small number of deposits around the stomach. (xiv) Possible for R0 or R1 surgery due to only CY1. (xv) No need of thoracotomy for resection.
OBJECTIVE
STUDY SETTING The study was a multi-institutional prospective, randomized Phase III trial, where 20 institutions are actively participating as of May 2013.
EXCLUSION CRITERIA (i) Synchronous or metachronous (within 5 years) malignancies other than carcinoma in situ. (ii) Cancer of the remnant stomach. (iii) Uncontrollable hypertension or uncontrollable diabetes mellitus. (iv) Continuous systemic steroid therapy. RANDOMIZATION
Data center services are funded by a non-profit organization, the Chubu Clinical Oncology Group (CCOG), Nagoya, Japan. All treatments have been approved as a general practice within the scope of general medical insurance.
The participants are to call to the CCOG Data Center by telephone during surgery after confirmation of the respectability and other criteria mentioned above. The patients are randomized to either EIPLþ arm or EIPL2 arm. The minimization method is used for randomization, balancing the arms according to the T-stage (T3/T4a/T4b), pre-operative chemotherapy (with/without) and institution.
ENDPOINTS
TREATMENT METHODS
The primary end-point is disease-free survival, and secondary end-points are overall survival, peritoneal recurrence-free survival and incidence of adverse events.
EIPL2ARM
RESOURCES
ELIGIBILITY CRITERIA
Total or distal gastrectomy with D2 lymphadenectomy is performed according to the Japanese gastric cancer treatment guideline (7). Peritoneal lavage is done with ,3 l of physiological saline before the closure of the abdominal wall.
Tumors are staged according to the Japanese Classification of Gastric Carcinoma (6).
EIPL1 ARM
INCLUSION CRITERIA
After total or distal gastrectomy with D2 lymphadenectomy, the peritoneal cavity is extensively rinsed 10 times with 1 l physiological saline at a time, followed by complete aspiration of the fluid. In total, 10 l saline is to be used.
Preoperative inclusion criteria: (i) Histologically proven primary gastric adenocarcinoma. (ii) Clinical T3(SS), T4a(SE) or T4b(SI) according to the Japanese Classification of Gastric Carcinoma, Third English edition (6). (iii) Clinical H0 and M0. (iv) Scheduled for open surgery. (v) Possible for R0 or R1 surgery by distal or total gastrectomy with D2 lymphadenectomy. (vi) Length of esophageal invasion 3 cm and no need of thoracotomy for resection.
FOLLOW-UP Adjuvant chemotherapy with S-1 for 1 year is recommended for patients with curative resection and pathological stage IIB, IIIA, IIIB or IIIC tumors. Patients are seen and assessed with physical examination and analysis of tumor markers every 3 months until the second year and every 6 months until the fifth year. Abdominal and pulmonary computed tomography is carried
Downloaded from http://jjco.oxfordjournals.org/ at North Dakota State University on June 7, 2015
The aim of this study was to demonstrate the superiority in disease-free survival of the addition of EIPL to the standard treatment in patients with T3 carcinoma of the stomach.
Jpn J Clin Oncol 2014;44(1)
out once every 6 months until the third year and once every year until the fifth year. Upper gastrointestinal endoscopy is carried out every year until the third year. When physicians suspect peritoneal recurrences either clinically or from computed tomography findings, they are requested to attempt to confirm the diagnosis with additional imaging examination such as enteroclysis and barium enema. In the event of no significant findings, physicians will need to decide on the diagnosis clinically based on the results of all of examinations and patient’s symptoms.
103
PARTICIPATING INSTITUTIONS Aichi Cancer Center Aichi Hospital, Aichi Cancer Center Hospital, Atsumi Hospital, Chunichi Hospital, Gifu Prefectural Tajimi Hospital, Ichinomiya Municipal Hospital, Kainan Hospital, Komaki Municipal Hospital, Konan Kosei Hospital, Meitetsu Hospital, Nagoya Central Hospital, Nagoya Medical Center, Nagoya Memorial Hospital, Nagoya University Hospital, Nakatsugawa Municipal Hospital, Okazaki Municipal Hospital, Tokai Central Hospital, Tosei General Hospital, Toyohashi Medical Center and Yokkaichi Municipal Hospital.
STUDY DESIGN AND STATISTICAL ANALYSIS
INTERIM ANALYSIS AND MONITORING Two interim analyses are planned: the first at the time when half of the total patients are registered and the second after the completion of registration. The Data and Safety Monitoring Committee will independently review the interim analysis reports and consider whether it is necessary to stop the trial prematurely. In-house interim monitoring will be performed by the Data Center to evaluate and improve the study progress and quality. UMIN CLINICAL TRIALS REGISTRY This trial was registered at the UMIN Clinical Trials Registry as UMIN000005907 (http://www.umin.ac.jp/ctr/index.htm) and was activated on 8 July 2011.
Funding This study was supported, in part, by Chubu Clinical Oncology Group (CCOG).
Conflict of interest statement None declared.
References 1. Nashimoto A, Nakajima T, Furukawa H, et al. Randomized trial of adjuvant chemotherapy with mitomycin, fluorouracil, and cytosine arabinoside followed by oral fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1. J Clin Oncol 2003;21: 2282– 7. 2. Yoo CH, Noh SH, Shin DW, Choi SH, Min JS. Recurrence following curative resection for gastric carcinoma. Br J Surg 2000;87:236– 42. 3. Sasako M, Sano T, Yamamoto S, et al. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med 2008;359:453– 62. 4. Kodera Y, Nakanishi H, Yamamura Y, et al. Prognostic value and clinical implications of disseminated cancer cells in the peritoneal cavity detected by reverse transcriptase-polymerase chain reaction and cytology. Int J Cancer 1998;79:429–33. 5. Kuramoto M, Shimada S, Ikeshima S, et al. Extensive intraoperative peritoneal lavage as a standard prophylactic strategy for peritoneal recurrence in patients with gastric carcinoma. Ann Surg 2009;250:242 –6. 6. Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101– 12. 7. Japanese Gastric Cancer A. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011;14:113– 23.
Downloaded from http://jjco.oxfordjournals.org/ at North Dakota State University on June 7, 2015
This randomized trial is designed to demonstrate that EIPLþ is superior to EIPL2 in terms of disease-free survival. The hypothesis is that the 3-year disease-free survival of EIPLþ arm is greater than that of the control (EIPL2, with estimated 3-year disease-free survival of 55%, which was assumed from the historical data of the similar cohort operated at Aichi Cancer Center Hospital between 2000 and 2004. This cohort consisted of pT3, pT4a and pT4b tumors at the proportion of 36:53:11). To ensure at least 80% power to detect the difference of 15% with a both-sided alpha of 5%, the planned sample size is 300 cases, 150 cases per arm, with 2 years of accrual and 3 years of follow-up. If a statistically significant improvement in 3-year disease-free survival is demonstrated, gastrectomy with EIPL will be the new standard treatment.
