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Asian J Endosc Surg ISSN 1758-5902
R E V I E W A RT I C L E
Current status of a randomized controlled trial examining laparoscopic gastrectomy for gastric cancer in Japan Hitoshi Katai Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan
Keyword Clinical trial; gastric cancer; laparoscopic gastrectomy Correspondence Hitoshi Katai, Gastric Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81 3 3542 2511 Fax: +81 3 3545 3567 Email: [email protected] Received 8 October 2014; revised 14 October 2014; accepted 29 December 2014
Abstract More than 20 years after the introduction of laparoscopic gastrectomy, two ongoing, large-scale randomized controlled trials are currently being conducted in Japan: JCOG0912 for patients with stage I disease and JLSSG0901 for patients with advanced cancer. Both trials are designed to evaluate the non-inferiority of laparoscopic-assisted distal gastrectomy to its open counterpart. The primary end-point of JCOG0912 is overall survival, whereas that of JLSSG0901 is relapse-free survival. Quality control for the surgeries is being strictly performed in each study; eligibility criteria apply to participating surgeons and a central review of the surgical procedure has been conducted. The accrual of patients for JCOG0912 and for JLSSG0901 (phase II) is complete, and the disclosure of level I evidence is being awaited.
DOI:10.1111/ases.12171
Introduction The number of patients undergoing laparoscopy-assisted gastrectomy (LAG) has been increasing. While some small-scale randomized controlled trials (RCT) have been conducted, an RCT with a sample size sufficient to investigate the benefits of LAG has never been reported. Advances in operative techniques and endoscopic instrumentation have led to the standardization of laparoscopy-assisted distal gastrectomy (LADG) with suprapancreatic node dissection among experienced laparoscopic surgeons. However, surgeons continue to
have concerns as to whether this modality is appropriate for cancer treatment. Recently, two multicenter prospective large-scale RCTs have been initiated.
Small-scale RCT (Table 1) There have been four small RCT (1–4). The target population for each of the studies was patients with cT1 tumors. The operative method was limited to LADG. The accrual period of these studies was from 1998 to 2006.
Table 1 Four Japanese small-scale randomized controlled trials Investigator
Kitano et al. (1)
Fujii et al. (2)
Hayashi et al. (3)
Takiguchi et al. (4)
UMIN ID Year Target
– 2002 cT1
– 2003 cT1
– 2005 cT1
Sample size LADG: ODG End-points
28 14:14 Postoperative QOL, morbidity
20 10:10 Immunological response
28 14:14 Postoperative QOL, immunological response, morbidity
000002547 2013 cStage IA/IB 20 10:10 Physical activity, postoperative QOL
LADG, laparoscopy-assisted distal gastrectomy; ODG, open distal gastrectomy; QOL, quality of life; UMIN ID, University hospital Medical Information Network identification.
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
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RCT for laparoscopic gastrectomy in Japan
H Katai
During this period, surgeons considered LAG to be indicated for patients with cT1 tumors that could be treated by distal gastrectomy. With regard to study end-points, each study focused on short-term outcomes, such as postoperative quality of life (QOL) and immune response. Safety of LADG Operation-related deaths were not observed in any of the studies. These studies demonstrated that the postoperative morbidity rates were similar for LADG and open distal gastrectomy (ODG). Postoperative QOL after LADG QOL was evaluated by several measures. The postoperative course, including the first episode of flatus, body temperature, and length of postoperative hospital stay, was evaluated. As measures of postoperative pain, the proportion of patients requesting an analgesic and a visual analog scale pain score were used (1,4). One study used a pulmonary function test (1). Another study assessed the recovery of physical activity using an accelerometer (4). Despite the small sample size, LADG resulted in a faster recovery of bowel movements, less pain, a shorter hospital stay, and better cosmetic outcomes than ODG. Fujii et al. showed that LADG contributed to the preservation of postsurgical T helper 1 cell cell-mediated immunefunction (2). Hayashi et al. reported a lower level of acute inflammatory parameters after LADG than after ODG (3). Long-term survival after LADG The four studies reported no recurrences in either the LADG or the ODG group. The number of patients was too small for survival to be discussed.
dissection for clinical stage I gastric cancer) to evaluate the safety of LADG with nodal dissection for clinical stage I gastric cancer patients (5). Subsequently, a multicenter phase III trial (JCOG0912: A phase III study of laparoscopy-assisted versus open distal gastrectomy with nodal dissection for clinical stage I gastric cancer) was initiated to confirm the non-inferiority of LADG to open gastrectomy in terms of overall survival (6). During the JCOG0703 recruitment period, experienced surgeons began to develop an interest in the application of LADG for the treatment of advanced gastric cancer. The Japanese Laparoscopic Surgery Study Group (JLSSG) is currently conducting a multicenter phase II/III trials (JLSSG0901: Randomized controlled trial to evaluate laparoscopic versus open surgery for advanced gastric cancer). Even though the target populations and phases of the two ongoing trials (JCOG0912 and JLSSG0901) differ, the study designs are similar. The details of these two RCT are described below. Eligibility The eligibility criteria do not differ between the two trials, but the target populations differ. All patients will undergo a distal gastrectomy. The target of JCOG0912 is histologically confirmed adenocarcinoma of the stomach consisting of a cStage IA (T1N0) or IB (T1N1/T2[muscularis propria (MP)]N0) tumor according to the Japanese classification of gastric carcinomas. The target of JLSSG0901 is a tumor MP, subserosa (SS), or deeper lesion without the involvement of other organs, N0–2 excluding bulky N2 and M0. During study planning, the target population of a clinical trial is usually determined based on pathological data, so the accuracy of the preoperative diagnosis is very important. For advanced tumors, in particular, the distribution of T stage has a large effect on overall survival. Randomization
Large-scale RCT (Table 2) Around 2006, experienced laparoscopic surgeons seemed to reach a consensus regarding the standardization of LADG with suprapancreatic node dissection. Because a prospective study with a sample size sufficient to investigate the short- and long-term survival outcomes of LADG had not yet been reported, Japanese surgeons believed that the safety of LADG should be confirmed as an initial step. Once the safety of LADG had been confirmed, long-term survival after LADG could then be evaluated as the next step. The Japan Clinical Oncology Group (JCOG) conducted a multicenter phase II trial (JCOG0703: A phase II study of laparoscopy-assisted distal gastrectomy with nodal
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Patients are randomized to either the ODG arm or the LADG arm by a minimization method. In JCOG0912, the arms are balanced according to the institution and patients’ clinical stage (IA/IB). In JLSSG0901, randomization occurs based on the institution, depth of tumor invasion (MP/SS/serosa (SE)), and status of lymph node metastasis (N0/N1/N2). Primary end-points Before JCOG0912 began, the safety of LADG with nodal dissection for clinical stage IA and IB gastric cancer was evaluated in a multi-institutional phase II trial (JCOG0703). In this previous phase II study, the proportion of patients with either anastomotic leakage or
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
RCT for laparoscopic gastrectomy in Japan
H Katai
Table 2 Japanese trials for laparoscopy-assisted distal gastrectomy JCOG0703
JCOG0912
JLSSG0901
UMIN00000874 II
UMIN000003319 III
UMIN000003420 II/III
cStage IA (T1N0) or IB (T1N1, T2[MP, SS]N0)
cStage IA (T1N0) or IB (T1N1, T2[MP]N0)
20–80 No indication of endoscopic treatment in a cN0 case No invasion to duodenum BMI < 30 kg/m2 Incidence of anastomotic leakage or pancreatic fistula
20–80 No indication of endoscopic treatment in a cN0 case No invasion to duodenum BMI < 30 kg/m2 Overall survival
MP, SS, or deeper lesion without involvement of other organs; N0–2 excluding bulky N2 and M0 according to the Japanese classification system 20–80
Secondary end-points
Overall survival, recurrence-free survival, proportion of LADG completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes
Relapse-free survival, proportion of LADG completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes, postoperative QOL
Sample size
170
920
– LADG JCOG
ODG with nodal dissection LADG with nodal dissection JCOG
ODG with D2 lymph node dissection LADG with D2 lymph node dissection JLSSG
Ministry of Health, Labour and Welfare Main results already published
Ministry of Health, Labour and Welfare No longer recruiting
JLSSG Open public recruiting
UMIN ID Phase Eligibility Target population
Age (years) Other eligibility criteria
Primary end-point
Treatment Control Intervention Name of primary sponsor Source of funding Recruitment
No invasion to duodenum BMI < 30 kg/m2 Phase II: incidence of anastomotic leakage or pancreatic fistula Phase III: relapse-free survival Overall survival, proportion of LADG completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes, number of retrieved lymph node, recurrent sites II: 180 III: 500
UMIN-CTR: http://www.umin.ac.jp/ctr/index.htm. JCOG, Japan Clinical Oncology Group; JLSSG, Japanese Laparoscopic Surgery Study Group; LADG, laparoscopy-assisted distal gastrectomy; MP, muscularis propria; ODG, open distal gastrectomy; QOL, quality of life; SS, subserosa; UMIN-CTR, University hospital Medical Information Network Clinical Trials Registry; UMIN ID, University hospital Medical Information Network identification.
pancreatic fistula was only 1.7% (3/173), which was much lower than the pre-specified threshold (8%) (7). (The primary end-point of this trial was to determine the incidence of anastomotic leakage or pancreatic fistula.)The overall proportion of in-hospital grade 3 or 4 adverse events was 5.1%.The safety of LADG was confirmed for clinical IA/IB gastric cancer by this trial. Therefore, the primary end-point of JCOG0912 is overall survival among all eligible patients. JLSSG0901 consists of a phase II part and a phase III part. The primary end-point of the phase II study is determining the incidence of either anastomotic leakage or pancreatic fistula, which is the same as that of the JCOG0703 trial. If the incidence of these two postoperative complications is as low as expected, a subsequent phase III trial will be performed to evaluate the non-inferiority of LADG to ODG in terms of relapse-free survival. In both studies, as long as the non-inferiority of LADG is confirmed, LADG will be identified as an option for
the standard treatment of gastric cancer in the target population. Secondary end-points In both studies, the short-term clinical outcomes consist of the following: (i) the time from the end of surgery until the first episode of flatus; (ii) the proportion of patients requesting an analgesic on postoperative days 5–10; (iii) the highest body temperatures during the first 3 days after surgery; and (iv) the highest body temperatures during hospitalization. In JCOG0912, in addition to these short-term clinical outcomes, postoperative QOL is being evaluated by the European Organization for Research and Treatment (EORTC) quality of life questionnaires (QLQ)-Core(C)30 and Gastric (STO)-22. The primary analysis of QOL will be performed using the global health status from EORTC QLQ-C30 on the 90th postoperative day. This will be one
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
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H Katai
of the largest QOL questionnaire surveys to be performed among patients who have undergone gastrointestinal surgery. Quality control of surgery Quality control is important for evaluating surgical procedures because surgeons are aware that LAG requires more experience to obtain sufficient skill than its conventional open counterpart. Eligibility of participating surgeons In the JCOG0912 trial, only surgeons with credentials from the study chair are eligible to perform both LADG and ODG. In the ODG arm, experience performing 60 or more open gastrectomies is needed to be certified as a credentialed surgeon. In the LADG arm, experience performing 30 or more LADG and certification or its equivalent from the Japan Society for Endoscopic Surgery according to the Endoscopic Surgical Skill Qualification System are needed (8). These strict criteria for the selection of attending surgeons are appropriate because in JCOG0703, which used the same criteria, the rate of in-hospital complications was very low, as previously described (7). This low complication rate also showed that experience performing 30 LADG procedures with suprapancreatic node dissection was sufficient to achieve proficiency. In JLSSG0901, the eligibility criteria for participating surgeons are stricter than those of JCOG0912. In the ODG arm, experience performing 50 or more open gastrectomies is Surgeon needs. Surgeons who can operate on patients in the LADG arm must be certified by the Japan Society for Endoscopic Surgery in institutions with experience performing at least 20 laparoscopic gastrectomies with D2 lymph node dissection. The Korean Laparoscopic Gastrointestinal Surgery Study (KLASS) Group is conducting an RCT to evaluate the long-term outcomes of laparoscopic distal gastrectomy for gastric cancer (cT1N0M0-cT2aN0M0, American Joint Committee on Cancer, 6th edition) (KLASS 01: ClinicalTrials.gov ID: NCT00452751). In total 1415 patients have been enrolled (9). In KLASS 01, the eligibility criteria for participating surgeons are almost identical to those used in JLSSG0901. Surgeons participating in the trial had to have performed at least 50 cases each of LADG and ODG, and should have performed more than 80 cases at their institution each year for surgical quality control. The report on the phase II part of KLASS 01 showed that the postoperative complication rates in the LADG and ODG groups were 10.5% (17/179) and 14.7% (24/163), respectively (P = 0.137). No significant difference in morbidity or mortality was observed between the groups (10).
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Central review In both studies, a central review of the surgical procedure in all the patients was conducted by evaluating photographs taken during the procedure. The results of JCOG0404 (an RCT to evaluate laparoscopic versus open surgery for colorectal cancer) suggested that the central review of photo documentation is an important tool to assure quality control of the surgical technique in phase III randomized controlled studies (11).
RCT for laparoscopic-assisted total gastrectomy The two large-scale RCT JCOG0912 and JLSSG0901 only cover distal gastrectomy. No planned RCT for total gastrectomy exists at this moment. The standardization of techniques for esophagojejunal anastomosis in total gastrectomy has been difficult even for experienced surgeons. LADG for clinical stage I disease has been allowed as an option for treatment according to new Japanese gastric cancer treatment guidelines (ver.4). However, both the Japanese Gastric Cancer Association and the Japan Society for Endoscopic Surgery have commented that the introduction of laparoscopic-assisted total gastrectomy should be performed with caution. Recently, a technique for esophagojejunal anastomosis has been established among expert laparoscopic surgeons. Surgeons now have the technical know-how to perform clinical trials for total gastrectomy for clinical stage I disease. The Japan Clinical Oncology Group is currently planning a phase II study to evaluate the safety of laparoscopic-assisted total gastrectomy with nodal dissection for clinical stage I disease. A subsequent phase III trial might not be designed because the survival data can likely be estimated by extrapolating the results of JCOG0912.
Conclusion Two large-scale RCT are ongoing. The accrual of patients for JCOG0912 is complete, and level I evidence for the short-term clinical outcomes of LADG for clinical stage I disease will soon be disclosed. The results of the QOL questionnaire survey are also attractive and eagerly awaited. The accrual of patients for JLSSG0901 (phase II part) has also been completed. A subsequent phase III part is awaited. The results of two RCT for open surgery, JCOG0110 (an RCT to evaluate a splenectomy as part of a total gastrectomy for proximal gastric carcinoma) and JCOG1001 (a phase III trial to evaluate a bursectomy for
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
RCT for laparoscopic gastrectomy in Japan
H Katai
patients with SS/SE gastric cancer) (12), will affect the operative methods used for advanced tumors. Surgeons should consider the results of these two trials when planning future RCT for more advanced tumors.
Acknowledgment The authors have no conflict of interests to declare.
References 1. Kitano S, Shiraishi N, Fujii K et al. A randomized controlled trial comparing open vs laparoscopy-assisted distal gastrectomy for the treatment of early gastric cancer: An interim report. Surgery 2002; 131 (1 Suppl):S306–S311. 2. Fujii K, Sonoda K, Izumi K et al. T lymphocyte subsets and Th1/Th2 balance after laparoscopy-assisted distal gastrectomy. Surg Endosc 2003; 17: 1440–1444. 3. Hayashi H, Ochiai T, Shimada H et al. Prospective randomized study of open versus laparoscopy-assisted distal gastrectomy with extraperigastric lymph node dissection for early gastric cancer. Surg Endosc 2005; 19: 1172–1176. 4. Takiguchi S, Fujiwara Y, Yamasaki M et al. Laparoscopyassisted distal gastrectomy versus open distal gastrectomy. A prospective randomized single-blind study. World J Surg 2013; 37: 2379–2386. 5. Kurokawa Y, Katai H, Fukuda H et al. Phase II study of laparoscopy-assisted distal gastrectomy with nodal dissection for clinical stage I gastric cancer: Japan Clinical Oncology Group Study JCOG0703. Jpn J Clin Oncol 2008; 38: 501–503.
6. Nakamura K, Katai H, Mizusawa J et al. A phase III study of laparoscopy-assisted versus open distal gastrectomy with nodal dissection for clinical stage IA/IB gastric Cancer (JCOG0912). Jpn J Clin Oncol 2013; 43: 324–327. 7. Katai H, Sasako M, Fukuda H et al. Safety and feasibility of laparoscopy-assisted distal gastrectomy with suprapancreatic nodal dissection for clinical stage I gastric cancer: A multicenter phase II trial (JCOG 0703). Gastric Cancer 2010; 13: 238–244. 8. Mori T, Kimura T, Kitajima M. Skill accreditation system for laparoscopic gastroenterologic surgeons in Japan. 2010; 19: 18–23. Minim Invasive Ther Allied Technol 9. Kim HH, Han SU, Kim MC et al. Prospective randomized controlled trial (phase III) to comparing laparoscopic distal gastrectomy with open distal gastrectomy for gastric adenocarcinoma (KLASS 01). J Korean Surg Soc 2013; 84: 123–130. 10. Kim HH, Hyung WJ, Cho GS et al. Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: An interim report – a phase III multicenter, prospective, randomized Trial (KLASS Trial). Ann Surg 2010; 251: 417–420. 11. Nakajima K, Inomata M, Akagi T et al. Quality control by photo documentation for evaluation of laparoscopic and open colectomy with D3 resection for stage II/III colorectal cancer: Japan Clinical Oncology Group Study JCOG 0404. Jpn J Clin Oncol 2014; 44: 799–806. 12. Sano T, Yamamoto S, Sasako M et al. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma: Japan Clinical Oncology Group Study JCOG 0110-MF. Jpn J Clin Oncol 2002; 32: 363–364.
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Asian J Endosc Surg ISSN 1758-5902
R E V I E W A RT I C L E
Current status of a randomized controlled trial examining laparoscopic gastrectomy for gastric cancer in Japan Hitoshi Katai Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan
Keyword Clinical trial; gastric cancer; laparoscopic gastrectomy Correspondence Hitoshi Katai, Gastric Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Tel: +81 3 3542 2511 Fax: +81 3 3545 3567 Email: [email protected] Received 8 October 2014; revised 14 October 2014; accepted 29 December 2014
Abstract More than 20 years after the introduction of laparoscopic gastrectomy, two ongoing, large-scale randomized controlled trials are currently being conducted in Japan: JCOG0912 for patients with stage I disease and JLSSG0901 for patients with advanced cancer. Both trials are designed to evaluate the non-inferiority of laparoscopic-assisted distal gastrectomy to its open counterpart. The primary end-point of JCOG0912 is overall survival, whereas that of JLSSG0901 is relapse-free survival. Quality control for the surgeries is being strictly performed in each study; eligibility criteria apply to participating surgeons and a central review of the surgical procedure has been conducted. The accrual of patients for JCOG0912 and for JLSSG0901 (phase II) is complete, and the disclosure of level I evidence is being awaited.
DOI:10.1111/ases.12171
Introduction The number of patients undergoing laparoscopy-assisted gastrectomy (LAG) has been increasing. While some small-scale randomized controlled trials (RCT) have been conducted, an RCT with a sample size sufficient to investigate the benefits of LAG has never been reported. Advances in operative techniques and endoscopic instrumentation have led to the standardization of laparoscopy-assisted distal gastrectomy (LADG) with suprapancreatic node dissection among experienced laparoscopic surgeons. However, surgeons continue to
have concerns as to whether this modality is appropriate for cancer treatment. Recently, two multicenter prospective large-scale RCTs have been initiated.
Small-scale RCT (Table 1) There have been four small RCT (1–4). The target population for each of the studies was patients with cT1 tumors. The operative method was limited to LADG. The accrual period of these studies was from 1998 to 2006.
Table 1 Four Japanese small-scale randomized controlled trials Investigator
Kitano et al. (1)
Fujii et al. (2)
Hayashi et al. (3)
Takiguchi et al. (4)
UMIN ID Year Target
– 2002 cT1
– 2003 cT1
– 2005 cT1
Sample size LADG: ODG End-points
28 14:14 Postoperative QOL, morbidity
20 10:10 Immunological response
28 14:14 Postoperative QOL, immunological response, morbidity
000002547 2013 cStage IA/IB 20 10:10 Physical activity, postoperative QOL
LADG, laparoscopy-assisted distal gastrectomy; ODG, open distal gastrectomy; QOL, quality of life; UMIN ID, University hospital Medical Information Network identification.
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
125
RCT for laparoscopic gastrectomy in Japan
H Katai
During this period, surgeons considered LAG to be indicated for patients with cT1 tumors that could be treated by distal gastrectomy. With regard to study end-points, each study focused on short-term outcomes, such as postoperative quality of life (QOL) and immune response. Safety of LADG Operation-related deaths were not observed in any of the studies. These studies demonstrated that the postoperative morbidity rates were similar for LADG and open distal gastrectomy (ODG). Postoperative QOL after LADG QOL was evaluated by several measures. The postoperative course, including the first episode of flatus, body temperature, and length of postoperative hospital stay, was evaluated. As measures of postoperative pain, the proportion of patients requesting an analgesic and a visual analog scale pain score were used (1,4). One study used a pulmonary function test (1). Another study assessed the recovery of physical activity using an accelerometer (4). Despite the small sample size, LADG resulted in a faster recovery of bowel movements, less pain, a shorter hospital stay, and better cosmetic outcomes than ODG. Fujii et al. showed that LADG contributed to the preservation of postsurgical T helper 1 cell cell-mediated immunefunction (2). Hayashi et al. reported a lower level of acute inflammatory parameters after LADG than after ODG (3). Long-term survival after LADG The four studies reported no recurrences in either the LADG or the ODG group. The number of patients was too small for survival to be discussed.
dissection for clinical stage I gastric cancer) to evaluate the safety of LADG with nodal dissection for clinical stage I gastric cancer patients (5). Subsequently, a multicenter phase III trial (JCOG0912: A phase III study of laparoscopy-assisted versus open distal gastrectomy with nodal dissection for clinical stage I gastric cancer) was initiated to confirm the non-inferiority of LADG to open gastrectomy in terms of overall survival (6). During the JCOG0703 recruitment period, experienced surgeons began to develop an interest in the application of LADG for the treatment of advanced gastric cancer. The Japanese Laparoscopic Surgery Study Group (JLSSG) is currently conducting a multicenter phase II/III trials (JLSSG0901: Randomized controlled trial to evaluate laparoscopic versus open surgery for advanced gastric cancer). Even though the target populations and phases of the two ongoing trials (JCOG0912 and JLSSG0901) differ, the study designs are similar. The details of these two RCT are described below. Eligibility The eligibility criteria do not differ between the two trials, but the target populations differ. All patients will undergo a distal gastrectomy. The target of JCOG0912 is histologically confirmed adenocarcinoma of the stomach consisting of a cStage IA (T1N0) or IB (T1N1/T2[muscularis propria (MP)]N0) tumor according to the Japanese classification of gastric carcinomas. The target of JLSSG0901 is a tumor MP, subserosa (SS), or deeper lesion without the involvement of other organs, N0–2 excluding bulky N2 and M0. During study planning, the target population of a clinical trial is usually determined based on pathological data, so the accuracy of the preoperative diagnosis is very important. For advanced tumors, in particular, the distribution of T stage has a large effect on overall survival. Randomization
Large-scale RCT (Table 2) Around 2006, experienced laparoscopic surgeons seemed to reach a consensus regarding the standardization of LADG with suprapancreatic node dissection. Because a prospective study with a sample size sufficient to investigate the short- and long-term survival outcomes of LADG had not yet been reported, Japanese surgeons believed that the safety of LADG should be confirmed as an initial step. Once the safety of LADG had been confirmed, long-term survival after LADG could then be evaluated as the next step. The Japan Clinical Oncology Group (JCOG) conducted a multicenter phase II trial (JCOG0703: A phase II study of laparoscopy-assisted distal gastrectomy with nodal
126
Patients are randomized to either the ODG arm or the LADG arm by a minimization method. In JCOG0912, the arms are balanced according to the institution and patients’ clinical stage (IA/IB). In JLSSG0901, randomization occurs based on the institution, depth of tumor invasion (MP/SS/serosa (SE)), and status of lymph node metastasis (N0/N1/N2). Primary end-points Before JCOG0912 began, the safety of LADG with nodal dissection for clinical stage IA and IB gastric cancer was evaluated in a multi-institutional phase II trial (JCOG0703). In this previous phase II study, the proportion of patients with either anastomotic leakage or
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
RCT for laparoscopic gastrectomy in Japan
H Katai
Table 2 Japanese trials for laparoscopy-assisted distal gastrectomy JCOG0703
JCOG0912
JLSSG0901
UMIN00000874 II
UMIN000003319 III
UMIN000003420 II/III
cStage IA (T1N0) or IB (T1N1, T2[MP, SS]N0)
cStage IA (T1N0) or IB (T1N1, T2[MP]N0)
20–80 No indication of endoscopic treatment in a cN0 case No invasion to duodenum BMI < 30 kg/m2 Incidence of anastomotic leakage or pancreatic fistula
20–80 No indication of endoscopic treatment in a cN0 case No invasion to duodenum BMI < 30 kg/m2 Overall survival
MP, SS, or deeper lesion without involvement of other organs; N0–2 excluding bulky N2 and M0 according to the Japanese classification system 20–80
Secondary end-points
Overall survival, recurrence-free survival, proportion of LADG completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes
Relapse-free survival, proportion of LADG completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes, postoperative QOL
Sample size
170
920
– LADG JCOG
ODG with nodal dissection LADG with nodal dissection JCOG
ODG with D2 lymph node dissection LADG with D2 lymph node dissection JLSSG
Ministry of Health, Labour and Welfare Main results already published
Ministry of Health, Labour and Welfare No longer recruiting
JLSSG Open public recruiting
UMIN ID Phase Eligibility Target population
Age (years) Other eligibility criteria
Primary end-point
Treatment Control Intervention Name of primary sponsor Source of funding Recruitment
No invasion to duodenum BMI < 30 kg/m2 Phase II: incidence of anastomotic leakage or pancreatic fistula Phase III: relapse-free survival Overall survival, proportion of LADG completion, proportion of conversion to open surgery, adverse events, short-term clinical outcomes, number of retrieved lymph node, recurrent sites II: 180 III: 500
UMIN-CTR: http://www.umin.ac.jp/ctr/index.htm. JCOG, Japan Clinical Oncology Group; JLSSG, Japanese Laparoscopic Surgery Study Group; LADG, laparoscopy-assisted distal gastrectomy; MP, muscularis propria; ODG, open distal gastrectomy; QOL, quality of life; SS, subserosa; UMIN-CTR, University hospital Medical Information Network Clinical Trials Registry; UMIN ID, University hospital Medical Information Network identification.
pancreatic fistula was only 1.7% (3/173), which was much lower than the pre-specified threshold (8%) (7). (The primary end-point of this trial was to determine the incidence of anastomotic leakage or pancreatic fistula.)The overall proportion of in-hospital grade 3 or 4 adverse events was 5.1%.The safety of LADG was confirmed for clinical IA/IB gastric cancer by this trial. Therefore, the primary end-point of JCOG0912 is overall survival among all eligible patients. JLSSG0901 consists of a phase II part and a phase III part. The primary end-point of the phase II study is determining the incidence of either anastomotic leakage or pancreatic fistula, which is the same as that of the JCOG0703 trial. If the incidence of these two postoperative complications is as low as expected, a subsequent phase III trial will be performed to evaluate the non-inferiority of LADG to ODG in terms of relapse-free survival. In both studies, as long as the non-inferiority of LADG is confirmed, LADG will be identified as an option for
the standard treatment of gastric cancer in the target population. Secondary end-points In both studies, the short-term clinical outcomes consist of the following: (i) the time from the end of surgery until the first episode of flatus; (ii) the proportion of patients requesting an analgesic on postoperative days 5–10; (iii) the highest body temperatures during the first 3 days after surgery; and (iv) the highest body temperatures during hospitalization. In JCOG0912, in addition to these short-term clinical outcomes, postoperative QOL is being evaluated by the European Organization for Research and Treatment (EORTC) quality of life questionnaires (QLQ)-Core(C)30 and Gastric (STO)-22. The primary analysis of QOL will be performed using the global health status from EORTC QLQ-C30 on the 90th postoperative day. This will be one
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
127
RCT for laparoscopic gastrectomy in Japan
H Katai
of the largest QOL questionnaire surveys to be performed among patients who have undergone gastrointestinal surgery. Quality control of surgery Quality control is important for evaluating surgical procedures because surgeons are aware that LAG requires more experience to obtain sufficient skill than its conventional open counterpart. Eligibility of participating surgeons In the JCOG0912 trial, only surgeons with credentials from the study chair are eligible to perform both LADG and ODG. In the ODG arm, experience performing 60 or more open gastrectomies is needed to be certified as a credentialed surgeon. In the LADG arm, experience performing 30 or more LADG and certification or its equivalent from the Japan Society for Endoscopic Surgery according to the Endoscopic Surgical Skill Qualification System are needed (8). These strict criteria for the selection of attending surgeons are appropriate because in JCOG0703, which used the same criteria, the rate of in-hospital complications was very low, as previously described (7). This low complication rate also showed that experience performing 30 LADG procedures with suprapancreatic node dissection was sufficient to achieve proficiency. In JLSSG0901, the eligibility criteria for participating surgeons are stricter than those of JCOG0912. In the ODG arm, experience performing 50 or more open gastrectomies is Surgeon needs. Surgeons who can operate on patients in the LADG arm must be certified by the Japan Society for Endoscopic Surgery in institutions with experience performing at least 20 laparoscopic gastrectomies with D2 lymph node dissection. The Korean Laparoscopic Gastrointestinal Surgery Study (KLASS) Group is conducting an RCT to evaluate the long-term outcomes of laparoscopic distal gastrectomy for gastric cancer (cT1N0M0-cT2aN0M0, American Joint Committee on Cancer, 6th edition) (KLASS 01: ClinicalTrials.gov ID: NCT00452751). In total 1415 patients have been enrolled (9). In KLASS 01, the eligibility criteria for participating surgeons are almost identical to those used in JLSSG0901. Surgeons participating in the trial had to have performed at least 50 cases each of LADG and ODG, and should have performed more than 80 cases at their institution each year for surgical quality control. The report on the phase II part of KLASS 01 showed that the postoperative complication rates in the LADG and ODG groups were 10.5% (17/179) and 14.7% (24/163), respectively (P = 0.137). No significant difference in morbidity or mortality was observed between the groups (10).
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Central review In both studies, a central review of the surgical procedure in all the patients was conducted by evaluating photographs taken during the procedure. The results of JCOG0404 (an RCT to evaluate laparoscopic versus open surgery for colorectal cancer) suggested that the central review of photo documentation is an important tool to assure quality control of the surgical technique in phase III randomized controlled studies (11).
RCT for laparoscopic-assisted total gastrectomy The two large-scale RCT JCOG0912 and JLSSG0901 only cover distal gastrectomy. No planned RCT for total gastrectomy exists at this moment. The standardization of techniques for esophagojejunal anastomosis in total gastrectomy has been difficult even for experienced surgeons. LADG for clinical stage I disease has been allowed as an option for treatment according to new Japanese gastric cancer treatment guidelines (ver.4). However, both the Japanese Gastric Cancer Association and the Japan Society for Endoscopic Surgery have commented that the introduction of laparoscopic-assisted total gastrectomy should be performed with caution. Recently, a technique for esophagojejunal anastomosis has been established among expert laparoscopic surgeons. Surgeons now have the technical know-how to perform clinical trials for total gastrectomy for clinical stage I disease. The Japan Clinical Oncology Group is currently planning a phase II study to evaluate the safety of laparoscopic-assisted total gastrectomy with nodal dissection for clinical stage I disease. A subsequent phase III trial might not be designed because the survival data can likely be estimated by extrapolating the results of JCOG0912.
Conclusion Two large-scale RCT are ongoing. The accrual of patients for JCOG0912 is complete, and level I evidence for the short-term clinical outcomes of LADG for clinical stage I disease will soon be disclosed. The results of the QOL questionnaire survey are also attractive and eagerly awaited. The accrual of patients for JLSSG0901 (phase II part) has also been completed. A subsequent phase III part is awaited. The results of two RCT for open surgery, JCOG0110 (an RCT to evaluate a splenectomy as part of a total gastrectomy for proximal gastric carcinoma) and JCOG1001 (a phase III trial to evaluate a bursectomy for
Asian J Endosc Surg 8 (2015) 125–129 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
RCT for laparoscopic gastrectomy in Japan
H Katai
patients with SS/SE gastric cancer) (12), will affect the operative methods used for advanced tumors. Surgeons should consider the results of these two trials when planning future RCT for more advanced tumors.
Acknowledgment The authors have no conflict of interests to declare.
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