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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 randomized controlled trials for laparoscopic gastric surgery for gastric cancer in Korea Cheulsu Byun & Sang-Uk Han Department of Surgery, School of Medicine, Ajou University, Suwon, Korea
Keywords Clinical trials; gastric cancer; laparoscopic gastrectomy Correspondence Sang-Uk Han, MD, PhD, Professor, Department of Surgery, School of Medicine, Ajou University San5, Wonchon-Dong, Yeongtong-Gu, Suwon 443-749, Korea. Tel: +82 31 219 5200 Fax: +82 31 219 5755 Email: [email protected] Received 24 November 2014; accepted 18 January 2015 DOI:10.1111/ases.12176
Abstract Laparoscopic gastrectomy for gastric cancer has rapidly gained popularity as a result of the increased incidence of early gastric cancer in Korea. Although laparoscopic gastrectomy has been considered as an investigational treatment because of the lack of solid evidence of efficacy and safety, it is increasingly regarded as a standard treatment for early gastric cancer. Moreover, solid evidence is anticipated from two studies in Korea, KLASS 01 and KLASS 02, the latter of which examines the suitability of laparoscopic gastrectomy for advanced gastric cancer. The use of cutting-edge techniques for laparoscopic gastrectomy enables surgeons to deliver various treatment options that offer the best possible quality of life after gastrectomy. In this review, we summarize the current status of clinical trials on laparoscopic gastrectomy in Korea and examine future perspectives regarding laparoscopic gastrectomy for the treatment of gastric cancer.
Introduction Since the first report of laparoscopic gastrectomy (LG) in Japan by Kitano et al. in 1994 (1), LG for gastric cancer has gained popularity because it offers the benefits of a minimally invasive approach, including decreased pain and increased quality of life (QoL) (2–6). However, many controversies still exist due to the lack of solid evidence to evaluate LG’s long-term outcomes (7), and LG has been recognized as an investigational treatment for early gastric cancer (EGC) but not as a standard procedure (8). In Korea, gastric cancer is the most common form of cancer (31 637 cases annually, 14.5% of the total malignancy) and the third leading cause of cancer death (9342 deaths annually, 12.7% of total cancer-related deaths) (9). Although LG was first performed in 1995, it was not performed again until 1999 because of strong criticism of it oncologic safety (10). However, based on the efforts and enthusiasm of laparoscopic gastric surgeons, LG has been spread rapidly as a treatment for EGC, and in 2009, 3083 laparoscopic gastrectomies (26% of gastric cancer surgeries) were performed, an almost five-fold increase over a 5-year period (11). In addition, with improved techniques, surgeons experienced in LG have suggested
130
that it could be applied to the treatment of advanced gastric cancer (AGC) (12–17). Now, through the academic activity of the Korean Gastric Cancer Association and the Korean Laparoscopic Gastrointestinal Surgery Study (KLASS) group, largescale, multicenter clinical trials and various wellperformed clinical trials have been initiated (10). In this article, we describe the current status of clinical trials examining LG in Korea and future perspectives regarding LG for the treatment of gastric cancer.
LG for EGC During the last two decades, the proportion of EGC in Korea has continuously increased from 24.8% to nearly 57.6% as a result of national screening programs and improved diagnostic techniques (11). Given that the prognosis of EGC is excellent, QoL has been the focus and LG has increasingly gained in popularity. Several randomized controlled trials (RCT) have revealed the feasibility and oncologic safety of laparoscopic distal gastrectomy (LDG) for EGC (2–6,18–20). However, the majority of these trials were limited by having a small sample size, being a single
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
3-yr overall survival Postoperative mortality Late postoperative complication Postoperative recovery index Postoperative quality of life 5-yr disease-free survival Morbidity and mortality Open conversion rate Quality of life Short-term clinical outcomes 5-yr disease-free survival Morbidity and mortality Quality of life Cost-effectiveness Inflammatory, immune response
CLASS, Chinese Laparoscopic Gastrointestinal Surgical; JCOG, Japan Clinical Oncology Group; JLSSG, Japanese Laparoscopic Surgery Study Group; KLASS, Korean Laparoscopic Gastrointestinal Surgery Study; LDG, laparoscopic distal gastrectomy; LN, lymph node; ODG, open distal gastrectomy; yr, year.
Primary outcome
Secondary outcome
CLASS 01(NCT01609309)
China 2012 III 1056 LDG vs ODG cT2/cT3/cT4a cN0-3 (except bulky LN) 3-yr relapse-free survival
Japan 2010 II/III II: 180, III: 500 LDG vs ODG cT2/cT3/cT4a cN0-2 (excluding bulky N2) II: morbidity III: 3-year relapse-free survival Overall survival Open conversion rate Adverse events Short-term clinical outcomes Number of retrieved LN
JLSSG0901(UMIN000003420) KLASS 02 (NCT01456598)
Korea 2011 III 1050 LDG vs ODG cT2/cT3/cT4a cN0-1 (including LN#7) 3-yr relapse-free survival Country Start year Phase Sample size (n) Intervention Inclusion criteria
JCOG0912 (UMIN000003319) KLASS 01 (NCT00452751)
Korea 2006 III 1400 LDG vs ODG cT1/cT2 cN0-1 5-yr overall survival
Trial
Japan 2010 III 920 LDG vs ODG cT1/cT2 cN0-1 5-yr overall survival
Advanced gastric cancer Early gastric cancer
Table 1 Ongoing randomized controlled trials of laparoscopic distal gastrectomy for the treatment of gastric cancer
center trial, and having short-term follow-up period. Recently, in a large-scale, case–control, and case-matched Korean multicenter study, long-term (median follow-up period, 70.8 months) results of curative intent LG (1477 patients) and open gastrectomy (OG) (1499 patients) were compared (21). In the case–control study, the overall survival, disease-specific survival, and recurrence-free survival were not statistically different at each cancer stage, with the exception of an increased overall survival rate for patients with stage IA cancer treated with laparoscopy (laparoscopic group, 95.3%; open group, 90.3%; P < 0.001). After patients were matched by a propensity scoring system, the overall survival, disease-specific survival, and recurrence-free survival rates were not statistically different at each stage. The Japanese Laparoscopic Surgery Study Group reported a multicenter study of the oncologic outcome after 1294 LG for EGC (22). The 5-year disease-free survival rates were 99.8%, 98.7%, and 87.5% for stage IA, IB, and II gastric cancer, respectively. Zeng et al. conducted a meta-analysis using 5 RCT and 17 non-RCT with 3411 patients and reported that LDG may reduce intraoperative blood loss, postoperative analgesic consumption, and hospital stay without increasing the total hospitalization costs and cancer recurrence rate (23). In spite of the current available evidence regarding LG’s advantages over OG, LG is considered an investigational treatment because there is no solid evidence from, for example, large-scale, multicenter, prospective, randomized clinical trials that have evaluated its long-term outcomes. Currently, the final results from two large-scale, multicenter RCT are being awaited: the KLASS trial (KLASS 01) and the Japanese Clinical Oncology Group trial (JCOG0912) (24,25). It is hoped that these studies will confirm the oncologic safety of LDG for gastric cancer (Table 1). The KLASS 01 trial is the first multicenter (13 institutions), randomized controlled clinical trial to compare open and laparoscopic surgery in patients with cT1N0M0 and cT2aN0M0 (American Joint Committee on Cancer, 6th edition). For surgical quality control, surgeons participating in this trial had to have performed at least 50 cases of both LDG and open distal gastrectomy (ODG), and their institution should have performed more than 80 cases of both LDG and ODG respectively. The primary end-point is overall survival, and the secondary endpoints are disease-free survival, morbidity and mortality, QoL, inflammatory and immune responses, and costeffectiveness (NCT00452751). From 2006 to 2010, 1416 patients (705 LDG patients and 711 ODG patients) were enrolled, and the final results are expected to be reported in 2015.
Morbidity and mortality 3-yr overall survival 3-yr recurrence pattern Postoperative recovery course Inflammatory, immune response
RCT for laparoscopic gastrectomy
C Byun and S-U Han
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RCT for laparoscopic gastrectomy
C Byun and S-U Han
In Japan, on the basis of multicenter phase II trials (JCOG0703) (26), the Japanese Clinical Oncology Group also started a multicenter RCT to compare LDG and ODG in 920 patients with cT1N0M0, T1N1M0, and T2(MP)N0M0 (the Japanese Classification of Gastric Carcinoma, 2nd English edition (27)) gastric cancer from 33 institutions (JCOG0912). For surgical quality control in the LDG arm, surgeons were required to have experience with at least 30 procedures as well as certification by (or the equivalent from) the Japan Society for Laparoscopic Endoscopic Surgery. For surgical quality control in the ODG arm, surgeons had to have experience in 60 or more ODG. The primary end-point of JCOG0912 is overall survival, and the secondary end-points are relapse-free survival, proportion of LDG completed and LDG converted to open surgery, adverse events, short-term clinical outcomes, and postoperative QoL (UMIN000003319).
LG for AGC In AGC or lymph node (+) gastric cancer, OG with D2 lymphadenectomy is the standard procedure in the major guidelines because D2 lymphadenectomy results in better patient survival than D1 lymphadenectomy (8,28,29). Application of LG for AGC remains controversial because of the technical difficulty of performing complete D2 lymphadenectomy, the innate risk of cancer cell dissemination to the peritoneal cavity, and the lack of information on long-term results based on well-designed RCT. However, as LG experience increased, some experts have extended the indication for LG to locally AGC. Indeed, due to inaccurate perioperative diagnoses, a significant number of patients with advanced or lymph node (+) gastric cancer have been treated with LG (30). Therefore, the application of LG to AGC should be investigated. Some experienced surgeons have reported acceptable outcomes of the LG for AGC. Park et al. reported the oncologic outcome of 239 gastrectomies (clinically EGC, but AGC per final pathological reports, D1+:D2 = 76:163) (30). They reported the overall 5-year survival rates were 90.5% in stage IB, 86.4% in IIA, 52.8% in IIIA, 52.9% in IIIB, and 37.5% in IIIc; these results were comparable to previous reports of AGC treated by OG. Cai et al. reported the surgical outcomes of a prospective randomized study comparing LG with D2 lymph node dissection for AGC (LG group, n = 49; OG group, n = 47) (31). The mean retrieved lymph nodes were 22.9 in the LG group and 22.8 in the OG, with no significant difference. The postoperative morbidity rates were 12.24% and 19.15% (P > 0.05), respectively, but pulmonary infection was observed more frequently in OG patients. After a mean follow-up period of 22.1 months, the estimated mean survival time was 29.3 months in the LG group and 28.9
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months in the OG group, with no significant difference. Based on the meta-analysis conducted by Qiu et al. (32), the laparoscopic approach may offer the benefits of a shorter hospital stay and a faster return to daily activities, without increased postoperative morbidity and mortality and despite a longer operation time. Recently, large-scale, multicenter RCT in East Asia have been started to access the feasibility of LDG for locally AGC (Table 1). Studies are currently underway in Korea (KLASS 02), Japan (JLSSG0901), and China (CLASS 01). The KLASS 02 trial is the first phase III trial to evaluate the efficacy of LDG with D2 lymph node dissection for AGC. During surgery for AGC, complete D2 lymphadenectomy is a mandatory procedure. However, D2 dissection is known to be technically challenging, and dissection quality and completeness varies among surgeons. Despite great efforts to enhance quality control, inadequate removal of lymph nodes during complete D2 lymphadenectomy has been reported to be 81.0% (33). Considering the high rate of inadequate D2 lymphadenectomy in open surgery, worse results have been anticipated in laparoscopic surgery because of its increased technical difficulty. As a result, to ensure objective comparisons and reduce inter-surgeon and intergroup variability in KLASS 02, we conducted a quality control study before initiating the study to build a consensus on D2 lymphadenectomy and to qualify surgeon (34). surgeons for application were required to submit six unedited videos of their procedures (three LDG and three ODG), which were then assessed by independent reviewers using evaluation criteria for completeness of D2 lymphadenectomy. According to the assessments, the review committee made decisions on whether a surgeon’s qualifications were sufficient to participate in KLASS 02 (NCT01283893). The estimated sample size of KLASS 02 is 1050. The primary end-point is 3-year relapse-free survival, and the secondary end-points are 3-year overall survival, morbidity and mortality, postoperative recovery index, and QoL (NCT0146598). From November 2011 to November 2014, 910 patients (87%) were enrolled; the last patient is expected to be enrolled in February 2015, and the final results are expected to be reported in 2018. The Japanese Laparoscopic Surgery Study Group launched a multicenter phase II/III study (JLSSG0901) to compare LDG and ODG in patients with cT2-T4aM0 gastric cancer. After safety assessment of the phase II trial (for major complications) with 180 patients, the trial will continue to phase III until 500 patients have been enrolled. The primary end-point is 3-year relapse-free survival, and the secondary end-points are 3-year overall survival, morbidity and mortality, open conversion rate
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
RCT for laparoscopic gastrectomy
C Byun and S-U Han
in the LDG arm, number of retrieved lymph nodes, and recurrence sites (UMIN000003420) (35). The Chinese Laparoscopic Gastrointestinal Surgical Study group also started a phase III study, CLASS 01(NCT01609309), in 2012. The estimated sample size is 1056, and the study design is similar to that of the KLASS 02.
Sentinel Node Navigation Surgery (SNNS) The clinical application of SNNS for EGC has been investigated for the purpose of increasing the patient’s QoL while maintaining oncologic safety. Although the accuracy of sentinel node biopsy has been controversial (36), the use of the dual-tracer method (isotope and blue dye) has helped increase the accuracy rate (37–39). A study group of the Japan Society of Sentinel Node Navigation Surgery recently conducted a multicenter, single-arm, phase II study of Sentinel Node mapping using a standardized dual-tracer method (40). The inclusion criterion was untreated stage cT1-2 adenocarcinoma with a tumor less than 4 cm in gross diameter. SN biopsy was performed in 397 eligible patients. The SN detection rate was 97.5%, and the accuracy of nodal evaluation for metastasis was 99%. In recent years, CT lymphangiography, infrared ray electronic endoscopy, and indocyanine green fluorescence imaging have emerged as new tracers for laparoscopic SN biopsy (41). In Korea, a phase III multicenter prospective trial (Sentinel Node Oriented Tailored Approach) comparing laparoscopic SNNS to conventional LG for clinical stage IA cancer (less than 3 cm, not indicated for endoscopic submucosal dissection (42), the tumor at least 2 cm from the pylorus and cardia) was launched in 2013 (NCT01804998). The estimated sample size was 580. The primary end-point was 3-year disease-free survival, and the secondary end-points were morbidity and QoL. For sentinel node biopsy accuracy and quality control, all participants were part of a quality control study (phase II, NCT01544413). Since March 2013, 12 surgeons at 10 institutions have passed the quality control evaluation, which has enrolled 187 (32.2%) patients (95 in conventional LG arm and 92 in SNNS arm) (Table 2).
Laparoscopic Function-Preserving Surgery As the EGC and clinical applications of LG have increased, patient QoL after gastrectomy has become the focus, and LG has generated interest in functionpreserving surgeries (e.g. pylorus-preserving gastrectomy [PPG], proximal gastrectomy [PG]). PPG was originally a surgical option for gastric ulcers, and it has been known to offer several advantages, including less
dumping syndrome, less bile reflux, less weight loss, and decreased gallstone formation, over conventional distal gastrectomy (43–45). In centrally located EGC, the chance of lymphatic metastasis to the suprapyloric and infrapyloric areas is rare, and PPG for gastric cancer is thought to guarantee oncologic safety (46–48). PPG for EGC in the middle portion of the stomach, with the distal tumor border at least 4 cm proximal to the pylorus, has been recognized as a modification of resection for EGC (8). However, using the laparoscopic approach for PPG is difficult because it should preserve the pyloric and hepatic branches of the vagus nerve and infrapyloric vessels (49–51). In Japan, Jiang et al. reported a retrospective analysis of the postoperative outcomes of 307 laparoscopic-assisted pylorus-preserving gastrectomies (LAPPG) (52). The mean operation time was 229.4 min, and the estimated blood loss was 49.1 mL. Complications developed in 53 patients (17.3%), and major complications were observed in 4 patients (1.3%). The mean serum total protein and albumin levels did not change significantly after surgery. In Korea, Suh et al. compared short- and long-term outcomes between 176 LADG and 116 LAPPG patients in a single center (53). The overall postoperative morbidity rate was similar, and delayed gastric emptying was less frequent in the LADG group (1.7% vs 7.8%). However, the rate of other complications was significantly higher in the LADG group (17.0% vs 7.8%). The 3-year recurrence-free survival was similar between the LADG and LAPPG groups (98.8% vs 98.2%), but decreases in serum protein and albumin were significantly greater in the LADG group than in the LAPPG group 1–6 months postoperatively, as were decreases in abdominal fat 1 year postoperatively. Based on these experiences, the KLASS group is now preparing a multicenter, prospective, RCT for LAPPG (KLASS 04). For gastric cancer located on the proximal side of the esophagogastric junction, PG should be considered because of the functional benefits it offers relative to total gastrectomy (TG), such as improved postoperative nutrition, less dumping syndrome, and decreased likelihood of anemia (8). As the incidence of proximal gastric cancer has increased (54,55), PG is an attractive option as a function-preserving surgery for proximal EGC. However, PG has not gained in popularity because severe esophageal reflux is a potential complication. To overcome these complications, various reconstruction methods, including jejunal interposition and double tract reconstruction (56– 58), have been developed that are considered to be superior to esophagogastrostomy in preventing postoperative esophageal reflux (59). Recently, PG has been performed laparoscopically with demonstrated clinical efficacy (60– 62). Based on these experiences, the KLASS group is now
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
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134
Ongoing II
168 LATG cT1N0
Morbidity and mortality Outcomes according to the reconstruction method
2012 2014
Status Phase
Sample size (n) Intervention Inclusion criteria
Primary outcome Secondary outcome
Start year Year of completion (estimated)
2013 2020
Quality of life
580 SNNS vs LAG cT1N0 Tumor size
Asian J Endosc Surg ISSN 1758-5902
R E V I E W A RT I C L E
Current status of randomized controlled trials for laparoscopic gastric surgery for gastric cancer in Korea Cheulsu Byun & Sang-Uk Han Department of Surgery, School of Medicine, Ajou University, Suwon, Korea
Keywords Clinical trials; gastric cancer; laparoscopic gastrectomy Correspondence Sang-Uk Han, MD, PhD, Professor, Department of Surgery, School of Medicine, Ajou University San5, Wonchon-Dong, Yeongtong-Gu, Suwon 443-749, Korea. Tel: +82 31 219 5200 Fax: +82 31 219 5755 Email: [email protected] Received 24 November 2014; accepted 18 January 2015 DOI:10.1111/ases.12176
Abstract Laparoscopic gastrectomy for gastric cancer has rapidly gained popularity as a result of the increased incidence of early gastric cancer in Korea. Although laparoscopic gastrectomy has been considered as an investigational treatment because of the lack of solid evidence of efficacy and safety, it is increasingly regarded as a standard treatment for early gastric cancer. Moreover, solid evidence is anticipated from two studies in Korea, KLASS 01 and KLASS 02, the latter of which examines the suitability of laparoscopic gastrectomy for advanced gastric cancer. The use of cutting-edge techniques for laparoscopic gastrectomy enables surgeons to deliver various treatment options that offer the best possible quality of life after gastrectomy. In this review, we summarize the current status of clinical trials on laparoscopic gastrectomy in Korea and examine future perspectives regarding laparoscopic gastrectomy for the treatment of gastric cancer.
Introduction Since the first report of laparoscopic gastrectomy (LG) in Japan by Kitano et al. in 1994 (1), LG for gastric cancer has gained popularity because it offers the benefits of a minimally invasive approach, including decreased pain and increased quality of life (QoL) (2–6). However, many controversies still exist due to the lack of solid evidence to evaluate LG’s long-term outcomes (7), and LG has been recognized as an investigational treatment for early gastric cancer (EGC) but not as a standard procedure (8). In Korea, gastric cancer is the most common form of cancer (31 637 cases annually, 14.5% of the total malignancy) and the third leading cause of cancer death (9342 deaths annually, 12.7% of total cancer-related deaths) (9). Although LG was first performed in 1995, it was not performed again until 1999 because of strong criticism of it oncologic safety (10). However, based on the efforts and enthusiasm of laparoscopic gastric surgeons, LG has been spread rapidly as a treatment for EGC, and in 2009, 3083 laparoscopic gastrectomies (26% of gastric cancer surgeries) were performed, an almost five-fold increase over a 5-year period (11). In addition, with improved techniques, surgeons experienced in LG have suggested
130
that it could be applied to the treatment of advanced gastric cancer (AGC) (12–17). Now, through the academic activity of the Korean Gastric Cancer Association and the Korean Laparoscopic Gastrointestinal Surgery Study (KLASS) group, largescale, multicenter clinical trials and various wellperformed clinical trials have been initiated (10). In this article, we describe the current status of clinical trials examining LG in Korea and future perspectives regarding LG for the treatment of gastric cancer.
LG for EGC During the last two decades, the proportion of EGC in Korea has continuously increased from 24.8% to nearly 57.6% as a result of national screening programs and improved diagnostic techniques (11). Given that the prognosis of EGC is excellent, QoL has been the focus and LG has increasingly gained in popularity. Several randomized controlled trials (RCT) have revealed the feasibility and oncologic safety of laparoscopic distal gastrectomy (LDG) for EGC (2–6,18–20). However, the majority of these trials were limited by having a small sample size, being a single
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
3-yr overall survival Postoperative mortality Late postoperative complication Postoperative recovery index Postoperative quality of life 5-yr disease-free survival Morbidity and mortality Open conversion rate Quality of life Short-term clinical outcomes 5-yr disease-free survival Morbidity and mortality Quality of life Cost-effectiveness Inflammatory, immune response
CLASS, Chinese Laparoscopic Gastrointestinal Surgical; JCOG, Japan Clinical Oncology Group; JLSSG, Japanese Laparoscopic Surgery Study Group; KLASS, Korean Laparoscopic Gastrointestinal Surgery Study; LDG, laparoscopic distal gastrectomy; LN, lymph node; ODG, open distal gastrectomy; yr, year.
Primary outcome
Secondary outcome
CLASS 01(NCT01609309)
China 2012 III 1056 LDG vs ODG cT2/cT3/cT4a cN0-3 (except bulky LN) 3-yr relapse-free survival
Japan 2010 II/III II: 180, III: 500 LDG vs ODG cT2/cT3/cT4a cN0-2 (excluding bulky N2) II: morbidity III: 3-year relapse-free survival Overall survival Open conversion rate Adverse events Short-term clinical outcomes Number of retrieved LN
JLSSG0901(UMIN000003420) KLASS 02 (NCT01456598)
Korea 2011 III 1050 LDG vs ODG cT2/cT3/cT4a cN0-1 (including LN#7) 3-yr relapse-free survival Country Start year Phase Sample size (n) Intervention Inclusion criteria
JCOG0912 (UMIN000003319) KLASS 01 (NCT00452751)
Korea 2006 III 1400 LDG vs ODG cT1/cT2 cN0-1 5-yr overall survival
Trial
Japan 2010 III 920 LDG vs ODG cT1/cT2 cN0-1 5-yr overall survival
Advanced gastric cancer Early gastric cancer
Table 1 Ongoing randomized controlled trials of laparoscopic distal gastrectomy for the treatment of gastric cancer
center trial, and having short-term follow-up period. Recently, in a large-scale, case–control, and case-matched Korean multicenter study, long-term (median follow-up period, 70.8 months) results of curative intent LG (1477 patients) and open gastrectomy (OG) (1499 patients) were compared (21). In the case–control study, the overall survival, disease-specific survival, and recurrence-free survival were not statistically different at each cancer stage, with the exception of an increased overall survival rate for patients with stage IA cancer treated with laparoscopy (laparoscopic group, 95.3%; open group, 90.3%; P < 0.001). After patients were matched by a propensity scoring system, the overall survival, disease-specific survival, and recurrence-free survival rates were not statistically different at each stage. The Japanese Laparoscopic Surgery Study Group reported a multicenter study of the oncologic outcome after 1294 LG for EGC (22). The 5-year disease-free survival rates were 99.8%, 98.7%, and 87.5% for stage IA, IB, and II gastric cancer, respectively. Zeng et al. conducted a meta-analysis using 5 RCT and 17 non-RCT with 3411 patients and reported that LDG may reduce intraoperative blood loss, postoperative analgesic consumption, and hospital stay without increasing the total hospitalization costs and cancer recurrence rate (23). In spite of the current available evidence regarding LG’s advantages over OG, LG is considered an investigational treatment because there is no solid evidence from, for example, large-scale, multicenter, prospective, randomized clinical trials that have evaluated its long-term outcomes. Currently, the final results from two large-scale, multicenter RCT are being awaited: the KLASS trial (KLASS 01) and the Japanese Clinical Oncology Group trial (JCOG0912) (24,25). It is hoped that these studies will confirm the oncologic safety of LDG for gastric cancer (Table 1). The KLASS 01 trial is the first multicenter (13 institutions), randomized controlled clinical trial to compare open and laparoscopic surgery in patients with cT1N0M0 and cT2aN0M0 (American Joint Committee on Cancer, 6th edition). For surgical quality control, surgeons participating in this trial had to have performed at least 50 cases of both LDG and open distal gastrectomy (ODG), and their institution should have performed more than 80 cases of both LDG and ODG respectively. The primary end-point is overall survival, and the secondary endpoints are disease-free survival, morbidity and mortality, QoL, inflammatory and immune responses, and costeffectiveness (NCT00452751). From 2006 to 2010, 1416 patients (705 LDG patients and 711 ODG patients) were enrolled, and the final results are expected to be reported in 2015.
Morbidity and mortality 3-yr overall survival 3-yr recurrence pattern Postoperative recovery course Inflammatory, immune response
RCT for laparoscopic gastrectomy
C Byun and S-U Han
131
RCT for laparoscopic gastrectomy
C Byun and S-U Han
In Japan, on the basis of multicenter phase II trials (JCOG0703) (26), the Japanese Clinical Oncology Group also started a multicenter RCT to compare LDG and ODG in 920 patients with cT1N0M0, T1N1M0, and T2(MP)N0M0 (the Japanese Classification of Gastric Carcinoma, 2nd English edition (27)) gastric cancer from 33 institutions (JCOG0912). For surgical quality control in the LDG arm, surgeons were required to have experience with at least 30 procedures as well as certification by (or the equivalent from) the Japan Society for Laparoscopic Endoscopic Surgery. For surgical quality control in the ODG arm, surgeons had to have experience in 60 or more ODG. The primary end-point of JCOG0912 is overall survival, and the secondary end-points are relapse-free survival, proportion of LDG completed and LDG converted to open surgery, adverse events, short-term clinical outcomes, and postoperative QoL (UMIN000003319).
LG for AGC In AGC or lymph node (+) gastric cancer, OG with D2 lymphadenectomy is the standard procedure in the major guidelines because D2 lymphadenectomy results in better patient survival than D1 lymphadenectomy (8,28,29). Application of LG for AGC remains controversial because of the technical difficulty of performing complete D2 lymphadenectomy, the innate risk of cancer cell dissemination to the peritoneal cavity, and the lack of information on long-term results based on well-designed RCT. However, as LG experience increased, some experts have extended the indication for LG to locally AGC. Indeed, due to inaccurate perioperative diagnoses, a significant number of patients with advanced or lymph node (+) gastric cancer have been treated with LG (30). Therefore, the application of LG to AGC should be investigated. Some experienced surgeons have reported acceptable outcomes of the LG for AGC. Park et al. reported the oncologic outcome of 239 gastrectomies (clinically EGC, but AGC per final pathological reports, D1+:D2 = 76:163) (30). They reported the overall 5-year survival rates were 90.5% in stage IB, 86.4% in IIA, 52.8% in IIIA, 52.9% in IIIB, and 37.5% in IIIc; these results were comparable to previous reports of AGC treated by OG. Cai et al. reported the surgical outcomes of a prospective randomized study comparing LG with D2 lymph node dissection for AGC (LG group, n = 49; OG group, n = 47) (31). The mean retrieved lymph nodes were 22.9 in the LG group and 22.8 in the OG, with no significant difference. The postoperative morbidity rates were 12.24% and 19.15% (P > 0.05), respectively, but pulmonary infection was observed more frequently in OG patients. After a mean follow-up period of 22.1 months, the estimated mean survival time was 29.3 months in the LG group and 28.9
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months in the OG group, with no significant difference. Based on the meta-analysis conducted by Qiu et al. (32), the laparoscopic approach may offer the benefits of a shorter hospital stay and a faster return to daily activities, without increased postoperative morbidity and mortality and despite a longer operation time. Recently, large-scale, multicenter RCT in East Asia have been started to access the feasibility of LDG for locally AGC (Table 1). Studies are currently underway in Korea (KLASS 02), Japan (JLSSG0901), and China (CLASS 01). The KLASS 02 trial is the first phase III trial to evaluate the efficacy of LDG with D2 lymph node dissection for AGC. During surgery for AGC, complete D2 lymphadenectomy is a mandatory procedure. However, D2 dissection is known to be technically challenging, and dissection quality and completeness varies among surgeons. Despite great efforts to enhance quality control, inadequate removal of lymph nodes during complete D2 lymphadenectomy has been reported to be 81.0% (33). Considering the high rate of inadequate D2 lymphadenectomy in open surgery, worse results have been anticipated in laparoscopic surgery because of its increased technical difficulty. As a result, to ensure objective comparisons and reduce inter-surgeon and intergroup variability in KLASS 02, we conducted a quality control study before initiating the study to build a consensus on D2 lymphadenectomy and to qualify surgeon (34). surgeons for application were required to submit six unedited videos of their procedures (three LDG and three ODG), which were then assessed by independent reviewers using evaluation criteria for completeness of D2 lymphadenectomy. According to the assessments, the review committee made decisions on whether a surgeon’s qualifications were sufficient to participate in KLASS 02 (NCT01283893). The estimated sample size of KLASS 02 is 1050. The primary end-point is 3-year relapse-free survival, and the secondary end-points are 3-year overall survival, morbidity and mortality, postoperative recovery index, and QoL (NCT0146598). From November 2011 to November 2014, 910 patients (87%) were enrolled; the last patient is expected to be enrolled in February 2015, and the final results are expected to be reported in 2018. The Japanese Laparoscopic Surgery Study Group launched a multicenter phase II/III study (JLSSG0901) to compare LDG and ODG in patients with cT2-T4aM0 gastric cancer. After safety assessment of the phase II trial (for major complications) with 180 patients, the trial will continue to phase III until 500 patients have been enrolled. The primary end-point is 3-year relapse-free survival, and the secondary end-points are 3-year overall survival, morbidity and mortality, open conversion rate
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
RCT for laparoscopic gastrectomy
C Byun and S-U Han
in the LDG arm, number of retrieved lymph nodes, and recurrence sites (UMIN000003420) (35). The Chinese Laparoscopic Gastrointestinal Surgical Study group also started a phase III study, CLASS 01(NCT01609309), in 2012. The estimated sample size is 1056, and the study design is similar to that of the KLASS 02.
Sentinel Node Navigation Surgery (SNNS) The clinical application of SNNS for EGC has been investigated for the purpose of increasing the patient’s QoL while maintaining oncologic safety. Although the accuracy of sentinel node biopsy has been controversial (36), the use of the dual-tracer method (isotope and blue dye) has helped increase the accuracy rate (37–39). A study group of the Japan Society of Sentinel Node Navigation Surgery recently conducted a multicenter, single-arm, phase II study of Sentinel Node mapping using a standardized dual-tracer method (40). The inclusion criterion was untreated stage cT1-2 adenocarcinoma with a tumor less than 4 cm in gross diameter. SN biopsy was performed in 397 eligible patients. The SN detection rate was 97.5%, and the accuracy of nodal evaluation for metastasis was 99%. In recent years, CT lymphangiography, infrared ray electronic endoscopy, and indocyanine green fluorescence imaging have emerged as new tracers for laparoscopic SN biopsy (41). In Korea, a phase III multicenter prospective trial (Sentinel Node Oriented Tailored Approach) comparing laparoscopic SNNS to conventional LG for clinical stage IA cancer (less than 3 cm, not indicated for endoscopic submucosal dissection (42), the tumor at least 2 cm from the pylorus and cardia) was launched in 2013 (NCT01804998). The estimated sample size was 580. The primary end-point was 3-year disease-free survival, and the secondary end-points were morbidity and QoL. For sentinel node biopsy accuracy and quality control, all participants were part of a quality control study (phase II, NCT01544413). Since March 2013, 12 surgeons at 10 institutions have passed the quality control evaluation, which has enrolled 187 (32.2%) patients (95 in conventional LG arm and 92 in SNNS arm) (Table 2).
Laparoscopic Function-Preserving Surgery As the EGC and clinical applications of LG have increased, patient QoL after gastrectomy has become the focus, and LG has generated interest in functionpreserving surgeries (e.g. pylorus-preserving gastrectomy [PPG], proximal gastrectomy [PG]). PPG was originally a surgical option for gastric ulcers, and it has been known to offer several advantages, including less
dumping syndrome, less bile reflux, less weight loss, and decreased gallstone formation, over conventional distal gastrectomy (43–45). In centrally located EGC, the chance of lymphatic metastasis to the suprapyloric and infrapyloric areas is rare, and PPG for gastric cancer is thought to guarantee oncologic safety (46–48). PPG for EGC in the middle portion of the stomach, with the distal tumor border at least 4 cm proximal to the pylorus, has been recognized as a modification of resection for EGC (8). However, using the laparoscopic approach for PPG is difficult because it should preserve the pyloric and hepatic branches of the vagus nerve and infrapyloric vessels (49–51). In Japan, Jiang et al. reported a retrospective analysis of the postoperative outcomes of 307 laparoscopic-assisted pylorus-preserving gastrectomies (LAPPG) (52). The mean operation time was 229.4 min, and the estimated blood loss was 49.1 mL. Complications developed in 53 patients (17.3%), and major complications were observed in 4 patients (1.3%). The mean serum total protein and albumin levels did not change significantly after surgery. In Korea, Suh et al. compared short- and long-term outcomes between 176 LADG and 116 LAPPG patients in a single center (53). The overall postoperative morbidity rate was similar, and delayed gastric emptying was less frequent in the LADG group (1.7% vs 7.8%). However, the rate of other complications was significantly higher in the LADG group (17.0% vs 7.8%). The 3-year recurrence-free survival was similar between the LADG and LAPPG groups (98.8% vs 98.2%), but decreases in serum protein and albumin were significantly greater in the LADG group than in the LAPPG group 1–6 months postoperatively, as were decreases in abdominal fat 1 year postoperatively. Based on these experiences, the KLASS group is now preparing a multicenter, prospective, RCT for LAPPG (KLASS 04). For gastric cancer located on the proximal side of the esophagogastric junction, PG should be considered because of the functional benefits it offers relative to total gastrectomy (TG), such as improved postoperative nutrition, less dumping syndrome, and decreased likelihood of anemia (8). As the incidence of proximal gastric cancer has increased (54,55), PG is an attractive option as a function-preserving surgery for proximal EGC. However, PG has not gained in popularity because severe esophageal reflux is a potential complication. To overcome these complications, various reconstruction methods, including jejunal interposition and double tract reconstruction (56– 58), have been developed that are considered to be superior to esophagogastrostomy in preventing postoperative esophageal reflux (59). Recently, PG has been performed laparoscopically with demonstrated clinical efficacy (60– 62). Based on these experiences, the KLASS group is now
Asian J Endosc Surg 8 (2015) 130–138 © 2015 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.
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Ongoing II
168 LATG cT1N0
Morbidity and mortality Outcomes according to the reconstruction method
2012 2014
Status Phase
Sample size (n) Intervention Inclusion criteria
Primary outcome Secondary outcome
Start year Year of completion (estimated)
2013 2020
Quality of life
580 SNNS vs LAG cT1N0 Tumor size
