Hur et al. BMC Cancer (2015) 15:355 DOI 10.1186/s12885-015-1365-z
STUDY PROTOCOL
Open Access
Efficacy of laparoscopic subtotal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer: the protocol of the KLASS-02 multicenter randomized controlled clinical trial Hoon Hur1, Hyun Yong Lee2, Hyuk-Joon Lee3, Min Chan Kim4, Woo Jin Hyung5, Young Kyu Park6, Wook Kim7 and Sang-Uk Han1*
Abstract Background: Despite the well-described benefits of laparoscopic surgery such as lower operative blood loss and enhanced postoperative recovery in gastric cancer surgery, the application of laparoscopic surgery in patients with locally advanced gastric cancer (AGC) remains elusive owing to a lack of clinical evidence. Recently, the Korean Laparoscopic Surgical Society Group launched a new multicenter randomized clinical trial (RCT) to compare laparoscopic and open D2 lymphadenectomy for patients with locally AGC. Here, we introduce the protocol of this clinical trial. Methods/design: This trial is an investigator-initiated, randomized, controlled, parallel group, non-inferiority trial. Gastric cancer patients diagnosed with primary tumors that have invaded into the muscle propria and not into an adjacent organ (cT2–cT4a) in preoperative studies are recruited. Another criterion for recruitment is no lymph node metastasis or limited perigastric lymph node (including lymph nodes around the left gastric artery) metastasis. A total 1,050 patients in both groups are required to statistically show non-inferiority of the laparoscopic approach with respect to the primary end-point, relapse-free survival of 3 years. Secondary outcomes include postoperative morbidity and mortality, postoperative recovery, quality of life, and overall survival. Surgeons who are validated through peer-review of their surgery videos can participate in this clinical trial. Discussion: This clinical trial was designed to maintain the principles of a surgical clinical trial with internal validity for participating surgeons. Through the KLASS-02 RCT, we hope to show the efficacy of laparoscopic D2 lymphadenectomy in AGC patients compared with the open procedure. Trial registration: ClinicalTrial.gov, NCT01456598. Keywords: Gastric neoplasm, Laparoscopy, D2 lymphadenectomy, Advanced gastric cancer
Background Since the first laparoscopic gastrectomy for gastric cancer was performed in 1994 [1], increasingly more surgeons have performed this procedure in East Asian countries such as Korea and Japan [2]. Nevertheless, the Japanese Gastric Cancer Association (JGCA) treatment guideline recommends that laparoscopic surgery for * Correspondence: [email protected] 1 Department of Surgery, Ajou University Medical Center, Ajou University School of Medicine, 206 Worldcup-ro, Youngtong-gu, Suwon 443-749, Korea Full list of author information is available at the end of the article
gastric cancer should not be performed as a general practice [3]. The reason for this recommendation is that despite the benefits of laparoscopic surgery, the longterm survival results from 2 multicenter randomized clinical trials (RCTs) in Japan (registered in the University Hospital Medical Information Network [UMIN] Clinical Trial Registry as UMIN000003319) and Korea (registered in the National Institutes of Health [NIH] Clinical Trail Registry as NCT0045251) have not been reported. However, the interim analysis of a multicenter RCT conducted by Korean surgeons described the safety
© 2015 Hur et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Hur et al. BMC Cancer (2015) 15:355
of laparoscopic surgery for early gastric cancer (EGC) [4]. In addition, several meta-analyses have showed that laparoscopic gastrectomy with limited lymphadenectomy for patients with EGC had non-inferior oncologic outcome relative to open surgery, and a benefit in terms of faster postoperative recovery [5-7]. Based on this evidence, most experienced surgeons have applied the laparoscopic procedure in patients with EGC. However, the use of laparoscopic surgery in patients with locally advanced gastric cancer (AGC) remains controversial. Several obstacles have been considered as the reasons for this limitation. First, extended (D2) lymphadenectomy is an essential procedure for performing curative resection in AGC patients, which requires more sophisticated surgical techniques to ensure patient safety. Owing to some limitations of laparoscopic surgery such as impossible palpation, unsecure bleeding control, among others, the experience and skill of surgeons is more important in laparoscopic surgery for AGC. Second, some researchers have expressed the concern that the laparoscopic procedure for advanced malignant disease might aggravate cancer progression via the intraoperative intraperitoneal pressure and circulating gas. However, there is no conclusive evidence to support this hypothesis to date. Taken together, the application of laparoscopic surgery in patients with locally AGC is possible if the technical and oncologic safety is ensured. A well-designed multicenter RCT recruiting a large sample of patients is the best option to obtain clinical evidence for novel technology in the surgical field. Considering the benefits of laparoscopic surgery, such as enhanced postoperative recovery and reduced postoperative pain, the application of laparoscopic surgery will likely be extended to more patients with AGC and EGC. Currently, the Korean Laparoscopic Surgical Society (KLASS) group launched the multicenter RCT (KLASS-02 RCT; registered at www.clinicaltrials.gov as NCT01456598) to compare the oncologic and surgical outcomes between laparoscopic and open extended lymphadenectomy in patients with locally AGC. In particular, since extended lymphadenectomy in gastric cancer surgery has been regarded as a convoluted procedure, the internal validity for the surgical technique of surgeons participating in this RCT is deemed a crucial prerequisite for this surgical RCT. Therefore, the KLASS-02-QC (registered at www.clinicaltrials.gov as NCT01283893), a study conducted to standardize the procedures of laparoscopic and open extended D2 lymphadenectomy, will be performed separately [8]. Surgeons validated through the strict qualification program of the KLASS-02-QC RCT can participate. In addition, this RCT is elaborately designed to minimize the sources of bias and distortion of the results, which can be exaggerated in a surgical clinical trial. Here, we introduce the protocol of the KLASS-02
Page 2 of 8
RCT comparing laparoscopic and open D2 lymphadenectomy for patients with locally AGC.
Methods Objectives
The purpose of the KLASS-02 RCT is to show the efficacy of laparoscopic distal gastrectomy with extended D2 lymphadenectomy for patients who are clinically diagnosed with locally AGC, compared with conventional open subtotal gastrectomy and D2 lymphadenectomy. Study design
This RCT is an investigator-initiated, randomized, controlled, parallel group, and non-inferiority trial comparing laparoscopic D2 lymphadenectomy for locally AGC patients with open conventional surgery. Before enrollment of first patient, this study was approved from the institutional review boards (AJIRB-MEDMDB-11-223) of Ajou university hospital, Soonchunhyang university hospital, Keimyung university hospital, Chonnam national university hwasun hospital, Incheon St. Mary’s hospital, Yeoeuido St. Mary’s hospital, DongA university hospital, Seoul national university hospital, Seoul national university bundang hospital, Yonsei university severance hospital, Yonsei university gangnam severance hospital, Ewha womans university hospital and National cancer center. All investigators progress this study in accordance with the Declaration of Helsinki [9]. An independent institutional review board of all institutions at which the participating surgeons are affiliated has approved this study. Written informed consent will be obtained from all patients before they are recruited. This RCT will be monitored by an independent data and safety monitoring committee (DSMC) organized by the Clinical Trial Center of Ajou University Hospital. Study population
The patient inclusion and exclusion criteria are as follows: Inclusion criteria Patients aged >20 and
STUDY PROTOCOL
Open Access
Efficacy of laparoscopic subtotal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer: the protocol of the KLASS-02 multicenter randomized controlled clinical trial Hoon Hur1, Hyun Yong Lee2, Hyuk-Joon Lee3, Min Chan Kim4, Woo Jin Hyung5, Young Kyu Park6, Wook Kim7 and Sang-Uk Han1*
Abstract Background: Despite the well-described benefits of laparoscopic surgery such as lower operative blood loss and enhanced postoperative recovery in gastric cancer surgery, the application of laparoscopic surgery in patients with locally advanced gastric cancer (AGC) remains elusive owing to a lack of clinical evidence. Recently, the Korean Laparoscopic Surgical Society Group launched a new multicenter randomized clinical trial (RCT) to compare laparoscopic and open D2 lymphadenectomy for patients with locally AGC. Here, we introduce the protocol of this clinical trial. Methods/design: This trial is an investigator-initiated, randomized, controlled, parallel group, non-inferiority trial. Gastric cancer patients diagnosed with primary tumors that have invaded into the muscle propria and not into an adjacent organ (cT2–cT4a) in preoperative studies are recruited. Another criterion for recruitment is no lymph node metastasis or limited perigastric lymph node (including lymph nodes around the left gastric artery) metastasis. A total 1,050 patients in both groups are required to statistically show non-inferiority of the laparoscopic approach with respect to the primary end-point, relapse-free survival of 3 years. Secondary outcomes include postoperative morbidity and mortality, postoperative recovery, quality of life, and overall survival. Surgeons who are validated through peer-review of their surgery videos can participate in this clinical trial. Discussion: This clinical trial was designed to maintain the principles of a surgical clinical trial with internal validity for participating surgeons. Through the KLASS-02 RCT, we hope to show the efficacy of laparoscopic D2 lymphadenectomy in AGC patients compared with the open procedure. Trial registration: ClinicalTrial.gov, NCT01456598. Keywords: Gastric neoplasm, Laparoscopy, D2 lymphadenectomy, Advanced gastric cancer
Background Since the first laparoscopic gastrectomy for gastric cancer was performed in 1994 [1], increasingly more surgeons have performed this procedure in East Asian countries such as Korea and Japan [2]. Nevertheless, the Japanese Gastric Cancer Association (JGCA) treatment guideline recommends that laparoscopic surgery for * Correspondence: [email protected] 1 Department of Surgery, Ajou University Medical Center, Ajou University School of Medicine, 206 Worldcup-ro, Youngtong-gu, Suwon 443-749, Korea Full list of author information is available at the end of the article
gastric cancer should not be performed as a general practice [3]. The reason for this recommendation is that despite the benefits of laparoscopic surgery, the longterm survival results from 2 multicenter randomized clinical trials (RCTs) in Japan (registered in the University Hospital Medical Information Network [UMIN] Clinical Trial Registry as UMIN000003319) and Korea (registered in the National Institutes of Health [NIH] Clinical Trail Registry as NCT0045251) have not been reported. However, the interim analysis of a multicenter RCT conducted by Korean surgeons described the safety
© 2015 Hur et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Hur et al. BMC Cancer (2015) 15:355
of laparoscopic surgery for early gastric cancer (EGC) [4]. In addition, several meta-analyses have showed that laparoscopic gastrectomy with limited lymphadenectomy for patients with EGC had non-inferior oncologic outcome relative to open surgery, and a benefit in terms of faster postoperative recovery [5-7]. Based on this evidence, most experienced surgeons have applied the laparoscopic procedure in patients with EGC. However, the use of laparoscopic surgery in patients with locally advanced gastric cancer (AGC) remains controversial. Several obstacles have been considered as the reasons for this limitation. First, extended (D2) lymphadenectomy is an essential procedure for performing curative resection in AGC patients, which requires more sophisticated surgical techniques to ensure patient safety. Owing to some limitations of laparoscopic surgery such as impossible palpation, unsecure bleeding control, among others, the experience and skill of surgeons is more important in laparoscopic surgery for AGC. Second, some researchers have expressed the concern that the laparoscopic procedure for advanced malignant disease might aggravate cancer progression via the intraoperative intraperitoneal pressure and circulating gas. However, there is no conclusive evidence to support this hypothesis to date. Taken together, the application of laparoscopic surgery in patients with locally AGC is possible if the technical and oncologic safety is ensured. A well-designed multicenter RCT recruiting a large sample of patients is the best option to obtain clinical evidence for novel technology in the surgical field. Considering the benefits of laparoscopic surgery, such as enhanced postoperative recovery and reduced postoperative pain, the application of laparoscopic surgery will likely be extended to more patients with AGC and EGC. Currently, the Korean Laparoscopic Surgical Society (KLASS) group launched the multicenter RCT (KLASS-02 RCT; registered at www.clinicaltrials.gov as NCT01456598) to compare the oncologic and surgical outcomes between laparoscopic and open extended lymphadenectomy in patients with locally AGC. In particular, since extended lymphadenectomy in gastric cancer surgery has been regarded as a convoluted procedure, the internal validity for the surgical technique of surgeons participating in this RCT is deemed a crucial prerequisite for this surgical RCT. Therefore, the KLASS-02-QC (registered at www.clinicaltrials.gov as NCT01283893), a study conducted to standardize the procedures of laparoscopic and open extended D2 lymphadenectomy, will be performed separately [8]. Surgeons validated through the strict qualification program of the KLASS-02-QC RCT can participate. In addition, this RCT is elaborately designed to minimize the sources of bias and distortion of the results, which can be exaggerated in a surgical clinical trial. Here, we introduce the protocol of the KLASS-02
Page 2 of 8
RCT comparing laparoscopic and open D2 lymphadenectomy for patients with locally AGC.
Methods Objectives
The purpose of the KLASS-02 RCT is to show the efficacy of laparoscopic distal gastrectomy with extended D2 lymphadenectomy for patients who are clinically diagnosed with locally AGC, compared with conventional open subtotal gastrectomy and D2 lymphadenectomy. Study design
This RCT is an investigator-initiated, randomized, controlled, parallel group, and non-inferiority trial comparing laparoscopic D2 lymphadenectomy for locally AGC patients with open conventional surgery. Before enrollment of first patient, this study was approved from the institutional review boards (AJIRB-MEDMDB-11-223) of Ajou university hospital, Soonchunhyang university hospital, Keimyung university hospital, Chonnam national university hwasun hospital, Incheon St. Mary’s hospital, Yeoeuido St. Mary’s hospital, DongA university hospital, Seoul national university hospital, Seoul national university bundang hospital, Yonsei university severance hospital, Yonsei university gangnam severance hospital, Ewha womans university hospital and National cancer center. All investigators progress this study in accordance with the Declaration of Helsinki [9]. An independent institutional review board of all institutions at which the participating surgeons are affiliated has approved this study. Written informed consent will be obtained from all patients before they are recruited. This RCT will be monitored by an independent data and safety monitoring committee (DSMC) organized by the Clinical Trial Center of Ajou University Hospital. Study population
The patient inclusion and exclusion criteria are as follows: Inclusion criteria Patients aged >20 and
