Dr Amalia Cochran: Hello, JAMA Surgery listeners. This is Amalia Cochran, the web and social media editor, and I'm here this month speaking with Dr. Toshiyasu Ojima
Dr. Toshiyasu Ojima: Yes, good afternoon.
AC: We are here today to talk about Short-term Outcomes of Robotic Gastrectomy vs Laparoscopic Gastrectomy for Gastric Cancer—A Randomized Clinical Trial. Interested listeners can read a transcript of this interview by following the link that is available in the show notes. Welcome. I always start our author interviews trying to understand why a question was of special interest to the researchers. Why were you interested in examining the difference in short-term outcomes from robotic versus laparoscopic gastrectomy for patients with gastric cancer?
TO: Since laparoscopic gastrectomy (LG) with radical lymphadenectomy for gastric cancer was developed in 1991, it has been widely accepted as a less invasive procedure than open gastrectomy. LG has several benefits for gastric cancer patients, such as reduced pain, early recovery of intestinal function, and shorter hospital stay. However, LG still has several drawbacks including the limited range of movement, amplification of hand tremors, and inconvenient surgical positioning. Laparoscopic lymph node dissection around the peripancreatic area, such as the supra-pancreatic or infra-pyloric lymph nodes, remains challenging. Indeed, postoperative pancreatic fistula occurs in around 5% of patients undergoing LG. Robotic gastrectomy (RG) for gastric cancer was developed in 2000 as an alternative, minimally invasive approach that may overcome the drawbacks of previous LG. It plays an essential role in ergonomics and offers advantages, such as wrist-like motion, less fatigue, tremor filtering, motion scaling, and 3D vision. So we proposed that this innovative technology can overcome some limitations of LG, and, as a result, the incidence of morbidity can be reduced by RG.
AC: Thank you for that Dr Ojima. Why did you select intra-abdominal infection as your primary outcome? And did you consider any of the secondary outcomes as possible primary outcomes instead?
TO: In our previous retrospective study published in Medicine 2019, we compared the safety and feasibility of surgical outcomes of LG and RG for patients with gastric cancer. Overall postoperative complication rates with higher than Clavien-Dindo grade 2 were comparable at 15% between the groups. On the other hand, intra-abdominal infectious complications were found in 11% of the LG group, including pancreatic fistula, abscess, and anastomotic leakage. In the RG group, however, they were not found. Our RG procedure may be associated with decreased incidence of intra-abdominal infectious complications. Therefore, we set the incidence of postoperative intra-abdominal infectious complications as primary endpoint instead of any complications.
Secondary endpoints in this trial were following four items: (First) incidence of any complications; (Second) surgical results, such as operation time, blood loss, transition rate to open or laparoscopic surgery, and the number of harvested lymph nodes; (Third) postoperative course; such as time to start of drinking, time to start of eating, time to first flatus, postoperative hospital stay, and the number of postoperative analgesic administrations; and (Fourth) oncological outcomes; such as overall survival (OS) and disease-free survival (DFS). Of these secondary endpoints, RG reduced the incidence of overall postoperative complications including surgical and medical issues.
AC: That’s very helpful for me to understand this better. We often see trials analyzed only using intention-to-treat or per protocol type of analysis; however, you chose to use both approaches. I am curious about why you chose to conduct the analysis in this way.
TO: We defined two different populations for analysis. The modified intention-to-treat population excluded patients who had been randomized and met the post-randomization exclusion criteria. We used the modified intention-to-treat population to analyze the differences of patient demographics and tumor characteristics between LG group and RG group. We used both modified intention-to-treat population and per protocol population for analysis of surgical results, postoperative recovery and postoperative complications. The eligibility criteria for the modified ITT population and treatments such as surgery they receive will be clearly defined in the study protocol but in practice not everything goes perfectly to plan. Therefore, we need to plan ahead for the inconsistencies that can occur, because of conversion to the surgical approach in this trial, and consider how we deal with them statistically.
Patients who converted to the surgical approach (conversion from LG to open gastrectomy, conversion from RG to LG or open gastrectomy) were excluded from the per protocol population. Indeed, two of 119 patients converted from laparoscopic surgery to the open surgery. Two of 117 patients converted from robotic surgery to the laparoscopic surgery, and 2 of 117 patients converted from robotic surgery to the open surgery. Analysis using the per protocol population thus reflected the pure surgical results after LG and RG.
AC: You have a number of interesting findings because of the thorough examination that you did of secondary outcomes for your study since the primary outcome did not achieve significance. Which finding or findings were the most surprising to you? And which finding or findings do you think are the most important?
TO: In this trial, there was no significant difference in the incidence of intra-abdominal infectious complications between LG group and RG group, and therefore, the primary endpoint of reducing intra-abdominal infectious complications in RG compared to LG for gastric cancer was not met. The most surprising and important result was RG had a lower incidence of all complications than LG. The decrease in the incidence of any complications in RG was mainly caused by decrease in medical complications, not by surgical complications. Although there is no significant difference, there were few respiratory complications in the RG group. Surgical tissue damage and the accompanying inflammatory response may lead to increased systemic complications, such as pneumoniae. Further research into inflammatory response after robotic surgery is needed in a larger scale RCT.
Regarding postoperative recovery, the median time to first flatus was shorter in the RG group than in the LG group. Rapid recovery of gastrointestinal peristalsis in robotic surgery might be associated with the stable and flexible movements of the robotic forceps, avoiding excessive traction on the tissue and accidental injury to the blood vessels, and less surgical trauma to the patients. In addition, the number of postoperative analgesic administrations was lower in the RG group than in the LG group. We hypothesized that rapid recovery of gastrointestinal peristalsis and milder surgical stress after RG may result in postoperative pain relief.
AC: You mention in the limitations that in this study you did not assess long-term oncologic outcomes. Do you have plans to compare oncologic outcomes between the two surgical techniques?
TO: Long-term oncological outcomes, 5-year overall survival and disease-free survival, is secondary endpoints of this trial. We are currently following all patients.
In this paper, we reported on the postoperative complications and recovery data, the primary and part of the secondary endpoints of this RCT. In the near future, we will submit a second paper analyzing the differences in survival between LG group and RG group.
AC: I look forward to seeing that. Do you have any new or additional research questions that resulted from this work?
TO: These findings suggest that robotic gastrectomy for gastric cancer patients is unable to reduce postoperative intra-abdominal infectious complications. However, we consider that RG may be a less invasive surgery without tissue trauma and noxious stimuli. The technique with the least surgical stress response is considered the best for the patient. Therefore, we plan to conduct detailed scientific research on surgical stress in robotic surgery, such as adrenaline, cortisol, IL-6, IL-10, noradrenaline and vasopressin.
AC: That will be extremely interesting. Are there any other aspects of this work that you think are important for our audience to understand?
TO: This RCT was established based on the hypothesis that robotic gastric cancer surgery has a lower rate than laparoscopic gastric cancer surgery of intra-abdominal infectious complications including postoperative pancreatic fistula, anastomotic leakage and abscess. However, the primary endpoint of this trial was not met. Findings from this study could not establish final evidence, but rather serve to inform the need for larger randomized multicenter phase III clinical trials comparing LG and RG. Large-scale multicenter RCT in progress in Japan (Japan Clinical Oncology Group Study JCOG1907, Mona-Lisa study) will prove the real benefit of the robotic gastric cancer surgery. This study will enroll 1040 patients, and will confirm the superiority of RG over LG for the safety of patients with clinical T1, 2 N0, 1, 2 gastric cancer. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, as in this study.
AC: It sounds to me that there is a lot of work to be done yet in this area. This is very exciting. Dr Ojima, thank you both very much for making the time to talk with me today. Again, this is Amalia Cochran, the JAMA Surgery web and social media editor speaking about Short-term Outcomes of Robotic Gastrectomy vs Laparoscopic Gastrectomy for Gastric Cancer—A Randomized Clinical Trial. For more author interviews and additional audio media, please go to jamanetworkaudio.com.