In the past, there has been ongoing debate about the therapeutic value of radiotherapy in resectable gastric cancer. The TOPGEAR study presented at the 2024 European Society for Medical Oncology (ESMO) Congress (September 13-17, Barcelona) evaluated the comparison between preoperative chemoradiotherapy and perioperative chemotherapy alone. Dr. Trevor Leong, the Principal Investigator from the University of Melbourne in Australia, was interviewed by us on site.

LBA58- A randomized phase III trial of perioperative chemotherapy (periop CT) with or without preoperative chemoradiotherapy (preop CRT) for resectable gastric cancer (AGITG TOPGEAR): Final results from an intergroup trial of AGITG, TROG, EORTC and CCTG

Dr Leong: The background of this trial is that for the last twenty years, there has been a debate about the role of radiotherapy in the treatment of resectable gastric cancer. Some of the earlier studies suggested a benefit with radiotherapy given after surgery, but the trouble with those trials is that when you give radiotherapy after surgery, most patients never complete it because they are too sick or deconditioned after surgery. So we thought that giving it before surgery was going to be much more effective, because patients are better able to tolerate the treatment. The trial set out to answer a burning question in gastroesophageal cancer that has been raging for the last twenty years. What we did was randomize approximately 600 patients to what is the current standard-of-care (perioperative chemotherapy with surgery) and compared that to the same treatment but with the addition of radiotherapy given before surgery. The rationale is that we felt that giving radiation before surgery would shrink tumors and therefore increase the pathological complete response rates, and then hopefully this would translate into better long-term outcomes in terms of survival for those patients. The trial was conducted across three continents – there were 70 sites in 15 countries. Half the patients (288) were randomized to receive chemotherapy and surgery alone. The other half were randomized to receive chemotherapy, surgery and also radiotherapy before surgery. What we found was that the treatment was very well tolerated. The addition of radiotherapy did not increase toxicity of treatment before surgery. The proportion of patients proceeding to surgery was very similar in both groups. At the time of surgery, when we reviewed the pathology, radiation did indeed shrink the tumors down moreso than chemotherapy alone. The pathological complete response rates in the radiotherapy group were about 17%, which is double what we saw in the chemotherapy alone group where it was only 8%. That was very encouraging. However, when we analyzed the survival results some five years later, these results did not translate to better outcomes in terms of survival for patients receiving radiation. In both groups, the five-year overall survival rates were very similar at about 45%. Also for progression-free survival, there were identical at 40%. So what we can conclude from this trial is that in patients who are having good quality surgery and having perioperative chemotherapy, there is no role at the moment for radiotherapy in treating these patients, either given before or after surgery. These results will be practice-changing because there are centers currently using preoperative radiotherapy routinely for gastric cancer. The other reason is that one-third of the patients in our cohort had tumors of the gastroesophageal junction, and for these tumors, preoperative chemoradiation is standard-of-care treatment in many countries around the world. Our results would suggest that radiation is probably not necessary, even for gastroesophageal junction tumors, and they could probably be treated with perioperative chemotherapy alone as well. In terms of future directions, where do we see the role of radiation now in patients with gastroesophageal adenocarcinomas? I am referring specifically to adenocarcinomas, not squamous cell carcinomas, which are probably more common in Asian countries. But for patients with resectable adenocarcinomas, I do not see a role for radiotherapy at the present time. There will be a large translational component to the TOPGEAR trial where we will be looking at biomarkers, which may point to specific subsets of patients that may benefit from radiation treatment, but that is still work to come. The other new area of future research would be to look at organ-sparing treatment for patients with resectable tumors. In other words, can we do away with surgery if we have really good responses to radiation and chemotherapy. I think the TOPGEAR trial was very eye-opening in letting us know that radiation does improve the pathological response rates compared to chemotherapy alone, so if we build on this, it may lead to strategies where we can combine very effective radiation with more effective chemotherapy to get more complete responses, and therefore accelerate that organ-sparing approach. Thank you very much.