TOPGEAR trial results show no significant benefit of preoperative chemoradiotherapy on long term survival

The results of the EORTC-22114-40111-GITCG-ROG TOPGEAR trial of preoperative therapy for gastric and gastroesophageal junction adenocarcinoma were presented at the European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain, and simultaneously published in the New England Journal of Medicine. 

This study was conducted as an intergroup trial led by the Australasian Gastro-Intestinal Trials Group (AGITG), in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC), the Trans-Tasman Radiation Oncology Group (TROG) and the Canadian Cancer Trials Group (CCTG). 

The primary objective of this phase II/III trial was to determine whether adding chemoradiotherapy to chemotherapy is superior to chemotherapy alone in the neoadjuvant setting by improving pathological complete response rates (phase II) and subsequently overall survival (phase III) in patients with resectable gastric and gastroesophageal junction cancer. 

Thanks to the combined efforts of AGITG, EORTC, TROG, and CCTG, 574 patients were recruited from 70 sites across 15 countries between September 2009 and May 2021. Of these, 171 patients were recruited by 20 EORTC centres across 7 countries (Belgium, Czech Republic, France, Germany, Israël, Slovenia, and Spain). 

Although a higher percentage of patients in the preoperative chemoradiotherapy group achieved a pathological complete response compared to the perioperative chemotherapy group (17% vs. 8%), the addition of preoperative chemoradiotherapy to perioperative chemotherapy did not improve progression-free survival or overall survival compared to perioperative chemotherapy alone. The median overall survival was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (hazard ratio for death, 1.05; 95% confidence interval, 0.83 to 1.31), and the median progression-free survival was 31 months and 32 months, respectively. The 5-year survival rate was approximately 45% in both groups. Therefore, it is recommended that preoperative chemoradiotherapy should not become a routine standard of care. 

“Cancer of the stomach, including the gastroesophageal junction, remains an aggressive and difficult-to-treat disease with a high incidence and mortality rate worldwide,” said Professor Florian Lordick of University Hospital Leipzig, Germany, who co-chaired the study on behalf of the EORTC GI Tract Cancer Group. “The EORTC 22114-40111 TOPGEAR trial is an excellent example of international collaboration between academic networks globally. Although the primary endpoint of the study was not met, the trial has yielded important findings: the TOPGEAR results consolidate our European standard of care, which is perioperative chemotherapy for patients with locally advanced resectable gastric and gastroesophageal junction cancer. We are now aiming to achieve better systemic control by improving perioperative drug therapy based on a deeper understanding of individual tumour biology,” Dr Lordick added. 

“The results of the TOPGEAR trial will be practice-changing for many centres worldwide,” said Professor Karin Haustermans of University Hospital Leuven, Belgium, who co-chaired the trial on behalf of the EORTC Radiation Oncology Group. “Preoperative chemoradiation has been used in some centres in North America for locally advanced resectable gastric cancer and has been the standard of care in Europe, Canada, and Australia for patients with locally advanced gastroesophageal junction cancer, who comprised one-third of the TOPGEAR patient cohort. Following the results of ESOPEC earlier this year, and now TOPGEAR, national and international guideline committees will need to reconsider the current role of radiation therapy in this setting. Our role as radiation oncologists is to incorporate new imaging and precision techniques into the multimodality management of patients with gastric cancer to help improve long-term outcomes for this still dangerous disease,” said Dr Haustermans. 

Further information on coordination and funding 

The study was coordinated by the NHMRC Clinical Trials Centre (NHMRC CTC) at the University of Sydney. Funding was provided by NHMRC grants and the Cancer Australia Priority-driven Collaborative Cancer Research Scheme Grant, as well as by AGITG and NHMRC CTC, with regional funding from EORTC and CCTG through the Canadian Institutes of Health Research and the Canadian Cancer Society.