Although the addition of preoperative chemoradiotherapy to perioperative chemotherapy doubled the percentage of patients with a pathological complete response (pCR) and led to a higher percentage of patients with tumour downstaging than perioperative chemotherapy alone, these improvements in a randomised phase III TOPGEAR study conducted among patients with resectable gastric and gastro-oesophageal junction (GEJ) adenocarcinoma, did not translate into improvements in overall survival (OS) or progression-free survival (PFS).
The results of TOPGEAR have implications for the treatment of patients with GEJ adenocarcinoma, who constituted one third of the patient population. At present, there is little, if any, role for radiation therapy in the management of resectable gastric cancer. The findings are reported at ESMO Congress 2024 along with a simultaneous publication by Dr. Trevor Leong of the Peter MacCallum Cancer Centre in Melbourne, VIC, Australia and colleagues on 14 September 2024 in The New England Journal of Medicine.
The authors wrote in the background that in Western countries, the current standard-of-care (SOC) for resectable gastric cancer is perioperative chemotherapy. Preoperative chemoradiotherapy is SOC for some patients with oesophageal cancer. Given the advantages of preoperative therapy, including tumour downstaging and a better side-effect profile than postoperative therapy, interest in the use of preoperative chemoradiotherapy for gastric cancer has been high, but data are limited as compared with perioperative chemotherapy alone.
In the Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma (TOPGEAR), the study team hypothesised that adding preoperative chemoradiotherapy to perioperative chemotherapy would increase the percentage of patients with a pCR and would improve OS as compared with perioperative chemotherapy alone.
TOPGEAR was an international collaboration led by the Australasian Gastro-Intestinal Trials Group, coordinated by the National Health and Medical Research Council Clinical Trials Centre, and undertaken in collaboration with the Trans-Tasman Radiation Oncology Group, the European Organisation for Research and Treatment of Cancer, and the Canadian Cancer Trials Group.
The study was conducted as a phase II/III randomised trial. The study team previously reported the results of the phase II component, which showed the safety and feasibility of preoperative chemoradiotherapy. They now report the final results of the phase III trial, including results for the primary endpoint of OS. Secondary endpoints included PFS, pCR, side-effects, and quality-of-life.
Patients with resectable gastric or GEJ adenocarcinoma were randomly assigned to receive preoperative chemoradiotherapy plus perioperative chemotherapy or perioperative chemotherapy alone. In both groups, patients received either epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel both before and after surgery; the preoperative chemoradiotherapy group also received chemoradiotherapy, 45 Gy in 25 fractions of radiation plus fluorouracil infusion. A total of 574 patients underwent randomisation at 70 sites in Australasia, Canada, and Europe, 286 to the preoperative chemoradiotherapy group and 288 to the perioperative chemotherapy group.
A higher percentage of patients in the preoperative chemoradiotherapy group than in the perioperative chemotherapy group had a pCR (17% versus 8%) and greater tumour downstaging after resection. At a median follow-up of 67 months, no significant between-group differences in OS or PFS were noted. The median OS 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 PFS was 31 months and 32 months, respectively.
Treatment-related side-effects were similar in the two groups. The overall incidence of gastrointestinal side-effects was 28% in the preoperative chemoradiotherapy group and 25% in the perioperative chemotherapy group, and the incidence of haematologic side-effects was 46% and 41%, respectively.
No significant between-group difference was seen with regard to the incidence of surgical complications, with 18% of the patients in the preoperative chemoradiotherapy group and 16% of those in the perioperative chemotherapy group having a surgical complication of grade 3 or higher. No meaningful between-group differences were noted in 30-day or 90-day operative mortality.
The authors concluded that with reporting of the TOPGEAR results, the management of resectable gastric cancer with radiation therapy has now come full circle: even when delivered as preoperative therapy, radiotherapy did not improve survival outcomes as compared with chemotherapy alone, despite improvements in pathological outcomes.
Future post hoc analyses may identify specific subgroups of patients who benefit from preoperative chemoradiotherapy, which will help guide the design of future trials. Better understanding of the biologic characteristics of gastric cancer, from genetics to the immune landscape, along with improvements in radiation therapy delivery and surgical technique, may allow for a more individualised, biomarker-driven treatment.
The study was supported by grants from the National Health and Medical Research Council, Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Health Research Council of New Zealand International Investment Opportunities Fund, European Organisation for Research and Treatment of Cancer Cancer Research Fund, and Cancer Australia Priority-Driven Collaborative Research Scheme.
References
- Leong T, Smithers BM, Michael M, et al. for the Australasian Gastro-Intestinal Trials Group, National Health and Medical Research Council Clinical Trials Centre, Trans-Tasman Radiation Oncology Group, European Organisation for Research and Treatment of Cancer, and Canadian Cancer Trials Group. Preoperative Chemoradiotherapy for Resectable Gastric Cancer. NEJM; Published online 14 September 2024. DOI: 10.1056/NEJMoa2405195
LBA58 - Leong T, Smithers BM, Michael M, et al. 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. Annals of Oncology 2024;35(Suppl 2):S1249.