Adding chemoradiation to perioperative chemotherapy improves pathologic complete response rates in patients with resectable gastric cancer but does not extend overall survival, according to data presented at the European Society for Medical Oncology (ESMO) Congress 2024¹ and published simultaneously in The New England Journal of Medicine.²

Results from the phase III TOPGEAR trial demonstrated higher rates of pathologic complete response and tumor downstaging in the chemoradiation arm compared with chemotherapy alone, but there was no statistically significant difference in 5-year overall survival or progression-free survival between the two treatment arms. Of note, the addition of radiation did not result in increased toxicity or surgical complications.

Trevor Leong, MBBS, MD, FRANZCR

“This study provides definitive evidence that preoperative chemoradiation improves [pathologic complete response] rates without adding undue toxicity in patients with resectable gastric and gastroesophageal junction adenocarcinoma,” said lead study author Trevor Leong, MBBS, MD, FRANZCR, Consultant Radiation Oncologist at Peter MacCallum Cancer Centre in Australia. “However, the lack of a survival benefit limits its broader clinical application.”

As Dr. Leong explained, gastric cancer remains a leading cause of cancer-related mortality worldwide, with more than half of patients succumbing to the disease within 5 years despite multimodal treatment advances. Perioperative chemotherapy has been the standard of care, with regimens like FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) replacing earlier approaches such as ECF (epirubicin, cisplatin, and fluorouracil). Radiation therapy, although historically explored in adjuvant settings, has not been definitively established as part of perioperative management, leaving a critical gap in localized disease control strategies.

Study Methods

The phase III TOPGEAR trial enrolled patients with resectable gastric or gastroesophageal junction cancer between 2009 and 2021. Participants were randomly assigned to two arms: one receiving standard perioperative chemotherapy and the other substituting one preoperative chemotherapy cycle with chemoradiation. The primary endpoint was overall survival, with secondary endpoints including pathologic complete response, progression-free survival, safety, and quality of life.

Patients in the trial underwent high-quality D2 lymphadenectomy surgery, ensuring adherence to rigorous surgical standards. Most patients presented with locally advanced disease, aligning with cohorts from prior studies like FLOT-4.

High Pathologic Complete Response and Enhanced Tumor Downstaging

As Dr. Leong reported, patients randomly assigned to chemoradiation vs chemotherapy alone demonstrated higher rates of pathologic complete response (16.8% vs 8.0%). The rate of major pathologic response was also higher in the chemoradiation vs chemotherapy group (50% vs 29%). Correspondingly, more tumors in the chemoradiation group were downstaged to T1 or T2 compared with those receiving chemotherapy alone (32% vs 25%).

“The TOPGEAR trial revealed significant insights into the role of preoperative chemoradiation in gastric cancer treatment, including the potential for nonoperative management strategies,” said Dr. Leong. However, the study’s primary endpoint of overall survival showed no statistically significant difference between the two groups. The 5-year overall survival rate was approximately 45% in both arms, indicating that the addition of radiation did not confer a survival advantage.

An analysis of treatment effect on overall survival according to prespecified subgroups did not reveal any subgroups that clearly benefited from preoperative chemoradiation. Estimated treatment effects were similar for each subgroup, with the possible exception of primary tumor location, which showed a trend toward poorer survival in those with lower-third tumors assigned preoperative chemoradiation when compared with upper-third and gastroesophageal junction tumors.

Progression-free survival, another key measure of treatment efficacy, also remained comparable across the study arms. Median progression free survival was 31 months in the chemoradiation group vs 32 months in the chemotherapy-alone group.

Of note, the integration of radiation therapy into the treatment regimen did not increase toxicity or surgical complications. The overall rates of gastrointestinal toxicity were 28% in the chemoradiation group and 25% in the chemotherapy-alone group, and the rate of hematologic toxicity was 46% vs 42%, respectively. Similarly, there was no significant difference in surgical complications, with 18% of patients in the chemoradiation group and 16% in the chemotherapy-alone group experiencing grade 3 or higher acute surgical complications. There was no difference in the 30- or 90-day operative mortality rate.

Compliance rates for postoperative chemotherapy were also consistent with prior studies like FLOT-4, with 47.7% of patients completing the treatment in the chemoradiation arm.³ According to the study authors, these findings provide reassurance about the safety of this approach while underlining its limitations in impacting long-term survival outcomes.

EXPERT POINT OF VIEW

Tania Fleitas Kanonnikoff, MD, PhD

Invited discussant Tania Fleitas Kanonnikoff, MD, PhD, a medical oncologist at Hospital Clínico Universitario de Valencia, Spain, underscored the importance of the TOPGEAR trial in addressing a critical, long-standing question in the management of localized resectable gastric cancer: whether perioperative chemoradiation adds value to treatment outcomes.

“Optimal management of locoregional gastric cancer remains an unmet need,” Dr. Fleitas Kanonnikoff noted, highlighting that despite advancements in multimodal therapies, half of the patients still die within 5 years. “While perioperative chemotherapy, including regimens like FLOT, has improved survival, the addition of neoadjuvant radiation didn’t show any benefit in the TOPGEAR study.”

Current guidelines from the European Society for Medical Oncology recommend dual-modality treatment only in specific cases after the multidisciplinary team discussion, said Dr. Fleitas Kanonnikoff, but this is controversial. This recommendation is primarily based on the INT0116 study, which demonstrated survival benefits but faced criticism due to limitations, such as low rates of adequate surgical staging (D2 dissection).

Reflecting on the evolution of gastric cancer treatment, Dr. Fleitas -Kanonnikoff outlined how practices shifted from perioperative ECF chemotherapy when the TOPGEAR trial began enrollment in 2009 to the adoption of FLOT as the standard in 2019. She also pointed to ongoing research on the integration of immunotherapy into treatment paradigms. Against this backdrop, the TOPGEAR trial was designed to maintain systemic control while substituting one chemotherapy cycle with chemoradiation.

Additional Thoughts About TOPGEAR

Dr. Fleitas Kanonnikoff commended the trial for its rigorous design, balanced patient population, and adherence to quality surgical standards. She noted that this is the first randomized phase III trial of neoadjuvant chemoradiation in the context of a perioperative multimodal approach in gastric cancer that meets the statistical power to answer this key research question.

The trial demonstrated improved pathologic response with chemoradiation, evidenced by better tumor downstaging and pathologic complete response rates. However, Dr. Fleitas Kanonnikoff noted the critical limitation: “This increased [pathologic complete response rate] and tumor downstaging is not reflected in survival outcomes.”

Although the survival outcomes were not impacted, Dr. Fleitas -Kanonnikoff highlighted specific cases where chemoradiation could be considered beneficial, such as in patients requiring significant tumor downstaging prior to surgery. She emphasized the importance of advancing biomarker research to identify patients who may derive the most benefit from this approach.

“Ultimately, we need to focus on tumor biology and biomarkers to optimize treatment for our patients,” Dr. Fleitas Kanonnikoff concluded, underscoring the need for personalized approaches in gastric cancer management.

DISCLOSURE: The study was funded by the National Health and Medical Research Council, Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, EORTC Cancer Research Fund, Cancer Australia, and Health Research Council of New Zealand. Dr. Leong reported no conflicts of interest. For full disclosures of the study authors, visit oncologypro.esmo.org. Dr. Fleitas Kanonnikoff disclosed financial relationships with Amgen, AstraZeneca, MSD, BeiGene, Gilead Sciences, Servier, Bayer, Lilly, and Roche; and has received institutional funding from Genentech, Adapt immune, Roche, BeiGene, Bayer, Servier, Astellas, BMS, and Daiichi Sankyo.

REFERENCES

1. Leong T, Smithers BM, Michael M, et al: A randomized phase III trial of perioperative chemotherapy with or without preoperative chemoradiotherapy for resectable gastric cancer (AGITG TOPGEAR): Final results from an intergroup trial of AGITG, TROG, EORTC and CCTG. ESMO Congress 2024. Abstract LBA58. Presented September 14, 2024.

2. Leong T, Smithers BM, Michael M, et al: Preoperative chemoradiotherapy for resectable gastric cancer. N Engl J Med 391:1810-1821, 2024.

3. Rencuzogullari A, Karahan SN, Selcukbiricik F, et al: The new era of total neoadjuvant FLOT therapy for locally advanced, resectable gastric cancer: A propensity-matched comparison with standard perioperative therapy. J Surg Oncol. October 13, 2024 (early release online).