A phase III trial, TOPGEAR, has demonstrated that adding chemoradiation to perioperative chemotherapy improves pathologic complete response rates in patients with resectable gastric cancer. However, this improvement did not translate into a statistically significant overall survival benefit. The findings, presented at the European Society for Medical Oncology (ESMO) Congress 2024 and published in The New England Journal of Medicine, highlight a nuanced role for chemoradiation in gastric cancer treatment.
The TOPGEAR trial enrolled patients with resectable gastric or gastroesophageal junction cancer between 2009 and 2021, randomizing them to perioperative chemotherapy alone or with the addition of chemoradiation. The primary endpoint was overall survival, with secondary endpoints including pathologic complete response, progression-free survival, safety, and quality of life.
Pathologic Response and Tumor Downstaging
The study revealed a significantly higher pathologic complete response rate in the chemoradiation arm (16.8%) compared to the chemotherapy-alone arm (8.0%). Major pathologic response was also more frequent in the chemoradiation group (50%) versus the chemotherapy group (29%). Furthermore, tumors in the chemoradiation arm were more likely to be downstaged to T1 or T2 (32%) compared to the chemotherapy arm (25%).
"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."
Survival Outcomes and Toxicity
Despite the improved pathologic response, the 5-year overall survival rate was approximately 45% in both arms, indicating no statistically significant difference. Median progression-free survival was 31 months in the chemoradiation group and 32 months in the chemotherapy-alone group.
Importantly, the addition of radiation 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, while hematologic toxicity rates were 46% and 42%, respectively. Surgical complication rates were similar, with 18% in the chemoradiation group and 16% in the chemotherapy-alone group experiencing grade 3 or higher acute surgical complications.
Expert Perspective
Tania Fleitas Kanonnikoff, MD, PhD, a medical oncologist at Hospital Clínico Universitario de Valencia, Spain, commented on the trial's significance. "Optimal management of locoregional gastric cancer remains an unmet need," she stated, noting that half of patients still die within 5 years despite multimodal therapies. While acknowledging the improved survival with perioperative chemotherapy regimens like FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel), she emphasized that the TOPGEAR study did not demonstrate a survival benefit with the addition of neoadjuvant radiation.
Dr. Fleitas Kanonnikoff highlighted specific cases where chemoradiation might be considered beneficial, such as patients requiring significant tumor downstaging prior to surgery. She underscored 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," she concluded.
The TOPGEAR trial's findings suggest that while perioperative chemoradiation can enhance pathologic response in resectable gastric cancer, it does not translate to improved overall survival. Further research is needed to identify specific patient subgroups who may benefit from this approach and to explore the role of biomarkers in personalizing treatment strategies.
