Debate Settled on Preop Chemoradiation in Gastric Cancer?

BARCELONA – Adding preoperative chemoradiation to standard-of-care perioperative chemotherapy did not improve overall or progression-free survival in patients with resectable adenocarcinoma of the stomach or gastroesophageal junction, according to findings from the phase 3 TOPGEAR study.
Results of the study, reported at the European Society of Medical Oncology (ESMO) and published simultaneously in the New England Journal of Medicine, largely end the debate on whether to use neoadjuvant radiotherapy in gastroesophageal cancer, said lead author Trevor Leong, MD, Department of Oncology, MacCallum Cancer Centre, University of Melbourne, Australia.
However, because the study showed a twofold higher pathologic complete response rate and increased tumor downstaging with preoperative chemoradiation, there could still be a limited role for the treatment, Leong added.
Since 2001, postoperative chemoradiation has been the standard of care for gastric cancer, particularly in North America, based on findings from that year’s INT0116 trial. 
But “studies show approximately half of patients are not able to complete treatment due to toxicity and disease progression,” Leong explained. “Preoperative chemoradiation has the advantages of tumor downstaging and better tolerability. And given that it is the standard of care for esophageal cancer, there has been a keen interest in its use for gastric cancer.”
TOPGEAR is the first randomized phase 3 trial evaluating preoperative chemoradiation in gastric cancer. 
Leong and colleagues recruited 574 patients with resectable adenocarcinoma of the stomach or gastroesophageal junction from 70 centers of excellence from 15 countries. The patients’ mean age was about 60 years, with about 35% of tumors located at the gastroesophageal junction, and 88% considered clinical stage T3 or greater, with about 40% being node-negative and 60% being node-positive or unknown. 
Patients were randomly assigned to receive either perioperative chemotherapy or preoperative chemoradiation. Perioperative chemotherapy consisted of three cycles of ECF (epirubicin, cisplatin, fluorouracil) or four cycles of FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) before and after surgery. Preoperative chemoradiation consisted of one less cycle of preoperative chemotherapy followed by chemoradiotherapy (45 Gy in 25 fractions of radiation plus infusional 5-fluorouracil) and surgery plus postoperative chemotherapy. 
The primary endpoint of the study was overall survival, and secondary endpoints included progression-free survival (PFS), pathologic complete response rates, and toxicity.
Most patients in both groups received all planned cycles of preoperative chemotherapy — 94% in the preoperative-chemoradiotherapy group and 91% in the perioperative-chemotherapy group — and most patients in the chemoradiotherapy group completed the full protocol dose of 45 Gy. A similar percentage of patients in both groups (84% and 91%, respectively) proceeded to surgery. The main difference was significantly fewer patients in the preoperative-chemoradiotherapy group started postoperative chemotherapy (56% vs 66% in the perioperative-chemotherapy group; P = .01)
After a median follow-up of 66.7 months, the study did not meet its primary endpoint. Median overall survival was 49.4 months in the perioperative-chemotherapy group compared to 46.4 months in the preoperative-chemoradiotherapy group (hazard ratio for death, 1.05; 95% CI, 0.83 – 1.31). At 5 years, 46% of patients who received perioperative chemotherapy were alive vs 44% who had preoperative chemoradiotherapy.
Median PFS was also almost the same between the groups — 32 months in the perioperative-chemotherapy group and 31 months in the preoperative-chemoradiotherapy group.
On the toxicity front, both groups experienced similar rates of any grade 3 or higher adverse event — 61% of patients in the perioperative-chemotherapy group and 66% in the preoperative-chemoradiotherapy group. More specifically, 25% of patients in the perioperative-chemotherapy group and 28% in the preoperative-chemoradiotherapy group experienced gastrointestinal adverse events, and 41% and 46%, respectively, experienced hematologic toxic effects.
The pathologic complete response, however, was about twofold higher in the preoperative-chemoradiotherapy group (16.8% vs 8%). More patients in the preoperative-chemoradiotherapy group had a major pathologic response (32.7% vs 21.3%) and had their tumors downstaged to pathological stage T1 or T2 (32% vs 25%).
Given the improvements in pathologic complete response and tumor downstaging, and the similar toxicity profiles, there may be a place for preoperative chemoradiotherapy in certain cases, said the paper’s discussant Tania Fleitas Kanonnikoff, MD, PhD, a medical oncologist at the University Hospital of Valencia in Spain. 
“Perhaps it is a strategy to individualize in those patients in whom it is necessary to reduce the tumor load to facilitate surgery,” Kanonnikoff told Medscape Medical News. ” The systemic control with chemoradiotherapy was good in the trial because it only replaced one cycle of perioperative chemo for the chemoradiation strategy, so you didn’t sacrifice anything, and there was no increase in toxicity. So, for some cases, we can consider this if you have a huge tumor that is difficult to remove.”
In an editorial audio commentary accompanying the study, Oladapo Yeku, MD, PhD, associate editor of NEJM Evidence, said the results were “surprising” in some ways. 
Previous research has demonstrated the efficacy of chemoradiotherapy alone, and although other studies have shown that adjuvant chemoradiation does not lead to improved overall survival, this may have been partly due to patients not completing the required course of treatment because of cumulative toxicities. 
However, consistent with other trials, this study showed improved pathologic response does not necessarily correlate with improved overall survival. Overall, “in solid tumor malignancy trials where definitive therapy is being offered and there is a risk of excessive cumulative toxicity and overtreatment, primary endpoints like overall survival are the most appropriate for exactly this reason,” Yeku said.
Leong reported no relevant financial relationships. Kanonnikoff reported consultant or advisory roles with Amgen, AstraZeneca, MSD, and BeiGene; research funding from Gilead; speaking engagements with Amgen, Servier, Bayer, BMS, MSD, Lilly, and Roche; and institutional funding from Genentech, Adaptimmune, Roche, BeiGene, Bayer, Servier, Astellas, BMS, and Daiichi Sankyo. 
The study was supported by grants from the National Health and Medical Research Council, the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Health Research Council of New Zealand, the European Organisation for Research and Treatment of Cancer, and the Cancer Australia Priority-Driven Collaborative Research Scheme. 
 
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