NEW YORK (Reuters Health) – In patients who had a D2 gastrectomy, perioperative administration of the oral fluoropyrimidine derivative S-1 and oxaliplatin (SOX) yielded better outcomes than adjuvant capecitabine and oxaliplatin (CapOx) in a phase 3 multicenter randomized trial in China.
As reported in The Lancet Oncology, Dr. Lin Shen of Peking University Cancer Hospital and Institute in Beijing and colleagues randomized 1,022 patients (median age about 59; about 75% men) from 2012-2017 to adjuvant CapOx, adjuvant SOX, or perioperative-SOX.
The adjuvant CapOx group received eight postoperative cycles of intravenous oxaliplatin 130 mg/m² on day one of each 21 day cycle plus oral capecitabine 1000 mg/m² twice a day. The adjuvant SOX group received eight postoperative cycles of intravenous oxaliplatin 130 mg/m² on day one of each 21 day cycle plus oral S-1 40 mg-60 mg twice a day. The perioperative SOX group received intravenous oxaliplatin 130 mg/m² on day one of each 21 day plus oral S-1 40 mg-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy.
The primary endpoint was three-year disease-free survival, to assess the superiority of perioperative-SOX compared with adjuvant SOX and the non-inferiority (hazard ratio non-inferiority margin of 1.33) of adjuvant SOX compared with adjuvant CapOx.
Three-year disease-free survival was 51.1% in the adjuvant-CapOx group; 56.5% in the adjuvant SOX group; and 59.4% in the perioperative-SOX group.
The hazard ratio was 0.77 for perioperative SOX compared with adjuvant-CapOx and 0.86 for adjuvant SOX compared with adjuvant CapOx.
The most common grade 3-4 adverse event was neutropenia, documented in 12% of the adjuvant CapOx group, 8% of the adjuvant SOX group, and 10% of the perioperative SOX group.
Serious adverse events were reported in seven (3%) patients in the adjuvant CapOx group (two treatment-related); eight (3%) in the adjuvant SOX group (two treatment-related); and seven (2%) in the perioperative SOX group (four treatment-related).
No treatment-related deaths were reported.
The authors conclude, “Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant CapOx…; adjuvant-SOX was non-inferior to adjuvant CapOx in these patients. Perioperative SOX could be considered a new treatment option for patients with locally advanced gastric cancer.”
Dr. Vadim Gushchin, Director of the Peritoneal Surface Malignancy Program at the Institute for Cancer Care at Mercy in Baltimore, noted in an email to Reuters Health that S1 is not available outside of Asia and “its toxicity is too high in European and American patients.”
“The take-home message for me was that the neo-adjuvant approach to treating resectable works better than the adjuvant,” he said. “It reinforces our practice of treating gastric cancer with chemotherapy first (FLOT, for example), followed by surgery, and followed by more chemotherapy. This is one of the standards of care in the Western world.”
Medical oncologist Dr. Peter Ledakis, also of Mercy, believes that SOX won’t be approved by the U.S. Food and Drug Administration “in the foreseeable future.” Furthermore,” he said, “ongoing research in optimizing the management of advanced gastric cancer has been focusing on the development of targeted agents as well utilization of immunotherapy.”
Surgical oncologist Dr. Spiros Hiotis of the Mount Sinai Health System in New York City is more optimistic about the clinical implications of the trial. “The trial establishes new practice patterns in Asia,” which has been slow to adopt perioperative treatment, he told Reuters Health by phone. “This trial is very compelling that perioperative chemotherapy is better in the selected patients.”
The trial itself was “spectacular” in that the authors could accrue a thousand patients with T4 gastric cancer in just five years and conduct the trial “with systematic rules and analyses,” he added. “It’s unlikely that we could ever conduct a trial like this in the U.S. or Europe because of the numbers of patients and the coordination required across hospitals.”
“The non-inferiority finding for SOX-1 versus adjuvant CapOx is a good message that I believe will lead to FDA approval,” he concluded.
The study was funded in part by Sanofi-Aventis and Hengrui Pharmaceutical. The authors declared no competing interests.
Dr. Shen did not respond to requests for a comment.
SOURCE: https://bit.ly/2VdY3GM The Lancet Oncology, online July 9, 2021.
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