February 8, 2012 — In patients with operable gastric cancer, adjuvant chemotherapy with capecitabine and oxaliplatin "should be considered a new treatment option," according to Asian investigators.
In a phase 3 trial, they found that a 6-month course of this chemotherapy combination after D2 gastrectomy improved 3-year disease-free survival, compared with the surgery alone (74% vs 59%; hazard ratio, 0.56; P < .0001)
However, the benefit was accompanied by a high rate of grade 3 or 4 adverse events (56%) in patients receiving the chemotherapy. The study of 1035 patients with stage II to IIIB gastric cancer was undertaken at 37 centers — mostly in South Korea — and is known as the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC).
CLASSIC has been stopped because of the benefit shown. The results from a prespecified interim efficacy analysis were published in the January 28 issue of the Lancet.
These findings "could be highly relevant for, and might be generalizable to, other regions when D2 surgery is done by experienced surgeons," write the study authors, led by Yung-Jue Bang, MD, from Seoul National University College of Medicine in South Korea.
However, in an accompanying editorial, an expert from Japan casts some doubt on the generalizability of the findings.
"In Asia, we now have 2 options available for adjuvant treatment," writes Toshirou Nishida, MD, from Osaka Police Hospital. The 2 options are the combination of capecitabine plus oxaliplatin and oral fluoropyrimidine S-1, which has been studied in this setting in the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC).
Dr. Nishida, who avoids saying that non-Asian countries also now have 2 options, suggests that a patient's country is of great importance in gastric cancer treatment.
"Adjuvant therapy is used to eradicate potential micrometastases after curative surgery and, therefore, therapeutic strategies vary dependent on anticipated locoregional disease control after surgery, and by institution and country," he writes.
Dr. Nishida says that, in Asia, D2 gastrectomy is standard, and systemic adjuvant chemotherapy is already "conventional" because of the earlier results from ACTS-GC. In non-Asian countries, D1 surgery is the most common surgery, he says.
The study authors also address the issue of generalizability. They acknowledge that their study population had less advanced disease (T3 and T4 lesions) than gastric cancer study populations in Europe and the United States, and that patients in Western studies have historically had worse outcomes than those in Asia. But the authors suggest that the favorable outcomes in their study are not likely the result of a population with less advanced disease.
"We suggest that the favorable outcomes in our study are a result of the consistent use of D2 surgery and the high quality of that surgery," they write.
And quality D2 surgery can be done outside of Asia, they suggest. After all, D2 gastrectomy is the "standard of care in both Europe and the USA," they write. But the study authors do not address any potential discrepancy between the standard of care and actual care.
Safety and Adherence Matter in Gastric Cancer
In CLASSIC, patients who had undergone curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of 8 three-week cycles of oral capecitabine (1000 mg/m² twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m² on day 1 of each cycle) for 6 months, or surgery only.
The study results generate a simple question, suggests Dr. Nishida: Should patients with operable gastric cancer undergo chemotherapy after surgery?
The answer is not simple, he explains. "Decision making by patients and physicians might be practically dependent on individual perceptions and judgment about recurrent risk, therapeutic burden including adverse events and cost, and benefit from the therapy," Dr. Nishida writes. A "substantial proportion" of patients are cured with surgery alone, he says.
In reviewing CLASSIC, Dr. Nishida highlights adverse events; in the treatment group, these were most commonly nausea (n = 326), neutropenia (n = 300), and decreased appetite (n = 294).
More than half of the patients in CLASSIC treated with capecitabine plus oxaliplatin had grade 3 or 4 adverse events, and nearly 10% withdrew from therapy because of adverse events, Dr. Nishida reports. The total number of patients who withdrew from the treatment group in the study was even greater — 33%.
The overall survival benefit of adjuvant capecitabine plus oxaliplatin is not yet established, says Dr. Nishida. A follow-up of at least 5 years will probably be needed to establish any would-be overall survival benefit, he says.
The study was funded by Hoffmann-La Roche and sanofi-aventis. Dr. Yung-Jue Bang reports acting as a consultant for Hoffmann-La Roche and sanofi-aventis, and receiving honoraria from Hoffman-La Roche. Other coauthors have financial relationships with industry, as detailed in the paper. One coauthor is an employee of Hoffman-La Roche.
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