|
The oral fluoropyrimidine S-1 rivals 5-fluorouracil for efficacy in patients with advanced gastric cancer, according to results of a three-armed phase III trial.
Dr. Narikazu Boku reported that patients had longer overall survival, progression-free survival, and time to treatment failure with S-1 than with 5-fluorouracil (5-FU).
The investigators also found a trend favoring irinotecan and cisplatin (CPT-11 + CDDP) over 5-FU in median survival, progression-free survival, time to treatment failure and response rate. Despite slightly better efficacy over 5-FU, severe toxicity led to withdrawal of 32% of the irinotecan-cisplatin cohort vs. less than 10% of the 5-FU and S-1 arms.
Because of its efficacy and safety profile, "S-1 should be considered ... the standard chemotherapy (for) unresectable or recurrent gastric cancer," said Dr. Boku of the Shizuoka (Japan) Cancer Center Hospital.
Noting that no established standard chemotherapy has shown a survival benefit over 5-FU alone in patients with advanced gastric cancer, the researchers designed this trial to test the superiority of cisplatin plus irinotecan and the noninferiority of S-1.
Between November 2000 and January 2006, 701 patients were randomized to receive either single agent 5-FU (800 mg/m² in a 5-day infusion, irinotecan (70 mg/m² on days 1 and 15) plus cisplatin (80 mg/m² on a 4-week cycle); or S-1 (40 mg/m² twice daily for 28 days with a 2-week break).
Patients (average age 63 years) were well-balanced among the three arms and were stratified by performance status, extent of prior therapy, and registering center. Only three patients had received prior adjuvant therapy and the arms had equal proportions of patients with intestinal and diffuse histologies, Dr. Boku said.
The superiority of irinotecan plus cisplatin to 5-FU fell just short of statistical significance (P = .055), while the noninferiority of S-1 to 5-FU had a P value of .001.
"The results with S-1 in this trial are impressive, particularly the 11.4-month median survival achieved with a single agent," said Dr. Robert J. Mayer in his discussion of the paper. He added, however, that it may be premature to anoint S-1 monotherapy as the standard chemotherapy for unresectable or recurrent gastric cancer in large part because of data from the Japanese SPIRITS trial, which was presented in the same oral session. That study, by Dr. Hiroyuki Narahara and colleagues concluded that S-1 combined with cisplatin is superior to S-1 alone in the treatment of advanced gastric cancer.
"Noteworthy in this trial was the finding that the median survival time for all three treatment cohorts was in excess of 10 months," said Dr. Mayer of the Dana-Farber Cancer Institute in Boston. He also underscored the fact that neither the 5-FU 5-day infusion nor the dosage of irinotecan plus cisplatin regimens as given in this trial are quite the same as those commonly used in the United States and Europe.
Taiho Pharmaceutical Co. developed S-1 in Japan, where it is approved for treatment of gastric, colorectal, head and neck, non-small cell lung, metastatic breast, and pancreatic cancers.
Sanofi Aventis is leading the development of S-1 in the United States and in Europe, where S-1 is still in phase III studies.
Dr. Boku and his colleagues reported research support from Taiho Pharmaceutical and Yakult Honsha Co.
Boku N. et al. Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912). Abstract LBA4513.