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A combination of cisplatin and the oral fluoropyrimidine, S-1, is superior to S-1 alone in the treatment of patients with advanced gastric cancer, Dr. Hiroyuki Narahara reported.
Phase III results of the multicenter SPIRITS trial showed that the combination had statistically significant advantages in terms of median survival, progression-free survival, and time to treatment failure, compared with S-1 alone, said Dr. Narahara, professor in the department of clinical oncology, Hiroshima University in Japan.
S-1, which is not approved in the United States but is widely used for advanced gastric cancer in Japan, is an oral formulation of Tegafur, 5 chloro-2,4-dihydroxypyridine and potassium oxonate which has shown good antitumor activity and low GI toxicity as both monotherapy and in combination with other anticancer agents.
At a median follow-up of 35 months, the median survival time was 11 months for the S-1 arm and 13 months in the combination arm. In addition, S-1 plus cisplatin was well tolerated, and no treatment-related deaths were observed.
In this trial of 298 evaluable patients, those in the S-1-only arm received the drug at a dose of 40 mg to 60 mg twice daily for 4 weeks with a 2-week rest, while patients in the combination arm received S-1 for 3 weeks followed by a 2-week rest. Cisplatin was administered intravenously on day 8 at 60 mg/m².
Patients had histologically confirmed gastric adenocarcinoma, had no prior chemotherapy, were expected to survive at least 3 months, and ranged in age from 20 to 74 years with a median of 62 years. About three-fourths of patients (237 patients) had unresectable disease, while the remainder (61 patients) had recurrent disease.
In the S-1-only arm, 1- and 2-year survival rates were 46.7% and 15.3%, respectively; in the S-1 plus cisplatin arm, the 1- and 2-year survival rates were 54.1% and 23.6%. Both differences were statistically significant.
Progression-free survival for 150 patients in the single-therapy arm was 4 months, and 6 months for 148 patients in the combination arm.
"The survival curve of S-1 plus cisplatin was clearly above that of S-1 alone," he said, adding that overall response in the two arms was 54% for s-1 plus cisplatin and 31% for S-1 alone. Although both regimens were generally well tolerated, grade 3-4 hematologic drug reactions occurred more frequently in the S-1 plus cisplatin arm, with a 59% rate of grade 3-4 neutropenia and a 38% rate of anemia. Anorexia and nausea also were concentrated in the combination arm.
In discussing the SPIRITS study, Dr. Robert J. Mayer said the results are encouraging and provocative but need to be confirmed by the large, international study that is now underway.
"I was very surprised when I read the data from the two Japanese S-1 trials presented at this meeting, and the drug gets more interesting as I read more about it," said Dr. Mayer of the Dana Farber Cancer Institute, Boston.
"S-1 averts a lot of the side effects that we see with capcitabine, so I think it's a winner and is even better when combined with cisplatin," he said. These results may not translate to populations outside Japan, where the biology of gastric cancer may differ. Asian and Caucasian individuals have different activation rates of Tegafur to 5FU, and early research suggests Westerners may respond better to a 25-mg dose of S-1 than the 40-mg dose used in Japan.
Narahara H. et al. Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer, Abstract 4514.