S-1 chemotherapy for pancreatic cancer extends overall survival in Japan

Last Updated: 2016-06-08

By Larry Hand

NEW YORK (Reuters Health) - Adjuvant S-1 chemotherapy may become a new standard care for resected pancreatic cancer patients in Japan, after a randomized trial showed it to be not only noninferior but superior to gemcitabine.

"The results of our trial were surprising to me, because our initial hypothesis was noninferiority of S-1, as described in the paper," Dr. Narikazu Boku of the National Cancer Center Hospital in Tokyo told Reuters Health by email.

Dr. Boku and colleagues conducted an open-label phase 3 trial at 33 hospitals in Japan. Between 2007 and 2010, they randomized patients 20 years or older with histologically proven invasive ductal carcinoma of the pancreas to either gemcitabine 1,000 mg/m2 intravenously or S-1 40 mg, 50 mg, or 60 mg.

S-1 is a combination of tegafur, gimeracil and oteracil developed by Taiho Pharmaceutical, which helped fund the study.

The team administered gemcitabine on days 1, 8, and 15 every four weeks for up to six cycles and S-1 orally twice a day according to body surface area for 28 days, followed by 14 days of rest every six weeks for up to four cycles.

In total, 195 patients were assigned to gemcitabine and 192 to S-1. The analysis, published online June 2 in The Lancet, covered 190 gemcitabine patients and 187 S-1 patients.

On September 15, 2012, the researchers discontinued the study, "because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been discontinued."

The hazard ratio for mortality was 0.57 (p<0.0001 for both noninferiority and superiority). Five-year overall survival came to 24.4% for the gemcitabine group and 44.1% for the S-1 group.

The researchers observed grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase more frequently in the gemcitabine group and stomatitis and diarrhea more frequently in the S-1 group.

A limitation of the study was that all patients were Asian residents of Japan, the researchers note. However, Dr. Boku thinks the results could be generalizable under certain conditions.

"Because the toxicity of S-1 depends on the duration of S-1 administration, there is much room to modify the method of S-1 administration to Western patients such as two weeks on, one week off. The usual method in Japan is four weeks on and one week off, as described in the paper. If the optimal dose and schedule of S-1 for Western patients is used, I believe that our results can be generalized to Western patients," he said.

"Doctors in the U.S. do not seem to like S-1. It's a pity for me," he said. "We made much effort to find the optimal dose and schedule of S-1 for Japanese patients. I hope that U.S. doctors are interested in S-1 and do their best for better clinical outcomes."

Dr. Andrew H. Ko, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, writes in an accompanying comment, "Undoubtedly, this study sets a new benchmark for success in the design of future clinical trials assessing novel adjuvant treatments in pancreatic cancer and changes the present standard of care (for Japan)."

However, he says, "The question of whether S-1 could be a worldwide game-changer for the adjuvant treatment of pancreatic cancer remains unresolved. Because this drug has not been approved in many high income countries, including the USA, market forces and practical considerations might have important roles in determining whether a much needed prospective trial ever comes to pass formally assessing S-1 in non-Asian patients for this specific disease indication."

"Especially because researchers have now been able to classify pancreatic cancer into different molecular subgroups with potential therapeutic implications, we are hopefully getting closer to the reality of finally bringing pancreatic cancer treatment into the modern era of precision medicine," he concludes.

The Pharma Valley Center, the Shizuoka Industrial Foundation, and Taiho Pharmaceutical funded the trial. Dr. Boku reported financial ties to Taiho, as did several co-authors.

SOURCE: http://bit.ly/1Um6GkW and http://bit.ly/25HpeUD

Lancet 2016.