'Incredibly Promising' Adjuvant Agent for Pancreatic Cancer

Adjuvant chemotherapy with the oral agent known as S-1 (Taiho Pharmaceutical) significantly increased overall survival in pancreatic cancer patients compared with gemcitabine, which is the current post-surgery treatment standard, according to a Japanese study.

The results are practice changing, said lead author Katsuhiko Uesaka, MD, PhD, medical deputy director at Shizuoka Cancer Center, Shizuoka, Japan.

"S-1 may be considered as the new standard treatment for resected pancreatic cancer patients," he said at a presscast today, held by the American Society of Clinical Oncology (ASCO) in advance of the 2013 Gastrointestinal Cancers Symposium, January 24 through 26, in San Francisco.

However, the implications of the study, which only involved Japanese patients, may be limited to Asian populations.

Dr. Uesaka said other studies have shown that, in white people, diarrhea related to S-1 treatment was problematic. Additional studies are needed, in which adjustments in dose and schedule might rectify this adverse event, he added.

In the current study, the investigators randomized 385 patients with stages I-III pancreatic cancer to postoperative treatment with S-1 or gemcitabine.

The 2-year survival rates were 70% and 53% for S-1 and gemcitabine, respectively, in an interim analysis (scheduled after 180 deaths; P < .0001 for superiority). This translated to 44% lower risk for death for the S1 patients compared with the gemcitabine patients.

Relapse rates were also better in the S-1 arm. The 2-year relapse-free survival rates were 49% and 29% for S-1 and gemcitabine, respectively.

The investigators will continue to follow the study participants for at least 5 years.

An expert agreed that S-1 can potentially change current practice. "For the first time, we now have another option…and it appears superior," said Neal J. Meropol, MD, who moderated the presscast. He is from the Case Western Reserve University School of Medicine in Cleveland, Ohio.

Dr. Meropol pointed out that, although most pancreatic cancer is detected at an advanced, inoperable stage, an estimated one-third of patients worldwide are eligible for surgery and adjuvant chemotherapy. "We've viewed gemcitabine as the standard therapy," he commented about adjuvant treatment.

S-1 will need to be further tested in other populations, Dr. Meropol added.

Another expert agreed. A clinical trial to determine the "appropriate use" in this setting is needed in the United States, said Kenneth Yu, MD, of Memorial Sloan-Kettering Cancer Center in New York City, who attended the press conference and provided independent commentary.

Nevertheless, Dr. Yu called the new results from Japan "very impressive" and "incredibly promising."

S-1 is taken orally as a single agent, but has 3 components including tegafur, a prodrug of 5-fluorouracil (5-FU), said Dr Meropol. Thus S-1, once in the blood, is converted into 5-FU, which is a "common chemotherapy" in the West. Dr. Meropol anticipated that S-1 will be licensed for use in the United States. S-1 is currently available in several Asian countries and most of Europe, but is not yet approved in the United States, according to ASCO press materials.

Better Tolerated

The study enrolled patients from 2007 to 2010 with histologically confirmed ductal adenocarcinoma of the pancreas, R0 or R1 resection, and pathological stage I, II, or III with resection of the celiac axis. They had no prior chemotherapy or radiotherapy within 3 years and adequate organ functions.

Patients received either gemcitabine (1000 mg/m² by drip intravenous infusion on days 1, 8, and 15, repeated every 4 weeks, for 6 courses) or S-1 (40 to 60 mg, according to the body surface, twice a day, for 4 weeks, repeated every 6 weeks, for 4 courses).

S-1 was well tolerated, with over 70% of the 187 patients in the arm completing the therapy, according to ASCO press materials.

Treatment discontinuation favored S-1. The reasons for stopping the drug were recurrence/toxicity/patient's refusal/others and occurred in 27/48/5/2 of patients in the gemcitabine arm and 9/40/3/0 of patients in the S-1 arm.

Incidences of grade 3/4 toxicities also, on the whole, favored S-1.

Grade ¾ toxicity	Gemcitabine (%)	S-1 (%)
fatigue	4.7	5.4
anorexia	5.8	8.0
leukopenia	38.7	8.6
thrombocytopenia	9.4	4.3
anemia	17.3	13.4
elevated AST	5.2	1.1

The drug was so successful that the study's safety and efficacy committee recommended early reporting of the results to speed adoption of S-1 as the new standard in Japan, Dr. Uesaka said.

The results of the study, known as the Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC) 01 trial, build upon earlier trials, he added.

A previous study in patients with unresectable pancreatic cancer showed that outcomes with S-1 were not inferior to outcomes with gemcitabine. The study, known as the GEST trial, positioned S-1 as a treatment option for advanced disease patients in Japan, Dr. Uesaka said.

S-1 is currently prescribed in Japan to treat stomach, colorectal, pancreatic, biliary, head and neck, non-small cell lung, and metastatic breast cancer, according to ASCO press materials.

2012 Gastrointestinal Cancers Symposium (GICS): Abstract 145. To be presented January 25, 2013.

Dr. Meropol is a consultant to Precision Therapeutics. Dr. Uesaka reports Honoraria from Taiho Pharmaceutical, Lilly.

The study was partially funded by Taiho Pharmaceutical.