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Gastric Cancer: Oral Fluoropyrimidine S-1, Good Standard Therapy in Japan, But Not At Least As Yet in US

Victorian, Brande

doi: 10.1097/01.COT.0000326180.88335.86

NEW YORK CITY—Oral fluoropyrimidine S-1, most widely used against advanced gastric cancer in Japan, is effective as a new standard therapy for patients with advanced and postoperative gastric cancer, according to research discussed here at the Chemotherapy Foundation Symposium by Wasaburo Koizumi, MD, of Kitasato University in Japan, who presented data from three Phase III trials demonstrating the benefits of S-1 compared with current therapies. Researchers in the United States, however, are hesitant to replace the current standard of fluorouracil (5-FU).

Dr. Koizumi began with the recently published ACTS-GC (Adjuvant Chemotherapy of TS-1 for Gastric Cancer) trial, published in the November 1 issue of the New England Journal of Medicine (2007;357:1810–1820), which evaluated the survival of curatively resected gastric cancer patients receiving chemotherapy versus surgery. A total of 1,059 patients were randomized to receive surgery alone or surgery followed by adjuvant chemotherapy with S-1 every six weeks for one year.

The three-year overall survival for the S-1 group was 80%, compared with 70% for the patients receiving surgery alone. The three-year relapse-free survival for the S-1 patients was higher as well, 72%, compared with 60% in the surgery-alone group.

Relapse-free and overall survival were significantly longer in the S-1 group, Dr. Koizumi said, and shows that “postoperative adjuvant chemotherapy with S-1 for gastric cancer is safe and highly effective.”

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In the Japan Clinical Oncology Group 9912 trial, reported at the most recent ASCO Annual Meeting as a late-breaking abstract, Dr. Koizumi and his team studied the superiority of irinotecan plus cisplatin (CPT-11 + CDDP) and the non-inferiority of S-1, compared with 5-FU in the overall survival of 704 randomized patients with unresectable or recurrent gastric adenocarcinoma.

The median survival time for the 5-FU group was 10.8 months; for the S-1 group, 11.4 months; and for the CPT-11 + CDDP group, 12.3 months.

Dr. Koizumi said that S-1 should be regarded as standard therapy for both unresectable and postoperative patients with gastric cancer, adding that in this study S-1 showed a significant non-inferiority to 5-FU, which was associated with milder toxicity and longer unhospitalized survival.

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Several Differences between Japan & US

However, asked for his opinion for this article, Manish Shah, MD, a gastric cancer specialist at Memorial Sloan-Kettering Cancer Center, said he is not convinced that S-1 provides superior benefit over 5-FU, which combined with radiation, is the standard treatment in the United States, he noted.

“Disease in Japan might be a little bit different than the disease here in the United States. The survival is a little bit different, surgery is a little bit different, and the dose of S-1 that is given is different,” Dr. Shah said in a telephone interview following the symposium. “People in the United States or in western countries can't tolerate the full dose of S-1, because we metabolize it differently.”

Although the results of this trial are encouraging, he added, he doesn't foresee S-1 replacing 5-FU just yet.

Given that S-1 was found to be non-inferior to 5-FU, Dr. Koizumi and fellow colleagues began looking at superior S-1 therapies. In the SPIRITS trial, (S-1 Plus cisplatin vs S-1 In a Randomized controlled trial In the Treatment of Stomach cancer), also reported at the 2007 ASCO Annual Meeting, S-1 was compared with a combination of S-1 and cisplatin.



The study included 305 participants who were randomized to receive either the S-1 monotherapy or combined treatment. The overall response rate in the S-1 group was 31%, compared with 54% in the S-1 plus cisplatin group; and median survival time in the S-1-alone group was 11 months, versus 13 months for patients receiving the combined therapy.

The one- and two-year survival times also differed significantly, the study showed. The one-year survival rate for the S-1 group was 47%; two-year survival was 15%. In the combination group, the one-year and two-year survival rates were 54% and 24%, respectively. Patients in the S-1 group had a progression-free survival time of four months, versus six months in the combination group.

These results show that S-1 combined with cisplatin is superior to S-1 alone, Dr. Koizumi said, adding that this combined approach is well tolerated and that no treatment-related death was observed in these patients, making the therapy a good candidate as a first-line standard treatment for advanced gastric cancer.

The study also showed the superiority of these results over those of recent Phase III trials investigating the benefits of other mono-therapies and combination treatments for advanced gastric cancer.

“The first Phase III trials of advanced gastric cancer show promising results,” Dr. Koizumi said, displaying his comparative chart. “But none of these trials demonstrated survival for more than one year; in the SPIRITS trial, median survival was more than one year in the S-1-plus-cisplatin arm.”

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Convenience of Being Oral Drug

Again, Dr. Shah, who is currently involved in a Phase I trial at Memorial-Sloan that is combining S-1 with oxaliplatin, said he is hesitant to call these results a breakthrough: “S-1 is just an oral form of a drug we've been using for 30 years,” he said, adding that the convenience of an oral medication is what makes the drug attractive.

“It [S-1] may be a better drug, but right now we don't know that. Right now we have to assume that it's equivalent to 5-FU.”

Now underway is the global Phase III FLAGS (First-Line Advanced Gastric cancer Study) involving approximately 1,050 patients in 24 countries. The trial, with the primary endpoint of overall survival, will compare the combined treatment of S-1 and cisplatin with the combination of 5-FU and cisplatin in patients with locally or advanced metastatic gastric cancer whose disease is unresectable and who have had no prior chemotherapy.

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