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Gastric cancer is the second-leading cause of cancer-related death worldwide and a leading cause of cancer-related mortality in Japan. In the U.S., treatment with postoperative 5-fluorouracil (5-FU), leucovorin, and radiation therapy lengthens survival compared with surgery alone. Despite adoption of this therapy regimen as the standard of care after gastric resection, it has substantial toxicity and is complex to administer; in addition, many patients do not recover sufficiently after gastric resection to tolerate such therapy. In the recent MAGIC trial from the U.K., investigators questioned the role of radiation therapy, because a survival benefit was achieved in gastric cancer patients who received pre- and postoperative chemotherapy with epirubicin, cisplatin, and 5-FU (ECF), without radiation therapy. An added controversy is whether surgical resections performed in the U.S. are adequate (most fail to meet minimum requirements of D1 or D2 lymph node resection; i.e., removing ≥15 lymph nodes).
Investigators from Japan now report the results of a multicenter trial of S-1–based adjuvant chemotherapy in patients who underwent gastric resection. S-1 combines the oral 5-FU prodrug tegafur with oteracil (which lowers bowel toxicity) and gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which prevents degradation of 5-FU and permits oral bioavailability of the agent). More than 1000 patients with stage II or III cancer and D2 resections were assigned randomly to S-1 or to observation. S-1–assigned patients received two doses of S-1 daily (40 mg/m2) for 4 consecutive weeks, followed by 2 weeks without S-1, for a total of 12 months. The treatment arms were balanced for pathologic stage and other pretreatment characteristics. Half the patients had stage II disease; 45% had T3–T4 disease; and 90% had node-positive disease.
The primary endpoint of the trial was overall survival. After the first interim analysis at a median follow-up of 2 years, significant survival differences prompted early reporting of the trial outcome. Adjuvant S-1 therapy, versus surgery alone, significantly lengthened overall survival: 26% of S-1 patients experienced death or recurrence, compared with 38% of surgery-alone patients (hazard ratio for death, 0.68; 95% confidence interval, 0.52–0.87; P=0.003). The 3-year overall survival rate was 80% in the S-1 group and 70% in the surgery-only group. HR for recurrence in the S-1 group was 0.62 (95% CI, 0.50–0.77; P<0.001). Seventy-eight percent of patients completed at least 6 months of therapy, and 71% completed all 12 months. Therapy was tolerated well, with grade 3 or 4 adverse events occurring rarely (e.g., anorexia in 6%, nausea in 4%, diarrhea in 3%).
Sakuramoto S et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007 Nov 1; 357:1810.
Comment
The positive results for adjuvant S-1 therapy are a landmark in the treatment of gastric cancer. This large, powerful, well-designed trial showed a significant survival benefit in a population who underwent optimal surgical resection and essentially ends the argument that more-extensive gastric resection would negate the benefit of adjuvant therapy. Although patients in this Asian trial tended to have less-advanced cancers than do most Western patients, a significant survival benefit was observed in all stage subgroups that were analyzed. Furthermore, longer survival was achieved with a single oral chemotherapy agent, which was tolerated well and was easy to administer.
Given that gastric cancer occurs largely in developed countries where delivery of oral adjuvant therapy is feasible, these results have substantial implications about the benefits of such therapy, although they also raise two important questions: Is monotherapy with oral S-1 adjuvant chemotherapy (similar to the U.S. practice of using 5-FU and leucovorin) as beneficial as the potentially more toxic and cumbersome combination of ECF (the U.K. practice)? And, given the survival benefits achieved with chemotherapy alone, is radiotherapy required? The relative merit of 5-FU versus ECF as adjuvant chemotherapy is being addressed in the U.S. CALGB 80101 Intergroup trial, in which patients also are receiving postoperative radiation therapy. However, the actual contribution of radiation therapy can be demonstrated only in a randomized trial in which adjuvant chemotherapy alone is compared with combined chemotherapy and radiotherapy. A final issue is the reportedly greater toxicity of S-1 in Western patients versus Japanese patients, which would necessitate substantially lower dosing of S-1 in the U.S. and Europe. Whether or not S-1 will retain its effectiveness at these lower doses administered to Western patients remains to be established.