Adjuvant therapy for gastric cancer: revisiting the past to clarify the future.

The initial publication in 2001 of the Intergroup trial 0116 (INT0116) was a watershed moment in the treatment of gastric and gastroesophageal junction adenocarcinoma, offering the first high-level evidence for improved survival from any adjuvant therapy in gastric cancer. Since that time, however, the evolution of adjuvant therapy for gastric cancer has been far from linear. No adjuvant regimen has definitively supplanted fluorouracil-based chemoradiotherapy, although alternative approaches have proliferated without direct comparison to the approach established by INT-0116. Five years after the initial publication of INT-0116, the British MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy Trial) trial demonstrated the superiority of epirubicin, cisplatin, and fluorouracil (ECF) administered before and after surgical resection when compared with surgery alone. Despite the omission of radiotherapy, perioperative ECF conferred a statistically and clinically significant reduction in death and cancer recurrence, establishing perioperative chemotherapy, without radiation therapy, as an alternative, reasonable standard in the adjuvant treatment of gastric cancer. More recently, clinical trials from Asia demonstrate the efficacy of adjuvant chemotherapy alone after curative resection for gastric cancer. Among 1,059 patients with resected gastric cancer, the Japanese ACTS-GC (Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer) study demonstrated a 33% improvement in overall survival (OS) for patients receiving 1 year of postoperative adjuvant S-1, an oral fluoropyrimidine not commercially available in the United States, when compared with surgery alone. Among 1,035 resected gastric cancer patients in South Korea, Japan, and Taiwan, the CLASSIC (Adjuvant Capecitabine and Oxaliplatin for Gastric Cancer After D2 Gastrectomy) study reported a 44% improvement in diseasefree survival (DFS) for patients randomly assigned to postoperative capecitabine and oxaliplatin (XELOX) when compared with observation. Of note, both ACTS-GC and CLASSIC limited enrollment to patients who had undergone a D2 lymph node dissection, commonplace in Asia, which contrasts to the limited D0 or D1 dissections more widespread in the United States. As such, the generalizability of both the ACTS-GC and CLASSIC trials to patients undergoing a D0 or D1 dissection is less certain. Moreover, the striking epidemiologic and prognostic differences in gastric cancer between Asian and Western populations further confound the application of these well-conducted Asian trials to Western patient populations. With a growing body of evidence supporting adjuvant approaches in resectable gastric cancer, it becomes critical to establish the relative contribution of individual components of adjuvant therapy. Two recently completed trials have directly compared distinct postoperative adjuvant regimens. Among 458 South Korean patients who had undergone a curative gastrectomy with D2 dissection, the ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial compared postoperative capecitabine and cisplatin (XP) to chemoradiotherapy (XP plus radiotherapy with capecitabine). Although the addition of radiotherapy to postoperative chemotherapy did not significantly improve DFS among all enrolled subjects (P .09), patients with node-positive disease (87% of the study population) did experience a superior DFS (P .04). On the other end of the spectrum, the North American Cancer and Leukemia Group B 80101 trial examined whether the benefit of postoperative chemoradiotherapy with fluorouracil and leucovorin (as shown in INT-0116) could be improved by utilizing a more intensive systemic therapy (ECF) with chemoradiotherapy. Interim results, however, find no survival benefit when comparing postoperative ECF chemotherapy before and after chemoradiotherapy to fluorouracil and leucovorin before and after chemoradiotherapy. Into this maelstrom of clinical reports, the INT-0116 investigators offer another critical contribution, featured in this issue of Journal of Clinical Oncology. The investigators report an updated analysis of their findings, now with 10-year median follow-up. Eleven years after the initial publication, is there more that we can learn from INT-0116 today? And, with half a dozen key trials reported since that initial publication, can we improve our understanding of adjuvant therapy in gastric cancer by going back to square one? The report by Smalley et al updates OS and recurrence-free survival (RFS) for the INT-0116 trial. It is reassuring to find that these survival outcomes are largely unchanged, with significant benefits in both OS and RFS. This finding perhaps comes as no surprise, given that the median survival time in both arms had been well surpassed at the time of the original report. Nevertheless, this latest update highlights the durable benefit of postoperative fluorouracil-based chemoradiotherapy in patients with resected gastric and gastroesophageal junction adenocarcinoma. Longer follow-up to confirm the results of a previously reported landmark clinical trial has certain merit in medical science. Beyond supplying confirmatory updated results of the primary treatment hypothesis, completed clinical trials can represent exceptional, well-designed prospective cohorts with detailed clinical data and biospecimens to explore critical questions that arise in the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 19 JULY 1 2012