Neoadjuvant Chemotherapy for Gastric Cancer: What are we Trying to Accomplish?

Gastric cancer remains the second leading cause of cancer death in the world and is the most common cancer in Japan. Although surgery is the mainstay of curative treatment, even after complete resection, more than half of patients with locally advanced tumors recur, and fewer than 40 % survive beyond 3 years. Accordingly, investigators around the world have explored a variety of adjuvant and neoadjuvant multimodality treatment approaches to this disease. In North America, the standard approach has long been upfront surgery followed by adjuvant chemoradiotherapy based on the findings of the Intergroup 0116 trial, which showed that postoperative 5-fluorouracil (5-FU)/ leucovorin-based chemoradiation increases overall survival compared with surgery alone. However, another standard of care for resectable gastric cancer in North America and Europe emerged with the publication of the MAGIC trial a few years later and the FNCLCC/FFCD multicenter phase III trial a few years after that. The MAGIC trial reported an improvement in overall survival with perioperative epirubicin, cisplatin, and 5-FU (ECF) compared with surgery alone, and the FNCLCC/FFCD trial showed an improved R0 resection rate and survival with perioperative 5-FU and cisplatin. In Japan, the standard approach to patients with T2 N or T3 gastric cancers is upfront surgery with D2 lymphadenectomy followed by 1 year of S-1 chemotherapy, based on the ACTS trial, a large phase III trial demonstrating a significant survival benefit to this approach over surgery alone. Nonetheless, even with adjuvant S-1 chemotherapy, the prognosis of Japanese patients with stage III gastric cancers in particular remains unsatisfactory, and so investigators in Japan recently have been evaluating various regimens of neoadjuvant chemotherapy followed by extended surgery in multiple phase II trials, including one to three courses of S-1 and cisplatin, two to three courses of irinotecan and cisplatin, and two to four courses of paclitaxel and cisplatin. The optimal duration and regimen of neoadjuvant chemotherapy has not yet been established. In this issue, Yoshikawa et al. report the early results of the COMPASS trial, a randomized, multi-institutional phase II trial comparing two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC), followed by surgery and postoperative S-1 chemotherapy, for macroscopically resectable locally advanced gastric cancer. A total of 83 patients were enrolled based on power calculations assuming a 10 % absolute improvement in 3-year overall survival in the four-course PC arm. The primary endpoint of the study is the 3-year overall survival rate, and the secondary endpoints include the clinical and pathologic response rates, chemotherapy-related toxicities, R0 resection rates, and surgical morbidity and mortality. This report summarizes only the early outcomes—that is, these secondary endpoints—because the data are not mature enough to report on the survival outcomes. Unfortunately, the eligibility criteria for this trial included patients with ‘‘resectable minimal peritoneal metastases confirmed by laparoscopy,’’ which is considered M1 (metastatic) disease in all staging systems and not ‘‘locally advanced’’ disease. In fact, 13 (16 %) of the 83 enrolled patients had M1 disease on initial staging as manifested by either gross peritoneal metastases (n = 5) or positive peritoneal cytology (n = 8) and thus did not have a realistic chance for cure at the outset. Accordingly, the 3-year overall survival rates for this trial are likely to be low, and Society of Surgical Oncology 2013