Neoadjuvant and Adjuvant Therapy for Gastric Cancer
Neoadjuvant chemotherapy has the benefit of “downstaging” locally advanced tumors to allow for curative resection. Phase 2 clinical trials have also demonstrated good pathologic response rates and high R0 resection rates following neoadjuvant chemotherapy.38,39 However, phase 3 trials to support this treatment approach are lacking. In the European Organisation for Research and Treatment of Cancer (EORTC) 40954 trial, patients with stage III or IV gastric or GEJ cancer were randomly assigned to surgery with or without preoperative cisplatin, leucovorin, and infusional fluorouracil (5-FU).40 The trial was stopped early due to poor accrual after 144 patients were randomized. The neoadjuvant chemotherapy arm had a higher R0 resection rate compared to the surgery alone arm (82% versus 67%, respectively, P = 0.036) but a higher postoperative complication rate (27% versus 16%, respectively, P = 0.09). More important, after a median follow-up of 4.4 years, a survival benefit could not be shown, with 2-year survival rates of 72.7% and 69.9% in the neoadjuvant and surgery-only arms, respectively (HR 0.84 [95% CI 0.52 to 1.35], P = 0.466). Due to the lack of large trials, a meta-analysis assessing the effectiveness of neoadjuvant chemotherapy combined with surgery versus surgery alone in advanced gastric and gastroesophageal cancer was performed.41 The analysis included 12 randomized controlled trials with a total of 1820 patients. Neoadjuvant chemotherapy was shown to slightly improve the survival rate (odds ratio [OR] 1.32 [95% CI 1.07 to 1.64], P = 0.01). It significantly improved the 3-year progression-free survival (PFS; OR 1.85 [95% CI 1.39 to 2.46], P < 0.0001), tumor down-staging rate (OR 1.71 [95% CI 1.26 to 2.33], P = 0.0006), and R0 resection rate (OR 1.38 [95% CI 1.08 to 1.78], P = 0.01). There were no differences between the 2 arms in terms of relapse rates, operative complications, perioperative mortality, and grade 3/4 adverse effects. While these results are encouraging, further randomized clinical trials are needed to clarify the role of neoadjuvant chemotherapy and its impact on overall survival.
Perioperative Chemotherapy
,The results of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial published in 2006 established perioperative chemotherapy as standard of care in patients with resectable gastric and gastroesophageal adenocarcinoma.42 A total of 503 patients with potentially resectable gastric and lower esophageal adenocarcinoma were randomly assigned to perioperative chemotherapy plus surgery or surgery alone. Perioperative chemotherapy consisted of 3 preoperative and postoperative cycles of epirubicin, cisplatin, and infusional 5-FU (ECF). At a median follow-up of 4 years, the perioperative-chemotherapy group had a significantly better PFS (HR 0.66 [95% CI 0.53 to 0.81], P < 0.001) as well as overall survival (HR 0.75 [95% CI 0.60 to 0.93], P = 0.009). The 5-year overall survival rate was 36.3% in the perioperative chemotherapy group and 23% in the surgery group. Of note, there was a greater proportion of stage T1/T2 tumors (52% versus 37%, P = 0.002) and N0/N1 disease (84% versus 71%) in the perioperative-chemotherapy group compared to the surgery alone group. In addition, only 42% of patients in the perioperative chemotherapy group completed all 6 cycles of chemotherapy.
The administration of ECF is often difficult since the 5-FU component requires a central venous access device and an ambulatory infusion pump and the cisplatin component is associated with nephrotoxicity and ototoxicity. The REAL-2 trial was a randomized phase 3 clinical trial that assessed whether 5-FU could be replaced by capecitabine and cisplatin by oxaliplatin in the ECF regimen.43 Between June 2000 and May 2005, a total of 1002 patients with locally advanced esophageal/GEJ/gastric cancer were enrolled. Patients were randomly assigned to 1 of 4 triplet therapies: epirubicin and cisplatin plus either 5-FU (ECF) or capecitabine (ECX) or epirubicin and oxaliplatin plus either 5-FU (EOF) or capecitabine (EOX). After a median follow-up of approximately 18 months, the overall survival in the capecitabine groups did not differ significantly from that in the 5-FU groups (HR 0.88 [95% CI 0.77 to 1.00], P = 0.06), nor did overall survival in the oxaliplatin groups differ significantly from that in the cisplatin groups (HR 0.91 [95% CI 0.79 to 1.04], P = 0.16). Interestingly, the 1-year survival rate was longer in the EOX group than in the ECF group (46.8% versus 37.7%, respectively; HR 0.80 [95% CI 0.66 to 0.97], P = 0.02). This translated into an overall survival of 11.2 months for the EOX group and 9.9 months for the ECF group. Therefore, EOX is preferred over ECF in clinical practice.
The French FNLCC/FFCD trial published in 2011 provided further support for perioperative chemotherapy.44 A total of 224 patients with adenocarcinoma of the lower esophagus, GEJ, or stomach were randomly assigned to perioperative chemotherapy plus surgery or surgery alone. The perioperative-chemotherapy group received 2 to 3 cycles of preoperative chemotherapy and 3 to 4 cycles of postoperative chemotherapy, consisting of infusional 5-FU (800 mg/m2 daily for days 1 to 5) and cisplatin (100 mg/m2 on day 1). In patients receiving preoperative chemotherapy, 38% experienced at least grade 3 to 4 toxicity. Among the 109 patients who received at least 1 cycle of preoperative chemotherapy, only 54 patients (50%) received postoperative chemotherapy. Despite this, the perioperative-chemotherapy group had a statistically significant higher R0 resection rate (84% versus 74%, P = 0.04) compared to the surgery alone group. At a median follow-up of 5.7 years, the perioperative chemotherapy group had an improved overall survival (HR for death 0.69 [95% CI 0.50 to 0.95], P = 0.02) and disease-free survival (DFS; HR for recurrence or death 0.65 [95% CI 0.48 to 0.89], P = 0.003). This translated into 5-year overall survival rates of 38% versus 24% and 5-year DFS rates of 34% versus 19%. One caveat to this study is that the majority of patients (64%) had GEJ cancer and only 25% had gastric cancer. In the multivariate analysis, the 2 significant prognostic factors for overall survival were the administration of preoperative chemotherapy (P = 0.01) and tumor site at the GEJ (P < 0.01).
