Neoadjuvant and Adjuvant Therapy for Gastric Cancer
Adjuvant Chemoradiotherapy
The INT-0116 (Intergroup 0116) study published in 2001 established adjuvant chemoradiotherapy as the standard approach for resectable gastric cancer in the United States. In this study, a total of 556 patients with resected gastric or GEJ cancer were randomly assigned to surgery alone or surgery followed by adjuvant 5-FU/leucovorin bolus chemotherapy, sandwiched with 5-FU–based chemoradiation (45 Gy).45 In the chemoradiotherapy group, 64% of patients completed treatment and grade 3 and 4 toxicity occurred in 41% and 32%, respectively. However, only 3 patients (1%) died from treatment-related toxicity. At a median follow-up of 5 years, the median overall survival was 36 months in the chemoradiation group and 27 months in the surgery group. Overall survival rate was 50% in the combined modality group and 41% in the surgery-alone group, with a HR of 1.35 (95% CI 1.09 to 1.66, P = 0.005). The 3-year DFS was 48% in the chemoradiotherapy group and 31% in the surgery-alone group, corresponding to a DFS of 30 months and 19 months, respectively. Even after a median follow-up of 10 years, these positive results were maintained, with a HR for survival of 1.32 (95% CI 1.10 to 1.60, P = 0.0046) and HR for DFS of 1.51 (95% CI 1.25 to 1.83, P < 0.001).46 A criticism of the INT-0116 study is that 54% of patients had less than a D1 lymph node dissection, suggesting that adjuvant chemoradiation may have compensated for suboptimal surgery.
CALGB 80101, a United States Intergroup study, compared the INT-0116 protocol regimen (bolus 5-FU/leucovorin with 5-FU plus concurrent radiotherapy) to postoperative ECF sandwiched with 5-FU plus concurrent radiotherapy.47 The study included patients with resected gastric or GEJ adenocarcinoma that extended beyond the muscularis propria or was node positive. The percentage of patients with gastric versus GEJ cancer was not reported. A total of 546 patients were randomized. Preliminary results were presented at the 2011 American Society of Clinical Oncology meeting. The ECF arm had lower rates of grade 3/4 toxicities, including neutropenia, diarrhea, and mucositis. However, there was no difference in overall survival (3-year overall survival of 52% versus 50% for ECF and 5-FU/leucovorin, respectively) or DFS (3-year DFS of 47% versus 46% for ECF and 5-FU/leucovorin, respectively). The trial was not adequately powered to assess noninferiority. The location of the primary tumor (GEJ versus proximal versus distal stomach) did not have any effect on treatment outcome.
,The Adjuvant Chemoradiation Therapy in Stomach Cancer (ARTIST) trial was the first study to compare adjuvant chemoradiotherapy with adjuvant chemotherapy in patients with D2-resected gastric cancer.48 A total of 458 patients were randomly assigned to 6 cycles of XP chemotherapy (capecitabine 2000 mg/m2 per day on days 1–14 and cisplatin 60 mg/m2 on day 1, every 3 weeks) or XP/radiotherapy/XP (2 cycles of XP followed by 45 Gy radiotherapy with concurrent daily capecitabine [825 mg/m2 twice daily] and 2 cycles of XP). After a median follow-up of 84 months, there was no difference in DFS or overall survival between treatment arms (HR for progression 0.74 [95% CI 0.52 to 1.05], P = 0.09; HR for death 1.13 [95% CI 0.78 to 1.65], P = 0.53).49 However, subgroup analysis showed that chemoradiotherapy significantly improved DFS in patients with node-positive disease (3-year DFS 76% versus 72%, P = 0.004).
Adjuvant Chemotherapy
Data supporting the use of adjuvant chemotherapy alone is largely derived from trials done in Asia, typically after a D2 lymph node dissection, and thus adjuvant chemotherapy has become the standard of care in that region. In the Japanese Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC), a total of 1059 patients with stage II or III gastric cancer who had undergone surgery with a D2 lymphadenectomy were randomly assigned to 1 year of S-1 (an oral fluoropyrimidine) or surgery alone.50 The 5-year overall survival rate was 72% in the S-1 group and 61% in the surgery-only group (HR 0.669 [95% CI 0.54 to 0.83]).51 The 5-year relapse-free survival was 65% in the S-1 group and 53% in the surgery-only group (HR 0.65 [95% CI 0.537 to 0.793]). Of note, both arms of the ACTS-GC trial had significantly higher 5-year overall survival rates compared to the INT-0116 and MAGIC trials: 43% versus 28% and 36% versus 23% for the treatment and control groups, respectively.42,45 Consequently, it is unclear if the benefit of adjuvant chemotherapy can be translated to Western countries.
The Korean Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) trial published in 2012 also established the role of adjuvant chemotherapy after D2 gastrectomy.52 A total of 1035 patients with stage II-IIIB gastric cancer who had curative D2 gastrectomy were randomly assigned to 8 cycles of adjuvant XELOX (capecitabine 1000 mg/m2 twice daily on days 1–14 plus oxaliplatin 130 mg/m2 on day 1, 21-day cycle) or surgery alone. Median follow-up was 34 months in both arms and 67% of patients in the chemotherapy arm completed all 8 cycles of planned chemotherapy. The 3-year DFS was 74% in the chemotherapy group and 59% in the surgery-only group (HR 0.56 [95% CI 0.44 to 0.72], P < 0.0001). There was a trend toward improvement in overall survival (83% versus 78%, HR 0.72 [95% CI 0.52 to 1.00]). After 5 years of follow-up, the improvement in overall survival became statistically significant (78% versus 69%, HR 0.66 [95% CI 0.51 to 0.85]).53
The benefit of adjuvant chemotherapy was reinforced by a 2010 meta-analysis comparing adjuvant chemotherapy to surgery alone in patients with resected gastric cancer.54 A total of 17 randomized controlled trials were included. Adjuvant fluorouracil-based chemotherapy was associated with a statistically significant improved overall survival (HR 0.82 [95% CI 0.76 to 0.90], P < 0.001) and DFS (HR 0.82 [95% CI 0.75 to 0.90], P < 0.001). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy.
