Adjuvant Chemoradiation

Encouraging effects on local control and survival were demonstrated in early-phase studies that evaluated chemoradiation in patients with localized gastric cancer Table 1 . Based on this, the larger phase 3 US Intergroup 0116 Study randomly assigned 556 patients following curative resection of gastric cancer (stage 1b–IV) to observation alone or adjuvant chemoradiotherapy. Adjuvant treatment consisted of 5 monthly cycles of bolus chemotherapy with 5-fluorouracil (5-FU) and leucovorin daily for 5 days with radiotherapy given concurrently with cycles 2 and 3 ( Table 1 ).

After 5 years of follow-up, the median overall survival was significantly longer after chemoradiation than after surgery alone (36 months vs 27 months; P = .005), and a marked benefit was also seen in progression-free survival (hazard ratio [HR] 1.52; 95% confidence interval [CI] 1.23–1.86; P <.001). Updated results with more than 10-year median follow-up also demonstrated continued benefit from the chemoradiation with overall survival (HR = 1.32; P = .004) and disease-free survival (HR 1.51; P <.001) favoring chemoradiation. Although this trial led to adjuvant chemoradiation being adopted as a standard therapy for patients with curatively resected gastric cancer in the United States, it has not gained worldwide acceptance because of concerns about the quality of surgery used and the toxicity of abdominal chemoradiation. In both arms the patients had high risk of relapse following surgery (more than two-thirds of patients had T3 or T4 tumors and 85% had positive lymph nodes), but most patients had what is considered a suboptimal surgery (54% had only D0 resection). The effects of the inadequate surgery were probably counterbalanced by adjuvant treatment in the chemoradiation arm, although in an update in 2004 no difference in treatment effect by the level of surgery performed was reported.

The recently presented CALGB 80101 trial assessed the benefit of using combination chemotherapy with epirubicin, cisplatin, and 5-FU (ECF) with postoperative chemoradiation in patients with resected adenocarcinoma of the stomach or GOJ. No benefit was demonstrated with the use of ECF chemotherapy before and after 5-FU chemoradiation in comparison with bolus 5-FU/leucovorin given before and after 5-FU/radiotherapy. However, this trial used only one cycle of full-dose ECF regimen before chemoradiation and 2 cycles of dose-attenuated ECF were given post chemoradiation, thereby making it difficult to draw any conclusions regarding the benefit or lack of benefit from the addition of triplet chemotherapy. Of interest, the median 3-year survival in the CALGB study was almost identical to that of the Intergroup 0116 ¹³ trial, which was conducted more than 10 years ago. At present, quality control data for surgery are not available to assess the quality of surgery, which was the subject of much criticism of the Intergroup 0116 ¹³ trial.

Whether adjuvant radiation is beneficial after optimal gastric surgery (D2 resection or higher) has been a matter of great controversy. In retrospective analyses, a benefit from adjuvant chemoradiation after surgery, and even after D2 resection, has been suggested. The role of adjuvant radiation after D2 resection will be evaluated prospectively by the randomized phase 3 Korean ARTIST study, which recently completed accrual of 458 patients after surgery to adjuvant cisplatin and capecitabine or cisplatin/capecitabine chemoradiation (see Table 2 ). Also, the ongoing phase 3 CRITICS trial will evaluate the benefits of adding postoperative chemoradiation to perioperative ECX (epirubicin, cisplatin, capecitabine) combination chemotherapy. Nevertheless, at present postoperative chemoradiation remains one of the standard options for treatment of patients with curatively resected gastric cancer, and is widely used in the United States.

Adjuvant Chemotherapy

Over the last 30 years, multiple randomized studies have evaluated the role of adjuvant chemotherapy in gastric cancer. Unfortunately, many of these were underpowered for survival and often used “suboptimal” regimens, with consequent variable results. The majority of these trials were conducted in East Asia, with only two small randomized trials conducted in the West demonstrating a survival benefit from adjuvant chemotherapy. Although until the late 1990s adjuvant chemotherapy was generally not considered to be of benefit in operable gastric cancer, a survival benefit, albeit small, was demonstrated on subsequent meta-analyses that were conducted to evaluate to role of adjuvant chemotherapy in gastric cancer. Recently, a large individual patient-level meta-analysis containing data from 17 randomized controlled trials (n = 3838) demonstrated significantly improved overall survival from postoperative adjuvant 5-FU–based chemotherapy when compared with surgery alone (55.3% vs 49.6%; HR 0.82; 95% CI 0.76–0.90; P <.001). No significant heterogeneity across randomized studies or for the choice of chemotherapy regimen used was reported in this meta-analysis.

Among randomized studies of adjuvant chemotherapy in gastric cancer, perhaps most intriguing are results of the two recent trials conducted in East Asia, the ACTS-GC and the CLASSIC study, which evaluated the role of chemotherapy after D2 resection surgery. The ACTS-GC study, a Japanese adjuvant trial, randomized 1059 patients with stage II or III D2 resected gastric cancer to observation, or 1 year’s treatment with adjuvant S-1 chemotherapy. S-1 is an orally active combination of tegafur (5-fluorouracil prodrug), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which degrades fluorouracil), and oteracil (inhibits phosphorylation of fluorouracil in the gastrointestinal tract) in a molar ratio of 1:0.4:1. The trial, which was stopped early because of positive efficacy results at interim analysis, demonstrated a significant 10% improvement in 3-year overall survival from adjuvant S-1 chemotherapy after surgery (80.1% vs 70.1%; P = .002). Updated results with longer follow-up have also confirmed the benefit of adjuvant S-1, with nearly 11% improvement in 5-year overall survival compared with surgery alone (72.6% vs 61.4%; HR 0.65; 95% CI 0.53–0.81). Most recently, a Korean study, the phase 3 CLASSIC study (n = 1035), reported a significant benefit in disease-free survival (DFS) from adjuvant combination chemotherapy. Following D2 resection, patients with stage II, IIIa, and IIIb gastric cancer were randomized to adjuvant CAPOX (capecitabine 1000 mg/m ² twice a day days 1–14 every 3 weeks, and oxaliplatin 130 mg/m ² day 1, every 3 weeks × 8 cycles) or observation alone. Although the data analysis was planned after 385 DFS events had occurred, the independent data-monitoring committee recommended a full evaluation and reporting of results following a significant preplanned interim analysis at 266 events. Patients treated with adjuvant XELOX had significantly improved 3-year DFS compared with the surgery-alone arm (74% vs 60%; HR 0.56; 95% CI 0.44–0.72; P <.0001) with a trend toward improved overall survival (HR 0.74; 95% CI 0.53–1.03; P = .0775), although the data were still immature for analysis of overall survival at this point. Data from both the ACTS-GC and CLASSIC study confirm that even after “optimal” (D-2) gastric resection surgery, there is a benefit to be gained from the use of adjuvant chemotherapy. Another large randomized controlled study (SAMIT trial), which recently completed accrual of 1495 patients in a 2 × 2 design to adjuvant fluoropyrimidine chemotherapy with UFT (uracil/tegafur) or S-1, or sequential paclitaxel and then UFT or S-1, will evaluate the role of taxanes in adjuvant treatment of gastric cancer (see Table 2 ).

Perioperative Chemotherapy

Curative resection (R0) is an important predictor of survival for patients with gastric cancer, and the proportion of patients with R0 resection decreases with increased tumor size and extension. Chemotherapy given before surgery aims to downstage the tumor and increase the chances of a curative resection, thereby leading to improved patient survival. A benefit from perioperative chemotherapy (given before and after surgery) has also been demonstrated in other tumor types such as metastatic colorectal cancer. Preoperative chemotherapy for gastric cancer is generally better tolerated than postoperative treatment, as major surgery (eg, total gastrectomy) can result in long delays before patients are fit enough to start adjuvant treatment, potentially allowing occult micrometastatic disease an opportunity to proliferate. This has been demonstrated by Biffi and colleagues, who directly compared preoperative chemotherapy with the same regimen given postoperatively after gastric surgery. Although this study was closed because of insufficient accrual, increased toxicity and decreased chemotherapy completion rate were observed in the postoperative arm in comparison with the preoperative arm, where the same chemotherapy regimen was given before surgery, thereby reinforcing the challenges involved in giving chemotherapy after gastric surgery.

The most compelling evidence for perioperative chemotherapy comes from the phase 3 United Kingdom Medical Research Adjuvant Gastric Cancer Study (MAGIC), which changed clinical practice across Europe following demonstration of a survival benefit from perioperative chemotherapy. In this trial 503 patients with resectable adenocarcinoma of the stomach, GOJ, or lower esophagus were randomly assigned to either perioperative chemotherapy and surgery or surgery alone. Chemotherapy consisted of 3 preoperative and 3 postoperative cycles of ECF chemotherapy (intravenous epirubicin 50 mg/m ² and cisplatin 60 mg/m ² on day 1, and a continuous infusion of 5-fluorouracil 200 mg/m ² per day for 21 days). The perioperative chemotherapy group demonstrated a significantly improved overall survival (HR 0.75; 95% CI 0.60–0.93; P = .009; 5-year survival rate, 36% vs 23%) and progression-free survival (HR 0.66; 95% CI 0.53–0.81; P <.001). Patients treated in the chemotherapy arm had a higher rate of curative resections (as deemed by the surgeon; 79.3% vs 70.3%, P = .03) and significantly smaller tumors and lower nodal burden than those treated with surgery alone. Preoperative chemotherapy did not increase complications from surgery, and similar rates of postoperative morbidity and 30-day mortality were seen in both arms. No heterogeneity of treatment effect according to the site of primary tumor (stomach, GOJ, or lower esophagus) was demonstrated. This trial also highlighted the challenges involved in delivering postoperative treatment in this patient population group, as 91% of patients who started preoperative chemotherapy completed all 3 cycles of preoperative chemotherapy but only 65% of those who had surgery were able to start postoperative treatment, with only 50% completing all 6 cycles of chemotherapy.

The perioperative approach is also supported by a second phase 3 study, the FNLCC ACCORD 07/FFCD 9703 phase 3 trial, which randomized 224 patients with resectable adenocarcinoma of the stomach, GOJ, or lower esophagus to surgery alone or surgery plus perioperative chemotherapy. Chemotherapy consisted of 2 to 3 preoperative cycles of CF regimen (5-fluorouracil and 800 mg/m ² /d as continuous intravenous infusion days 1–5 and cisplatin 100 mg/m ² as a 1-hour infusion, every 28 days), and 3 to 4 postoperative cycles of the same regimen in patients who tolerated preoperative treatment well and with no evidence of progressive disease after preoperative chemotherapy, for a total of 6 cycles. The 5-year overall survival was improved by 14% in the chemotherapy arm (38% vs 24%; HR 0.69; 95% CI 0.50–0.95; P = .02) compared with the surgery-alone group, and the 5-year DFS was also improved from 21% to 34% with the use of perioperative chemotherapy (HR 0.69; 95% CI 0.50–0.95; P = .021). In addition, perioperative chemotherapy significantly improved the rate of curative resection (84% vs 73%; P = .04). Although there was increased toxicity in the chemotherapy arm, postoperative morbidity was similar in the two groups. Consistent with the results of the MAGIC study, only 50% of patients could manage to have postoperative chemotherapy compared with nearly 87% who received at least 2 cycles of preoperative chemotherapy, again highlighting the importance of delivering chemotherapy before surgery.

Based on the results of these studies, perioperative chemotherapy with the MAGIC regimen is now widely accepted as a standard treatment across Europe for treating patients with operable, locally advanced adenocarcinoma of the stomach, GOJ, or lower esophagus. Current clinical trials are also using this regimen as a standard to evaluate newer drugs in this setting, although capecitabine has largely replaced infusional 5-fluorouracil, due to the ease of administration and extrapolation from noninferiority data reported in the advanced disease setting. At present there are no data to support a purely neoadjuvant strategy for patients with operable gastric cancer, and patients undergoing preoperative chemotherapy should be treated with postoperative chemotherapy where feasible.

A persistent problem is a relatively low response rate for preoperative chemotherapy, which can occur in up to one-third of patients thus treated. In recent years, response evaluation on positron emission tomography (PET) scan, as measured by a decrease in the tumor glucose standard uptake value (SUV), has been used to predict response to preoperative chemotherapy in patients with tumors of the GOJ. Following treatment with preoperative chemotherapy, early metabolic response in the tumor on the PET scan has been shown to correlate well with the clinical and pathologic response and survival, and perhaps this strategy could potentially help identify patients who fail to respond to preoperative treatment, thereby providing an opportunity to change or intensify their treatment in order to improve treatment outcomes.