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Adjuvant Irradiation Plus Chemotherapy
Postoperative EBRT Plus Chemotherapy
Phase II single-institution gastric cancer trials that showed promise for combination postoperative adjuvant therapy were reported from MGH,181 Israel (Hadassah),182 Thomas Jefferson University Hospital,183 the University of Pennsylvania,184 and the Mayo Clinic.185 Gunderson and associates,181 from the MGH, reported a median survival time of 24 months and 4-year survival rate of 43% in 14 patients who had complete resection of tumors with extension beyond the wall, nodal involvement, or both. Patients received postoperative irradiation (45 to 52 Gy, 1.8 Gy/d) plus concomitant 5-FU-based chemotherapy. Subsequent local-regional relapse was documented in only 2 of the 14 (14%), in contrast with a 42% incidence in similar high-risk patients treated with surgery alone at MGH.121
A prospective randomized trial conducted at the Mayo Clinic included 62 patients with poor-prognosis completely resected gastric cancers who were randomly assigned to either surgery alone or surgery followed by irradiation (37.5 Gy in 24 fractions over 4 to 5 weeks) plus concomitant 5-FU (15 mg/kg, days 1 to 3 by IV bolus).186 A nonstratified, prerandomization scheme was used, with a 2:3 ratio favoring treatment. Informed consent was requested only of the 39 patients randomly assigned to treatment. Of the 39 patients, 10 refused further therapy and were observed. When analyzed by intent to treat, the adjuvant arm had statistically significant improvement in both relapse-free and overall survival (5-year OS 23% vs. 4%, P < 0.05; Table 75-6 and E-Table 75-4). When patient outcome was compared by actual treatment received (29 adjuvant treatment, 33 surgery alone), 5-year survival rate still favored the adjuvant group (20% vs. 12%), but the differences were not statistically significant in view of small patient numbers. As seen in Table 75-6, the 10 patients who refused assignment to adjuvant treatment had more favorable prognostic findings than the other two groups of patients. When the two groups with equally poor prognostic factors were compared, the 5-year OS rate was 20% versus 4%, with an advantage to those receiving adjuvant treatment.186 When analyzed by treatment delivered, local-regional relapse was decreased with adjuvant treatment (54% incidence with surgery alone vs. 39% with irradiation plus 5-FU).
Because of conflicting results in earlier small phase III studies, a confirmatory U.S. GI trial (INT 0116) was initiated to evaluate postoperative combined 5-FU-based chemotherapy and irradiation to the gastric bed and regional nodes versus surgery only in completely resected but high-risk gastric cancer patients.120 Eligibility included patients with stages IB, II, IIIA, IIIB, and IV nonmetastatic adenocarcinoma of the stomach or GEJ (extension beyond muscularis propria [T2–4N0] or involved nodes [T1–2N1–3]). After an en bloc resection, 556 patients were randomly assigned to either surgery alone or postoperative combined-modality therapy consisting of one 5-day cycle of 5-FU plus leucovorin followed by concurrent chemoradiation (45 Gy in 25 fractions plus concurrent 5-FU and leucovorin, 4-day cycle on week 1, 3-day cycle on week 5) and subsequently by two additional 5-day cycles of 5-FU and leucovorin given at 1-month intervals. Nodal metastases were present in 85% of patients. With median follow-up period of 5 years, RFS at 3 years is 48% for adjuvant treatment and 31% for observation (P = 0.001); 3-year OS rate is 50% for treatment and 41% for observation (P = 0.005; see Table 75-6). The median OS in the surgery-only group was 27 months, as compared with 36 months in the chemoradiation therapy (CRT) group. The median duration of RFS was 30 months in the CRT group and 19 months in the surgery-only group. Patterns of relapse were based on the site of first relapse only and were categorized as local, regional, or distant. Local recurrence occurred in 29% of the patients who relapsed in the surgery-only group and 19% of those who relapsed in the CRT group. Regional relapse—typically abdominal carcinomatosis—was reported in 72% of those who relapsed in the surgery-only group and 65% of those who relapsed in the CRT group. Extraabdominal distant metastasis was diagnosed in 18% of those who relapsed in the surgery-only group and 33% of those who relapsed in the CRT group. Treatment was tolerable, with 3 (1%) toxic deaths. Grade 3 and 4 toxicity occurred in 41% and 32% of cases, respectively.
The results of the large randomized phase III U.S. GI trial (INT 0116) demonstrate a clear survival advantage to the use of postoperative CRT in resected high-risk patients. 120 Furthermore, the results strongly support the integration of postoperative CRT into the routine care of individuals with curatively resected high-risk carcinoma of the stomach and GEJ. This approach is now viewed by many as the standard of care in the United States.
Quality control of irradiation field design in INT 0116 was conducted during the cycle of chemotherapy given before the start of concurrent CRT. 187 The initial quality control provided the mechanism to correct most of the major or minor deviations (35% incidence) in irradiation field design before the start of treatment, and resulted in only a 6.5% final major deviation rate. Use of initial quality control may have been a key factor in achieving a positive survival advantage for adjuvant CRT.
An updated long-term outcomes analysis was performed of INT 0116 with more than 10-year median follow-up. 188 Overall and relapse-free survival data demonstrate continued strong benefit from adjuvant postoperative chemoradiation (OS: HR 1.32, P = 0.0046; RFS: HR 1.51, P < 0.0001). Reduction in local-regional relapse accounted for the majority of overall relapse reduction.
The successor U.S. GI Intergroup replacement phase III randomized trial was designed to build on the positive results of INT 0116 by testing 5-FU infusion versus bolus 5-FU + leucovorin as the concurrent chemotherapy during EBRT, and ECF chemotherapy versus 5-FU + leucovorin as the maintenance component of chemotherapy. The irradiation treatment fields in both the phase II and successor phase III trials were based on idealized field design related to site of the primary lesion and TN stage of disease. 189 Preliminary results did not demonstrate improvements in survival when compared with the chemoradiation control arm from INT 0116. 190
Postoperative Chemoradiation Plus D2 Resection
Because extended node dissections were not commonly performed as a component of surgery in the U.S. GI trial INT 0116, some have questioned whether postoperative CRT would give added benefit following a D2 nodal resection. A South Korea analysis by Kim et al. evaluated the potential role of postoperative CRT in a series of 990 patients with D2 resection who were at high risk for relapse. 191 Disease and patient characteristics and the method of chemoradiation treatment paralleled the U.S. GI INT 0116 trial. Both disease control and survival were improved in the 544 patients who received postoperative CRT when compared with the 446 patients treated with surgery alone (5-year OS, 57% vs. 51%, P = 0.02; 5-year RFS, 54.5% vs. 47.9%, P = 0.016; local-regional relapse, 14.9% vs. 21%, P = 0.005; Tables 75-6 and 75-7).
A phase III randomized trial was subsequently conducted in South Korea in 458 patients to compare postoperative chemotherapy with capecitabine plus cisplatin (XP [n = 228] versus XP plus concurrent chemoradiation (n = 230 patients). 192 Patients on the chemoradiation arm received 2 cycles of XP followed by 45 Gy/25 fractions/5 wk plus concurrent capecitabine 825 mg/m 2 twice daily during EBRT. On univariate analysis, 3-year DFS was slightly higher in the CRT arm at 78.2% versus 74.2% (P = 0.0862); in the subgroup of 396 patients with involved nodes, patients in the CRT arm achieved superior 3-year DFS (77.5 vs. 72.3%, P = 0.0365). On multivariate analysis with stage and treatment arm, the addition of EBRT to XP demonstrated significantly prolonged DFS with an HR of 0.6865, P = 0.0471.
Preoperative EBRT Plus Chemotherapy
Randomized trials testing preoperative EBRT plus chemotherapy for gastric cancer alone have not yet been published, but four phase III trials for patients with esophagus cancer (alone or combined with GEJ or cardia lesions) included patients with adenocarcinoma. This includes studies by Walsh et al., 193 Urba et al., 194 Tepper et al., 195 and van Hagen et al. 196
In the Dublin trial by Walsh et al., patients were randomly assigned to either immediate surgery (control arm) versus preoperative EBRT (40 Gy in 15 fractions), 5-FU (15 mg/kg/d continuous infusion [this is approximately equivalent to 600 mg/m 2 ] for 5 days, weeks 1 and 6), and cisplatin (75 mg/m 2 on the first day of each 5-FU infusion), followed by surgical resection 8 weeks after completion of EBRT plus chemotherapy. 193 A highly significant difference in survival was observed with combined-modality therapy (intent to treat median survival time, 16 vs. 11 months, 3-year OS, 32% vs. 6%, P = 0.01). Survival rates for the control group of patients were inferior to other historical data.
Urba and colleagues found a borderline survival advantage for patients treated with preoperative chemoradiation versus surgery alone in a small single-institution trial of 100 patients at the University of Michigan. 194 Preoperative treatment consisted of EBRT (45 Gy/1.5 Gy BID/3 wk) plus concurrent three-drug chemotherapy (5-FU, cisplatin and vinblastine). Patients with either squamous cell carcinoma (SCC) or adenocarcinoma were eligible; 75 patients had adenocarcinoma. Survival differences favoring chemoradiation were seen after several years of follow-up but did not reach statistical significance in view of the small series (3-year OS 30 vs. 16%, P = 0.09 on multivariate analysis).
Two confirmatory studies have also shown an advantage to pre- operative chemoradiation versus surgery alone for esophageal or GEJ cancers (squamous or adenocarcinoma)—U.S. GI Intergroup and Cross phase III trials. 195,196 The U.S. GI Intergroup trial was performed in North America but was stopped prematurely because of poor accrual. Despite the low accrual (n = 56), patients randomized to trimodality treatment had a survival benefit when compared with patients randomized to surgery alone (median OS 54 vs. 21.6 months; 5-year OS, 39% vs. 16%, P = 0.008). 195 In the larger Cross trial (n = 368 patients), trimodality treatment again had a survival advantage over surgery alone (median OS 50 vs. 24 months, 2-year OS 67% vs. 52%, 3-year OS 59% vs. 48%, P = 0.011). 196
GEJ—Preoperative Chemoradiation Versus Chemotherapy (POET Trial)
The POET phase III trial by Stahl et al. included 120 eligible patients with T3-4 adenocarcinoma of the GEJ treated with either preoperative chemoradiation (CRT; n = 60) or chemotherapy alone (n = 60). 197 All patients received 2 cycles of PLF chemotherapy weeks 1 to 6/7 to 13 (cisplatin 50 mg/m 2 /1 h on days 1, 15, and 29; leucovorin 500 mg/m 2 /2 h and 5-FU 2 mg/m 2 /24 h infusion on days 1, 8, 15, 22, 29, and 36) followed by either PLF alone (weeks 14 to 17) or CRT with 30 Gy EBRT/15 × 2 Gy/3 wk (weeks 14 to 17) plus concurrent PE week 1 of EBRT (cisplatin 50 mg/m 2 /1 h on days 2 and 8; etoposide 80 mg/m 2 /1 h days 3 to 5). Outcomes analyses trends favored preoperative CRT over chemotherapy alone with regard to both OS (P = 0.07) and freedom from local relapse (P = 0.06; Table 75-6).
SEER Analysis, Gastric Cancer—Adjuvant Irradiation or Chemoradiation
Coburn et al. evaluated the impact of postoperative adjuvant EBRT or CRT in 4,041 patients who had resection of nonmetastatic gastric adenocarcinoma from May 2000 to December 2003 (SEER database). 198 Patients treated with postoperative EBRT (alone or plus concurrent chemotherapy) versus surgery alone had improved median OS for stages III (31 vs. 24 months, P = 0.005) and IVM0 (20 vs. 15 months, P < 0.001) and the difference approached significance for stage II (P = 0.0535). Adjusted analysis using a propensity score suggested that the benefit of adjuvant irradiation was similar for stage II and III patients (HR of death 0.733 and 0.773 respectively).
Meta-Analyses, Gastric/Esophageal Cancer—EBRT, Chemoradiation, Chemotherapy
A meta-analysis by Fiorica et al. evaluated the impact of adjuvant EBRT or CRT in the reduction of all-cause mortality in patients with resectable gastric adenocarcinoma (nine published phase III trials—four preoperative EBRT and five postoperative CRT). 199 For patients treated with preoperative EBRT, the HR for all-cause mortality was 0.62 (P = 0.002). In patients treated with postoperative CRT, the HR for all-cause mortality was 0.45 (P < 0.00001).
An Australian meta-analysis published by Gebski et al. evaluated the impact of either preoperative CRT or preoperative chemotherapy in patients with resectable esophagus adenocarcinoma or SCC. 200 For patients treated with preoperative CRT, the HR for all-cause mortality was 0.81 (P = 0.002), with similar results for patients with adenocarcinoma (HR: 0.75, P = 0.02) and SCC (HR: 0.84, P = 0.04). In patients treated with preoperative chemotherapy, the HR for all-cause mortality was 0.90 (P = 0.05), with significant benefit found for patients with adenocarcinoma (HR: 0.78, P = 0.014) but no benefit for those with SCC (HR: 0.88, P = 0.12).
Summary—Adjuvant Irradiation Alone or Plus Chemotherapy
In summary, both preoperative irradiation 180 and postoperative CRT 120,188 have been demonstrated to be superior to surgery alone for resectable gastric and gastroesophageal cancers in randomized phase III trials and meta-analyses. Preoperative chemoradiation has been shown to be potentially advantageous to preoperative chemotherapy alone in the POET phase III trial for GEJ cancers. 197