Does adjuvant chemoradiation benefit patients with lymph node-positive biliary tract cancer? A secondary analysis of SWOG S0809.
Authors: Gholami Sepideh , Duong Mai T. , Horowitz David Paul , Guthrie Katherine A , Ben-Josef Edgar , El-Khoueiry Anthony B. , Blanke Charles David , Philip Philip Agop , Ahmad Syed A. , Rocha Flavio G. 
Published: June 2021

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Background: Biliary tract cancers are rare tumors with a median overall survival (OS) of 16 months for node-positive (N+) and 37 months for node-negative (N0) disease despite resection. Lymph node status is a known strong prognostic factor for local recurrence with an average estimated 2-year disease-free survival (DFS): 65.5% for N0 and 29.7% for N+ tumors. The Phase II Intergroup Trial S0809 showed that adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine improved OS in patients with extrahepatic cholangiocarcinoma (EHCC) and gallbladder cancer (GBC) compared to historical controls. We hypothesized that nodal status is a prognostic factor for local recurrence in this patient population who received adjuvant therapy. Methods: This analysis included patients with stage pT2-4, N+ or positive margin EHCC or GBC. Treatment included four cycles of gemcitabine (1,000 mg/m2 intravenously on days 1 and 8) and capecitabine (1,500 mg/m2 per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m2 per day) and radiotherapy (45 Gy to regional lymphatics; 52.5 to 59.4 Gy to tumor bed). S0809 patients who did not receive radiotherapy were excluded from analysis. Correlations between nodal status, resection margin, and other clinicopathological factors, patterns of recurrence and survival were analyzed, and Cox regression models were used to estimate the prognostic significance of nodal status. A Z-test was used to compare DFS rates between these patients and historical data. Results: A total of 69 patients [EHCC n = 46 (66%); GBCA n = 23 (33%)] were evaluated with a median age of 61.7 (26.1-80.6). The majority of N0 patients were female (17/24, 70.8%), whereas most N+ patients were male (25/45, 55.6%; p < 0.04). Distribution of R0 (66.7%) and R1 (33.3%) resections was similar in the N0 and N+ groups. Thirty-four patients with EHCC had N+ disease (73.9%) compared with 11 patients with GBCA (47.8%, p = 0.03). Nodal status did not significantly impact OS (HR = 2.03, 95% CI 0.92-4.49, p = 0.08) or DFS (HR = 1.75, 95% CI 0.85-3.59, p = 0.13). Two-year OS was 70.6% for N0 and 60.9% for N+ disease (p = 0.11). Nodal status was not significantly associated with 2-year DFS: 62.5% for N0 and 49.8% for N+ (p = 0.20). N+ vs N0 tumors showed higher rates of distant failure (51.1% vs 25.0%, p < 0.04), but similar local recurrence (17.8% vs 12.5%, p = 0.88). The observed 2-year DFS in patients with N+ tumors was significantly longer compared to the historical rate of 29.7% (p = 0.004). Conclusions: This combination adjuvant treatment regimen following curative resection for EHCC and GBCA provides favorable outcomes regardless of nodal status. These data suggest that adjuvant chemoradiation may positively impact local control in N+ patients. These findings need to be validated in future clinical trials. Clinical trial information: NCT00789958.