SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma

Abstract

Purpose The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. Patients and Methods Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received 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; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. Results A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. Conclusion This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.

Cholangiocarcinoma — evolving concepts and therapeutic strategies

“…Results of a multi-institutional, single-arm phase II study 86 demonstrated the safety and promising efficacy of adjuvant therapy consisting of gemcitabine plus capecitabine followed by conformal EBRT with concurrent capecitabine for patients with resected pCCA/dCCA and gallbladder cancer. The majority of patients (81%) received IMRT 86 .…”

“…Results of a multi-institutional, single-arm phase II study 86 demonstrated the safety and promising efficacy of adjuvant therapy consisting of gemcitabine plus capecitabine followed by conformal EBRT with concurrent capecitabine for patients with resected pCCA/dCCA and gallbladder cancer. The majority of patients (81%) received IMRT 86 . In the 54 patients with resected pCCA/dCCA, the 2-year overall survival and local control rates were 68% and 87%, respectively; no differences in overall survival or DFS were observed between patients with R0 versus R1 resection 86 .…”

Surgical management of carcinoma in situ at ductal resection margins in patients with extrahepatic cholangiocarcinoma

“…Despite curative‐intent resection, positive ductal resection margins are sometimes confirmed after pathological examination. Adjuvant therapy has been advocated to improve these poor outcomes 66, 67, 68, 69, 70, 71. However, given the rarity of extrahepatic cholangiocarcinoma, most of the data regarding adjuvant therapy have come from small, single‐center studies or retrospective single‐arm reviews.…”

“…However, given the rarity of extrahepatic cholangiocarcinoma, most of the data regarding adjuvant therapy have come from small, single‐center studies or retrospective single‐arm reviews. Recent relatively large studies and systematic reviews/meta‐analyses have suggested that adjuvant chemoradiotherapy, radiotherapy, or chemotherapy are associated with improved survival in patients with biliary tract cancer and high‐risk characteristics, including positive ductal resection margins 66, 67, 68. However, the intention‐to‐treat analyses in all the large randomized clinical studies of adjuvant chemotherapy for biliary tract cancer reported thus far have failed to demonstrate its efficacy 69, 70, 71.…”

Systemic Therapy of Cholangiocarcinoma

“…In contrast, patients with R1 resection or positive lymph nodes could be treated by chemoradiotherapy. The SWOG-S0809 study recently showed that sequential chemotherapy with gemcitabine and capecitabine for 12 weeks followed by radiochemotherapy led to promising results [9]. The further role of adjuvant chemotherapy will be evaluated in three large, currently ongoing phase III studies (BILCAP, PRODIGE-12, ACTICCA-1) in three different European countries (France, Germany, UK).…”