Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study

Abstract

PURPOSE No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.

A meta-analysis of the efficacy of postoperative adjuvant radiotherapy versus no radiotherapy for extrahepatic cholangiocarcinoma and gallbladder carcinoma

“…The BILCAP trial suggested that capecitabine, comparing with observation, can improve OS in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery; however, this study did not meet its primary endpoint of improving OS in the intention-to treat population [44]. In a randomized phase III study conducted by Edeline J et al, adjuvant gemcitabine and oxaliplatin was found to offer no benefit in resected biliary tract cancer patients [45]. From the two trials, we can see that the benefit of adjuvant CT was unclear and patients may not receive much benefit from adjuvant CT, so it is necessary to explore the effect of ART with or without adjuvant CT.…”

“…Currently, there is no standard adjuvant treatment for patients with GBC or EHCC, and the controversy regarding whether the addition of ART improves OS in these patients has not yet been resolved [38][39][40][41][42][43]. Data are emerging from several prospective trials on the efficiency of adjuvant chemotherapy for GBC or biliary tract cancers, but prospective trials involving ART are scarce [44][45][46]. The BILCAP trial suggested that capecitabine, comparing with observation, can improve OS in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery; however, this study did not meet its primary endpoint of improving OS in the intention-to treat population [44].…”

<p>The Significance of Adjuvant Therapy for Extrahepatic Cholangiocarcinoma After Surgery</p>

“…Another randomized Phase III study (PRODIGE 12-ACCORD) compared the effect of gemcitabine and oxaliplatin (Gemox) chemotherapy with observation group. 18 Similarly, there were no benefits of adjuvant Gemox in OS (HR=1.08, 95% CI 0.70-1.66, P=0.74) and RFS (HR=0.88, 95% CI 0.62-1.25, P=0.48). In the BILCAP study, which is from England in 2019, 447 patients with completely excisional CC or GBC were randomized to receive either adjuvant capecitabine or observation.…”

“…14 There are a few data evaluating the role of adjuvant chemotherapy in EHCC, 15,16 and only three prospective studies could be found so far. [17][18][19] A retrospective study in a Japanese center was published in 2009. 20 The study included 103 patients with HCC, DCC, ampullary carcinoma and gallbladder cancer (GBC) who underwent aggressive surgical resection.…”

Combined treatment for locally advanced cholangiocellular liver cancer - the case report

“…Standard adjuvant chemotherapy for biliary cancer patients is presented by capecitabine usage in monoregimen after BILCAP work is published [13]. There are no randomized trials which demonstrate the advantages of other schemes in adjuvant regimen compared to common cohort [14], but their usage can be justified in case of unfavorable factors are revealed [15,16].…”