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Page 10 of 19 Hewitt et al. Hepatoma Res 2021;7:75 https://dx.doi.org/10.20517/2394-5079.2021.83

months vs. 5.0 months, P < 0.001) and tumor control rate (81.4% vs. 71.8%, P = 0.049). On prespecified
subgroup analysis, there was no difference in the hazard ratio for death according to the primary tumor site.
These data provided evidence that cisplatin plus gemcitabine is an effective treatment for locally advanced
[126]
or metastatic biliary tract cancer . These results were utilized as the basis of using gemcitabine with
cisplatin in the adjuvant setting and set the stage for following clinical trials .
[120]
PRODIGE-12/ACCORD-18
In a phase II study, Gemcitabine Oxaliplatin (GEMOX) was demonstrated to be tolerable and active in
[127]
patients with advanced biliary tract cancers . The PRODIGE-12/ACCORD-18 was a phase III multi-
institutional study performed to determine if adjuvant GEMOX could improve outcomes compared to
[128]
surgery alone in patients who received R0 or R1 resection of localized biliary tract cancer . The primary
endpoints were relapse-free survival and time to definitive deterioration of health-related quality of life
(HRQOL). Secondary endpoints included OS, toxicity, and exploratory translational endpoints. Of the 196
patients included, 38 patients had gallbladder cancer, while 86 patients had ICCA, 15 PCCA, and 55 DCCA.
At a median follow-up of 46.5 months, there was no significant difference in relapse-free survival between
patients who received GEMOX and those who had surgery alone (30.4 months vs. 18.5 months; hazard ratio
= 0.88; 95%CI: 0.62-1.25; P = 0.48). In addition, there was no difference in time to deterioration of HRQOL.
OS was not statistically significant between groups (75.8 months vs. 50.8 months; hazard ratio = 1.08;
95%CI: 0.70-1.66; P = 0.74). Furthermore, on pre-planned subgroup analysis, disease site, lymph node
status, or margin status did not identify a subgroup that would benefit from GEMOX. This study has been
criticized as being underpowered to detect an effect size hazard ratio of 0.6, as well as including a low
proportion of patients who are considered to be high-risk (13% had R1 resections and 37% had lymph node-
[120]
positive disease) who would benefit the most from adjuvant therapy .
BILCAP
The BILCAP study was a phase III multi-institutional study that compared adjuvant capecitabine to
observation in patients with biliary tract cancer who underwent macroscopically complete resection with
[129]
curative intent . The primary endpoint was OS, and secondary endpoints included a per-protocol analysis
of outcomes, RFS, toxicity, health economics, and quality of life. Of the 447 patients randomized, 84 patients
had ICCA, 128 PCCA, 156 DCCA, and 79 gallbladder cancer. At a median follow-up of 60 months, in the
intention-to-treat analysis, the median OS was 51.1 months in the capecitabine group compared to 36.4
months in the observation group (adjusted hazard ratio = 0.81, 95%CI: 0.63-1.04; P = 0.097) and RFS of 24.4
months in the capecitabine group and 17.5 months in the observation group (P = 0.033). In a prespecified
per-protocol analysis, median OS was 53 months in the capecitabine group and 36 months in the
observation group (adjusted hazard ratio = 0.75, 95%CI: 0.58-0.97; P = 0.028), as well as a median RFS of
25.9 months in the capecitabine group and 17.4 months in the observation group (P = 0.0093) . However,
[129]
there was no evidence of a difference in RFS beyond 24 months, indicating capecitabine may delay
recurrence [120,129] .

Based on the results of the BILCAP trial, patients with resected biliary tract cancers should receive 6 months
of adjuvant capecitabine . However, the BILCAP trial has been criticized as only having a significant
[47]
improvement in OS in the adjusted and per-protocol analyses. Additionally, the R1 resection margin and
lymph node metastasis rate were relatively high, which has been proposed to account for the different
results between the BILCAP trail and PRODIGE-12/ACCORD-18 and Bile Duct Cancer Adjuvant Trial
[119]
(BCAT) trials .