Adjuvant therapies for resectable cholangiocarcinomas

The role of adjuvant chemotherapy/chemoradiation in patients with resected biliary tract cancer is poorly defined. Although it is widely used and recommended in guidelines from expert groups, the survival benefit of any adjuvant strategy has been proven mainly in retrospective studies rather than designed randomized clinical trials.

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The benefit of adjuvant therapy for biliary tract cancer continues although being unclear. Available literature mainly consists of uncontrolled institutional series and registry analysis with conflicting results, although these seem to favor an adjuvant approach.36

This uncertainty led Horgan et al to carry out a systematic review and meta-analysis in an attempt to determine the impact of adjuvant treatments on survival.37

This included 20 studies (including 6,712 patients) assessing the results of chemotherapy, radiotherapy, or chemo-radiotherapy as adjuvant approaches to a radical surgery for these patients.37

The pooled analysis showed nonsignificant benefit in unselected patients in OS with any adjuvant treatment compared with surgery alone, but in those with node positivity or margins involved, adjuvant therapy seemed to provide advantages in the same parameter. Those receiving chemotherapy or chemoradiotherapy had more significant benefit than radiotherapy alone.37

Horgan et al concluded that adjuvant therapy is supported for resected disease in patients with high-risk features, particularly in cholangiocarcinoma. Prospective randomized trials are needed to provide better rationale for this strategy. The above-mentioned authors also suggested two active comparators rather than a no-treatment arm among patients with lymphadenopathy (LN) positive or R1 disease.37

Adjuvant chemotherapy

For node-positive disease, the evidence supports chemotherapy as an adjuvant approach.

Two randomized clinical trials have examined its benefit following resection. Takada et al carried out a randomized controlled trial comparing the benefit of postoperative adjuvant chemotherapy with surgery alone in patients with resected pancreatobiliary carcinoma.38

Patients were randomized to surveillance only or to receive mitomycin C and 5-fluorouracil (5-FU) followed by 5-FU until disease recurrence. Primary end point was OS. Although the five-year survival rate in gallbladder cancer was significantly better with chemotherapy (26 vs. 14%, P = 0.0367), this was not statistically significant in the intention-to-treat analysis. Those patients had a benefit in disease-free survival (20.3 vs. 11.6%). The study did not show any benefit with chemotherapy in patients with bile duct carcinomas (five-year survival, 27 vs. 24%). Unfortunately, this trial was underpowered to prove definitively a treatment benefit.38

A single-center retrospective analysis showed a benefit in survival when gemcitabine-based adjuvant treatment was administered in cholangiocarcinoma patients.39

Another clinical trial evaluated the role of 5-FU or gemcitabine in patients with resected periampullary adenocarcinomas.

Four hundred and twenty-eight patients were randomly assigned to one of three arms: observation, 6 months of leucovorin-modulated 5-FU, or 6 months of gemcitabine. Adjuvant chemotherapy produced a benefit though not statistically significant (median 43 vs. 35 months, hazard ratio 0.86, 95% confidence interval: 0.66–1.11). However, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy, specifically for gemcitabine.40

Whether single-agent versus doublet chemotherapy show better results remains to be determined.

Other clinical trials are either still recruiting patients or awaiting presentation of results.

ACTICCA-1 is a randomized, multidisciplinary, and multinational phase III trial. It will evaluate the efficacy of gemcitabine and cisplatin versus observation alone in terms of disease-free survival in patients with bile tract carcinomas after complete surgical resection. Two different cohorts will be included, cholangiocarcinomas and gallbladder carcinoma.

The French PRODIGE-12 evaluating gemcitabine and oxaliplatin and the British BILCAP using capecitabine are two clinical trials from which we are still expecting the results.

BILCAP is a multicenter prospective, randomized phase III trial examining the role of adjuvant chemotherapy with oral fluoropyrimidine (capecitabine) in patients following potentially curative surgical resection of a biliary tract cancer. It has already completed the accrual, and results are expected to be reported soon.41

There are two further ongoing studies in Japan. The BCAT (registration UMIN-CTR; ID UMIN000000820) evaluating gemcitabine monotherapy versus surgery alone, and this study is already closed. The other trial is the ASCOT (registration UMIN-CTR; ID UMIN000011688) evaluating the role of S-1 versus surgery alone, and this study is still open, recruiting participants.

Their results will give more light to the questions about the adjuvant chemotherapy for this disease.