Biliary tract cancers (BTCs) are rare but deadly diseases, subdivided into intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder carcinoma (GBCA). Known risk factors include primary sclerosing cholangitis, liver flukes, choledochal cysts, viral hepatitis, obesity, and gallstones, among others. BTCs, which represent less than 2% of all new cancer cases annually, result in 5-year survival rates of 5% for IHCC and 17% for EHCC, according to a recent European analysis.

Although the management of these rare tumors has been limited by a paucity of evidence in the past, there have been several recent trials with practice-changing implications for the care of patients with BTC.

The only curative treatment option at this time is surgical resection, but a majority of patients will have disease recurrence. Adjuvant chemotherapy for completely resected disease historically has been controversial, with previous study results showing little to no benefit in biliary cancers.

 Many agents have been used, most notably gemcitabine, platinums, methotrexate, mitomycin C, 5-fluorouracil, irinotecan, and docetaxel, and combinations of these agents. Until recently, there was no standard regimen in this population. One large meta-analysis did find benefit from adjuvant therapy generally, but mostly in the node- and margin-positive subgroup.

 However, the patients received a variety of regimens, leaving clinicians without a clear direction for treatment. Several recent trials have sought to clarify the role of adjuvant therapy in localized disease.

The Southwest Oncology Group’s phase II S0809 trial (NCT00789958), published in 2015, investigated the use of adjuvant capecitabine and gemcitabine followed by radiotherapy with concurrent capecitabine in BTCs. Seventy-nine patients with GBCA and EHCC were enrolled. Following resection, patients received gemcitabine (1000 mg/m2 ) on days 1 and 8 and capecitabine (1500 mg/m2 ) daily on days 1 through 14 every 21 days for 4 cycles. This was followed by capecitabine (1330 mg/m2 ) daily and radiotherapy (45 Gy to lymphatics, 54-59.5 Gy to tumor bed). Either intensity-modulated radiotherapy or 3D planning could be used.

One primary outcome was median overall survival (OS), which was an average of 35 months between negative margin (R0) and microscopically positive (R1) resections. The 2-year survival rate was 65% (95% CI, 53%-74%) averaged between R0 and R1 resections. Local recurrence was roughly 11% overall (95% CI, 4%-18%), with a larger proportion occurring in R1 resections.4 Larger, controlled trials are warranted on the basis of these provocative survival results to further define the role of radiation in the treatment of BTCs.

PRODIGE 12-ACCORD 18 (UNICANCER GI, NCT01313377) was a phase III, randomized trial conducted across 33 centers in France with 196 participants. After complete resection (R0, R1) for nonmetastatic disease, patients with BTC were randomized to gemcitabine/oxaliplatin 85 mg/m2 (GEMOX 85) for 12 cycles versus observation only. Primary objectives were disease-free survival (DFS) and quality of life (QoL).

Results were presented at the 2017 Gastrointestinal Cancers Symposium in January. For those receiving GEMOX, relapse-free survival (RFS) was not statistically significant from the observation group (HR, 0.83; 95% CI, 0.58-1.19; 

 = .31). Grade 3 adverse events were reported in 57.5% of participants in the treatment group versus 22.2% in the observation-only group. Grade 4 events were observed in 17.0% of those treated versus 9.1% with observation. QoL scores were not different at 12 (70.8 vs 83.3; 

 = 0.50).5 Based on these results, the role of adjuvant chemotherapy became even less clear. Because gemcitabine with a platinum agent was standard in the metastatic setting, many anticipated that GEMOX would result in improved survival, but it did not.

Most recently, the groundbreaking BILCAP study (ISRCTN72785446), presented at the 2017 American Society of Clinical Oncology Annual Meeting in June, investigated the effect of adjuvant capecitabine rather than gemcitabine/ platinum in biliary cancer. It was designed as a phase III, randomized trial across multiple centers in the United Kingdom. Eligible patients had BTC and had completed R0 or R1 resection. They were randomized to receive oral capecitabine (1250 mg/m2 ) twice daily for 14 days every 3 weeks for 8 cycles in the absence of disease progression or serious toxicity versus observation alone. The primary outcome was 2-year OS.

There were 223 participants randomized to the treatment arm and 224 on observation. Patients were stratified by disease location (35% extrahepatic, 28% hilar, 19% intrahepatic, and 18% with muscle-invasive gallbladder cancer). The majority of patients (62%) had R0 resection margins and 46% were node negative. In the intent-totreat analysis, median OS was 51 months for capecitabine (95% CI, 35-59) and 36 months for observation (95% CI, 30-45) with an HR of 0.80 (95% CI, 0.63-1.04; 

The per-protocol analysis had similar results, with a median OS of 53 months for capecitabine (95% CI, 40-not reached) and 36 months for observation (95% CI, 30-44) with an HR of 0.75 (95% CI, 0.58-0.97; 

 = .028). Grade 3-4 toxicity was noted to be less than anticipated.

Based on the results of BILCAP, capecitabine was established as a new standard of care for the adjuvant treatment of biliary cancers.

Because of these data, further investigation into adjuvant therapy for biliary cancers is planned. The ACTICCA-1 (NCT02170090) trial is a phase III, randomized, multicenter trial comparing gemcitabine plus cisplatin with capecitabine after curative resection in biliary cancers. This trial is currently recruiting and the enrollment goal is 440 participants. Eligibility criteria include histologically confirmed adenocarcinoma of the biliary tract, R0/R1 resection, good performance status, and no concomitant treatment (although prior chemotherapy is allowed). In the original protocol, the treatment group was to receive gemcitabine (1000 mg/m

 ) on days 1 and 8 every 3 weeks for 8 cycles. However, given the results of the BILCAP study making capecitabine the new standard of care, the investigators agreed to alter the study protocol to compare gemcitabine and cisplatin with oral capecitabine. Primary outcome is DFS and secondary endpoints include OS, safety, tolerability, QoL, and patterns of disease recurrence. Preliminary results have yet to be reported.

 This and other studies will hopefully define whether better chemotherapy regimens or radiation play a role in improving outcomes for resected BTCs. Unfortunately, many patients present with disease too advanced for resection.

As with many other malignancies, there is growing interest in targeted therapies for the treatment of BTCs. Several mutations have been implicated in the pathogenesis of BTCs, including 

, and aberrations in the HER2 and MAPK pathways, among others. The prevalence of these aberrations varies depending on the location of malignancy in the biliary tree.

 Fibroblast growth factor receptor (FGFR) is a tyrosine kinase intimately involved in cellular repair and reproduction. In BTCs, specifically IHCC, multiple fusion proteins with FGFR2 have been found.

Based on preliminary success in early-phase studies, several agents were developed and are being tested, including BGJ398 (NCT02150967) and ARQ 087 (NCT03230318), among others.

 mutations have been reported in up to 28% of intrahepatic cholangiocarcinomas.

Although the role of IDH in BTC tumorigenesis is established, the relation to survival in patients is unclear. However, based on early-phase disease control, AG-120 is now in a phase III randomized controlled trial in patients with advanced solid tumors including cholangiocarcinoma (NCT02073994).

Immunotherapy also has become of greater interest in the world of BTCs after showing success in multiple other organ systems. BTCs have been found to harbor mismatch-repair deficiency (dMMR), but the exact prevalence is not clear. In the initial study of pembrolizumab in dMMR malignancies including colorectal cancer (CRC) and other sites, 4 participants with cholangiocarcinoma or ampullary carcinoma were included. The immune-related objective response rate (ORR) by RECIST criteria was 40% in dMMR CRC and 71% in dMMR cancers of other sites while MMR-proficient CRC showed an ORR of 0.

 Although these early results are promising, further trials specific to BTCs are ongoing.

Because interinstitutional collaboration is becoming more commonplace, details regarding molecular profiles are becoming clearer and more interesting patterns can inform our clinical care of these patients. One such example, the Cholangiocarcinoma In The Young (CITY) Project, presented its findings at the 2017 Gastrointestinal Cancers Symposium. After analysis of more than 600 individuals with the disease, 

 aberrations were found to be more prevalent in younger patients (19.1% vs 5.8%; 

 = .002). Diagnosis at a younger age also correlated with a longer median OS (21.5 vs 16.0 months; 

 Collaborations such as these are supported by the robust advocacy of the Cholangiocarcinoma Foundation and the International Cholangiocarcinoma Research Network, both of which are working to bring researchers together to focus on improving the care of our patients with BTC.

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Biliary tract cancers are rare but deadly diseases, subdivided into intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma.

Marc Roth, MD

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