While the incidence of biliary tract cancer is increasing, the prognosis remains poor, with a 5-year survival rate of about 5-15% (DeOliveira ). Surgical resection remains the only curative option in patients affected by biliary tract cancer. Unfortunately, only about one third of patients is diagnosed with resectable disease and 5-year overall survival (OS) after surgery has been reported in the range of 25-35%. The prognosis is reported to be worse in patients with positive lymph nodes or resection margins. The high rates of locoregional and distal relapse after resection provide the rationale for adjuvant therapy.
A meta-analysis of mostly retrospective data including 6712 patients has suggested an improved overall survival in patients receiving adjuvant therapy, particularly in those with node-positive disease and who underwent and R1 resection (Horgan ).
Recently, three randomised trials prospectively compared chemotherapy versus observation in the adjuvant setting. The phase III PRODIGE-12 trial failed to demonstrate a significant relapse-free survival (RFS) benefit with adjuvant GEMOX compared with only observation in patients affected by cholangiocarcinoma (CCA) and gallbladder carcinoma (Edeline ). In the phase III BCAT trial, adjuvant gemcitabine was not significantly superior if compared with observation in patients with perihilar and distal cholangiocarcinoma (Ebata ).
The BILCAP trial was a randomised, controlled, multicentre, open-label, phase III study, that enrolled 447 patients between 2006 and 2014 across 44 UK centres (Primrose ). Eligible patients had a performance status of 0-2 and histologically confirmed cholangiocarcinoma (19% intrahepatic CCA, 28% perihilar CCA, 35% extrahepatic CCA) or gallbladder carcinoma (18%) with a macroscopically complete resection. Patients were randomly assigned (1:1 ratio) to receive oral capecitabine or observation. In the experimental arm, capecitabine was started within 12 weeks from surgery (exceptionally within 16 weeks) with a classical schedule (1250 mg/m2 twice a days on days 1 to 14 of a 21-day cycle) for 24 weeks (8 cycles).
Treatment was not masked and patients were randomised using a computerised minimisation algorithm and stratified by surgical centre, site of disease, resection status and performance status. The primary outcome was overall survival. Statistical analysis was based on the assumption that the 24-month overall survival would be 20% in the observation arm and that capecitabine would improve it by 12%.
Baseline characteristics were well balanced in the two arms. The majority of patients had cholangiocarcinoma (82%), R0 resection (62% and 63% in the experimental and observational arm, respectively) and no positive lymph nodes (52% and 54% respectively).
The study did not meet its primary endpoint. The median OS by intention-to-treat was 51.1 months (95% CI 34.6-59.1) in the capecitabine arm compared with 36.4 months (29.7-44.5) in the observation arm (hazard ratio [HR] 0.81, 95% CI 0.63-1.04; p=0.097). However, overall survival benefit became significant in a planned sensitivity analysis adjusting for nodal status, disease grade and sex (HR 0.71, 95% CI 0.55-0.92; p=0.010). A per-protocol analysis (that excluded 17 patients who were either found to be ineligible or were randomly assigned to but did not receive capecitabine) showed a longer median overall survival in the experimental arm compared to observation arm (53 months versus 36 months, HR 0.75, 95% CI 0.58-0.97; p=0.028). It has to be noticed that 24-month overall survival found in the observation arm (60%) was considerably higher than originally thought (20%).
In the intention-to-treat analysis, median RFS was longer with capecitabine (24.4 months [95% CI 18.6-35.9]) compared with observation (17.5 months [95% CI 12.0-23.8]). However, no different risk of relapse was demonstrated after 24 months (HR 1.48, 95% CI 0.80-2.77; p=0.21), suggesting the hypothesis that capecitabine can only defer recurrence, as the authors state.
Toxicities of capecitabine are well known. In this study 44% of patients had grade 3 toxicities (most frequently hand-foot syndrome, diarrhoea and fatigue) and there was only one case of grade 4 event (cardiac ischaemia). A limitation of this study is the long recruitment period over than 10 years. However we have to acknowledge that this study includes the largest population enrolled in an adjuvant trial in biliary tract cancer to date.
The long overall survival reported in the control arm probably reflects an improved surgical selection and management, as well as a strict patient selection.
Although the overall survival primary endpoint was not met in the intention-to-treat analysis, the survival difference of 14.7 months observed is clinically significant. The authors conclude that capecitabine should be considered the new standard of care in resected biliary cancer. ASCO guidelines have been recently updated recommending the use of adjuvant therapy with capecitabine (Shroff ). In the commentary on the study by Malka and Edeline, they suggest the use of capecitabine in this setting, underlining its cost-effectiveness, given the large observed overall survival effect size (more than 9% at 2 years), the convenience of oral administration, affordability and tolerability (Malka and Primrose ).
Based on these results, capecitabine should be considered the new standard control in trials in this setting. In this regard, the ongoing phase III ACTICCA-1 trial, which investigates the use of gemcitabine and cisplatin, has recently been amended changing the surveillance group for a capecitabine group.
In BILCAP trial slightly over half (55%) of patients received the planned eight cycles of adjuvant therapy. It opens questions about an eventual role of neoadjuvant or perioperative therapy in biliary tract cancer.
In the adjuvant setting, the role of radiotherapy remains unclear, since prospective randomised controlled trials lack. The benefit of adding radiation therapy seems to be greater in extrahepatic cholangiocarcinoma or gallbladder cancer with R1 resection (Shroff ).
In the last years, an increasing number of genomic alterations has been identified, showing a specific molecular profile in different biliary tract cancer subtypes. This led to the spread of clinical trials with selected targeted agents in the metastatic setting. Although there are signs of efficacy using a molecular-based strategy, it is still premature considering it in an adjuvant setting. However, the identification of molecular prognostic factors could also be helpful in guiding the choice of systemic treatment in resected patients.
- DeOliveira, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007. May; 245(5):755-62
- Horgan, et al. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 2012. Jun 1; 30(16):1934-40
- Edeline, et al. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol 2019 Mar 10; 37(8):658-667
- Ebata, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg 2018 Feb; 105(3):192-202
- Primrose, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol 2019 Mar 25. pii: S1470-2045(18)30915-X
- Shroff, et al. Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline. J Clin Oncol 2019 Apr 20;37(12):1015-1027
- Malka and Primrose. Adjuvant capecitabine in biliary tract cancer: a standard option? Lancet Oncol. 2019 Mar 25. pii: S1470-2045(19)30022-1
- Is capecitabine the new standard of care in biliary tract cancer?
- What is the role of radiotherapy in this setting?
- Will a molecular-driven strategy have a role also in the adjuvant setting?