Introduction

Cholangiocarcinoma, also known as bile duct cancer, is a rare cancer with an incidence of 0.3 – 6 per 100,000 people per year, accounting for about 3% of all gastrointestinal cancers.¹ It is classified by anatomical site into 2 types: intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). Extrahepatic cholangiocarcinoma can be further categorised as either perihilar (pCCA) or distal (dCCA), depending on the tumour location.

The prognosis of cholangiocarcinoma is generally poor, as patients often present symptoms and are diagnosed at an advanced or metastatic stage with an aggressive tumour. Common clinical symptoms, which vary with tumour location and size, include abdominal pain, fatigue, jaundice, dark-coloured urine and clay-coloured stools. Surgical resection remains the only potentially curative way to treat cholangiocarcinoma decisively. However, the majority of patients are diagnosed at stages where surgery is not feasible. In such cases, systemic drug therapy and radiotherapy are considered. Even in resected cases, adjuvant systemic therapy or radiotherapy may be used to reduce the risk of local recurrence, particularly in patients with positive surgical margins.^1,2

Treatment strategies for cholangiocarcinoma vary from case to case, considering tumour size and location, disease stage, gene mutations and clinical treatment response. Systemic drug therapy includes chemotherapy, targeted therapy and immunotherapy. Traditional chemotherapy, such as 5-fluorouracil (5-FU), capecitabine and cisplatin, acts by interfering with the tumour cell life cycle. Targeted therapy, like dabrafenib and trastuzumab, is employed in patients with certain identified gene mutations. Immunotherapy, including immune checkpoint inhibitors pembrolizumab and nivolumab, enhances the immune system to fight against tumour cells.

This article will focus on the role of traditional chemotherapy as adjuvant and neoadjuvant therapy in the management of cholangiocarcinoma.

Adjuvant chemotherapy in cholangiocarcinoma

Adjuvant therapy is defined as additional treatment given to patients after primary treatment, especially surgery, aims to kill remaining cancer cells in the body and reduce the risk of recurrence. Due to the higher recurrence rate of cholangiocarcinoma after surgical resection, many studies have been conducted to explore the benefits of adjuvant chemotherapy to potentially lower the risk of metastasis and disease relapse. The following section will summarise key clinical trials that have investigated the role of adjuvant chemotherapy in cholangiocarcinoma³. 

Relevant clinical trials

Bile duct cancer adjuvant trial (BCAT)⁴ 

The BCAT trial was a randomised, open-label, phase 3 clinical trial conducted across multiple centres in Japan between 2007 and 2011. It enrolled patients with extrahepatic bile duct cancer (pCCA or d CCA only) who had undergone surgical resection within 10 weeks. Participants were allocated randomly to the gemcitabine or observation groups.

Gemcitabine, an antimetabolite chemotherapy, acts as a nucleoside analogue that interferes with DNA replication by competing with deoxycytidine. In the trial, patients in the gemcitabine group received gemcitabine intravenously at a dose of 1000 mg/m² over 30 min on days 1, 8 and 15, followed by a rest period of 1 week (1 cycle). Patients in the observation group did not receive any pharmacological treatment after surgery.

A total of 226 patients were enrolled (117 patients in the gemcitabine group and 108 in the observation group). Results showed no significant difference in overall survival rate and relapse-free survival rate between the gemcitabine and observation groups. However, significant haematological toxicity in the gemcitabine group was observed, including abnormal leucocytes, neutrophils, haemoglobin and platelet levels.

Conclusion: Adjuvant gemcitabine did not improve survival outcomes in resected extrahepatic bile duct cancer.

PRODIGE12-ACCORD18 (UNICANCER GI group) study⁵ 

This randomised, open-label, phase 3 clinical trial was conducted in France between 2009 and 2014. Patients with resected biliary tract cancer (cholangiocarcinoma or gallbladder cancer) within 3 months of surgery were randomised to GEMOX or surveillance groups.

The GEMOX regimen consisted of gemcitabine and oxaliplatin. Oxaliplatin, a third-generation platinum compound, disrupts DNA replication and transcription by forming bulky ligand covalent bonds with DNA. Patients in the GEMOX groups were given gemcitabine 1,000 mg/m² intravenously with a fixed-dose infusion rate over 100 minutes on day 1 and oxaliplatin 85 mg/m² over 2 hours on day 2 every 2 weeks for up to 12 cycles. 

A total of 196 patients were enrolled (95 in the GEMOX group and 99 in the surveillance group). Unfortunately, there was no significant improvement in the relapse-free survival rate and the overall survival rate with GEMOX compared to surveillance. Patients in the GEMOX group experienced higher rates of haematologic, neurologic and hepatic side effects, including a decrease in neutrophil counts, elevation of liver enzyme GGT and peripheral neuropathy.

Conclusion: Adjuvant GEMOX did not improve survival in resected biliary tract cancer.

BILCAP study⁶ 

The BILCAP trial was a randomised, controlled, phase 3 clinical trial conducted in the UK from 2006 to 2014. Patients with cholangiocarcinoma or muscle-invasive gallbladder cancer who completed resection within 16 weeks were included to be allocated into the capecitabine and observation groups.

Capecitabine is an oral prodrug converted into the active form 5-fluorouracil (5-FU), which inhibits thymidylate synthase to disrupt DNA synthesis.  Patients received capecitabine 1250 mg/m² orally twice a day on days one to 14 of a 21-day cycle for eight cycles (24 weeks).

A total of 447 patients were enrolled among the intention-to-treat population (223 patients in the capecitabine group and 224 in the observation group). In the protocol-specified sensitivity analysis, among patients who fully adhered to the trial protocol, there were 210 patients in the capecitabine group and 220 in the observation group.

Results in protocol-specified sensitivity analysis demonstrated a significant improvement in overall survival and recurrence-free survival in the capecitabine groups, compared to the observation group. Common adverse effects observed in the capecitabine group were hand-foot syndrome, fatigue, diarrhoea and haematological abnormalities.

Conclusion: Despite a non-significant overall survival benefit in the intention-to-treat analysis, per-protocol results and recurrence-free survival benefit established capecitabine as the standard adjuvant therapy after resection of biliary tract cancer.

Ongoing ACTICCA-1 trial

The ACTICCA-1 is an ongoing randomised, phase 3 trial comparing gemcitabine and cisplatin versus capecitabine alone (current standard treatment) as adjuvant therapy in patients with resected cholangiocarcinoma or gall bladder cancer. Recruitment has been completed, and results are awaited.

Guideline recommendations

1. National Comprehensive Cancer Network (NCCN): After-surgery systemic therapy for removable bile duct cancer: capecitabine (preferred)⁷
2. European Society for Medical Oncology (ESMO): Adjuvant therapy with capecitabine should be considered for patients with cholangiocarcinoma (CCA) or gallbladder carcinoma (GBC) following resection⁸
3. American Society of Clinical Oncology (ASCO): Patients with resected biliary tract cancer should be offered adjuvant capecitabine chemotherapy for a duration of 6 months⁹
4. British Society of Gastroenterology (BSG): Patients who have undergone surgical resection for CCA should be considered for 24 weeks of adjuvant chemotherapy (currently capecitabine)¹⁰

Neoadjuvant chemotherapy in cholangiocarcinoma

Neoadjuvant therapy is a type of treatment administered to patients before the main treatment to reduce the size of the tumour or stop the spread to other sites (“micrometastases”). This approach aims to improve resectability, enhance treatment effectiveness and increase the likelihood of success in cancer treatment.

Clinical studies

Meta-analysis of small case series or retrospective studies showed that neoadjuvant treatment with chemotherapy (using regimens such as 5-FU, gemcitabine or S-1) plus radiotherapy has potential benefits in the R0 resection rate in cholangiocarcinoma. However, the evidence remains limited, and the role of neoadjuvant chemotherapy is not yet well established. Current research efforts are investigating whether treatment strategies used in pancreatic cancer can be applied to bile duct cancers.

1. A phase 2 study is assessing the potential of the FOLFOXIRI regimen, including fluorouracil, folinic acid, irinotecan and oxaliplatin for patients with borderline resectable cholangiocarcinoma
2. Another phase trial is evaluating the regimen of gemcitabine, cisplatin and Nab-paclitaxel in patients with stage IB-III iCCA
3. A phase 3 trial has completed data collection on cisplatin plus gemcitabine in biliary tract cancers and is awaiting results to determine its impact on overall survival^{11, 12}

Guidelines and expert opinions

Currently, there is no consensus guideline supporting the routine use of neoadjuvant chemotherapy in cholangiocarcinoma. Available evidence is derived mainly from small retrospective cohorts and case series. Both the National Comprehensive Cancer Network (NCCN) and the British Society of Gastroenterology (BSG) emphasise that neoadjuvant therapy is not standard of care for resectable CCA. The BSG specifically advises against routine use of neoadjuvant chemotherapy in these patients. Stronger evidence from ongoing phase II and III trials is awaited before recommendations can be revised (7, 10).

Conclusion

Cholangiocarcinoma remains a highly aggressive cancer with a poor prognosis, largely due to late diagnosis and limited curative treatment options. Surgical resection is the only potentially curable treatment strategy, but recurrence rates remain high. Evidence from pivotal trials such as BILCAP has established capecitabine as the current standard adjuvant therapy following resection to eliminate residual cancer cells and lower the chance of relapse. However, the role of neoadjuvant chemotherapy in cholangiocarcinoma remains unclear. Available data are limited to small retrospective series and early-phase studies, suggesting possible improvements in resectability and R0 resection rates, but without sufficient evidence to support routine use.

Overall, adjuvant therapy with capecitabine remains the evidence-based standard of care after resection, while neoadjuvant chemotherapy is investigational and should only be considered in the context of clinical trials or highly selected cases within a multidisciplinary team. Future trial outcomes are expected to clarify the potential role of neoadjuvant strategies in improving survival outcomes for patients with cholangiocarcinoma.