Biliary Tract Cancer (BTC)
Conditions
Keywords
biliary tract cancer, hepatic arterial infusion chemotherapy, systemic therapy
Brief summary
Biliary tract cancer (BTC), including cholangiocarcinoma and gallbladder cancer (GBC), is a group of malignancies with highly heterogeneous, highly aggressiveness, and poor prognosis. Surgery is recognized as the only curative treatment for BTC, however, only about 20% BTC patients are eligible for curative resection since most patients with BTC are diagnosed at an advanced stage. The median overall survival (OS) in patients with unresectable BTC is typically less than 6 months. For patients with unresectable BTC, gemcitabine plus cisplatin (GemCis) had been recommended as the standard first-line treatment for many years. However, the objective response rate (ORR) of this regimen is only 26.1%, and the survival benefit remains limited, with a median OS of less than one year. In recent years, two phase III trials (TOPAZ-1 and KEYNOTE-966) have demonstrated that combining immune checkpoint inhibitors (durvalumab or pembrolizumab) with the GemCis regimen could further prolong survival in patients with BTC, achieving a median OS of 12.9 months and 12.7 months, respectively. Based on this evidence, many guidelines worldwide had recommended GemCis plus durvalumab or pembrolizumab as the preferred standard first-line treatment for patients with unresectable BTC. However, survival benefits from this combination therapy remain relatively limited, and tumor response is suboptimal, with an ORR of only 26.7%-29%. Hepatic arterial infusion chemotherapy (HAIC) enables continuous infusion of chemotherapeutic agents via the hepatic artery, significantly increasing local drug concentration at the tumor site, maximizing antitumor efficacy, and achieving a higher ORR (50%-60%) with substantial reduction in tumor burden. In recent years, HAIC has been increasingly used in the treatment of unresectable BTC, with its efficacy supported by many clinical studies. Firstly, HAIC provides survival benefits comparable to surgery in patients with multifocal intrahepatic cholangiocarcinoma (iCCA), and significantly outperforms systemic therapy. In 2022, a retrospective study enrolled 141 patients who received HAIC and 178 patients who underwent surgical resection from 12 centers. The results showed the median OS was 20.3 months in the HAIC group and 18.9 months in the resection group (P = 0.32), indicating comparable survival outcomes between HAIC and surgery. Given the risks of post-hepatectomy complications, HAIC may serve as an effective alternative treatment strategy for multifocal iCCA. Furthermore, for locally advanced unresectable iCCA, the results in a study in 2024 comparing HAIC with GemCis regimen chemotherapy revealed that although patients in the HAIC group had a higher tumor burden (proportion of multifocal disease: 73.4% vs. 55.3%, P = 0.023), the median OS in HAIC group remained significantly superior to that in the GemCis group (27.7 months vs. 11.8 months, P \< 0.001). Secondly, HAIC has also been demonstrated to be effective in treating perihilar cholangiocarcinoma (pCCA). In 2017, a single-arm, prospective phase II trial conducted in our center showed HAIC with oxaliplatin and fluorouracil yielded an ORR of 67.6%, a median progression-free survival (PFS) of 12.2 months, and a median OS of 20.5 months in treating perihilar cholangiocarcinoma (pCCA). Furthermore, HAIC also has clinical potential in treating advanced GBC. In 2021, a retrospectively study in our center enrolled 26 patients with advanced GBC who received HAIC with oxaliplatin and fluorouracil, of whom 23.1% had failed prior systemic therapy and 34.6% had contraindications to systemic treatment. The results showed that HAIC achieved a median PFS of 10 months and a median OS of 13.5 months, with an ORR of 69.2% and a disease control rate (DCR) of 92.3%. In recent years, many studies have demonstrated that HAIC combined with systemic therapy could yield significant survival benefits in patients with unresectable BTC. A phase II clinical trial in 2022 evaluated the efficacy of HAIC with floxuridine plus systemic gemcitabine and oxaliplatin (GEMOX) in unresectable iCCA. The results showed that the combination therapy achieved a median PFS of 11.8 months and a median OS of 25 months, with a 6-month DCR of 84%, and 58% of patients achieved partial response (PR). Additionally, the association of benefit of combining HAIC with systemic chemotherapy and stage of BTC has been reported, and that patients with locally advanced cholangiocarcinoma may not derive such benefit from this combination. In 2025, a phase II clinical trial conducted in our center evaluated the efficacy and safety of HAIC (bevacizumab, oxaliplatin, and fluorouracil) combined with toripalimab as a first-line treatment for unresectable BTC. The results showed a median PFS of 13.2 months and a median OS of 19 months, with an ORR as high as 84.38%. Some patients achieved successful conversion resection following this combination therapy, and postoperative pathology confirmed pathological complete res
Interventions
PROCEDUREHAIC(GOLF)
Hepatic arterial chemotherapy consisted of infusions of gemcitabin (1000 mg/m2 for 2 hours, d1), oxaliplatin (35 mg/m2 for 2 hours, d1-2), followed by 5-fluorouracil (750 mg/m2 for 22 hours, d1-2) every 3-4 weeks.
DRUGBevacizumab
7.5 mg/kg intravenously before HAIC every 3-4 weeks
PD-1/PD-L1 inhibitor injection intravenously or percutaneously every 3-4 week
PROCEDUREHAIC (FOLFOX)
Hepatic arterial chemotherapy consisted of infusions of oxaliplatin (35 mg/m2 for 2 hours, d1-2), followed by 5-fluorouracil (750 mg/m2 for 22 hours, d1-2) every 3-4 weeks.
DRUGGemcitabin
1000 mg/m2 intravenously
PROCEDUREDe-escalation strategy
curative treatment (surgery, ablation, SIRT, or SBRT) or maintenance treatment (S-1, Bevacizumab, and PD-1/PD-L1 inhibitor) when tumor response got CR, PR, or SD
PROCEDURESecond-line treatment
Other treatments when tumor response got PD
Sponsors
Peking University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age: 18-80 years, both genders. * Diagnosis of biliary tract cancer (including intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, and gallbladder cancer) and confirmed by histopathological or cytopathological examination. * Treatment-naive. * ECOG PS score \< 2. * Child-Pugh score: Class A or B (≤7). * Normal major organ function, meeting the following standards:(1) Blood routine examination:A. Hb≥90 g/L;B. ANC≥1.5×10\^9/L;C. PLT≥75×10\^9/L;(2) Biochemical examination:A. ALB ≥30g/L;B. ALT and AST\<5×ULN;C. TBiL ≤2×ULN;D. Creatinine ≤1.5×ULN;(3) Coagulation function:A. International normalized ratio (INR) ≤1.5×ULN;B. Activated partial thromboplastin time (APTT) ≤1.5×ULN.
Exclusion criteria
* Coexistent or synchronous malignancies. * Distal cholangiocarcinoma. * Allergic to contrast agents or oxaliplatin. * Pregnant or lactating women. * Multiple extrahepatic metastases or combined malignant pleural and peritoneal effusions. * History of organ transplantation. * With infections requiring anti-infection treatment. * Severe and irreparable coagulation dysfunction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OS | From date of treatment beginning until the date of death from any cause, assessed up to 36 months. | The time from treatment initiation to death due to any cause |
| clinical complete response rate | From date of treatment beginning until the date of first documented progression disease, up to 36 months. | The proportion of participants in the analysis population who have clinical complete response (CR) determined by investigators using mRECIST criteria at any time during the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS | From date of treatment beginning until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | The time from treatment initiation to the first documented disease progression or death due to any cause, whichever occurs firstly. |
| ORR | From date of treatment beginning until the date of first documented progression disease, up to 36 months. | The proportion of participants in the analysis population who have complete response (CR) or partial response (PR) determined by investigators using mRECIST criteria at any time during the study. |
| Number of patients with treatment-related adverse events | From date of treatment beginning until the date of study treatment completion, up to 36 months. | Number of patients with AE, treatment-related AE (TRAE), serious adverse event (SAE) assessed by CTCAE v5.0. |
Countries
China
Contacts
CONTACTXiaodong Wang
STUDY_DIRECTORXiaodong Wang
Peking University Cancer Hospital & Institute
Outcome results
None listed