Bile duct cancer is mostly seen in middle-aged and elderly men aged 50-70 years old, and most of them are highly, moderately or poorly differentiated adenocarcinomas, with few other tissue types. Cholangiocarcinoma has a complex etiology, insidious onset and atypical symptoms, and most patients are already in advanced local stage or have distant metastasis when diagnosed. Its malignancy is high, treatment is difficult and prognosis is very poor. More than 80% of patients die within one year after diagnosis, and the 5-year survival rate is only about 5%.
Surgery is the only treatment that can cure bile duct cancer radically, but it is important to consider whether the tumor invades the surrounding blood vessels and lymphatic vessels; in fact, only about 10% of early stage patients can receive radical surgical resection. Meanwhile, because of the limited role of radiotherapy in advanced cholangiocarcinoma, palliative chemotherapy is the main treatment modality for locally advanced cholangiocarcinoma that is inoperable or accompanied by distant metastases. However, cholangiocarcinoma is not sensitive to chemotherapy and is less sensitive than other gastrointestinal tract tumors. However, if administered appropriately, chemotherapy can help relieve symptoms caused by the tumor (such as jaundice and pain) and improve the patient’s quality of life, thus prolonging survival.
At present, the first-line chemotherapy drug choices for advanced cholangiocarcinoma mainly include the following.
I. Single-agent chemotherapy
(1) Fluorouracil
The results of the phase II clinical study showed that the objective efficiency rate (ORR) of 5-FU alone was about 0-40%, and the median overall survival (OS) was about 2-12 months; the ORR of tegeo alone was about 35.0%, the 1-year survival rate was about 40.0% (95% CI,26.5-53.1%), and the median OS was about 9.0-9.4 months; the ORR of capecitabine alone was about 6%, with a median OS of about 8.1 months (95% CI,7.4-8.9 months).
(2) Gemcitabine
The results of a phase II clinical study showed that the ORR of gemcitabine alone was about 9.4-26.1%, median progression-free survival (PFS) was about 4.3-8.1 months, and median OS was about 9.2-13.1 months; while in a multicenter randomized controlled phase III clinical study reported by ValleJ et al, the disease control rate of gemcitabine alone in first-line treatment of advanced bile duct cancer (DCR) was 71.8%, with median OS and PFS of 8.2 months and 6.5 months, respectively.
Combination chemotherapy
(1) Gemcitabine in combination with platinum
The results of the multicenter randomized controlled phase III clinical study (UK-ABC-02) conducted by ValleJ et al. showed that the DCR of gemcitabine combined with cisplatin in first-line treatment of advanced cholangiocarcinoma was 81.4%, and the median OS and PFS were 11.7 months and 8.5 months, respectively. Another multicenter, open-label, randomized controlled phase III clinical study by LeeJ et al. showed that gemcitabine in combination with oxaliplatin had an ORR of 15.8%, median OS and PFS of 9.5 months and 4.2 months, respectively, for the first-line treatment of advanced cholangiocarcinoma/cholangiocarcinoma, with a well-tolerated toxic response. The toxic response was well tolerated.
(2) Gemcitabine in combination with fluorouracil
Two phase II studies showed that the ORR of gemcitabine combined with tegeo in first-line treatment of advanced cholangiocarcinoma was about 20.0%, the 1-year survival rate was about 52.9% (95% CI, 38.5-65.5%), and the median OS and PFS were about 8.9-12.5 months and 5.6 months. Two other phase II clinical studies investigated the efficacy of gemcitabine in combination with capecitabine in the first-line treatment of inoperable advanced cholangiocarcinoma/biliary cyst cancer, showing an ORR of approximately 31-35.6%, a DCR of approximately 73%, a 6-month survival rate of approximately 55% (95% CI,41-69%), a median OS of 7.0-14.0 months, and a median PFS of approximately 7 months, and further stratified analysis showed that the median OS and PFS of patients with bile duct cancer were 19.0 and 9.0 months, respectively.
(3) Platinum in combination with fluorouracil
The results of a phase II clinical study showed that the 6-month PFS rate was 34.7% and the median OS was 9.9 months for patients with advanced cholangiocarcinoma treated with tegeo in combination with cisplatin in one line, while another phase II clinical study noted that the ORR for advanced cholangiocarcinoma/gallbladder cancer treated with capecitabine in combination with cisplatin in one line was 40.6% (95% CI,23.7-59.4%) and the median OS and PFS The median OS and PFS were 12.4 months (95% CI,6.3-18.5 months) and 3.5 months (95% CI,1.3-5.8 months), respectively.
(4) Other combination chemotherapy regimens
In a phase II clinical study, 43 patients with advanced cholangiocarcinoma received first-line epirubicin and cisplatin in combination with capecitabine for a total of 187 cycles, with a median cycle number of 5 (range, 1-9). 17 patients achieved partial remission (40%, 95% CI, 21-49%) and 10 had stable disease with a median OS of 8 months (95% CI, 6-10 months) after 18 months of follow-up. ) with tolerable toxic effects; RaoS et al. conducted a phase III clinical study comparing the FELV regimen (5-FU, pedialyte glycosides, calcium folinate) with the ECF regimen (epirubicin, cisplatin, 5-FU), which enrolled only 54 patients over 6 years and forced the study to close midway. The results showed a median OS of 12.03 months (95% CI,9.3-14.7 months) and 9.02 months (95% CI,6.46-11.51 months) in the FELV and ECF groups, respectively, with ORRs of 15% (95% CI,3.2-37.9%) and 19.2% (95% CI,6.55-39.3%), respectively. The authors concluded that chemotherapy may provide good disease control and appears to prolong patient survival, but the study was not weighted enough to be of much reference value and cannot be routinely recommended.
In conclusion, for first-line chemotherapy in advanced cholangiocarcinoma, the UK-ABC-02 study is the most complete and largest sample size clinical study to date, showing the survival benefit of gemcitabine combined with cisplatin regimen, which is now the first-line standard of care for palliative chemotherapy in advanced cholangiocarcinoma.
In the selection of chemotherapy regimens, patients’ tumor status, physical status, willingness to treat and tolerance to chemotherapy need to be fully considered, so that the right chemotherapy can be administered to the right patient at the right time to ultimately help patients relieve tumor-induced symptoms (such as jaundice and pain), improve quality of life and prolong survival.