Abstract
Biliary tract cancer (BTC) is the fifth most common cancer in digestive tract tumors. It is divided into three subtypes – intrahepatic BTC, perihilar BTC, and distal BTC – according to the locations of tumors in the biliary tract trees. For early-stage BTC, radical resection is the most effective and first choice. However, the all-stage 5-year overall survival (OS) rate is less than 20% owing to aggressive behavior and late symptomatic presentation. 1 Therefore, anticancer medicine treatment is important for locally advanced or metastatic BTC to improve prognosis. 2
We read with interest the recent article by Wang et al. 3 entitled ‘Efficacy and safety of a triple combination of atezolizumab, bevacizumab plus GEMOX for advanced biliary tract cancer: a multicenter, single-arm, retrospective study’. The authors concluded that the best overall response rate was 76.7%, the disease control rate was 90.0%, the median progression-free survival (PFS) was 12.0 months, and the median OS was not reached in patients suffering from advanced BTC treated with atezolizumab, bevacizumab, and gemcitabine plus oxaliplatin (GEMOX). We agree with the authors about the effects and safety of the triple combination treatment but have some comments on it.
Patients with advanced BTC are mainly treated with systemic therapy, including chemotherapy, targeted therapy, and immunotherapy. As a single approach is not quite effective, comprehensive treatments are usually needed. Because of the different types and heterogeneity of BTC, its clinical manifestations, genotypes, surgical methods, and drug therapy vary. At present, the main drug treatment for BTC is chemotherapy. Gemcitabine plus cisplatin is still the first-line therapy for patients with advanced BTC, based on the ABC-02 trial, which showed that the median OS and median PFS were 11.7 and 8.0 months, respectively. 4 However, there is no established standard treatment after failure of first-line chemotherapy. The FOLFOX regimen (oxaliplatin + 5-fluorouracil + calcium folinate) and capecitabine are alternative second-line adjuvant chemotherapies, especially for intrahepatic BTC.
The progression of BTC is rapid, and chemotherapy is highly resistant. It is important to screen for other treatment methods to improve the survival of patients. Immunotherapy has achieved satisfactory therapeutic effects in some cancers. 5 For unresectable BTC, the National Comprehensive Cancer Network guidelines recommend performing coarse needle biopsy to provide cytological and histological pathological information. After obtaining tissue biopsy samples, proceeding to the detection of microsatellite instability (MSI)/mismatch repair defects (dMMR) and tumor mutational burden (TMB) to screen out potential immunotherapy beneficiaries is recommended, as BTC patients with MSI-high, MMR deficiency, and TMB-high tumors may benefit from immunotherapy. Pembrolizumab is recommended in advanced BTC patients with dMMR or MSI-high disease in the first-line treatment. 6
In contrast to extrahepatic BTC, the treatment of which mainly relies on gemcitabine plus cisplatin, there are specialized targeted drugs for intrahepatic BTC. Comprehensive genomic profiling has identified several potentially actionable oncogenic alterations in patients with BTC. 7 Next-generation sequencing should be performed to select relevant targeted drugs. Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements, occurring in 10–16% of patients, are found almost exclusively in intrahepatic BTC. In a multicenter study by Abou-Alfa et al. that enrolled intrahepatic BTC patients who had progressed after at least one systemic therapy, 35.5% of patients with FGFR2 fusions or rearrangements treated with pemigatinib achieved an objective response. The median PFS and OS were 6.9 and 21.1 months, respectively. 8 A phase III study on advanced isocitrate dehydrogenase 1 (IDH1)-mutant BTC showed that PFS was longer for patients in the ivosidenib group than for those in the placebo group (2.7 and 1.4 months, p < 0.0001). 9 Although targeted therapy has achieved certain therapeutic effects in intrahepatic BTC, due to different tumor origin cells and a lack of understanding of the molecular structure, there is no precise and effective targeted drug recommended for extrahepatic BTC. Furthermore, due to insufficient understanding of the molecular pathological mechanisms of BTC, targeted treatment for intrahepatic BTC is mostly limited to small sample clinical studies, and large-scale clinical trials are needed in the future to determine the effectiveness of targeted treatment.
In addition, intrahepatic BTC can be treated locally, such as with transcatheter arterial chemoembolization, radiofrequency ablation, hepatic artery infusion chemotherapy, and Yttrium 90 selective internal radiotherapy treatment. Therefore, the first-line treatment of advanced intrahepatic BTC is mainly based on gemcitabine plus platinum, which could be followed by combination therapy with immunotherapy plus targeted therapy as the second-line treatment. Furthermore, local treatment for intrahepatic BTC could also be performed if necessary. 10
Due to the different clinical manifestations, genotyping, surgical methods, and drug treatment plans of intra- and extrahepatic BTC, studying BTC in different locations together could lead to biased results. Comprehensive treatment and multidisciplinary treatment modes could provide patients with more personalized treatment plans and improve OS. In the future, BTC could be studied in different locations, and multicenter large-scale clinical studies are needed to draw more clinically meaningful conclusions.
