BTC is a rare but highly malignant tumor. 60% − 70% of new BTC cases are diagnosed as advanced stage[3, 15]. Patients of advanced BTC have a very poor prognosis with a median OS less than 12 months[15]. Even for operable BTC, there is still a high recurrence and distant metastasis rate after surgery. Advanced BTC is dominated by systemic medications. Prospective randomized control studies have shown that systemic chemotherapy can prolong the survival of patients with advanced BTC compared with optimal supportive care.
Based on the results of a phase III randomized controlled ABC-02 study, gemcitabine and cisplatin are recommended as the first-line standard treatment regimen for advanced, which can reduce the OS of patients with advanced BTC from 8.1 Month increased to 11. 7 months[16]. In the meantime, gemcitabine combined with S-1 was also recommended as first-line treatment options for advanced BTC[17, 18]. However, there are no clear second-line treatment options for those with disease progression after first-line treatment. New treatment strategies are urgently needed.
Currently, cancer therapy has entered the era of molecular therapy, and targeted therapy based on genetic changes has become an effective strategy for cancer[19]. A better understanding of the molecular pathology of BTC can help identify appropriate therapeutic targets. Numerous studies have demonstrated the landscape of molecular mutations in BTC, including EGFR pathway, HER2 (ERBB2), VEGF pathway, PI3K/mTOR signaling cascade, FGFR pathway, IDH1, MEK pathway and etc[20–23]. VEGF overexpression occurs in more than half of cases of BTC,and the VEGF pathway mediates its tumorigenic potential not just by angiogenesis or vascular permeability, but also by cell signaling for tumor initiation[1]. Previous studies have confirmed the therapeutic effects and application prospects of VEGF inhibitors in BTC, including bevacizumab[24], ramucirumab, cediranib[25], vandetanib[26] and sunitinib[27].
As a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2), apatinib has showed good clinical efficacy in a variety of solid tumors. Previous study demonstrated that apatinib inhibits VEGF-mediated cell migration and invasion of CCA cell lines[14], and apatinib promotes apoptosis in intrahepatic cholangiocarcinoma[28], which highlight the potential clinical utility of apatinib in BTC. However, clinical use of apatinib in BTC has not been reported to date. To our knowledge, this is the first report to investigate the clinical efficacy and safety of apatinib in advanced or recurrent BTC.
In our present study, treatment efficacy of apatinib was evaluated in the 28 patients with advanced or recurrent BTC who progressed after prior systemic therapies. Although CR was not observed, the ORR and DCR reached to 21.4% and 75.0% respectively, median PFS and OS were 4.3 month and 6.2 months. There are very few studies on standard second-line treatment regimens after first-line chemotherapy failure in BTC. In the phase III randomized controlled ABC-06 study, oxaliplatin combined with 5-FU (mFOLFOX) solution second-line chemotherapy increased OS from 5.3 months to 6.2 months, with a median PFS of 4.0 months. In another randomized phase II study of second-line XELIRI regimen versus irinotecan monotherapy in BTC, median PFS were 3.7 and 2.4 months respectively[29]. PFS and OS survival in our present study was superior. It is noteworthy that, approximately 60% patients received apatinib as third- or fourth-line treatment, but still got a good response and improved survival.
Apatinib targeted therapeutics showed efficacy both in apatinib monotherapy and combination therapy patients. In combination therapy population, 3 patients received apatinib plus PD-1 inhibitor, of which one patient achieved PR, and the other 2 patients had SD. Our study suggested that compared with traditional pure cytotoxic drugs, targeted therapy has unique advantages and application prospects. For patients with advanced BTC, targeted therapy or targeted therapy combined with chemotherapy and immunotherapy may be new treatment strategies, and more clinical researches should be conducted[30].
Advanced or recurrent BTC is incurable, and its treatment is palliative, with the goal of extending survival. Gentle, effective and concerned about the quality of life are the basic principles of treatment. Therefore, treatment-related toxicity is also a major evaluation indicator. Commonly reported apatinib-related AEs included secondary hypertension, hand and foot syndrome, fatigue and proteinuria, a similar safety profile was observed in the present study. Most of the adverse events were grade 1–2 in severity, and no unexpected side effects or treatment-related death were observed. Dose reduction occurred in only two patients adjusting the dosage from 500 to 250 mg due to adverse events in apatinib monotherapy population. In combination therapy population, the above incidence of apatinib-related adverse reactions is lower, but the incidence of hematological toxicity is relatively higher due to utilization of chemotherapy. In general, apatinib treatment was well tolerated.
Our study has some limitations, because it is a retrospective study obtained from a single center, and the number of cases enrolled is not very large. However, the efficacy that median PFS in the 28 patients with advanced or recurrent BTC patients who had undergone prior systemic therapies reached to 4.3 months is still encouraging. Thus, large randomized controlled trials from multi-center are needed to confirm the clinical value of apatinib in advanced or recurrent BTC.