Apatinib Monotherapy as a Second-Line Treatment for Patients with Advanced Biliary Tract Cancer: a Retrospective Single-Center Observational Study

Apatinib Monotherapy as a Second-Line Treatment for Patients with Advanced Biliary Tract Cancer: a Retrospective Single-Center Observational Study Yue Zhao1, #,*, Wenqian Gu2, #, Jianmei Li1, Chunyuan Tian1 1Department of Oncology, Qinhuangdao Fourth Hospital, 64 Guangming Rd, 066000, Hebei Province, China 2Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 165, 8200 Aarhus N, Denmark Research Open Access Journal of Cancer Research and Therapeutic Oncology


Introduction
Biliary tract cancer (BTC) is a lethal malignancy encompassing gallbladder carcinoma and cholangiocarcinoma.
The latter is further subdivided into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma [1]. Though it is less common in the Western world, where the annual incidence is 0.35 to 2 per 100,000, the prevalence in Hispanic and Asian populations is much higher [2]. For instance, the incidence may be up 40-fold higher in China than in the United Kingdom [3,4].
At present, a satisfactory outcome of BTC hinges on early diagnosis and complete surgical resection. However, due to its slow-growing nature and non-specific symptomatology, BTC is often diagnosed at an advanced stage when surgical options are limited [5,6]. Even in patients undergoing successful resection, recurrence rates may reach 49-64%, and most cases will eventually progress to metastatic disease, which highlighting the importance of advancing adjuvant therapies [7][8][9].
According to the guideline of the National Comprehensive Cancer Network, Version 2.2019, standard first-line chemotherapeutic regimens for BTC include gemcitabine-based or gemcitabine-cisplatin combination therapy for the metastatic or unresectable disease [10]. However, no clear guidance exists for second-line treatment following disease progression under first-line chemotherapy. Many clinical trials are currently being conducted to evaluate the efficacy of a multitude of agents targeting the molecular level in second-line settings [11]. However, the results of these trials have not yet been published. Angiogenesis, a physiological process through which new blood vessels form from pre-existing vessels is responsible for tumor growth and disease progression [12,13]. In recent years, anti-angiogenic treatment has become an essential tool in the armamentarium against advanced cancers. Vascular endothelial growth factor (VEGF) and its cognate receptor, VEGFR-2 is recognized as the most prominent regulators of angiogenesis [14], and have therefore become the main target of current antiangiogenic agents.
Thus, strategies focus on antiangiogenesis therapy via VEGF pathway inhibition might have clinical benefits in the treatment of patients with advanced BTC [15]. A number of agents targeting the VEGF/VEGFR signaling pathway, including bevacizumab, aflibercept, and ramucirumab, have been developed and approved for several indications by the U.S. Food and Drug Administration [13]. VEGF is over expressed in 40-75% of patients with BTC [16]. In a phase II trial, bevacizumab was added to second-line chemotherapy for advanced BTC and reported to have a modest benefit as well as a tolerable safety profile [17]. Moreover, in another phase II trial of treatment of advanced BTC, ramu-cirumab showed limited activity but still infrequent grade 3-4 treatment-related adverse events (AEs) when combined with pembrolizumab in a second-line setting [18].
Apatinib is an oral tyrosine kinase inhibitor selectively inhibiting VEGFR-2, thereby suppressing tumor growth by obstructing angiogenesis. It has been approved in China for advanced or metastatic gastric cancer and has shown promising therapeutic effects against a variety of other cancer types, including ovarian cancer [19], breast cancer [20][21][22], lung cancer [23,24], hepatocellular carcinoma [25][26][27], sarcoma [28][29][30], and thyroid cancer [31,32]. Nevertheless, research evaluating the effect of apatinib on advanced BTC is limited. As a broad-spectrum anticancer agent, apatinib has been a frequent option for patients with advanced BTC after first-line treatment failure in our hospital at the discretion of the treating physicians and showed favorable effects.
In the present study, we hypothesized that apatinib is an effective second-line regimen for the treatment of patients with advanced BTC. Therefore, we retrospectively assessed the effects of apatinib monotherapy in a second-line setting after the failure of first-line systemic chemotherapy with gemcitabine or gemcitabine-cisplatin in patients with advanced BTC. 98

Eligibility criteria
The study was conducted retrospectively on patients

Treatment Methods
Following disease progression after first-line treatment, patients were offered apatinib at a dose of 500 mg once daily until disease progression or intolerable. One dose reduction (to 250 mg) due to drug-related toxicity was allowed. Dose-limiting toxicity was defined as possibly or definitely drug-related grades 3-4 toxic responses. Apatinib was provided by Jiangsu Hengrui Medicine Co., Ltd and was administered orally. One treatment cycle was 28 days long.

Evaluation of efficacy and safety
Clinical and radiologic evaluations were conducted at baseline and at 1 month; thereafter every 2 months or whenever clinically indicated until disease progression. At 1 month and 6 months following apatinib administration, tumor response was assessed as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Definitions of the four categories of tumor response are listed in Table 1. Progression-free survival (PFS) was defined as the length of time from enrollment (1st apatinib administration) to investigator-assessed disease progression or death from any cause, whichever occurred first. Objective response rate (ORR) was defined as the percentage of patients with an objective response among all cases and calculated as the CR rate plus the PR rate. Disease control rate (DCR) was defined as the percentage of patients with CR or PR, or SD. Treatment efficacy was evalu- A schematic illustration of the study overview is shown in Figure   1.

Category
Definition Complete response (CR) Complete disappearance of all target lesions Partial response (PR) ≥30 % decrease in tumor diameter from baseline Stable disease (SD) Small changes that do not meet the above criteria Progressive disease (PD) >20% increase in tumor diameter from baseline

Patient characteristic
Before data cutoff, 18 patients with advanced BTC received their first dose of apatinib, including 12 patients (67%) with cholangiocarcinoma and 6 patients (33%) with gallbladder carcinoma. The metastatic site included liver, retroperitoneal node, lungs, and supraclavicular lymph node. All pathological results were confirmed at Qinhuangdao Forth Hospital, China. Patient characteristics at baseline are summarized in Table 2. Within 4 months before apatinib administration, all patients had received gemcitabine as a single agent or in combination with cisplatin for 2-6 cycles (only 3 patients who were over 60 years old received gemcitabine monotherapy; all other patients received the combined regimen) and, unfortunately, the disease progressed. The patients' median age was 55 years and males counted for 78%.
Eight cases (44%) were post-surgery recurrence, while the other 10 (56%) were initially diagnosed, patients. All patients started apatinib at a dosage of 500 mg; in 6 patients (33%), the apatinib dose was reduced to 250 mg daily within the first10 days due to intolerable toxicity. (2 with gallbladder carcinoma, 2 with cholangiocarcinoma) had PD, which resulted in a DCR of 44%. All patients were followed up until progression of the disease. All 18 patients, including 6discontinued cases, were counted for Kaplan-Meier analysis for PFS.

Evaluation of efficacy
The median PFS was 8 months for the whole population; it was 2.5 months for gallbladder carcinoma and 8 months for cholangiocarcinoma. Kaplan-Meier curve for PFS presenting the whole cohort is depicted in Figure 2A; Figure Table 3. Four patients required apatinib discontinuation due to grade 3 AEs, including 2 hypertension cases, 1 diarrhea and 1 hand-foot syndrome case; and all recovered after drug withdrawal. Two patients gave up cancer treatment due to grade 3 hypertension and fatigue and for personal reasons. No bleeding cases, grade 4 AEs, or drug-related deaths occurred.

Discussion
To our knowledge, this is the first study evaluating the efficacy and safety profile of apatinib as a second-line treatment in patients with advanced BTC. The median PFS was 8 months, while the 1-month ORR was 33% and DCR was 72%, the 6-month DCR was 44%. Furthermore, apatinib had a manageable toxicity profile.
Even though surgery is potentially curative, BTC has a high recurrence rate due to its aggressive nature. The vast majority of patients therefore also received systemic chemotherapy, where the current standard therapy is gemcitabine plus cisplatin [33]. and P13K/AKT pathways [37]. Furthermore, in a case report, apatinib was used for a 23-year-old female with advanced unresectable intrahepatic cholangiocarcinoma as second-line treatment and a PFS of 6 months were observed [38].
To further study the response to apatinib, we retrospectively analyzed the safety and efficacy data of apatinib as a second-line regimen in patients with advanced BTC, revealing a median PFS of 8 months. In the present study, the outcome of apatinib monotherapy was associated with a longer median PFS time than what has previously been reported with chemotherapy [34, 35,39], and our findings mirror the above-mentioned result from the case report [38]. This indicates that targeted therapy, especially with agents targeting VEGF pathway, might constitute a breakthrough in establishing a second-line treatment for advanced BTC.
Though both cholangiocarcinoma and gallbladder carcinoma fall under BTC, they may be in fact distinct diseases with differences in prognosis and patterns of recurrence [40].
Additionally, immunohistochemical analysis for BTC samples has revealed the tumor somatic variants and genomic heterogeneity between the two diseases [41]. In this study, cholangiocarcinoma seemed more responsive to apatinib mono-

Ethical Statement
Approval for this study was obtained from the ethics committee of Qinhuangdao Forth Hospital, China; all procedures performed in this study were in accordance with the ethical standards of the institutional and national research committees and with the principles of the Declaration of Helsinki.

Disclosure
The authors declare that they have no conflicts of interest in this work.

Acknowledgments
The authors would like to thank Associate Professor,

Data Availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.