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Efficacy and Safety of Apatinib for the Treatment of Advanced or Recurrent Cervical Cancer: A Single-Arm Meta-Analysis Among Chinese Patients

Background: Although various effective compounds for the second- and third-line treatment of advanced or recurrent cervical cancer improved the overall survival, the optimal regimen remains controversial. Previous studies revealed that apatinib had extensive anti-tumor activities. However, almost all studies on apatinib in recurrent cervical cancer are non-randomized controlled trials with small sample sizes, different first-line treatments, and uncontrolled statistical analysis, which may result in a lack of effective metrics to evaluate the efficacy and safety of apatinib. Here, this meta-analysis aims to evaluate the efficacy and safety of apatinib in patients with advanced or recurrent cervical cancer. Methods: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for relevant studies. Outcomes including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were extracted for further analysis. Results: Seven studies involving 243 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 22.9% and 68.6%, respectively. With regard to survival analysis, the pooled PFS and OS were 5.19 months and 10.63 months, respectively. The most common treatment-related adverse events of apatinib were hand–foot syndrome (all grade: 39.6%, ≥grade III: 7.5%), hypertension (all grade: 34.5%, ≥grade III: 9.2%), and fatigue (all grade: 28.0%, ≥grade III: 5.1%). Conclusions: In summary, this meta-analysis demonstrated that apatinib has promising efficacy and safety for patients with advanced or recurrent cervical cancer. Systematic Review Registration: https://inplasy.com/inplasy-2022-7-0049/, identifier INPLASY202270049


INTRODUCTION
Cervical cancer is the fourth most common cancer in women worldwide, with approximately 570,000 new cases and 312,000 deaths annually (Bray et al., 2018). Despite early cervical cancer screening and subsequent surgical removal of the precancerous lesion help reducing the cancer incidence and mortality, more than 70% of cervical cancer cases in developing countries are diagnosed at an advanced stage of the disease (Sahasrabuddhe et al., 2012;Liu et al., 2019). Compared to local or early cervical cancer, outcomes for patients with advanced or recurrent disease are poor. Previous studies have shown that the 5year survival rate for advanced cervical cancer is less than 40%, and for patients with stage IV, the survival rate remains only 5-15% (Tewari and Monk, 2005). Though platinum-based chemotherapies are still the cornerstone treatment for the majority of these patients, the prognosis is unsatisfactory due to multidrug resistance and side effects. Also, follow-up treatments are just palliative for the purpose of prolonging or maintaining patients' survival (Elst et al., 2007;Pfaendler and Tewari, 2016). Hence, it is urgent to develop new methods to improve long-term disease control for advanced or recurrent cervical cancer.
Against this background, anti-angiogenic therapy is an attractive and promising treatment option for patients with advanced or recurrent cervical cancer. The results from the phase III GOG240 trial directly recommended that the combination of platinum-based chemotherapy and bevacizumab was the standard frontline treatment in advanced or recurrent cervical cancer, which showed an improvement in overall survival from 13.3 to 17 months (Tewari et al., 2014a). However, other angiogenesis inhibitors have also been tested, but there is no consensus on the benefit of second-and third-line chemotherapy in this disease. Apatinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor 2(VEGFR-2). Several clinical trials have shown that apatinib could improve tumor response and survival in various cancer types of middle-late solid tumors (Hu et al., 2014;Lan et al., 2018;Qin et al., 2021;Zhao et al., 2021). However, almost all studies on apatinib in recurrent cervical cancer are non-randomized controlled trials with small sample sizes, different first-line treatments, and uncontrolled statistical analysis, which may result in a lack of effective measurement for evaluating the efficacy and safety of apatinib. Thus, this meta-analysis was carried out to evaluate the efficacy and safety of apatinib in advanced or recurrent cervical cancer patients and hoped that the results of this study might provide more options for clinical treatments.

Search Strategy
Four databases (PubMed, Embase, the Cochrane Library, and Web of Science) were comprehensively searched for relevant studies. The date of the last search was 25 June 2021. The following MeSH and free words were used in the searches: "Uterine Cervical Neoplasms OR Uterine Cervical Cancer OR Cervical Cancer OR Cancer of the Cervix" AND "Apatinib OR rivoceranib mesylate OR YN968D1 OR rivoceranib OR apatinib mesylate". The language was confined to English. In addition, we evaluated the references of included articles and selected more relevant studies.

Selection Criteria
Studies were included in this meta-analysis if they met the following inclusion criteria: 1) population: patients were diagnosed with advanced or recurrent cervical cancer, irrespective of the subtype; 2) intervention: patients were treated with apatinib, either with single-agent therapy or in combination with chemotherapy; 3) study type: phase II clinical trials or retrospective analysis; and 4) outcomes: patients were reported with interested clinical tumor outcomes, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The tumor response was evaluated using the Response Evaluation Criteria in Solid  Numbers I-Ⅷ in heading signified: Ⅰ, representatives of the exposed cohort; Ⅱ, selection of the non-exposed cohort; Ⅲ, ascertainment of exposure; Ⅳ, demonstration that outcome of interest was present at the start of the study; Ⅴ, comparability of cohorts on the basis of the design or analysis; Ⅵ, assessment of the outcome; Ⅶ, was follow-up long enough for outcomes to occur? Ⅷ, adequacy of follow-up of cohorts.
Frontiers in Pharmacology | www.frontiersin.org August 2022 | Volume 13 | Article 843905 Tumors (RECIST) version1.1 (Eisenhauer et al., 2009). Toxic effects were evaluated for their incidence and severity using the Common Terminology Criteria for Adverse Events (CTCAE) (Trotti et al., 2003). The exclusion criteria were as follows: 1) animal experiments, cell research, reviews, meta-analyses, duplicates, case reports, or letters were not taken into consideration; and 2) studies with patient number less than 10 were excluded. Two investigators independently identified potential eligible articles through inclusion and exclusion criteria.
Any disagreement regarding study inclusion was resolved between these two or with a third investigator.

Data Extraction and Quality Assessment
The required data from all included studies were independently extracted by two investigators, and the quality assessment of the studies was performed afterward. The extracted characteristics were summarized as follows: authors, publication year, nation, sample size, prior therapeutic regimen, median age, median follow-up, and reported endpoints. Indexes for clinical and safety outcomes included ORR, DCR, OS, PFS, the incidence of any AEs, and ≥grade 3 AEs. Also, two investigators independently assessed and extracted the required data from all included studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of including non-controlled trials (Stang, 2010). Also, the retrospective studies were assessed by the JBI Critical Appraisal Checklist for Case Series (TJB, 2016).

Statistical Analysis
All data in this meta-analysis were analyzed with STATA 14.2 software (StataCorp LP, College Station, TX, United States). Heterogeneity was measured using the chisquared test and I 2 statistic. p < 0.1 indicated a statistically significant difference. If significant heterogeneity (p-value <0.1 and I 2 >50%) existed, a random-effect model was performed. Otherwise, the fixed-effects model was used . Moreover, sensitivity analysis was performed to analyze the stability and reliability of the pooled results. Finally, a potential publication bias was accessed by Begg's and Egger's tests.

Study Selection
The initial search yielded a total of 123 published relevant studies from four databases (PubMed = 20, Embase = 42, Web of Frontiers in Pharmacology | www.frontiersin.org August 2022 | Volume 13 | Article 843905 5 Science = 44, and Cochrane Library = 17). About 14 studies were retained after removing duplicates and screening the titles and abstracts. Then, the remaining full-text articles were assessed carefully, and seven studies were excluded due to unavailable full text, small sample size, or non-chemotherapy drugs. Finally, seven studies with a total of 243 patients met the inclusion criteria and were included in this meta-analysis (Su et al., 2019;Yu et al., 2019;Li et al., 2020;Xia et al., 2020;Xiao et al., 2020;Zhang et al., 2020;Yang et al., 2021).The flowchart of the selection process is shown in Figure 1. The details of each included study are described in Table 1.

Quality Assessment
Two non-randomized studies were assessed using the Newcastle-Ottawa Scale (NOS), which categorized studies into three dimensions based on eight items, including population election, comparability, and outcome (cohort studies) or exposure (case-control studies) evaluation (Stang, 2010). Five retrospective studies were assessed using the JBI Critical Appraisal Checklist for Case Series, which contains ten items that assess the quality of case reports from the selection of cases, disease or health problem evaluation, and presentation of case data. The quality assessment details are shown in Table 2.

Survival
All studies included in the analysis reported OS and PFS for all patients after administration of apatinib. In the random-effects model (I 2 = 76.1%, p = 0.000), the pooled median OS was 10.63 months (95% CI 8.57-12.68 months), as shown in Figure 3A. With regard to PFS, the fixed-effects model was performed (I 2 = 48.3%, p = 0.071), and the results showed that the pooled median PFS was 5.25 months (95% CI: 4.73-5.76 months) ( Figure 3B).

Sensitivity Analysis
Sensitivity analysis was conducted by omitting one study at a time to assess its effect on pooled results. As indicated by the results of the analysis, all of the pooled results with 95% CIs were not remarkably influenced by any individual study. This demonstrated that the results of this meta-analysis were relatively reliable in total. The results of sensitivity analysis are shown in Supplementary Figure S3.

Publication Bias
To ensure the validity of the meta-analysis results, Egger's and Begg's tests were used to estimate the publication bias. The test results were consistent with most of the results except the ORR (Egger's test: 0.001; Begg's test: 0.035). With regard to safety, we considered that the publication bias exists for proteinuria, fatigue and diarrhea, and nausea (Supplementary Table S1).

DISCUSSION
Tumor angiogenesis is heterogeneous and has different histopathological characteristics of normal blood vessels, and it creates a tumor microenvironment characterized by hypoxia, hyperpermeability, poor perfusion, and acidosis in tissues, which promotes tumor growth, invasiveness, and metastasis (Matsumoto et al., 2011;Viallard and Larrivée, 2017). Antiangiogenic therapy could remodel the structure and function of abnormal vessels, which transiently normalize angiogenesis by decreasing tumor vessel hyperpermeability and increasing tumor perfusion and blood supply, thus improving the hypoxia and acidosis environments and enhancing the benefits of chemotherapeutic drugs and radiotherapy (Lin and Sessa, 2004;Goel et al., 2011;Li et al., 2021). So far, the vital role of the vascular endothelial growth factor (VEGF)/VEGF-receptor (VEGFR) signaling pathway in the development and progression of advanced cervical cancer has been identified (Dobbs et al., 1997;Tomao et al., 2014;Garcia et al., 2020). Bevacizumab, an anti-VEGF monoclonal antibody, is one of the most extensively researched anti-angiogenetic treatments. A phase II clinical trial assessed the efficacy of bevacizumab monotherapy in patients with recurrent or metastatic cervical cancer, and the results showed that the median PFS and OS were 3.40 and 7.29 months, respectively, and the ORR was 11%. But the pathological type involved in this study was only squamous cell carcinoma (SCC); hence the clinical benefits of cervical adenocarcinoma remained to be investigated (Monk et al., 2009). Though, to some extent, anti-angiogenic therapy alone can bring survival benefits to patients, the effect was modest. Therefore, the combination of anti-angiogenic and cytotoxic compounds was expected to achieve better efficacy results. There is a large amount of published literature proving that bevacizumab has survival benefits when combined with platinum-based chemotherapy for advanced and recurrent cervical cancer. Also, the combination therapy showed no significant deterioration in health-related quality of life. Despite the use of bevacizumab in cervical cancer showed efficacy, its high cost also limits its use (Tewari et al., 2014b;Fisher and Schefter, 2015;Rosen et al., 2017). Previous studies also evaluated other alternative anti-angiogenic strategies, including pazopanib, lapatinib, gefitinib, and sunitinib (Goncalves et al., 2008;Mackay et al., 2010;Monk et al., 2010), but the results were hardly satisfactory. The ORRs of pazopanib, lapatinib, gefitinib, and sunitinib were 9.5%, 5.1%, 0%, and 0%, respectively. Also, DCRs of pazopanib, lapatinib, gefitinib and sunitinib were 52.7%, 48.7%, 20%, and 84.2%, respectively. From the perspective of survival data, the median PFS of pazopanib, lapatinib, and sunitinib was 18.1, 17.1 weeks, and 3.5 months, respectively. The median OS of pazopanib and lapatinib was 50.7 and 39.1 weeks, respectively.
Apatinib, another novel anti-angiogenic drug, showed satisfactory short-term effects in tumor treatment. It selectively binds to and inhibits VEGFR-2, leading to decreased vascular endothelial cell proliferation and tumor vascular assembly (Tian et al., 2011;Scott et al., 2015).Based on the results, apatinib was approved for the third-line treatment of advanced gastric patients in China (Li et al., 2013). In this meta-analysis, seven clinical studies with 243 patients were included to evaluate the efficacy and safety of apatinib in treating advanced or recurrent cervical cancer. The pooled analyses presented that apatinib exhibited efficacy and manageable safety with promising ORR, DCR, OS, and PFS. Despite the disease status, treatment of the cancer, and subtypes, the pooled results showed that the ORR and DCR were 22.9% and 68.6%, respectively, and the median OS and PFS were 10.63 months and 5.25 months, respectively. The subgroup analysis indicated that it was likely that initial use of antiangiogenic inhibitors resulted in an increased ORR (24.5% vs. 19.3%) and DCR (73.6% vs. 53.4%). The aforementioned results demonstrated that apatinib monotherapy has a better effect in patients with advanced or recurrent cervical cancer. Considering that bevacizumab may affect the evaluation of apatinib efficacy, we reanalyzed two studies that used bevacizumab as first-line treatment. The results showed that the pooled ORR and DCR were 19.3% and 53.4%, respectively. However, because bevacizumab is not approved by the China Food and Drug Administration for the treatment of recurrent cervical cancer, the proportion of those patients in our study was relatively small, and this might exaggerate the response to apatinib. Nevertheless, multivariate Cox regression showed that first-line bevacizumab therapy was not associated with survival, which suggested that cross-resistance might not exist between apatinib and bevacizumab. Thus, patients might still respond to other VEGFR inhibitors after failure of first-line VEGF therapy (Xia et al., 2020). Furthermore, the role of bevacizumab or apatinib in advanced cervical cancer has been demonstrated, and we cannot help thinking that whether these anti-angiogenic inhibitors have a greater therapeutic effect in combination with radiotherapy. Interestingly, multiple preclinical studies observed an enhanced effect of the combinatorial approach, such as in locally advanced pancreatic cancer and rectal cancer (Mauceri et al., 1998;Crane et al., 2006;Czito et al., 2007). In cervical cancer, a prospective phase II trial was conducted to investigate the efficacy of bevacizumab with standard chemoradiotherapy for untreated locally advanced cervical carcinoma. Initial clinical results are encouraging, as association of bevacizumab with chemoradiotherapy resulted in a 3-year OS of 81.3%, diseasefree survival (DFS) of 68.7%, and locoregional failure (LRF) of 23.2% (Schefter et al., 2014). Also, multivariate analysis demonstrated that the biomarker of VEGF was an independent predictor of poor prognosis in advanced cervical cancer patients after treating with radiotherapy (Gaffney et al., 2003). Since there is evidence that adequate tumor vascularization increases tumor perfusion and oxygenation, thereby enhancing radiotherapy efficacy, more clinical trials are needed to evaluate the impact of anti-angiogenic inhibitors in combination with radiotherapy on the efficacy of cervical cancer. Except for the promising efficacy of apatinib in cervical cancer treatment, the safety of this anti-angiogenic drug is also encouraging. Our study showed that the most commonly reported AEs with the highest incidence were hypertension (34.5%), hand-foot syndrome (39.6%), and fatigue (28%). Most AEs were of grades 1-2, and the incidence of grade ≥ III adverse events was significantly lower, rarely exceeding 10%. Even the most commonly reported incidences of AEs such as hypertension, hand-foot syndrome, and fatigue were only 9.2%, 7.5%, and 3.0%, respectively. According to these results, the safety of apatinib in treating advanced or recurrent cervical cancer patients is acceptable.
Tumor immunotherapy has emerged as one of the hottest research fields in recent years. Currently, hundreds of clinical trials are being carried out to evaluate the efficacy of immune checkpoint inhibitors (ICIs) for tumor patients, and most of them result in prolonged OS, PFS, or higher ORR (Darvin et al., 2018; Frontiers in Pharmacology | www.frontiersin.org August 2022 | Volume 13 | Article 843905 Motzer et al., 2019). A multicenter, single-arm phase II clinical trial reported that combining camrelizumab with apatinib yielded higher ORR and DCR (55.6% and 82.2%, respectively), and most AEs were manageable (Lan et al., 2020). This demonstrated that the effect of immunotherapy combined with anti-angiogenesis is encouraging and attractive in the treatment of cervical cancer. However, since the follow-up time was short and survival data was incomplete, the benefits of immunotherapy combined with anti-angiogenic therapy on extended survival still need to be explored. Based on the currently published clinical data, the programmed death-1 (PD-1) pembrolizumab conferred a satisfactory outcome, with three complete and nine partial responses of ORR being 12.2% and thirty patients stable disease of DCR being 30.6% (Chung et al., 2019). The phase II clinical study responses were only seen in patients with programmed death-1(PD-L1) + tumors. Interestingly, PD-L1 expression is observed in 34.4-96% of cervical cancer tissues and programmed death-ligand 1 (PD-L1) expression varies from 51% to 88%, particularly in squamous cell carcinoma (SCC) (Mezache et al., 2015;Enwere et al., 2017;Reddy et al., 2017).
The results led to FDA approval of pembrolizumab as a secondline treatment in this patient population. Nivolumab, another PD-L1 ICI, is approved for the treatment of various cancers. The effects of nivolumab were studied in 19 patients in the phase 1-2 study CheckMate358, and the ORR was 26.3%, regardless of PD-L1 expression, with a DCR of 68% (Naumann et al., 2019). In the meantime, several clinical trials have already evaluated the efficacy of ICIs combined with anti-angiogenic therapy in the recurrent or metastatic setting. It was reported that atezolizumab plus bevacizumab achieved no confirmed response in advanced cervical cancer (Friedman et al., 2020), but camrelizumab plus apatinib therapy achieved an ORR of 55.6% for all histological subtypes of cervical cancer (Lan et al., 2020). Despite the contradictions in the data, and camrelizumab or atezolizumab and apatinib, which represent two completely different therapy mechanisms, each of them has been proved to have promising anti-tumor activity. However, to prove whether the combination of immune checkpoint inhibitors and anti-angiogenic inhibitors or monotherapy can prolong the overall prognosis survival time of those patients needs more clinical trials. Fortunately, more and more PD-1/PD-L1 inhibitors are being evaluated in other cervical cancer trials (Cohen et al., 2020). An phase III randomized trial is comparing PFS and OS among patients receiving standard platinum-based chemotherapy plus pembrolizumab compared to standard therapy plus placebo (Colombo et al., 2021). Another phase III randomized trial is exploring OS among patients treated with cisplatin, paclitaxel, and bevacizumab with and without atezolizumab (Grau et al., 2020). Avelumab and durvalumab are also being explored in clinical trials. There is a reason to believe that it will bring us surprising results in the near future (Thigpen et al., 1981;Thigpen et al., 1983;Xiong et al., 2019).
There were some limitations in the current meta-analysis. First, there was high heterogeneity that existed among the included studies. We only performed a subgroup analysis of the prior treatment regimens. Other factors, such as baseline characteristics and histological classification, could also result in heterogeneity. Second, the included studies were all noncontrolled trials with small sample size, and thus we only evaluated the efficacy and risk without definite conclusions. Third, due to the lack of sufficient pathological data of cervical cancer, we were unable to analyze the efficacy of apatinib for different histological types of cervical cancer. Further analysis of the efficacy of apatinib on different histological types of cervical cancer is still needed in the future to achieve accurate treatment. Fourth, the trials in this analysis included only Chinese patients and the number of patients was relatively small. Whether these results are consistent in other populations still needs further validation. Therefore, more large-scale RCTs should be designed to confirm the clinical role of apatinib in comparison to that of other drugs and the population.

CONCLUSION
In summary, our meta-analysis demonstrates the efficacy and safety of apatinib in patients with advanced or recurrent cervical cancer, providing evidence for its future clinical application. However, since there are limited clinical data, future largescale and multiple-center RCTs are required to confirm this conclusion.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author.