Apatinib in Treating Clinical and Biochemical Recurrent Ovarian Cancer

Apatinib in Treating Clinical and Biochemical Recurrent Ovarian Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Apatinib in Treating Clinical and Biochemical Recurrent Ovarian Cancer Zhongyu Wang, Yake Huang, Ling Long, Li Zhou, Yan Huang, Lei Gan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-78764/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background: Biochemical recurrence is defined according to the combined results of serum carbohydrate antigen and image; noteworthily, it generally precedes the onset of clinical evidence. Now treatment strategies of biochemical recurrence ovarian cancer (OC) remain controversial. Apatinib as monotherapy or in combination with other chemotherapeutic agents has shown its effect in the treatment of some advanced malignancies. In our study, we focused on the efficacy of apatinib in recurrent OC, especially its clinical activity in biochemical-only recurrent OC patients. Methods: We retrospectively analyzed clinical material of 41 recurrent patients who had received apatinib monotherapy or apatinib plus chemotherapy between June 2016 and August 2018. Apatinib was administered at a 500 mg daily dose. Response was determined according to measurable disease or serum carbohydrate antigen (CA)-125 levels. Progression-free survival (PFS) was estimated by Kaplan-Meier method. Results: All patients were evaluable, 19 (46.34%) had biochemical relapse and 22 (53.66%) had clinical relapse. The objective response rate (ORR) and disease control rate (DCR) in the overall population were 31.71% and 78.05%, respectively. The median PFS was 7 months (95% confidence interval 5.43-8.57). And in patients with biochemical-only relapse, the median PFS was 6 months, with ORR of 26.32% and DCR of 89.47%. Conclusions: Apatinib is a well-tolerated and effective agent to delay clinical progression of patients with biochemical-only recurrent OC. More important, our study shows the promising prospect for treating OC patients with asymptomatic biochemical relapse. Cancer Biology Oncology Ovarian cancer Apatinib Biochemical relapse Anti-angiogenetic agents Figures Figure 1 Background Ovarian cancer (OC) is the first-leading cause of death due to gynecological malignancies [1]. Due to a lack of specific symptoms, nearly 75% of patients are diagnosed with advanced OC at the initial visit, contributing to the low 5-year survival rate (approximately 20%) [2]. Cytoreductive surgery and platinum-paclitaxel combination chemotherapy are established as the primary treatments for advanced OC. However, the majority of patients who respond to initial treatment eventually experience a relapse and show low response to retreatment with cytotoxic therapy. Thus, the investigation of other effective treatment strategies remains a substantial clinical need. Biochemical recurrence is defined as rising serum carbohydrate antigen (CA)-125 levels exceeding twice the upper limit of the normal range, without the disease being visualized on scans; noteworthily, it generally precedes the onset of clinical evidence by an average of 2 to 6 months [3,4]. In such cases, the choice between either a watch-and-wait policy or early therapeutic intervention remains controversial. Thus, it urgently needs a breakthrough to optimize therapy, to delay clinical disease progression to the extent that would require intravenous chemotherapy. Recently, the strategy of targeting angiogenesis has achieved success for the treatment of OC. Bevacizumab, a humanized monoclonal antibody that binds to all vascular endothelial growth factors (VEGF), has been approved by the European drug administration for the treatment of advanced ovarian carcinoma, specifically for recurrent platinum-sensitive or -resistant OC [5]. Apatinib is an oral vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor that inhibits tumor angiogenesis by blocking downstream signaling [6]. In China, apatinib has shown its effects in the third-line treatment of advanced gastric adenocarcinoma and adenocarcinoma in the gastric-esophageal junction [7-9]. Some studies also suggested the use of apatinib in other advanced malignancies [10-17]. Therefore, in OC, apatinib has got increasing attention about its efficacy and safety [18-22]; however, to our knowledge, apatinib’s efficacy in recurrent cancer, especially in biochemical-only recurrent OC, is still unknown. Hence, we conducted this study to report the efficacy of apatinib in recurrent OC, and aimed to preliminarily assessing the outcome of apatinib monotherapy in biochemical recurrent OC patients. Methods Patients In this retrospective study, we gathered the material of patients diagnosed with OC via pathologic evaluation, who had received apatinib monotherapy or treatment with apatinib plus chemotherapy between June 2016 and August 2018 in the first and second affiliated hospital of the Third Military Medical University. Patients were considered eligible for analysis if: 1) they received at least one line standard chemotherapy after debulking surgery and 2) relapse of disease was demonstrated by a measurable tumor or by an elevated level of CA-125. The study also enrolled patients who were intolerant to chemotherapy. Additional inclusion criteria included appropriate renal, hepatic, and hematopoietic function and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Patients with a history of bleeding, hypertension, ischemic cardiovascular disease, or proteinuria were ineligible for this study. The patients participating in this study provided written informed consent before study initiation. Treatments The administration of apatinib as monotherapy or in combination with chemotherapy was determined according to different patient needs. Apatinib monotherapy was applied to patients who were no longer tolerant to chemotherapy or patients with biochemical recurrence of disease. Patients with relapse of a measurable tumor received treatment with apatinib and chemotherapy based on a taxane or etoposide. The recommended initial dose of apatinib was 500 mg, po qd, half an hour after a meal at the same time every day. Chemotherapy was given simultaneously with apatinib for 28 days of one cycle. If intolerable toxicity occurred, the patient was informed to gradually reduce the dose to 250 mg or discontinue the medication. Evaluation The first evaluation for clinical efficacy and safety was performed at the end of the first cycle. Subsequently, the interval of assessment changed to every two cycles. Treatment efficacy in patients with measurable disease was assessed by CT, MRI, and ultrasound scans. Complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1). Responses of biochemical recurrent patients were determined through serum CA-125 levels. The CA-125 definition for response rate was based on the Rustin criteria [23]. A reduction of CA-125 to normalization that was maintained for at least 4 weeks was defined as CR, a 50% reduction as PR, a 25% increase as PD, and a situation beyond the above criteria was recognized as SD [24]. CR plus PR was categorized as objective response rate (ORR) and CR, PR, plus SD was defined as disease control rate (DCR). The period from initial treatment to disease progression or death was defined as progression-free survival (PFS). Drug-related adverse effects were evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.0). Statistical analysis The percentage method was used for categorical variables and drug safety analysis. PFS was analyzed by the Kaplan-Meier method, and the corresponding figures were drawn using GraphPad Prism 8.0 software (GraphPad Software Inc., San Diego, CA, USA). A P value <0.05 was regarded statistically significant. Results Patient characteristics Between June 2016 and August 2018, a total of 41 advanced OC patients were enrolled in this study. The median age was 53 years (range, 36-67). Most patients (33, 80.48%) presented with stage IIIC (Federation International of Gynecology and Obstetrics FIGO) disease. The histological type included serous carcinoma (high grade 70.73%; low grade 21.95%), mucinous carcinoma (4.88%), and endometrioid carcinoma (2.44%). Of 41 patients, 14 (34.15%) had optimal debulking surgery, whereas the remaining 27 (65.85%) received suboptimal debulking surgery. All were tumor recurrent patients after previous therapy; of these, 19 (46.34%) patients had biochemical recurrence and 22 (53.66%) patients had a visible tumor. Among the included patients, 29 (70.73%) had receivedBaseline patients’ characteristics 1-2 lines of chemotherapy and 12 (29.27%) had received 3-5 lines of treatment before participating. In this study, 13 of 41 (31.71%) patients were treated with apatinib in combination with chemotherapy and 28 patients (68.69%) received apatinib monotherapy. Most patients (75.61%) had good Eastern Cooperative Oncology Group performance status (ECOG PS) (0), and patients with ECOG PS of 1 and 2 accounted for 14.63% and 9.76%, respectively. Detailed baseline clinical characteristics of the patients are shown in Table 1. Table 1 Baseline patients’ characteristics Characteristics No. % Median age(rang)(years) 53(36-67) FIGO stage IIIA IIIB IIIC IV 1 (2.44%) 3 (7.32%) 33 (80.48%) 4 (9.76%) ECOG PS 0 1 2 31 (75.61%) 6 (14.63%) 4 (9.76%) Histology Type High-grade serous carcinoma Low-grade serous carcinoma Mucinous carcinoma Endometrioid carcinoma 29 (70.73%) 9 (21.95%) 2 (4.88%) 1 (2.44%) Debulking Surgery Optimal Suboptimal 14 (34.15%) 27 (65.85%) Biochemical recurrence Yes No 19 (46.34%) 22 (53.66%) Previous chemotherapy lines 1-2 3-5 29 (70.73%) 12 (29.27%) Treatment regimen Combined chemotherapy Single drug 13 (31.71%) 28 (68.29%) FIGO, International Federation of Gynecology and Obstetrics; ECOG PS, Eastern Cooperative Group Performance Status. Efficacy During a follow up in July 2019, all patients were evaluated. Efficacy analysis indicated that none of the 41 patients achieved Complete remission (CR), 13 patients achieved partial remission (PR), 19 patients maintain stable disease (SD), and 9 patients had progressive disease (PD), resulting in an objective response rate (ORR) of 31.71% and a disease control rate (DCR) of 78.05% (Table 2). The median progression-free survival (PFS) was 7 months (95% CI 5.43-8.57, Fig. 1A). Among the patients with biochemical relapse, ORR and DCR were 26.32% and 89.47% respectively (Table 2), with median PFS of 6 months (95% CI 4.39-7.61, Fig. 1B). Table 2 Treatment response Imageological response Biochemical response Overall response Complete response (CR) 0 0 0 Partial response (PR) 8(36.36) 5(26.32) 13(31.71) Stable disease (SD) 7(31.82) 12(63.16) 19(46.34) Progressive disease (PD) 7(31.82) 2(10.53) 9(21.95) Objective response rate (ORR) 8(36.36) 5(26.32) 13(31.71) Disease control rate (DCR) 15(68.18) 17(89.47) 32(78.05) Safety Adverse reactions were assessed and are summarized in Table 3. In general, most patients were tolerant to apatinib without any grade 4 adverse events (AEs). The most common grade 1-3 AE was hand-foot syndrome (46.4%). Other common AEs were mucositis (41.5%), fatigue (39.0%), anorexia (39.0%), proteinuria (36.6%), hypertension (34.1%), and thrombocytopenia (26.8%). Table 3 Adverse events Adverse events Grades 1 (n, %) 2 (n, %) 3 (n, %) 4 (n, %) Total (n, %) Hand-foot syndrome 5 (12.2%) 9 (22.0%) 5 (12.2%) 0 19 (46.4%) Mucositis 3 (7.3%) 6 (14.6%) 8 (19.5%) 0 17 (41.5%) Anorexia 12 (29.3%) 3 (7.3%) 1 (2.4%) 0 16 (39.0%) Fatigue 4 (9.8%) 7 (17.1%) 5 (12.2%) 0 16 (39.0%) Pain 6 (14.6%) 4 (9.8%) 1 (2.4%) 0 11 (26.8%) Hypertension 5 (12.2%) 6 (14.6%) 3 (7.3%) 0 14 (34.1%) Proteinuria 11 (26.8%) 4 (9.8%) 0 0 15 (36.6%) Diarrhea 1 (2.4%) 2 (4.9%) 0 0 3 (7.3%) Transaminase increased 1 (2.4%) 3 (7.3%) 1 (2.4%) 0 5 (12.2%) Neutropenia 2 (4.9%) 2 (4.9%) 1 (2.4%) 0 5 (12.2%) Thrombocytopenia 6 (14.6%) 3 (7.3%) 2 (4.9%) 0 11 (26.8%) Discussion Traditional therapies for OC, including debulking surgery and chemotherapy, cannot yield a good response rate in all relapsed OC patients. Efforts to understand OC biology have facilitated the development of new targeted antineoplastic agents. In cancer, angiogenesis contributes to tumor growth and invasion [ 25 ]. Multiple growth factors play proangiogenic roles, including VEGF, epidermal growth factor (EGF), and platelet-derived growth factors (PDGF); of these, the VEGF pathway is pivotal in angiogenesis [ 26 ]. Bevacizumab, a monoclonal antibody targeting VEGF-A, has been approved for the treatment of recurrent platinum-sensitive or -resistant OC [ 5 ]. Several multitargeted receptor tyrosine kinase inhibitors (TKIs), such as imatinib, cediranib, sorafenib, sunitinib, and pazopanib, target VEGFR, PDGFR, and FGFR. Many of these inhibitors have been or are being evaluated in clinical trials in OC, and some agents have exhibited inhibitory effects [ 5 ]. Most of the studies demonstrating clinical activity in advanced OC are small case reports. Only two prospective studies tested the efficacy of apatinib treatment in advanced OC. One is a single arm clinical study, which assessed the efficacy and safety of apatinib as monotherapy in patients with recurrent platinum-resistant epithelial OC [ 19 ]. The ORR and DCR in 28 patients receiving apatinib 500 mg daily were 41.4% and 68.9%, respectively, and the median PFS and OS were 5.1 months and 14.5 months [ 19 ]. The other study assessed the activity of apatinib plus etoposide in the treatment of patients with platinum-resistant or -refractory OC, showing an ORR of 54% and DCR of 86% [ 18 ]. The toxicity of apatinib in monotherapy and combined therapy were both manageable [ 18 , 19 ]. In our study, we found that, in the overall population, the median PFS was 7 months, and that the ORR was 31.71% and DCR was 78.05%, supporting the clinical activity of apatinib in recurrent OC. The safety of apatinib at a dose of 500 mg daily was similar to that reported in the above studies. The National Comprehensive Cancer Network (NCCN) guidelines for OC suggest that biochemical recurrent patients may: 1) enroll in a clinical trial; 2) delay treatment until clinical relapse; 3) receive immediate platinum-based recurrence therapy; or 4) undergo best supportive care [ 27 ]. Thus, several studies aimed to investigate low-toxicity agents to delay the appearance of measurable disease in these patients [ 28 ]. However, no efficacy agent was confirmed until now. In our study, we demonstrated the efficacy of apatinib in biochemical recurrent OC patients with a median PFS of 6 months. This result implied that early treatment using apatinib in biochemical-only recurrent OC may extend time to clinical disease progression and delay time to intravenous chemotherapy, with low toxicity. However, a large sample study is needed to confirm the effect of apatinib in biochemical relapse. One of the potential shortcomings of this study is that it was a relatively small-scale retrospective study; only 19 biochemical recurrent patients were evaluable. Prospective studies on a large sample cohort are needed to confirm the value of apatinib for the treatment of biochemical relapse patients. Additionally, this study failed to find a biomarker to predict the efficacy in biochemical recurrent patients. In this study, patients experienced similar grades of AEs to previous studies of apatinib treatment in OC. Hand-foot syndrome, mucositis, fatigue, anorexia, proteinuria, and hypertension were the most common adverse effects; however, all were tolerable. Conclusions In this study, we focused on the activity of apatinib in biochemical recurrent OC patients. Results indicate that apatinib might be promising for such patients to delay clinical disease progression and intravenous chemotherapy. More important, our study brought the potential breakthrough for treating OC patients with asymptomatic biochemical relapse. Abbreviations OC: Ovarian Cancer; CR: Complete Remission; PR: Partial Remission; SD: Stable Disease (SD); PD: Progressive Disease; ORR: Objective Response Rate; DCR: Disease Control Rate; PFS: Progression-Free Survival; AE: Adverse Event. Declarations Ethics approval and consent to participate This retrospective study was approved by the institutional review board of Xinqiao Hospital, Third Military Medical University, China. The patients participating in this study provided written informed consent before study initiation. Consent for publication Not applicable. Availability of data and materials The datasets used and analyzed in the current study are available from the corresponding author upon reasonable request. Competing interests The authors have no conflicts of interest. Funding This work was supported by Scientific and Technological Innovation Program of Social Undertakings and People’s Livelihood Guarantee of Chongqing (cstc2016shms-ztzx10004 to R.X.) and the National Natural Science Foundation of China (Number 81372271 to R.X., Number 81802865 to Z.W.). Authors’ contributions Rongkai Xie designed the research study and revised the manuscript; Zhongyu Wang and Yake Huang performed statistical analysis and drafted the manuscript; Ling Long, Li Zhou, Yan Huang, Aiming Pu, and Sufen Li participated in the cases recruit and follow-up of this study; Lei Gan assisted in the statistical analysis. All authors read and approved the final manuscript. Acknowledgements The authors sincerely thank all the patients and their families for participating in this study, and other investigators involved in this research. References Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. Martin LP, Schilder RJ. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revision 03 Nov, 2020 Review # 1 received at journal 02 Nov, 2020 Review # 2 received at journal 01 Nov, 2020 Reviewers invited by journal 14 Oct, 2020 Reviewer # 1 agreed at journal 14 Oct, 2020 Reviewer # 2 agreed at journal 14 Oct, 2020 Editor assigned by journal 16 Sep, 2020 First submitted to journal 15 Sep, 2020 Submission checks completed at journal 15 Sep, 2020 Editor invited by journal 15 Sep, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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10:43:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-78764/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-78764/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":2809819,"identity":"37b04f56-bf3d-42de-8963-91b37fb370c1","added_by":"auto","created_at":"2020-10-06 17:52:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":181696,"visible":true,"origin":"","legend":"Kaplan-Meyer survival curve for estimated progression-free survival (PFS) in overall population (A) and in patients with biochemical relapse (B).","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-78764/v1/05c8c0dfad5086eb5d765380.jpg"},{"id":13601165,"identity":"f4a28d5c-426c-46cd-8757-09c571d1b428","added_by":"auto","created_at":"2021-09-17 05:46:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":324575,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-78764/v1/5e0c3479-1831-4eb8-8f24-7271c60d0761.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eApatinib in Treating Clinical and Biochemical Recurrent Ovarian Cancer\u003c/p\u003e","fulltext":[{"header":" Background","content":"\u003cp\u003eOvarian cancer (OC) is the first-leading cause of death due to gynecological malignancies [1]. Due to a lack of specific symptoms, nearly 75% of patients are diagnosed with advanced OC at the initial visit, contributing to the low 5-year survival rate (approximately 20%) [2]. Cytoreductive surgery and platinum-paclitaxel combination chemotherapy are established as the primary treatments for advanced OC. However, the majority of patients who respond to initial treatment eventually experience a relapse and show low response to retreatment with cytotoxic therapy. Thus, the investigation of other effective treatment strategies remains a substantial clinical need.\u003c/p\u003e\n\u003cp\u003eBiochemical recurrence is defined as rising serum carbohydrate antigen (CA)-125 levels exceeding twice the upper limit of the normal range, without the disease being visualized on scans; noteworthily, it generally precedes the onset of clinical evidence by an average of 2 to 6 months [3,4]. In such cases, the choice between either a watch-and-wait policy or early therapeutic intervention remains controversial. Thus, it urgently needs a breakthrough to optimize therapy, to delay clinical disease progression to the extent that would require intravenous chemotherapy.\u003c/p\u003e\n\u003cp\u003eRecently, the strategy of targeting angiogenesis has achieved success for the treatment of OC. Bevacizumab, a humanized monoclonal antibody that binds to all vascular endothelial growth factors (VEGF), has been approved by the European drug administration for the treatment of advanced ovarian carcinoma, specifically for recurrent platinum-sensitive or -resistant OC [5].\u003c/p\u003e\n\u003cp\u003eApatinib is an oral vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor that inhibits tumor angiogenesis by blocking downstream signaling [6]. In China, apatinib has shown its effects in the third-line treatment of advanced gastric adenocarcinoma and adenocarcinoma in the gastric-esophageal junction [7-9]. Some studies also suggested the use of apatinib in other advanced malignancies [10-17]. Therefore, in OC, apatinib has got increasing attention about its efficacy and safety [18-22]; however, to our knowledge, apatinib\u0026rsquo;s efficacy in recurrent cancer, especially in biochemical-only recurrent OC, is still unknown. Hence, we conducted this study to report the efficacy of apatinib in recurrent OC, and aimed to preliminarily assessing the outcome of apatinib monotherapy in biochemical recurrent OC patients.\u003c/p\u003e"},{"header":" Methods","content":"\u003ch2\u003ePatients\u003c/h2\u003e\n\u003cp\u003eIn this retrospective study, we gathered the material of patients diagnosed with OC via pathologic evaluation, who had received apatinib monotherapy or treatment with apatinib plus chemotherapy between June 2016 and August 2018 in the first and second affiliated hospital of the Third Military Medical University. Patients were considered eligible for analysis if: 1) they received at least one line standard chemotherapy after debulking surgery and 2) relapse of disease was demonstrated by a measurable tumor or by an elevated level of CA-125. The study also enrolled patients who were intolerant to chemotherapy. Additional inclusion criteria included appropriate renal, hepatic, and hematopoietic function and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Patients with a history of bleeding, hypertension, ischemic cardiovascular disease, or proteinuria were ineligible for this study. The patients participating in this study provided written informed consent before study initiation.\u003c/p\u003e\n\u003ch2\u003eTreatments\u003c/h2\u003e\n\u003cp\u003eThe administration of apatinib as monotherapy or in combination with chemotherapy was determined according to different patient needs. Apatinib monotherapy was applied to patients who were no longer tolerant to chemotherapy or patients with biochemical recurrence of disease. Patients with relapse of a measurable tumor received treatment with apatinib and chemotherapy based on a taxane or etoposide. The recommended initial dose of apatinib was 500 mg, po qd, half an hour after a meal at the same time every day. Chemotherapy was given simultaneously with apatinib for 28 days of one cycle. If intolerable toxicity occurred, the patient was informed to gradually reduce the dose to 250 mg or discontinue the medication.\u003c/p\u003e\n\u003ch2\u003eEvaluation\u003c/h2\u003e\n\u003cp\u003eThe first evaluation for clinical efficacy and safety was performed at the end of the first cycle. Subsequently, the interval of assessment changed to every two cycles. Treatment efficacy in patients with measurable disease was assessed by CT, MRI, and ultrasound scans. Complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1). Responses of biochemical recurrent patients were determined through serum CA-125 levels. The CA-125 definition for response rate was based on the Rustin criteria [23]. A reduction of CA-125 to normalization that was maintained for at least 4 weeks was defined as CR, a 50% reduction as PR, a 25% increase as PD, and a situation beyond the above criteria was recognized as SD [24]. CR plus PR was categorized as objective response rate (ORR) and CR, PR, plus SD was defined as disease control rate (DCR). The period from initial treatment to disease progression or death was defined as progression-free survival (PFS). Drug-related adverse effects were evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.0).\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eThe percentage method was used for categorical variables and drug safety analysis. PFS was analyzed by the Kaplan-Meier method, and the corresponding figures were drawn using GraphPad Prism 8.0 software (GraphPad Software Inc., San Diego, CA, USA). A P value \u0026lt;0.05 was regarded statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003ePatient characteristics\u003c/h2\u003e\n\u003cp\u003eBetween June 2016 and August 2018, a total of 41 advanced OC patients were enrolled in this study. The median age was 53 years (range, 36-67). Most patients (33, 80.48%) presented with stage IIIC (Federation International of Gynecology and Obstetrics FIGO) disease. The histological type included serous carcinoma (high grade 70.73%; low grade 21.95%), mucinous carcinoma (4.88%), and endometrioid carcinoma (2.44%). Of 41 patients, 14 (34.15%) had optimal debulking surgery, whereas the remaining 27 (65.85%) received suboptimal debulking surgery. All were tumor recurrent patients after previous therapy; of these, 19 (46.34%) patients had biochemical recurrence and 22 (53.66%) patients had a visible tumor. Among the included patients, 29 (70.73%) had receivedBaseline patients\u0026rsquo; characteristics 1-2 lines of chemotherapy and 12 (29.27%) had received 3-5 lines of treatment before participating. In this study, 13 of 41 (31.71%) patients were treated with apatinib in combination with chemotherapy and 28 patients (68.69%) received apatinib monotherapy. Most patients (75.61%) had good Eastern Cooperative Oncology Group performance status (ECOG PS) (0), and patients with ECOG PS of 1 and 2 accounted for 14.63% and 9.76%, respectively. Detailed baseline clinical characteristics of the patients are shown in Table 1.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline patients\u0026rsquo; characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eNo. %\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eMedian age(rang)(years)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e53(36-67)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eFIGO stage\u003c/p\u003e\n\u003cp\u003eIIIA\u003c/p\u003e\n\u003cp\u003eIIIB\u003c/p\u003e\n\u003cp\u003eIIIC\u003c/p\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1 (2.44%)\u003c/p\u003e\n\u003cp\u003e3 (7.32%)\u003c/p\u003e\n\u003cp\u003e33 (80.48%)\u003c/p\u003e\n\u003cp\u003e4 (9.76%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eECOG PS\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; 0\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; 1\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; 2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e31 (75.61%)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;6 (14.63%)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;4 (9.76%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eHistology Type\u003c/p\u003e\n\u003cp\u003eHigh-grade serous carcinoma\u003c/p\u003e\n\u003cp\u003eLow-grade serous carcinoma\u003c/p\u003e\n\u003cp\u003eMucinous carcinoma\u003c/p\u003e\n\u003cp\u003eEndometrioid carcinoma\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e29 (70.73%)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;9 (21.95%)\u003c/p\u003e\n\u003cp\u003e2 (4.88%)\u003c/p\u003e\n\u003cp\u003e1 (2.44%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eDebulking Surgery\u003c/p\u003e\n\u003cp\u003eOptimal\u003c/p\u003e\n\u003cp\u003eSuboptimal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e14 (34.15%)\u003c/p\u003e\n\u003cp\u003e27 (65.85%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eBiochemical recurrence\u003c/p\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e19 (46.34%)\u003c/p\u003e\n\u003cp\u003e22 (53.66%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003ePrevious chemotherapy lines\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;1-2\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;3-5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e29 (70.73%)\u003c/p\u003e\n\u003cp\u003e12 (29.27%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003eTreatment regimen\u003c/p\u003e\n\u003cp\u003eCombined chemotherapy\u003c/p\u003e\n\u003cp\u003eSingle drug\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"277\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e13 (31.71%)\u003c/p\u003e\n\u003cp\u003e28 (68.29%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"277\"\u003e\n\u003cp\u003eFIGO, International Federation of Gynecology and Obstetrics; ECOG PS, Eastern Cooperative Group Performance Status.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003eEfficacy\u003c/h2\u003e\n\u003cp\u003eDuring a follow up in July 2019, all patients were evaluated. Efficacy analysis indicated that none of the 41 patients achieved Complete remission (CR), 13 patients achieved partial remission (PR), 19 patients maintain stable disease (SD), and 9 patients had progressive disease (PD), resulting in an objective response rate (ORR) of 31.71% and a disease control rate (DCR) of 78.05% (Table 2). The median progression-free survival (PFS) was 7 months (95% CI 5.43-8.57, Fig. 1A). Among the patients with biochemical relapse, ORR and DCR were 26.32% and 89.47% respectively (Table 2), with median PFS of 6 months (95% CI 4.39-7.61, Fig. 1B).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eTreatment response\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003eImageological\u003c/p\u003e\n\u003cp\u003eresponse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003eBiochemical\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eresponse\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003eOverall\u003c/p\u003e\n\u003cp\u003eresponse\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003eComplete response (CR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e0\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e0\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003ePartial response (PR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e8(36.36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e5(26.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e13(31.71)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003eStable disease (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e7(31.82)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e12(63.16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e19(46.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003eProgressive disease (PD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e7(31.82)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e2(10.53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e9(21.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003eObjective response rate (ORR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e8(36.36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e5(26.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e13(31.71)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"217\"\u003e\n\u003cp\u003eDisease control rate (DCR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e15(68.18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e17(89.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"91\"\u003e\n\u003cp\u003e32(78.05)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003ch2\u003e\u003cbr /\u003eSafety\u003c/h2\u003e\n\u003cp\u003eAdverse reactions were assessed and are summarized in Table 3. In general, most patients were tolerant to apatinib without any grade 4 adverse events (AEs). The most common grade 1-3 AE was hand-foot syndrome (46.4%). Other common AEs were mucositis (41.5%), fatigue (39.0%), anorexia (39.0%), proteinuria (36.6%), hypertension (34.1%), and thrombocytopenia (26.8%).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAdverse events\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"142\"\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" width=\"416\"\u003e\n\u003cp\u003e\u003cstrong\u003eGrades\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e\u003cstrong\u003e2 \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e\u003cstrong\u003e3 \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e\u003cstrong\u003e4 (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal (n, %)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eHand-foot syndrome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5 (12.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e9 (22.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e5 (12.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e19 (46.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eMucositis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3 (7.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e6 (14.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e8 (19.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e17 (41.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eAnorexia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e12 (29.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e3 (7.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e1 (2.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e16 (39.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eFatigue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4 (9.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e7 (17.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e5 (12.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e16 (39.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003ePain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e6 (14.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e4 (9.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e1 (2.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e11 (26.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5 (12.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e6 (14.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e3 (7.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e14 (34.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eProteinuria\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e11 (26.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e4 (9.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e15 (36.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eDiarrhea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1 (2.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e2 (4.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e3 (7.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eTransaminase increased\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1 (2.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e3 (7.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e1 (2.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e5 (12.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eNeutropenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2 (4.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e2 (4.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e1 (2.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e5 (12.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"142\"\u003e\n\u003cp\u003eThrombocytopenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e6 (14.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"88\"\u003e\n\u003cp\u003e3 (7.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"84\"\u003e\n\u003cp\u003e2 (4.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"92\"\u003e\n\u003cp\u003e11 (26.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eTraditional therapies for OC, including debulking surgery and chemotherapy, cannot yield a good response rate in all relapsed OC patients. Efforts to understand OC biology have facilitated the development of new targeted antineoplastic agents. In cancer, angiogenesis contributes to tumor growth and invasion [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Multiple growth factors play proangiogenic roles, including VEGF, epidermal growth factor (EGF), and platelet-derived growth factors (PDGF); of these, the VEGF pathway is pivotal in angiogenesis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Bevacizumab, a monoclonal antibody targeting VEGF-A, has been approved for the treatment of recurrent platinum-sensitive or -resistant OC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Several multitargeted receptor tyrosine kinase inhibitors (TKIs), such as imatinib, cediranib, sorafenib, sunitinib, and pazopanib, target VEGFR, PDGFR, and FGFR. Many of these inhibitors have been or are being evaluated in clinical trials in OC, and some agents have exhibited inhibitory effects [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMost of the studies demonstrating clinical activity in advanced OC are small case reports. Only two prospective studies tested the efficacy of apatinib treatment in advanced OC. One is a single arm clinical study, which assessed the efficacy and safety of apatinib as monotherapy in patients with recurrent platinum-resistant epithelial OC [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The ORR and DCR in 28 patients receiving apatinib 500\u0026nbsp;mg daily were 41.4% and 68.9%, respectively, and the median PFS and OS were 5.1 months and 14.5 months [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The other study assessed the activity of apatinib plus etoposide in the treatment of patients with platinum-resistant or -refractory OC, showing an ORR of 54% and DCR of 86% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The toxicity of apatinib in monotherapy and combined therapy were both manageable [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our study, we found that, in the overall population, the median PFS was 7 months, and that the ORR was 31.71% and DCR was 78.05%, supporting the clinical activity of apatinib in recurrent OC. The safety of apatinib at a dose of 500\u0026nbsp;mg daily was similar to that reported in the above studies.\u003c/p\u003e \u003cp\u003eThe National Comprehensive Cancer Network (NCCN) guidelines for OC suggest that biochemical recurrent patients may: 1) enroll in a clinical trial; 2) delay treatment until clinical relapse; 3) receive immediate platinum-based recurrence therapy; or 4) undergo best supportive care [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Thus, several studies aimed to investigate low-toxicity agents to delay the appearance of measurable disease in these patients [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, no efficacy agent was confirmed until now. In our study, we demonstrated the efficacy of apatinib in biochemical recurrent OC patients with a median PFS of 6 months. This result implied that early treatment using apatinib in biochemical-only recurrent OC may extend time to clinical disease progression and delay time to intravenous chemotherapy, with low toxicity. However, a large sample study is needed to confirm the effect of apatinib in biochemical relapse.\u003c/p\u003e \u003cp\u003eOne of the potential shortcomings of this study is that it was a relatively small-scale retrospective study; only 19 biochemical recurrent patients were evaluable. Prospective studies on a large sample cohort are needed to confirm the value of apatinib for the treatment of biochemical relapse patients. Additionally, this study failed to find a biomarker to predict the efficacy in biochemical recurrent patients. In this study, patients experienced similar grades of AEs to previous studies of apatinib treatment in OC. Hand-foot syndrome, mucositis, fatigue, anorexia, proteinuria, and hypertension were the most common adverse effects; however, all were tolerable.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eIn this study, we focused on the activity of apatinib in biochemical recurrent OC patients. Results indicate that apatinib might be promising for such patients to delay clinical disease progression and intravenous chemotherapy. More important, our study brought the potential breakthrough for treating OC patients with asymptomatic biochemical relapse.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eOC: Ovarian Cancer; CR: Complete Remission; PR: Partial Remission; SD: Stable Disease (SD); PD: Progressive Disease; ORR: Objective Response Rate; DCR: Disease Control Rate; PFS: Progression-Free Survival; AE: Adverse Event.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThis retrospective study was approved by the institutional review board of Xinqiao Hospital, Third Military Medical University, China. The patients participating in this study provided written informed consent before study initiation.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used and analyzed in the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors have no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work was supported by Scientific and Technological Innovation Program of Social Undertakings and People\u0026rsquo;s Livelihood Guarantee of Chongqing (cstc2016shms-ztzx10004 to R.X.) and the National Natural Science Foundation of China (Number 81372271 to R.X., Number 81802865 to Z.W.).\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e\n\u003cp\u003eRongkai Xie designed the research study and revised the manuscript; Zhongyu Wang and Yake Huang performed statistical analysis and drafted the manuscript; Ling Long, Li Zhou, Yan Huang, Aiming Pu, and Sufen Li participated in the cases recruit and follow-up of this study; Lei Gan assisted in the statistical analysis. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThe authors sincerely thank all the patients and their families for participating in this study, and other investigators involved in this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.\u003c/li\u003e\n\u003cli\u003eMartin LP, Schilder RJ. Management of recurrent ovarian carcinoma: current status and future directions. Semin Oncol. 2009;36(2):112-25.\u003c/li\u003e\n\u003cli\u003eHising C, Anjegard IM, Einhorn N. Clinical relevance of the CA 125 assay in monitoring of ovarian cancer patients. Am J Clin Oncol. 1991;14(2):111-4.\u003c/li\u003e\n\u003cli\u003eTuxen MK, Soletormos G, Dombernowsky P. Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up. 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J Cancer. 2018;9(16):2773-7.\u003c/li\u003e\n\u003cli\u003eLuo H, Zhang L, Yang B, Feng Y, Xiong Y, Zhang S, et al. A randomized phase 2 trial of apatinib vs observation as maintenance treatment following first-line induction chemotherapy in extensive- stage small cell lung cancer. Invest New Drugs. 2019.\u003c/li\u003e\n\u003cli\u003eTang J, Li XY, Liang JB, Wu D, Peng L, Li X. Apatinib Plus Chemotherapy Shows Clinical Activity in Advanced NSCLC: A Retrospective Study. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics. 2019;27(6):635-41.\u003c/li\u003e\n\u003cli\u003eChen X, Qiu T, Zhu Y, Sun J, Li P, Wang B, et al. A Single-Arm, Phase II Study of Apatinib in Refractory Metastatic Colorectal Cancer. The oncologist. 2019;24(7):883-e407.\u003c/li\u003e\n\u003cli\u003eLi F, Liao Z, Zhao J, Zhao G, Li X, Du X, et al. Efficacy and safety of Apatinib in stage IV sarcomas: experience of a major sarcoma center in China. Oncotarget. 2017;8(38):64471-80.\u003c/li\u003e\n\u003cli\u003eXie L, Xu J, Sun X, Tang X, Yan T, Yang R, et al. Apatinib for Advanced Osteosarcoma after Failure of Standard Multimodal Therapy: An Open Label Phase II Clinical Trial. The oncologist. 2019;24(7):e542-e50.\u003c/li\u003e\n\u003cli\u003eLan C-Y, Wang Y, Xiong Y, Li J-D, Shen J-X, Li Y-F, et al. Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study. The Lancet Oncology. 2018;19(9):1239-46.\u003c/li\u003e\n\u003cli\u003eMiao M, Deng G, Luo S, Zhou J, Chen L, Yang J, et al. A phase II study of apatinib in patients with recurrent epithelial ovarian cancer. Gynecol Oncol. 2018;148(2):286-90.\u003c/li\u003e\n\u003cli\u003eCheng Y, Zhang J, Geng H, Qin S, Hua H. Multiline treatment combining apatinib with toptecan for platinum-resistant recurrent ovarian cancer patients: a report of three cases. Onco Targets Ther. 2018;11:1989-95.\u003c/li\u003e\n\u003cli\u003eDeng L, Wang Y, Lu W, Liu Q, Wu J, Jin J. Apatinib treatment combined with chemotherapy for advanced epithelial ovarian cancer: a case report. Onco Targets Ther. 2017;10:1521-5.\u003c/li\u003e\n\u003cli\u003eZhang M, Tian Z, Sun Y. Successful treatment of ovarian cancer with apatinib combined with chemotherapy: A case report. Medicine (Baltimore). 2017;96(45):e8570.\u003c/li\u003e\n\u003cli\u003eRustin, G.J., Use of CA-125 to assess response to new agents in ovarian cancer trials. J Clin Oncol, 2003. 21(10 Suppl): p. 187s-193s.\u003c/li\u003e\n\u003cli\u003eWright, J.D., et al., Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis. Cancer, 2006. 107(1): p. 83-9.\u003c/li\u003e\n\u003cli\u003eFolkman, J., What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst, 1990. 82(1): p. 4-6.\u003c/li\u003e\n\u003cli\u003eFerrara, N. and R.S. Kerbel, Angiogenesis as a therapeutic target. Nature, 2005. 438(7070): p. 967-74.\u003c/li\u003e\n\u003cli\u003eNetwork, N.C.C., \u0026lt;NCCN clinical practice guidelines in oncology.Ovarian Cancer. Version 1.2019.pdf\u0026gt;.\u003c/li\u003e\n\u003cli\u003eKristeleit, R., et al., A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer. Gynecol Oncol, 2017. 146(3): p. 484-490.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ovarian cancer, Apatinib, Biochemical relapse, Anti-angiogenetic agents","lastPublishedDoi":"10.21203/rs.3.rs-78764/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-78764/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eBiochemical recurrence is defined according to the combined results of serum carbohydrate antigen and image; noteworthily, it generally precedes the onset of clinical evidence. Now treatment strategies of biochemical recurrence ovarian cancer (OC) remain controversial. Apatinib as monotherapy or in combination with other chemotherapeutic agents has shown its effect in the treatment of some advanced malignancies. In our study, we focused on the efficacy of apatinib in recurrent OC, especially its clinical activity in biochemical-only recurrent OC patients.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We retrospectively analyzed clinical material of 41 recurrent patients who had received apatinib monotherapy or apatinib plus chemotherapy between June 2016 and August 2018. Apatinib was administered at a 500 mg daily dose. Response was determined according to measurable disease or serum carbohydrate antigen (CA)-125 levels. Progression-free survival (PFS) was estimated by Kaplan-Meier method.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAll patients were evaluable, 19 (46.34%) had biochemical relapse and 22 (53.66%) had clinical relapse. The objective response rate (ORR) and disease control rate (DCR) in the overall population were 31.71% and 78.05%, respectively. The median PFS was 7 months (95% confidence interval 5.43-8.57). And in patients with biochemical-only relapse, the median PFS was 6 months, with ORR of 26.32% and DCR of 89.47%. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eApatinib is a well-tolerated and effective agent to delay clinical progression of patients with biochemical-only recurrent OC. More important, our study shows the promising prospect for treating OC patients with asymptomatic biochemical relapse.\u003c/p\u003e","manuscriptTitle":"Apatinib in Treating Clinical and Biochemical Recurrent Ovarian Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-06 17:52:26","doi":"10.21203/rs.3.rs-78764/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-11-04T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-11-03T00:00:00+00:00","index":1,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nIn this manuscript the authors analyzed clinical material of 41 recurrent OC patients who had received apatinib monotherapy or apatinib plus chemotherapy between June 2016 and August 2018. The dose of apatinib was administered 500mg each day. Biochemical relapse and clinical relapse were achieved in 19 (31.71%) and 22(53.66%) of 41 patients, respectively. Finally, the authors analyzed the objective response rate is 31.71%, disease control rate is 78.05%, the median PFS was 7 months, but for the patients who have biochemical-only relapse, the median PFS was 6 months, with ORR of 26.32% and DCR of 89.47%.\n\nThe authors provided valuable data about therapy in ovarian cancer throughout the manuscript. There are a couple of question noted during review:\n\n1. In this study, 13 patients were treated with apatinib in combination with other chemotherapy, and other 28 patients only received apatinib monotherapy, can the authors describe the results of monotherapy and combination therapy, respectively?\n\n2. Based on the first question, 29 patients had received 1-2 lines of chemotherapy, and other patients had received 3-5 lines treatment before participating apatinib therapy. Does the patient have tolerance to pervious medications? Is the current result based on the analysis after the patient has resistant? Such as Chun-Yan Lan et al has published apatinib combined with oral etoposide in patients with platinum-resistant in OC.\n\n3. Are there any patients showed adverse drug reaction under 500mg daily? If so, is this related to pervious medications? In Mingming Mao's publication, 31% of patients have dose reduction during the 12 months follow-up.\n\n4. Enrolled 41 patients between June 2016 and August 2018 in this research. Have the patients continued this study after two years? Could you please update the further data? Or provide the new patient data in recent two years to make the data robust.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-11-02T00:00:00+00:00","index":2,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nThe manuscript addresses the role of apatinib in treating recurrent ovarian cancer. The author performed retrospective study and found apatinib could delay clinical progression of patients with biochemical recurrent ovarian cancer. It has been demonstrated that apatinib has good efficacy and safety for treating advanced ovarian cancer. This author focused on the activity of apatinib in biochemical recurrent ovarian cancer patients. The clinical data from the paper supported the conclusion the author proposed. There are still some issues below. \n1) The title for the paper should show the role of apatinib in treating recurrent ovavian cancer. From the conclusion of the paper, the author mainly want to emphasize apatinib in treating patients with biochemical-only recurrent ovarian cancer. The current title does not reflect this point.\n2) There are 19 patients with biochemical recurrence and 22 patients with visible tumor in the paper. According to the treatment description \"Apatinib monotherapy was applied to patients who were no longer tolerant to chemotherapy or patients with biochemical recurrence of disease. Patients with relapse of a measurable tumor received treatment with apatinib and chemotherapy based on a taxane or etoposide\", those 19 patients with biochemical recurrence should receive apatinib monotherapy. However, it is not consistent with the following description \"In this study, 13 of 41 (31.71%) patients were treated with apatinib in combination with chemotherapy and 28 patients (68.69%) received apatinib monotherapy\". The author should clearly shows the treatment on patients and calculate the ORR, DCR and PFS based on the treatment and patient status.\n3) Given that the author focused on apatinib in treating patients with biochemical relapse, the author should add the CA-125 data including before and after treatment to the paper.\n\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. 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