Efficacy and safety of apatinib or apatinib combined with etoposide in patients with biochemical recurrent platinum- resistance/refractoriness ovarian cancer: A retrospective study

Efficacy and safety of apatinib or apatinib combined with etoposide in patients with biochemical recurrent platinum- resistance/refractoriness ovarian cancer: A retrospective study | 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 Efficacy and safety of apatinib or apatinib combined with etoposide in patients with biochemical recurrent platinum- resistance/refractoriness ovarian cancer: A retrospective study Jiangchun Wu, Qinhao Guo, Yong Wu, Siyu chen, Simin Wang, Xiaohua Wu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1811340/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Although apatinib or apatinib combined with etoposide has been widely used in the treatment of platinum-resistant or refractory ovarian cancer (OC), certain effects have been achieved. This study focused on the effect of low-dose apatinib or combined with etoposide in the treatment of platinum-resistant or refractory OC with biochemical recurrence. Methods Patients with platinum-refractory or platinum-resistant OC treated with apatinib monotherapy or in combination with etoposide between March 2017 and May 2018 in Fudan University Shanghai Cancer Center (FUSCC) were enrolled. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan–Meier method. Objective response rate (ORR) and disease control rate (DCR) were evaluated based on the Rustin criteria. Adverse events (AEs) were graded according to the Adverse Events of National Cancer Institute Common Terminology Criteria (Version 4.03). Results Among 31 patients in apatinib monotherapy group, the disease control rate (DCR) reached 77.41% and the objective response rate (ORR) reached 32.25%. The patient’s mPFS was 5.3 months (95% confidence interval (CI), 2.671–7.929); mOS was 24 months (95% CI, 12.746–35.254). In the combined group, the DCR reached 90%, and the ORR reached 50%. The patient’s mPFS was 6.33 months (95% CI, 4.498–8.162); mOS was 27 months (95% CI: 17.703–36.297). Conclusion In conclusion, we recommend 250mg apatinib or in combination with etoposide in patients with platinum-resistant or refractory OC at the time of biochemical recurrence. Apatinib apatinib in combination with etoposide biochemical recurrence Figures Figure 1 Figure 2 Figure 3 Introduction Ovarian cancer (OC) is the first-leading deadly gynecologic malignancy in women worldwide [ 1 ]. Due to the lack of early specific symptoms, most patients are detected at an advanced stage, leading to poor five-year survival [ 2 ]. Cytoreductive surgical debulking accompanied by platinum-based chemotherapy has been recognized as the standard treatment for epithelial ovarian cancer (EOC) [ 3 ]. Unfortunately, approximately 20–30% of patients will relapse or progress within 3 or 6 months. These patients were defined as platinum-refractory or platinum-resistant and were associated with a poor median survival of 12-18months [ 4 ]. Clinically, platinum-resistant OC patients have poor responses to alternative single-agent chemotherapy, thus, it is essential to discover novel drugs against this recurrent disease. Several antiangiogenesis drugs were shown to be effective in recurrent EOC. Apatinib is an oral, novel angiogenesis inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2) with a binding affinity 10 times that of sorafenib or vatalanib [ 5 ]. Previously, two prospective phases II studies reported promising efficacy of apatinib 500mg/d in the treatment of recurrent and platinum-resistant OC, in which dose reductions related to adverse events (AEs) occurred in 82% of the patients for apatinib combined with chemotherapy [ 6 , 7 ]. Several studies show that using 250 mg/d is effective [ 8 , 9 ]. Our previous studies also showed that apatinib 250mg/d is a feasible treatment in platinum-refractory or platinum-resistant EOC patients, in which the DCR reached 61.5% and the median progression-free survival (mPFS) reached 4.0 months [ 10 ]. Biochemical recurrence is defined as increased serum carbohydrate antigen (CA)-125 levels more than 2 times the upper limit of normal, generally 2 to 6 months before clinical recurrence [ 11 , 12 ]. In such cases, the choice between either early aggressive therapeutic intervention or waiting for clinical recurrence remains controversial. In another study, apatinib and oral etoposide combination reached 86% DCR and 8.1 months mPFS [ 6 ]. Therefore, our study is the first to demonstrate the efficacy of 250mg apatinib or 250mg apatinib in combination with etoposide in patients with platinum-resistant or platinum-refractory biochemical relapse. Methods Patient cohort All procedures were approved by the institutional Ethics Review Committee of Fudan University Shanghai Cancer Center (FUSCC). Written informed consent was obtained from all patients before sample collection. Patients with platinum-refractory or platinum-resistant OC treated with apatinib monotherapy or in combination with etoposide between March 2017 and May 2018 in our institution were enrolled. Patients were considered eligible if: 1) they received at least one line of standard chemotherapy before or after debulking surgery, 2) patients who were intolerant to chemotherapy, and 3) relapse was diagnosed with an elevated level of CA-125. Patients with a history of hypertension, ischemic cardiovascular disease, bleeding, or proteinuria was ineligible for this study. Treatment The administration of apatinib as monotherapy or in combination with etoposide was determined according to the patient’s needs. Both treatments are used in patients who cannot tolerate chemotherapy and have a concurrent biochemical relapse. In this study, apatinib with an initial dose of 250mg/d was administered continuously. Etoposide was administered orally at 50mg/d for 14 consecutive days in a 21-day cycle [ 6 , 10 ]. Patients were temporarily stopped taking apatinib when experienced grade 3 hematologic AEs or non-AEs, such as hand and foot syndrome, proteinuria, hypertension, etc. Evaluation Biochemical recurrent of OC patients was defined by serum CA-125 levels, whose response rate was based on the Rustin criteria [ 13 , 14 ]. A reduction of CA-125 levels to normalization (<35U/ml) for at least four weeks was defined as complete response (CR), a 50% reduction was defined as partial response (PR), and an increase of more than 25% was defined as progressive disease (PD), and anything else was defined as stable disease (SD) [ 15 ]. The objective response rate (ORR) was defined as the percentage of patients who achieved CR, and PR. Disease control rate (DCR) was the percentage of patients who achieved CR, PR, or SD. Overall survival (OS) was defined as the time from initial treatment to death or the last follow-up, and progression-free survival (PFS) was defined as the time from initial treatment to disease progression or death. AEs were graded according to the Adverse Events of National Cancer Institute Common Terminology Criteria (Version 4.03) [ 16 ]. Statistical analysis Statistical analysis was performed with IBM SPSS 23.0 (Chicago, IL, USA), GraphPad Prism 8, and R language. Comparisons between two conditions were based on a two-sided Student’s test. The survival curve was drawn by the Kaplan-Meier method for prognosis follow-up. The results of all statistical analyses were reported as P values from two-tailed tests, and P <0.05 was judged to be statistically significant ( * P <0.05, ** P <0.01, and *** P <0.001). Results Patient characteristics Between March 2017 and May 2018, a total of 80 patients were enrolled in this study. Sixty patients received Apatinib monotherapy and twenty patients received apatinib in combination with etoposide. In the apatinib monotherapy group, six patients were stopped using apatinib because of AEs, eleven patients were excluded because of insufficient data and twelve patients were lost to follow-up. However, in the combined treatment group, two patients were stopped using apatinib because of AEs, two patients who self-adjusted the dose were excluded, and six patients were lost to follow-up. Consequently, thirty-one patients in the apatinib monotherapy group and ten in the combined group were analyzed (Fig. 1 ). The main clinicopathological characteristics of patients are showed in Table 1 . There was no difference in all the characteristics between patients in the apatinib monotherapy group and patients in the combined therapy group. Table 1 Patients’ Characteristics Characteristics Apatinib group N (%) Combined group N (%) Number 31 (100) 10 (100) Median age (years) 54.5 (38–70) 54.5 (37–67) FIGO Stage IIIA 2 (6.45) 0 (0) IIIB 3 (9.68) 1 (10) IIIC 21 (67.74) 8 (80) IV 5 (16.13) 1 (10) PS ECOG 0 2 (6.45) 1 (10) 1 23 (74.19) 6 (60) 2 5 (16.13) 2 (20) 3 1 (3.23) 1 (10) Histologic type Serous carcinoma 29 (93.54) 8 (80) Clear cell carcinoma 0 (0) 0 (0) Endometrioid carcinoma 2 (9.68) 2(20) Not available 0 (6.46) 0 (0) Lines of prior anticancer therapy 1–3 7 (22.58) 2 (20) >3 24 (77.42) 8 (80) Platinum status Refractory 9 (29.03) 3 (30) Resistant 22 (70.97) 7 (70) Efficacy Among 31 patients in apatinib monotherapy analysis with an evaluable best response, 10 patients (32.25%) achieved PR and 14 patients (45.16%) had SD. This resulted in a DCR of 77.41%, and the ORR was 32.25% (Table 2 ). The tumor response in serum CA-125 levels is shown in Fig. 2 . The patient’s mPFS was 5.3 months (95% confidence interval (CI), 2.671–7.929); mOS was 24 months (95% CI, 12.746–35.254) (Fig. 3AB). Table 2 Treatment response to apatinib monotherapy or combined therapy Apatinib monotherapy response (n = 31, %) Combined therapy response (n = 10, %) CR 0 0 PR 10 (32.25) 5 (50) SD 14 (45.16) 4 (40) PD 7 (22.58) 1 (10) ORR 10 (32.25) 5 (50) DCR 24 (77.41) 9 (90) In the combined group, 5 patients (50%) achieved PR and 4 patients (40%) had SD. This resulted in a DCR of 90%, and the ORR was 50% (Table 2 ). The patient’s mPFS was 6.33 months (95% CI, 4.498–8.162); mOS was 27 months (95% CI: 17.703–36.297) (Fig. 3CD). Safety AEs that occurred in treatment are shown in Table 3 . In the two compared group, the grade 3 treatment related AEs were hand-foot syndrome (apatinib group vs combined group, 6.45 (2/31) vs 30% (3/10)), hypertension (3.23 (1/31) vs 10% (1/10)), Nausea and vomiting (3.23 (1/31) vs 10% (1/10)), pain (0% (0/31) vs 10% (1/10)), transaminase increased (0 (0/31) vs 10% (1/10)), neutropenia (3.23 (1/31) vs 0% (0/10)), thrombocytopenia (0 (0/31) vs 10% (1/10)) (Table 3 ). There was no treatment-related death. One patient in each group experienced hypertension and discontinued treatment for 1 week. Table 3 Adverse events according to CTCAE 4.0 Adverse event Apatinib group N (%) Combined group N (%) Grade1-2 Grade 3 Total Grade1-2 Grade 3 Total Hand-foot syndrome 5 (16.13) 2 (6.45) 7 (22.58) 2 (20) 1 (10) 3 (30) Hypertension 6 (19.35) 1 (3.23) 7 (22.58) 2 (20) 1 (10) 3 (30) Nausea and vomiting 1 (3.23) 1 (3.23) 2 (6.45) 1 (10) 1 (10) 2 (20) Pain 3 (9.68) 0 (0) 3 (9.68) 1 (10) 1 (10) 2 (20) Transaminase increased 2 (6.45) 0 (0) 2 (6.45) 1 (10) 1 (10) 2 (20) Neutropenia 4 (12.90) 1 (3.23) 5 (16.13) 1 (10) 0 (0) 1 (10) Thrombocytopenia 3 (9.68) 0 (0) 3 (9.68) 1 (10) 1 (10) 2 (20) Fatigue 2 (6.45) 0 (0) 2 (6.45) 1 (10) 0 (0) 1 (10) Diarrhea and constipation 2 (6.45) 0 (0) 2 (6.45) 1 (10) 0 (0) 1 (10) Anorexia 1 (3.23) 0 (0) 1 (3.23) 1 (10) 0 (0) 1 (10) Discussion Advanced recurrent platinum-resistant or refractory OC has always been a difficult problem for gynecological tumor treatment. Currently, the treatment methods are limited, and most patients undergo too many lines or multiple courses of chemotherapy, often with a poor physical condition. Initially, two prospective studies demonstrated that apatinib orally administered 500mg per day in patients with platinum-resistant or platinum-refractory OC showed good results. Miao et al. reported the ORR reached 41.4%, DCR reached 68.9% and mPFS reached 5.1 months. But at the same time, the side effects of high doses of Apatinib can seriously affect patient compliance and quality of life [ 7 ]. In another phase II study of 500 mg apatinib for EOC, 39.3% of the patients had to interrupt the dose within 1 month, and 32.1% of the patients had to reduce the dose due to severe hand-foot syndrome and hypertension [ 6 ]. In our previous published retrospective study, apatinib was the first to show a 61.5% DCR and 4.0 months median PFS in patients with platinum-resistant or platinum-refractory OC treated with 250mg apatinib daily. Because the toxicity was largely tolerable and controllable, the older age group showed higher DCR and longer PFS [ 10 ]. Another retrospective study on platinum-resistant or refractory OC showed in patients with biochemical-only relapse, the mPFS was 6 months, with ORR of 26.32% and DCR of 89.47%. And in patients with clinical relapse, the ORR was 36.36% and DCR was 68.18% [ 17 ]. This suggests a higher DCR when patients are treated with apatinib for biochemical relapse. Besides, a study combining etoposide with 500mg apatinib showed 54% ORR, 86% DCR and 8.1 months mPFS [ 6 ]. This suggests that apatinib combined with etoposide can produce higher DCR and mPFS. For patients with platinum-resistant or refractory OC, appropriate prolongation of the platinum-free interval will lead to re-sensitization to platinum drugs, which is critical for later platinum reapplication. As a result, a series of platinum-free chemotherapy schemes have emerged and shown certain results. In this study, 250mg apatinib or 250mg apatinib combined with etoposide was given to patients with platinum-resistant or platinum-refractory OC with biochemical recurrence, and ORR, DCR, mPFS, and mOS were analyzed. Compared with the “intention-to-treat” group in our previous published study, this apatinib monotherapy group had better ORR (32.25% vs 27.7%), and longer mPFS (5.3m vs 4.0m), and higher DCR (77.41% vs 49.2%) [ 10 ]. This may be because we started treatment at the time of biochemical relapse in patients in this study, which could inhibit the recurrence of micrometastases earlier. There were no significant differences in patient characteristics and AEs between the two groups. In this study, when etoposide combination therapy was also given, better ORR (50% vs 32.25%), higher DCR (90% vs 77.41%), longer mPFS (5.3m vs 6.33m), and mOS (24m vs 27m) were obtained compared with the apatinib monotherapy group. There was also no significant difference in AEs between the two groups. This study has many shortcomings. Firstly, it is a single-center retrospective study with inherent shortcomings and bias. Secondly, the number of patients in the study was small and there were individual differences. Finally, drop-out and loss of follow-up are also causes of efficacy and safety bias. Conclusions In conclusion, we recommend 250mg apatinib or in combination with etoposide in patients with platinum-resistant or refractory OC at the time of biochemical recurrence. Declarations Funding This work was supported, in part, by grants from the Beijing Kanghua Foundation for the Development of Traditional Chinese and Western Medicine (KH-2021-LLZX-037). Author Contributions JC W, QH G: Conceptualization, Data curation, Investigation, Writing - original draft. Y W: Conceptualization, Data curation, Investigation, Writing - original draft, Formal analysis, Methodology, Resources, Software, Validation, Visualization. SY C, SM W: Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing. XZ J, J Z, XH W: Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing. Data Availability Statement The data that support the results of this study are available from the corresponding author upon reasonable request. Ethics Approval and Consent to Participate All study surgical procedures and experiment protocols have been approved by the Ethics Committee of Experimental Research, Shanghai Medical College, Fudan University. All participants have been informed of the potential risks and benefits and each patient has signed the informed consent form. Consent for publication Not applicable. Conflict of Interest The authors declare no conflict of interest. References Siegel, R.L., et al., Cancer statistics, 2022 . CA Cancer J Clin, 2022. 72 (1): p. 7–33. Korkmaz, T., S. Seber, and G. Basaran, Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; In the light of completed trials . Crit Rev Oncol Hematol, 2016. 98 : p. 180–8. Vergote, I., et al., Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer . N Engl J Med, 2010. 363 (10): p. 943–53. Lheureux, S., M. Braunstein, and A.M. Oza, Epithelial ovarian cancer: Evolution of management in the era of precision medicine . CA Cancer J Clin, 2019. 69 (4): p. 280–304. Li, J., et al., Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies . BMC Cancer, 2010. 10 : p. 529. Lan, C.Y., 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 . Lancet Oncol, 2018. 19 (9): p. 1239–1246. Miao, M., et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer . Gynecol Oncol, 2018. 148 (2): p. 286–290. Wang, Y., et al., The efficacy and safety of apatinib in Ewing's sarcoma: a retrospective analysis in one institution . Cancer Manag Res, 2018. 10 : p. 6835–6842. Zeng, D.X., et al., Low dosage of apatinib monotherapy as rescue treatment in advanced lung squamous cell carcinoma . Cancer Chemother Pharmacol, 2019. 83 (3): p. 439–442. Chen, W., et al., Efficacy and safety of low-dose apatinib in ovarian cancer patients with platinum-resistance or platinum-refractoriness: A single-center retrospective study . Cancer Med, 2020. 9 (16): p. 5899–5907. Tuxen, M.K., G. Soletormos, and P. Dombernowsky, Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up . Scand J Clin Lab Invest, 2002. 62 (3): p. 177–88. Hising, C., I.M. Anjegard, and N. Einhorn, Clinical relevance of the CA 125 assay in monitoring of ovarian cancer patients . Am J Clin Oncol, 1991. 14 (2): p. 111–4. Rustin, 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. Guppy, A.E., et al., A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer . Br J Cancer, 2004. 90 (4): p. 810–4. Wright, J.D., et al., Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis . Cancer, 2006. 107 (1): p. 83–9. Trotti, A., et al., CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment . Semin Radiat Oncol, 2003. 13 (3): p. 176–81. Wang, Z., et al., Apatinib treatment efficiently delays biochemical-only recurrent ovarian cancer progression . J Ovarian Res, 2021. 14 (1): p. 91. Additional Declarations No competing interests reported. Supplementary Files Highlights.docx Cite Share Download PDF Status: Posted Version 1 posted 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1811340","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":117747556,"identity":"cc1154c0-9dac-495e-9999-be6ce06b80a9","order_by":0,"name":"Jiangchun Wu","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiangchun","middleName":"","lastName":"Wu","suffix":""},{"id":117747557,"identity":"49aa5848-b10d-48f5-a01d-f980b5359f03","order_by":1,"name":"Qinhao Guo","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qinhao","middleName":"","lastName":"Guo","suffix":""},{"id":117747558,"identity":"6e75fc93-f2d0-49e1-a7a4-b77e36199073","order_by":2,"name":"Yong Wu","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Wu","suffix":""},{"id":117747559,"identity":"1b32be9a-24ef-4619-a379-372bb0a518c5","order_by":3,"name":"Siyu chen","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Siyu","middleName":"","lastName":"chen","suffix":""},{"id":117747561,"identity":"8a0fee08-9164-4941-9946-a532383d72da","order_by":4,"name":"Simin Wang","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Simin","middleName":"","lastName":"Wang","suffix":""},{"id":117747563,"identity":"7d34c62e-97c0-4ef3-b6ee-8c45813a437c","order_by":5,"name":"Xiaohua Wu","email":"","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaohua","middleName":"","lastName":"Wu","suffix":""},{"id":117747564,"identity":"c3516452-2bc1-4d00-9e2f-f8498cb66d9b","order_by":6,"name":"Xingzhu Ju","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYDACZiBmbABh5gMHPlSQpoUt8eCMM8TaBNLCwMBjfJi3hQjVBsd5D7/8ueMwA/OMnA8HeBsY5PnFDuDXItnMl2YheeYwA+OM3A0HJHcwGM6cnYBfCz8zj5mBYRtUi+EZhgSD2wS0sIG0JIK15Dw4kNhGhBagLcYPDkK0MBw4SIwWyWYeM8bGtnQGxp5nBgcbzkgQ9ovB+TPGH3+2WTMYtic//vynwkaeX5qAFpB3JIBE/cYGMEeCoHIQYP4AIuWJUjsKRsEoGAUjEgAAQNZGjcM8hWEAAAAASUVORK5CYII=","orcid":"","institution":"Fudan University Shanghai Cancer Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xingzhu","middleName":"","lastName":"Ju","suffix":""}],"badges":[],"createdAt":"2022-06-30 10:59:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1811340/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1811340/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":23602147,"identity":"06bc525f-437f-47cc-8c35-eb64066fea96","added_by":"auto","created_at":"2022-07-07 18:59:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":200221,"visible":true,"origin":"","legend":"\u003cp\u003eStudy algorithm\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1811340/v1/eda67db9084b22b3481e66fc.jpg"},{"id":23602148,"identity":"a43b726e-5f32-417a-8a46-3c2eb7f94aa3","added_by":"auto","created_at":"2022-07-07 18:59:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":145927,"visible":true,"origin":"","legend":"\u003cp\u003eBest percentage changes from baseline in serum CA-125 levels (n=41).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1811340/v1/03a7cf6f5c29b813b7e28c33.jpg"},{"id":23602145,"identity":"35c03924-702a-4cfd-9e22-1f3f714a97f3","added_by":"auto","created_at":"2022-07-07 18:59:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":107763,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier (K-M) estimates of progression-free survival (PFS) \u003cstrong\u003e(A) \u003c/strong\u003eand overall survival (OS) \u003cstrong\u003e(B) \u003c/strong\u003ein patients with apatinib monotherapy treatment. K-M estimates of progression-free survival (PFS) \u003cstrong\u003e(C) \u003c/strong\u003eand overall survival (OS) \u003cstrong\u003e(D) \u003c/strong\u003ein patients with combined therapy.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-1811340/v1/9698216f4846fdbb1597d1d1.png"},{"id":24761462,"identity":"4d24771e-b2ac-46b7-952a-59bc5434e109","added_by":"auto","created_at":"2022-08-04 06:14:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":591513,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1811340/v1/fba21b57-30ec-4b1e-95f2-0bc50650dd0d.pdf"},{"id":23602549,"identity":"d03f9177-65cc-49e1-aefe-a8e7e73e6fea","added_by":"auto","created_at":"2022-07-07 19:04:30","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":17554,"visible":true,"origin":"","legend":"","description":"","filename":"Highlights.docx","url":"https://assets-eu.researchsquare.com/files/rs-1811340/v1/102e747f0b3b81f1bf77cd13.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of apatinib or apatinib combined with etoposide in patients with biochemical recurrent platinum- resistance/refractoriness ovarian cancer: A retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOvarian cancer (OC) is the first-leading deadly gynecologic malignancy in women worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Due to the lack of early specific symptoms, most patients are detected at an advanced stage, leading to poor five-year survival [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cytoreductive surgical debulking accompanied by platinum-based chemotherapy has been recognized as the standard treatment for epithelial ovarian cancer (EOC) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Unfortunately, approximately 20\u0026ndash;30% of patients will relapse or progress within 3 or 6 months. These patients were defined as platinum-refractory or platinum-resistant and were associated with a poor median survival of 12-18months [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Clinically, platinum-resistant OC patients have poor responses to alternative single-agent chemotherapy, thus, it is essential to discover novel drugs against this recurrent disease.\u003c/p\u003e \u003cp\u003eSeveral antiangiogenesis drugs were shown to be effective in recurrent EOC. Apatinib is an oral, novel angiogenesis inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2) with a binding affinity 10 times that of sorafenib or vatalanib [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Previously, two prospective phases II studies reported promising efficacy of apatinib 500mg/d in the treatment of recurrent and platinum-resistant OC, in which dose reductions related to adverse events (AEs) occurred in 82% of the patients for apatinib combined with chemotherapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Several studies show that using 250 mg/d is effective [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our previous studies also showed that apatinib 250mg/d is a feasible treatment in platinum-refractory or platinum-resistant EOC patients, in which the DCR reached 61.5% and the median progression-free survival (mPFS) reached 4.0 months [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBiochemical recurrence is defined as increased serum carbohydrate antigen (CA)-125 levels more than 2 times the upper limit of normal, generally 2 to 6 months before clinical recurrence [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In such cases, the choice between either early aggressive therapeutic intervention or waiting for clinical recurrence remains controversial. In another study, apatinib and oral etoposide combination reached 86% DCR and 8.1 months mPFS [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, our study is the first to demonstrate the efficacy of 250mg apatinib or 250mg apatinib in combination with etoposide in patients with platinum-resistant or platinum-refractory biochemical relapse.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient cohort\u003c/h2\u003e\n\u003cp\u003eAll procedures were approved by the institutional Ethics Review Committee of Fudan University Shanghai Cancer Center (FUSCC). Written informed consent was obtained from all patients before sample collection. Patients with platinum-refractory or platinum-resistant OC treated with apatinib monotherapy or in combination with etoposide between March 2017 and May 2018 in our institution were enrolled. Patients were considered eligible if: 1) they received at least one line of standard chemotherapy before or after debulking surgery, 2) patients who were intolerant to chemotherapy, and 3) relapse was diagnosed with an elevated level of CA-125. Patients with a history of hypertension, ischemic cardiovascular disease, bleeding, or proteinuria was ineligible for this study.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eTreatment\u003c/h2\u003e\n\u003cp\u003eThe administration of apatinib as monotherapy or in combination with etoposide was determined according to the patient\u0026rsquo;s needs. Both treatments are used in patients who cannot tolerate chemotherapy and have a concurrent biochemical relapse. In this study, apatinib with an initial dose of 250mg/d was administered continuously. Etoposide was administered orally at 50mg/d for 14 consecutive days in a 21-day cycle [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. Patients were temporarily stopped taking apatinib when experienced grade 3 hematologic AEs or non-AEs, such as hand and foot syndrome, proteinuria, hypertension, etc.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eEvaluation\u003c/h2\u003e\n\u003cp\u003eBiochemical recurrent of OC patients was defined by serum CA-125 levels, whose response rate was based on the Rustin criteria [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. A reduction of CA-125 levels to normalization (\u0026lt;35U/ml) for at least four weeks was defined as complete response (CR), a 50% reduction was defined as partial response (PR), and an increase of more than 25% was defined as progressive disease (PD), and anything else was defined as stable disease (SD) [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. The objective response rate (ORR) was defined as the percentage of patients who achieved CR, and PR. Disease control rate (DCR) was the percentage of patients who achieved CR, PR, or SD. Overall survival (OS) was defined as the time from initial treatment to death or the last follow-up, and progression-free survival (PFS) was defined as the time from initial treatment to disease progression or death. AEs were graded according to the Adverse Events of National Cancer Institute Common Terminology Criteria (Version 4.03) [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eStatistical analysis was performed with IBM SPSS 23.0 (Chicago, IL, USA), GraphPad Prism 8, and R language. Comparisons between two conditions were based on a two-sided Student\u0026rsquo;s test. The survival curve was drawn by the Kaplan-Meier method for prognosis follow-up. The results of all statistical analyses were reported as \u003cem\u003eP\u003c/em\u003e values from two-tailed tests, and \u003cem\u003eP\u003c/em\u003e \u0026lt;0.05 was judged to be statistically significant (\u003cstrong\u003e*\u003c/strong\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, \u003cstrong\u003e**\u003c/strong\u003e \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01, and \u003cstrong\u003e***\u003c/strong\u003e \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eBetween March 2017 and May 2018, a total of 80 patients were enrolled in this study. Sixty patients received Apatinib monotherapy and twenty patients received apatinib in combination with etoposide. In the apatinib monotherapy group, six patients were stopped using apatinib because of AEs, eleven patients were excluded because of insufficient data and twelve patients were lost to follow-up. However, in the combined treatment group, two patients were stopped using apatinib because of AEs, two patients who self-adjusted the dose were excluded, and six patients were lost to follow-up. Consequently, thirty-one patients in the apatinib monotherapy group and ten in the combined group were analyzed (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThe main clinicopathological characteristics of patients are showed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There was no difference in all the characteristics between patients in the apatinib monotherapy group and patients in the combined therapy group.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatients\u0026rsquo; Characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eApatinib group\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCombined group\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.5 (38\u0026ndash;70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.5 (37\u0026ndash;67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIGO Stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (9.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (67.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (16.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePS ECOG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (74.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (16.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistologic type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (93.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClear cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndometrioid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (9.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot available\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (6.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLines of prior anticancer therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u0026ndash;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (22.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (77.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlatinum status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRefractory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (29.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eResistant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (70.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cp\u003eAmong 31 patients in apatinib monotherapy analysis with an evaluable best response, 10 patients (32.25%) achieved PR and 14 patients (45.16%) had SD. This resulted in a DCR of 77.41%, and the ORR was 32.25% (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The tumor response in serum CA-125 levels is shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The patient\u0026rsquo;s mPFS was 5.3 months (95% confidence interval (CI), 2.671\u0026ndash;7.929); mOS was 24 months (95% CI, 12.746\u0026ndash;35.254) (Fig.\u0026nbsp;3AB).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment response to apatinib monotherapy or combined therapy\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eApatinib monotherapy response (n\u0026thinsp;=\u0026thinsp;31, %)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCombined therapy response (n\u0026thinsp;=\u0026thinsp;10, %)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (32.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 (45.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (22.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (32.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (77.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (90)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the combined group, 5 patients (50%) achieved PR and 4 patients (40%) had SD. This resulted in a DCR of 90%, and the ORR was 50% (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The patient\u0026rsquo;s mPFS was 6.33 months (95% CI, 4.498\u0026ndash;8.162); mOS was 27 months (95% CI: 17.703\u0026ndash;36.297) (Fig.\u0026nbsp;3CD).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAEs that occurred in treatment are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. In the two compared group, the grade 3 treatment related AEs were hand-foot syndrome (apatinib group vs combined group, 6.45 (2/31) vs 30% (3/10)), hypertension (3.23 (1/31) vs 10% (1/10)), Nausea and vomiting (3.23 (1/31) vs 10% (1/10)), pain (0% (0/31) vs 10% (1/10)), transaminase increased (0 (0/31) vs 10% (1/10)), neutropenia (3.23 (1/31) vs 0% (0/10)), thrombocytopenia (0 (0/31) vs 10% (1/10)) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). There was no treatment-related death. One patient in each group experienced hypertension and discontinued treatment for 1 week.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAdverse events according to CTCAE 4.0\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eAdverse event\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eApatinib group\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eCombined group\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade1-2\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade1-2\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHand-foot syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (16.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (22.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6 (19.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (22.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea and vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (9.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (9.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTransaminase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (12.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (16.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (9.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (9.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea and constipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (6.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (3.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAdvanced recurrent platinum-resistant or refractory OC has always been a difficult problem for gynecological tumor treatment. Currently, the treatment methods are limited, and most patients undergo too many lines or multiple courses of chemotherapy, often with a poor physical condition. Initially, two prospective studies demonstrated that apatinib orally administered 500mg per day in patients with platinum-resistant or platinum-refractory OC showed good results. Miao et al. reported the ORR reached 41.4%, DCR reached 68.9% and mPFS reached 5.1 months. But at the same time, the side effects of high doses of Apatinib can seriously affect patient compliance and quality of life [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In another phase II study of 500 mg apatinib for EOC, 39.3% of the patients had to interrupt the dose within 1 month, and 32.1% of the patients had to reduce the dose due to severe hand-foot syndrome and hypertension [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In our previous published retrospective study, apatinib was the first to show a 61.5% DCR and 4.0 months median PFS in patients with platinum-resistant or platinum-refractory OC treated with 250mg apatinib daily. Because the toxicity was largely tolerable and controllable, the older age group showed higher DCR and longer PFS [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother retrospective study on platinum-resistant or refractory OC showed in patients with biochemical-only relapse, the mPFS was 6 months, with ORR of 26.32% and DCR of 89.47%. And in patients with clinical relapse, the ORR was 36.36% and DCR was 68.18% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This suggests a higher DCR when patients are treated with apatinib for biochemical relapse. Besides, a study combining etoposide with 500mg apatinib showed 54% ORR, 86% DCR and 8.1 months mPFS [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This suggests that apatinib combined with etoposide can produce higher DCR and mPFS.\u003c/p\u003e \u003cp\u003eFor patients with platinum-resistant or refractory OC, appropriate prolongation of the platinum-free interval will lead to re-sensitization to platinum drugs, which is critical for later platinum reapplication. As a result, a series of platinum-free chemotherapy schemes have emerged and shown certain results. In this study, 250mg apatinib or 250mg apatinib combined with etoposide was given to patients with platinum-resistant or platinum-refractory OC with biochemical recurrence, and ORR, DCR, mPFS, and mOS were analyzed.\u003c/p\u003e \u003cp\u003eCompared with the \u0026ldquo;intention-to-treat\u0026rdquo; group in our previous published study, this apatinib monotherapy group had better ORR (32.25% vs 27.7%), and longer mPFS (5.3m vs 4.0m), and higher DCR (77.41% vs 49.2%) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This may be because we started treatment at the time of biochemical relapse in patients in this study, which could inhibit the recurrence of micrometastases earlier. There were no significant differences in patient characteristics and AEs between the two groups.\u003c/p\u003e \u003cp\u003eIn this study, when etoposide combination therapy was also given, better ORR (50% vs 32.25%), higher DCR (90% vs 77.41%), longer mPFS (5.3m vs 6.33m), and mOS (24m vs 27m) were obtained compared with the apatinib monotherapy group. There was also no significant difference in AEs between the two groups.\u003c/p\u003e \u003cp\u003eThis study has many shortcomings. Firstly, it is a single-center retrospective study with inherent shortcomings and bias. Secondly, the number of patients in the study was small and there were individual differences. Finally, drop-out and loss of follow-up are also causes of efficacy and safety bias.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, we recommend 250mg apatinib or in combination with etoposide in patients with platinum-resistant or refractory OC at the time of biochemical recurrence.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported, in part, by grants from the Beijing Kanghua Foundation for the Development of Traditional Chinese and Western Medicine (KH-2021-LLZX-037).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJC W, QH G: Conceptualization, Data curation, Investigation, Writing - original draft. Y W: Conceptualization, Data curation, Investigation, Writing - original draft, Formal analysis, Methodology, Resources, Software, Validation, Visualization. SY C, SM W: Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review \u0026amp; editing. XZ J, J Z, XH W: Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the results of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll study surgical procedures and experiment protocols have been approved by the Ethics Committee of Experimental Research, Shanghai Medical College, Fudan University. All participants have been informed of the potential risks and benefits and each patient has signed the informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel, R.L., et al., \u003cem\u003eCancer statistics, 2022\u003c/em\u003e. CA Cancer J Clin, 2022. \u003cb\u003e72\u003c/b\u003e(1): p.\u0026nbsp;7\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorkmaz, T., S. Seber, and G. Basaran, \u003cem\u003eReview of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; In the light of completed trials\u003c/em\u003e. Crit Rev Oncol Hematol, 2016. \u003cb\u003e98\u003c/b\u003e: p.\u0026nbsp;180\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVergote, I., et al., \u003cem\u003eNeoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer\u003c/em\u003e. N Engl J Med, 2010. \u003cb\u003e363\u003c/b\u003e(10): p.\u0026nbsp;943\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLheureux, S., M. Braunstein, and A.M. Oza, \u003cem\u003eEpithelial ovarian cancer: Evolution of management in the era of precision medicine\u003c/em\u003e. CA Cancer J Clin, 2019. \u003cb\u003e69\u003c/b\u003e(4): p.\u0026nbsp;280\u0026ndash;304.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, J., et al., \u003cem\u003eSafety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies\u003c/em\u003e. BMC Cancer, 2010. \u003cb\u003e10\u003c/b\u003e: p.\u0026nbsp;529.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLan, C.Y., et al., \u003cem\u003eApatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study\u003c/em\u003e. Lancet Oncol, 2018. \u003cb\u003e19\u003c/b\u003e(9): p.\u0026nbsp;1239\u0026ndash;1246.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiao, M., et al., \u003cem\u003eA phase II study of apatinib in patients with recurrent epithelial ovarian cancer\u003c/em\u003e. Gynecol Oncol, 2018. \u003cb\u003e148\u003c/b\u003e(2): p.\u0026nbsp;286\u0026ndash;290.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, Y., et al., \u003cem\u003eThe efficacy and safety of apatinib in Ewing's sarcoma: a retrospective analysis in one institution\u003c/em\u003e. Cancer Manag Res, 2018. \u003cb\u003e10\u003c/b\u003e: p.\u0026nbsp;6835\u0026ndash;6842.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeng, D.X., et al., \u003cem\u003eLow dosage of apatinib monotherapy as rescue treatment in advanced lung squamous cell carcinoma\u003c/em\u003e. Cancer Chemother Pharmacol, 2019. \u003cb\u003e83\u003c/b\u003e(3): p.\u0026nbsp;439\u0026ndash;442.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, W., et al., \u003cem\u003eEfficacy and safety of low-dose apatinib in ovarian cancer patients with platinum-resistance or platinum-refractoriness: A single-center retrospective study\u003c/em\u003e. Cancer Med, 2020. \u003cb\u003e9\u003c/b\u003e(16): p.\u0026nbsp;5899\u0026ndash;5907.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuxen, M.K., G. Soletormos, and P. Dombernowsky, \u003cem\u003eSerum tumor marker CA 125 for monitoring ovarian cancer during follow-up\u003c/em\u003e. Scand J Clin Lab Invest, 2002. \u003cb\u003e62\u003c/b\u003e(3): p.\u0026nbsp;177\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHising, C., I.M. Anjegard, and N. Einhorn, \u003cem\u003eClinical relevance of the CA 125 assay in monitoring of ovarian cancer patients\u003c/em\u003e. Am J Clin Oncol, 1991. \u003cb\u003e14\u003c/b\u003e(2): p.\u0026nbsp;111\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRustin, G.J., \u003cem\u003eUse of CA-125 to assess response to new agents in ovarian cancer trials\u003c/em\u003e. J Clin Oncol, 2003. \u003cb\u003e21\u003c/b\u003e(10 Suppl): p.\u0026nbsp;187s-193s.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuppy, A.E., et al., \u003cem\u003eA phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer\u003c/em\u003e. Br J Cancer, 2004. \u003cb\u003e90\u003c/b\u003e(4): p.\u0026nbsp;810\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright, J.D., et al., \u003cem\u003eBevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis\u003c/em\u003e. Cancer, 2006. \u003cb\u003e107\u003c/b\u003e(1): p.\u0026nbsp;83\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrotti, A., et al., \u003cem\u003eCTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment\u003c/em\u003e. Semin Radiat Oncol, 2003. \u003cb\u003e13\u003c/b\u003e(3): p.\u0026nbsp;176\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, Z., et al., \u003cem\u003eApatinib treatment efficiently delays biochemical-only recurrent ovarian cancer progression\u003c/em\u003e. J Ovarian Res, 2021. \u003cb\u003e14\u003c/b\u003e(1): p.\u0026nbsp;91.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Apatinib, apatinib in combination with etoposide, biochemical recurrence","lastPublishedDoi":"10.21203/rs.3.rs-1811340/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1811340/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlthough apatinib or apatinib combined with etoposide has been widely used in the treatment of platinum-resistant or refractory ovarian cancer (OC), certain effects have been achieved. This study focused on the effect of low-dose apatinib or combined with etoposide in the treatment of platinum-resistant or refractory OC with biochemical recurrence.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with platinum-refractory or platinum-resistant OC treated with apatinib monotherapy or in combination with etoposide between March 2017 and May 2018 in Fudan University Shanghai Cancer Center (FUSCC) were enrolled. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan\u0026ndash;Meier method. Objective response rate (ORR) and disease control rate (DCR) were evaluated based on the Rustin criteria. Adverse events (AEs) were graded according to the Adverse Events of National Cancer Institute Common Terminology Criteria (Version 4.03).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 31 patients in apatinib monotherapy group, the disease control rate (DCR) reached 77.41% and the objective response rate (ORR) reached 32.25%. The patient\u0026rsquo;s mPFS was 5.3 months (95% confidence interval (CI), 2.671\u0026ndash;7.929); mOS was 24 months (95% CI, 12.746\u0026ndash;35.254). In the combined group, the DCR reached 90%, and the ORR reached 50%. The patient\u0026rsquo;s mPFS was 6.33 months (95% CI, 4.498\u0026ndash;8.162); mOS was 27 months (95% CI: 17.703\u0026ndash;36.297).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn conclusion, we recommend 250mg apatinib or in combination with etoposide in patients with platinum-resistant or refractory OC at the time of biochemical recurrence.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of apatinib or apatinib combined with etoposide in patients with biochemical recurrent platinum- resistance/refractoriness ovarian cancer: A retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-07-07 18:59:28","doi":"10.21203/rs.3.rs-1811340/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f364d840-d10b-4cca-abe1-b0333438ed9d","owner":[],"postedDate":"July 7th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-08-04T06:14:15+00:00","versionOfRecord":[],"versionCreatedAt":"2022-07-07 18:59:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1811340","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1811340","identity":"rs-1811340","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}