Efficacy and Safety of Bevacizumab-Combined Single-Agent Chemotherapy for Platinum-Resistant Ovarian Cancer that Recurred During PARP Inhibitor Treatment

Efficacy and Safety of Bevacizumab-Combined Single-Agent Chemotherapy for Platinum-Resistant Ovarian Cancer that Recurred During PARP Inhibitor Treatment | 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 Bevacizumab-Combined Single-Agent Chemotherapy for Platinum-Resistant Ovarian Cancer that Recurred During PARP Inhibitor Treatment Eriko takatori, Tadahiro Shoji, Ami Jo, Miku Musashi, Shunsuke Tatsuki, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7904976/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Currently, there are no reports on the subsequent treatment of patients with ovarian cancer who exhibited platinum-resistant recurrence during treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. This retrospective study was aimed at evaluating the efficacy and safety of single-agent chemotherapy combined with bevacizumab (BEV) in such patients. Patients and Methods The efficacy and safety of the treatment were evaluated in 16 patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer diagnosed with platinum-resistant recurrence during PARP inhibitor treatment between April 2019 and June 2025. Chemotherapy was administered with paclitaxel alone or nogitecan alone in combination with BEV and generally continued until the disease progressed. Results The median number of single-agent chemotherapy cycles with BEV was 6 (range: 1–20). The objective response and disease control rates were 31.3% and 75.0%, respectively. The median progression-free survival and overall survival were 5.5 months [95% confidence interval (CI) = 4.0–6.0) and 17 months (95%CI = 10.0–29.0), respectively. Grade 3 or higher hematological toxicities were observed, including leukopenia, neutropenia, anemia, and thrombocytopenia in 7, 9, 1, and 3 patients, respectively. Non-hematological toxicities included hypertension in three patients and nausea, vomiting, fatigue, proteinuria, thrombosis, ileus, and heart failure in one patient each. None of the patients discontinued chemotherapy because of adverse events or treatment-related deaths. Conclusion BEV-combined single-agent chemotherapy has potential efficacy even in the challenging setting of platinum-resistant recurrence during PARP inhibitor treatment of ovarian cancer. Ovarian cancer PARP inhibitor platinum-resistant recurrence bevacizumab single-agent chemotherapy Figures Figure 1 1. Introduction Ovarian cancer is the third most common gynecological malignancy after cervical and endometrial cancers. In 2020, approximately 314,000 new cases of ovarian cancer and 207,000 ovarian cancer-related deaths were reported globally [ 1 ]. In the United States, it is estimated that 19,680 new cases of ovarian cancer were diagnosed in 2024, with 12,740 ovarian cancer-related deaths. Deaths due to ovarian cancer exceed those caused by endometrial and cervical cancers [ 2 ]. Paclitaxel plus carboplatin therapy is the gold standard first-line chemotherapy for ovarian cancer [ 3 ]. Nevertheless, the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors has significantly altered the therapeutic landscape for ovarian cancer, particularly in patients with BRCA mutations or homologous recombination deficiency (HRD). Clinical trials such as the SOLO1, PAOLA-1, PRIMA, and PRIME trials have demonstrated prolonged progression-free survival (PFS) with maintenance PARP inhibitor treatment, leading to their widespread adoption in clinical practice [ 4 – 7 ]. The SOLO1 trial reported a 7-year survival rate of 67%, and 45.3% of the patients did not receive second-line treatment [ 4 ]. These findings suggest that long-term disease control may be achieved in selected patients. However, reports on the subsequent treatment of patients with recurrent ovarian cancer during and after treatment with PARP inhibitors are limited. In particular, the recurrence of the disease owing to platinum resistance during PARP inhibitor maintenance poses a significant therapeutic challenge. To date, no established treatment guidelines or published data specifically address this clinical scenario. Platinum-based chemotherapy for platinum-sensitive recurrence during or after PARP inhibitor treatment has been reported to result in lower response rate and shorter PFS [ 8 – 10 ]. In contrast, we previously reported favorable outcomes with platinum-based chemotherapy combined with bevacizumab (BEV) for platinum-sensitive recurrent ovarian cancer during and after treatment with PARP inhibitors [ 11 ]. Therefore, the aim of this retrospective, two-institutional analysis was to evaluate the efficacy and safety of single-agent chemotherapy combined with BEV in patients with ovarian cancer who developed platinum-resistant recurrence during treatment with PARP inhibitors. 2. Patients and Methods This study was approved by the Institutional Review Board of the Iwate Medical University School of Medicine (approval no. MH2024-26). 2.1. Patients Sixteen patients diagnosed with platinum-resistant recurrent ovarian, fallopian tube, or primary peritoneal cancer during treatment with PARP inhibitors, and treated with single-agent chemotherapy combined with BEV between April 2019 and June 2025 at the Department of Obstetrics and Gynecology of Iwate Medical University Hospital and Hachinohe Red Cross Hospital were included. Informed consent was obtained through the institutional website using the opt-out method. Patients who opted out of the study were excluded. 2.2. Treatment Chemotherapy was administered according to the JGOG 2023 trial protocol [ 12 ]. The platinum-free interval (PFI) was defined as the time from the last platinum agent administration to subsequent disease progression based on radiographic evaluation using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [ 13 ]. The dosing schedule for each chemotherapy regimen was as follows: paclitaxel was administered intravenously at 80 mg/m 2 on days 1, 8, and 15 over a cycle of 21 days; nogitecan was administered intravenously at 1.25 mg/m 2 on days 1, 2, 3, 4, and 5 over a cycle of 21 days; and BEV was administered intravenously at 15 mg/kg on day 1. BEV was administered when the score was less than 5 points, according to our “institutional bevacizumab administration criteria” [ 11 ]. As a rule, treatment was continued until disease progression unless adverse events (AEs) were observed, which made continuation impossible. 2.3. Statistical analysis The primary endpoint was PFS, and the secondary endpoints were overall survival (OS), anti-tumor efficacy, and AEs. Anti-tumor efficacy was defined as the best response to the treatment and evaluated using RECIST version 1.1, in terms of complete response, partial response, stable disease or disease progression [ 13 ]. Recurrence was diagnosed using computed tomography or positron emission tomography. The incidence and severity of AEs and treatment-related AEs were evaluated according to the Common Toxicity Criteria for Adverse Events version 5.0, JCOG Japanese version (CTCAE version 5.0-JCOG) [ 14 ]. The data cutoff was set at June 30, 2025. PFS and OS were calculated from the start date of BEV-combined single-agent chemotherapy for recurrence after PARP inhibitor treatment to the documented date of progression, death, or last follow-up, whichever occurred first. The effect on survival was assessed by constructing Kaplan–Meier curves using a log-rank test. In a multivariate Cox proportional hazards model, we included the following clinically relevant variables as covariates: performance status (PS), number of prior chemotherapy regimens (< 3 vs. ≥3), prior use of BEV (yes vs. no), and PFI (< 3 months vs. ≥3 months). These variables were chosen based on prior evidence suggesting their association with clinical outcomes in platinum-resistant ovarian cancer, as well as their biological plausibility in influencing the treatment response. All statistical analyses were performed using EZR version 1.54 (available on our website ( http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html ; Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria), with a p-value of < 0.05 deemed as statistically significant. Specifically, it is a modified version of the R Commander, designed to incorporate statistical functions commonly used in biostatistics [ 15 ]. 3. Results 3.1. Patient characteristics Table 1 summarizes the background characteristics of the 16 patients enrolled in this study. The median age was 65.5 years (range: 48–79 years). The PS was 0 in 13 patients (81.2%) and 1 in 3 patients (18.8%). The histological type was high-grade serous carcinoma in 13 patients (81.2%), endometrioid carcinoma in 2 (12.5%), and clear cell carcinoma in 1 (6.3%). Of the 16 patients, one had a BRCA mutation and two had HRD. Overall, 11 patients (68.7%) received one or two regimens of prior chemotherapy and 5 (31.3%) received three or more regimens. Ten (62.5%) patients received BEV and 6 (37.5%) did not. The previously administered PARP inhibitors were olaparib and niraparib in 8 patients (50.0%). The PFI was <3 months in 6 patients (37.5%) and between 3 and 6 months in 10 patients (62.5%). The recurrence sites were intraperitoneal in 15 patients (93.7%) and distant in 1 patient (6.3%). The chemotherapy administered to the enrolled patients included paclitaxel + BEV therapy in 9 patients (56.2%) and nogitecan + BEV therapy in 7 patients (43.8%). 3.2. Anti-tumor response and subsequent treatment Table 2 summarizes the anti-tumor effects observed in the 16 patients. The median number of cycles of chemotherapy with BEV was 6 (range: 1–20). Partial response was observed in 5 patients (31.3%), stable disease in 7 (43.7%), and progressive disease in 4 (25.0%). Objective response and disease control rates were 31.3% [95% confidence interval (CI): 11.0–58.7] and 75.0% (95% CI: 47.6–92.7), respectively. Treatment after recurrence included a change in regimen in 12 patients and switching to best supportive care in 4 patients. Ten patients received single-agent chemotherapy, and two received platinum-based chemotherapy. Eleven of the 12 patients received a regimen with BEV, but only one patient, who had hypertension, chose single-agent chemotherapy without BEV. 3.3. Adverse events The AEs identified in this study are listed in Table 3. Grade 3 or higher hematological toxicities occurred leucopenia in 7 patients (43.7%), neutropenia in 9 (56.2%), anemia in 1 (6.2%), and thrombocytopenia in 3 (18.7%). In contrast, non-hematological toxicities of grade 3 or higher included hypertension in 3 patients (18.7%) and protein urea, thrombosis, nausea, vomiting, fatigue, ileus, and heart failure in 1 patient (6.2%). No treatment interruptions or treatment-related deaths due to AEs were observed. 3.4. Survival analysis Figure 1 shows the PFS and OS of all the patients. The median follow-up period was 14 months (range: 5–37 months), and the median PFS and OS were 5.5 months (95% CI: 4.0–6.0) and 17 months (95% CI: 10.0–29.0), respectively. In multivariate analysis, none of the evaluated factors were identified as independent prognostic indicators for either PFS or OS. All variables included in the model (PS, number of prior regimens, prior BEV administration, and PFI) had p-values > 0.05. The hazard ratios (HRs), 95% CIs, and corresponding p-values are presented in Table 4. None of the covariates demonstrated statistical significance in predicting PFS or OS, with all p-values exceeding 0.05, indicating the absence of independent prognostic factors in this patient cohort. 4. Discussion In this retrospective study, the benefits of single-agent chemotherapy combined with BEV for platinum-resistant recurrence during treatment of ovarian cancer with PARP inhibitors were examined. It was conducted because no subsequent treatment has been reported for patients with platinum-resistant recurrence, and the benefit of platinum-based chemotherapy with BEV has been reported in patients with platinum-sensitive recurrence during treatment with PARP inhibitors [ 8 ]. We found no articles that clearly described the rate of recurrence of platinum-resistant ovarian cancer when PARP inhibitors were administered as maintenance therapy. Although the platinum-resistant recurrence rate cannot be determined based on the PFS curve alone, it has been estimated to be approximately 5–10% in the SOLO1 trial [ 4 ], 20–25% in the PRIMA trial [ 6 ] and 10–15% in the PAOLA-1 trial [ 5 ]. Thus, the small number of patients with platinum-resistant ovarian cancer that recurred during maintenance therapy with PARP inhibitors resulted in the small sample size of this study. Treatment outcomes of single-agent chemotherapy with BEV in patients with platinum-resistant recurrence in the absence of prior PARP inhibitors have been reported to have a response rate of 25–31%, median PFS of 4.1–6.7 months, and median OS of 15.3–16.6 months [ 16 , 17 ]. In contrast, single-agent chemotherapy without BEV has been reported to have a response rate of 6.1–8.3%, median PFS of 3.1–3.7 months, and median OS of 12.7–13.5 months [ 18 , 19 ]. In this study, the median PFS and OS for single-agent chemotherapy with BEV for platinum-resistant recurrence during PARP inhibitor treatment were 5.5 and 17 months, respectively. These results are similar to those reported for platinum-resistant recurrence without prior PARP inhibitor treatment. However, the effect of BEV on platinum-resistant recurrence during treatment with PARP inhibitors without concomitant BEV remains unknown, because no historical data are available. In a subgroup analysis, Lin et al. reported that single-agent chemotherapy combined with BEV was more effective than single-agent chemotherapy alone for platinum-resistant recurrence during PARP inhibitor administration. They reported an HR of 0.31 in six patients, but did not report the response rate, PFS, or OS [ 20 ]. There are two reasons for the slightly longer median OS compared with previous reports. First, BEV was continued in subsequent treatments based on the MITO-16B/MaNGO2 and JGOG3023 trials, which administered BEV beyond progressive disease. Second, our research institution actively conducts platinum challenges. Patients who received single-agent chemotherapy with BEV and had a PFI > 6 months received a platinum challenge. Platinum challenge was performed in two patients in the current study, with an OS of 24 and 37 months, respectively. Tatsuki et al. reported favorable results with the platinum challenge for platinum-resistant recurrent ovarian cancer, with median PFS and OS of 8.5 months and 35.8 months, respectively [ 21 ]. AEs of grade 3 or higher hematologic toxicity were observed but were not severe and manageable. Non-hematological AEs of grade 3 or higher included hypertension (18.7%), increased urinary protein levels, and thrombosis (6.2%). This was thought to be due to the use of BEV, the frequency of which was similar to that in the AURELIA and JGOG3023 trials [ 16 , 17 ]. One case each of grade 3 ileus and heart failure was observed, but the ileus was considered to indicate disease progression and heart failure was considered to be an incidental AE. PD-L1 antibodies and antibody–drug conjugates are expected to be new agents for the treatment of platinum-resistant recurrence. The AGO-OVAR 2.29/ENGOT-ov34 and MIRASOL trials on these agents are ongoing in other countries. Atezolizumab and mirvetuximab sorafenib may also be effective for patients who cannot use BEV owing to complications, and future research is warranted. The mechanisms underlying the resistance to PARP inhibitors remain to be fully elucidated. The use of PARP inhibitors may cause BRCA function reversal (reversion mutation). This may eliminate HRD and lead to resistance to platinum-based agents and PARP inhibitors [ 22 , 23 ]. It is speculated that BEV improves drug delivery by controlling the tumor microenvironment, and that changes in the microenvironment (e.g., hypoxia) increase the sensitivity of cytotoxic anticancer agents, thereby preventing a decrease in the response rate. Our results suggested that even in the setting of platinum-resistant recurrence during PARP inhibitor therapy, the combination of BEV with single-agent chemotherapy could offer clinical benefits. These findings support the consideration of BEV-containing regimens as viable options for this unique clinical scenario; however, further prospective studies are required to validate this strategy. This study has a few limitations. First, this was a two-center retrospective study with a small number of patients. Therefore, prognostic factors could not be identified. Second, because many patients started treatment before the BRCA and HRD tests were covered by insurance, there were missing data; thus, it was not possible to compare prognoses by BRCA or HRD status. Third, three patients received more than four prior regimens, which could be the reason for the non-prolonged median PFS and OS. Additionally, the quality of life of the patients was not evaluated in this study. In conclusion, despite the limitations inherent to its retrospective design and small sample size, this study provides novel insights into a previously unexplored clinical scenario. The results suggest that BEV-containing regimens may offer a viable therapeutic option for platinum-resistant recurrence during treatment with PARP inhibitors, a setting with no current standard of care. Prospective trials are warranted to validate these findings and refine the patient selection criteria. Declarations Authors’ Contributions Takatori E and Shoji T conceived the study. Jo A, Musashi M, Tatsuki S, Jonai N, Chiba Y, Sato S, Kaido Y, Nagasawa T, and Kagabu M performed a literature search. Takahashi F performed analysis and interpretation of data. Takatori E prepared the original manuscript. Shoji T, Baba T, and Aida T performed drafting and revising the article. All Authors have read and agreed to the published version of the manuscript. Acknowledgements The authors would like to thank Editage (www. honya kucen ter. jp) for the English language review. Conflict of interest None of the authors of this manuscript has any conflicts of interest to declare. 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Mol Cancer 24: 55. http://doi. 10.1186/s12943-025-02355-1 Tables Table1 Patient characteristics （ N ＝ 16 ） Age,years Median 66 Range 48-79 PS 0 13 1 3 Diagnosis Ovary 10 Pritoneum 6 FIGO stage I 1 II 0 III 12 IV 3 Histological type Serous 13 Endometrioid 2 Clear 1 BRCA status Positive 1 Negative 5 Unknown 10 HRD status Positive 2 Negative 1 Unknown 13 Number of prior regimens 1,2 11 > 3 5 Prior BEV administration Yes 10 No 6 Kind of PARP inhibitor last administered Olaparib 8 Niraparib 8 Platinum-free interval 3<, ＜6 months 10 < 3 months 6 Site of recurrenc Intraperitoneal 15 Distant metastasis 1 Regimens of chemotherapy with BEV PTX+BEV 9 NGT+BEV 7 Abbreviations: PS; performance status, HRD; homologous recombination repair deficiency, PARP; poly ADP-ribose polymerase, BEV; bevacizumab, PTX; paclitaxel, NGT; nogitecan Table2: Anti-tumor response （ N ＝ 16 ） N % CR 0 0 PR 5 31.3 SD 7 43.7 PD 4 25.0 Overall response 5 31.3 Disease control 12 75.0 Abbreviations: CR ; complete response, PR ; partial response, SD ; stable disease , PD ; progressive disease Table 3 Adverse events Grade1 Grade2 Grade3 Grade4 ≧Grade3 (%) Leucopenia 2 4 6 1 7 (43.7) Neutropenia 2 2 5 4 9 (56.2) Anemia 4 10 1 0 1 (6.2) Thrombocytopenia 1 5 1 2 3 (18.7) Febrile neutropenia 0 0 0 0 0 Nausea 1 0 1 0 1 (6.2) Vomiting 0 0 1 0 1 (6.2) Fatigue 2 0 1 0 1 (6.2) Sensory neuropathy 4 7 0 0 0 Eczema 5 1 0 0 0 Mucositis 2 0 0 0 0 Ileus 0 0 1 0 1 (6.2) Heart failure 0 0 1 0 1 (6.2) Hypertension 5 5 3 0 3 (18.7) Protein urea 8 6 1 0 1 (6.2) Thrombosis 2 0 1 0 1 (6.2) GIP 0 0 0 0 0 Constipation 3 0 0 0 0 Edema 1 0 0 0 0 GIP; gastrointestinal perforation Table4 Multivariate analyses of PFS and OS PFS HR 95%CI P value PS (0/1) 1.04 0.18-5.96 0.959 number of prior regimens (1,2/ > 3) 0.74 0.22-2.44 0.624 Prior bevacizumab administration (yes/no) 1.65 0.31-8.64 0.552 PFI ( 3, 3) 2.16 0.46-9.97 0.321 Prior bevacizumab administration (yes/no) 1.49 0.24-9.33 0.665 PFI ( 3, <6 months) 1.85 0.27-12.54 0.527 Abbreviations: PFS; progression-free survival, OS; overall survival, PS; performance status, PARP; poly ADP-ribose polymerase, PFI; platinum-free interval, HR; hazard ratio, 95%CI; 95% confidence interval Cite Share Download PDF Status: Published Journal Publication published 17 Jan, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 20 Nov, 2025 Reviewers agreed at journal 24 Oct, 2025 Reviewers invited by journal 24 Oct, 2025 Editor assigned by journal 23 Oct, 2025 First submitted to journal 20 Oct, 2025 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. 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Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Shunsuke","middleName":"","lastName":"Tatsuki","suffix":""},{"id":534381007,"identity":"c6629847-fdd5-4d92-81bc-2243c1bbe15f","order_by":5,"name":"Nanako Jonai","email":"","orcid":"","institution":"Iwate Medical University: Iwate Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Nanako","middleName":"","lastName":"Jonai","suffix":""},{"id":534381008,"identity":"214da390-3833-4d23-b172-5b53154c4541","order_by":6,"name":"Yohei Chiba","email":"","orcid":"","institution":"Iwate Medical University: Iwate Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yohei","middleName":"","lastName":"Chiba","suffix":""},{"id":534381009,"identity":"8ff3e4da-ca04-42f7-b52b-4e73a17e882a","order_by":7,"name":"Sho Sato","email":"","orcid":"","institution":"Iwate Medical University: Iwate Ika 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04:16:25","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90325,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7904976/v1/cb3ff26afec3ef831a257f18.html"},{"id":95260128,"identity":"c11b98b6-aca4-496b-bd5e-1164b0e3cbc4","added_by":"auto","created_at":"2025-11-06 04:16:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45452,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for PFS and OS. The median PFS for patients was 5.5months (95% CI, 4.0–6.0), median OS was 17 months (95% CI, 10.0–29.0)\u003c/p\u003e","description":"","filename":"Figure.png","url":"https://assets-eu.researchsquare.com/files/rs-7904976/v1/b4de337d7637d2cda6b25927.png"},{"id":100616115,"identity":"23b43f9c-789b-482b-a1b6-d16035f4bdd3","added_by":"auto","created_at":"2026-01-19 17:40:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":768719,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7904976/v1/c59eee0b-1197-48ab-b86e-a8586e6d67c4.pdf"}],"financialInterests":"","formattedTitle":"Efficacy and Safety of Bevacizumab-Combined Single-Agent Chemotherapy for Platinum-Resistant Ovarian Cancer that Recurred During PARP Inhibitor Treatment","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOvarian cancer is the third most common gynecological malignancy after cervical and endometrial cancers. In 2020, approximately 314,000 new cases of ovarian cancer and 207,000 ovarian cancer-related deaths were reported globally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In the United States, it is estimated that 19,680 new cases of ovarian cancer were diagnosed in 2024, with 12,740 ovarian cancer-related deaths. Deaths due to ovarian cancer exceed those caused by endometrial and cervical cancers [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePaclitaxel plus carboplatin therapy is the gold standard first-line chemotherapy for ovarian cancer [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Nevertheless, the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors has significantly altered the therapeutic landscape for ovarian cancer, particularly in patients with \u003cem\u003eBRCA\u003c/em\u003e mutations or homologous recombination deficiency (HRD). Clinical trials such as the SOLO1, PAOLA-1, PRIMA, and PRIME trials have demonstrated prolonged progression-free survival (PFS) with maintenance PARP inhibitor treatment, leading to their widespread adoption in clinical practice [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The SOLO1 trial reported a 7-year survival rate of 67%, and 45.3% of the patients did not receive second-line treatment [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These findings suggest that long-term disease control may be achieved in selected patients.\u003c/p\u003e\u003cp\u003eHowever, reports on the subsequent treatment of patients with recurrent ovarian cancer during and after treatment with PARP inhibitors are limited. In particular, the recurrence of the disease owing to platinum resistance during PARP inhibitor maintenance poses a significant therapeutic challenge. To date, no established treatment guidelines or published data specifically address this clinical scenario. Platinum-based chemotherapy for platinum-sensitive recurrence during or after PARP inhibitor treatment has been reported to result in lower response rate and shorter PFS [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In contrast, we previously reported favorable outcomes with platinum-based chemotherapy combined with bevacizumab (BEV) for platinum-sensitive recurrent ovarian cancer during and after treatment with PARP inhibitors [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTherefore, the aim of this retrospective, two-institutional analysis was to evaluate the efficacy and safety of single-agent chemotherapy combined with BEV in patients with ovarian cancer who developed platinum-resistant recurrence during treatment with PARP inhibitors.\u003c/p\u003e"},{"header":"2. Patients and Methods","content":"\u003cp\u003e This study was approved by the Institutional Review Board of the Iwate Medical University School of Medicine (approval no. MH2024-26).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Patients\u003c/h2\u003e\u003cp\u003eSixteen patients diagnosed with platinum-resistant recurrent ovarian, fallopian tube, or primary peritoneal cancer during treatment with PARP inhibitors, and treated with single-agent chemotherapy combined with BEV between April 2019 and June 2025 at the Department of Obstetrics and Gynecology of Iwate Medical University Hospital and Hachinohe Red Cross Hospital were included. Informed consent was obtained through the institutional website using the opt-out method. Patients who opted out of the study were excluded.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Treatment\u003c/h2\u003e\u003cp\u003eChemotherapy was administered according to the JGOG 2023 trial protocol [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The platinum-free interval (PFI) was defined as the time from the last platinum agent administration to subsequent disease progression based on radiographic evaluation using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The dosing schedule for each chemotherapy regimen was as follows: paclitaxel was administered intravenously at 80 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1, 8, and 15 over a cycle of 21 days; nogitecan was administered intravenously at 1.25 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1, 2, 3, 4, and 5 over a cycle of 21 days; and BEV was administered intravenously at 15 mg/kg on day 1. BEV was administered when the score was less than 5 points, according to our \u0026ldquo;institutional bevacizumab administration criteria\u0026rdquo; [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. As a rule, treatment was continued until disease progression unless adverse events (AEs) were observed, which made continuation impossible.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e\u003cp\u003eThe primary endpoint was PFS, and the secondary endpoints were overall survival (OS), anti-tumor efficacy, and AEs. Anti-tumor efficacy was defined as the best response to the treatment and evaluated using RECIST version 1.1, in terms of complete response, partial response, stable disease or disease progression [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recurrence was diagnosed using computed tomography or positron emission tomography. The incidence and severity of AEs and treatment-related AEs were evaluated according to the Common Toxicity Criteria for Adverse Events version 5.0, JCOG Japanese version (CTCAE version 5.0-JCOG) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe data cutoff was set at June 30, 2025. PFS and OS were calculated from the start date of BEV-combined single-agent chemotherapy for recurrence after PARP inhibitor treatment to the documented date of progression, death, or last follow-up, whichever occurred first. The effect on survival was assessed by constructing Kaplan\u0026ndash;Meier curves using a log-rank test.\u003c/p\u003e\u003cp\u003eIn a multivariate Cox proportional hazards model, we included the following clinically relevant variables as covariates: performance status (PS), number of prior chemotherapy regimens (\u0026lt;\u0026thinsp;3 vs. \u0026ge;3), prior use of BEV (yes vs. no), and PFI (\u0026lt;\u0026thinsp;3 months vs. \u0026ge;3 months). These variables were chosen based on prior evidence suggesting their association with clinical outcomes in platinum-resistant ovarian cancer, as well as their biological plausibility in influencing the treatment response.\u003c/p\u003e\u003cp\u003eAll statistical analyses were performed using EZR version 1.54 (available on our website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html\u003c/span\u003e\u003cspan address=\"http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmed.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e; Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria), with a p-value of \u0026lt;\u0026thinsp;0.05 deemed as statistically significant. Specifically, it is a modified version of the R Commander, designed to incorporate statistical functions commonly used in biostatistics [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1. Patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 summarizes the background characteristics of the 16 patients enrolled in this study. The median age was 65.5 years (range: 48\u0026ndash;79 years). The PS was 0 in 13 patients (81.2%) and 1 in 3 patients (18.8%). The histological type was high-grade serous carcinoma in 13 patients (81.2%), endometrioid carcinoma in 2 (12.5%), and clear cell carcinoma in 1 (6.3%). Of the 16 patients, one had a \u003cem\u003eBRCA\u003c/em\u003e mutation and two had HRD. Overall, 11 patients (68.7%) received one or two regimens of prior chemotherapy and 5 (31.3%) received three or more regimens. Ten (62.5%) patients received BEV and 6 (37.5%) did not. The previously administered PARP inhibitors were olaparib and niraparib in 8 patients (50.0%). The PFI was \u0026lt;3 months in 6 patients (37.5%) and between 3 and 6 months in 10 patients (62.5%). The recurrence sites were intraperitoneal in 15 patients (93.7%) and distant in 1 patient (6.3%). The chemotherapy administered to the enrolled patients included paclitaxel + BEV therapy in 9 patients (56.2%) and nogitecan + BEV therapy in 7 patients (43.8%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. Anti-tumor response and subsequent treatment\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 summarizes the anti-tumor effects observed in the 16 patients. The median number of cycles\u003c/p\u003e\n\u003cp\u003eof chemotherapy with BEV was 6 (range: 1\u0026ndash;20). Partial response was observed in 5 patients (31.3%), stable disease in 7 (43.7%), and progressive disease in 4 (25.0%). Objective response and disease control rates were 31.3% [95% confidence interval (CI): 11.0\u0026ndash;58.7] and 75.0% (95% CI: 47.6\u0026ndash;92.7), respectively.\u003c/p\u003e\n\u003cp\u003eTreatment after recurrence included a change in regimen in 12 patients and switching to best supportive care in 4 patients. Ten patients received single-agent chemotherapy, and two received platinum-based chemotherapy. Eleven of the 12 patients received a regimen with BEV, but only one patient, who had hypertension, chose single-agent chemotherapy without BEV.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. Adverse events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe AEs identified in this study are listed in Table 3. Grade 3 or higher hematological toxicities occurred leucopenia in 7 patients (43.7%), neutropenia in 9 (56.2%), anemia in 1 (6.2%), and thrombocytopenia in 3 (18.7%). In contrast, non-hematological toxicities of grade 3 or higher included hypertension in 3 patients (18.7%) and\u0026nbsp;protein urea,\u0026nbsp;thrombosis, nausea, vomiting, fatigue, ileus, and heart failure in 1 patient (6.2%). No treatment interruptions or treatment-related deaths due to AEs were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4. Survival analysis\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 shows the PFS and OS of all the patients. The median follow-up period was 14 months (range: 5\u0026ndash;37 months), and the median PFS and OS were 5.5 months (95% CI: 4.0\u0026ndash;6.0) and 17 months (95% CI: 10.0\u0026ndash;29.0), respectively. In multivariate analysis, none of the evaluated factors were identified as independent prognostic indicators for either PFS or OS. All variables included in the model (PS, number of prior regimens, prior BEV administration, and PFI) had p-values \u0026gt; 0.05. The hazard ratios (HRs), 95% CIs, and corresponding p-values are presented in Table 4. None of the covariates demonstrated statistical significance in predicting PFS or OS, with all p-values exceeding 0.05, indicating the absence of independent prognostic factors in this patient cohort.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this retrospective study, the benefits of single-agent chemotherapy combined with BEV for platinum-resistant recurrence during treatment of ovarian cancer with PARP inhibitors were examined. It was conducted because no subsequent treatment has been reported for patients with platinum-resistant recurrence, and the benefit of platinum-based chemotherapy with BEV has been reported in patients with platinum-sensitive recurrence during treatment with PARP inhibitors [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe found no articles that clearly described the rate of recurrence of platinum-resistant ovarian cancer when PARP inhibitors were administered as maintenance therapy. Although the platinum-resistant recurrence rate cannot be determined based on the PFS curve alone, it has been estimated to be approximately 5\u0026ndash;10% in the SOLO1 trial [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], 20\u0026ndash;25% in the PRIMA trial [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and 10\u0026ndash;15% in the PAOLA-1 trial [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Thus, the small number of patients with platinum-resistant ovarian cancer that recurred during maintenance therapy with PARP inhibitors resulted in the small sample size of this study.\u003c/p\u003e\u003cp\u003eTreatment outcomes of single-agent chemotherapy with BEV in patients with platinum-resistant recurrence in the absence of prior PARP inhibitors have been reported to have a response rate of 25\u0026ndash;31%, median PFS of 4.1\u0026ndash;6.7 months, and median OS of 15.3\u0026ndash;16.6 months [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In contrast, single-agent chemotherapy without BEV has been reported to have a response rate of 6.1\u0026ndash;8.3%, median PFS of 3.1\u0026ndash;3.7 months, and median OS of 12.7\u0026ndash;13.5 months [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, the median PFS and OS for single-agent chemotherapy with BEV for platinum-resistant recurrence during PARP inhibitor treatment were 5.5 and 17 months, respectively. These results are similar to those reported for platinum-resistant recurrence without prior PARP inhibitor treatment. However, the effect of BEV on platinum-resistant recurrence during treatment with PARP inhibitors without concomitant BEV remains unknown, because no historical data are available.\u003c/p\u003e\u003cp\u003eIn a subgroup analysis, Lin et al. reported that single-agent chemotherapy combined with BEV was more effective than single-agent chemotherapy alone for platinum-resistant recurrence during PARP inhibitor administration. They reported an HR of 0.31 in six patients, but did not report the response rate, PFS, or OS [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. There are two reasons for the slightly longer median OS compared with previous reports. First, BEV was continued in subsequent treatments based on the MITO-16B/MaNGO2 and JGOG3023 trials, which administered BEV beyond progressive disease. Second, our research institution actively conducts platinum challenges. Patients who received single-agent chemotherapy with BEV and had a PFI\u0026thinsp;\u0026gt;\u0026thinsp;6 months received a platinum challenge. Platinum challenge was performed in two patients in the current study, with an OS of 24 and 37 months, respectively. Tatsuki et al. reported favorable results with the platinum challenge for platinum-resistant recurrent ovarian cancer, with median PFS and OS of 8.5 months and 35.8 months, respectively [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAEs of grade 3 or higher hematologic toxicity were observed but were not severe and manageable. Non-hematological AEs of grade 3 or higher included hypertension (18.7%), increased urinary protein levels, and thrombosis (6.2%). This was thought to be due to the use of BEV, the frequency of which was similar to that in the AURELIA and JGOG3023 trials [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. One case each of grade 3 ileus and heart failure was observed, but the ileus was considered to indicate disease progression and heart failure was considered to be an incidental AE.\u003c/p\u003e\u003cp\u003ePD-L1 antibodies and antibody\u0026ndash;drug conjugates are expected to be new agents for the treatment of platinum-resistant recurrence. The AGO-OVAR 2.29/ENGOT-ov34 and MIRASOL trials on these agents are ongoing in other countries. Atezolizumab and mirvetuximab sorafenib may also be effective for patients who cannot use BEV owing to complications, and future research is warranted.\u003c/p\u003e\u003cp\u003eThe mechanisms underlying the resistance to PARP inhibitors remain to be fully elucidated. The use of PARP inhibitors may cause \u003cem\u003eBRCA\u003c/em\u003e function reversal (reversion mutation). This may eliminate HRD and lead to resistance to platinum-based agents and PARP inhibitors [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. It is speculated that BEV improves drug delivery by controlling the tumor microenvironment, and that changes in the microenvironment (e.g., hypoxia) increase the sensitivity of cytotoxic anticancer agents, thereby preventing a decrease in the response rate. Our results suggested that even in the setting of platinum-resistant recurrence during PARP inhibitor therapy, the combination of BEV with single-agent chemotherapy could offer clinical benefits. These findings support the consideration of BEV-containing regimens as viable options for this unique clinical scenario; however, further prospective studies are required to validate this strategy.\u003c/p\u003e\u003cp\u003eThis study has a few limitations. First, this was a two-center retrospective study with a small number of patients. Therefore, prognostic factors could not be identified. Second, because many patients started treatment before the BRCA and HRD tests were covered by insurance, there were missing data; thus, it was not possible to compare prognoses by \u003cem\u003eBRCA\u003c/em\u003e or HRD status. Third, three patients received more than four prior regimens, which could be the reason for the non-prolonged median PFS and OS. Additionally, the quality of life of the patients was not evaluated in this study.\u003c/p\u003e\u003cp\u003eIn conclusion, despite the limitations inherent to its retrospective design and small sample size, this study provides novel insights into a previously unexplored clinical scenario. The results suggest that BEV-containing regimens may offer a viable therapeutic option for platinum-resistant recurrence during treatment with PARP inhibitors, a setting with no current standard of care. Prospective trials are warranted to validate these findings and refine the patient selection criteria.\u003c/p\u003e\u003cp\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTakatori E and Shoji T conceived the study. Jo A, Musashi M, Tatsuki S, Jonai N, Chiba Y, Sato S, Kaido Y, Nagasawa T, and Kagabu M performed a literature search. Takahashi F performed analysis and interpretation of data. Takatori E prepared the original manuscript. Shoji T, Baba T, and Aida T performed drafting and revising the article. All Authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Editage (www. honya kucen ter. jp) for the English language review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors of this manuscript has any conflicts of interest to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCabasag\u003cem\u003e \u003c/em\u003eCJ,\u003cem\u003e \u003c/em\u003eFagan\u003cem\u003e \u003c/em\u003ePJ,\u003cem\u003e \u003c/em\u003eFerlay\u003cem\u003e \u003c/em\u003eJ et al (2022) Ovarian\u003cem\u003e \u003c/em\u003ecancer\u003cem\u003e \u003c/em\u003etoday\u003cem\u003e \u003c/em\u003eand\u003cem\u003e \u003c/em\u003etomorrow:\u003cem\u003e \u003c/em\u003eA\u003cem\u003e \u003c/em\u003eglobal\u003cem\u003e \u003c/em\u003eassessment\u003cem\u003e \u003c/em\u003eby\u003cem\u003e \u003c/em\u003eworld\u003cem\u003e \u003c/em\u003eregion\u003cem\u003e \u003c/em\u003eand\u003cem\u003e \u003c/em\u003eHuman\u003cem\u003e \u003c/em\u003eDevelopment\u003cem\u003e \u003c/em\u003eIndex\u003cem\u003e \u003c/em\u003eusing\u003cem\u003e \u003c/em\u003eGLOBOCAN\u003cem\u003e \u003c/em\u003e2020.\u003cem\u003e \u003c/em\u003eInt J Cancer 151 :1535-1541. https://doi.org/10.1002/ijc.34002\u003c/li\u003e\n\u003cli\u003eSiegel RL, Giaquinto AN, Jemal A (2024) Cancer statistics, 2024. CA Cancer J Clin 74:12-49. https://doi.org/10.3322/caac.21820\u003c/li\u003e\n\u003cli\u003eOzols RF, Bundy BN, Greer BE et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21: 3194-3200.\u003c/li\u003e\n\u003cli\u003eDiSilvestro P, Banerjee S, Colombo N et al (2023) Overall survival with maintenance olaparib at a 7‑year follow‑up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol 41:609\u0026ndash;617. https://doi.10.1200/JCO.22.01549 \u003c/li\u003e\n\u003cli\u003eRay‑Coquard I, Leary A, Pignata S et al (2023) Olaparib plus bevacizumab first‑line maintenance in ovarian cancer: final overall survival results from the PAOLA‑1/ENGOT‑ov25 trial. Ann Oncol 34: 681\u0026ndash;692. https://doi.10.1016/j.annonc.2023.05.005\u003c/li\u003e\n\u003cli\u003eGonz\u0026aacute;lez-Mart\u0026iacute;n A, Pothuri B, Vergote I et al (2019) Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 381: 2391-2402. https://doi.org/10.1056/NEJMoa1910962\u003c/li\u003e\n\u003cli\u003eLi N, Zhu J, Yin R et al (2023) Treatment with niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer: a phase 3 randomized clinical trial. JAMA Oncol 9:1230\u0026ndash;1237. http://doi.10.1001/jamaoncol.2023.2283\u003c/li\u003e\n\u003cli\u003eCecere SC, Giannone G, Salutari V et al (2020) Olaparib as maintenance therapy in patients with BRCA 1-2 mutated recurrent platinum sensitive ovarian cancer: Real world data and post progression outcome. Gynecol Oncol 156: 38-44. https:// doi.org/10.1016/j.ygyno.2019.10.023\u003c/li\u003e\n\u003cli\u003eRose PG, Yao M, Chambers LM et al (2021) PARP inhibitors decrease response to subsequent platinum-based chemotherapy in patients with BRCA mutated ovarian cancer. Anticancer Drugs 32:1086-1092. https://doi.org/10.1097/CAD.0000000000001219\u003c/li\u003e\n\u003cli\u003eGadducci A, Cosio S, Landoni F et al (2022) Response to Chemotherapy and Clinical Outcome of Patients With Recurrent Epithelial Ovarian Cancer After PARP Inhibitor Maintenance Treatment: A Multicenter Retrospective Italian Study. Anticancer Res 42: 2017-2022. https://doi.org/10.21873/anticanres.15681\u003c/li\u003e\n\u003cli\u003eAbe M, Shoji T, Chiba Y et al (2023). Efficacy and safety of platinum‑based chemotherapy with bevacizumab followed by bevacizumab maintenance for recurrent ovarian, fallopian tube, and primary peritoneal cancer during PARP inhibitor therapy: a multicenter retrospective study. Anticancer Res 43:1265\u0026ndash;1272. http://doi.10.21873/anticanres.16273\u003c/li\u003e\n\u003cli\u003eShoji T, Komiyama S, Kigawa J et al (2018) An open‑label, randomized, phase II trial evaluating the efficacy and safety of standard of care with or without bevacizumab in platinum‑resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer patients previously treated with bevacizumab for front‑line or platinum‑sensitive ovarian cancer: rationale, design, and methods of the Japanese Gynecologic Oncology Group study JGOG3023. BMC Cancer 18:771. http://doi.10.1186/s12885-018-4505-4 \u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: 228-247. https://doi.org/10.1016/j.ejca.2008.10.026\u003c/li\u003e\n\u003cli\u003eCommon Toxicity Criteria for Adverse Events version 5.0 (CTCAE). Available at: Common Terminology Criteria for Adverse Events (CTCAE) https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf [Last accessed February 23, 2025]\u003c/li\u003e\n\u003cli\u003eKanda, Y (2013) Investigation of the freely available easy-to-use software \u0026lsquo;EZR\u0026rsquo; for medical statistics. Bone Marrow Transplant. 48, 452-458.\u003c/li\u003e\n\u003cli\u003ePujade‑Lauraine E, Hilpert F, Weber B et al (2014) Bevacizumab combined with chemotherapy for platinum‑resistant recurrent ovarian cancer: the AURELIA open‑label randomized phase III trial. J Clin Oncol 32:1302\u0026ndash;1308. http://doi.10.1200/JCO.2013.51.4489\u003c/li\u003e\n\u003cli\u003eShoji T, Enomoto T, Abe M et al (2022) Efficacy and safety of standard of care with/without bevacizumab for platinum‑resistant ovarian/fallopian tube/peritoneal cancer previously treated with bevacizumab: the Japanese Gynecologic Oncology Group study JGOG3023. Cancer Sci 113:240\u0026ndash;250. http://doi.10.1111/cas.15185\u003c/li\u003e\n\u003cli\u003eMutch DG, Orlando M, Goss T et al (2007) Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum‑resistant ovarian cancer. J Clin Oncol 25: 2811\u0026ndash;2818.\u003c/li\u003e\n\u003cli\u003eColombo N, Kutarska E, Dimopoulos M et al (2012) Randomized, open‑label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum‑refractory or ‑resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. J Clin Oncol 30: 3841\u0026ndash;3847. http://doi.10.1200/JCO.2011.38.8082\u003c/li\u003e\n\u003cli\u003eZhong L, Wang H, Lei C et al (2025) Bevacizumab combined with chemotherapy could be superior to chemotherapy alone in relapsed ovarian cancer after PARPi: evidence from a multi-center propensity score-matched analysis. Gynecol Oncol 36: e36. doi:10.3802/jgo.2025.36.e36.\u003c/li\u003e\n\u003cli\u003eTatsuki S, Shoji T, Abe M et al (2022) Efficacy and safety of platinum rechallenge in patients with platinum‑resistant ovarian, fallopian tube or primary peritoneal cancer: a multicenter retrospective study. Anticancer Res 42:4603\u0026ndash;4610. http. //doi.10.21873/anticanres.15964.\u003c/li\u003e\n\u003cli\u003eValenza C, Cardellino GG, Spadola S et al (2023) Reversion mutations in BRCA genes in high‑grade serous ovarian cancer: implications for platinum and PARP inhibitor resistance. Gynecol Oncol 172: 403\u0026ndash;410. http://doi. 10.1016/j.ygyno.2023.03.007\u003c/li\u003e\n\u003cli\u003eZou Y, Li Z, Zhu Y et al (2025) PARP inhibitor resistance in ovarian cancer: mechanisms and therapeutic strategies. Mol Cancer 24: 55. http://doi. 10.1186/s12943-025-02355-1\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable1 Patient characteristics\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003cstrong\u003e＝\u003c/strong\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eAge,years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e48-79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003ePS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eOvary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ePritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eFIGO stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eHistological type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eSerous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eEndometrioid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eClear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA\u003c/em\u003e status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eHRD status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eNumber of prior regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1,2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026gt;\u003c/u\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003ePrior BEV administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eKind of PARP\u0026nbsp;inhibitor last administered\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eOlaparib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eNiraparib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003ePlatinum-free interval\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e3\u0026lt;,\u0026nbsp;＜6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026lt; 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eSite of recurrenc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eIntraperitoneal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eDistant metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003eRegimens of chemotherapy\u0026nbsp;with BEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ePTX+BEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 302px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eNGT+BEV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e7\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\u003eAbbreviations: PS; performance status, HRD; homologous recombination repair deficiency, PARP;\u0026nbsp;poly ADP-ribose polymerase,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBEV; bevacizumab, PTX; paclitaxel, NGT; nogitecan\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable2: Anti-tumor response\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003cstrong\u003e＝\u003c/strong\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"406\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e31.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e43.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eOverall response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e31.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003eDisease control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e75.0\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\u003eAbbreviations: CR ; complete response, PR ; partial response, SD ; stable disease ,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePD ; progressive disease\u003c/p\u003e\n\u003cp\u003eTable 3 Adverse events\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"538\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGrade1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eGrade2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eGrade3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGrade4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e≧Grade3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eLeucopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e7 (43.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9 (56.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3 (18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eFebrile neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eSensory neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eEczema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eMucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eIleus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eHeart failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3 (18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eProtein urea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eThrombosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eGIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eEdema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eGIP; gastrointestinal perforation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable4\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eMultivariate analyses of PFS\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and OS\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePFS\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePS (0/1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.04 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.18-5.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.959\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003enumber of prior regimens (1,2/\u003cu\u003e\u0026gt;\u003c/u\u003e3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.74 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.22-2.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.624\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePrior bevacizumab administration (yes/no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.65 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.31-8.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.552\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePFI (\u0026lt;3 / \u003cu\u003e\u0026gt;\u003c/u\u003e3, \u0026lt;6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2.96 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.49-17.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;OS\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePS (0/1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2.09 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.23-18.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.507\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003enumber of prior regimens (1,2/\u003cu\u003e\u0026gt;\u003c/u\u003e3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2.16 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.46-9.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.321\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePrior bevacizumab administration (yes/no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.49 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.24-9.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.665\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 312px;\"\u003e\n \u003cp\u003ePFI (\u0026lt;3 / \u003cu\u003e\u0026gt;\u003c/u\u003e3, \u0026lt;6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.85 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.27-12.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.527\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: PFS; progression-free survival, OS; overall survival, PS; performance status,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePARP; poly ADP-ribose polymerase, PFI; platinum-free interval, HR; hazard ratio, 95%CI; 95% confidence interval\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Ovarian cancer, PARP inhibitor, platinum-resistant recurrence, bevacizumab, single-agent chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-7904976/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7904976/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCurrently, there are no reports on the subsequent treatment of patients with ovarian cancer who exhibited platinum-resistant recurrence during treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. This retrospective study was aimed at evaluating the efficacy and safety of single-agent chemotherapy combined with bevacizumab (BEV) in such patients.\u003c/p\u003e\u003ch2\u003ePatients and Methods\u003c/h2\u003e\u003cp\u003eThe efficacy and safety of the treatment were evaluated in 16 patients with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer diagnosed with platinum-resistant recurrence during PARP inhibitor treatment between April 2019 and June 2025. Chemotherapy was administered with paclitaxel alone or nogitecan alone in combination with BEV and generally continued until the disease progressed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe median number of single-agent chemotherapy cycles with BEV was 6 (range: 1\u0026ndash;20). The objective response and disease control rates were 31.3% and 75.0%, respectively. The median progression-free survival and overall survival were 5.5 months [95% confidence interval (CI)\u0026thinsp;=\u0026thinsp;4.0\u0026ndash;6.0) and 17 months (95%CI\u0026thinsp;=\u0026thinsp;10.0\u0026ndash;29.0), respectively. Grade 3 or higher hematological toxicities were observed, including leukopenia, neutropenia, anemia, and thrombocytopenia in 7, 9, 1, and 3 patients, respectively. Non-hematological toxicities included hypertension in three patients and nausea, vomiting, fatigue, proteinuria, thrombosis, ileus, and heart failure in one patient each. None of the patients discontinued chemotherapy because of adverse events or treatment-related deaths.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eBEV-combined single-agent chemotherapy has potential efficacy even in the challenging setting of platinum-resistant recurrence during PARP inhibitor treatment of ovarian cancer.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Bevacizumab-Combined Single-Agent Chemotherapy for Platinum-Resistant Ovarian Cancer that Recurred During PARP Inhibitor Treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-06 04:16:20","doi":"10.21203/rs.3.rs-7904976/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2025-11-20T06:06:56+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-10-24T08:56:43+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-24T08:24:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-23T16:27:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-10-20T07:01:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3090a359-22f9-4a26-a6f1-82798aee69f1","owner":[],"postedDate":"November 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:06:21+00:00","versionOfRecord":{"articleIdentity":"rs-7904976","link":"https://doi.org/10.1007/s10147-026-02959-7","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2026-01-17 16:30:16","publishedOnDateReadable":"January 17th, 2026"},"versionCreatedAt":"2025-11-06 04:16:20","video":"","vorDoi":"10.1007/s10147-026-02959-7","vorDoiUrl":"https://doi.org/10.1007/s10147-026-02959-7","workflowStages":[]},"version":"v1","identity":"rs-7904976","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7904976","identity":"rs-7904976","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}