{"paper_id":"1dc6a819-b0b6-48f1-8c05-29ca450fc835","body_text":"Heterogeneous effects of cytotoxic chemotherapies for platinum-resistant ovarian cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Heterogeneous effects of cytotoxic chemotherapies for platinum-resistant ovarian cancer Katsuhiko Nara, Ayumi Taguchi, Takehito Yamamoto, Konan Hara, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2759326/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jun, 2023 Read the published version in International Journal of Clinical Oncology → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Single-agent chemotherapy with or without bevacizumab (Bev) is a standard therapy for platinum-resistant ovarian cancer (PR-OC). However, there is a lack of literature on chemotherapy agent selection in heterogenous PR-OC. Therefore, we aimed to clarify the heterogeneous treatment effects of each chemotherapy agent. Methods: Patients who underwent single-drug chemotherapy agents or Bev combination therapy for PR-OC between January 2009 and June 2022 were included in this study. We assessed the impact of each chemotherapy agent on the time to treatment failure (TTF) according to histological type, platinum-free interval (PFI), and Bev usage. Results: A total of 158 patients received 343 different chemotherapy regimens. In patients with clear cell carcinoma/mucinous carcinoma (CC/MC), gemcitabine (GEM) had the strongest effect with a median TTF of 5.3 months, whilst nedaplatin (NDP) had the lowest effect with a median TTF of 1.4 months. In contrast, in the non-CC/MC group, irinotecan (CPT-11) and NDP had a better TTF than GEM and pegylated liposomal doxorubicin (PLD). There were notable differences in the treatment efficacy of NDP according to PFI. Specifically, NDP prolonged the TTF in patients with a PFI ≥3 months. Compared with GEM alone, GEM+Bev tended to prolong the TTF more effectively; however, an additive effect was not observed with PLD+Bev. Conclusions: This study demonstrated that the effect of chemotherapy agents differed according to the tumor and background characteristics of the patient. Our findings will improve selection of effective therapies for patients with PR-OC by considering their background characteristics. platinum-resistant ovarian cancer heterogeneous treatment effect adverse event histology platinum-free interval Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Worldwide, ovarian cancer (OC) is the eighth most common cancer and the eight most common cause of cancer-related death in women [ 1 ]. The OC morbidity rate is increasing in Japan and its age-adjusted mortality rate is increasing worldwide (3.2 in 10,000 people) [ 2 ]. The standard therapies for OC are surgery and platinum-based chemotherapy [ 3 , 4 ]. The standard treatment protocol for platinum-sensitive recurrent OC (platinum-free interval [PFI] ≥ 6 months [Mos]) is re-administration of platinum combination chemotherapy given the expected response to platinum agents. In contrast, a single-drug chemotherapy agent is recommended for platinum-resistant OC (PR-OC; PFI ≤ 6 Mos) based on therapeutic efficacy and adverse events (AEs) [ 3 , 4 ]. However, single-drug chemotherapy agents often have an insufficient therapeutic effect, with a response rate of 10–20% and progression-free survival (PFS) of 3–4 Mos [ 5 – 9 ]. Chemotherapy agents combined with bevacizumab (Bev) therapy significantly prolong PFS in patients with PR-OC and are increasingly used for patients without contraindications to concomitant Bev therapy [ 8 , 10 ]. The sensitivity of PR-OC to chemotherapy agents differs according to histologic type; specifically, serous carcinoma (SC) and endometrioid carcinoma (EMC) have good sensitivity, while clear cell carcinoma (CC) and mucinous carcinoma (MC) have poor sensitivity [ 11 – 13 ]. Furthermore, the distribution of histologic types of PR-OC varies according to ethnicity. For example, SC accounts for ≥ 2/3 and 2/5 of patients in Western countries and Japan, respectively [ 2 , 14 ]. In contrast, CC accounts for only ~ 10% and ~ 30% of patients abroad and in Japan, respectively [ 14 ]. Moreover, the treatment line, PFI, presence of ascites, cancer antigen (CA) 125 levels, age, and performance status influence the efficacy of chemotherapy agents [ 15 – 18 ]. Furthermore, the efficacy of Bev differs across chemotherapy agents [ 10 , 19 ]. Therefore, treatment choice for PR-OC should be based on patient background and tumor characteristics; however, the heterogeneous effects of each drug for PR-OC remain unclear. Quality of life should be considered when determining therapeutic strategies for PR-OC since patients with recurrent OC have decreased physical fitness and bone marrow reserves after undergoing multiple treatment regimens. Moreover, there are several life-threatening AEs related to chemotherapy agents, including thromboembolic events and interstitial pneumonia (IP); therefore, it is important to elucidate the incidence and timing of their occurrence. This retrospective study aimed to examine the therapeutic effects and AEs in patients with PR-OC who underwent single-drug chemotherapy agent or Bev combination therapy according to the patient’s background and tumor characteristics. Materials And Methods Patients and chemotherapy We included patients with PR-OC from The University of Tokyo Hospital who were treated with a single chemotherapy agent (irinotecan [CPT-11], pegylated liposomal doxorubicin [PLD], gemcitabine [GEM], paclitaxel [PTX], nogitecan [NGT], nedaplatin [NDP], or docetaxel [Doc]) or Bev combination therapy between January 2009 and June 2022. All single chemotherapy agents were administered intravenously, CPT-11 at a dose of 100 mg/m 2 over 90 min on Days 1, 8, and 15 per cycle, PLD at a dose of 50 mg/m 2 over 90 min on Day 1 per cycle, GEM at a dose of 1000 mg/m 2 for 30 min on Days 1, 8, and 15 per cycle, PTX at a dose of 80 mg/m 2 over 60 min on Days 1, 8, and 15 per cycle; NGT at a dose of 1.5 mg/m 2 for 30 min from Day 1 to Day 5 per cycle, NDP at a dose of 80 mg/m 2 over 60 min on Day 1 per cycle, and Doc at a dose of 70 mg/m 2 over 60 min on Day 1 per cycle. Bev combination therapy comprised adding Bev 15 mg/kg on Day 1 to the dosing schedule of PLD, PTX, and NGT. GEM + Bev was intravenously administered at a dose of 1000 mg/m 2 for 30 min on Days 1 and 8 per cycle, as well as Bev 15 mg/kg on Day 1. Bev was administered over 90, 60, and 30 min for the first, second, and third (and subsequent) times, respectively. Cycle duration was 28 days for all drugs, except Doc and GEM + Bev (both 21 days). The initial dose of chemotherapy agents was reduced in accordance with the patient's condition. The exclusion criteria were pathological diagnosis of squamous cell carcinoma or neuroendocrine tumor and death from causes other than the primary disease within a week after chemotherapy initiation. Data collection and clinical outcomes We obtained the following data from the electronic medical records: the International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, treatment history of platinum-based chemotherapy, PFI, time to treatment failure (TTF), platinum resistance (primary platinum resistance, secondary platinum resistance, or more), treatment line after platinum resistance (first line, second line, or more), histology (CC/MC or non-CC/MC), background characteristics before starting chemotherapy for platinum resistance (age, body mass index [BMI]), metastatic sites, ascites status, use of Bev, initial dose, and AEs. The primary study endpoint was TTF because the decision to continue treatment is often based not only on disease progression but also on a comprehensive assessment of AEs and quality of life. TTF was defined as the interval from the date of chemotherapy initiation to death due to primary disease, primary disease progression, or treatment discontinuation due to AEs, whichever occurred first. AEs were assessed based on the Common Terminology Criteria for Adverse Events version 5.0 and were assessed at intervals between the start and end of each chemotherapy regimen. Platinum resistance was defined as recurrence occurring ≤ 6 Mos after completion of platinum-based chemotherapy. PFI was defined as the interval from the date of the last platinum-based chemotherapy dose to the date of first diagnosis of platinum-resistant recurrence. We evaluated metastatic sites, the presence/absence of ascites, and the use of Bev before the administration of each chemotherapy agent. Statistical analyses The Kaplan–Meier method was used to analyze TTF. The log-rank test was used to analyze differences in TTF according to chemotherapy agent, histology, PFI, usage of Bev, and treatment line. Differences in TTF among CPT-11, GEM, PLD, and NDP in the CC/MC, non-CC/MC, PFI ≥ 3 Mos, and PFI < 3 Mos groups were evaluated by the log-rank test. Differences in TTF between GEM and GEM + Bev and between PLD and PLD + Bev were also analyzed using the log-rank test. Using the univariate Cox proportional hazards model, we estimated the hazard ratio (HR) for TTF events according to chemotherapy agent between each factor including histology, PFI, usage of Bev, and metastatic sites. The incidence rate of each Grade ≥ 3 AE, including neutropenia, thrombocytopenia, anemia, febrile neutropenia, anorexia, nausea, diarrhea, aspartate transaminase (AST)/alanine transaminase (ALT) increase, hand-foot syndrome (HFS), rash, fatigue, oral mucositis, IP, and thromboembolic events, was calculated according to chemotherapy agent. All tests were two-tailed. Statistical significance was set at P < 0.05. All statistical analyses were performed using SPSS Statistics for Windows version 24 (IBM Corp., Armonk, NY). Ethics approval The study protocol was approved by the ethics committee of the Faculty of Medicine, University of Tokyo (Approval number: 2654, 3084). The institutional review board granted an opt-out recruitment approach and waived the need for written informed consent. This study adhered to the Declaration of Helsinki. Results Patient background Among 161 patients who received chemotherapy for PR-OC, we excluded three patients. The median age of the patients was 61.1 years and > 70% of patients had FIGO stage ≥ 3 at diagnosis (Table 1 a). Approximately 50% of the patients had SC and 25% had CC. CPT-11 was the most commonly administered drug, followed by GEM and PLD. Table 1 b summarizes the usage characteristics of each chemotherapy agent. Approximately 80% of patients who received CPT-11 received it as first-line treatment, while 70% of patients who received NDP and PTX received it as third- or fourth-line treatment. Most patients who received PTX were on combination therapy with Bev, but only 24–31% of patients who received GEM and PLD were on combination therapy with Bev. Table 1 a. Characteristics of patients before the first-line chemotherapy Characteristics All patients (n = 158) Age [year], median (range) 61.1 (36.4–84.5) Age ≥ 65 years, n (%) 65 (41.1) BMI [kg/m 2 ], median (range) 21.5 (12.2–36.2) FIGO stage (≥ 3), n (%) 125 (79.1) Primary site, ovarian (%) 144 (91.1) Histology, n (%) Serous 79 (50.0) Clear cell 41 (25.9) Endometrioid 16 (10.1) Mucinous 5 (3.2) Others 17 (10.8) Type of metastatic sites, n (%) Peritoneal 112 (70.9) Lymph node 61 (38.6) Liver 17 (10.8) Lung 13 (8.2) No. of metastatic sites, median (range) 1 (1–3) Ascites, n (%) 68 (43.0) History of platinum-based chemotherapy plus bevacizumab, n (%) 41 (25.9) Platinum resistance, n (%) Primary 73 (46.2) Secondary or more 85 (53.8) Platinum-free interval < 3 months, n (%) 100 (63.3) Platinum-resistant cytotoxic chemotherapy, n (%) Irinotecan 92 (58.2) Gemcitabine 90 (57.0) Pegylated liposomal doxorubicin 82 (51.9) Nedaplatin 33 (20.9) Paclitaxel 18 (11.4) Nogitecan 14 (8.9) Docetaxel 14 (8.9) Bevacizumab combination therapy, n (%) 49 (31.0) BMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics Table 1 b. Background of platinum-resistant chemotherapy agents Characteristics CPT-11 GEM PLD NDP PTX NGT Doc (n = 92) (n = 90) (n = 82) (n = 33) (n = 18) (n = 14) (n = 14) Treatment line after platinum resistance 1st line 70 (76.1) 36 (40.0) 40 (48.8) 0 (0.0) 3 (16.7) 1 (7.1) 7 (50.0) 2nd line 21 (22.8) 33 (36.7) 22 (26.8) 10 (30.3) 2 (11.1) 5 (35.7) 3 (21.4) 3rd line 1 (1.1) 16 (17.8) 14 (17.1) 15 (45.5) 7 (38.9) 1 (7.1) 2 (14.3) 4th line 0 (0.0) 5 (5.6) 6 (7.3) 8 (24.2) 6 (33.3) 7 (50.0) 2 (14.3) Bevacizumab therapy 0 (0.0) 28 (31.1) 20 (24.4) 0 (0.0) 16 (88.9) 2 (14.3) 0 (0.0) Treatment line of bevacizumab therapy 1st line 0 (0.0) 18 (20.0) 13 (15.9) 0 (0.0) 3 (16.7) 1 (7.1) 0 (0.0) 2nd line 0 (0.0) 8 (8.9) 3 (3.7) 0 (0.0) 2 (11.1) 1 (7.1) 0 (0.0) 3rd line or more 0 (0.0) 2 (2.2) 4 (4.9) 0 (0.0) 11 (61.1) 0 (0.0) 0 (0.0) Initial dose, full dose 45 (48.9) 36 (40.0) 39 (47.6) 31 (93.9) 16 (88.9) 12 (85.7) 12 (85.7) Platinum-free interval < 3 months, n (%) 58 (63.0) 55 (61.1) 50 (61.0) 18 (54.5) 8 (44.4) 6 (42.9) 9 (64.3) Platinum resistance Primary 46 (50.0) 42 (46.7) 30 (36.6) 17 (51.5) 7 (38.9) 4 (28.6) 8 (57.1) Secondary or more 46 (50.0) 48 (53.3) 52 (63.4) 16 (48.5) 11 (61.1) 10 (71.4) 6 (42.9) Histology Serous 40 (43.5) 45 (50.0) 50 (61.0) 20 (60.6) 14 (77.8) 10 (71.4) 7 (50.0) Endometrioid 11 (12.0) 8 (8.9) 10 (12.2) 2 (6.1) 2 (11.1) 0 (0.0) 2 (14.3) Clear cell 26 (28.3) 24 (26.7) 11 (13.4) 7 (21.2) 1 (5.6) 2 (14.3) 3 (21.4) Mucinous 2 (2.2) 1 (1.1) 4 (4.9) 0 (0.0) 0 (0.0) 0 (0.0) 1 (7.1) Others 13 (14.1) 12 (13.3) 7 (8.5) 4 (12.1) 1 (5.6) 2 (14.3) 1 (7.1) Type of metastatic sites Peritoneal 62 (67.4) 68 (75.6) 57 (69.5) 24 (72.7) 16 (88.9) 13 (92.9) 12 (85.7) Lymph node 36 (39.1) 41 (45.6) 37 (45.1) 20 (60.6) 8 (44.4) 6 (42.9) 6 (42.9) Liver 12 (13.0) 15 (16.7) 12 (14.6) 4 (12.1) 1 (5.6) 3 (21.4) 1 (7.1) Lung 9 (9.8) 6 (6.7) 10 (12.2) 6 (18.2) 1 (5.6) 2 (14.3) 2 (14.3) Ascites 37 (40.2) 37 (41.1) 32 (39.0) 12 (36.4) 9 (50.0) 6 (42.9) 4 (28.6) Data are shown as n (%). CPT-11, irinotecan; PLD, pegylated liposomal doxorubicin; GEM, gemcitabine, PTX, paclitaxel, NGT, nogitecan, NDP, nedaplatin, Doc, docetaxel Comparison of TTF according to chemotherapy agent, background, and tumor characteristics TTF was compared according to chemotherapy agent, background characteristics, and tumor characteristics. The comparison of TTF by chemotherapy agent was performed with four frequently used chemotherapy agents: CPT-11, GEM, PLD, and NDP. The median TTF of each drug ranged from 2–4 Mos, with no significant differences (Fig. 1 ). There were no significant differences in TTF among the histological types (Supporting Information Fig. 1a), between PFI ≥ 3 Mos and < 3 Mos (Supporting Information Fig. 1b), or between first-line treatment and second- or later-line treatments (Supporting Information Fig. 1c). Patients who used Bev or those without ascites had a better TTF than those who did not use Bev or those with ascites (Supporting Information Fig. 1d, e). Histology Figure 2 summarizes the TTF and HR of the chemotherapy agents for each histologic type (CC/MC vs. non-CC/MC). PTX, NGT, and Doc were classified as “others” since they were administered only to a few patients. TTF tended to be worse in the CC/MC group (HR: 1.126, 95% confidence interval [CI]: 0.875–1.450). However, the effectiveness of the chemotherapy agents differed according to the histological type. Specifically, the TTF of CPT-11 and NDP was significantly longer in the non-CC/MC group than in the CC/MC group (HR: 2.109 and 5.268, respectively) (Fig. 2 a). Further, the TTF of GEM was significantly longer in the CC/MC group than in the non-CC/MC group (HR: 0.575), and the TTF of PLD tended to be longer in the CC/MC group than in the non-CC/MC group (HR: 0.697). We next compared the efficacy of each chemotherapy agent separately for each histologic type. In the CC/MC, GEM had the strongest effect with a median TTF of 5.3 Mos and NDP had the weakest effect with a median TTF of 1.4 Mos (Fig. 2 b). In the non-CC/MC group, CPT-11 and NDP had a better TTF than GEM and PLD (Fig. 2 c). Platinum-free interval Comparison of TTF of the chemotherapy agents according to PFI (< 3 Mos vs. ≥3 Mos) (Fig. 3 ) showed that TTF did not differ according to PFI (HR: 1.135; 95% CI: 0.912–1.411). The TTF of NDP was most strongly influenced by PFI; specifically, TTF was significantly shorter in patients with PFI < 3 Mos (HR: 2.707) (Fig. 3 a). Moreover, NDP showed the best TTF in the Kaplan–Meier curve for patients with PFI ≥ 3 Mos; however, TTF did not differ among chemotherapy agents in patients with PFI < 3 Mos (Fig. 3 b, c). Bevacizumab Comparison of the TTF of each chemotherapy agent according to Bev (Fig. 4 ) showed that combination therapy with Bev significantly improved TTF (HR: 0.724; 95% CI: 0.536–0.978). However, the improvement effects of Bev on prognosis differed according to the type of chemotherapy agent. Specifically, the Bev combination therapies were most effective in “Others” including PTX and NGT (Fig. 4 a), followed by GEM (Fig. 4 a, b), while the PLD + Bev combination did not improve TTF (Fig. 4 a, c). Metastatic sites Patients with ascites had a worse TTF, regardless of the type of chemotherapy agent administered (Supporting Information Fig. 2). Incidence rate and timing of AEs Table 2 summarizes the Grade ≥ 3 AEs for CPT-11, GEM, PLD, and NDP. The incidence of febrile neutropenia, nausea, and diarrhea was highest with CPT-11 usage, and GEM users showed the highest incidence of neutropenia and AST/ALT elevation (46.5% and 4.7%, respectively). PLD users showed the highest incidence of thromboembolic events, IP, HFS, and oral mucositis. Notably, the incidence of thrombotic events was 10.1%, suggesting that PLD should be administered with awareness of the risk of thromboembolic events. The main AE associated with NDP was myelosuppression. There were no cases of non-hematologic toxicity in Grade ≥ 3 AEs. Table 2 Adverse events of CPT-11, GEM, PLD, and NDP Adverse events Grade ≥ 3 CPT-11 (n = 92) GEM (n = 90) PLD (n = 82) NDP (n = 33) Neutropenia 30 (32.6) 41 (45.6) 25 (30.5) 5 (15.2) Thrombocytopenia 0 (0.0) 5 (5.6) 2 (2.4) 3 (9.1) Anemia 10 (10.9) 13 (14.4) 12 (14.6) 6 (18.2) Febrile neutropenia 6 (6.5) 2 (2.2) 1 (1.2) 0 (0.0) Anorexia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Nausea 6 (6.5) 0 (0.0) 0 (0.0) 0 (0.0) Diarrhea 8 (8.7) 0 (0.0) 0 (0.0) 0 (0.0) AST/ALT increase 1 (1.1) 4 (4.4) 2 (2.4) 0 (0.0) Hand-foot syndrome 0 (0.0) 0 (0.0) 3 (3.7) 0 (0.0) Rash 0 (0.0) 1 (1.1) 0 (0.0) 0 (0.0) Fatigue 1 (1.1) 0 (0.0) 1 (1.2) 0 (0.0) Oral mucositis 0 (0.0) 0 (0.0) 3 (3.7) 0 (0.0) Interstitial pneumonia 0 (0.0) 1 (1.1) 3 (3.7) 0 (0.0) Thromboembolic event 3 (3.3) 1 (1.1) 8 (9.8) 0 (0.0) Data are shown as n (%). CPT-11, irinotecan; PLD, pegylated liposomal doxorubicin; GEM, gemcitabine, NDP, nedaplatin; AST, aspartate transaminase; ALT, alanine transaminase. Among the AEs, we investigated the timing of the onset of thromboembolic events and IP for all grades (Supporting Information Fig. 3). Although the incidence of both AEs was high during the first- and second- line treatments, thromboembolic events also occurred after the fourth treatment course, which suggests the importance of monitoring for thromboembolic events during chemotherapy. Discussion We investigated the TTF of chemotherapy agents as well as the factors against PR-OC. We found that the impact of histological type, PFI, and Bev usage was dependent on the type of chemotherapy agent. Regarding the AE profiles, PLD showed the highest incidence of thromboembolic events and IP. There is insufficient evidence for selecting chemotherapy agents for OC based on patient background and tumor characteristics. Accordingly, chemotherapy agents for PR-OC are selected based on treatment history, residual toxicity, cost, convenience, and patient preference [ 20 ]. Our findings confirmed that the therapeutic effects of chemotherapy agents differ according to patient background and tumor characteristics. The therapeutic effect of each drug differed according to histological type (Fig. 2 ). Specifically, GEM showed the strongest therapeutic effect in the CC/MC group with TTF > 5 Mos, whilst it showed a poor therapeutic effect in the non-CC/MC group. A preclinical study demonstrated the potential efficacy of GEM for CC [ 21 ]. Additionally, a multi-center Italian trial on OC (MITO)-09 confirmed a high response rate of CC to GEM [ 22 ]. These data suggest that GEM is the preferred therapeutic candidate in CC/MC. In contrast, NDP showed the strongest and weakest therapeutic effects in the non-CC/MC and CC/MC groups, respectively. Similar to NDP, CPT-11 showed a strong therapeutic effect in the non-CC/MC group, whilst the effect was not strong in those with CC/MC. For patients with CC, combination therapy of CPT-11 and cisplatin (CPT-P) have been used as an alternative to PTX and carboplatin (TC) therapy [ 23 , 24 ]. However, a prospective randomized controlled trial failed to demonstrate the superiority of CPTP therapy over TC therapy as a postoperative adjuvant therapy for CC [25]. This suggests that CPT-11 is not a particularly superior treatment for CC. Taken together, GEM might be recommended for patients with CC/MC, whilst CPT-11 and NDP might be recommended for those with non-CC/MC. NDP has demonstrated limited efficacy for PR-OC. However, extending the platinum-free interval (using a nonplatinum-based regimen) might restore platinum sensitivity [ 26 ]. Patients with PR-OC who responded well to NDP had a longer PFI owing to treatment without platinum analogs after development of platinum resistance [ 27 ]. In our cohort, > 70% of NDP users received NDP after the third-line treatment after platinum resistance, indicating a sufficiently long platinum-free period post-platinum resistance diagnosis. Our findings demonstrated that a PFI ≥ 3 Mos could be a biomarker for an improved therapeutic effect of NDP against PR-OC (Fig. 3 ). Although platinum combination therapy is usually avoided in patients with PR-OC who have a PFI < 6 Mos given the unfavorable relationship between intensity and efficacy, NDP might be an alternative treatment for patients with PFI ≥ 3 Mos after a sufficient platinum-free period. There is accumulating evidence that Bev combination therapies significantly improve the PFS of patients with PR-OC [ 8 – 10 ]. In our study, Bev significantly improved TTF when combined with GEM and “others” (PTX and NGT), but not when combined with PLD, which is consistent with the JGOG3023 study [ 10 ] (Fig. 4 ). The background characteristics of our patients were more similar to those of the JGOG3023 study than the AURELIA study. Specifically, ~ 60% of patients had a PFI < 3 Mos and ~ 50% prevalence rate of SC, and there was no exclusion of third- or later-line treatments. Further large-scale cohort studies are warranted to validate the additive effect of Bev with PLD; however, it should be carefully considered given the increased risk of AEs. The presence of ascites indicates a poor prognosis, regardless of the chemotherapy type. Preclinical studies on OC have shown that the presence of ascites promoted multidrug resistance in patients with OC [ 28 , 29 ]. Our findings demonstrated that the presence of ascites was a hallmark of chemoresistance, regardless of chemotherapy type. Moreover, ascites volume positively correlated with the risk of AEs in CPT-11 users [ 30 ]; therefore, early CPT-11 use is recommended for PR-OC, especially for patients with non-CC/MC. Although the presence of ascites decreases the efficacy of chemotherapy agents, Bev can be used to control ascites [ 10 ]. Therefore, GEM + Bev or PTX + Bev might be better treatment options based on the compatibility of GEM and PTX with Bev. Diarrhea and HFS/oral mucositis occurred only among CPT-11 and PLD users, respectively [ 5 , 14 ]. Additionally, PLD users showed the highest incidence of Grade ≥ 3 thromboembolic events (~ 10%). The incidence of thromboembolic events among PLD users varies among different studies [ 6 , 7 , 14 ]. The incidence of Grade ≥ 3 thromboembolic events in the AURELIA and REBECA trials among patients with PR-OC was ≤ 5% [ 8 , 31 ]. In our study, the frequency of PLD-induced thromboembolic events was higher than that observed in these previous studies. Since our patients received more advanced- or late-line treatments than those in the AURELIA and REBECA trials, the high incidence of PLD-induced thromboembolic events might be partly attributed to cancer-related thrombosis accompanied by advanced cancer. Notably, PLD users showed the highest incidence of IP (3.8%), with most patients developing IP during the first two treatment cycles. Since thromboembolic events and IP could be life-threatening AEs, caution should be applied when administering PLD, especially in the first two treatment courses. This study had a few limitations. First, we did not consider confounding factors when evaluating the efficacy of the drugs in terms of TTF. Therefore, our findings should be cautiously interpreted. Second, this was a single-center, retrospective, observational study. Accordingly, there may have been biases or tendencies in the selection of chemotherapy agents. For example, CPT-11 and NDP tended to be used in the first- and later-line treatments, respectively. The timing of drug use and selection of patients may have resulted in differences in treatment effects. Therefore, large-scale multi-center cohort studies are warranted to assess the heterogeneous effects of chemotherapy agents. Despite this, to the best of our knowledge, this is the largest single-center cohort study, which is based on data from 343 different treatments in 158 patients, making our findings more convincing. In conclusion, we identified factors influencing the treatment efficacy of each chemotherapy agent used to treat patients with PR-OC. CPT-11/NDP and GEM were effective candidates for patients with non-CC/MC and CC/MC, respectively. NDP can be used as a late-line regimen for patients with PFI ≥ 3 Mos. Finally, PLD showed a relatively high incidence of thromboembolic events. 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Lancet Oncol 14:1020–1026 Machida H, Matsuo K, Yamagami W et al (2019) Trends and characteristics of epithelial ovarian cancer in Japan between 2002 and 2015: A JSGO-JSOG joint study. Gynecol Oncol 153:589–596 Hanker LC, Loibl S, Burchardi N et al (2012) The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol 23:2605–2612 Trillsch F, Mahner S, Hilpert F et al (2016) Prognostic and predictive effects of primary versus secondary platinum resistance for bevacizumab treatment for platinum-resistant ovarian cancer in the AURELIA trial. Ann Oncol 27:1733–1739 Kato MK, Yunokawa M, Bun S et al (2020) Treatment strategies for recurrent ovarian cancer in older adult patients in Japan: A study based on real-world data. J Cancer Res Clin Oncol 146:1335–1341 Kobayashi-Kato M, Yunokawa M, Bun S et al (2019) Platinum-free interval affects efficacy of following treatment for platinum-refractory or -resistant ovarian cancer. Cancer Chemother Pharmacol 84:33–39 Poveda AM, Selle F, Hilpert F et al (2015) Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: Analysis by chemotherapy cohort of the randomized Phase III AURELIA trial. J Clin Oncol 33:3836–3838 Pujade-Lauraine E, Banerjee S et al (2019) Management of platinum-resistant, relapsed epithelial ovarian cancer and new drug perspectives. J Clin Oncol 37:2437–2448 Kuroda T, Ogiwara H, Sasaki M et al (2019) Therapeutic preferability of gemcitabine for ARID1A-deficient ovarian clear cell carcinoma. Gynecol Oncol 155:489–498 Esposito F, Cecere SC, Magazzino F et al (2014) Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the multicenter Italian trials in ovarian cancer (MITO-9). Oncology 86:351–358 Sugiyama T, Yakushiji M, Kamura T et al (2002) Irinotecan (CPT-11) and cisplatin as first-line chemotherapy for advanced ovarian cancer. Oncology 63:16–22 Takano M, Kikuchi Y, Yaegashi N et al (2006) Adjuvant chemotherapy with irinotecan hydrochloride and cisplatin for clear cell carcinoma of the ovary. Oncol Rep 16:1301–1306 Sugiyama T, Okamoto A, Enomoto T et al (2016) Randomized phase III trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first-line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG trial. J Clin Oncol 34:2881–2887 Tatsuki 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 42:4603–4610 Goto T, Takano M, Ohishi R et al (2010) Single nedaplatin treatment as salvage chemotherapy for platinum/taxane-resistant/refractory epithelial ovarian, tubal and peritoneal cancers. J Obstet Gynaecol Res 36:764–768 Mo L, Pospichalova V, Huang Z et al (2015) Ascites increases expression/function of multidrug resistance proteins in ovarian cancer cells. PLoS ONE 10:e0131579 Asem M, Young A, Oyama C et al (2020) Ascites-induced compression alters the peritoneal microenvironment and promotes metastatic success in ovarian cancer. Sci Rep 10:11913 Shiozawa T, Tadokoro J, Fujiki T et al (2013) Risk factors for severe adverse effects and treatment-related deaths in Japanese patients treated with irinotecan-based chemotherapy: A postmarketing survey. Jpn J Clin Oncol 43:483–491 Lee JY, Park JY, Park SY et al (2019) Real-world effectiveness of bevacizumab based on Aurelia in platinum-resistant recurrent ovarian cancer (REBECA): A Korean Gynecologic Oncology Group study (KGOG 3041). Gynecol Oncol 152:61–67 Supplementary Files FigureS1S3.pptx Supplementary Material Fig. S1 Kaplan-Meier estimates of the time to treatment failure according to each factor Fig. S2 Forest plot of the time to treatment failure according to metastatic sites Fig. S3 Timing of adverse events Cite Share Download PDF Status: Published Journal Publication published 22 Jun, 2023 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 22 Apr, 2023 Reviewers agreed at journal 01 Apr, 2023 Editor assigned by journal 31 Mar, 2023 First submitted to journal 30 Mar, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-2759326\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":188295520,\"identity\":\"1e6d222d-c2a8-4d27-b221-359802fa628c\",\"order_by\":0,\"name\":\"Katsuhiko Nara\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Katsuhiko\",\"middleName\":\"\",\"lastName\":\"Nara\",\"suffix\":\"\"},{\"id\":188295521,\"identity\":\"695ac145-238c-4384-baeb-4cf625c243fa\",\"order_by\":1,\"name\":\"Ayumi Taguchi\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"https://orcid.org/0000-0002-5491-3871\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":true,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ayumi\",\"middleName\":\"\",\"lastName\":\"Taguchi\",\"suffix\":\"\"},{\"id\":188295522,\"identity\":\"dddeda8a-989d-4401-ae1d-e4d07cdfe719\",\"order_by\":2,\"name\":\"Takehito Yamamoto\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Takehito\",\"middleName\":\"\",\"lastName\":\"Yamamoto\",\"suffix\":\"\"},{\"id\":188295523,\"identity\":\"0ba893ef-96c9-4f0f-a31d-bd4d94bb9aa9\",\"order_by\":3,\"name\":\"Konan Hara\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UA: The University of Arizona\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Konan\",\"middleName\":\"\",\"lastName\":\"Hara\",\"suffix\":\"\"},{\"id\":188295524,\"identity\":\"e3c3005c-454d-44cc-8dca-bee5bef2ffa6\",\"order_by\":4,\"name\":\"Yuri Tojima\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuri\",\"middleName\":\"\",\"lastName\":\"Tojima\",\"suffix\":\"\"},{\"id\":188295525,\"identity\":\"adbba560-73d4-4f14-ad1c-3c4b3218c078\",\"order_by\":5,\"name\":\"Harunori Honjoh\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Harunori\",\"middleName\":\"\",\"lastName\":\"Honjoh\",\"suffix\":\"\"},{\"id\":188295526,\"identity\":\"aaa6ce5c-a518-4fa2-afb0-0f83d8b08b89\",\"order_by\":6,\"name\":\"Akira Nishijima\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Akira\",\"middleName\":\"\",\"lastName\":\"Nishijima\",\"suffix\":\"\"},{\"id\":188295527,\"identity\":\"0fadbd6f-f340-4bf4-99f6-8fff89b4c75f\",\"order_by\":7,\"name\":\"Satoko Eguchi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Satoko\",\"middleName\":\"\",\"lastName\":\"Eguchi\",\"suffix\":\"\"},{\"id\":188295528,\"identity\":\"01c9f380-1735-4792-8c97-2b0479a4a4e0\",\"order_by\":8,\"name\":\"Yuichiro Miyamoto\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuichiro\",\"middleName\":\"\",\"lastName\":\"Miyamoto\",\"suffix\":\"\"},{\"id\":188295529,\"identity\":\"5223d95e-e682-4c1a-a08b-69d797335494\",\"order_by\":9,\"name\":\"Kenbun Sone\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Kenbun\",\"middleName\":\"\",\"lastName\":\"Sone\",\"suffix\":\"\"},{\"id\":188295530,\"identity\":\"543b450b-023d-465f-8e5f-e35f63ba7a76\",\"order_by\":10,\"name\":\"Mayuyo Mori\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mayuyo\",\"middleName\":\"\",\"lastName\":\"Mori\",\"suffix\":\"\"},{\"id\":188295531,\"identity\":\"aa916a8a-d879-4710-87c6-90a5f953663b\",\"order_by\":11,\"name\":\"Tappei Takada\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tappei\",\"middleName\":\"\",\"lastName\":\"Takada\",\"suffix\":\"\"},{\"id\":188295532,\"identity\":\"cb5a916f-f55a-484b-8fd3-26371cf0718a\",\"order_by\":12,\"name\":\"Yutaka Osuga\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"The University of Tokyo: Tokyo Daigaku\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yutaka\",\"middleName\":\"\",\"lastName\":\"Osuga\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2023-03-31 05:44:04\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-2759326/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-2759326/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1007/s10147-023-02367-1\",\"type\":\"published\",\"date\":\"2023-06-22T21:17:22+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":35211787,\"identity\":\"9cf09937-9518-4ef2-9f7a-db52637a8662\",\"added_by\":\"auto\",\"created_at\":\"2023-04-03 15:12:20\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":69860,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eKaplan–Meier estimates of the time to treatment failure according to the type of chemotherapy agent\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTTF according to the type of chemotherapy. The differences in TTF between each factor were evaluated using the log-rank test.\\u003c/p\\u003e\\n\\u003cp\\u003eTTF, time to treatment failure; CPT-11, irinotecan; GEM, gemcitabine; PLD, pegylated liposomal doxorubicin; NDP, nedaplatin; mTTF, median time to treatment failure; CI, confidence interval\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"OnlineFig1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2759326/v1/5310f671c92812d19e16252f.png\"},{\"id\":35211480,\"identity\":\"c2f98c9e-c62d-4a5a-a10d-6cd423069487\",\"added_by\":\"auto\",\"created_at\":\"2023-04-03 15:04:20\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":113228,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eForest plot and Kaplan–Meier estimates of the time to treatment failure according to histology (CC/MC vs. non-CC/MC)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe median TTF calculated by the Kaplan–Meier analysis and the HR calculated by the univariate Cox proportional hazard model for each chemotherapy agent are shown in part (a). The TTF of each chemotherapy for CC/MC (b) and non-CC/MC (c) is shown. In parts (b) and (c), differences in TTF between each factor were evaluated using the log-rank test.\\u003c/p\\u003e\\n\\u003cp\\u003eTTF, time to treatment failure; CC/MC, clear cell carcinoma/mucinous carcinoma; CPT-11, irinotecan; GEM, gemcitabine; PLD, pegylated liposomal doxorubicin; NDP, nedaplatin; HR, hazard ratio; CI, confidence interval; mTTF, median time to treatment failure\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"OnlineFig2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2759326/v1/e62b5c2a2353248fd6962330.png\"},{\"id\":35211788,\"identity\":\"002f7222-9eba-45ec-960e-15d8555abe2a\",\"added_by\":\"auto\",\"created_at\":\"2023-04-03 15:12:20\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":105397,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eForest plot and Kaplan–Meier estimates of the time to treatment failure of platinum-free interval (PFI ≥ 3 Mos vs. PFI \\u0026lt; 3 Mos)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe median TTF calculated by the Kaplan–Meier curve and the HR calculated by the univariate Cox proportional hazard model for each chemotherapy agent are shown in part (a). The TTF of each chemotherapy agent for patients with PFI ≥ 3 Mos (b) and those with PFI \\u0026lt; 3 Mos (c) is shown. In parts (b) and (c), differences in TTF between each factor were evaluated using the log-rank test.\\u003c/p\\u003e\\n\\u003cp\\u003eTTF, time to treatment failure; PFI, platinum-free interval; Mos, months; CPT-11, irinotecan; GEM, gemcitabine; PLD, pegylated liposomal doxorubicin; NDP, nedaplatin; HR, hazard ratio; CI, confidence interval; mTTF, median time to treatment failure\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"OnlineFig3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2759326/v1/9ee1fba135fa1a6d36427e34.png\"},{\"id\":35211482,\"identity\":\"4ee5d43d-0d17-4788-bdf0-7e1863e92058\",\"added_by\":\"auto\",\"created_at\":\"2023-04-03 15:04:20\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":85416,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eForest plot and Kaplan–Meier estimates of the time to treatment failure with/without bevacizumab\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe median TTF calculated by the Kaplan–Meier curve and HR calculated by the univariate Cox proportional hazard model for each chemotherapy agent are shown in part (a). The TTF of GEM/GEM+Bev (b) and PLD/PLD+Bev (c) is shown. The differences in TTF between each factor were evaluated using the log-rank test.\\u003c/p\\u003e\\n\\u003cp\\u003eTTF, time to treatment failure; Bev, bevacizumab; CPT-11, irinotecan; GEM, gemcitabine; PLD, pegylated liposomal doxorubicin; NDP, nedaplatin; HR, hazard ratio; CI, confidence interval; mTTF, median time to treatment failure\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"OnlineFig4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2759326/v1/70f4280c684fe9f04d313123.png\"},{\"id\":44731524,\"identity\":\"7c519f2c-462d-417d-bb56-932c5f63983d\",\"added_by\":\"auto\",\"created_at\":\"2023-10-16 21:45:21\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1042652,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2759326/v1/58215f5e-076f-44c1-989b-d76542a5559e.pdf\"},{\"id\":35211484,\"identity\":\"1766482d-aebf-4a02-903b-fea4060e156a\",\"added_by\":\"auto\",\"created_at\":\"2023-04-03 15:04:20\",\"extension\":\"pptx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":571749,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eSupplementary Material\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFig. S1 \\u003c/strong\\u003eKaplan-Meier estimates of the time to treatment failure according to each factor\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFig. S2 \\u003c/strong\\u003eForest plot of the time to treatment failure according to metastatic sites\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFig. S3 \\u003c/strong\\u003eTiming of adverse events\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"FigureS1S3.pptx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2759326/v1/fa7f82033c2100c7af574235.pptx\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Heterogeneous effects of cytotoxic chemotherapies for platinum-resistant ovarian cancer\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eWorldwide, ovarian cancer (OC) is the eighth most common cancer and the eight most common cause of cancer-related death in women [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. The OC morbidity rate is increasing in Japan and its age-adjusted mortality rate is increasing worldwide (3.2 in 10,000 people) [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThe standard therapies for OC are surgery and platinum-based chemotherapy [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. The standard treatment protocol for platinum-sensitive recurrent OC (platinum-free interval [PFI]\\u0026thinsp;\\u0026ge;\\u0026thinsp;6 months [Mos]) is re-administration of platinum combination chemotherapy given the expected response to platinum agents. In contrast, a single-drug chemotherapy agent is recommended for platinum-resistant OC (PR-OC; PFI\\u0026thinsp;\\u0026le;\\u0026thinsp;6 Mos) based on therapeutic efficacy and adverse events (AEs) [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. However, single-drug chemotherapy agents often have an insufficient therapeutic effect, with a response rate of 10\\u0026ndash;20% and progression-free survival (PFS) of 3\\u0026ndash;4 Mos [\\u003cspan additionalcitationids=\\\"CR6 CR7 CR8\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. Chemotherapy agents combined with bevacizumab (Bev) therapy significantly prolong PFS in patients with PR-OC and are increasingly used for patients without contraindications to concomitant Bev therapy [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThe sensitivity of PR-OC to chemotherapy agents differs according to histologic type; specifically, serous carcinoma (SC) and endometrioid carcinoma (EMC) have good sensitivity, while clear cell carcinoma (CC) and mucinous carcinoma (MC) have poor sensitivity [\\u003cspan additionalcitationids=\\\"CR12\\\" citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. Furthermore, the distribution of histologic types of PR-OC varies according to ethnicity. For example, SC accounts for \\u0026ge;\\u0026thinsp;2/3 and 2/5 of patients in Western countries and Japan, respectively [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. In contrast, CC accounts for only\\u0026thinsp;~\\u0026thinsp;10% and ~\\u0026thinsp;30% of patients abroad and in Japan, respectively [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Moreover, the treatment line, PFI, presence of ascites, cancer antigen (CA) 125 levels, age, and performance status influence the efficacy of chemotherapy agents [\\u003cspan additionalcitationids=\\\"CR16 CR17\\\" citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. Furthermore, the efficacy of Bev differs across chemotherapy agents [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e]. Therefore, treatment choice for PR-OC should be based on patient background and tumor characteristics; however, the heterogeneous effects of each drug for PR-OC remain unclear.\\u003c/p\\u003e \\u003cp\\u003eQuality of life should be considered when determining therapeutic strategies for PR-OC since patients with recurrent OC have decreased physical fitness and bone marrow reserves after undergoing multiple treatment regimens. Moreover, there are several life-threatening AEs related to chemotherapy agents, including thromboembolic events and interstitial pneumonia (IP); therefore, it is important to elucidate the incidence and timing of their occurrence.\\u003c/p\\u003e \\u003cp\\u003eThis retrospective study aimed to examine the therapeutic effects and AEs in patients with PR-OC who underwent single-drug chemotherapy agent or Bev combination therapy according to the patient\\u0026rsquo;s background and tumor characteristics.\\u003c/p\\u003e\"},{\"header\":\"Materials And Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatients and chemotherapy\\u003c/h2\\u003e \\u003cp\\u003eWe included patients with PR-OC from The University of Tokyo Hospital who were treated with a single chemotherapy agent (irinotecan [CPT-11], pegylated liposomal doxorubicin [PLD], gemcitabine [GEM], paclitaxel [PTX], nogitecan [NGT], nedaplatin [NDP], or docetaxel [Doc]) or Bev combination therapy between January 2009 and June 2022. All single chemotherapy agents were administered intravenously, CPT-11 at a dose of 100 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e over 90 min on Days 1, 8, and 15 per cycle, PLD at a dose of 50 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e over 90 min on Day 1 per cycle, GEM at a dose of 1000 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e for 30 min on Days 1, 8, and 15 per cycle, PTX at a dose of 80 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e over 60 min on Days 1, 8, and 15 per cycle; NGT at a dose of 1.5 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e for 30 min from Day 1 to Day 5 per cycle, NDP at a dose of 80 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e over 60 min on Day 1 per cycle, and Doc at a dose of 70 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e over 60 min on Day 1 per cycle. Bev combination therapy comprised adding Bev 15 mg/kg on Day 1 to the dosing schedule of PLD, PTX, and NGT. GEM\\u0026thinsp;+\\u0026thinsp;Bev was intravenously administered at a dose of 1000 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e for 30 min on Days 1 and 8 per cycle, as well as Bev 15 mg/kg on Day 1. Bev was administered over 90, 60, and 30 min for the first, second, and third (and subsequent) times, respectively. Cycle duration was 28 days for all drugs, except Doc and GEM\\u0026thinsp;+\\u0026thinsp;Bev (both 21 days). The initial dose of chemotherapy agents was reduced in accordance with the patient's condition. The exclusion criteria were pathological diagnosis of squamous cell carcinoma or neuroendocrine tumor and death from causes other than the primary disease within a week after chemotherapy initiation.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eData collection and clinical outcomes\\u003c/h2\\u003e \\u003cp\\u003eWe obtained the following data from the electronic medical records: the International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, treatment history of platinum-based chemotherapy, PFI, time to treatment failure (TTF), platinum resistance (primary platinum resistance, secondary platinum resistance, or more), treatment line after platinum resistance (first line, second line, or more), histology (CC/MC or non-CC/MC), background characteristics before starting chemotherapy for platinum resistance (age, body mass index [BMI]), metastatic sites, ascites status, use of Bev, initial dose, and AEs. The primary study endpoint was TTF because the decision to continue treatment is often based not only on disease progression but also on a comprehensive assessment of AEs and quality of life. TTF was defined as the interval from the date of chemotherapy initiation to death due to primary disease, primary disease progression, or treatment discontinuation due to AEs, whichever occurred first. AEs were assessed based on the Common Terminology Criteria for Adverse Events version 5.0 and were assessed at intervals between the start and end of each chemotherapy regimen. Platinum resistance was defined as recurrence occurring\\u0026thinsp;\\u0026le;\\u0026thinsp;6 Mos after completion of platinum-based chemotherapy. PFI was defined as the interval from the date of the last platinum-based chemotherapy dose to the date of first diagnosis of platinum-resistant recurrence.\\u003c/p\\u003e \\u003cp\\u003eWe evaluated metastatic sites, the presence/absence of ascites, and the use of Bev before the administration of each chemotherapy agent.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analyses\\u003c/h2\\u003e \\u003cp\\u003eThe Kaplan\\u0026ndash;Meier method was used to analyze TTF. The log-rank test was used to analyze differences in TTF according to chemotherapy agent, histology, PFI, usage of Bev, and treatment line. Differences in TTF among CPT-11, GEM, PLD, and NDP in the CC/MC, non-CC/MC, PFI\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 Mos, and PFI\\u0026thinsp;\\u0026lt;\\u0026thinsp;3 Mos groups were evaluated by the log-rank test. Differences in TTF between GEM and GEM\\u0026thinsp;+\\u0026thinsp;Bev and between PLD and PLD\\u0026thinsp;+\\u0026thinsp;Bev were also analyzed using the log-rank test. Using the univariate Cox proportional hazards model, we estimated the hazard ratio (HR) for TTF events according to chemotherapy agent between each factor including histology, PFI, usage of Bev, and metastatic sites. The incidence rate of each Grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 AE, including neutropenia, thrombocytopenia, anemia, febrile neutropenia, anorexia, nausea, diarrhea, aspartate transaminase (AST)/alanine transaminase (ALT) increase, hand-foot syndrome (HFS), rash, fatigue, oral mucositis, IP, and thromboembolic events, was calculated according to chemotherapy agent. All tests were two-tailed. Statistical significance was set at \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05. All statistical analyses were performed using SPSS Statistics for Windows version 24 (IBM Corp., Armonk, NY).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eEthics approval\\u003c/h2\\u003e \\u003cp\\u003e The study protocol was approved by the ethics committee of the Faculty of Medicine, University of Tokyo (Approval number: 2654, 3084). The institutional review board granted an opt-out recruitment approach and waived the need for written informed consent. This study adhered to the Declaration of Helsinki.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatient background\\u003c/h2\\u003e \\u003cp\\u003eAmong 161 patients who received chemotherapy for PR-OC, we excluded three patients. The median age of the patients was 61.1 years and \\u0026gt;\\u0026thinsp;70% of patients had FIGO stage\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 at diagnosis (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003ea). Approximately 50% of the patients had SC and 25% had CC. CPT-11 was the most commonly administered drug, followed by GEM and PLD. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eb summarizes the usage characteristics of each chemotherapy agent. Approximately 80% of patients who received CPT-11 received it as first-line treatment, while 70% of patients who received NDP and PTX received it as third- or fourth-line treatment. Most patients who received PTX were on combination therapy with Bev, but only 24\\u0026ndash;31% of patients who received GEM and PLD were on combination therapy with Bev.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003ea. Characteristics of patients before the first-line chemotherapy\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"2\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCharacteristics\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eAll patients (n\\u0026thinsp;=\\u0026thinsp;158)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge [year], median (range)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e61.1 (36.4\\u0026ndash;84.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge\\u0026thinsp;\\u0026ge;\\u0026thinsp;65 years, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e65 (41.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBMI [kg/m\\u003csup\\u003e2\\u003c/sup\\u003e], median (range)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e21.5 (12.2\\u0026ndash;36.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFIGO stage (\\u0026ge;\\u0026thinsp;3), n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e125 (79.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePrimary site, ovarian (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e144 (91.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHistology, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSerous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e79 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eClear cell\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e41 (25.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEndometrioid\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e16 (10.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMucinous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5 (3.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOthers\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e17 (10.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eType of metastatic sites, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePeritoneal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e112 (70.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLymph node\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e61 (38.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLiver\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e17 (10.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLung\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e13 (8.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNo. of metastatic sites, median (range)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1 (1\\u0026ndash;3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAscites, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e68 (43.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHistory of platinum-based chemotherapy plus bevacizumab, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e41 (25.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePlatinum resistance, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePrimary\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e73 (46.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSecondary or more\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e85 (53.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePlatinum-free interval\\u0026thinsp;\\u0026lt;\\u0026thinsp;3 months, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e100 (63.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePlatinum-resistant cytotoxic chemotherapy, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eIrinotecan\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e92 (58.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eGemcitabine\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e90 (57.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePegylated liposomal doxorubicin\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e82 (51.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNedaplatin\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e33 (20.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePaclitaxel\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e18 (11.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNogitecan\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e14 (8.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDocetaxel\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e14 (8.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBevacizumab combination therapy, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e49 (31.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"2\\\"\\u003eBMI, body mass index; FIGO, International Federation of Gynecology and Obstetrics\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eb. Background of platinum-resistant chemotherapy agents\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"8\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"1\\\" rowspan=\\\"2\\\"\\u003e \\u003cp\\u003eCharacteristics\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCPT-11\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eGEM\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePLD\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNDP\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003ePTX\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eNGT\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eDoc\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;92)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;90)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;82)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;33)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;18)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;14)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;14)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTreatment line after platinum resistance\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1st line\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e70 (76.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e36 (40.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e40 (48.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3 (16.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e1 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e7 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2nd line\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e21 (22.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e33 (36.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e22 (26.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e10 (30.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2 (11.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e5 (35.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e3 (21.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e3rd line\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1 (1.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e16 (17.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e14 (17.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e15 (45.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e7 (38.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e1 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e4th line\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (5.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e6 (7.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e8 (24.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e6 (33.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e7 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eBevacizumab therapy\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e28 (31.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e20 (24.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e16 (88.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eTreatment line of bevacizumab therapy\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1st line\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e18 (20.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e13 (15.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e3 (16.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e1 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2nd line\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e8 (8.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 (3.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2 (11.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e1 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e3rd line or more\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (2.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4 (4.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e11 (61.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInitial dose, full dose\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e45 (48.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e36 (40.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e39 (47.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e31 (93.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e16 (88.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e12 (85.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e12 (85.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePlatinum-free interval\\u0026thinsp;\\u0026lt;\\u0026thinsp;3 months, n (%)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e58 (63.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e55 (61.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e50 (61.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e18 (54.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e8 (44.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e6 (42.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e9 (64.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePlatinum resistance\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePrimary\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e46 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e42 (46.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e30 (36.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e17 (51.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e7 (38.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e4 (28.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e8 (57.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSecondary or more\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e46 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e48 (53.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e52 (63.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e16 (48.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e11 (61.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e10 (71.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e6 (42.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHistology\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eSerous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e40 (43.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e45 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e50 (61.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e20 (60.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e14 (77.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e10 (71.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e7 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eEndometrioid\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11 (12.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e8 (8.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10 (12.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e2 (6.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2 (11.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eClear cell\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e26 (28.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e24 (26.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e11 (13.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e7 (21.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1 (5.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e3 (21.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMucinous\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2 (2.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (1.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4 (4.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e1 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOthers\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e13 (14.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e12 (13.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e7 (8.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4 (12.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1 (5.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e1 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eType of metastatic sites\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePeritoneal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e62 (67.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e68 (75.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e57 (69.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e24 (72.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e16 (88.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e13 (92.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e12 (85.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLymph node\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e36 (39.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e41 (45.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e37 (45.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e20 (60.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e8 (44.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e6 (42.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e6 (42.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLiver\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e12 (13.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e15 (16.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e12 (14.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e4 (12.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1 (5.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3 (21.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e1 (7.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eLung\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e9 (9.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6 (6.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e10 (12.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e6 (18.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1 (5.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e2 (14.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAscites\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e37 (40.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e37 (41.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e32 (39.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e12 (36.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e9 (50.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e6 (42.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e4 (28.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"8\\\"\\u003eData are shown as n (%). CPT-11, irinotecan; PLD, pegylated liposomal doxorubicin; GEM, gemcitabine, PTX, paclitaxel, NGT, nogitecan, NDP, nedaplatin, Doc, docetaxel\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eComparison of TTF according to chemotherapy agent, background, and tumor characteristics\\u003c/h2\\u003e \\u003cp\\u003eTTF was compared according to chemotherapy agent, background characteristics, and tumor characteristics. The comparison of TTF by chemotherapy agent was performed with four frequently used chemotherapy agents: CPT-11, GEM, PLD, and NDP. The median TTF of each drug ranged from 2\\u0026ndash;4 Mos, with no significant differences (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). There were no significant differences in TTF among the histological types (Supporting Information Fig.\\u0026nbsp;1a), between PFI\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 Mos and \\u0026lt;\\u0026thinsp;3 Mos (Supporting Information Fig.\\u0026nbsp;1b), or between first-line treatment and second- or later-line treatments (Supporting Information Fig.\\u0026nbsp;1c). Patients who used Bev or those without ascites had a better TTF than those who did not use Bev or those with ascites (Supporting Information Fig.\\u0026nbsp;1d, e).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eHistology\\u003c/h2\\u003e \\u003cp\\u003eFigure \\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e summarizes the TTF and HR of the chemotherapy agents for each histologic type (CC/MC vs. non-CC/MC). PTX, NGT, and Doc were classified as \\u0026ldquo;others\\u0026rdquo; since they were administered only to a few patients. TTF tended to be worse in the CC/MC group (HR: 1.126, 95% confidence interval [CI]: 0.875\\u0026ndash;1.450). However, the effectiveness of the chemotherapy agents differed according to the histological type. Specifically, the TTF of CPT-11 and NDP was significantly longer in the non-CC/MC group than in the CC/MC group (HR: 2.109 and 5.268, respectively) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003ea). Further, the TTF of GEM was significantly longer in the CC/MC group than in the non-CC/MC group (HR: 0.575), and the TTF of PLD tended to be longer in the CC/MC group than in the non-CC/MC group (HR: 0.697). We next compared the efficacy of each chemotherapy agent separately for each histologic type. In the CC/MC, GEM had the strongest effect with a median TTF of 5.3 Mos and NDP had the weakest effect with a median TTF of 1.4 Mos (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eb). In the non-CC/MC group, CPT-11 and NDP had a better TTF than GEM and PLD (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003ec).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003ePlatinum-free interval\\u003c/h2\\u003e \\u003cp\\u003eComparison of TTF of the chemotherapy agents according to PFI (\\u0026lt;\\u0026thinsp;3 Mos vs. \\u0026ge;3 Mos) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e) showed that TTF did not differ according to PFI (HR: 1.135; 95% CI: 0.912\\u0026ndash;1.411). The TTF of NDP was most strongly influenced by PFI; specifically, TTF was significantly shorter in patients with PFI\\u0026thinsp;\\u0026lt;\\u0026thinsp;3 Mos (HR: 2.707) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003ea). Moreover, NDP showed the best TTF in the Kaplan\\u0026ndash;Meier curve for patients with PFI\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 Mos; however, TTF did not differ among chemotherapy agents in patients with PFI\\u0026thinsp;\\u0026lt;\\u0026thinsp;3 Mos (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003eb, c).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eBevacizumab\\u003c/h2\\u003e \\u003cp\\u003e Comparison of the TTF of each chemotherapy agent according to Bev (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e) showed that combination therapy with Bev significantly improved TTF (HR: 0.724; 95% CI: 0.536\\u0026ndash;0.978). However, the improvement effects of Bev on prognosis differed according to the type of chemotherapy agent. Specifically, the Bev combination therapies were most effective in \\u0026ldquo;Others\\u0026rdquo; including PTX and NGT (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ea), followed by GEM (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ea, b), while the PLD\\u0026thinsp;+\\u0026thinsp;Bev combination did not improve TTF (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003ea, c).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section3\\\"\\u003e \\u003ch2\\u003eMetastatic sites\\u003c/h2\\u003e \\u003cp\\u003ePatients with ascites had a worse TTF, regardless of the type of chemotherapy agent administered (Supporting Information Fig.\\u0026nbsp;2).\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec14\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eIncidence rate and timing of AEs\\u003c/h2\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e summarizes the Grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 AEs for CPT-11, GEM, PLD, and NDP. The incidence of febrile neutropenia, nausea, and diarrhea was highest with CPT-11 usage, and GEM users showed the highest incidence of neutropenia and AST/ALT elevation (46.5% and 4.7%, respectively). PLD users showed the highest incidence of thromboembolic events, IP, HFS, and oral mucositis. Notably, the incidence of thrombotic events was 10.1%, suggesting that PLD should be administered with awareness of the risk of thromboembolic events. The main AE associated with NDP was myelosuppression. There were no cases of non-hematologic toxicity in Grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 AEs.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eAdverse events of CPT-11, GEM, PLD, and NDP\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"5\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAdverse events Grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;3\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCPT-11\\u003c/p\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;92)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eGEM\\u003c/p\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;90)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003ePLD\\u003c/p\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;82)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eNDP\\u003c/p\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;33)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNeutropenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e30 (32.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e41 (45.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e25 (30.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e5 (15.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eThrombocytopenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (5.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2 (2.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e3 (9.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAnemia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10 (10.9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e13 (14.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e12 (14.6)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e6 (18.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFebrile neutropenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (6.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (2.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1 (1.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAnorexia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNausea\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6 (6.5)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eDiarrhea\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8 (8.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAST/ALT increase\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1 (1.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4 (4.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2 (2.4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eHand-foot syndrome\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 (3.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eRash\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (1.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFatigue\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1 (1.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e1 (1.2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eOral mucositis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 (3.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInterstitial pneumonia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (1.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e3 (3.7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eThromboembolic event\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3 (3.3)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (1.1)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e8 (9.8)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0 (0.0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"5\\\"\\u003eData are shown as n (%). CPT-11, irinotecan; PLD, pegylated liposomal doxorubicin; GEM, gemcitabine, NDP, nedaplatin; AST, aspartate transaminase; ALT, alanine transaminase.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eAmong the AEs, we investigated the timing of the onset of thromboembolic events and IP for all grades (Supporting Information Fig.\\u0026nbsp;3). Although the incidence of both AEs was high during the first- and second- line treatments, thromboembolic events also occurred after the fourth treatment course, which suggests the importance of monitoring for thromboembolic events during chemotherapy.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eWe investigated the TTF of chemotherapy agents as well as the factors against PR-OC. We found that the impact of histological type, PFI, and Bev usage was dependent on the type of chemotherapy agent. Regarding the AE profiles, PLD showed the highest incidence of thromboembolic events and IP.\\u003c/p\\u003e \\u003cp\\u003eThere is insufficient evidence for selecting chemotherapy agents for OC based on patient background and tumor characteristics. Accordingly, chemotherapy agents for PR-OC are selected based on treatment history, residual toxicity, cost, convenience, and patient preference [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. Our findings confirmed that the therapeutic effects of chemotherapy agents differ according to patient background and tumor characteristics.\\u003c/p\\u003e \\u003cp\\u003eThe therapeutic effect of each drug differed according to histological type (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Specifically, GEM showed the strongest therapeutic effect in the CC/MC group with TTF\\u0026thinsp;\\u0026gt;\\u0026thinsp;5 Mos, whilst it showed a poor therapeutic effect in the non-CC/MC group. A preclinical study demonstrated the potential efficacy of GEM for CC [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. Additionally, a multi-center Italian trial on OC (MITO)-09 confirmed a high response rate of CC to GEM [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. These data suggest that GEM is the preferred therapeutic candidate in CC/MC. In contrast, NDP showed the strongest and weakest therapeutic effects in the non-CC/MC and CC/MC groups, respectively. Similar to NDP, CPT-11 showed a strong therapeutic effect in the non-CC/MC group, whilst the effect was not strong in those with CC/MC. For patients with CC, combination therapy of CPT-11 and cisplatin (CPT-P) have been used as an alternative to PTX and carboplatin (TC) therapy [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]. However, a prospective randomized controlled trial failed to demonstrate the superiority of CPTP therapy over TC therapy as a postoperative adjuvant therapy for CC [25]. This suggests that CPT-11 is not a particularly superior treatment for CC. Taken together, GEM might be recommended for patients with CC/MC, whilst CPT-11 and NDP might be recommended for those with non-CC/MC.\\u003c/p\\u003e \\u003cp\\u003eNDP has demonstrated limited efficacy for PR-OC. However, extending the platinum-free interval (using a nonplatinum-based regimen) might restore platinum sensitivity [\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]. Patients with PR-OC who responded well to NDP had a longer PFI owing to treatment without platinum analogs after development of platinum resistance [\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]. In our cohort, \\u0026gt;\\u0026thinsp;70% of NDP users received NDP after the third-line treatment after platinum resistance, indicating a sufficiently long platinum-free period post-platinum resistance diagnosis. Our findings demonstrated that a PFI\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 Mos could be a biomarker for an improved therapeutic effect of NDP against PR-OC (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). Although platinum combination therapy is usually avoided in patients with PR-OC who have a PFI\\u0026thinsp;\\u0026lt;\\u0026thinsp;6 Mos given the unfavorable relationship between intensity and efficacy, NDP might be an alternative treatment for patients with PFI\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 Mos after a sufficient platinum-free period.\\u003c/p\\u003e \\u003cp\\u003eThere is accumulating evidence that Bev combination therapies significantly improve the PFS of patients with PR-OC [\\u003cspan additionalcitationids=\\\"CR9\\\" citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. In our study, Bev significantly improved TTF when combined with GEM and \\u0026ldquo;others\\u0026rdquo; (PTX and NGT), but not when combined with PLD, which is consistent with the JGOG3023 study [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e] (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e). The background characteristics of our patients were more similar to those of the JGOG3023 study than the AURELIA study. Specifically, ~\\u0026thinsp;60% of patients had a PFI\\u0026thinsp;\\u0026lt;\\u0026thinsp;3 Mos and ~\\u0026thinsp;50% prevalence rate of SC, and there was no exclusion of third- or later-line treatments. Further large-scale cohort studies are warranted to validate the additive effect of Bev with PLD; however, it should be carefully considered given the increased risk of AEs.\\u003c/p\\u003e \\u003cp\\u003eThe presence of ascites indicates a poor prognosis, regardless of the chemotherapy type. Preclinical studies on OC have shown that the presence of ascites promoted multidrug resistance in patients with OC [\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]. Our findings demonstrated that the presence of ascites was a hallmark of chemoresistance, regardless of chemotherapy type. Moreover, ascites volume positively correlated with the risk of AEs in CPT-11 users [\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]; therefore, early CPT-11 use is recommended for PR-OC, especially for patients with non-CC/MC. Although the presence of ascites decreases the efficacy of chemotherapy agents, Bev can be used to control ascites [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]. Therefore, GEM\\u0026thinsp;+\\u0026thinsp;Bev or PTX\\u0026thinsp;+\\u0026thinsp;Bev might be better treatment options based on the compatibility of GEM and PTX with Bev.\\u003c/p\\u003e \\u003cp\\u003eDiarrhea and HFS/oral mucositis occurred only among CPT-11 and PLD users, respectively [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Additionally, PLD users showed the highest incidence of Grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 thromboembolic events (~\\u0026thinsp;10%). The incidence of thromboembolic events among PLD users varies among different studies [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. The incidence of Grade\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 thromboembolic events in the AURELIA and REBECA trials among patients with PR-OC was \\u0026le;\\u0026thinsp;5% [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]. In our study, the frequency of PLD-induced thromboembolic events was higher than that observed in these previous studies. Since our patients received more advanced- or late-line treatments than those in the AURELIA and REBECA trials, the high incidence of PLD-induced thromboembolic events might be partly attributed to cancer-related thrombosis accompanied by advanced cancer. Notably, PLD users showed the highest incidence of IP (3.8%), with most patients developing IP during the first two treatment cycles. Since thromboembolic events and IP could be life-threatening AEs, caution should be applied when administering PLD, especially in the first two treatment courses.\\u003c/p\\u003e \\u003cp\\u003eThis study had a few limitations. First, we did not consider confounding factors when evaluating the efficacy of the drugs in terms of TTF. Therefore, our findings should be cautiously interpreted. Second, this was a single-center, retrospective, observational study. Accordingly, there may have been biases or tendencies in the selection of chemotherapy agents. For example, CPT-11 and NDP tended to be used in the first- and later-line treatments, respectively. The timing of drug use and selection of patients may have resulted in differences in treatment effects. Therefore, large-scale multi-center cohort studies are warranted to assess the heterogeneous effects of chemotherapy agents. Despite this, to the best of our knowledge, this is the largest single-center cohort study, which is based on data from 343 different treatments in 158 patients, making our findings more convincing.\\u003c/p\\u003e \\u003cp\\u003eIn conclusion, we identified factors influencing the treatment efficacy of each chemotherapy agent used to treat patients with PR-OC. CPT-11/NDP and GEM were effective candidates for patients with non-CC/MC and CC/MC, respectively. NDP can be used as a late-line regimen for patients with PFI\\u0026thinsp;\\u0026ge;\\u0026thinsp;3 Mos. Finally, PLD showed a relatively high incidence of thromboembolic events. Our findings could inform better selection of chemotherapy agents for PR-OC based on patient background and tumor characteristics.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eAcknowledgements\\u003c/h2\\u003e \\u003cp\\u003eWe thank Editage (\\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003e\\u003ca href=\\\"http://www.editage.jp\\\" target=\\\"_blank\\\"\\u003ewww.editage.jp\\u003c/a\\u003e\\u003c/span\\u003e\\u003cspan address=\\\"http://www.editage.jp\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e) for English language editing.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eBray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394\\u0026ndash;424\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYamagami W, Nagase S, Takahashi F et al (2017) Clinical statistics of gynecologic cancers in Japan. J Gynecol Oncol 28:e32\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTokunaga H, Mikami M, Nagase S et al (2021) The 2020 Japan Society of Gynecologic Oncology guidelines for the treatment of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. J Gynecol Oncol 32:e49\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eArmstrong DK, Alvarez RD, Bakkum-Gamez JN et al (2021) Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 19:191\\u0026ndash;226\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMatsumoto K, Katsumata N, Yamanaka Y et al (2006) The safety and efficacy of the weekly dosing of irinotecan for platinum- and taxanes-resistant epithelial ovarian cancer. Gynecol Oncol 100:412\\u0026ndash;416\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\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/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGordon AN, Fleagle JT, Guthrie D et al (2001) Recurrent epithelial ovarian carcinoma: A randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312\\u0026ndash;3322\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\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\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMarkman M, Hall J, Spitz D et al (2002) Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol 20:2365\\u0026ndash;2369\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\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. 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Ann Oncol 27:1733\\u0026ndash;1739\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKato MK, Yunokawa M, Bun S et al (2020) Treatment strategies for recurrent ovarian cancer in older adult patients in Japan: A study based on real-world data. J Cancer Res Clin Oncol 146:1335\\u0026ndash;1341\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKobayashi-Kato M, Yunokawa M, Bun S et al (2019) Platinum-free interval affects efficacy of following treatment for platinum-refractory or -resistant ovarian cancer. Cancer Chemother Pharmacol 84:33\\u0026ndash;39\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePoveda AM, Selle F, Hilpert F et al (2015) Bevacizumab combined with weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian cancer: Analysis by chemotherapy cohort of the randomized Phase III AURELIA trial. J Clin Oncol 33:3836\\u0026ndash;3838\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePujade-Lauraine E, Banerjee S et al (2019) Management of platinum-resistant, relapsed epithelial ovarian cancer and new drug perspectives. J Clin Oncol 37:2437\\u0026ndash;2448\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKuroda T, Ogiwara H, Sasaki M et al (2019) Therapeutic preferability of gemcitabine for ARID1A-deficient ovarian clear cell carcinoma. Gynecol Oncol 155:489\\u0026ndash;498\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eEsposito F, Cecere SC, Magazzino F et al (2014) Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the multicenter Italian trials in ovarian cancer (MITO-9). Oncology 86:351\\u0026ndash;358\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSugiyama T, Yakushiji M, Kamura T et al (2002) Irinotecan (CPT-11) and cisplatin as first-line chemotherapy for advanced ovarian cancer. Oncology 63:16\\u0026ndash;22\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTakano M, Kikuchi Y, Yaegashi N et al (2006) Adjuvant chemotherapy with irinotecan hydrochloride and cisplatin for clear cell carcinoma of the ovary. Oncol Rep 16:1301\\u0026ndash;1306\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSugiyama T, Okamoto A, Enomoto T et al (2016) Randomized phase III trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first-line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG trial. J Clin Oncol 34:2881\\u0026ndash;2887\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\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\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGoto T, Takano M, Ohishi R et al (2010) Single nedaplatin treatment as salvage chemotherapy for platinum/taxane-resistant/refractory epithelial ovarian, tubal and peritoneal cancers. J Obstet Gynaecol Res 36:764\\u0026ndash;768\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMo L, Pospichalova V, Huang Z et al (2015) Ascites increases expression/function of multidrug resistance proteins in ovarian cancer cells. PLoS ONE 10:e0131579\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAsem M, Young A, Oyama C et al (2020) Ascites-induced compression alters the peritoneal microenvironment and promotes metastatic success in ovarian cancer. Sci Rep 10:11913\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eShiozawa T, Tadokoro J, Fujiki T et al (2013) Risk factors for severe adverse effects and treatment-related deaths in Japanese patients treated with irinotecan-based chemotherapy: A postmarketing survey. Jpn J Clin Oncol 43:483\\u0026ndash;491\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLee JY, Park JY, Park SY et al (2019) Real-world effectiveness of bevacizumab based on Aurelia in platinum-resistant recurrent ovarian cancer (REBECA): A Korean Gynecologic Oncology Group study (KGOG 3041). Gynecol Oncol 152:61\\u0026ndash;67\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\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\":\"info@researchsquare.com\",\"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\":\"platinum-resistant ovarian cancer, heterogeneous treatment effect, adverse event, histology, platinum-free interval\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-2759326/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-2759326/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground:\\u003c/strong\\u003e Single-agent chemotherapy with or without bevacizumab (Bev) is a standard therapy for platinum-resistant ovarian cancer (PR-OC). However, there is a lack of literature on chemotherapy agent selection in heterogenous PR-OC. Therefore, we aimed to clarify the heterogeneous treatment effects of each chemotherapy agent.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e Patients who underwent single-drug chemotherapy agents or Bev combination therapy for PR-OC between January 2009 and June 2022 were included in this study. We assessed the impact of each chemotherapy agent on the time to treatment failure (TTF) according to histological type, platinum-free interval (PFI), and Bev usage.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e A total of 158 patients received 343 different chemotherapy regimens. In patients with clear cell carcinoma/mucinous carcinoma (CC/MC), gemcitabine (GEM) had the strongest effect with a median TTF of 5.3 months, whilst nedaplatin (NDP) had the lowest effect with a median TTF of 1.4 months. In contrast, in the non-CC/MC group, irinotecan (CPT-11) and NDP had a better TTF than GEM and pegylated liposomal doxorubicin (PLD). There were notable differences in the treatment efficacy of NDP according to PFI. Specifically, NDP prolonged the TTF in patients with a PFI ≥3 months. Compared with GEM alone, GEM+Bev tended to prolong the TTF more effectively; however, an additive effect was not observed with PLD+Bev.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions:\\u003c/strong\\u003e This study demonstrated that the effect of chemotherapy agents differed according to the tumor and background characteristics of the patient. Our findings will improve selection of effective therapies for patients with PR-OC by considering their background characteristics.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Heterogeneous effects of cytotoxic chemotherapies for platinum-resistant ovarian cancer\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2023-04-03 15:04:15\",\"doi\":\"10.21203/rs.3.rs-2759326/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Major revisions\",\"date\":\"2023-04-23T03:40:09+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2023-04-01T09:10:24+00:00\",\"index\":0,\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2023-04-01T01:39:18+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"International Journal of Clinical Oncology\",\"date\":\"2023-03-31T01:43:37+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"e34c14a7-4361-4490-94d3-ce4df479666d\",\"owner\":[],\"postedDate\":\"April 3rd, 2023\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2023-10-16T21:28:10+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-2759326\",\"link\":\"https://doi.org/10.1007/s10147-023-02367-1\",\"journal\":{\"identity\":\"international-journal-of-clinical-oncology\",\"isVorOnly\":false,\"title\":\"International Journal of Clinical Oncology\"},\"publishedOn\":\"2023-06-22 21:17:22\",\"publishedOnDateReadable\":\"June 22nd, 2023\"},\"versionCreatedAt\":\"2023-04-03 15:04:15\",\"video\":\"\",\"vorDoi\":\"10.1007/s10147-023-02367-1\",\"vorDoiUrl\":\"https://doi.org/10.1007/s10147-023-02367-1\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-2759326\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-2759326\",\"identity\":\"rs-2759326\",\"version\":[\"v1\"]},\"buildId\":\"cBFmMYwuxLRRLfASyISRj\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}