Pretreatment Thrombocytosis as an Independent Predictive Factor for Chemoresistance and Poor Survival in Epithelial Ovarian Cancer

Pretreatment Thrombocytosis as an Independent Predictive Factor for Chemoresistance and Poor Survival in Epithelial 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 Pretreatment Thrombocytosis as an Independent Predictive Factor for Chemoresistance and Poor Survival in Epithelial Ovarian Cancer Sari Nakao, Takeo Minaguchi, Hiroya Itagaki, Yoshihiko Hosokawa, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.24476/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 May, 2020 Read the published version in Journal of Ovarian Research → Version 2 posted 4 You are reading this latest preprint version Show more versions Abstract Background Thrombocytosis is related to tumor stage and survival in ovarian cancer in addition to the common complications of malignant diseases, such as anemia and inflammation. The aim of our study was to clarify the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer. Methods We retrospectively analyzed 280 consecutive patients who were treated for epithelial ovarian cancer at our institution between 2001 and 2011. Results Pretreatment thrombocytosis was observed in 18.9% of all patients and was associated with advanced FIGO stage, primary treatment, operation achievement, histologic subtype, microcytic hypochromic anemia (MHA), and nonmalignant inflammatory condition ( P =0.0018, 0.0028, 0.00050, 0.034, 0.00090 and 0.0022). In the patients who relapsed after primary adjuvant chemotherapy (n=126), thrombocytosis was associated with a shorter treatment-free interval (TFI) ( P =0.0091). The univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA ( P =0.021 and 0.0091). Patients with thrombocytosis had worse progression-free survival (PFS) and overall survival (OS) than those without thrombocytosis ( P <0.0001 and <0.0001). The multivariate analyses for prognostic factors demonstrated that thrombocytosis was significant for poor PFS and OS ( P =0.0050 and 0.022) independent of stage, histology, primary treatment, operation achievement, nonmalignant inflammatory condition and MHA. Conclusions The current findings indicate that the detrimental survival impact of pretreatment thrombocytosis in epithelial ovarian cancer may be independent of tumor extent but rather attributed to chemoresistance, further supporting the therapeutic potential of targeting thrombopoietic cytokines in the disease. Cancer Biology Oncology Obstetrics & Gynecology thrombocytosis ovarian cancer survival Figures Figure 1 Figure 2 Background Approximately half of all patients with ovarian cancer are diagnosed with advanced-stage disease(1), as early-stage patients tend to rarely have subjective symptoms due to the anatomical location of the ovary as an intraperitoneal organ. The principal treatment for epithelial ovarian cancer is maximal cytoreduction, which typically comprises surgery followed by chemotherapy, and the amount of residual tumor is one of the most important prognostic factors(2-5). Accordingly, the elucidation of mechanisms for tumor growth and metastasis will contribute to improving patient prognosis. Thrombocytosis is traditionally known to be associated with patient prognosis in ovarian cancer(6-15). Platelets are involved in tumor growth, angiogenesis, and metastasis(16). The functions of cytokines on platelet-mediated tumor proliferation and progression have been widely investigated(16). Recently, antiplatelet therapies including molecular agents targeting thrombopoietic cytokines have been investigated by clinical trials in patients with ovarian cancer(17, 18). However, the precise prognostic significance of paraneoplastic thrombocytosis is yet to be determined. Thrombocytosis is known to be induced by iron-deficiency anemia and nonmalignant inflammatory conditions in addition to malignant disease, and ovarian cancer patients, especially those with advanced-stage disease, may have these complications. The aim of our study was to investigate the detailed prognostic impact of thrombocytosis on ovarian cancer patients in order to elucidate the underlying mechanism and to identify the target patients who will benefit more from antiplatelet therapies. Methods Patients We retrospectively reviewed the clinical records of a total of 280 consecutive patients who were treated for epithelial ovarian cancer at the University of Tsukuba Hospital between 2001 and 2011. The study protocol was approved by the Ethics Committee University of Tsukuba Hospital (H27-143). We excluded patients with multiple primary cancers, a past history of cancer, or hepatic disease from our study. Patients diagnosed with malignant transformation of mature cystic teratoma were also excluded. Thrombocytosis was defined as a platelet count > 400,000/mm³ before treatment, which was calculated as the mean value of the initial and pretreatment examinations. For survival analyses, progression-free survival (PFS) was defined as the interval between the dates of the initial treatment and the first recurrence or progression of disease, and overall survival (OS) was defined as the interval between the dates of the initial treatment and the last follow-up. The treatment-free interval (TFI) was defined as the interval between the dates of the end of primary adjuvant chemotherapy and the first disease progression (n=126). The stages were classified according to the International Federation of Gynecology and Obstetrics system (FIGO, 1988). The median follow-up period excluding patients who died was 81.4 months (range, 0.7-178). The patient demographics are summarized in Table 1. Treatment The basic surgical procedure for epithelial ovarian cancer consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy. Following primary debulking surgery (PDS), a combination of paclitaxel (175 mg/m 2 , day 1) and carboplatin (AUC=6, day 1) (TC regimen) was administered every 3 weeks. Four cycles of TC were performed in patients with stage IA clear cell carcinoma. Six to eight cycles were performed in patients with stage IC or higher disease. Neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) was selected for patients with apparent stage III/IV disease and chemosensitive tumor histology, i.e., serous or endometrioid as estimated by CT, excessively elevated CA125 levels, and cytological findings of ascites(19). For NAC, 4 cycles of TC were administered, and IDS was followed by an additional 4 cycles. Statistical analysis Differences in proportions were evaluated by the χ 2 test or Fisher’s exact test where appropriate. Differences in continuous variables were evaluated by the Wilcoxon rank-sum test. Logistic regression was used for the univariate and multivariate analyses of the clinicopathologic factors associated with thrombocytosis. Kaplan-Meier survival curves were generated and compared statistically by the log-rank test. The Cox proportional hazard model was used for the univariate and multivariate analyses for prognostic factors. P -values < 0.05 were considered statistically significant. All statistical analyses were performed using JMP11.0 software (SAS Institute, Cary, NC). Results Thrombocytosis was observed in 18.9% of all patients (Table 1). We first examined the relationships between thrombocytosis and the clinicopathologic parameters. The rate of thrombocytosis significantly increased as the FIGO stage progressed: the rate was 9.9% (9/91) for stage I, 10.3% (4/39) for stage II, 23.6% (26/110) for stage III, and 35.0% (14/40) for stage IV (Table 2). Additionally, thrombocytosis was found to be significantly associated with microcytic hypochromic anemia (MHA), primary treatment (NAC vs. PDS), histologic subtype (serous, clear cell, or others), operation achievement (complete, optimal, or suboptimal resection), nonmalignant inflammatory condition, and CA125 level (Table 2). We subsequently conducted univariate and multivariate analyses of the clinicopathologic factors associated with thrombocytosis. Among the factors significantly associated with thrombocytosis in Table 2, we selected MHA, FIGO stage, histologic subtype, operation achievement, and nonmalignant inflammatory condition as the factors to be analyzed (Table 3). To include the factor of TFI as well, we confined the analyses to the 126 patients who showed disease progression after primary adjuvant chemotherapy. Among the 4 significant factors from the univariate analysis, MHA and TFI were found to be significantly and independently associated with thrombocytosis (Table 3). Next, we compared PFS and OS according to the presence or absence of thrombocytosis. In all patients, those with thrombocytosis showed significantly poorer PFS (5-year PFS rate, 25.2% vs. 61.8%; Figure 1A) and OS (5-year OS rate, 41.4% vs. 75.5%; Figure 1B) compared to those without thrombocytosis. When the analysis was confined to the patients with stage III/IV disease, thrombocytosis was still significantly associated with poor PFS (5-year PFS rate, 0.0% vs. 34.0%; Figure 2A) and OS (5-year OS rate, 26.1% vs. 56.9%; Figure 2B), in contrast with the patients with stage I/II disease who showed no difference in PFS (5-year PFS rate, 86.0% vs. 83.9%; Figure 2C) or OS (5-year OS rate, 92.0% vs. 90.1%; Figure 2D). Last, we performed a multivariate analysis of pretreatment thrombocytosis for OS and PFS, adjusted for age, MHA, histologic subtype, FIGO stage, primary treatment, nonmalignant inflammatory condition, and operation achievement (Table 4). Pretreatment thrombocytosis was found to be an independent prognostic factor for poor PFS and OS (Table 4). Discussion We observed pretreatment thrombocytosis, defined as a platelet count > 400,000/mm³, in 18.9% of the patients with stage I-IV epithelial ovarian cancer, which is in line with previous reports using the same cutoff value as ours (7.4-42.5%)(10-12, 15). Our analyses of the relationships between thrombocytosis and clinicopathologic parameters showed that thrombocytosis was significantly associated with MHA, primary treatment, FIGO stage, histologic subtype, operation achievement, nonmalignant inflammatory condition, CA125 level, and TFI (Tables 2 and 3). Among these significant factors, FIGO stage, CA125 level, operation achievement, and primary treatment are considered to reflect the tumor extent, which has been reportedly associated with pretreatment thrombocytosis(6, 20). MHA and nonmalignant inflammatory condition are clinically well known to induce thrombocytosis. We subsequently conducted univariate and multivariate analyses for associations with thrombocytosis in patients who relapsed after adjuvant chemotherapy, excluding the 2 factors of CA125 level and primary treatment, which are considered to be closely related to FIGO stage. We found that MHA and TFI were significantly and independently associated with thrombocytosis (Table 3). Accordingly, thrombocytosis is suggested to possibly contribute to chemoresistance, as TFI is known to be an important surrogate marker for the chemosensitivity of ovarian cancer(21-23). Regarding MHA, iron deficiency anemia caused by intratumoral hemorrhage in ovarian cancer is likely to be involved. Our survival analyses showed that patients with thrombocytosis had worse PFS and OS than those without thrombocytosis (Figures 1A, B). In addition, when the analysis was confined to stage III/IV patients, there was still a significant difference in PFS and OS (Figures 2A, B), whereas stage I/II patients showed no difference in survival according to the presence/absence of pretreatment thrombocytosis (Figures 2C, D). These findings indicate that thrombocytosis affects survival mainly in advanced diseases, consistent with our above finding that thrombocytosis was significantly and independently associated with TFI, an established predictor of chemosensitivity in the treatment of recurrence, as recurrence is prone to occur in advanced diseases. Furthermore, our multivariate analysis for prognostic factors demonstrated that thrombocytosis was significant for unfavorable PFS and OS independent of age, histology, and FIGO stage (Table 4). These findings indicate that pretreatment thrombocytosis may be an ideal predictive biomarker for treatment outcome and a reasonable therapeutic target in epithelial ovarian cancer. Tumor cells first increase and activate platelets via various cytokines, including interleukin-6 (IL-6)(16). Activated platelets in turn facilitate tumor growth and angiogenesis through growth factors and angiogenic factors, including VEGF and PDGF(16, 24). Activated platelets also promote metastasis through epithelial mesenchymal transition (EMT) and defense by platelet-tumor interactions against blood flow and the immune system, including NK cells, in circulation(16, 24). In addition, platelets contribute to chemoresistance through MAPK and PI3-kinase/Akt pathways and drug efflux proteins(24). Moreover, chemoresistance in ovarian cancer cells is suggested to involve the interaction between the surrounding immune system and cancer stem cells in the tumor microenvironment, where platelets play key roles(25, 26). Therefore, thrombocytosis can possibly affect patient prognosis via both tumor progression and chemoresistance. However, we found that thrombocytosis was significantly and independently associated with TFI but not with FIGO stage (Table 3) and that thrombocytosis was significantly associated with PFS independent of FIGO stage (Table 4). These findings suggest that the prognostic impact of thrombocytosis may be independent of tumor extent but rather attributed to chemoresistance. Indeed, platelets have been reported to be involved in chemoresistance in ovarian cancer by in vitro and in vivo basic studies. Radziwon-Balicka et al. reported that platelets decreased paclitaxel-induced apoptosis in human ovarian adenocarcinoma cells in vitro(27). Bottsford-Miller et al. reported that the combined administration of platelet-depleting antibodies and docetaxel caused a 62% decrease in tumor weight compared to docetaxel treatment in orthotopic mouse models of human ovarian cancer(6). They further found that platelet transfusion blocked the effect of docetaxel on tumor growth, and aspirinization blocked the effect of transfusion. However, clinical evidence suggesting the link between thrombocytosis and chemoresistance in ovarian cancer is very limited, as most studies only correlate thrombocytosis with survival after chemotherapy. Bottsford-Miller et al. reported changes in platelet counts during first-line chemotherapy in responsive and refractory groups matched for stage, histology, grade, and primary therapy(28). In patients with a durable response, only 50% had pretreatment thrombocytosis, and all of them achieved a normal platelet count during therapy, whereas all had pretreatment thrombocytosis, and only 50% achieved a normal count during therapy in patients with refractory disease. However, the possibility that platelet count only reflects the real-time residual tumor amount cannot be excluded. Feng et al. reported that preoperative thrombocytosis was significantly associated with chemoresistance determined based on the interval between disease progression and adjuvant chemotherapy in high-grade serous ovarian cancer(20). However, thrombocytosis was not significant after stratification based on residual tumors after surgery. In our study, pretreatment thrombocytosis was not associated with operation achievement and was significantly associated with TFI independent of FIGO stage (Table 3). Moreover, pretreatment thrombocytosis was a significant prognostic factor for poor PFS and OS independent of FIGO stage and operation achievement (Table 4). These observations strongly support the involvement of thrombocytosis in chemoresistance, implicating that molecular therapy targeting thrombocytosis may improve prognosis by attenuating chemoresistance. Based on the current findings, we assume that the combination of chemotherapeutics and antiplatelet therapies may be efficacious for ovarian cancer patients with thrombocytosis. Notably, patients with MHA or nonmalignant inflammatory conditions may have to be excluded from the treatment subjects, as the pathways for thrombocytosis in these patients must be different from those for paraneoplastic thrombocytosis. Stone et al. proposed that increased hepatic thrombopoietin synthesis in response to tumor-derived IL-6 was a mechanism for paraneoplastic thrombocytosis(29). They further reported that treatment with siltuximab, an anti-IL-6 antibody, significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. Regarding clinical trials, a phase II study in patients with platinum-resistant ovarian cancer reported that siltuximab treatment showed a partial response in one patient and disease stabilization in 7 of 18 of the evaluated patients(30). Regarding the combination with chemotherapeutics, a phase I trial in patients with recurrent epithelial ovarian cancer reported that the combination of carboplatin/doxorubicin and tocilizumab, an anti-IL-6 receptor antibody, and interferon-α2b showed complete response in 3, partial response in 8, and stable disease in 6 of the 21 evaluated patients, and they showed that the toxicity was tolerable(31). Additional clinical trials and the examination of clinical samples are warranted to evaluate the usefulness and to investigate the underlying mechanism of anti-IL-6 therapies in ovarian cancer. Our study has the following limitations. First, the sample size of the subset analyses was relatively small. Second, the strengthening of our hypothesis by basic study data was lacking. Third, the retrospective study design potentially caused selection biases. Prospective studies are required to verify our findings. Conclusions We reported here on the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer. Univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA. Thrombocytosis was correlated with poor OS and PFS in advanced stages but showed no difference in early stages of disease. The multivariate analysis for prognostic factors demonstrated that thrombocytosis was significant for OS and PFS independent of stage, histology, primary treatment, operation achievement, nonmalignant inflammatory condition, and MHA. The current findings implicate that the unfavorable prognostic impact of thrombocytosis may be ascribed to chemoresistance, further supporting the therapeutic potential of targeting thrombopoietic cytokines in epithelial ovarian cancer. Abbreviations FIGO: International Federation of Gynecology and Obstetrics IDS: Interval debulking surgery MHA: Microcytic hypochromic anemia NAC: Neoadjuvant chemotherapy OS: Overall survival PDS: Primary debulking surgery PFS: Progression-free survival TC: Paclitaxel and carboplatin TFI: Treatment-free interval Declarations Ethics approval and consent to participate The present study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Committee University of Tsukuba Hospital (H27-143) with a waiver of informed consent. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Authors’ contributions SN and KM contributed to the conception and design; SN analyzed the data and drafted the manuscript; TM revised the manuscript; HI, YH, AS, NT, AA, HO, KM and TS critically reviewed the manuscript; SN, TM, HI, YH, AS, NT, AA, HO, KM and TS treated the patients; and TS supervised the study. All authors read and approved the final manuscript. Acknowledgements Not applicable. References Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95 Suppl 1:S161-92. Winter WE, 3rd, Maxwell GL, Tian C, Sundborg MJ, Rose GS, Rose PG, et al. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2008;26(1):83-9. Winter WE, 3rd, Maxwell GL, Tian C, Carlson JW, Ozols RF, Rose PG, et al. 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A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha2b in patients with recurrent epithelial ovarian cancer. Ann Oncol. 2015;26(10):2141-9. Tables Due to technical limitations the Tables are available as a download in the Supplemental Files. Table 1. Patient characteristics. Table 2. Relationships between pretreatment thrombocytosis and clinicopathologic parameters. Table 3. Univariate and multivariate analyses of risk factors for pretreatment thrombocytosis. Table 4. Univariate and multivariate analyses of prognostic factors for PFS and OS. Supplementary Files PlateletsTable3.xlsx PlateletsTable4.xlsx PlateletsTable2.xlsx PlateletsTable1.xlsx Cite Share Download PDF Status: Published Journal Publication published 06 May, 2020 Read the published version in Journal of Ovarian Research → Version 2 posted Editorial decision: Accept 15 Apr, 2020 Editor assigned by journal 14 Apr, 2020 Submission checks completed at journal 13 Apr, 2020 Editor invited by journal 13 Apr, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-15035","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":490591,"identity":"349b5f2b-3b29-4aff-b49f-1541e330ac4f","order_by":1,"name":"Sari Nakao","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sari","middleName":"","lastName":"Nakao","suffix":""},{"id":490592,"identity":"fdc8acc2-482a-4fc7-bb43-0bbd25b7e771","order_by":2,"name":"Takeo Minaguchi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIiWNgGAWjYDACZgiVwMbAfICBB8TkYWCDyh0goIWNLQGo2oAILVCQwMDGY4CuBTvQbec9+PFrm10en3zP1w1vGP7YG5w5Y/bgB4OdPAPjWazWmB3mS5aWbUsuZmPj3XZzDoNB4oazPeaGPQzJhg0M5xKwa+ExkJZsO5DYBtRyG+iwBIPzPGYSPAzMQOVnDHBoMf4N0cLzDKTFHqRF8g9DPT4tZpIfIVrYQFoYgQ4zk+ZhOIxXizXDuWSgljSzm3MMjBNnnjlWbixjcNywDZdfzp8xvvmjzC5xfvPhZzfeVMjZ851J3vbwTUW1PL8E9hADAWYeONMAicEmcQaXDgbGH9jF+XtwahkFo2AUjIIRBQDPf1yAEIXaLgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3577-5124","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Takeo","middleName":"","lastName":"Minaguchi","suffix":""},{"id":490593,"identity":"7e626e8b-d2f4-4491-9746-29d644f2e286","order_by":3,"name":"Hiroya Itagaki","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroya","middleName":"","lastName":"Itagaki","suffix":""},{"id":490594,"identity":"720690d8-7131-4f9b-bef7-5e8f17ebaab3","order_by":4,"name":"Yoshihiko Hosokawa","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yoshihiko","middleName":"","lastName":"Hosokawa","suffix":""},{"id":490595,"identity":"5ce8ae43-535c-472e-abf7-3dd46aa4ce1e","order_by":5,"name":"Ayumi Shikama","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ayumi","middleName":"","lastName":"Shikama","suffix":""},{"id":490596,"identity":"e86a338a-74b1-4571-95ae-db57ff6d60fa","order_by":6,"name":"Nobutaka Tasaka","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nobutaka","middleName":"","lastName":"Tasaka","suffix":""},{"id":490597,"identity":"9fa3eba8-8998-4f8b-b4c2-803ff97294e3","order_by":7,"name":"Azusa Akiyama","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Azusa","middleName":"","lastName":"Akiyama","suffix":""},{"id":490598,"identity":"a8b96963-399e-4c47-9a3b-cb9fd6ca9ad7","order_by":8,"name":"Hiroyuki Ochi","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Ochi","suffix":""},{"id":490599,"identity":"a99fc3d6-390e-4501-9f75-4fa8e625399c","order_by":9,"name":"Koji Matsumoto","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Matsumoto","suffix":""},{"id":490600,"identity":"2052c0d7-de07-427d-908b-0dd204b4d59a","order_by":10,"name":"Toyomi Satoh","email":"","orcid":"","institution":"Tsukuba Daigaku Igaku Iryokei","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Toyomi","middleName":"","lastName":"Satoh","suffix":""}],"badges":[],"createdAt":"2020-02-22 13:41:34","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.2.24476/v2","doiUrl":"https://doi.org/10.21203/rs.2.24476/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13048-020-00651-6","type":"published","date":"2020-05-06T21:01:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":924139,"identity":"a1960382-0c5f-4536-88d9-8fcc97f4f687","added_by":"auto","created_at":"2020-04-17 17:51:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35225,"visible":true,"origin":"","legend":"Survival curves in all patients according to the presence/absence of pretreatment thrombocytosis (n= 280). A, PFS in all patients. B, OS in all patients.","description":"","filename":"FIgure1.png","url":"https://assets-eu.researchsquare.com/files/rs-15035/v2/FIgure1.png"},{"id":924141,"identity":"7a863707-ead3-44c7-89d0-49c6f50bd1a8","added_by":"auto","created_at":"2020-04-17 17:51:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":76271,"visible":true,"origin":"","legend":"Survival curves in patients with stage III/IV (n=150) or I/II (n=130) disease according to the presence/absence of pretreatment thrombocytosis. A, PFS in stage III/IV patients. B, OS in stage III/IV patients. C, PFS in stage I/II patients. D, OS in stage I/II patients.","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-15035/v2/Figure2.png"},{"id":13498964,"identity":"febbbd6e-f0bb-401b-becb-325b1dd5e027","added_by":"auto","created_at":"2021-09-16 23:00:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":325579,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-15035/v2/195a6e81-3b56-4a8c-b14e-ad7272e1dd37.pdf"},{"id":924143,"identity":"4fb99bee-8758-451b-9ff6-5cfbf5467433","added_by":"auto","created_at":"2020-04-17 17:51:16","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":12489,"visible":true,"origin":"","legend":"","description":"","filename":"PlateletsTable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-15035/v2/PlateletsTable3.xlsx"},{"id":924142,"identity":"470cc705-d024-46bc-9cc3-efa9688d1f9f","added_by":"auto","created_at":"2020-04-17 17:51:16","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":13749,"visible":true,"origin":"","legend":"","description":"","filename":"PlateletsTable4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-15035/v2/PlateletsTable4.xlsx"},{"id":924140,"identity":"762e6c46-32ca-4f51-bb2a-c0ce13899f88","added_by":"auto","created_at":"2020-04-17 17:51:16","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":12915,"visible":true,"origin":"","legend":"","description":"","filename":"PlateletsTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-15035/v2/PlateletsTable2.xlsx"},{"id":924138,"identity":"dd5851b1-44a9-43bc-91f0-a8a842139ed7","added_by":"auto","created_at":"2020-04-17 17:51:16","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":12400,"visible":true,"origin":"","legend":"","description":"","filename":"PlateletsTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-15035/v2/PlateletsTable1.xlsx"}],"financialInterests":"","formattedTitle":"Pretreatment Thrombocytosis as an Independent Predictive Factor for Chemoresistance and Poor Survival in Epithelial Ovarian Cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eApproximately half of all patients with ovarian cancer are diagnosed with advanced-stage disease(1), as early-stage patients tend to rarely have subjective symptoms due to the anatomical location of the ovary as an intraperitoneal organ. The principal treatment for epithelial ovarian cancer is maximal cytoreduction, which typically comprises surgery followed by chemotherapy, and the amount of residual tumor is one of the most important prognostic factors(2-5). Accordingly, the elucidation of mechanisms for tumor growth and metastasis will contribute to improving patient prognosis. Thrombocytosis is traditionally known to be associated with patient prognosis in ovarian cancer(6-15). Platelets are involved in tumor growth, angiogenesis, and metastasis(16). The functions of cytokines on platelet-mediated tumor proliferation and progression have been widely investigated(16). Recently, antiplatelet therapies including molecular agents targeting thrombopoietic cytokines have been investigated by clinical trials in patients with ovarian cancer(17, 18). However, the precise prognostic significance of paraneoplastic thrombocytosis is yet to be determined. Thrombocytosis is known to be induced by iron-deficiency anemia and nonmalignant inflammatory conditions in addition to malignant disease, and ovarian cancer patients, especially those with advanced-stage disease, may have these complications. The aim of our study was to investigate the detailed prognostic impact of thrombocytosis on ovarian cancer patients in order to elucidate the underlying mechanism and to identify the target patients who will benefit more from antiplatelet therapies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively reviewed the clinical records of a total of 280 consecutive patients who were treated for epithelial ovarian cancer at the University of Tsukuba Hospital between 2001 and 2011. The study protocol was approved by the Ethics Committee University of Tsukuba Hospital (H27-143). We excluded patients with multiple primary cancers, a past history of cancer, or hepatic disease from our study. Patients diagnosed with malignant transformation of mature cystic teratoma were also excluded. Thrombocytosis was defined as a platelet count \u003cu\u003e\u0026gt;\u003c/u\u003e 400,000/mm\u0026sup3; before treatment, which was calculated as the mean value of the initial and pretreatment examinations. For survival analyses, progression-free survival (PFS) was defined as the interval between the dates of the initial treatment and the first recurrence or progression of disease, and overall survival (OS) was defined as the interval between the dates of the initial treatment and the last follow-up. The treatment-free interval (TFI) was defined as the interval between the dates of the end of primary adjuvant chemotherapy and the first disease progression (n=126). The stages were classified according to the International Federation of Gynecology and Obstetrics system (FIGO, 1988). The median follow-up period excluding patients who died was 81.4 months (range, 0.7-178). The patient demographics are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe basic surgical procedure for epithelial ovarian cancer consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy. Following primary debulking surgery (PDS), a combination of paclitaxel (175 mg/m\u003csup\u003e2\u003c/sup\u003e, day 1) and carboplatin (AUC=6, day 1) (TC regimen) was administered every 3 weeks. Four cycles of TC were performed in patients with stage IA clear cell carcinoma. Six to eight cycles were performed in patients with stage IC or higher disease. Neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) was selected for patients with apparent stage III/IV disease and chemosensitive tumor histology, i.e., serous or endometrioid as estimated by CT, excessively elevated CA125 levels, and cytological findings of ascites(19). For NAC, 4 cycles of TC were administered, and IDS was followed by an additional 4 cycles.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDifferences in proportions were evaluated by the \u0026chi;\u003csup\u003e2\u003c/sup\u003e test or Fisher\u0026rsquo;s exact test where appropriate. Differences in continuous variables were evaluated by the Wilcoxon rank-sum test. Logistic regression was used for the univariate and multivariate analyses of the clinicopathologic factors associated with thrombocytosis. Kaplan-Meier survival curves were generated and compared statistically by the log-rank test. The Cox proportional hazard model was used for the univariate and multivariate analyses for prognostic factors. \u003cem\u003eP\u003c/em\u003e-values \u0026lt; 0.05 were considered statistically significant. All statistical analyses were performed using JMP11.0 software (SAS Institute, Cary, NC).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThrombocytosis was observed in 18.9% of all patients (Table 1). We first examined the relationships between thrombocytosis and the clinicopathologic parameters. The rate of thrombocytosis significantly increased as the FIGO stage progressed: the rate was 9.9% (9/91) for stage I, 10.3% (4/39) for stage II, 23.6% (26/110) for stage III, and 35.0% (14/40) for stage IV (Table 2). Additionally, thrombocytosis was found to be significantly associated with microcytic hypochromic anemia (MHA), primary treatment (NAC \u003cem\u003evs.\u003c/em\u003e PDS), histologic subtype (serous, clear cell, or others), operation achievement (complete, optimal, or suboptimal resection), nonmalignant inflammatory condition, and CA125 level (Table 2).\u003c/p\u003e\n\u003cp\u003eWe subsequently conducted univariate and multivariate analyses of the clinicopathologic factors associated with thrombocytosis. Among the factors significantly associated with thrombocytosis in Table 2, we selected MHA, FIGO stage, histologic subtype, operation achievement, and nonmalignant inflammatory condition as the factors to be analyzed (Table 3). To include the factor of TFI as well, we confined the analyses to the 126 patients who showed disease progression after primary adjuvant chemotherapy. Among the 4 significant factors from the univariate analysis, MHA and TFI were found to be significantly and independently associated with thrombocytosis (Table 3).\u003c/p\u003e\n\u003cp\u003eNext, we compared PFS and OS according to the presence or absence of thrombocytosis. In all patients, those with thrombocytosis showed significantly poorer PFS (5-year PFS rate, 25.2% \u003cem\u003evs.\u003c/em\u003e 61.8%; Figure 1A) and OS (5-year OS rate, 41.4% \u003cem\u003evs.\u003c/em\u003e 75.5%; Figure 1B) compared to those without thrombocytosis. When the analysis was confined to the patients with stage III/IV disease, thrombocytosis was still significantly associated with poor PFS (5-year PFS rate, 0.0% \u003cem\u003evs.\u003c/em\u003e 34.0%; Figure 2A) and OS (5-year OS rate, 26.1% \u003cem\u003evs.\u003c/em\u003e 56.9%; Figure 2B), in contrast with the patients with stage I/II disease who showed no difference in PFS (5-year PFS rate, 86.0% \u003cem\u003evs.\u003c/em\u003e 83.9%; Figure 2C) or OS (5-year OS rate, 92.0% \u003cem\u003evs.\u003c/em\u003e 90.1%; Figure 2D).\u003c/p\u003e\n\u003cp\u003eLast, we performed a multivariate analysis of pretreatment thrombocytosis for OS and PFS, adjusted for age, MHA, histologic subtype, FIGO stage, primary treatment, nonmalignant inflammatory condition, and operation achievement (Table 4). Pretreatment thrombocytosis was found to be an independent prognostic factor for poor PFS and OS (Table 4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe observed pretreatment thrombocytosis, defined as a platelet count \u003cu\u003e\u0026gt;\u003c/u\u003e 400,000/mm\u0026sup3;, in 18.9% of the patients with stage I-IV epithelial ovarian cancer, which is in line with previous reports using the same cutoff value as ours (7.4-42.5%)(10-12, 15). Our analyses of the relationships between thrombocytosis and clinicopathologic parameters showed that thrombocytosis was significantly associated with MHA, primary treatment, FIGO stage, histologic subtype, operation achievement, nonmalignant inflammatory condition, CA125 level, and TFI (Tables 2 and 3). Among these significant factors, FIGO stage, CA125 level, operation achievement, and primary treatment are considered to reflect the tumor extent, which has been reportedly associated with pretreatment thrombocytosis(6, 20). MHA and nonmalignant inflammatory condition are clinically well known to induce thrombocytosis. We subsequently conducted univariate and multivariate analyses for associations with thrombocytosis in patients who relapsed after adjuvant chemotherapy, excluding the 2 factors of CA125 level and primary treatment, which are considered to be closely related to FIGO stage. We found that MHA and TFI were significantly and independently associated with thrombocytosis (Table 3). Accordingly, thrombocytosis is suggested to possibly contribute to chemoresistance, as TFI is known to be an important surrogate marker for the chemosensitivity of ovarian cancer(21-23). Regarding MHA, iron deficiency anemia caused by intratumoral hemorrhage in ovarian cancer is likely to be involved.\u003c/p\u003e\n\u003cp\u003eOur survival analyses showed that patients with thrombocytosis had worse PFS and OS than those without thrombocytosis (Figures 1A, B). In addition, when the analysis was confined to stage III/IV patients, there was still a significant difference in PFS and OS (Figures 2A, B), whereas stage I/II patients showed no difference in survival according to the presence/absence of pretreatment thrombocytosis (Figures 2C, D). These findings indicate that thrombocytosis affects survival mainly in advanced diseases, consistent with our above finding that thrombocytosis was significantly and independently associated with TFI, an established predictor of chemosensitivity in the treatment of recurrence, as recurrence is prone to occur in advanced diseases. Furthermore, our multivariate analysis for prognostic factors demonstrated that thrombocytosis was significant for unfavorable PFS and OS independent of age, histology, and FIGO stage (Table 4). These findings indicate that pretreatment thrombocytosis may be an ideal predictive biomarker for treatment outcome and a reasonable therapeutic target in epithelial ovarian cancer.\u003c/p\u003e\n\u003cp\u003eTumor cells first increase and activate platelets via various cytokines, including interleukin-6 (IL-6)(16). Activated platelets in turn facilitate tumor growth and angiogenesis through growth factors and angiogenic factors, including VEGF and PDGF(16, 24). Activated platelets also promote metastasis through epithelial mesenchymal transition (EMT) and defense by platelet-tumor interactions against blood flow and the immune system, including NK cells, in circulation(16, 24). In addition, platelets contribute to chemoresistance through MAPK and PI3-kinase/Akt pathways and drug efflux proteins(24). Moreover, chemoresistance in ovarian cancer cells is suggested to involve the interaction between the surrounding immune system and cancer stem cells in the tumor microenvironment, where platelets play key roles(25, 26). Therefore, thrombocytosis can possibly affect patient prognosis via both tumor progression and chemoresistance. However, we found that thrombocytosis was significantly and independently associated with TFI but not with FIGO stage (Table 3) and that thrombocytosis was significantly associated with PFS independent of FIGO stage (Table 4). These findings suggest that the prognostic impact of thrombocytosis may be independent of tumor extent but rather attributed to chemoresistance. Indeed, platelets have been reported to be involved in chemoresistance in ovarian cancer by \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo \u003c/em\u003ebasic studies. Radziwon-Balicka et al. reported that platelets decreased paclitaxel-induced apoptosis in human ovarian adenocarcinoma cells in vitro(27). Bottsford-Miller et al. reported that the combined administration of platelet-depleting antibodies and docetaxel caused a 62% decrease in tumor weight compared to docetaxel treatment in orthotopic mouse models of human ovarian cancer(6). They further found that platelet transfusion blocked the effect of docetaxel on tumor growth, and aspirinization blocked the effect of transfusion. However, clinical evidence suggesting the link between thrombocytosis and chemoresistance in ovarian cancer is very limited, as most studies only correlate thrombocytosis with survival after chemotherapy. Bottsford-Miller et al. reported changes in platelet counts during first-line chemotherapy in responsive and refractory groups matched for stage, histology, grade, and primary therapy(28). In patients with a durable response, only 50% had pretreatment thrombocytosis, and all of them achieved a normal platelet count during therapy, whereas all had pretreatment thrombocytosis, and only 50% achieved a normal count during therapy in patients with refractory disease. However, the possibility that platelet count only reflects the real-time residual tumor amount cannot be excluded. Feng et al. reported that preoperative thrombocytosis was significantly associated with chemoresistance determined based on the interval between disease progression and adjuvant chemotherapy in high-grade serous ovarian cancer(20). However, thrombocytosis was not significant after stratification based on residual tumors after surgery. In our study, pretreatment thrombocytosis was not associated with operation achievement and was significantly associated with TFI independent of FIGO stage (Table 3). Moreover, pretreatment thrombocytosis was a significant prognostic factor for poor PFS and OS independent of FIGO stage and operation achievement (Table 4). These observations strongly support the involvement of thrombocytosis in chemoresistance, implicating that molecular therapy targeting thrombocytosis may improve prognosis by attenuating chemoresistance. Based on the current findings, we assume that the combination of chemotherapeutics and antiplatelet therapies may be efficacious for ovarian cancer patients with thrombocytosis. Notably, patients with MHA or nonmalignant inflammatory conditions may have to be excluded from the treatment subjects, as the pathways for thrombocytosis in these patients must be different from those for paraneoplastic thrombocytosis.\u003c/p\u003e\n\u003cp\u003eStone et al. proposed that increased hepatic thrombopoietin synthesis in response to tumor-derived IL-6 was a mechanism for paraneoplastic thrombocytosis(29). They further reported that treatment with siltuximab, an anti-IL-6 antibody, significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. Regarding clinical trials, a phase II study in patients with platinum-resistant ovarian cancer reported that siltuximab treatment showed a partial response in one patient and disease stabilization in 7 of 18 of the evaluated patients(30). Regarding the combination with chemotherapeutics, a phase I trial in patients with recurrent epithelial ovarian cancer reported that the combination of carboplatin/doxorubicin and tocilizumab, an anti-IL-6 receptor antibody, and interferon-\u0026alpha;2b showed complete response in 3, partial response in 8, and stable disease in 6 of the 21 evaluated patients, and they showed that the toxicity was tolerable(31). Additional clinical trials and the examination of clinical samples are warranted to evaluate the usefulness and to investigate the underlying mechanism of anti-IL-6 therapies in ovarian cancer.\u003c/p\u003e\n\u003cp\u003eOur study has the following limitations. First, the sample size of the subset analyses was relatively small. Second, the strengthening of our hypothesis by basic study data was lacking. Third, the retrospective study design potentially caused selection biases. Prospective studies are required to verify our findings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe reported here on the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer. Univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA. Thrombocytosis was correlated with poor OS and PFS in advanced stages but showed no difference in early stages of disease. The multivariate analysis for prognostic factors demonstrated that thrombocytosis was significant for OS and PFS independent of stage, histology, primary treatment, operation achievement, nonmalignant inflammatory condition, and MHA. The current findings implicate that the unfavorable prognostic impact of thrombocytosis may be ascribed to chemoresistance, further supporting the therapeutic potential of targeting thrombopoietic cytokines in epithelial ovarian cancer.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eFIGO: International Federation of Gynecology and Obstetrics\u003c/p\u003e\n\u003cp\u003eIDS: Interval debulking surgery\u003c/p\u003e\n\u003cp\u003eMHA: Microcytic hypochromic anemia\u003c/p\u003e\n\u003cp\u003eNAC: Neoadjuvant chemotherapy\u003c/p\u003e\n\u003cp\u003eOS: Overall survival\u003c/p\u003e\n\u003cp\u003ePDS: Primary debulking surgery\u003c/p\u003e\n\u003cp\u003ePFS: Progression-free survival\u003c/p\u003e\n\u003cp\u003eTC: Paclitaxel and carboplatin\u003c/p\u003e\n\u003cp\u003eTFI: Treatment-free interval\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe present study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Committee University of Tsukuba Hospital (H27-143) with a waiver of informed consent.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions\u003c/p\u003e\n\u003cp\u003eSN and KM contributed to the conception and design; SN analyzed the data and drafted the manuscript; TM revised the manuscript; HI, YH, AS, NT, AA, HO, KM and TS critically reviewed the manuscript; SN, TM, HI, YH, AS, NT, AA, HO, KM and TS treated the patients; and TS supervised the study. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003cstrong\u003e\u003cbr /\u003e \u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHeintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Creasman WT, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95 Suppl 1:S161-92.\u003c/li\u003e\n\u003cli\u003eWinter WE, 3rd, Maxwell GL, Tian C, Sundborg MJ, Rose GS, Rose PG, et al. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2008;26(1):83-9.\u003c/li\u003e\n\u003cli\u003eWinter WE, 3rd, Maxwell GL, Tian C, Carlson JW, Ozols RF, Rose PG, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25(24):3621-7.\u003c/li\u003e\n\u003cli\u003eEisenhauer EL, Abu-Rustum NR, Sonoda Y, Aghajanian C, Barakat RR, Chi DS. The effect of maximal surgical cytoreduction on sensitivity to platinum-taxane chemotherapy and subsequent survival in patients with advanced ovarian cancer. Gynecol Oncol. 2008;108(2):276-81.\u003c/li\u003e\n\u003cli\u003eChi DS, Eisenhauer EL, Lang J, Huh J, Haddad L, Abu-Rustum NR, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol. 2006;103(2):559-64.\u003c/li\u003e\n\u003cli\u003eAllensworth SK, Langstraat CL, Martin JR, Lemens MA, McGree ME, Weaver AL, et al. Evaluating the prognostic significance of preoperative thrombocytosis in epithelial ovarian cancer. Gynecol Oncol. 2013;130(3):499-504.\u003c/li\u003e\n\u003cli\u003eCohen JG, Tran AQ, Rimel BJ, Cass I, Walsh CS, Karlan BY, et al. Thrombocytosis at secondary cytoreduction for recurrent ovarian cancer predicts suboptimal resection and poor survival. Gynecol Oncol. 2014;132(3):556-9.\u003c/li\u003e\n\u003cli\u003eMenczer J. Preoperative elevated platelet count and thrombocytosis in gynecologic malignancies. Arch Gynecol Obstet. 2017;295(1):9-15.\u003c/li\u003e\n\u003cli\u003eDigklia A, Voutsadakis IA. Thrombocytosis as a prognostic marker in stage III and IV serous ovarian cancer. Obstet Gynecol Sci. 2014;57(6):457-63.\u003c/li\u003e\n\u003cli\u003eChen Y, Zhang L, Liu W-X, Liu X-Y. Prognostic significance of preoperative anemia, leukocytosis and thrombocytosis in chinese women with epithelial ovarian cancer. Asian Pac J Cancer Prev. 2015;16(3):933-9.\u003c/li\u003e\n\u003cli\u003eCozzi GD, Samuel JM, Fromal JT, Keene S, Crispens MA, Khabele D, et al. Thresholds and timing of pre-operative thrombocytosis and ovarian cancer survival: analysis of laboratory measures from electronic medical records. BMC Cancer. 2016;16:612.\u003c/li\u003e\n\u003cli\u003eGungor T, Kanat-Pektas M, Sucak A, Mollamahmutoglu L. The role of thrombocytosis in prognostic evaluation of epithelial ovarian tumors. Archives of gynecology and obstetrics. 2009;279(1):53-6.\u003c/li\u003e\n\u003cli\u003eLee M, Kim SW, Nam EJ, Yim GW, Kim S, Kim YT. The impact of pretreatment thrombocytosis and persistent thrombocytosis after adjuvant chemotherapy in patients with advanced epithelial ovarian cancer. Gynecologic oncology. 2011;122(2):238-41.\u003c/li\u003e\n\u003cli\u003eLi AJ, Madden AC, Cass I, Leuchter RS, Lagasse LD, Karlan BY. The prognostic significance of thrombocytosis in epithelial ovarian carcinoma. Gynecologic oncology. 2004;92(1):211-4.\u003c/li\u003e\n\u003cli\u003eQiu J, Yu Y, Fu Y, Ye F, Xie X, Lu W. Preoperative plasma fibrinogen, platelet count and prognosis in epithelial ovarian cancer. Journal of Obstetrics and Gynaecology Research. 2012;38(4):651-7.\u003c/li\u003e\n\u003cli\u003eBuergy D, Wenz F, Groden C, Brockmann MA. Tumor-platelet interaction in solid tumors. Int J Cancer. 2012;130(12):2747-60.\u003c/li\u003e\n\u003cli\u003eDijkgraaf E, Santegoets S, Reyners A, Goedemans R, Wouters M, Kenter G, et al. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-\u0026alpha;2b in patients with recurrent epithelial ovarian cancer. Annals of Oncology. 2015;26(10):2141-9.\u003c/li\u003e\n\u003cli\u003eAngevin E, Tabernero J, Elez E, Cohen SJ, Bahleda R, Van Laethem J-L, et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clinical Cancer Research. 2014;20(8):2192-204.\u003c/li\u003e\n\u003cli\u003eSatoh T, Oki A, Uno K, Sakurai M, Ochi H, Okada S, et al. High incidence of silent venous thromboembolism before treatment in ovarian cancer. Br J Cancer. 2007;97(8):1053-7.\u003c/li\u003e\n\u003cli\u003eFeng Z, Wen H, Bi R, Duan Y, Yang W, Wu X. Thrombocytosis and hyperfibrinogenemia are predictive factors of clinical outcomes in high-grade serous ovarian cancer patients. BMC Cancer. 2016;16:43.\u003c/li\u003e\n\u003cli\u003eColombo N, Gore M. Treatment of recurrent ovarian cancer relapsing 6\u0026ndash;12 months post platinum-based chemotherapy. Critical reviews in oncology/hematology. 2007;64(2):129-38.\u003c/li\u003e\n\u003cli\u003eMarkman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol. 1991;9(3):389-93.\u003c/li\u003e\n\u003cli\u003eHarries M, Gore M. Part II: Chemotherapy for epithelial ovarian cancer-treatment of rcurrent disease. The lancet oncology. 2002;3(9):537-45.\u003c/li\u003e\n\u003cli\u003eHuong PT, Nguyen LT, Nguyen XB, Lee SK, Bach DH. The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells. Cancers (Basel). 2019;11(2).\u003c/li\u003e\n\u003cli\u003eLagana AS, Sofo V, Vitale SG, Triolo O. Epithelial ovarian cancer inherent resistance: May the pleiotropic interaction between reduced immunosurveillance and drug-resistant cells play a key role? Gynecol Oncol Rep. 2016;18:57-8.\u003c/li\u003e\n\u003cli\u003eChiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC, et al. FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells. Oncotarget. 2015;6(4):2349-65.\u003c/li\u003e\n\u003cli\u003eRadziwon-Balicka A, Medina C, O'Driscoll L, Treumann A, Bazou D, Inkielewicz-Stepniak I, et al. Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs: mechanisms and implications for chemoresistance. Br J Pharmacol. 2012;167(4):787-804.\u003c/li\u003e\n\u003cli\u003eBottsford-Miller J, Choi HJ, Dalton HJ, Stone RL, Cho MS, Haemmerle M, et al. Differential platelet levels affect response to taxane-based therapy in ovarian cancer. Clin Cancer Res. 2015;21(3):602-10.\u003c/li\u003e\n\u003cli\u003eStone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, et al. Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med. 2012;366(7):610-8.\u003c/li\u003e\n\u003cli\u003eCoward J, Kulbe H, Chakravarty P, Leader D, Vassileva V, Leinster DA, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 2011;17(18):6083-96.\u003c/li\u003e\n\u003cli\u003eDijkgraaf EM, Santegoets SJ, Reyners AK, Goedemans R, Wouters MC, Kenter GG, et al. A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-alpha2b in patients with recurrent epithelial ovarian cancer. Ann Oncol. 2015;26(10):2141-9.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations the Tables are available as a download in the Supplemental Files.\u003c/p\u003e\n\u003cp\u003eTable 1. Patient characteristics.\u003c/p\u003e\n\u003cp\u003eTable 2. Relationships between pretreatment thrombocytosis and clinicopathologic parameters.\u003c/p\u003e\n\u003cp\u003eTable 3. Univariate and multivariate analyses of risk factors for pretreatment thrombocytosis.\u003c/p\u003e\n\u003cp\u003eTable 4. Univariate and multivariate analyses of prognostic factors for PFS and OS.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"thrombocytosis, ovarian cancer, survival","lastPublishedDoi":"10.21203/rs.2.24476/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.24476/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground Thrombocytosis is related to tumor stage and survival in ovarian cancer in addition to the common complications of malignant diseases, such as anemia and inflammation. The aim of our study was to clarify the precise prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer. \u003c/p\u003e\u003cp\u003eMethods We retrospectively analyzed 280 consecutive patients who were treated for epithelial ovarian cancer at our institution between 2001 and 2011. \u003c/p\u003e\u003cp\u003eResults Pretreatment thrombocytosis was observed in 18.9% of all patients and was associated with advanced FIGO stage, primary treatment, operation achievement, histologic subtype, microcytic hypochromic anemia (MHA), and nonmalignant inflammatory condition ( P =0.0018, 0.0028, 0.00050, 0.034, 0.00090 and 0.0022). In the patients who relapsed after primary adjuvant chemotherapy (n=126), thrombocytosis was associated with a shorter treatment-free interval (TFI) ( P =0.0091). The univariate and multivariate analyses revealed that thrombocytosis was independently associated with TFI and MHA ( P =0.021 and 0.0091). Patients with thrombocytosis had worse progression-free survival (PFS) and overall survival (OS) than those without thrombocytosis ( P \u0026lt;0.0001 and \u0026lt;0.0001). The multivariate analyses for prognostic factors demonstrated that thrombocytosis was significant for poor PFS and OS ( P =0.0050 and 0.022) independent of stage, histology, primary treatment, operation achievement, nonmalignant inflammatory condition and MHA. \u003c/p\u003e\u003cp\u003eConclusions The current findings indicate that the detrimental survival impact of pretreatment thrombocytosis in epithelial ovarian cancer may be independent of tumor extent but rather attributed to chemoresistance, further supporting the therapeutic potential of targeting thrombopoietic cytokines in the disease.\u003c/p\u003e","manuscriptTitle":"Pretreatment Thrombocytosis as an Independent Predictive Factor for Chemoresistance and Poor Survival in Epithelial Ovarian Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-04-17 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