Prognostic Value of Chemotherapy Response Score in Advanced Ovarian Cancer: A Single-Center Analysis

Prognostic Value of Chemotherapy Response Score in Advanced Ovarian Cancer: A Single-Center Analysis | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic Value of Chemotherapy Response Score in Advanced Ovarian Cancer: A Single-Center Analysis Hamdullah Sozen, Yagmur Minareci, Atahan Toyran, İbrahim Yalçın, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5425478/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Chemotherapy response score (CRS) is a histopathological tool to assess tumor response in patients with high-grade serous ovarian carcinoma (HGSC) undergoing neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). This study aimed to evaluate the prognostic significance of omental and adnexal CRS for predicting overall survival (OS) and disease-free survival (DFS). Methods Data from 79 patients with advanced HGSC treated with NACT followed by interval debulking surgery (IDS) between 2010 and 2017 were analyzed. CRS was applied to both omental and adnexal samples, and its association with OS and DFS was evaluated. Statistical analyses were performed using univariate and multivariate methods, with a significance level of p < 0.05. Results Omental CRS 1–2 was identified as an independent predictor of decreased OS (HR 2.69; 95% CI 1.26–5.76, p = 0.010), whereas adnexal CRS 1–2 did not significantly impact DFS or OS in multivariate analysis. Patients with omental CRS 3 had superior outcomes, with a 5-year OS rate of 72.0% compared to 30.8% in the CRS 1–2 group. The median DFS for the CRS 1–2 group was 19 months, while it was 35 months for the CRS 3 group (p = 0.005). Conclusion Omental CRS is a strong independent predictor of OS in advanced HGSC, while adnexal CRS demonstrated limited prognostic value. CRS should be considered in clinical practice for guiding treatment decisions, and further research is warranted to refine its use with molecular and radiologic markers. Chemotherapy Response Score High-Grade Serous Ovarian Carcinoma Overall Survival Disease-Free Survival Figures Figure 1 Figure 2 Figure 3 Introduction Ovarian cancer, though not the most common, is the deadliest gynecological malignancy. The World Health Organization reports that annually, approximately 225,500 new cases are diagnosed, and 140,200 deaths occur, making it the seventh most prevalent and the eighth leading cause of cancer-related deaths among women globally [ 1 , 2 ]. Approximately 80% of cases are diagnosed at advanced stage with high-grade serous carcinoma (HGSC) being the most common histological type [ 3 , 4 ]. Surgery, often combined with chemotherapy either as neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) or as primary debulking surgery (PDS) followed by adjuvant chemotherapy remains the cornerstone of treatment for advanced stage ovarian cancer. The use of NACT and IDS has increased in recent years due to favourable results from two randomized phase III trials, which showed similar progression-free survival (PFS) and overall survival (OS) with lower surgical morbidity and mortality compared to PDS [ 5 , 6 ]. Another advantage of NACT followed by IDS is that it can provide an opportunity for future prognostic risk assessment through histopathologic evaluation of tumor response to chemotherapy. Böhm et al. developed chemotherapy response score (CRS), a simple and reproducible scoring system based on post-therapy evaluation of the tumoral architecture and microenvironment in the omental site. In their study, Böhm et al. demonstrated that the CRS showed a significant correlation with PFS, while the results for OS were mixed [ 7 ]. Böhm et al. proposed a simplified three-tier system: CRS 1: minimal tumor response; CRS 2: moderate tumor response with easily identifiable residual neoplastic foci; CRS 3: complete or near-complete response, with no residual neoplastic cells or minimal irregularly scattered tumor cells up to 2 mm in maximum size. This three-tier scoring system demonstrated a significant prognostic difference between CRS 1–2 and CRS 3 groups and improved interobserver reproducibility. Consequently, the three-tiered CRS has been incorporated into the International Collaboration on Cancer Reporting (ICCR) and the College of American Pathologists (CAP) guidelines for the histopathologic reporting of ovarian carcinoma [ 7 , 8 ]. Currently, the ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer state that CRS performed at IDS on an omental (preferred) or adnexal specimen provides valuable prognostic information and is recommended [ 9 ]. The aim of this study was to validate the prognostic role of the CRS system in a cohort of patients from a clinic that primarily performs PDS followed by adjuvant chemotherapy and reserves NACT IDS decisions for a very limited group of patients. Materials and Methods Study Population and Acquisition of Data Approval for this study was obtained from the İstanbul University, İstanbul School of Medicine Institutional Review Board. All patients provided informed consent regarding research use of their medical information at admission. All operations were performed by gynecologic oncologists. Women with a postoperative histopathological diagnosis of advanced HGSC who had been treated between January 1, 2010, and December 31, 2017 were reviewed. Selection of patients for NACT at our center is based on both tumor burden and preoperative assessment of the surgical ability to achieve optimal debulking, as well as on patients’ characteristics, such as comorbid conditions and age, that might limit extensive surgery. Surgical pathology reports and/or clinical records were reviewed for each case to identify patients who received neoadjuvant platinum based chemotherapy with carboplatin and taxol. Of this cohort, 141 women had received NACT prior to interval cytoreductive surgery. Since the use of the CRS has been validated and recommended only for HGSC, all other epithelial ovarian cancer histotypes were initially excluded from the present study. We excluded patients who had synchronous malignancies, those with incomplete clinicopathologic records, and those who did not have optimal cytoreductive surgery. Women with platinum-refractory disease were also excluded. The study sequence is summarized in Fig. 1. The ICCR issued guidelines on reporting of serous ovarian cancer and advised towards inclusion of a 3-point scoring system described by Steffen Böhm as standard for assessment of tumor regression following NACT [ 7 ]. All available hematoxylin and eosin stained slides from the surgical specimens that were diagnosed as HGSC in the Pathology Department of Istanbul Faculty of Medicine were re-evaluated by three pathologists including an expert gynecologic pathologist. Each slides representing omentum and adnexa were scored by the pathologists independently according to the three-tier system. The summary of the scoring system proposed by Böhm et al. is as follows: Score 1: No or minimal tumor response (mainly viable tumor with no or minimal regression-associated fibroinflammatory changes, limited to a few foci); Score 2: Partial tumor response (both tumor groups and regression-associated fibroinflammatory changes are easily identifiable); Score 3: Complete or near-complete response (mainly regression, with few irregularly scattered individual tumor cells or cell groups, all measuring < 2 mm, or no residual tumor identified) [ 7 ]. The cases that did not receive the same score from all three pathologists were evaluated together, and a consensus was established for outcome analysis. Patients’ data including age, disease stage, histology, CA125 levels at diagnosis and at completion of NACT, and residual tumor after IDS were collected from computerized medical records. The level of CA-125 reduction attributable to NACT was defined as the difference between the highest pretreatment and the presurgical CA-125 measurements. The survival status of the patients was determined as alive or dead at the time of the last follow-up. For all study subjects with a recorded death, this was confirmed by performing a social security death index search. After initial diagnosis, recurrence was defined as documentation of metastasis with serum CA125 measurement and imaging techniques after a DFS ≥ 3 months. Disease-free survival (DFS) was defined as the time from surgery to the first identification of recurrence by radiologic imaging and serum CA125 measurement, or death from any cause, whichever occurred first, or the date of last contact for patients remaining alive without recurrent disease. OS was calculated as the time period between initial diagnosis of HGSC to the date of death or the last contact. Surviving patients were censored at their last known follow-up. Survival analysis was based on the Kaplan–Meier method, and the results were compared using a log-rank test. The chi-squared test and Student’s t-test for unpaired data were used for statistical analysis. Cox regression analysis was used to determine factors affecting survival, presented as hazard ratios (HRs) and 95% confidence interval (CI), unadjusted or adjusted for all factors. All variables with a p value < 0.05 in univariate analysis were included in the multivariate analysis. All statistical analyses were performed with SPSS software version 23.0 (SPSS, Inc., Chicago, IL, USA). A p value < 0.05 was considered to indicate statistical significance. Results A total of 62 patients were excluded for the following reasons: non-HGSC histology, platinum-refractory disease, synchronous colon cancer, and incomplete medical records. Table 1 compares the baseline characteristics of the 79 patients in the study. 23 ovarian CRS 3 cases were compared to 56 ovarian CRS 1–2 cases. Age, Menopausal status, pre NACT Ca-125 levels, post NACT Ca-125 levels, percent of Ca-125 drop, stage, presence of ascites at surgery, NACT cycles and recurrence rates were similar between the groups. The time to chemotherapy after IDS (47 days vs. 30 days, respectively) and median follow-up (72 months vs. 48.50 months, respectively) was statistically longer in ovarian CRS 3 cases when compared to ovarian CRS 1–2 cases. Patients with ovarian CRS 3 were more likely to have high omentum CRS than ovarian CRS 1–2 patiens (69.6% vs %30.4, respectively). For the entire cohort, univariate analysis revealed adnexa CRS 1–2 (p = 0.016) and Omentum CRS 1–2 (p = 0.007) as significant factors for decreased DFS (Table 2). At the end of multivariate analysis, none of them was determined as independent risk factors for decreased DFS (Table 2). For the entire cohort, univariate analysis revealed the presence of ascites (p = 0.002), adnexa CRS 1–2 (p = 0.011) and omentum CRS 1–2 (p < 0.001) as significant factors for decreased OS. At the end of multivariate analysis, only omentum CRS 1–2 (HR 2.69; 95% CI 1.26–5.76, p = 0.010) was identified as independent predictor of decreased OS as shown in Table 3. Because only omentum CRS was identified as independent predictor of decreased OS, log rank analysis was performed to asses impact of omentum CRS on survival. The median DFS for women with omentum CRS 1–2 was 19 months (95% CI 14.8–23.1, SE 2.11) compared to 35 months (95% CI 13.1–56.8, SE 11.14) in the omentum CRS 3 group (p = 0.005) (Fig. 2 ). The 5-year DFS rates was superior in omentum CRS 3 group (38.5% in omentum CRS 3 group vs 14.9% in omentum CRS 1–2 group. The median OS of the omentum CRS 1–2 group was 46 months (95% CI 38.8–53.1 SE 3.67), while the median OS of the omentum CRS 3 group has not been reached yet (p < 0.001) (Fig. 3 ). When the 5-year OS rates were examined; superior outcomes were observed in omentum CRS 3 cases than omentum CRS 1–2 cases (72.0% vs 30.8%, respectively). At the time of reporting, of 33 women with omentum CRS 3 group, 12 (25.5%) were dead whereas 21 (65.6%) were alive. The corresponding figures were found to be 35 (74.5%) and 11 (34.4%), respectively, in the omentum CRS 1–2 group. Discussion In this study, we investigated the prognostic significance of the CRS in patients with advanced-stage HGSC, with a particular focus on the differences in outcomes based on ovarian and omental CRS. Our results demonstrated that omental CRS 1–2 was a significant independent predictor for decreased OS, while neither adnexal CRS 1–2 nor omental CRS 1–2 were independent predictors for decreased DFS in the multivariate analysis. These findings reinforce the importance of omental CRS as a critical site for assessing chemotherapy response in HGSC. The CRS system, initially developed and validated by Böhm et al., has been accepted as a reliable and reproducible marker for evaluating histopathologic response to NACT [ 7 ]. Although the importance of the CRS score is emphasized in the ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer, the relationship between the CRS score and PFS and OS outcomes is inconsistent in studies in the literature (Table 4 ) [ 7 , 9 – 18 ]. Our findings align with previous studies that established the prognostic value of CRS, particularly in the omentum, where higher CRS 3 is associated with significantly improved OS compared to CRS 1–2​ [ 14 – 16 , 19 ]. In line with the work of Santoro et al., we found that omental CRS 3 patients had superior survival outcomes, with a 5-year OS rate of 72.0%, compared to 30.8% in omental CRS 1–2 patients​ [ 14 ]. One of the notable findings in our study is the absence of prognostic significance for adnexal CRS 1–2 in the multivariate analysis for DFS, which contrasts with some reports suggesting the relevance of adnexal CRS in predicting survival outcomes [ 13 , 14 , 17 , 20 ]. This discrepancy may stem from the inherent challenges in scoring adnexal disease, as previously noted in the literature. The adnexal site is often less reproducible, and adnexal CRS has shown variable prognostic significance across studies [ 21 ]. Further research is needed to standardize the assessment of CRS in adnexal tissue and to determine its potential utility in guiding clinical decision-making​ [ 19 ]. Our study further underscores the critical role of omental CRS in predicting long-term survival. As demonstrated in the meta-analysis by Cohen et al., omental CRS 3 remains a strong independent predictor of both PFS and OS​ [ 19 ]. In our cohort, the median OS for the omentum CRS 1–2 group was 46 months (95% CI 38.8–53.1, SE 3.67), indicating a shorter survival compared to the omentum CRS 3 group, for which the median OS has not yet been reached. These results suggest that the extent of chemotherapy response in the omentum can serve as a valuable surrogate for predicting treatment response and overall prognosis. Despite the strengths of our study, including a well-characterized cohort and comprehensive follow-up data, there are limitations that must be acknowledged. The relatively small sample size may limit the generalizability of our findings. Moreover, the exclusion of patients with platinum-refractory disease may introduce selection bias, potentially underestimating the true prognostic significance of CRS. Conclusion Our study highlights the prognostic value of omental CRS in advanced epithelial ovarian cancer, particularly for predicting OS. The use of CRS, especially in omental tissue, should be further explored as a clinical tool to guide therapeutic decision-making and follow-up strategies. Future research should focus on refining the CRS system and integrating it with molecular and radiologic markers to enhance its prognostic utility. Declarations Informed consent was obtained from all patients involved in this study. Patient anonymity has been rigorously maintained. Conflict of Interest The authors declare that they have no conflict of interest. Author Contribution H.S. and Y.M made substantial contributions to the conception and design of the work.H.S. and A.T. and İ.Y. wrote the main manuscript text.S.Ö. and A.B. and S.B. performed the re-evaluation of the pathology specimens.M.A.T made substantial contributions to the acquisition of data.İ.Y. and S.T. made substantial contributions to the analysis and interpretation of data.P.M.S and Y.S. ensured the revision of the article and addressed its deficiencies.All authors reviewed the manuscript. Acknowledgement There is not a non-author contributor for this article. The authors certify that this work is original and has not been published elsewhere and is not currently being considered for publication elsewhere. No funding was received for this study. Data Availability The dataset can be provided upon request. References Jemal A et al (2011) Global cancer statistics. 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Diagnostics (Basel) 12(3). https://doi.org/10.3390/diagnostics12030633 Rodolakis I et al (2023) Chemotherapy Response Score in Ovarian Cancer Patients: An Overview of Its Clinical Utility. J Clin Med 12(6). https://doi.org/10.3390/jcm12062155 Tables Table 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files tables123.docx table4summarytable.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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 In Review Editorial Policies 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-5425478","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":376432262,"identity":"77a1085b-0d81-4811-ab34-9b05482e2b74","order_by":0,"name":"Hamdullah Sozen","email":"","orcid":"","institution":"Istanbul University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hamdullah","middleName":"","lastName":"Sozen","suffix":""},{"id":376432263,"identity":"e52ce963-cd8a-47d0-bf62-b501692fa43c","order_by":1,"name":"Yagmur Minareci","email":"","orcid":"","institution":"Istanbul 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10:38:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5425478/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5425478/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71513368,"identity":"a2e1326f-dd3a-42c7-ac6a-813f09024f5d","added_by":"auto","created_at":"2024-12-16 10:46:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":214004,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study\u003c/p\u003e","description":"","filename":"Onlinefloatimage116.png","url":"https://assets-eu.researchsquare.com/files/rs-5425478/v1/ee1db4fdbb449154c290d7ba.png"},{"id":71513367,"identity":"04ea2dae-3a5e-4a9c-b114-72f14c49027b","added_by":"auto","created_at":"2024-12-16 10:46:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45046,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Curve Showing Disease-Free Survival Based on Omentum CRS (1-2 vs. 3)\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5425478/v1/02174603941f23abdd1b0e49.png"},{"id":71513369,"identity":"338ae583-a1c1-4bd9-be2e-6f5a7229db45","added_by":"auto","created_at":"2024-12-16 10:46:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43662,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier Curve Showing Overall Survival Based on Omentum CRS (1-2 vs. 3)\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5425478/v1/bc79c267f9d8da9a0fee9935.png"},{"id":71517388,"identity":"9166cb41-1ce9-48fc-8ab9-b496148cfb2d","added_by":"auto","created_at":"2024-12-16 11:10:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":579942,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5425478/v1/dcaac6c0-74a1-4c14-93de-34498054739a.pdf"},{"id":71514633,"identity":"8bfc71c9-0a75-48b2-a2fb-60be54443501","added_by":"auto","created_at":"2024-12-16 10:54:02","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":23609,"visible":true,"origin":"","legend":"","description":"","filename":"tables123.docx","url":"https://assets-eu.researchsquare.com/files/rs-5425478/v1/ab440fa75031b8caaed3749b.docx"},{"id":71513366,"identity":"ee923879-6039-4d3b-aae8-f230e53dcdee","added_by":"auto","created_at":"2024-12-16 10:46:02","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25200,"visible":true,"origin":"","legend":"","description":"","filename":"table4summarytable.docx","url":"https://assets-eu.researchsquare.com/files/rs-5425478/v1/a759b2fafb8b1c1c73972123.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic Value of Chemotherapy Response Score in Advanced Ovarian Cancer: A Single-Center Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOvarian cancer, though not the most common, is the deadliest gynecological malignancy. The World Health Organization reports that annually, approximately 225,500 new cases are diagnosed, and 140,200 deaths occur, making it the seventh most prevalent and the eighth leading cause of cancer-related deaths among women globally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Approximately 80% of cases are diagnosed at advanced stage with high-grade serous carcinoma (HGSC) being the most common histological type [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSurgery, often combined with chemotherapy either as neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) or as primary debulking surgery (PDS) followed by adjuvant chemotherapy remains the cornerstone of treatment for advanced stage ovarian cancer. The use of NACT and IDS has increased in recent years due to favourable results from two randomized phase III trials, which showed similar progression-free survival (PFS) and overall survival (OS) with lower surgical morbidity and mortality compared to PDS [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother advantage of NACT followed by IDS is that it can provide an opportunity for future prognostic risk assessment through histopathologic evaluation of tumor response to chemotherapy. B\u0026ouml;hm et al. developed chemotherapy response score (CRS), a simple and reproducible scoring system based on post-therapy evaluation of the tumoral architecture and microenvironment in the omental site. In their study, B\u0026ouml;hm et al. demonstrated that the CRS showed a significant correlation with PFS, while the results for OS were mixed [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eB\u0026ouml;hm et al. proposed a simplified three-tier system: CRS 1: minimal tumor response; CRS 2: moderate tumor response with easily identifiable residual neoplastic foci; CRS 3: complete or near-complete response, with no residual neoplastic cells or minimal irregularly scattered tumor cells up to 2 mm in maximum size. This three-tier scoring system demonstrated a significant prognostic difference between CRS 1\u0026ndash;2 and CRS 3 groups and improved interobserver reproducibility. Consequently, the three-tiered CRS has been incorporated into the International Collaboration on Cancer Reporting (ICCR) and the College of American Pathologists (CAP) guidelines for the histopathologic reporting of ovarian carcinoma [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Currently, the ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer state that CRS performed at IDS on an omental (preferred) or adnexal specimen provides valuable prognostic information and is recommended [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The aim of this study was to validate the prognostic role of the CRS system in a cohort of patients from a clinic that primarily performs PDS followed by adjuvant chemotherapy and reserves NACT IDS decisions for a very limited group of patients.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e Study Population and Acquisition of Data Approval for this study was obtained from the İstanbul University, İstanbul School of Medicine Institutional Review Board. All patients provided informed consent regarding research use of their medical information at admission. All operations were performed by gynecologic oncologists.\u003c/p\u003e \u003cp\u003eWomen with a postoperative histopathological diagnosis of advanced HGSC who had been treated between January 1, 2010, and December 31, 2017 were reviewed. Selection of patients for NACT at our center is based on both tumor burden and preoperative assessment of the surgical ability to achieve optimal debulking, as well as on patients\u0026rsquo; characteristics, such as comorbid conditions and age, that might limit extensive surgery. Surgical pathology reports and/or clinical records were reviewed for each case to identify patients who received neoadjuvant platinum based chemotherapy with carboplatin and taxol. Of this cohort, 141 women had received NACT prior to interval cytoreductive surgery. Since the use of the CRS has been validated and recommended only for HGSC, all other epithelial ovarian cancer histotypes were initially excluded from the present study. We excluded patients who had synchronous malignancies, those with incomplete clinicopathologic records, and those who did not have optimal cytoreductive surgery. Women with platinum-refractory disease were also excluded. The study sequence is summarized in Fig.\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eThe ICCR issued guidelines on reporting of serous ovarian cancer and advised towards inclusion of a 3-point scoring system described by Steffen B\u0026ouml;hm as standard for assessment of tumor regression following NACT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll available hematoxylin and eosin stained slides from the surgical specimens that were diagnosed as HGSC in the Pathology Department of Istanbul Faculty of Medicine were re-evaluated by three pathologists including an expert gynecologic pathologist. Each slides representing omentum and adnexa were scored by the pathologists independently according to the three-tier system. The summary of the scoring system proposed by B\u0026ouml;hm et al. is as follows: Score 1: No or minimal tumor response (mainly viable tumor with no or minimal regression-associated fibroinflammatory changes, limited to a few foci); Score 2: Partial tumor response (both tumor groups and regression-associated fibroinflammatory changes are easily identifiable); Score 3: Complete or near-complete response (mainly regression, with few irregularly scattered individual tumor cells or cell groups, all measuring\u0026thinsp;\u0026lt;\u0026thinsp;2 mm, or no residual tumor identified) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The cases that did not receive the same score from all three pathologists were evaluated together, and a consensus was established for outcome analysis.\u003c/p\u003e \u003cp\u003ePatients\u0026rsquo; data including age, disease stage, histology, CA125 levels at diagnosis and at completion of NACT, and residual tumor after IDS were collected from computerized medical records. The level of CA-125 reduction attributable to NACT was defined as the difference between the highest pretreatment and the presurgical CA-125 measurements. The survival status of the patients was determined as alive or dead at the time of the last follow-up. For all study subjects with a recorded death, this was confirmed by performing a social security death index search. After initial diagnosis, recurrence was defined as documentation of metastasis with serum CA125 measurement and imaging techniques after a DFS\u0026thinsp;\u0026ge;\u0026thinsp;3 months. Disease-free survival (DFS) was defined as the time from surgery to the first identification of recurrence by radiologic imaging and serum CA125 measurement, or death from any cause, whichever occurred first, or the date of last contact for patients remaining alive without recurrent disease. OS was calculated as the time period between initial diagnosis of HGSC to the date of death or the last contact. Surviving patients were censored at their last known follow-up. Survival analysis was based on the Kaplan\u0026ndash;Meier method, and the results were compared using a log-rank test. The chi-squared test and Student\u0026rsquo;s t-test for unpaired data were used for statistical analysis. Cox regression analysis was used to determine factors affecting survival, presented as hazard ratios (HRs) and 95% confidence interval (CI), unadjusted or adjusted for all factors. All variables with a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in univariate analysis were included in the multivariate analysis. All statistical analyses were performed with SPSS software version 23.0 (SPSS, Inc., Chicago, IL, USA). A p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 62 patients were excluded for the following reasons: non-HGSC histology, platinum-refractory disease, synchronous colon cancer, and incomplete medical records. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e compares the baseline characteristics of the 79 patients in the study. 23 ovarian CRS 3 cases were compared to 56 ovarian CRS 1\u0026ndash;2 cases. Age, Menopausal status, pre NACT Ca-125 levels, post NACT Ca-125 levels, percent of Ca-125 drop, stage, presence of ascites at surgery, NACT cycles and recurrence rates were similar between the groups. The time to chemotherapy after IDS (47 days vs. 30 days, respectively) and median follow-up (72 months vs. 48.50 months, respectively) was statistically longer in ovarian CRS 3 cases when compared to ovarian CRS 1\u0026ndash;2 cases. Patients with ovarian CRS 3 were more likely to have high omentum CRS than ovarian CRS 1\u0026ndash;2 patiens (69.6% vs %30.4, respectively).\u003c/p\u003e \u003cp\u003eFor the entire cohort, univariate analysis revealed adnexa CRS 1\u0026ndash;2 (p\u0026thinsp;=\u0026thinsp;0.016) and Omentum CRS 1\u0026ndash;2 (p\u0026thinsp;=\u0026thinsp;0.007) as significant factors for decreased DFS (Table\u0026nbsp;2). At the end of multivariate analysis, none of them was determined as independent risk factors for decreased DFS (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eFor the entire cohort, univariate analysis revealed the presence of ascites (p\u0026thinsp;=\u0026thinsp;0.002), adnexa CRS 1\u0026ndash;2 (p\u0026thinsp;=\u0026thinsp;0.011) and omentum CRS 1\u0026ndash;2 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) as significant factors for decreased OS. At the end of multivariate analysis, only omentum CRS 1\u0026ndash;2 (HR 2.69; 95% CI 1.26\u0026ndash;5.76, p\u0026thinsp;=\u0026thinsp;0.010) was identified as independent predictor of decreased OS as shown in Table\u0026nbsp;3.\u003c/p\u003e \u003cp\u003eBecause only omentum CRS was identified as independent predictor of decreased OS, log rank analysis was performed to asses impact of omentum CRS on survival. The median DFS for women with omentum CRS 1\u0026ndash;2 was 19 months (95% CI 14.8\u0026ndash;23.1, SE 2.11) compared to 35 months (95% CI 13.1\u0026ndash;56.8, SE 11.14) in the omentum CRS 3 group (p\u0026thinsp;=\u0026thinsp;0.005) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The 5-year DFS rates was superior in omentum CRS 3 group (38.5% in omentum CRS 3 group vs 14.9% in omentum CRS 1\u0026ndash;2 group. The median OS of the omentum CRS 1\u0026ndash;2 group was 46 months (95% CI 38.8\u0026ndash;53.1 SE 3.67), while the median OS of the omentum CRS 3 group has not been reached yet (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e3\u003c/span\u003e). When the 5-year OS rates were examined; superior outcomes were observed in omentum CRS 3 cases than omentum CRS 1\u0026ndash;2 cases (72.0% vs 30.8%, respectively).\u003c/p\u003e \u003cp\u003eAt the time of reporting, of 33 women with omentum CRS 3 group, 12 (25.5%) were dead whereas 21 (65.6%) were alive. The corresponding figures were found to be 35 (74.5%) and 11 (34.4%), respectively, in the omentum CRS 1\u0026ndash;2 group.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we investigated the prognostic significance of the CRS in patients with advanced-stage HGSC, with a particular focus on the differences in outcomes based on ovarian and omental CRS. Our results demonstrated that omental CRS 1\u0026ndash;2 was a significant independent predictor for decreased OS, while neither adnexal CRS 1\u0026ndash;2 nor omental CRS 1\u0026ndash;2 were independent predictors for decreased DFS in the multivariate analysis. These findings reinforce the importance of omental CRS as a critical site for assessing chemotherapy response in HGSC.\u003c/p\u003e \u003cp\u003eThe CRS system, initially developed and validated by B\u0026ouml;hm et al., has been accepted as a reliable and reproducible marker for evaluating histopathologic response to NACT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although the importance of the CRS score is emphasized in the ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer, the relationship between the CRS score and PFS and OS outcomes is inconsistent in studies in the literature (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e4\u003c/span\u003e) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Our findings align with previous studies that established the prognostic value of CRS, particularly in the omentum, where higher CRS 3 is associated with significantly improved OS compared to CRS 1\u0026ndash;2​ [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In line with the work of Santoro et al., we found that omental CRS 3 patients had superior survival outcomes, with a 5-year OS rate of 72.0%, compared to 30.8% in omental CRS 1\u0026ndash;2 patients​ [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne of the notable findings in our study is the absence of prognostic significance for adnexal CRS 1\u0026ndash;2 in the multivariate analysis for DFS, which contrasts with some reports suggesting the relevance of adnexal CRS in predicting survival outcomes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This discrepancy may stem from the inherent challenges in scoring adnexal disease, as previously noted in the literature. The adnexal site is often less reproducible, and adnexal CRS has shown variable prognostic significance across studies [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Further research is needed to standardize the assessment of CRS in adnexal tissue and to determine its potential utility in guiding clinical decision-making​ [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study further underscores the critical role of omental CRS in predicting long-term survival. As demonstrated in the meta-analysis by Cohen et al., omental CRS 3 remains a strong independent predictor of both PFS and OS​ [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our cohort, the median OS for the omentum CRS 1\u0026ndash;2 group was 46 months (95% CI 38.8\u0026ndash;53.1, SE 3.67), indicating a shorter survival compared to the omentum CRS 3 group, for which the median OS has not yet been reached. These results suggest that the extent of chemotherapy response in the omentum can serve as a valuable surrogate for predicting treatment response and overall prognosis.\u003c/p\u003e \u003cp\u003eDespite the strengths of our study, including a well-characterized cohort and comprehensive follow-up data, there are limitations that must be acknowledged. The relatively small sample size may limit the generalizability of our findings. Moreover, the exclusion of patients with platinum-refractory disease may introduce selection bias, potentially underestimating the true prognostic significance of CRS.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study highlights the prognostic value of omental CRS in advanced epithelial ovarian cancer, particularly for predicting OS. The use of CRS, especially in omental tissue, should be further explored as a clinical tool to guide therapeutic decision-making and follow-up strategies. Future research should focus on refining the CRS system and integrating it with molecular and radiologic markers to enhance its prognostic utility.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eInformed consent was obtained from all patients involved in this study. Patient anonymity has been rigorously maintained.\u003c/p\u003e\u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eH.S. and Y.M made substantial contributions to the conception and design of the work.H.S. and A.T. and İ.Y. wrote the main manuscript text.S.\u0026Ouml;. and A.B. and S.B. performed the re-evaluation of the pathology specimens.M.A.T made substantial contributions to the acquisition of data.İ.Y. and S.T. made substantial contributions to the analysis and interpretation of data.P.M.S and Y.S. ensured the revision of the article and addressed its deficiencies.All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThere is not a non-author contributor for this article. The authors certify that this work is original and has not been published elsewhere and is not currently being considered for publication elsewhere. No funding was received for this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe dataset can be provided upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJemal A et al (2011) Global cancer statistics. CA Cancer J Clin 61(2):69\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3322/caac.20107\u003c/span\u003e\u003cspan address=\"10.3322/caac.20107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerlay J et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. 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Int J Gynecol Cancer 28(9):1676\u0026ndash;1682. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/IGC.0000000000001366\u003c/span\u003e\u003cspan address=\"10.1097/IGC.0000000000001366\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantoro A et al (2019) Pathological Chemotherapy Response Score in Patients Affected by High Grade Serous Ovarian Carcinoma: The Prognostic Role of Omental and Ovarian Residual Disease. 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Gynecol Oncol 154(2):441\u0026ndash;448. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ygyno.2019.04.679\u003c/span\u003e\u003cspan address=\"10.1016/j.ygyno.2019.04.679\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantoro A et al (2022) Prognostic Value of Chemotherapy Response Score (CRS) Assessed on the Adnexa in Ovarian High-Grade Serous Carcinoma: A Systematic Review and Meta-Analysis. Diagnostics (Basel) 12(3). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/diagnostics12030633\u003c/span\u003e\u003cspan address=\"10.3390/diagnostics12030633\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRodolakis I et al (2023) Chemotherapy Response Score in Ovarian Cancer Patients: An Overview of Its Clinical Utility. J Clin Med 12(6). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/jcm12062155\u003c/span\u003e\u003cspan address=\"10.3390/jcm12062155\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chemotherapy Response Score, High-Grade Serous Ovarian Carcinoma, Overall Survival, Disease-Free Survival","lastPublishedDoi":"10.21203/rs.3.rs-5425478/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5425478/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eChemotherapy response score (CRS) is a histopathological tool to assess tumor response in patients with high-grade serous ovarian carcinoma (HGSC) undergoing neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). This study aimed to evaluate the prognostic significance of omental and adnexal CRS for predicting overall survival (OS) and disease-free survival (DFS).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData from 79 patients with advanced HGSC treated with NACT followed by interval debulking surgery (IDS) between 2010 and 2017 were analyzed. CRS was applied to both omental and adnexal samples, and its association with OS and DFS was evaluated. Statistical analyses were performed using univariate and multivariate methods, with a significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOmental CRS 1\u0026ndash;2 was identified as an independent predictor of decreased OS (HR 2.69; 95% CI 1.26\u0026ndash;5.76, p\u0026thinsp;=\u0026thinsp;0.010), whereas adnexal CRS 1\u0026ndash;2 did not significantly impact DFS or OS in multivariate analysis. Patients with omental CRS 3 had superior outcomes, with a 5-year OS rate of 72.0% compared to 30.8% in the CRS 1\u0026ndash;2 group. The median DFS for the CRS 1\u0026ndash;2 group was 19 months, while it was 35 months for the CRS 3 group (p\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOmental CRS is a strong independent predictor of OS in advanced HGSC, while adnexal CRS demonstrated limited prognostic value. CRS should be considered in clinical practice for guiding treatment decisions, and further research is warranted to refine its use with molecular and radiologic markers.\u003c/p\u003e","manuscriptTitle":"Prognostic Value of Chemotherapy Response Score in Advanced Ovarian Cancer: A Single-Center Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 10:45:57","doi":"10.21203/rs.3.rs-5425478/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"68480b5c-328f-400b-9e66-8ba364abc05e","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-16T10:45:59+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-16 10:45:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5425478","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5425478","identity":"rs-5425478","version":["v1"]},"buildId":"pf3fE39SIOqb-0xH_OWvX","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}