A predictive score for optimal cytoreduction at interval debulking surgery in epithelial ovarian cancer: a two- centers experience

A predictive score for optimal cytoreduction at interval debulking surgery in epithelial ovarian... Background: Optimal cytoreduction (macroscopic Residual Tumor, RT = 0) is the best survival predictor factor in epithelial ovarian cancer (EOC). It doesn’t exist a consolidated criteria to predict optimal surgical resection at interval debulking surgery (IDS). The aim of this study is to develop a predictive model of complete cytoreduction at IDS. Methods: We, retrospectively, analyzed 93 out of 432 patients, with advanced EOC, underwent neoadjuvant chemotherapy (NACT) and IDS from January 2010 to December 2016 in two referral cancer centers. The correlation between clinical-pathological variables and residual disease at IDS has been investigated with univariate and multivariate analysis. A predictive score of cytoreduction (PSC) has been created by combining all significant variables. The performance of each single variable and PSC has been reported and the correlation of all significant variables with progression free survival (PFS) has been assessed. Results: At IDS, 65 patients (69,8%) had complete cytoreduction with no residual disease (R = 0). Three criteria independently predicted R > 0: age ≥ 60 years (p = 0.014), CA-125 before NACT > 550 UI/dl (p = 0.044), and Peritoneal Cancer Index (PCI) > 16 (p < 0.001). A PSC ≥ 3 has been associated with a better accuracy (85,8%), limiting the number of incomplete surgeries to 16,5%. Moreover, a PCI > 16, a PSC ≥ 3 and the presence of R > 0 after IDS were all significantly associated with shorter PFS (p < 0.001, p < 0.001 and p = 0.004 respectively). Conclusions: Our PSC predicts, in a large number of patients, complete cytoreduction at IDS, limiting the rate of futile extensive surgeries in case of presence of residual tumor (R > 0). The PSC should be prospectively validated in a larger series of EOC patients undergoing NACT-IDS. Keywords: Ovarian cancer, Interval debulking surgery, Optimal cytoreduction, Predictive score, Peritoneal cancer index * Correspondence: giorgio.valabrega@ircc.it Candiolo Cancer Institute FPO-IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, TO, Italy Department of Oncology, University of Torino, Turin, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 2 of 7 Background of the chest, abdomen and pelvis with intravenous Ovarian cancer is the leading cause of death from contrast and serum Ca-125 assessment. In all cases, a gynecological malignancies. In 2017, 22,400 new cases are multidisciplinary board, including a gynecologist and/or expected in the United States. Currently, more than 75% a surgeon, a medical oncologist and a radiologist with of women with ovarian cancer have advanced disease specific training and expertise in ovarian cancer evalu- [International Federation of Gynecology and Obstetrics ated the feasibility of surgical resection. The patients (FIGO) stage IIIC or IV] at diagnosis and their 5-years underwent PDS when optimal cytoreduction has been survival rate is less than 30% [1]. deemed achievable, while NACT - IDS was the pre- Primary debulking surgery (PDS) followed by ferred option when the extent/localization of the dis- platinum-based chemotherapy has long been consid- ease would likely preclude optimal cytoreduction and/ ered the only standard treatment for advanced epithe- or the patient would not tolerate extensive surgery due lial ovarian cancer (EOC) [2]. This approach validity to age or co-morbidities. All 93 patients who under- has been supported by several retrospective studies went both NACT and IDS were included in the present consistently demonstrating that upfront optimal cytor- study. The following variables has been prospectively eduction (residual tumor nodules ≤1cmor R ≤ 1) is entered into a database and retrospectively analyzed: associated with longer survival [3, 4]. Unfortunately, PDS age, performance status (PS) according to Eastern is not always associated with optimal cytoreduction and Cooperative Oncology Group (ECOG), comorbidities can be complicated by severe perioperative morbidity [5, according to the Chronic Disease Score (CDS) [18], FIGO 6]. More recently, neoadjuvant chemotherapy (NACT) stage, grade and histology, serum CA-125 at diagnosis with delayed surgery (interval debulking surgery, IDS) is before surgery and after IDS [19], type of chemotherapy, increasingly adopted in patients with advanced EOC [7]. peritoneal cancer index (PCI) according to Sugarbaker This tendency is sustained by the results of two random- [20] at IDS assessed during laparoscopy, residual disease ized phase III trials, showing that NACT-IDS improves (R) after IDS, date of radiological progression (PD) after optimal debulking rates and reduces surgery-related chemotherapy or last follow-up. complications with no detrimental effect on survival, in All patients signed a written informed consent and the comparison with PDS, at least in patients with high tumor institutional review board of our Institutions provided load [8, 9]. However both trials have been criticized for their approval. the poor performances of PDS arm [10, 11]. However, a significant proportion of patients cannot Statistical analysis be optimally cytoreduced even after NACT-IDS and this We performed univariate and multivariate logistic re- leads to the morbidity of surgery with no expected sur- gression analysis, Fisher exact test and chi-square test vival benefit [12–14]. Although it is common practice to to search patients’ and tumors’ characteristics that were attempt IDS only in patients responding to NACT, this predictive of complete cytoreduction. Receiver Operat- approach causes several unnecessary laparotomies, if ing Curve (ROC) analysis has been also adopted to as- optimal cytoreduction cannot be achieved, and in other sess the best cut-off values to predict the likelihood of cases they are not applied also if the conditions are incomplete cytoreduction at IDS of continuous vari- appropriate. Single variables have been combined into ables. We used all significant variables at multivariate predictive cytoreduction models to improve accuracy in analysis to create a predictive score of cytoreduction the settings of PDS [15] and recurrent disease [16, 17]. (PSC). We assigned one or two points to each criterion, Unfortunately, predictive models have not been developed according to accuracy (1 point if < 75%, 2 points if for patients undergoing IDS. ≥75%). We estimated progression-free survival (PFS) Therefore, the aim of this study is to develop a pre- with the Kaplan-Meier method and we compared it dictive model of surgical outcome at IDS, to improve the using the log-rank test. We considered p <0.05 statisti- selection of patients that can benefit of a maximal surgi- cally significant. We performed all analyses using the cal effort. SPSS statistical software program, version 22.0 (IBM SPSS Inc., Chicago, IL, United States of America). Methods Study population Results A total of 432 patients with histologically confirmed Ninety-three patients with predominantly advanced stage diagnosis EOC have been operated between January 1st, (FIGO IIIC-IV: 75,3%), serous high grade (87%) EOC 2010, and December 31st, 2016 at Candiolo Cancer undergoing NACT and IDS were enrolled. At the time Institute-IRCCS and Sant’Anna Hospital, two high-volume of diagnosis, median CA-125 was 2121 UI/dL (range gynecological cancer centers in the North-West of Italy. 28–10,454 UI/dL) and Chronic Disease Score (CDS) All patients had preoperative computed tomography (CT) was ≥2 in 34,4% of the patients. Carboplatin plus Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 3 of 7 paclitaxel was the most utilized chemotherapeutic levels before NACT > 550 UI/dL, CA-125 levels after regimen (87,3%), with only three patients receiving NACT > 33 UI/dL, CA-125 reduction after NACT < 96% carboplatin single-agent and two patients receiving and PCI > 16 as optimal cut-offs to predict the surgical carboplatin plus pegylated lyposomal doxorubicin, due to outcome. All the above mentioned variables were sig- hypersensitivity to paclitaxel. Sixty-five patients (69,8%) nificantly correlated with incomplete cytoreduction at had complete cytoreduction at IDS. For continuous vari- univariate analysis. However, at multivariate analysis, ables, ROC analysis identified age ≥ 60 years, CA-125 only age (p = 0.007), CA-125 before NACT (p = 0.014) Table 1 Univariate and multivariate analysis of variables associated with incomplete cytoreduction at interval debulking surgery Total (93Pts.) R0 (65Pts.) Non-R0 (28 Pts.) Uni-variate p value Multi-variate p value Age, years Median (range) 60 (36–82) 59,5 (36–82) 65,7 (47–82) NS Age ≥ 60 54 (58%) 32 (49,2%) 22 (78,6%) 0.011 0.007 FIGO stage IIIA 9 (9,7%) 6 (9,2%) 3 (10,7%) IIIB 14 (15%) 9 (13,8%) 5 (17,9%) NS IIIC 58 (62,4%) 43 (66,2%) 15 (53,5%) IV 12 (12,9%) 7 (10,8%) 5 (17,9%) Histology High-grade serous 81(87%) 57 (87,6%) 24 (85,7%) Endometroid 4 (4,3%) 2 (3,1%) 2(7,1%) NS Mucinous 2 (2,2%) 1 (1,5%) 1 (3,6%) Clear cell 2 (2,2%) 2 (3,1%) 0 Other/non specified 4 (4,3%) 3 (4,6%) 1 (3,6%) ECOG Performance Status 0 34 (37%) 26 (40%) 8 (29,6%) NS 1 44 (47,8%) 30 (46,2%) 14 (51,9%) 2 15 (15,2%) 9 (13,8%) 6 (21,4%) Ca 125 values, UI/dl Median CA-125 at diagnosis (range) 2121 (10454–28) 1964 2793 NS NS CA-125 at diagnosis > 550 71 (76,3%) 46 (70,8%) 25 (89,3%) 0.044 0.014 Median CA-125 post NACT (range) 342 (2620–7) 163 598 0.055 NS Ca 125 post NACT > 33 60 (65,9%) 35 (55,6%) 25 (89,3%) 0.002 NS CA 125 reduction post NACT < 96% 34 (38,2%) 26 (41,9%) 8 (29,6%) 0.034 NS Chronic Disease Score (CDS) 1 61 (65,6%) 44 (67,7%) 17 (60,7%) 2 24 (25,8%) 17 (26,2%) 7 (25%) NS 3 8 (8,6%) 4 (6,2%) 4 (14,3%) Peritoneal Cancer Index 0–16 68 (73,1%) 58 (85,3%) 10 (35,8%) < 0.001 < 0.001 > 16 25 (26,9%) 7 (10,7%) 18 (64,2%) Chemotherapy regimen - Carboplatin plus paclitaxel 81 (87,3%) 57 (87,6%) 24 (85,7%) NS - Single agent carboplatin 3 (3,2%) 2 (3,1%) 1 (3,6%) - Carboplatin plus PLD 2(2,2%) 2 (3,1%) 0 - Carboplatin plus paclitaxel plus bevacizumab 7 (7,6%) 4 (6,2%) 3 (10,7%) Pts patients, R0 complete cytoreduction, FIGO International Federation of Gynaecology and Obstretics, ECOG Eastern Cooperative Oncology Group, NACT neoadjuvant chemotherapy, PLD pegylated liposomal doxorubicin, NS not significant Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 4 of 7 Table 2 Diagnostic performance and assigned score of significant variables of incomplete cytoreduction at interval debulking surgery Variable Sens (%) Spec (%) NPV (%) PPV (%) Acc (%) Assigned score Age > 60 years 78,6 50,7 84,6 40,7 59,1 1 CA-125 at diagnosis ≥550 UI/dl 89,2 29,2 86,3 35,2 47,3 1 PCI > 16 62,5 90,1 85,9 71,4 82,3 2 To develop a predictive score of cytoreduction (PSC) for each criterion 1 point was assigned if accuracy is < 75% and 2 points if > 75%. SE sensitivity, SP specificity, NPV negative predictive value, PPV positive predictive value, Acc accuracy and PCI (p < 0.001) maintained the statistical signifi- response [26]. As recently reported, there is still an ab- cance. For complete baseline patients’ characteristics sence of selecting criteria for patients suitable for and statistical correlations see Table 1. NACT/IDS underlining that this approach is still object PCI was the best predictor of surgical outcome, with of debate [27]. accuracy more than 80% (Table 2). Therefore, we mod- Resection of all visible disease should always be the eled a predictive score of incomplete cytoreduction goal in advanced EOC, but it may be particularly im- (PSC) by assigning a value of 1 point to age and CA-125 portant after NACT when patients face their last best at diagnosis and 2 points to PCI according to accuracy. chance to receive an effective surgery. Furthermore, se- If applied, a PSC ≥3 could have selected all patients lection is crucial, since patients who can be cytoreduced for whom complete cytoreduction was not achievable to no macroscopic residual disease may be the only once (100%) by limiting at 16,5% the rate of surgical attempts gaining a survival benefit from surgery at IDS. This leading to a R > 1 cm (Table 3). opinion is sustained by the randomized study of Vergote After a mean follow up of 27 months (range et al. where the hazard ratio (HR) of overall survival was 19.6–34.6 months), 39 patients showed disease pro- not significantly different for R = 0 at IDS (HR 1.11; gression. Among the variables considered, a PCI > 16 p = 0.561) or R ≤ 1 cm at PDS (HR 1.37; p = 0.130) as at IDS (p < 0.001), a PSC ≥3(p < 0.001) and the pres- compared to R = 0 at PDS (reference), but was signifi- ence of residual disease after IDS (p =0.004) were all cantly worse for R ≤ 1 cm at IDS (HR 1.73; p = .0054) significantly associated with shorter PFS (Fig. 1). [8]. The randomized phase III trial TRUST (NCT02828618) is investigating the role of PDS versus Discussion NACT+IDS in large volume comprehensive cancer cen- A key issue in patients with advanced EOC is the selec- ters and has already enrolled one third of 686 estimated tion of patients suitable for complete surgical cytoreduc- patients; final results are expected for 2019. tion. Predictive models of surgical outcome based on Computed tomography, serum markers and staging computed tomography alone [15], or integrated by laparoscopy have all been investigated for the prediction serum CA-125 levels [21, 22], patient age and perform- of complete resection at IDS with variable results. Evalu- ance status [23] have been developed to assist physicians ation of response to NACT by computed tomography is in the decision between PDS or NACT – IDS. Laparo- challenging [28] and serum CA-125 variations [29–31] scopic scores have also been proposed [24], with a recent or thresholds [32, 33] have limited accuracy. It has been randomized study demonstrating that triage laparoscopy reported that a laparoscopic score could identify all pa- could limit the rate of laparotomies leading to incom- tients likely to be optimally debulked at IDS, but with plete cytoreduction (“futile laparotomies”) at 10% [25]. the drawback of 32.6% futile laparotomies [34]. If the choice between PDS and NACT-IDS is complex At our Institutions, patients with clinical/radiological [7], even more controversial is the optimal clinical progressive disease during the first 3–4 courses of NACT, management of women who undergo NACT according either underwent diagnostic laparoscopy or withdrew to the indication, timing and extent of IDS based on chemotherapy, were excluded from the current study. In their stage, comorbidities and, most of all, clinical patients with radiological response/stable disease to Table 3 Diagnostic performance of significant variables of incomplete cytoreduction at interval debulking surgery Variable NPV (%) Unnecessarily explored (1-NPV) (%) PPV (%) Inappropriately unexplored (1-PPV) (%) Age > 60 years 84,6 15,4 40,7 59,1 CA-125 at diagnosis > 550 UI/dl 86,3 13.7 35,2 64,6 PCI > 16 85,9 14,1 71,4 28,6 PSC > 3 83,5 16,5 100 0 CA-125 Cancer Antigen 125, PCI Peritoneal Cancer Index, PSC Predictive score of cytoreduction, NPV negative predictive value, PPV positive predictive value, Acc accuracy, Unnecessary explored (1-NPV): number of cases that would be considered as resectable disease but non-optimally cytoreduced at laparotomy; Inappropriately unexplored (1-PPV): number of cases that would be considered as unresectable but optimally cytoreduced after laparotomy Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 5 of 7 Fig. 1 Kaplan-Meyer curves of Progression Free Survival (PFS). a PFS according to residual disease at interval debulking surgery (IDS), R = 0 vs not; b PFS according to Peritoneal Cancer Index (PCI) at IDS, PCI ≤16 vs > 16; c PFS according to predictive score of complete cytoreduction (PSC) at IDS, PSC < 3 vs ≥ 3 NACT we rely on laparotomy to define if radical sur- Conclusions gery is appropriate or not. In fact, direct visualization In conclusion, we showed that our PSC might help and palpation of the whole abdominal cavity is essential surgeons to give a surgical chance to all patients that for accurate PCI estimation, which is in turn correlated could be completely debulked, therefore limiting the num- with tumor resectability and prognosis [20, 35]. Al- ber of suboptimal surgeries at 16.5%. Both patient’sand though we acknowledge that the role of PCI in ovarian tumor’s characteristics likely concur to determine the cancer is under discussion [36, 37]due to itsassess- chance of complete debulking at IDS. Although the influ- ment, its low reproducibility and limited utilization, in ence of tumor chemosensitivity on survival may supersede our series PCI outperformed all other significant the once of surgery, the selection of those patients who predictors and a cut-off < 16 was able to identify almost can be cytoreduced to R = 0 after NACT is crucial to de- 90% of patients who could be completely debulked. rive the best trade-off from the benefits and the risks of an Nevertheless, this high PPV was obtained with the extensive surgical effort. Our preliminary results suggest drawback of 28,6% of unexplored laparotomies. There- that IDS after NACT should be performed in patients with fore, we assessed whether other information could add a PSC up to 2, while the value of surgery in patients scor- predictive value to PCI by modeling a PSC. Four signifi- ing 4 is likely minimal. In our analysis, we provide a two cant variables reflecting patient (age) and tumor char- high-volume-centers experience with standardized multi- acteristics (PCI and preoperative Ca 125), as well as disciplinary care of EOC. The extrapolation equivalence of response to NACT (CA 125 decrease) has been used. PDS and NACT-IDS from the results of randomized stud- Our results indicate that, with a cut a cut-off set at > 4, ies [8, 9], has been questioned due to patients selection our PSC may allow to identify all patients who cannot and their poor surgical quality, which led to low both be completely cytoreduced at the price of 15% of futile cytoreduction and survival rates [43]. At IDS we obtained laparotomies. a 69% complete cytoreduction rate by performing opera- In our series, R = 0 after IDS was the only parameter tions characterized by high surgical complexity, that were significantly associated with PFS. Conversely, in a recent guided by the same objective and performed with the retrospective series from the Mayo Clinic, older age (HR same effort as PDS. A prospective validation of the PSC 1.60 per 10-years increase in age) and elevated CA-125 has been already planned at our Institutions. before IDS (HR 2.30 for CA-125 > 35 U/mL) were nega- Abbreviations tively correlated with OS, while residual disease after CA-125: cancer antigen-125; CDS: Chronic Disease Score.; CT: Computed IDS did not reach statistical significance (median OS 1.9 tomography.; ECOG: Eastern Cooperative Oncology Group (ECOG).; vs. 2.6 years; P = 0.08) [38]. Indeed, some studies suggest EOC: epithelial ovarian cancer; FIGO: International Federation of Gynecology and Obstetric; HR: Hazard ratio; IDS: interval debulking surgery; that the degree of pathological response to chemother- NACT: neodjuvant chemotherapy; PCI: peritoneal cancer index; PDS: Primary apy could be more closely correlated to OS than the ab- debulking surgery.; PFS: progression free survival; PS: performance status; sence of residual tumor at IDS [39–42]. Although only PSC: predictive score of cytoreduction; R: Residual tumor; ROC: Receiver Operating Curve analysis R = 0 reached statistical significance, the limited number of events of our study may have hindered associations Acknowledgements between PFS and other variables, such as age and CA We are grateful to Prof. Di Renzo for insightful discussion and to Ms. Ann 125 decrease after NACT. Wright for careful proof reading of the manuscript. Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 6 of 7 Funding 9. Kehoe S, et al. Primary chemotherapy versus primary surgery for newly This work was supported by grant VALG_RIC_ LOC_14_01 (G Valabrega); diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, Fondazione del Piemonte per l’Oncologia (FPRC Onlus) 5 X 1000 fondi controlled, non-inferiority trial. Lancet. 2015;386(9990):249–57. Ministero della Salute 2012 (R. Ponzone and M. De Simone). 10. Gasparri ML, Panici PB, Papadia A. Primary chemotherapy versus primary surgery for ovarian cancer. Lancet. 2015;386(10009):2142–3. 11. Meyer LA, et al. Use and effectiveness of neoadjuvant chemotherapy for Availability of data and materials treatment of ovarian Cancer. J Clin Oncol. 2016;34(32):3854–63. All data are available in the manuscript. 12. Tangjitgamol S, Manusirivithaya S, Laopaiboon M, Lumbiganon P, Bryant A. Interval debulking surgery for advanced epithelial ovarian cancer. Cochrane Authors’ contributions Database Syst Rev. 2016; no. 1, p. 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Abstract

Background: Optimal cytoreduction (macroscopic Residual Tumor, RT = 0) is the best survival predictor factor in epithelial ovarian cancer (EOC). It doesn’t exist a consolidated criteria to predict optimal surgical resection at interval debulking surgery (IDS). The aim of this study is to develop a predictive model of complete cytoreduction at IDS. Methods: We, retrospectively, analyzed 93 out of 432 patients, with advanced EOC, underwent neoadjuvant chemotherapy (NACT) and IDS from January 2010 to December 2016 in two referral cancer centers. The correlation between clinical-pathological variables and residual disease at IDS has been investigated with univariate and multivariate analysis. A predictive score of cytoreduction (PSC) has been created by combining all significant variables. The performance of each single variable and PSC has been reported and the correlation of all significant variables with progression free survival (PFS) has been assessed. Results: At IDS, 65 patients (69,8%) had complete cytoreduction with no residual disease (R = 0). Three criteria independently predicted R > 0: age ≥ 60 years (p = 0.014), CA-125 before NACT > 550 UI/dl (p = 0.044), and Peritoneal Cancer Index (PCI) > 16 (p < 0.001). A PSC ≥ 3 has been associated with a better accuracy (85,8%), limiting the number of incomplete surgeries to 16,5%. Moreover, a PCI > 16, a PSC ≥ 3 and the presence of R > 0 after IDS were all significantly associated with shorter PFS (p < 0.001, p < 0.001 and p = 0.004 respectively). Conclusions: Our PSC predicts, in a large number of patients, complete cytoreduction at IDS, limiting the rate of futile extensive surgeries in case of presence of residual tumor (R > 0). The PSC should be prospectively validated in a larger series of EOC patients undergoing NACT-IDS. Keywords: Ovarian cancer, Interval debulking surgery, Optimal cytoreduction, Predictive score, Peritoneal cancer index * Correspondence: giorgio.valabrega@ircc.it Candiolo Cancer Institute FPO-IRCCS, Strada Provinciale 142 km 3.95, 10060 Candiolo, TO, Italy Department of Oncology, University of Torino, Turin, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 2 of 7 Background of the chest, abdomen and pelvis with intravenous Ovarian cancer is the leading cause of death from contrast and serum Ca-125 assessment. In all cases, a gynecological malignancies. In 2017, 22,400 new cases are multidisciplinary board, including a gynecologist and/or expected in the United States. Currently, more than 75% a surgeon, a medical oncologist and a radiologist with of women with ovarian cancer have advanced disease specific training and expertise in ovarian cancer evalu- [International Federation of Gynecology and Obstetrics ated the feasibility of surgical resection. The patients (FIGO) stage IIIC or IV] at diagnosis and their 5-years underwent PDS when optimal cytoreduction has been survival rate is less than 30% [1]. deemed achievable, while NACT - IDS was the pre- Primary debulking surgery (PDS) followed by ferred option when the extent/localization of the dis- platinum-based chemotherapy has long been consid- ease would likely preclude optimal cytoreduction and/ ered the only standard treatment for advanced epithe- or the patient would not tolerate extensive surgery due lial ovarian cancer (EOC) [2]. This approach validity to age or co-morbidities. All 93 patients who under- has been supported by several retrospective studies went both NACT and IDS were included in the present consistently demonstrating that upfront optimal cytor- study. The following variables has been prospectively eduction (residual tumor nodules ≤1cmor R ≤ 1) is entered into a database and retrospectively analyzed: associated with longer survival [3, 4]. Unfortunately, PDS age, performance status (PS) according to Eastern is not always associated with optimal cytoreduction and Cooperative Oncology Group (ECOG), comorbidities can be complicated by severe perioperative morbidity [5, according to the Chronic Disease Score (CDS) [18], FIGO 6]. More recently, neoadjuvant chemotherapy (NACT) stage, grade and histology, serum CA-125 at diagnosis with delayed surgery (interval debulking surgery, IDS) is before surgery and after IDS [19], type of chemotherapy, increasingly adopted in patients with advanced EOC [7]. peritoneal cancer index (PCI) according to Sugarbaker This tendency is sustained by the results of two random- [20] at IDS assessed during laparoscopy, residual disease ized phase III trials, showing that NACT-IDS improves (R) after IDS, date of radiological progression (PD) after optimal debulking rates and reduces surgery-related chemotherapy or last follow-up. complications with no detrimental effect on survival, in All patients signed a written informed consent and the comparison with PDS, at least in patients with high tumor institutional review board of our Institutions provided load [8, 9]. However both trials have been criticized for their approval. the poor performances of PDS arm [10, 11]. However, a significant proportion of patients cannot Statistical analysis be optimally cytoreduced even after NACT-IDS and this We performed univariate and multivariate logistic re- leads to the morbidity of surgery with no expected sur- gression analysis, Fisher exact test and chi-square test vival benefit [12–14]. Although it is common practice to to search patients’ and tumors’ characteristics that were attempt IDS only in patients responding to NACT, this predictive of complete cytoreduction. Receiver Operat- approach causes several unnecessary laparotomies, if ing Curve (ROC) analysis has been also adopted to as- optimal cytoreduction cannot be achieved, and in other sess the best cut-off values to predict the likelihood of cases they are not applied also if the conditions are incomplete cytoreduction at IDS of continuous vari- appropriate. Single variables have been combined into ables. We used all significant variables at multivariate predictive cytoreduction models to improve accuracy in analysis to create a predictive score of cytoreduction the settings of PDS [15] and recurrent disease [16, 17]. (PSC). We assigned one or two points to each criterion, Unfortunately, predictive models have not been developed according to accuracy (1 point if < 75%, 2 points if for patients undergoing IDS. ≥75%). We estimated progression-free survival (PFS) Therefore, the aim of this study is to develop a pre- with the Kaplan-Meier method and we compared it dictive model of surgical outcome at IDS, to improve the using the log-rank test. We considered p <0.05 statisti- selection of patients that can benefit of a maximal surgi- cally significant. We performed all analyses using the cal effort. SPSS statistical software program, version 22.0 (IBM SPSS Inc., Chicago, IL, United States of America). Methods Study population Results A total of 432 patients with histologically confirmed Ninety-three patients with predominantly advanced stage diagnosis EOC have been operated between January 1st, (FIGO IIIC-IV: 75,3%), serous high grade (87%) EOC 2010, and December 31st, 2016 at Candiolo Cancer undergoing NACT and IDS were enrolled. At the time Institute-IRCCS and Sant’Anna Hospital, two high-volume of diagnosis, median CA-125 was 2121 UI/dL (range gynecological cancer centers in the North-West of Italy. 28–10,454 UI/dL) and Chronic Disease Score (CDS) All patients had preoperative computed tomography (CT) was ≥2 in 34,4% of the patients. Carboplatin plus Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 3 of 7 paclitaxel was the most utilized chemotherapeutic levels before NACT > 550 UI/dL, CA-125 levels after regimen (87,3%), with only three patients receiving NACT > 33 UI/dL, CA-125 reduction after NACT < 96% carboplatin single-agent and two patients receiving and PCI > 16 as optimal cut-offs to predict the surgical carboplatin plus pegylated lyposomal doxorubicin, due to outcome. All the above mentioned variables were sig- hypersensitivity to paclitaxel. Sixty-five patients (69,8%) nificantly correlated with incomplete cytoreduction at had complete cytoreduction at IDS. For continuous vari- univariate analysis. However, at multivariate analysis, ables, ROC analysis identified age ≥ 60 years, CA-125 only age (p = 0.007), CA-125 before NACT (p = 0.014) Table 1 Univariate and multivariate analysis of variables associated with incomplete cytoreduction at interval debulking surgery Total (93Pts.) R0 (65Pts.) Non-R0 (28 Pts.) Uni-variate p value Multi-variate p value Age, years Median (range) 60 (36–82) 59,5 (36–82) 65,7 (47–82) NS Age ≥ 60 54 (58%) 32 (49,2%) 22 (78,6%) 0.011 0.007 FIGO stage IIIA 9 (9,7%) 6 (9,2%) 3 (10,7%) IIIB 14 (15%) 9 (13,8%) 5 (17,9%) NS IIIC 58 (62,4%) 43 (66,2%) 15 (53,5%) IV 12 (12,9%) 7 (10,8%) 5 (17,9%) Histology High-grade serous 81(87%) 57 (87,6%) 24 (85,7%) Endometroid 4 (4,3%) 2 (3,1%) 2(7,1%) NS Mucinous 2 (2,2%) 1 (1,5%) 1 (3,6%) Clear cell 2 (2,2%) 2 (3,1%) 0 Other/non specified 4 (4,3%) 3 (4,6%) 1 (3,6%) ECOG Performance Status 0 34 (37%) 26 (40%) 8 (29,6%) NS 1 44 (47,8%) 30 (46,2%) 14 (51,9%) 2 15 (15,2%) 9 (13,8%) 6 (21,4%) Ca 125 values, UI/dl Median CA-125 at diagnosis (range) 2121 (10454–28) 1964 2793 NS NS CA-125 at diagnosis > 550 71 (76,3%) 46 (70,8%) 25 (89,3%) 0.044 0.014 Median CA-125 post NACT (range) 342 (2620–7) 163 598 0.055 NS Ca 125 post NACT > 33 60 (65,9%) 35 (55,6%) 25 (89,3%) 0.002 NS CA 125 reduction post NACT < 96% 34 (38,2%) 26 (41,9%) 8 (29,6%) 0.034 NS Chronic Disease Score (CDS) 1 61 (65,6%) 44 (67,7%) 17 (60,7%) 2 24 (25,8%) 17 (26,2%) 7 (25%) NS 3 8 (8,6%) 4 (6,2%) 4 (14,3%) Peritoneal Cancer Index 0–16 68 (73,1%) 58 (85,3%) 10 (35,8%) < 0.001 < 0.001 > 16 25 (26,9%) 7 (10,7%) 18 (64,2%) Chemotherapy regimen - Carboplatin plus paclitaxel 81 (87,3%) 57 (87,6%) 24 (85,7%) NS - Single agent carboplatin 3 (3,2%) 2 (3,1%) 1 (3,6%) - Carboplatin plus PLD 2(2,2%) 2 (3,1%) 0 - Carboplatin plus paclitaxel plus bevacizumab 7 (7,6%) 4 (6,2%) 3 (10,7%) Pts patients, R0 complete cytoreduction, FIGO International Federation of Gynaecology and Obstretics, ECOG Eastern Cooperative Oncology Group, NACT neoadjuvant chemotherapy, PLD pegylated liposomal doxorubicin, NS not significant Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 4 of 7 Table 2 Diagnostic performance and assigned score of significant variables of incomplete cytoreduction at interval debulking surgery Variable Sens (%) Spec (%) NPV (%) PPV (%) Acc (%) Assigned score Age > 60 years 78,6 50,7 84,6 40,7 59,1 1 CA-125 at diagnosis ≥550 UI/dl 89,2 29,2 86,3 35,2 47,3 1 PCI > 16 62,5 90,1 85,9 71,4 82,3 2 To develop a predictive score of cytoreduction (PSC) for each criterion 1 point was assigned if accuracy is < 75% and 2 points if > 75%. SE sensitivity, SP specificity, NPV negative predictive value, PPV positive predictive value, Acc accuracy and PCI (p < 0.001) maintained the statistical signifi- response [26]. As recently reported, there is still an ab- cance. For complete baseline patients’ characteristics sence of selecting criteria for patients suitable for and statistical correlations see Table 1. NACT/IDS underlining that this approach is still object PCI was the best predictor of surgical outcome, with of debate [27]. accuracy more than 80% (Table 2). Therefore, we mod- Resection of all visible disease should always be the eled a predictive score of incomplete cytoreduction goal in advanced EOC, but it may be particularly im- (PSC) by assigning a value of 1 point to age and CA-125 portant after NACT when patients face their last best at diagnosis and 2 points to PCI according to accuracy. chance to receive an effective surgery. Furthermore, se- If applied, a PSC ≥3 could have selected all patients lection is crucial, since patients who can be cytoreduced for whom complete cytoreduction was not achievable to no macroscopic residual disease may be the only once (100%) by limiting at 16,5% the rate of surgical attempts gaining a survival benefit from surgery at IDS. This leading to a R > 1 cm (Table 3). opinion is sustained by the randomized study of Vergote After a mean follow up of 27 months (range et al. where the hazard ratio (HR) of overall survival was 19.6–34.6 months), 39 patients showed disease pro- not significantly different for R = 0 at IDS (HR 1.11; gression. Among the variables considered, a PCI > 16 p = 0.561) or R ≤ 1 cm at PDS (HR 1.37; p = 0.130) as at IDS (p < 0.001), a PSC ≥3(p < 0.001) and the pres- compared to R = 0 at PDS (reference), but was signifi- ence of residual disease after IDS (p =0.004) were all cantly worse for R ≤ 1 cm at IDS (HR 1.73; p = .0054) significantly associated with shorter PFS (Fig. 1). [8]. The randomized phase III trial TRUST (NCT02828618) is investigating the role of PDS versus Discussion NACT+IDS in large volume comprehensive cancer cen- A key issue in patients with advanced EOC is the selec- ters and has already enrolled one third of 686 estimated tion of patients suitable for complete surgical cytoreduc- patients; final results are expected for 2019. tion. Predictive models of surgical outcome based on Computed tomography, serum markers and staging computed tomography alone [15], or integrated by laparoscopy have all been investigated for the prediction serum CA-125 levels [21, 22], patient age and perform- of complete resection at IDS with variable results. Evalu- ance status [23] have been developed to assist physicians ation of response to NACT by computed tomography is in the decision between PDS or NACT – IDS. Laparo- challenging [28] and serum CA-125 variations [29–31] scopic scores have also been proposed [24], with a recent or thresholds [32, 33] have limited accuracy. It has been randomized study demonstrating that triage laparoscopy reported that a laparoscopic score could identify all pa- could limit the rate of laparotomies leading to incom- tients likely to be optimally debulked at IDS, but with plete cytoreduction (“futile laparotomies”) at 10% [25]. the drawback of 32.6% futile laparotomies [34]. If the choice between PDS and NACT-IDS is complex At our Institutions, patients with clinical/radiological [7], even more controversial is the optimal clinical progressive disease during the first 3–4 courses of NACT, management of women who undergo NACT according either underwent diagnostic laparoscopy or withdrew to the indication, timing and extent of IDS based on chemotherapy, were excluded from the current study. In their stage, comorbidities and, most of all, clinical patients with radiological response/stable disease to Table 3 Diagnostic performance of significant variables of incomplete cytoreduction at interval debulking surgery Variable NPV (%) Unnecessarily explored (1-NPV) (%) PPV (%) Inappropriately unexplored (1-PPV) (%) Age > 60 years 84,6 15,4 40,7 59,1 CA-125 at diagnosis > 550 UI/dl 86,3 13.7 35,2 64,6 PCI > 16 85,9 14,1 71,4 28,6 PSC > 3 83,5 16,5 100 0 CA-125 Cancer Antigen 125, PCI Peritoneal Cancer Index, PSC Predictive score of cytoreduction, NPV negative predictive value, PPV positive predictive value, Acc accuracy, Unnecessary explored (1-NPV): number of cases that would be considered as resectable disease but non-optimally cytoreduced at laparotomy; Inappropriately unexplored (1-PPV): number of cases that would be considered as unresectable but optimally cytoreduced after laparotomy Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 5 of 7 Fig. 1 Kaplan-Meyer curves of Progression Free Survival (PFS). a PFS according to residual disease at interval debulking surgery (IDS), R = 0 vs not; b PFS according to Peritoneal Cancer Index (PCI) at IDS, PCI ≤16 vs > 16; c PFS according to predictive score of complete cytoreduction (PSC) at IDS, PSC < 3 vs ≥ 3 NACT we rely on laparotomy to define if radical sur- Conclusions gery is appropriate or not. In fact, direct visualization In conclusion, we showed that our PSC might help and palpation of the whole abdominal cavity is essential surgeons to give a surgical chance to all patients that for accurate PCI estimation, which is in turn correlated could be completely debulked, therefore limiting the num- with tumor resectability and prognosis [20, 35]. Al- ber of suboptimal surgeries at 16.5%. Both patient’sand though we acknowledge that the role of PCI in ovarian tumor’s characteristics likely concur to determine the cancer is under discussion [36, 37]due to itsassess- chance of complete debulking at IDS. Although the influ- ment, its low reproducibility and limited utilization, in ence of tumor chemosensitivity on survival may supersede our series PCI outperformed all other significant the once of surgery, the selection of those patients who predictors and a cut-off < 16 was able to identify almost can be cytoreduced to R = 0 after NACT is crucial to de- 90% of patients who could be completely debulked. rive the best trade-off from the benefits and the risks of an Nevertheless, this high PPV was obtained with the extensive surgical effort. Our preliminary results suggest drawback of 28,6% of unexplored laparotomies. There- that IDS after NACT should be performed in patients with fore, we assessed whether other information could add a PSC up to 2, while the value of surgery in patients scor- predictive value to PCI by modeling a PSC. Four signifi- ing 4 is likely minimal. In our analysis, we provide a two cant variables reflecting patient (age) and tumor char- high-volume-centers experience with standardized multi- acteristics (PCI and preoperative Ca 125), as well as disciplinary care of EOC. The extrapolation equivalence of response to NACT (CA 125 decrease) has been used. PDS and NACT-IDS from the results of randomized stud- Our results indicate that, with a cut a cut-off set at > 4, ies [8, 9], has been questioned due to patients selection our PSC may allow to identify all patients who cannot and their poor surgical quality, which led to low both be completely cytoreduced at the price of 15% of futile cytoreduction and survival rates [43]. At IDS we obtained laparotomies. a 69% complete cytoreduction rate by performing opera- In our series, R = 0 after IDS was the only parameter tions characterized by high surgical complexity, that were significantly associated with PFS. Conversely, in a recent guided by the same objective and performed with the retrospective series from the Mayo Clinic, older age (HR same effort as PDS. A prospective validation of the PSC 1.60 per 10-years increase in age) and elevated CA-125 has been already planned at our Institutions. before IDS (HR 2.30 for CA-125 > 35 U/mL) were nega- Abbreviations tively correlated with OS, while residual disease after CA-125: cancer antigen-125; CDS: Chronic Disease Score.; CT: Computed IDS did not reach statistical significance (median OS 1.9 tomography.; ECOG: Eastern Cooperative Oncology Group (ECOG).; vs. 2.6 years; P = 0.08) [38]. Indeed, some studies suggest EOC: epithelial ovarian cancer; FIGO: International Federation of Gynecology and Obstetric; HR: Hazard ratio; IDS: interval debulking surgery; that the degree of pathological response to chemother- NACT: neodjuvant chemotherapy; PCI: peritoneal cancer index; PDS: Primary apy could be more closely correlated to OS than the ab- debulking surgery.; PFS: progression free survival; PS: performance status; sence of residual tumor at IDS [39–42]. Although only PSC: predictive score of cytoreduction; R: Residual tumor; ROC: Receiver Operating Curve analysis R = 0 reached statistical significance, the limited number of events of our study may have hindered associations Acknowledgements between PFS and other variables, such as age and CA We are grateful to Prof. Di Renzo for insightful discussion and to Ms. Ann 125 decrease after NACT. Wright for careful proof reading of the manuscript. Ghisoni et al. Journal of Ovarian Research (2018) 11:42 Page 6 of 7 Funding 9. 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Journal of Ovarian ResearchSpringer Journals

Published: May 30, 2018

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