J Gynecol Oncol. 2021 Nov;32(6):e78 https://doi.org/10.3802/jgo.2021.32.e78 pISSN 2005-0380·eISSN 2005-0399 Original Article Effect of tumor burden and radical surgery on survival difference between upfront, early interval or delayed cytoreductive surgery in ovarian cancer Martina Aida Angeles ,1 Bastien Cabarrou ,2 Antonio Gil-Moreno ,3 Asunción Pérez-Benavente ,3 Emanuela Spagnolo ,4 Agnieszka Rychlik ,5 Carlos Martínez-Gómez ,1,6 Frédéric Guyon ,7 Ignacio Zapardiel ,4 Denis Querleu ,8 Claire Illac ,9 Federico Migliorelli ,10 Sarah Bétrian ,11 Gwénaël Ferron ,1,12 Alicia Hernández ,4 Alejandra Martinez 1,6 Department of Surgical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse 1 Oncopole (IUCT-Oncopole), Toulouse, France Received: Mar 15, 2021 2 Biostatistics Unit, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse Oncopole (IUCT- Revised: Jun 2, 2021 Oncopole), Toulouse, France Accepted: Jun 15, 2021 3 Department of Gynaecological Oncology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain Correspondence to 4 Gynecologic Oncology Unit, La Paz University Hospital, Instituto de Investigación Hospital Universitario La Alejandra Martinez Paz (IdiPAZ), Madrid, Spain Department of Surgical Oncology, Institut 5 Department of Gynaecologic Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Claudius Regaud, Institut Universitaire Warsaw, Poland du Cancer de Toulouse Oncopole (IUCT- 6 INSERM CRCT 1, Toulouse, France Oncopole), 1 avenue Irène Joliot-Curie 31059 7 Department of Surgical Oncology, Institut Bergonié, Bordeaux, France TOULOUSE Cedex 9, Toulouse, France. 8 Honorary Professor of the University of Toulouse, France E-mail: Martinez.Alejandra@iuct-oncopole.fr 9 Department of Anatomopathology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse Oncopole (IUCT-Oncopole), Toulouse, France Copyright © 2021. Asian Society of 10 Department of Gynaecology and Obstetrics, Centre Hospitalier Intercommunal des Vallées de l'Ariège, St Gynecologic Oncology, Korean Society of Jean de Verges, France Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse 11 Gynecologic Oncology, and Japan Society of Oncopole (IUCT-Oncopole), Toulouse, France Gynecologic Oncology 12 INSERM CRCT 19, Toulouse, France This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https:// creativecommons.org/licenses/by-nc/4.0/) ABSTRACT which permits unrestricted non-commercial use, distribution, and reproduction in any Objective: We sought to evaluate the impact on survival of tumor burden and surgical medium, provided the original work is properly cited. complexity in relation to the number of cycles of neoadjuvant chemotherapy (NACT) in patients with advanced ovarian cancer (OC) with minimal (CC-1) or no residual disease (CC-0). ORCID iDs Methods: This retrospective study included patients with International Federation of Martina Aida Angeles Gynaecology and Obstetrics IIIC–IV stage OC who underwent debulking surgery at 4 high- https://orcid.org/0000-0003-4401-3084 volume institutions between January 2008 and December 2015. We assessed the overall Bastien Cabarrou https://orcid.org/0000-0003-1477-6013 survival (OS) of primary debulking surgery (PDS group), early interval debulking surgery Antonio Gil-Moreno after 3–4 cycles of NACT (early IDS group) and delayed debulking surgery after 6 cycles (DDS https://orcid.org/0000-0003-1106-5590 group) with CC-0 or CC-1 according to peritoneal cancer index (PCI) and Aletti score. Asunción Pérez-Benavente Results: Five hundred forty-nine women were included: 175 (31.9%) had PDS, 224 (40.8%) https://orcid.org/0000-0003-1872-9003 early IDS and 150 (27.3%) DDS. Regardless of Aletti score, median OS after PDS was Emanuela Spagnolo https://orcid.org/0000-0001-5566-8479 significantly higher than after early IDS or DDS, but the survival difference was higher in Agnieszka Rychlik women with an Aletti score <8. Among patients with PCI ≤10, median OS after PDS was https://orcid.org/0000-0002-8860-8883 significantly higher than after early IDS or DDS. In women with PCI >10, there were no https://ejgo.org 1/13 Impact of tumor load and surgical radicality Carlos Martínez-Gómez differences between PDS and early IDS, but DDS was associated with decreased OS. https://orcid.org/0000-0002-9652-7880 Conclusion: The benefit of complete PDS compared with NACT was maximal in patients Frédéric Guyon with a low complexity score. In patients with low tumor burden, there was a survival https://orcid.org/0000-0002-2647-3004 benefit of PDS over early IDS or DDS. In women with high tumor load, DDS impaired the Ignacio Zapardiel https://orcid.org/0000-0002-9175-7767 oncological outcome. Denis Querleu https://orcid.org/0000-0002-8240-8231 Keywords: Ovarian Neoplasms; Fallopian Tube Neoplasms; Peritoneal Neoplasms; Claire Illac Cytoreduction Surgical Procedures; Neoadjuvant Therapy; Tumor Burden https://orcid.org/0000-0003-1423-1398 Federico Migliorelli https://orcid.org/0000-0002-2185-369X Sarah Bétrian INTRODUCTION https://orcid.org/0000-0001-5369-9378 Gwénaël Ferron Complete cytoreduction with no residual disease is the main prognostic factor in advanced https://orcid.org/0000-0002-1003-9916 epithelial ovarian cancer (OC) [1,2]. The gold standard treatment in these patients is the Alicia Hernández combination of complete cytoreductive surgery (CRS) with platinum and taxane-based https://orcid.org/0000-0002-2494-3041 Alejandra Martinez chemotherapy [3]. In patients with completely resectable disease and good performance https://orcid.org/0000-0002-7633-3536 status, primary debulking surgery (PDS) is the first option to consider, as it has been consistently associated with improved survival outcomes in retrospective studies [4-6]. Conflict of Interest Neoadjuvant chemotherapy (NACT) is associated with lower morbidity and postoperative No potential conflict of interest relevant to this article was reported. mortality [7,8], and it is preferred in medically non-operable patients or in the low likelihood of achieving complete cytoreduction, with non-inferior survival benefit [7,9,10]. Classically, Author Contributions interval debulking surgery (IDS) is performed after three or four cycles of NACT, and 2 or Conceptualization: A.M.A., C.B., G.A., P.A., 3 cycles of adjuvant chemotherapy are delivered after CRS to complete a total of 6 cycles of S.E., R.A., M.C., G.F., Z.I., Q.D., I.C., M.F., B.S., F.G., H.A., M.A.; Data curation: A.M.A., chemotherapy. However, reports evaluating the role of IDS after more than four cycles of C.B., S.E., R.A., M.C.; Formal analysis: C.B.; NACT are controversial. While some have shown that survival is similar to that of patients Investigation: A.M.A., C.B., G.A., P.A., S.E., undergoing IDS after three cycles of NACT [11-14], other studies have described an impaired R.A., M.C., G.F., Z.I., Q.D., I.C., M.F., B.S., F.G., prognosis of delayed IDS [15,16]. H.A., M.A.; Methodology: A.M.A., C.B., G.A., P.A., S.E., R.A., M.C., G.F., Z.I., Q.D., I.C., M.F., The incorporation of extensive upper abdominal procedures in CRS has increased the rate B.S., F.G., H.A., M.A.; Project administration: A.M.A., C.B., G.A., P.A., S.E., R.A., M.C., G.F., of optimal cytoreduction as well as improved the survival of advanced OC patients [17]. Z.I., Q.D., I.C., M.F., B.S., F.G., H.A., M.A.; However, ultraradical procedures are associated with higher morbidity and postoperative Resources: A.M.A., C.B., G.A., P.A., S.E., mortality [18-20]. Likewise, high intraabdominal tumor load has a negative impact on R.A., M.C., G.F., Z.I., Q.D., I.C., M.F., B.S., F.G., survival [21-23]. The aim of our study was to evaluate the survival impact of tumor burden and H.A., M.A.; Software: C.B.; Supervision: H.A., surgical complexity in relation to the number of NACT cycles in patients with advanced OC M.A.; Validation: A.M.A., C.B., G.A., P.A., S.E., R.A., M.C., G.F., Z.I., Q.D., I.C., M.F., B.S., F.G., with minimal or no residual disease after CRS. H.A., M.A.; Visualization: A.M.A., C.B., G.A., P.A., S.E., R.A., M.C., G.F., Z.I., Q.D., I.C., M.F., B.S., F.G., H.A., M.A.; Writing - original draft: MATERIALS AND METHODS A.M.A.; Writing - review & editing: C.B., G.A., P.A., S.E., R.A., M.C., G.F., Z.I., Q.D., I.C., M.F., 1. Patients and study design B.S., F.G., H.A., M.A. A computer-generated search in the institutional patient database was performed to identify retrospectively all patients who underwent upfront, interval or closure complete CRS with complete cytoreduction (CC-0) or cytoreduction to minimal residual disease (CC-1) for stage IIIC–IV epithelial ovarian, fallopian, or primary peritoneal cancer between January 2008 and December 2015 in four institutions meeting the requirements of the European Society of Gynaecological Oncology quality indicators from France and Spain. National and Institutional Review Board approval was obtained from our centres (SLN/MFI/AR193997 and HULP code PI-3432). https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 2/13 Impact of tumor load and surgical radicality 2. Preoperative assessment, surgery principles and chemotherapy treatment All patients underwent a preoperative imaging study including a computed tomography (CT) of the chest, abdomen and pelvis. In selected cases of extra-abdominal disease suspicion, a positron emission tomography (PET)/CT was performed. An exploratory laparoscopy was routinely performed at diagnosis to assess resectability and to obtain a histological diagnosis. All surgical procedures were performed or supervised by experienced oncological surgeons. The surgical technique of CRS was performed following Surgarbaker principles of peritonectomy [24]. The extent and distribution of the disease throughout the 13 abdominopelvic regions were evaluated with the peritoneal cancer index (PCI) [25]. The surgical goal was to achieve complete cytoreduction, evaluated using the Completeness of Cytoreduction score (CC-0: no residual tumor; CC-1: residual disease less than 2.5 mm in diameter; CC-2: residual nodules between 2.5 mm and 2.5 cm; and CC-3 residual nodules greater than 2.5 cm or a confluence of unresectable disease) [25]. Hysterectomy and bilateral salpingo-oophorectomy, infragastric omentectomy and pelvic plus paraaortic lymphadenectomy were the procedures systematically performed during CRS. However, some patients referred from external hospitals had already undergone uni- or bilateral salpingo-oophorectomy with or without hysterectomy at diagnosis. Moreover, as the study period preceded the LION trial [26], lymphadenectomy could be spared only in some selected patients without lymph node involvement at diagnosis to decrease operative time and surgical morbidity. The Aletti score was used to quantify surgical complexity with a cut-off value ≥8 being considered as high complexity [27]. Postoperative complications were documented according to the Clavien-Dindo classification [28]. Patients with deep infiltration of the small bowel mesentery, diffuse carcinomatosis involving large parts of the small bowel, stomach, infiltration of the duodenum or pancreas (not limited to the pancreatic tail) were considered non-resectable and were selected for primary chemotherapy. NACT was also indicated in patients unfit to withstand multivisceral resection due to medical co-morbidities or poor performance status, or when too extensive surgery was needed to achieve complete cytoreduction. After three or four cycles of platinum and taxane-based chemotherapy, a clinical, biological and imaging evaluation by thoraco-abdomino-pelvic CT or PET/CT was performed. In the event of poor response or bad performance status, three additional cycles of NACT were administered before IDS. In selected patients with stable disease on CT after NACT, an exploratory laparoscopy was performed before IDS to assess resectability. Adjuvant chemotherapy was delivered, when feasible, within one or two months after CRS with carboplatin and paclitaxel until a total of six cycles had been completed. In the event of high tumor burden, CC-1 or poor response to NACT, antiangiogenic maintenance treatment with bevacizumab was added after discussion by the tumor board. When surgery was performed after 6 cycles of NACT, two to three additional cycles of chemotherapy were added to the antiangiogenic maintenance treatment with bevacizumab. No maintenance treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors was administered during the study period. Patients with residual disease ≥2.5 mm (≥CC-2) and patients with non-epithelial subtype histology or borderline tumors were excluded from the study. 3. Study data Medical databases were carefully examined to collect all relevant information. Patient demographic data, World Health Organization (WHO) performance status, cancer https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 3/13 Impact of tumor load and surgical radicality antigen-125 (CA-125) dosage, ascites at diagnosis, NACT, PCI scores recorded during CRS, surgical procedures, surgical complexity according to Aletti score, histologic data, adjuvant treatment and follow-up data were retrieved from medical records. Patients were classified in 3 groups according to the surgical timing: upfront surgery and 6 cycles of adjuvant chemotherapy (PDS group), IDS after 3–4 cycles of NACT and 2–3 cycles of adjuvant chemotherapy to achieve a total of 6 cycles (early IDS group), and delayed debulking surgery (DDS) after 6 cycles of NACT (DDS group). The latter group included patients undergoing delayed IDS after 6 cycles of NACT and receiving 2 additional cycles of adjuvant chemotherapy due to poor response to NACT, and patients undergoing closure debulking surgery after 6 cycles of NACT without adjuvant chemotherapy. 4. Statistical analysis Data were summarised by frequency and percentage for categorical variables and by median and range for continuous variables. Comparisons between groups were performed using the χ2 or Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous variables. Overall survival (OS) was defined as the time from diagnosis until death from any cause or last follow-up news (censored data) and was estimated using the Kaplan-Meier method. Comparisons between groups were performed using the Logrank test. The Cox proportional hazards model was used to perform multivariable analysis and to estimate hazard ratio (HR) and adjusted hazard ratios (HRadj) with their 95% confidence interval (95% CI). All statistical tests were two-sided and p-values <0.05 were considered statistically significant. Statistical analyses were conducted using STATA 16 (StataCorp, College Station, TX, USA) software. RESULTS During the study period, 549 patients met the inclusion criteria (Fig. S1). Among them, 175 patients (31.9%) had upfront surgery, 224 (40.8%) underwent early IDS, and 150 (27.3%) had DDS. Within patients undergoing DDS, 106 had a delayed IDS and 44 underwent closure debulking surgery. Baseline characteristics of the three subgroups are shown in Table 1. Patients in the PDS group were significantly younger than those in the early IDS and DDS groups and they had a significantly better performance status. CA-125 was significantly higher with the increasing number of cycles of NACT. In the PDS group, there was a higher proportion of patients with stage IIIC disease and non-serous histology, and ascites at diagnosis was significantly lower. All surgical data is displayed in Table 2. Median PCI at CRS was 11.5, 10 and 7 in the PDS, early IDS and DDS groups, respectively (p<0.001). Regarding surgical procedures, patients who received PDS had significantly more large bowel resections than patients who received debulking surgery either after 3–4 or 6 cycles of NACT. Women undergoing DDS had fewer diaphragm stripping and extended peritonectomies compared to patients after PDS or early IDS. The proportion of patients undergoing a CRS with an Aletti score ≥8 progressively decreased in the PDS, early IDS and DDS groups (p=0.006). The overall rate of major surgical complications (grade III–V) according to the Clavien-Dindo classification was higher after PDS (28.6%, 50/175) than after IDS at 3-4 cycles of NACT (23.2%, 52/224) or after DDS (14.0%, 21/150) (p=0.007). Table S1 shows the overall postoperative complications in the 3 groups. However, among women with a high Aletti score, the major https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 4/13 Impact of tumor load and surgical radicality Table 1. Baseline characteristics of patients. Characteristics PDS (n=175) Early IDS (n=224) DDS (n=150) p-value Age (yr) 58 (22–88) 62 (21–82) 63 (36–88) 0.010 BMI (kg/m2) 24.2 (16.5–44.1) 24.0 (15.6–52.0) 24.6 (15.6–43.9) 0.484 Missing 7 2 11 WHO performance status classification <0.001 0 137 (79.2) 122 (56.2) 96 (65.3) 1 32 (18.5) 83 (38.2) 44 (29.9) ≥2 4 (2.3) 12 (5.5) 7 (4.8) Missing 2 7 3 CA-125 (UI/mL) at diagnosis 463 (7–23,762) 800 (11–42,956) 1,000 (5–86,000) <0.001 Missing 24 15 13 FIGO stage 0.002 IIIC 158 (90.3) 176 (78.6) 115 (76.7) IV 17 (9.7) 48 (21.4) 35 (23.3) Histological subtype <0.001 Serous 140 (80.0) 207 (93.2) 142 (95.3) Non-serous 35 (20.0) 15 (6.8) 7 (4.7) Missing 0 2 Ascites (liter) at diagnosis) 0.1 (0–7) 1 (0–10) 1 (0–8) <0.001 Missing 15 29 24 Values are presented as median (range) or number of patients (%). Bold-faced p-values indicate statistical significance. BMI, body mass index; CA-125, cancer antigen-125; DDS, delayed debulking surgery; Early IDS, early interval debulking surgery; FIGO, International Federation of Gynaecology and Obstetrics; PDS, primary debulking surgery; WHO, World Health Organization. surgical complication rate was not significantly different between the three groups: 35.8% (34/95) after PDS, 31.3% (31/99) after early IDS, and 18.2% (10/55) after DDS (p=0.073). Furthermore, among patients with a low Aletti score, the rate of major surgical complications was not significantly different in the three groups: 20.0% (16/80) for PDS, 16.8% (21/125) for early IDS and 11.6% (11/96) for DDS (p=0.302). Postoperative mortality rates were 1.1% (2/175) after PDS, 2.2% (5/224) after early IDS, and 2.0% (3/150) after DDS (p=0.723). Median follow-up was 63.5 months (95% CI=59.6–70.5) in the PDS group, 62.6 months (95% CI=57.0–69.7) in the early IDS group, and 83.0 months (95% CI=68.1–90.1) in the DDS group. Median OS after PDS, IDS at 3–4 cycles and DDS groups were 84.0 months (95% CI=68.3– 111.0), 50.7 months (95% CI=44.6–59.5) and 47.5 months (95% CI=39.3–52.9), respectively (p<0.001), without significant differences between the 2 groups of NACT (p=0.525). Among patients undergoing DDS, there was no survival difference between patients undergoing delayed IDS (median OS=47.5 months; 95% CI=39.3–52.4) and patients undergoing closure debulking surgery (median OS=51.8 months; 95% CI=25.9–104.9; p=0.612). In multivariable analysis, the number of cycles of NACT (early IDS: HR=1.61; 95% CI=1.18– 2.20; p=0.003 and DDS: HR=1.88; 95% CI=1.35–2.62; p<0.001, respectively), PCI >10 (HR=1.37; 95% CI=1.04–1.81; p=0.027), and Aletti score ≥8 (HR=1.36; 95% CI=1.03–1.79; p=0.028) were significantly associated with worse OS, while age (HR=1.01; 95% CI=1.00– 1.02; p=0.082), WHO performance status ≥1 (HR=1.06; 95% CI=0.82–1.37; p=0.658), non- serous histological subtype (HR=1.33; 95% CI=0.90–1.96; p=0.157), International Federation of Gynaecology and Obstetrics (FIGO) stage IV (HR=0.95; 95% CI=0.69–1.31; p=0.772), CC-1 (HR=1.34; 95% CI=0.96–1.88; p=0.082), and maintenance treatment with bevacizumab (HR=0.93; 95% CI=0.68–1.29; p=0.673) were not significantly associated with OS. Table 3 shows OS according to surgical timing and surgical complexity measured with the Aletti score. In women with an Aletti score ≥8, median OS at PDS, early IDS and DDS was 80.5, 42.4, and 45.8 months (p=0.014), respectively; and in women with an Aletti score <8, https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 5/13 Impact of tumor load and surgical radicality Table 2. Surgical data of patients Variables PDS (n=175) Early IDS (n=224) DDS (n=150) p-value PCI 11.5 (2–33) 10 (0–39) 7 (0–31) <0.001 Missing 3 1 2 PCI <0.001 PCI ≤10 76 (44.2) 112 (50.2) 99 (66.9) PCI >10 96 (55.8) 111 (49.8) 49 (33.1) Missing 3 1 2 Surgical procedures Hysterectomy 167 (95.4) 203 (90.6) 121 (80.7) <0.001 Unilateral or bilateral salpingoophorectomy 164 (93.7) 210 (93.8) 128 (85.3) 0.007 Pelvic lymphadenectomy 158 (90.3) 205 (91.5) 132 (88.0) 0.533 Aortic lymphadenectomy 158 (90.3) 201 (89.7) 129 (86.0) 0.412 Infragastric omentectomy 173 (98.9) 222 (99.1) 145 (96.7) 0.212 Small bowel resection 20 (11.4) 14 (6.3) 10 (6.7) 0.130 Large bowel resection 96 (54.9) 81 (36.2) 48 (32.0) <0.001 If large bowel resection, rectosigmoid resection (n=225) 86 (89.6) 73 (90.1) 45 (93.8) 0.798 Multiple bowel resection 19 (10.9) 19 (8.5) 10 (6.7) 0.405 Appendectomy 93 (53.1) 111 (49.6) 74 (49.3) 0.724 Right diaphragm stripping 108 (61.7) 150 (67.0) 69 (46.0) <0.001 Left diaphragm stripping 56 (32.0) 78 (34.8) 29 (19.3) 0.004 If diaphragm stripping, diaphragm resection (n=330) 31 (28.7) 26 (17.1) 15 (21.4) 0.083 Atypical hepatic resection 4 (2.3) 6 (2.7) 5 (3.3) 0.895 Cholecystectomy 20 (11.4) 19 (8.5) 6 (4.0) 0.051 Celiac lymph node resection 24 (13.7) 29 (12.9) 12 (8.0) 0.226 Splenectomy 43 (24.6) 53 (23.7) 31 (20.7) 0.687 Distal pancreatectomy 6 (3.4) 14 (6.3) 11 (7.3) 0.277 Partial gastrectomy 5 (2.9) 4 (1.8) 2 (1.3) 0.689 Extended peritonectomy 89 (50.9) 117 (52.2) 50 (33.3) <0.001 Glissonectomy 15 (9.5) 16 (8.3) 15 (12.7) 0.447 Mesentery or bowel vaporisation 39 (22.3) 59 (26.3) 27 (18.0) 0.166 Partial abdominal wall resection 15 (8.6) 53 (23.7) 32 (21.3) <0.001 Partial cystectomy or ureteral resection 4 (2.3) 2 (0.9) 2 (1.3) 0.509 Cardiophrenic lymph node resection 1 (0.6) 3 (1.3) 6 (4.0) 0.085 Inguinal lymph node resection 4 (2.3) 7 (3.1) 2 (1.3) 0.562 Axillary lymph node resection 0 (0) 1 (0.4) 1 (0.7) 0.739 CC-score 0.567 CC-0 157 (89.7) 195 (87.1) 129 (86.0) CC-1 18 (10.3) 29 (12.9) 21 (14.0) Aletti score 0.006 <8 80 (45.7) 125 (55.8) 95 (63.3) ≥8 95 (54.3) 99 (44.2) 55 (36.7) HIPEC 0.001 No 174 (99.4) 223 (99.6) 142 (94.7) Yes 1 (0.6) 1 (0.4) 8 (5.3) IP chemotherapy <0.001 No 156 (89.1) 224 (100) 150 (100) Yes 19 (10.9) 0 (0) 0 (0) Bevacizumab <0.001 No 143 (81.7) 164 (73.2) 135 (90.0) Yes 32 (18.3) 60 (26.8) 15 (10.0) Values are presented as median (range) or number of patients (%). Bold-faced p-values indicate statistical significance. CC-score, Completeness of Cytoreduction score; DDS, delayed debulking surgery; Early IDS, early interval debulking surgery; Extended peritonectomy, peritonectomy of more than three abdominal regions; HIPEC, hyperthermic intraperitoneal chemotherapy; IP, intraperitoneal; PCI, peritoneal cancer index; PDS, primary debulking surgery; PH, porta hepatis; Partial abdominal wall resection, partial resection of anterior abdominal wall sheath, omphalectomy or port site resection. median OS was 106.6, 56.7, and 47.5 months (p=0.013), respectively. No significant differences between the 2 groups of NACT were observed. In both subsets of patients with an Aletti score <8 and an Aletti score ≥8, the risk of death was increased after early IDS or DDS compared to upfront surgery. The hazard ratios for death with an Aletti score <8 increased progressively https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 6/13 Impact of tumor load and surgical radicality Table 3. Analysis of OS according to surgical timing and Aletti surgical complexity score Aletti score PDS Early IDS DDS Aletti <8 Median OS (95%CI) (mo) 106.6 (68.0–NR) 56.7 (48.0–80.7) 47.5 (39.3–65.8) HR (95% CI) 1.00 (ref.) 1.69 (1.08–2.66) 1.96 (1.24–3.10) HRadj (95% CI) 1.00 (ref.) 1.79 (1.13–2.86) 2.14 (1.32–3.46) Aletti ≥8 Median OS (95% CI) (mo) 80.5 (50.5–86.1) 42.4 (36.2–56.8) 45.8 (22.8–52.9) HR (95% CI) 1.00 (ref.) 1.70 (1.15–2.53) 1.69 (1.08–2.62) HRadj (95% CI) 1.00 (ref.) 1.66 (1.11–2.47) 1.76 (1.12–2.78) Bold-faced p-values indicate statistical significance. CI, confidence interval; DDS, delayed debulking surgery; Early IDS, early interval debulking surgery; HR, hazard ratio; HRadj, adjusted hazard ratio for age, International Federation of Gynaecology and Obstetrics stage, peritoneal cancer index score and Completeness of Cytoreduction score; NR, not reached; OS, overall survival; PDS, primary debulking surgery. A Aletti score < 8 B Aletti score ≥ 8 1.0 1.0 0.8 0.8 0.6 0.6 OS OS 0.4 0.4 0.2 0.2 0 0 0 12 24 36 48 60 72 84 96 108 120 132 0 12 24 36 48 60 72 84 96 108 120 132 Time (mo) Time (mo) PDS Early IDS DDS PDS Early IDS DDS Fig. 1. OS according to surgical timing in patients with an Aletti score <8 (A) and an Aletti score ≥8 (B). DDS, delayed debulking surgery; Early IDS, early interval debulking surgery; OS, overall survival; PDS, primary debulking surgery. with the increasing number of cycles. Fig. 1 shows OS curves of PDS, early IDS and DDS in the subset of patients with an Aletti score <8 and ≥ 8. Table 4 shows OS according to surgical timing and tumor burden assessed by PCI. In women with PCI >10, median OS at PDS, early IDS and DDS was 67.4, 53.6, and 31.4 months (p<0.001), respectively. The difference was significant between early IDS and DDS (p=0.002) but not between PDS and early IDS (p=0.406). In women with PCI ≤10, median OS was 106.6, Table 4. Analysis of OS according to surgical timing and PCI PCI PDS Early IDS DDS PCI ≤10 Median OS (95% CI) (mo) 106.6 (80.8–NR) 49.2 (43.7–62.0) 52.9 (46.0–91.9) HR (95% CI) 1.00 (ref.) 2.57 (1.56–4.23) 2.09 (1.26–3.46) HRadj (95% CI) 1.00 (ref.) 2.55 (1.53–4.26) 2.06 (1.23–3.46) PCI >10 Median OS (95% CI) (mo) 67.4 (44.7–86.1) 53.6 (40.0–76.6) 31.4 (19.8–43.9) HR (95% CI) 1.00 (ref.) 1.17 (0.80–1.71) 2.16 (1.42–3.29) HRadj (95% CI) 1.00 (ref.) 1.23 (0.84–1.80) 2.07 (1.36–3.17) Bold-faced p-values indicate statistical significance. CI, confidence interval; DDS, delayed debulking surgery; Early IDS, early interval debulking surgery; HR, hazard ratio; HRadj, adjusted hazard ratio for age, International Federation of Gynaecology and Obstetrics stage, Aletti score and Completeness of Cytoreduction score; NR, not reached; OS, overall survival; PCI, peritoneal cancer index; PDS, primary debulking surgery. https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 7/13 Impact of tumor load and surgical radicality A PCI ≤ 10 B PCI > 10 1.0 1.0 0.8 0.8 0.6 0.6 OS OS 0.4 0.4 0.2 0.2 0 0 0 12 24 36 48 60 72 84 96 108 120 132 0 12 24 36 48 60 72 84 96 108 120 132 Time (mo) Time (mo) PDS Early IDS DDS PDS Early IDS DDS Fig. 2. OS according to surgical timing in patients with PCI ≤10 (A) and PCI >10 (B). DDS, delayed debulking surgery; Early IDS, early interval debulking surgery; OS, overall survival; PCI, peritoneal cancer index; PDS, primary debulking surgery. 49.2, and 52.9 months (p<0.001), respectively. No significant differences were observed between the two groups of NACT in this subset of patients. Among patients with PCI ≤10, the risk of death was increased after debulking surgery, either after 3–4 or 6 cycles of NACT when compared to PDS. Among patients with PCI >10, the risk of death was higher after DDS, but early IDS did not yield an increased risk of death. Fig. 2 displays OS curves of PDS, early IDS and DDS in the subset of patients with a PCI ≤10 and >10. DISCUSSION We found a survival benefit of upfront surgery over NACT, with an additional 33 months of OS in patients undergoing PDS compared with patients undergoing early IDS or DDS. Our findings are concordant with several previous reports showing that upfront cytoreduction offers a survival benefit over IDS [4,5,29,30]. Hypothetically, delaying CRS after NACT promotes the selection of chemoresistant tumor cells, as the probability of developing chemoresistance increases with the increasing number of tumor cells. Therefore, even if IDS were to remove all macroscopic disease, the remaining microscopic residual tumor might have a reduced chemosensitivity [31]. In fact, Petrillo et al. demonstrated a worse disease behavior in terms of timing, pattern, and type of recurrence in patients undergoing IDS compared to patients treated with PDS, as patients treated with NACT more frequently presented platinum-resistant recurrences, carcinomatosis and a shorter platinum-free interval. These findings suggest that upfront surgery reduces the probability of development of resistant tumor clones [32]. However, due to the retrospective design of our series, patients in the PDS group might have had a better baseline prognosis as they were not selected for NACT, so this may have contributed to their improved survival. Classically, when NACT is indicated, IDS is scheduled after three or four cycles of chemotherapy. However, some reports have assessed the impact of late IDS performed after more than four cycles of NACT [11-14]. In our study, there were no significant differences in survival between IDS at 3–4 cycles or at 6 cycles of NACT. Yoneoka et al. [11] found that in patients with non-resectable disease after three cycles of NACT, delivering 3 additional https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 8/13 Impact of tumor load and surgical radicality cycles before CRS offered a similar survival to that of patients undergoing IDS after 3 cycles of NACT. Similarly, Stoeckle et al. [14] found that survival of late IDS was not worse than with early IDS, and that the rate of complete cytoreduction was higher in patients undergoing late IDS. Other studies reported similar survival rates between patients receiving ≤4 or ≥5 cycles of NACT before IDS [12,13]. Our findings contrast with those of Colombo et al. [15], whose patients undergoing complete IDS after more than 4 cycles of NACT had a poorer prognosis. Xu et al. [16] reported an impaired oncological outcome of patients undergoing 5 or more cycles of NACT and they recommended not exceeding 4 cycles of NACT before IDS. A previous meta-analysis suggested that there is a gradual development of chemoresistant disease with the cumulative number of NACT cycles. However, most studies included patients undergoing suboptimal surgeries [5]. In contrast, our findings in the overall cohort suggest that when chemoresistant tumor cells have been selected by NACT, additional cycles do not impact survival. Another explanation could be that only patients with minimal or no residual disease were included in the present series. In our study, surgical radicality was higher in women undergoing upfront surgery (54%) and decreased with the increasing number of cycles of NACT. The proportion of patients with an Aletti score ≥8 was 44% after IDS at 3–4 cycles and 37% after 6 cycles, although the difference was not significant. Surgical procedures such as diaphragmatic stripping, extended peritonectomy and large bowel resection were more frequent at PDS. This is concordant with previous studies as NACT is often associated with less extended surgical procedures and lower surgical morbi-mortality [8,10]. In a previous study, we showed that high surgical complexity according to the Aletti score was independently associated with a decreased disease-free survival [6]. In the present study, median OS decreased with the increasing number of NACT cycles in patients with an Aletti score <8. The difference in median OS between PDS and early or delayed IDS among patients with an Aletti score <8 was 50 and almost 60 months, respectively. In patients undergoing more radical surgeries (Aletti score ≥8), the benefit of PDS over early or delayed IDS was lower (38 and 35 months, respectively). In other words, the negative impact of a high Aletti score decreased with NACT. The difference in median OS between Aletti ≥8 and Aletti <8 after PDS was 26 months, while this difference was about 14 and less than 2 months after early and delayed IDS, respectively. Little is known regarding the effect of radical surgery on the survival benefit offered by upfront surgery. Our results contrast with a previous study which did not show a significantly different prognostic outcome between patients receiving radical or simple upfront surgical procedures [21]. This contradiction may be explained by different definitions of radical surgery, as in the current study we assessed surgical complexity with Aletti score, which includes different items to define radical surgery [27]. Extended peritoneal disease requiring ultraradical procedures probably has an adverse tumor biology and surgical efforts may not completely overcome this deleterious effect [33]. Even if the benefit of PDS is impaired by high surgical radicality, we still found a survival advantage of upfront surgery with complete cytoreduction over IDS of almost 40 months in these patients. PDS should remain the mainstay of surgical treatment, even when complex procedures are required to achieve microscopic or no residual tumor. Concordantly with previous reports, we found that NACT was associated with lower morbidity, 29% after PDS versus 23% after early IDS and 14% after DDS [7,8]. However, among patients with high surgical complexity, the rate of major surgical complications was not associated with NACT. https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 9/13 Impact of tumor load and surgical radicality No residual tumor is widely recognized as the most powerful predictor of clinical outcome in advanced OC [2,34]. However, even in the event of complete cytoreduction, intraabdominal tumor burden still has a negative impact on survival [6,33]. Tentes et al. [35] demonstrated that PCI accurately reflects peritoneal spread and disease burden in advanced OC patients. Some studies have reported that PCI is an independent prognostic factor and that a cut-off value above 10 negatively impacts survival [6,35,36]. Moreover, in the subset of patients with no residual disease, high PCI scores remain associated with poor survival rates [6,37]. Even though the benefit of optimal cytoreduction has been shown to decrease with increasing tumor volume, there is still a significant survival benefit conferred by complete CRS in patients with high disease burden [33]. The impact of high tumor burden on survival according to the number of NACT cycles is unknown. To our knowledge, this is the first study to assess this issue. In our study, median PCI score at CRS progressively decreased in PDS, early IDS and delayed IDS. The OS advantage of upfront CRS compared to NACT was enhanced in patients with low tumor burden. In this group, there was a survival difference of more than 50 months between upfront surgery and the NACT groups. In addition, our results concordantly showed that among patients with high disease burden, there was no survival difference between PDS and early IDS. Our findings are concordant with the recent randomised SCORPION trial, which included only patients with high tumor load. It reported that PDS and NACT with 3–4 cycles had superimposable survival outcomes in this subset of patients [18]. However, in our study, DDS after 6 cycles of NACT in patients with high PCI at CRS yielded the worst survival rates. Owing to the retrospective nature of our study, it is unclear whether the inferior clinical outcome of this subgroup was due to chemoresistance induced by additional cycles of NACT or to the selection of patients with a poorer prognosis who were not considered good surgical candidates after 3–4 cycles of NACT. In addition, among the patients who underwent DDS, there was no survival difference between those who had delayed IDS and those undergoing closure debulking surgery. It is unclear whether adjuvant chemotherapy after DDS did not improve clinical outcome or if patients receiving adjuvant chemotherapy had a worse prognosis due to the poor response to NACT. The strengths of our study include a large homogeneous cohort with more than 500 patients with minimal or no residual disease after CRS and a long-term follow-up. Surgical complexity and tumor load were assessed using validated and objective systems such as the Aletti score and PCI [25,27]. The main weakness of the study is its retrospective design with the intrinsic risk of selection bias. As NACT was indicated in medically non-operable patients or in case of non-resectable carcinomatosis, patients with more extended disease were probably included in early IDS and DDS groups, which might have influenced our results. Another important limitation is that PCI was collected at CRS instead of at diagnosis, which would have allowed a more reliable comparison of tumor load between the 3 groups. Unfortunately, although our patients systematically underwent laparoscopy at diagnosis, PCI at this surgery was not available in the surgical report for most patients. The unexpected and uncontrolled significant differences in the baseline characteristics between the three groups could have influenced these findings. The role of early and delayed IDS according to surgical complexity and disease burden needs to be confirmed in prospective multicentric studies. In conclusion, PDS is associated with higher survival rates than early or delayed IDS. The survival benefit of PDS over NACT is higher in women requiring less complex surgeries, even if radical upfront procedures are still associated with a survival advantage over NACT. https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 10/13 Impact of tumor load and surgical radicality Similarly, low tumor load at CRS enhances the survival benefit of PDS over early or delayed IDS. In patients with high tumor load, delayed IDS yields impairs the oncological outcome. ACKNOWLEDGEMENTS The project that gave rise to these results received the support of a fellowship from “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/EU18/11650038. SUPPLEMENTARY MATERIALS Table S1 Postoperative complications according to Clavien-Dindo classification Click here to view Fig. S1 Flow chart of the eligible and the included patients. Click here to view REFERENCES 1. Chi 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;103:559-64. PUBMED | CROSSREF 2. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248-59. PUBMED | CROSSREF 3. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21:3194-200. PUBMED | CROSSREF 4. Chiva L, Lapuente F, Castellanos T, Alonso S, Gonzalez-Martin A. What should we expect after a complete cytoreduction at the time of interval or primary debulking surgery in advanced ovarian cancer? Ann Surg Oncol 2016;23:1666-73. PUBMED | CROSSREF 5. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol 2006;103:1070-6. PUBMED | CROSSREF 6. Angeles MA, Rychlik A, Cabarrou B, Spagnolo E, Guyon F, Pérez-Benavente A, et al. A multivariate analysis of the prognostic impact of tumor burden, surgical timing and complexity after complete cytoreduction for advanced ovarian cancer. Gynecol Oncol 2020;158:614-21. PUBMED | CROSSREF 7. Wright AA, Bohlke K, Armstrong DK, Bookman MA, Cliby WA, Coleman RL, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of clinical oncology clinical practice guideline. J Clin Oncol 2016;34:3460-73. PUBMED | CROSSREF 8. Bartels HC, Rogers AC, McSharry V, McVey R, Walsh T, O'Brien D, et al. A meta-analysis of morbidity and mortality in primary cytoreductive surgery compared to neoadjuvant chemotherapy in advanced ovarian malignancy. Gynecol Oncol 2019;154:622-30. PUBMED | CROSSREF https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 11/13 Impact of tumor load and surgical radicality 9. Vergote I, Coens C, Nankivell M, Kristensen GB, Parmar MKB, Ehlen T, et al. Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials. Lancet Oncol 2018;19:1680-7. PUBMED | CROSSREF 10. Onda T, Satoh T, Saito T, Kasamatsu T, Nakanishi T, Nakamura K, et al. Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in a phase III randomised trial: Japan Clinical Oncology Group Study JCOG0602. Eur J Cancer 2016;64:22-31. PUBMED | CROSSREF 11. Yoneoka Y, Ishikawa M, Uehara T, Shimizu H, Uno M, Murakami T, et al. Treatment strategies for patients with advanced ovarian cancer undergoing neoadjuvant chemotherapy: interval debulking surgery or additional chemotherapy? J Gynecol Oncol 2019;30:e81. PUBMED | CROSSREF 12. Akladios C, Baldauf JJ, Marchal F, Hummel M, Rebstock LE, Kurtz JE, et al. Does the number of neoadjuvant chemotherapy cycles before interval debulking surgery influence survival in advanced ovarian cancer? Oncology 2016;91:331-40. PUBMED | CROSSREF 13. Phillips A, Sundar S, Singh K, Nevin J, Elattar A, Kehoe S, et al. Complete cytoreduction after five or more cycles of neo-adjuvant chemotherapy confers a survival benefit in advanced ovarian cancer. Eur J Surg Oncol 2018;44:760-5. PUBMED | CROSSREF 14. Stoeckle E, Boubli B, Floquet A, Brouste V, Sire M, Croce S, et al. Optimal timing of interval debulking surgery in advanced ovarian cancer: yet to be defined? Eur J Obstet Gynecol Reprod Biol 2011;159:407-12. PUBMED | CROSSREF 15. Colombo PE, Labaki M, Fabbro M, Bertrand M, Mourregot A, Gutowski M, et al. Impact of neoadjuvant chemotherapy cycles prior to interval surgery in patients with advanced epithelial ovarian cancer. Gynecol Oncol 2014;135:223-30. PUBMED | CROSSREF 16. Xu X, Deng F, Lv M, Chen X. The number of cycles of neoadjuvant chemotherapy is associated with prognosis of stage IIIc-IV high-grade serous ovarian cancer. Arch Gynecol Obstet 2017;295:451-8. PUBMED | CROSSREF 17. Chi DS, Eisenhauer EL, Zivanovic O, Sonoda Y, Abu-Rustum NR, Levine DA, et al. Improved progression- free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol 2009;114:26-31. PUBMED | CROSSREF 18. Fagotti A, Ferrandina MG, Vizzielli G, Pasciuto T, Fanfani F, Gallotta V, et al. Randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer (SCORPION- NCT01461850). Int J Gynecol Cancer 2020;30:1657-64. PUBMED 19. Chi DS, Zivanovic O, Levinson KL, Kolev V, Huh J, Dottino J, et al. The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas. Gynecol Oncol 2010;119:38-42. PUBMED | CROSSREF 20. Gerestein CG, Damhuis RA, Burger CW, Kooi GS. Postoperative mortality after primary cytoreductive surgery for advanced stage epithelial ovarian cancer: a systematic review. Gynecol Oncol 2009;114:523-7. PUBMED | CROSSREF 21. Martinez A, Ngo C, Leblanc E, Gouy S, Luyckx M, Darai E, et al. Surgical complexity impact on survival after complete cytoreductive surgery for advanced ovarian cancer. Ann Surg Oncol 2016;23:2515-21. PUBMED | CROSSREF 22. Horowitz NS, Miller A, Rungruang B, Richard SD, Rodriguez N, Bookman MA, et al. Does aggressive surgery improve outcomes? Interaction between preoperative disease burden and complex surgery in patients with advanced-stage ovarian cancer: an analysis of GOG 182. J Clin Oncol 2015;33:937-43. PUBMED | CROSSREF 23. Crawford SC, Vasey PA, Paul J, Hay A, Davis JA, Kaye SB. Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial. J Clin Oncol 2005;23:8802-11. PUBMED | CROSSREF 24. Sugarbaker PH. Peritonectomy procedures. Ann Surg 1995;221:29-42. PUBMED | CROSSREF https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 12/13 Impact of tumor load and surgical radicality 25. Gilly FN, Cotte E, Brigand C, Monneuse O, Beaujard AC, Freyer G, et al. Quantitative prognostic indices in peritoneal carcinomatosis. Eur J Surg Oncol 2006;32:597-601. PUBMED | CROSSREF 26. Harter P, Sehouli J, Lorusso D, Reuss A, Vergote I, Marth C, et al. A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms. N Engl J Med 2019;380:822-32. PUBMED | CROSSREF 27. Aletti GD, Santillan A, Eisenhauer EL, Hu J, Aletti G, Podratz KC, et al. A new frontier for quality of care in gynecologic oncology surgery: multi-institutional assessment of short-term outcomes for ovarian cancer using a risk-adjusted model. Gynecol Oncol 2007;107:99-106. PUBMED | CROSSREF 28. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13. PUBMED | CROSSREF 29. Xiao Y, Xie S, Zhang N, Wang J, Lv C, Guo J, et al. Platinum-based neoadjuvant chemotherapy versus primary surgery in ovarian carcinoma International Federation of Gynecology and Obstetrics stages IIIc and IV: a systematic review and meta-analysis. Gynecol Obstet Invest 2018;83:209-19. PUBMED | CROSSREF 30. Qin M, Jin Y, Ma L, Zhang YY, Pan LY. The role of neoadjuvant chemotherapy followed by interval debulking surgery in advanced ovarian cancer: a systematic review and meta-analysis of randomized controlled trials and observational studies. Oncotarget 2017;9:8614-28. PUBMED | CROSSREF 31. Cooke SL, Brenton JD. Evolution of platinum resistance in high-grade serous ovarian cancer. Lancet Oncol 2011;12:1169-74. PUBMED | CROSSREF 32. Petrillo M, Ferrandina G, Fagotti A, Vizzielli G, Margariti PA, Pedone AL, et al. Timing and pattern of recurrence in ovarian cancer patients with high tumor dissemination treated with primary debulking surgery versus neoadjuvant chemotherapy. Ann Surg Oncol 2013;20:3955-60. PUBMED | CROSSREF 33. Zivanovic O, Sima CS, Iasonos A, Hoskins WJ, Pingle PR, Leitao MM Jr, et al. The effect of primary cytoreduction on outcomes of patients with FIGO stage IIIC ovarian cancer stratified by the initial tumor burden in the upper abdomen cephalad to the greater omentum. Gynecol Oncol 2010;116:351-7. PUBMED | CROSSREF 34. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002;20:1248-59. PUBMED | CROSSREF 35. Chang SJ, Hodeib M, Chang J, Bristow RE. Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis. Gynecol Oncol 2013;130:493-8. PUBMED | CROSSREF 36. Tentes AA, Tripsiannis G, Markakidis SK, Karanikiotis CN, Tzegas G, Georgiadis G, et al. Peritoneal cancer index: a prognostic indicator of survival in advanced ovarian cancer. Eur J Surg Oncol 2003;29:69-73. PUBMED | CROSSREF 37. Llueca A, Escrig J; MUAPOS working group (Multidisciplinary Unit of Abdominal Pelvic Oncology Surgery). Prognostic value of peritoneal cancer index in primary advanced ovarian cancer. Eur J Surg Oncol 2018;44:163-9. PUBMED | CROSSREF 38. Gasimli K, Braicu EI, Richter R, Chekerov R, Sehouli J. Prognostic and predictive value of the peritoneal cancer index in primary advanced epithelial ovarian cancer patients after complete cytoreductive surgery: study of Tumor Bank Ovarian Cancer. Ann Surg Oncol 2015;22:2729-37. PUBMED | CROSSREF https://ejgo.org https://doi.org/10.3802/jgo.2021.32.e78 13/13