Survival benefit of cytoreductive surgery in patients with primary stage IV endometrial cancer: a systematic review & meta-analysis

Survival benefit of cytoreductive surgery in patients with primary stage IV endometrial cancer: a systematic review & meta-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 Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Survival benefit of cytoreductive surgery in patients with primary stage IV endometrial cancer: a systematic review & meta-analysis Eveline Ngoc Bao Pham, Nanda Horeweg, Jacolien Marel, Linda Suzanne Nooij This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3951101/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background . This systematic review and meta-analysis aimed to investigate the survival outcomes following cytoreductive surgery (CRS) in patients with primary stage IV endometrial cancer (EC). The role of CRS in this context is debatable, given the limited evidence from large studies and the inherent heterogeneity among patients with stage IV EC. Methods . We systematically searched the Cochrane Library, Embase, MEDLINE/PubMed, and Web of Science for original studies reporting survival outcomes of primary stage IV EC after complete, optimal, and incomplete CRS. Pooled hazard ratios (HRs) for overall survival (OS) per CRS outcome were calculated using a random-effects model. Heterogeneity was assessed using the I2 and the Q-test. Results. Twelve studies, including 748 patients, were analysed. 187 patients underwent complete CRS, and 146 patients optimal CRS. Ten studies reported a significant OS benefit after complete (18–48 months) and optimal CRS (13–34 months) compared to incomplete CRS (7–19 months). A benefit was also observed in patients with serous EC or extra- abdominal metastasis. Meta-analysis showed improved OS after complete/optimal vs. incomplete CRS (HR = 0.38, 95% CI 0.21–0.69, p = 0.0016). Heterogeneity was substantial between studies (I2 = 76.7%, p < 0.0001). Conclusion . Complete/optimal CRS results in an OS benefit for patients with primary stage IV EC, including serous EC or extra-abdominal metastasis. PROSPERO registration . CRD42022302968 on May 10th, 2022. Figures Figure 1 Figure 2 Figure 3 Background Primary FIGO (International Federation of Gynecology and Obstetrics) stage IV endometrial cancer (EC) accounts for only 3% of all EC diagnoses and has a dismal prognosis with a five-year overall survival (OS) of 15–21%. 1 At this moment, several systemic therapies have shown to improve survival in patients with stage IV EC 2,3 , but the value of surgery, specifically cytoreductive surgery (CRS), in the primary treatment of stage IV EC is still debated. The ESGO/ESTRO/ESP consensus guideline 4 , NCCN Clinical Practice Guidelines in Oncology 5 and National Cancer Institute's PDQ Endometrial cancer information 6 recommend CRS in patients with primary stage IV EC if complete resection is deemed feasible, following the rationale of CRS for ovarian cancer. 7–11 However, these recommendations are based on several observational studies which should be interpreted cautiously due to the limited sample size, potential selection bias, and heterogeneity of patients included in the study. Furthermore, the survival benefit of CRS in patients with EC is not as clear as in ovarian cancer for whom complete and optimal CRS give a substantial survival benefit compared to incomplete or no CRS. 12,13 Consequently, there is still reluctance to perform CRS in patients with primary stage IV EC. The low incidence of primary stage IV EC, along with its heterogeneous nature, presents a complex challenge for clinicians. The heterogeneity arises not only from patient-specific factors such as comorbidities and WHO performance status, but also from heterogeneity in the extensiveness of stage IV EC, including intra-abdominal and/or distant metastases. When extra-abdominal disease is present, there may be even more reservations towards performing extensive intra-abdominal surgery. Prior systematic reviews and meta-analyses have shown the potential benefit of complete CRS on OS in advanced stage EC, however these meta-analyses also included studies on recurrent EC, stage III EC or solely stage IVB. 14–16 The aim of this study is to obtain insight into the benefit of CRS in patients with primary stage IV EC, and summarize the evidence for future treatment recommendations. We conducted a systematic review to comprehensively evaluate the existing literature on the survival benefit of CRS in patients with primary stage IV EC specifically. Additionally, a meta-analysis was performed to estimate the pooled effect of completeness of CRS on OS in women with primary stage IV EC. Methods This study was designed according to the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines 17 and registered at PROSPERO prior to abstract screening (registration number CRD42022302968). Literature search A systematic literature search was performed in October 2022 in the Cochrane Library, Embase, MEDLINE, PubMed, and Web of Science using a search strategy including terms representing ‘endometrial cancer’, ‘cytoreductive surgery’, and ‘survival’. A detailed search is outlined in appendix A. Eligibility criteria To be eligible for inclusion, original studies had to enrol at least 10 patients with primary stage IV EC who underwent CRS. These studies were required to report data on progression-free survival (PFS) and/or OS stratified by the extent of cytoreduction, which is complete (no residual disease), optimal (residual disease ≤ 1cm) or incomplete (gross residual disease > 1 cm). If studies included patients with other stages of EC or recurrent EC, they were considered if survival data for primary stage IV patients were reported separately. Conference abstracts, case reports, review articles, meta-analyses, editorials, letters to the editor, and guidelines were excluded, as were studies on uterine sarcomas or those that involved HIPEC. Study selection The eligibility of all studies identified through the systematic search was evaluated by at least two of three reviewers (JM, EP, and LN) independently. EndNote reference manager was utilized for the initial screening. The screening was based on the article title and abstract, and those selected underwent a full-text review to determine if they met the inclusion criteria. Throughout the selection process, the independent findings were compared, and any discrepancies were resolved by discussion until consensus was reached. Data extraction Data was extracted and recorded by EP, LN and JM in a database with predefined variables. Extracted variables included median age, performance status, histological diagnosis, treatment, number of patients who received CRS, outcome of CRS, definitions of PFS and OS and the median PFS and OS, Kaplan-Meier estimates, hazard ratios (HR), 95% confidence intervals (95% CI), and p-values. Assessment of risk of bias A modified Newcastle-Ottawa scale for the assessment of cohort studies was utilized to assess the quality of the included studies. 18 The scale was adjusted for application in our study with patients with complete/optimal CRS as the exposed cohort and incomplete CRS as the non-exposed cohort. Adequate follow-up time was set at a median follow up of at least 18 months (see Appendix B). Data synthesis All studies that were included in the systematic review were reviewed for eligibility for pooling in the meta-analysis by EP and NH. The objective of the meta-analysis was to estimate a pooled HR for PFS and/or OS by completeness of CRS. Studies were eligible for the meta-analysis if PFS and/or OS was compared between patients with a complete, optimal or incomplete CRS. If the HR and 95%CI were reported in the article, direct calculation of the natural logarithm of HR and its’ variance were performed (Appendix C). If not, imputation according to the methodology of Tierney et al. 19 was performed using other data provided in the article (Appendix D). For the meta-analysis, pooled estimates of the HR were calculated using random-effects models with the DerSimonian-Laird estimator for the amount of heterogeneity. Each study contributed according to their sample size using inverse variance weights. Statistical significance was pre-defined as a (two-sided) p-value of 50% combined with a Q-test p-value of < 0.05. Analyses were performed in R version 3.6.1 ( http://www.r-project . org/) using the metafor package ( https://cran.r-project.org/web/packages/metafor/index.html ). Results Study selection and quality assessment A total of 812 unique studies were found and screened for eligibility. 759 studies were excluded based on title and abstract screening for various reasons, including eligibility of the study population (such as no primary stage IV EC or different tumour types), no CRS, or case report, or no original study. For 52 studies, the full-texts were evaluated, which led to the exclusion of another 40 studies. 23 of these 40 studies did not report data on patients with primary stage IV EC at all, or the data were not reported separately for the included subgroup of patients with primary stage IV EC. The remaining 17 studies that were excluded did not report survival outcomes by outcome of CRS. This resulted in the inclusion of 12 studies for the systematic review. 20–31 Of these 12 included studies for the systematic review, two studies could not be included in the meta-analysis because the available data did not provide enough information for a pooled analysis. 23,30 The remaining ten studies were evaluated for the meta-analysis. 20–22,24-29,31 As most studies only compared survival outcomes between the combined subgroup of complete and optimal CRS vs. incomplete CRS, a meta-analysis comparing complete CRS with either optimal or incomplete CRS was not feasible. The study of Shih et al. 29 had to be excluded as the authors compared the survival outcomes of complete CRS vs. optimal CRS vs. incomplete CRS. Hence, nine studies were pooled in the meta-analysis. As only two of these nine studies reported data on PFS 26,31 , we decided not to pool the data on PFS. An overview of the selection process is described in Fig. 1 . The quality of the included studies was high in general with almost all studies scoring 7 or 8 out of 8 points (see Appendix B). Definition of abbreviation: EC = endometrial carcinoma Study and patient characteristics The 12 studies that were included in the systematic review contained data on 768 patients with primary stage IV EC, of whom 748 (97%) underwent CRS. An overview of the study characteristics is shown in Table 1 . The studies were published between 1997 and 2022, Table 1 Study characteristics Patient characteristics Histology Surgery Adjuvant therapy Study, year No. of patients Median age (range, in years) Extra-abdominal metastases %EEC %SEC %Other* Total CRS Complete CRS Optimal CRS CT RT Ayhan, 2002 37 62 (43–73) Yes (< 50%) 78% 8% 13% 37 32% 27% 54% 54% Bristow, 2000 65 65 (29–85) Yes (< 50%) 34% 32% 24% 65 40% 15% 63% 38% Bristow, 2001 31 65 (36–84) Yes (< 50%) 0% 100% 0% 31 19% 32% 87% 3% Chi, 1997 55 67 (42–87) Yes (< 50%) 60% 22% 18% 55 NR 44%** 71% 25% Eto, 2012 248 59 (30–89) Yes (< 50%) 60% 17% 22% 248 41% 21% 84% 14% Lee, 2014 48 70 (53–87) No 0% 100% 0% 48 46% 29% 50% 44% McEachron, 2022 68 67 (44–89) NR 0% 100% 0% 68 16% 57% 100% 18% Moller, 2004 52 67 (46–89) NR 0% 100% 0% 49 NR 53% 69% 15% Patsavas, 2011 32 67 (47–90)*** NR 0% 100% 0% 32 NR 53% 72% 0% Shih, 2011 58 65 (42–86) NR 100% 0% 0% 52 17% 21% 66% 21% Tanioka, 2010 41 62 (38–80) Yes (< 50%) 59% 20% 22% 33 NR 70% 49% 10% Ueda, 2010 33 63 (48–77) Yes (= 50%). 73% 24% 3% 30 NR 67%** 91% 0% Definition of abbreviations: EEC = endometrioid endometrial cancer, SEC = serous endometrial cancer, CRS = cytoreductive surgery, CT = chemotherapy, RT = radiotherapy, NR = not reported * other histological types were clear cell, carcinosarcoma, squamous, mixed, mucinous, small cell, and poorly or undifferentiated ** optimal CRS was defined as ≤ 2.0 cm, *** mean age, for the total population (not only stage IV). were all retrospective, and mostly single-centre studies. Besides the study by Eto et al. 24 which included 248 patients, most studies had included a small number of patients (range 31–68 patients). The majority of the included patients were postmenopausal. Four studies reported the pre-operative WHO performance status of patients (total of 386 patients) 22,24,30,31 , which was good in the majority of patients in studies (WHO 0–1, n = 351, 91% of 386 patients). Seven 20–24,30,31 of the 12 studies also included patients with extra-abdominal disease (n = 195), but the majority of the patients had intra-abdominal metastases only. If mentioned, the extra-abdominal metastases were mostly pulmonary metastases (n = 85 in seven studies), pleural effusion (n = 16), liver metastasis (n = 25), or inguinal, supraclavicular or mediastinal lymph nodes (n = 60). Ueda et al. 31 separately reported the outcomes of patients with intra-abdominal metastases only (n = 15) and patients with extra-abdominal metastases (n = 15). The most common histological subtype was endometroid EC (n = 339, 44%) and serous EC (n = 326, 42%). Complete CRS was specifically defined by three studies as no visible disease. 25,26,29 Optimal CRS was defined as a reduction of the tumour mass to ≤ 1cm in 10 studies 20–22,24-30 , and as reduction to ≤ 2cm in two studies. 23,31 Definitions of survival were ‘from date of diagnosis’, or ‘date of surgery’ 22–26,28-30 until ‘clinical/radiological recurrence’ (PFS) or ‘death’ or ‘last contact’ (OS). Four studies did not report a definition of survival. 20,21,27,31 Treatment 748 patients (97% of the study population) underwent CRS. In seven studies (549 patients) the outcomes of CRS were reported separately for complete, optimal, or incomplete CRS 20–22,24-26,29 , which were 187 (34.1%), 146 (26.6%) and 216 (39.3%) patients respectively. In the remaining five studies (including 199 patients) 23,27,28,30,31 completeness of CRS was reported for complete and optimal together, being 105 patients (52.8%). To achieve complete or optimal CRS, additional surgical procedures were performed in a total of 123 patients (21% of the total study population of these studies, n = 596) besides the standard procedure of hysterectomy with bilateral salpingo-oophorectomy and omentectomy. These additional surgical procedures were described in nine studies, and included bowel resections (n = 61), appendectomies (n = 47), splenectomies (n = 2), liver resections (n = 3), lung resections (n = 2), and ureter/bladder resections (n = 3). 21–24,26-28,30,31 No details were provided on the placement of a stoma. The surgical treatment of the extra-abdominal metastases was described in three of the seven studies that specifically mentioned patients with extra-abdominal disease. In the study by Ayhan et al. 20 in three of the six patients the extra-abdominal metastases (lung, inguinal lymph node and supraclavicular lymph node) were completely resected. In the study of Eto et al. 24 a total of 93 patients (38% of the study population) had extra-abdominal disease. In 14 of them surgical removal was attempted, which was successful in 13 patients. Another study that reported on the treatment of extra-abdominal disease was the study by Ueda et al. 31 In this study 18 patients out of a total of 33 patients had one or more extra-abdominal metastases, located at the lungs (n = 8), liver (n = 7), pleural effusion (n = 5), supraclavicular lymph nodes (n = 5) and inguinal lymph nodes (n = 2). Surgical removal of these metastases was performed for the liver metastases (n = 2), supraclavicular lymph node metastases (n = 2), lung metastases (n = 1), and inguinal lymph node metastases (n = 1). Peri- and postoperative complications were reported in only five of 12 studies. 20–22,24,27 Four of these studies provided the number of patients experiencing any peri-and postoperative complications 20–23,27 , with a total of 46 out of 182 patients having complications (25.3%). The most comprehensive descriptions were reported by Ayhan et al. 20 , Bristow et al. 21 , and Moller et al. 27 , with complication rates of 40.5% (n = 15), 51.6% (n = 16), and 23% (n = 12) respectively. The latter study revealed that the rate of complications did not differ between patients who underwent complete/optimal or incomplete CRS (p-value = 0.33). Among the reported complications, two were fatal (0.5% of 430 patients in total), one patient died due to pulmonary embolism and the other due to small bowel obstruction followed by sepsis. 20,21 The five studies collectively documented 21 patients with major or severe complications (5% of 430 patients), including: myocardial infarction, gastrointestinal haemorrhage, anastomotic gastrointestinal leak, cerebrovascular accident, thrombosis, and pulmonary embolism. Fourteen patients experienced mild complications according to the authors (3% of 430 patients). The majority of patients (n = 575, 75% of total study population) received chemotherapy. In two studies it was separately reported that four patients had received neo-adjuvant chemotherapy 25,30 , in the remaining studies neo-adjuvant or adjuvant chemotherapy was not separately mentioned. The adjuvant chemotherapy treatment regimens differed among studies. Platinum-based chemotherapy (carboplatin or cisplatin) was the only agent or combined with paclitaxel. Other frequently administered chemotherapy agents were doxorubicin) or cyclophosphamide. Less common chemotherapy regimens included agents such as docetaxel, epirubicine, ifosfamide, irinotecan, vinorelbine, and 5-fluorouracil. Adjuvant radiotherapy was given in almost all studies to a small proportion of the patients (n = 155, 20%), and consisted of external beam radiotherapy in the majority of the patients or vaginal brachytherapy or both. 20–27,29,30 In four studies, a total of 66 patients (9%) received hormonal treatment as adjuvant therapy. 23,27,29–31 Survival All included studies reported on OS data and ten studies found a significant advantage of complete and/or optimal CRS compared to incomplete CRS in patients with primary stage IV EC (Table 2 ). 20–26,28,29,31 Only three studies reported the OS separately for complete, optimal, and incomplete CRS. 20,24,26 In these three studies, OS was longer for patients who had complete CRS (48, 48, and 18 months) compared to patients with incomplete CRS (10, 14, and 7 months). Patients with optimal CRS had intermediate OS times which were closer to those of incomplete CRS in two out of three of the studies (13, 23, and 17 months). Ayhan et al. 20 and McEachron et al. 26 provided p-values that compared complete vs. optimal CRS. In the first study, the p-value was 0.001 (OS of 48 months after complete CRS and 13 months after optimal CRS), whilst for the study of McEachron et al. 26 the p-value was 0.67 (OS of 18 months after complete CRS and 17 months after optimal CRS). Both of these studies found a significant benefit of complete/optimal CRS vs. incomplete CRS (both < 0.001). Shih et al. 29 reported a significant difference (p = < 0.001) in OS among patients who underwent complete CRS (42 months) vs. optimal/incomplete CRS (19 months) vs. irresectable (2.2 months). In seven studies, the results of patients with complete and optimal CRS were combined and compared to incomplete CRS. 21–23,25,27,28,31 The complete/optimal CRS patients had an OS that ranged from 15 to 57 months, which was significantly better than after incomplete CRS (6–13 months), in all but two studies. 27,30 Five studies 21,25–28 focused solely on patients with serous EC. Despite that OS seemed substantially shorter in these studies, four out of five studies demonstrated a significant OS benefit of complete/optimal CRS compared to incomplete CRS. 21,25,26,28 McEachron et al. 26 reported an OS of 18 months for patients who had complete CRS, 17 months for optimal CRS, and 7 months for patients after incomplete CRS (p-value < 0.001). In the remaining three studies 21,25,28 , results of patients with complete/optimal CRS showed an OS ranging from 15 to 31 months, compared to 8 to 13 months after incomplete CRS. Two studies reported on OS after CRS in patients with extra-abdominal metastases. 24,31 Both showed a benefit of complete/optimal CRS regardless of their extra-abdominal metastases. In the study of Ueda et al. 31 , patients with extra-abdominal metastases had an OS of 57 months after complete/optimal CRS (residual disease ≤ 2cm), compared to 6 months after incomplete CRS (p-value = 0.0016). Similarly, Eto et al. 24 reported an OS after a complete CRS of 58 months vs. 11 months after optimal and incomplete CRS (p-value = 0.0012). Table 2 Overall survival after cytoreductive surgery Overall survival in months Study, year Total study population Complete CRS Optimal CRS Incomplete CRS p-value univariate analysis p-value multivariate analysis Ayhan, 2002 15 48 13 10 0.001 and < 0.001* Bristow, 2000 NR NR 34 11 0.0001 0.0001 Bristow, 2001 14 NR 21 10 0.004 Chi, 1997 NR NR 31 12 < 0.01** Eto, 2012 24 48 23 14 < 0.0001 < 0.001 Lee, 2014 NR NR 27 13 < 0.001 McEachron, 2022 13 18 17 7 0.67 and 0.05 Patsavas, 2011 22 NR 31 10 < 0.001 Shih, 2011 19** 42 NR 19 < 0.001*** < 0.001*** Tanioka, 2010 21 NR NR NR 0.066 Ueda, 2010 - I cohort 22 NR 43 6 0.0007 0.03 Ueda, 2010 – E cohort 20 NR 57 6 0.16 0.026 Definition of abbreviations: CRS = cytoreductive surgery, NR = not reported, I cohort = patients with intra-abdominal metastasis only, E cohort = patients with extra-abdominal metastasis * First p-value for complete CRS vs. optimal CRS, second p-value for complete/optimal CRS vs. incomplete CRS ** Compared to optimal vs. incomplete vs. irresectable *** Compared complete vs. optimal/incomplete vs. irresectable, median OS of patients which were irresectable is not reported in the table Meta-analysis The meta-analysis included nine eligible studies that all reported OS data on primary stage IV EC patients who underwent complete/optimal CRS vs. incomplete CRS. 20–22,24−28,31 Ueda et al. 31 provided the data on the OS for patients with intra-abdominal metastasis only and patients with additional extra-abdominal metastasis separately. Therefore, the data from this study were included in the meta-analysis as two separate cohorts of one study. Five studies reported a HR with 95%CI of OS for complete/optimal vs. incomplete CRS 21,24–26,31 , while for the remaining four studies 20,22,27,28 the HR was imputed by the method outlined by Tierney et al. 19 (Appendix C). The meta-analysis showed that complete/optimal CRS was associated with a significant better OS, compared to incomplete CRS in patients with primary stage IV EC (pooled HR 0.38, 95% CI 0.21–0.69) (Fig. 2 ). Among the studies included in our meta-analysis, the study by Eto et al. 24 carries the most weight in the meta-analysis because it has the largest population. This study, along with the study conducted by Moller et al. 27 showed the least favourable effect of complete/optimal CRS. Both patient groups in the study conducted by Ueda et al. 31 (intra-abdominal disease only (n = 15), and extra-abdominal disease (n = 15)) had a significant benefit of complete/optimal CRS. Sensitivity analysis showed that the estimate of the pooled HR was robust against study effects (see Appendix D). There was significant heterogeneity between studies (I 2 of 76.7%, Q test p < 0.0001, Fig. 2 ). The funnel plot (Fig. 3 ) shows substantial asymmetry favouring small positive studies, which indicates publication bias towards a beneficial effect of complete/optimal CRS, compared to incomplete CRS. This was confirmed by the test for asymmetry (p = 0.0014). Discussion The aim of this systematic review and meta-analysis was to determine the survival benefit of CRS in patients with primary stage IV EC. Through a comprehensive search across five databases, we included twelve studies. Ten studies showed a favourable effect on OS of complete/optimal CRS compared to incomplete CRS. Meta-analysis showed a pooled HR of 0.38 (95% CI 0.28–0.69, p = 0.0016) in favour of complete/optimal CRS. Three studies provided OS data for complete CRS vs. optimal vs. incomplete CRS and one for complete CRS vs. incomplete CRS. Three of them reported an OS of more than 40 months after complete CRS compared to 13–23 months after optimal and 7–14 months after incomplete CRS. Our results highlight the value of complete/optimal CRS, applying the same paradigm of high-stage ovarian cancer for EC. 7 Current guidelines cautiously recommend CRS in women with advanced EC if complete resection is deemed feasible. 4–6 However, reluctance among clinicians remains, due to the challenges of CRS in patients with stage IV EC which are also opposed in our study. Primary stage IV EC comprises a heterogeneous patient population due to several factors, firstly due to the presence of extra-abdominal metastases in some patients with stage IV EC. In our review, the majority of the patients had intra-abdominal metastasis only, however details on intra-abdominal localization were scarcely provided by the included studies. The significance of differentiation between pelvic, abdominal, and extra-abdominal metastases is demonstrated in the study by Height et al. 32 These authors applied the updated 2023 FIGO stage for endometrial cancer 33 , which classifies pelvic metastases as stage III and extra-abdominal metastases as stage IVC. Their findings revealed a significant prolonged OS among patients with stage III under the updated classification, while these patients were classified as stage IV in the FIGO 2009 system. Furthermore, current guidelines do not specify whether CRS should be attempted in the presence of extra-abdominal disease. Within our review, three of the seven studies that included patients with extra-abdominal disease provided information regarding the treatment of these metastases. These studies documented the surgical removal in some patients with extra-abdominal metastases located in the lungs, liver, supraclavicular and inguinal lymph nodes, umbilicus/skin, and breast. On the contrary, surgical removal of bone and brain metastases was not performed. Additionally, in one study (Eto et al. 24 ) radiotherapy was administered for extra-abdominal metastases. The majority of this cohort with extra-abdominal metastases had metastasis localized in a single anatomical region. These authors, together with Ueda et al. 31 reported a significant longer OS in patients who underwent complete or optimal CRS, regardless of the presence of extra-abdominal metastases. Guo et al. 34 have demonstrated a survival benefit after the surgical removal of lung, bone, or multiple organ metastasis. In contrast, surgical and/or radio therapeutic treatment of brain metastases does not seem to lead to a survival benefit. 34,35 Consequently, considering the findings of our and the abovementioned studies, we oppose the notion that complete/optimal CRS provides a benefit even if extra-abdominal disease is present, particularly if is the extra-abdominal metastasis is localized in a single anatomical region other than the brain. Additionally, the histologic subtype of EC introduces heterogeneity in patients with primary stage IV EC. Consequently, certain studies have focused on patients with a specific histological subtype, including only patients with endometroid EC or only patients with serous EC. Serous EC, characterized by its high-grade nature and aggressiveness, is more frequently detected in advanced stages of the disease. 36,37 This is also reflected in the number of patients with serous EC in our population (42%), despite the overall incidence of serous EC across all stages of EC being only 10%. 4,38 It has been suggested that less aggressive tumours are better suited for complete resection, implying that observed survival benefit may also be attributed to the histological characteristics of the tumour rather than solely the surgical intervention itself. 20,23,31 In our review five studies included patients with serous EC only, and four reported a significant advantage in OS after complete or optimal CRS compared to incomplete CRS. These findings demonstrate that CRS can be advantageous for both endometroid and serous stage IV EC patients. Lastly, due to patient heterogeneity it is not feasible to establish a uniform recommendation. Patients with EC typically exhibit characteristics such as advanced age, frailty, and potential comorbidities. These factors contribute to possible prolonged post-surgical recovery and an increased risk of peri- and postoperative complications and mortality 26 , particularly when extensive surgical procedures, including bowel resection, are needed for complete/optimal CRS. Notably, in our review, a considerable proportion of patients (40–47%) had macroscopic residual disease larger than 1 or 2 cm following CRS. Unfortunately, the studies included in our review provided limited information on peri- and postoperative complications. However, when reported, a notable percentage of patients experienced complications, with rates ranging from 23–51.6%. Furthermore, there are two reported patients with fatal surgery-related complications. Objective tools such as frailty assessment questionnaires like the G8 questionnaire 39 and WHO performance status can help predict post-surgical morbidity rates. Of the studies in our review, Bristow et al. 22 identified age and a good performance status, in addition to complete/optimal CRS, as significant predictors of survival. Eto et al. 24 further supported this notion, finding that patients with a good performance score and limited metastases were more likely suitable candidates for complete CRS. In conclusion, the treatment of elderly, frail women with primary stage IV EC poses additional challenges, requiring a delicate balance between the risk of complications and the potential survival benefits, where the focus should not be solely on age but also on physical health and patients’ preferences. We observed variations in the definition of optimal CRS among the studies included in our systematic review and meta-analysis. While most studies defined optimal CRS as ≤ 1cm residual disease, some studies used a less strict criterion of ≤ 2cm residual disease. Despite the difference in cut-off values, both optimal CRS definitions were associated with improved survival outcomes. Importantly, the survival benefit was superior in patients who underwent complete CRS compared to patients who underwent with optimal CRS. In our study cohort, a significant proportion (40 to 47%) still had residual macroscopic disease exceeding 1 or 2 cm following surgery. This emphasizes the importance of accurate pre-operative imaging and the need for innovative tools and techniques to maximize the chances of achieving complete CRS. Based on our findings, we recommend a thorough pre-operative assessment to determine the feasibility of complete CRS and only perform surgery if complete CRS appears achievable. In patients in whom complete CRS is not feasible during surgery, efforts should be made to achieve optimal CRS. Residual disease ≤ 1cm is more effectively managed through adjuvant radiotherapy or systemic therapy, emphasizing the importance of striving for the best possible surgical outcome. This study and two previously published systematic review and meta-analyses 14–16 have investigated the benefit of complete and/or optimal CRS in patients with advanced stage EC. The most recent study, a systematic review by Capozzi et al. 16 has investigated the optimal management for stage IVB EC and stated that determining the optimal treatment for these patients remains complex due to the lack of comprehensive evidence. Regarding the role of CRS in management for these patients the authors, similar to our perspective, conclude after the systematic review that optimal CRS remains crucial, however this effect is not quantified in a meta-analysis. The systematic review and meta-analysis by Albright et al. 14 , included studies on patients with both stage III and stage IV EC. Thirty-four studies were selected, which included a total of 1329 patients. Eleven of these studies were also included in our meta-analysis. The studies not included in our analysis focused on stage III EC, or did not report the survival data of patients with stage IV EC separately. To impute the HR of studies that were only reporting on median survival, Albright et al. 14 calculated the HR by dividing the median survival in the two groups, rather than taking the whole survival curves into account as recommended by Tierney et al. 19 . The estimated effect of complete/optimal CRS was similar to our meta-analysis. This does, however, not imply that the results presented in the meta-analysis of Albright et al. 18 can be extrapolated to patients with primary stage IV EC because patients with stage III EC are more often treated with emphasis on curative treatment, in contrast to patients with stage IV EC. In 2010, Barlin et al. 15 conducted a meta-analysis to determine prognostic factors for OS in patients with stage III and IV and recurrent EC. The authors selected 14 studies, including a total of 672 patients, of which 157 had recurrent EC. Their analysis also showed that complete CRS was significantly associated with a longer OS (9.3 months increase, range 0.1–18.5, p = 0.04). In their analysis, optimal CRS also positively impacted on OS (16 months increase, range − 0.7–32.7) compared to incomplete CRS, though this was on the verge of significance (p = 0.05). Hence, both meta-analyses concluded, in line with our meta-analysis, that complete CRS and optimal CRS are associated with improved survival outcomes. Future studies should prospectively investigate the effect of CRS in patients with primary stage IV EC on survival, morbidity and quality of life. Recording details on pre-operative imaging, surgical decision-making, and the extent of surgery might shed light on the predictability of achieving complete CRS, for example with the frailty assessment questionnaires. 39 Moreover, the heterogeneity resulting from the intra- or extra-abdominal localization of metastases can be more effectively classified through the incorporation of the updated 2023 FIGO stage for endometrial cancer. 33 Additionally, the role of the molecular classification 40 , both prognostic impact and predictive for completeness of CRS should be investigated. In stage I-III EC, the different molecular EC classes are known to have a distinct prognosis and respond differently to adjuvant chemotherapy and radiotherapy. 41–43 Besides one study in recurrent EC, which showed prognostic significance 44 , the value of molecularly classifying advanced EC has not been explored. Given the rarity of primary stage IV EC, a multi-center, international prospective study is most likely needed. To our knowledge, this study stands out as the sole systematic review and meta-analysis that specifically focuses on CRS in patients diagnosed with primary stage IV EC. The comprehensive analysis of the available literature presented here is particularly valuable, as the heterogeneity within the stage IV EC patient group is substantial, which often leads to reluctance in considering CRS. We conducted a comprehensive and systematic search across five databases to ensure the inclusion of all relevant studies that reported on survival outcomes after CRS in patients with primary stage IV EC. There was optimal use of the available data by advanced imputation techniques and performed state-of-the-art statistical analyses. The aim was to investigate the role of complete CRS in primary stage IV EC. However, due to limitations in the available data from the included studies, we could only investigate the effect of complete/optimal CRS versus incomplete CRS. The quality of every meta-analysis depends on the quality of the original studies that are pooled. Here, only relatively small, retrospective studies were available, which are hampered by selection bias, registration bias, and confounding by indication. In addition, our analysis showed that there is significant publication bias in this field, in favour of small studies showing a positive impact of complete/optimal CRS on survival. Hence, the estimated benefit of complete/optimal CRS might be overestimated. Another limitation is the substantial heterogeneity between the included studies. This causes additional uncertainty in the pooled estimate of the HR that is not fully addressed by the 95% confidence interval. Conclusion Primary stage IV EC is a rare and heterogeneous disease which is associated with a dismal prognosis. This systematic review and meta-analysis provides an overview of current evidence on the value of CRS and shows a benefit in OS in patients who underwent complete/optimal CRS, with a few of the included studies indicating a superior effect of complete compared to optimal CRS. This benefit seems also present in patients with extra-abdominal disease, and irrespective of the histological subtype of EC. These findings support the consideration of CRS in all patients with primary stage IV EC if achieving complete resection is deemed feasible. It is, however, crucial to take the harms and benefits of this extensive treatment into account and to adopt shared-decision making in these patients. Declarations Acknowledgements Not applicable. Author Contributions E. N.B. Pham : data curation, formal analysis, investigation, methodology, resources, visualization, writing - original draft, and writing - review & editing ; N. Horeweg : formal analysis, investigation, methodology, Resources, Software, validation, visualization, writing - review & editing. J. van der Marel : conceptualization, investigation, methodology, writing - review & editing; L.S. Nooij : conceptualization, investigation, methodology, supervision, writing - review & editing. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Data availability statement Research data are stored in an institutional repository and can be shared upon request to the corresponding author. Competing interest The authors declare no competing interest related to this work. Funding source The author(s) received no specific funding for this work. References Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet . 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Supplementary Files AppendixA.docx AppendixB.docx AppendixC.docx AppendixD.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 19 Apr, 2024 Reviews received at journal 18 Apr, 2024 Reviews received at journal 15 Apr, 2024 Reviewers agreed at journal 07 Apr, 2024 Reviewers agreed at journal 07 Apr, 2024 Reviewers agreed at journal 20 Mar, 2024 Reviewers agreed at journal 27 Feb, 2024 Reviewers invited by journal 27 Feb, 2024 Editor assigned by journal 20 Feb, 2024 Submission checks completed at journal 13 Feb, 2024 First submitted to journal 12 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3951101","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":272638579,"identity":"ca4ddeba-f67e-42c1-bb21-abbf454f7eed","order_by":0,"name":"Eveline Ngoc Bao Pham","email":"","orcid":"","institution":"Leiden University Medical Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eveline","middleName":"Ngoc Bao","lastName":"Pham","suffix":""},{"id":272638580,"identity":"ef78282f-4feb-4025-8689-180444a10f8e","order_by":1,"name":"Nanda Horeweg","email":"","orcid":"","institution":"Leiden University Medical Centre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nanda","middleName":"","lastName":"Horeweg","suffix":""},{"id":272638581,"identity":"ccba063d-24a8-49f6-a3a4-e6603a8763ee","order_by":2,"name":"Jacolien Marel","email":"","orcid":"","institution":"Rooseveltkliniek","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jacolien","middleName":"","lastName":"Marel","suffix":""},{"id":272638582,"identity":"0ba62f56-4175-49f5-8400-823c89ecc652","order_by":3,"name":"Linda Suzanne Nooij","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYBACPijNw9je3IAighOwwbX0HGxAESGohYFBIpFoLewPmAsqbGSYZz5sk7pRw5BHhBYeA+YZZ9J4GGcntknnHGMoJkYLAzNv22GIltwGhsQ2ohwG1jLzINFaGAwgWmYwEquFmcfgMA/ILz2JzdY5xyQIa+Fnb3/4mKfCxt6w/fDB2zk1Non9hLQwMDMwHADRhg1grgRBDQggT4LaUTAKRsEoGGEAAAtdMDL1PJUMAAAAAElFTkSuQmCC","orcid":"","institution":"Leiden University Medical Centre","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Linda","middleName":"Suzanne","lastName":"Nooij","suffix":""}],"badges":[],"createdAt":"2024-02-12 13:31:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3951101/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3951101/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51185715,"identity":"ddd4fec1-dbba-4a74-ab57-ec79b9c9a301","added_by":"auto","created_at":"2024-02-15 15:54:18","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82090,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eOverview of study selection for the systematic review and meta-analysis. \u003cbr\u003e\n Definition of abbreviation: EC = endometrial carcinoma\u003c/em\u003e\u003c/p\u003e","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/f2a6af3ab8ff66684e8f27f6.jpeg"},{"id":51185722,"identity":"4ff541a3-4a2a-4b44-b9cc-791776dd6e4a","added_by":"auto","created_at":"2024-02-15 15:54:20","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52153,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eForest plot of the meta-analysis comparing complete and optimal CRS vs incomplete CRS. The p-values are the values reported in original studies.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eI cohort=patients with intra-abdominal metastasis only, E cohort=patients with extra-abdominal metastasis\u003c/em\u003e\u003c/p\u003e","description":"","filename":"groupimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/abcfba4af4440e99e0da3385.jpeg"},{"id":51185713,"identity":"b7a497fd-977a-42bd-84eb-9b9317c77bc7","added_by":"auto","created_at":"2024-02-15 15:54:18","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":22493,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFunnel plot of the hazard ratio of complete/optimal CRS vs incomplete CRS by the standard error of the HR to assess publication bias. The studies are represented by dots. The dashed vertical line represents the pooled HR. Substantial asymmetry of the studies compared to the line of the pooled estimate is observed. The test for funnel plot asymmetry is significant and confirms the presence of publication bias.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"groupimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/726a74b45fcaac77fd4ff130.jpeg"},{"id":51185775,"identity":"f4285bf3-03db-4dbe-a504-16ed33c95109","added_by":"auto","created_at":"2024-02-15 15:54:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":504035,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/9402843b-5529-4cdb-8c70-224b0b906f46.pdf"},{"id":51185725,"identity":"5d00c03a-c32e-4d68-9fbe-491df9180296","added_by":"auto","created_at":"2024-02-15 15:54:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23678,"visible":true,"origin":"","legend":"","description":"","filename":"AppendixA.docx","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/c8d5f0383f2455e9c237b1c1.docx"},{"id":51185711,"identity":"b964bd82-c6fc-4bd9-8b22-062fa3cfc447","added_by":"auto","created_at":"2024-02-15 15:54:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":39564,"visible":true,"origin":"","legend":"","description":"","filename":"AppendixB.docx","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/26292b555e2375be001c728c.docx"},{"id":51185712,"identity":"3ec80325-6541-48d1-b76e-b8c13c69fa4a","added_by":"auto","created_at":"2024-02-15 15:54:18","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":42805,"visible":true,"origin":"","legend":"","description":"","filename":"AppendixC.docx","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/f2d0b36492bdc221af6b1a4a.docx"},{"id":51185727,"identity":"82a95a74-1c28-4c43-a870-57ae6c83c285","added_by":"auto","created_at":"2024-02-15 15:54:21","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":38750,"visible":true,"origin":"","legend":"","description":"","filename":"AppendixD.docx","url":"https://assets-eu.researchsquare.com/files/rs-3951101/v1/acabaa2bb757c4f216524080.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Survival benefit of cytoreductive surgery in patients with primary stage IV endometrial cancer: a systematic review \u0026 meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003ePrimary FIGO (International Federation of Gynecology and Obstetrics) stage IV endometrial cancer (EC) accounts for only 3% of all EC diagnoses and has a dismal prognosis with a five-year overall survival (OS) of 15\u0026ndash;21%.\u003csup\u003e1\u003c/sup\u003e At this moment, several systemic therapies have shown to improve survival in patients with stage IV EC\u003csup\u003e2,3\u003c/sup\u003e, but the value of surgery, specifically cytoreductive surgery (CRS), in the primary treatment of stage IV EC is still debated. The ESGO/ESTRO/ESP consensus guideline\u003csup\u003e4\u003c/sup\u003e, NCCN Clinical Practice Guidelines in Oncology\u003csup\u003e5\u003c/sup\u003e and National Cancer Institute's PDQ Endometrial cancer information\u003csup\u003e6\u003c/sup\u003e recommend CRS in patients with primary stage IV EC if complete resection is deemed feasible, following the rationale of CRS for ovarian cancer.\u003csup\u003e7\u0026ndash;11\u003c/sup\u003e However, these recommendations are based on several observational studies which should be interpreted cautiously due to the limited sample size, potential selection bias, and heterogeneity of patients included in the study. Furthermore, the survival benefit of CRS in patients with EC is not as clear as in ovarian cancer for whom complete and optimal CRS give a substantial survival benefit compared to incomplete or no CRS.\u003csup\u003e12,13\u003c/sup\u003e Consequently, there is still reluctance to perform CRS in patients with primary stage IV EC. The low incidence of primary stage IV EC, along with its heterogeneous nature, presents a complex challenge for clinicians. The heterogeneity arises not only from patient-specific factors such as comorbidities and WHO performance status, but also from heterogeneity in the extensiveness of stage IV EC, including intra-abdominal and/or distant metastases. When extra-abdominal disease is present, there may be even more reservations towards performing extensive intra-abdominal surgery.\u003c/p\u003e \u003cp\u003ePrior systematic reviews and meta-analyses have shown the potential benefit of complete CRS on OS in advanced stage EC, however these meta-analyses also included studies on recurrent EC, stage III EC or solely stage IVB.\u003csup\u003e14\u0026ndash;16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe aim of this study is to obtain insight into the benefit of CRS in patients with primary stage IV EC, and summarize the evidence for future treatment recommendations. We conducted a systematic review to comprehensively evaluate the existing literature on the survival benefit of CRS in patients with primary stage IV EC specifically. Additionally, a meta-analysis was performed to estimate the pooled effect of completeness of CRS on OS in women with primary stage IV EC.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis study was designed according to the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines\u003csup\u003e17\u003c/sup\u003e and registered at PROSPERO prior to abstract screening (registration number CRD42022302968).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eLiterature search\u003c/h2\u003e \u003cp\u003eA systematic literature search was performed in October 2022 in the Cochrane Library, Embase, MEDLINE, PubMed, and Web of Science using a search strategy including terms representing \u0026lsquo;endometrial cancer\u0026rsquo;, \u0026lsquo;cytoreductive surgery\u0026rsquo;, and \u0026lsquo;survival\u0026rsquo;. A detailed search is outlined in appendix A.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003eTo be eligible for inclusion, original studies had to enrol at least 10 patients with primary stage IV EC who underwent CRS. These studies were required to report data on progression-free survival (PFS) and/or OS stratified by the extent of cytoreduction, which is complete (no residual disease), optimal (residual disease\u0026thinsp;\u0026le;\u0026thinsp;1cm) or incomplete (gross residual disease\u0026thinsp;\u0026gt;\u0026thinsp;1 cm). If studies included patients with other stages of EC or recurrent EC, they were considered if survival data for primary stage IV patients were reported separately. Conference abstracts, case reports, review articles, meta-analyses, editorials, letters to the editor, and guidelines were excluded, as were studies on uterine sarcomas or those that involved HIPEC.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003cp\u003eThe eligibility of all studies identified through the systematic search was evaluated by at least two of three reviewers (JM, EP, and LN) independently. EndNote reference manager was utilized for the initial screening. The screening was based on the article title and abstract, and those selected underwent a full-text review to determine if they met the inclusion criteria. Throughout the selection process, the independent findings were compared, and any discrepancies were resolved by discussion until consensus was reached.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData extraction\u003c/h2\u003e \u003cp\u003eData was extracted and recorded by EP, LN and JM in a database with predefined variables. Extracted variables included median age, performance status, histological diagnosis, treatment, number of patients who received CRS, outcome of CRS, definitions of PFS and OS and the median PFS and OS, Kaplan-Meier estimates, hazard ratios (HR), 95% confidence intervals (95% CI), and p-values.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of risk of bias\u003c/h2\u003e \u003cp\u003eA modified Newcastle-Ottawa scale for the assessment of cohort studies was utilized to assess the quality of the included studies.\u003csup\u003e18\u003c/sup\u003e The scale was adjusted for application in our study with patients with complete/optimal CRS as the exposed cohort and incomplete CRS as the non-exposed cohort. Adequate follow-up time was set at a median follow up of at least 18 months (see Appendix B).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData synthesis\u003c/h2\u003e \u003cp\u003e All studies that were included in the systematic review were reviewed for eligibility for pooling in the meta-analysis by EP and NH. The objective of the meta-analysis was to estimate a pooled HR for PFS and/or OS by completeness of CRS. Studies were eligible for the meta-analysis if PFS and/or OS was compared between patients with a complete, optimal or incomplete CRS. If the HR and 95%CI were reported in the article, direct calculation of the natural logarithm of HR and its\u0026rsquo; variance were performed (Appendix C). If not, imputation according to the methodology of Tierney et al.\u003csup\u003e19\u003c/sup\u003e was performed using other data provided in the article (Appendix D).\u003c/p\u003e \u003cp\u003eFor the meta-analysis, pooled estimates of the HR were calculated using random-effects models with the DerSimonian-Laird estimator for the amount of heterogeneity. Each study contributed according to their sample size using inverse variance weights. Statistical significance was pre-defined as a (two-sided) p-value of \u0026lt;\u0026thinsp;0.05. Heterogeneity in effect size between studies was assessed using the I\u003csup\u003e2\u003c/sup\u003e and the Q-test. Statistical significance of heterogeneity was defined as I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% combined with a Q-test p-value of \u0026lt;\u0026thinsp;0.05. Analyses were performed in R version 3.6.1 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.r-project\u003c/span\u003e\u003cspan address=\"http://www.r-project\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. org/) using the metafor package (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://cran.r-project.org/web/packages/metafor/index.html\u003c/span\u003e\u003cspan address=\"https://cran.r-project.org/web/packages/metafor/index.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and quality assessment\u003c/h2\u003e \u003cp\u003eA total of 812 unique studies were found and screened for eligibility. 759 studies were excluded based on title and abstract screening for various reasons, including eligibility of the study population (such as no primary stage IV EC or different tumour types), no CRS, or case report, or no original study. For 52 studies, the full-texts were evaluated, which led to the exclusion of another 40 studies. 23 of these 40 studies did not report data on patients with primary stage IV EC at all, or the data were not reported separately for the included subgroup of patients with primary stage IV EC. The remaining 17 studies that were excluded did not report survival outcomes by outcome of CRS. This resulted in the inclusion of 12 studies for the systematic review.\u003csup\u003e20\u0026ndash;31\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOf these 12 included studies for the systematic review, two studies could not be included in the meta-analysis because the available data did not provide enough information for a pooled analysis.\u003csup\u003e23,30\u003c/sup\u003e The remaining ten studies were evaluated for the meta-analysis.\u003csup\u003e20\u0026ndash;22,24-29,31\u003c/sup\u003e As most studies only compared survival outcomes between the combined subgroup of complete and optimal CRS vs. incomplete CRS, a meta-analysis comparing complete CRS with either optimal or incomplete CRS was not feasible. The study of Shih et al.\u003csup\u003e29\u003c/sup\u003e had to be excluded as the authors compared the survival outcomes of complete CRS vs. optimal CRS vs. incomplete CRS. Hence, nine studies were pooled in the meta-analysis. As only two of these nine studies reported data on PFS\u003csup\u003e26,31\u003c/sup\u003e, we decided not to pool the data on PFS. An overview of the selection process is described in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The quality of the included studies was high in general with almost all studies scoring 7 or 8 out of 8 points (see Appendix B).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eDefinition of abbreviation: EC\u0026thinsp;=\u0026thinsp;endometrial carcinoma\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy and patient characteristics\u003c/h2\u003e \u003cp\u003eThe 12 studies that were included in the systematic review contained data on 768 patients with primary stage IV EC, of whom 748 (97%) underwent CRS. An overview of the study characteristics is shown in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The studies were published between 1997 and 2022,\u003c/p\u003e \u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eStudy characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cem\u003ePatient characteristics\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cem\u003eHistology\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003eSurgery\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cem\u003eAdjuvant therapy\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStudy, year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age (range, in years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eExtra-abdominal metastases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e%EEC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e%SEC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e%Other*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal CRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eComplete CRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOptimal CRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAyhan, 2002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62 (43\u0026ndash;73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (\u0026lt;\u0026thinsp;50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e32%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBristow, 2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (29\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (\u0026lt;\u0026thinsp;50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBristow, 2001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (36\u0026ndash;84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (\u0026lt;\u0026thinsp;50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e19%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChi, 1997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (42\u0026ndash;87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (\u0026lt;\u0026thinsp;50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44%**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEto, 2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e248\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (30\u0026ndash;89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (\u0026lt;\u0026thinsp;50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e248\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e41%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLee, 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70 (53\u0026ndash;87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e46%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMcEachron, 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (44\u0026ndash;89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e16%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMoller, 2004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (46\u0026ndash;89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e69%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatsavas, 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (47\u0026ndash;90)***\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShih, 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (42\u0026ndash;86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e17%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTanioka, 2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62 (38\u0026ndash;80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (\u0026lt;\u0026thinsp;50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUeda, 2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (48\u0026ndash;77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (=\u0026thinsp;50%).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67%**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"14\"\u003eDefinition of abbreviations: EEC\u0026thinsp;=\u0026thinsp;endometrioid endometrial cancer, SEC\u0026thinsp;=\u0026thinsp;serous endometrial cancer, CRS\u0026thinsp;=\u0026thinsp;cytoreductive surgery, CT\u0026thinsp;=\u0026thinsp;chemotherapy, RT\u0026thinsp;=\u0026thinsp;radiotherapy, NR\u0026thinsp;=\u0026thinsp;not reported\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"14\"\u003e* other histological types were clear cell, carcinosarcoma, squamous, mixed, mucinous, small cell, and poorly or undifferentiated\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"14\"\u003e** optimal CRS was defined as \u0026le;\u0026thinsp;2.0 cm,\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e*** mean age, for the total population (not only stage IV).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003ewere all retrospective, and mostly single-centre studies. Besides the study by Eto et al.\u003csup\u003e24\u003c/sup\u003e which included 248 patients, most studies had included a small number of patients (range 31\u0026ndash;68 patients). The majority of the included patients were postmenopausal. Four studies reported the pre-operative WHO performance status of patients (total of 386 patients)\u003csup\u003e22,24,30,31\u003c/sup\u003e, which was good in the majority of patients in studies (WHO 0\u0026ndash;1, n\u0026thinsp;=\u0026thinsp;351, 91% of 386 patients). Seven\u003csup\u003e20\u0026ndash;24,30,31\u003c/sup\u003e of the 12 studies also included patients with extra-abdominal disease (n\u0026thinsp;=\u0026thinsp;195), but the majority of the patients had intra-abdominal metastases only. If mentioned, the extra-abdominal metastases were mostly pulmonary metastases (n\u0026thinsp;=\u0026thinsp;85 in seven studies), pleural effusion (n\u0026thinsp;=\u0026thinsp;16), liver metastasis (n\u0026thinsp;=\u0026thinsp;25), or inguinal, supraclavicular or mediastinal lymph nodes (n\u0026thinsp;=\u0026thinsp;60). Ueda et al.\u003csup\u003e31\u003c/sup\u003e separately reported the outcomes of patients with intra-abdominal metastases only (n\u0026thinsp;=\u0026thinsp;15) and patients with extra-abdominal metastases (n\u0026thinsp;=\u0026thinsp;15). The most common histological subtype was endometroid EC (n\u0026thinsp;=\u0026thinsp;339, 44%) and serous EC (n\u0026thinsp;=\u0026thinsp;326, 42%). Complete CRS was specifically defined by three studies as no visible disease.\u003csup\u003e25,26,29\u003c/sup\u003e Optimal CRS was defined as a reduction of the tumour mass to \u0026le;\u0026thinsp;1cm in 10 studies\u003csup\u003e20\u0026ndash;22,24-30\u003c/sup\u003e, and as reduction to \u0026le;\u0026thinsp;2cm in two studies.\u003csup\u003e23,31\u003c/sup\u003e Definitions of survival were \u0026lsquo;from date of diagnosis\u0026rsquo;, or \u0026lsquo;date of surgery\u0026rsquo;\u003csup\u003e22\u0026ndash;26,28-30\u003c/sup\u003e until \u0026lsquo;clinical/radiological recurrence\u0026rsquo; (PFS) or \u0026lsquo;death\u0026rsquo; or \u0026lsquo;last contact\u0026rsquo; (OS). Four studies did not report a definition of survival.\u003csup\u003e20,21,27,31\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003e748 patients (97% of the study population) underwent CRS. In seven studies (549 patients) the outcomes of CRS were reported separately for complete, optimal, or incomplete CRS\u003csup\u003e20\u0026ndash;22,24-26,29\u003c/sup\u003e, which were 187 (34.1%), 146 (26.6%) and 216 (39.3%) patients respectively. In the remaining five studies (including 199 patients)\u003csup\u003e23,27,28,30,31\u003c/sup\u003e completeness of CRS was reported for complete and optimal together, being 105 patients (52.8%).\u003c/p\u003e \u003cp\u003eTo achieve complete or optimal CRS, additional surgical procedures were performed in a total of 123 patients (21% of the total study population of these studies, n\u0026thinsp;=\u0026thinsp;596) besides the standard procedure of hysterectomy with bilateral salpingo-oophorectomy and omentectomy. These additional surgical procedures were described in nine studies, and included bowel resections (n\u0026thinsp;=\u0026thinsp;61), appendectomies (n\u0026thinsp;=\u0026thinsp;47), splenectomies (n\u0026thinsp;=\u0026thinsp;2), liver resections (n\u0026thinsp;=\u0026thinsp;3), lung resections (n\u0026thinsp;=\u0026thinsp;2), and ureter/bladder resections (n\u0026thinsp;=\u0026thinsp;3).\u003csup\u003e21\u0026ndash;24,26-28,30,31\u003c/sup\u003e No details were provided on the placement of a stoma.\u003c/p\u003e \u003cp\u003eThe surgical treatment of the extra-abdominal metastases was described in three of the seven studies that specifically mentioned patients with extra-abdominal disease. In the study by Ayhan et al.\u003csup\u003e20\u003c/sup\u003e in three of the six patients the extra-abdominal metastases (lung, inguinal lymph node and supraclavicular lymph node) were completely resected. In the study of Eto et al.\u003csup\u003e24\u003c/sup\u003e a total of 93 patients (38% of the study population) had extra-abdominal disease. In 14 of them surgical removal was attempted, which was successful in 13 patients. Another study that reported on the treatment of extra-abdominal disease was the study by Ueda et al.\u003csup\u003e31\u003c/sup\u003e In this study 18 patients out of a total of 33 patients had one or more extra-abdominal metastases, located at the lungs (n\u0026thinsp;=\u0026thinsp;8), liver (n\u0026thinsp;=\u0026thinsp;7), pleural effusion (n\u0026thinsp;=\u0026thinsp;5), supraclavicular lymph nodes (n\u0026thinsp;=\u0026thinsp;5) and inguinal lymph nodes (n\u0026thinsp;=\u0026thinsp;2). Surgical removal of these metastases was performed for the liver metastases (n\u0026thinsp;=\u0026thinsp;2), supraclavicular lymph node metastases (n\u0026thinsp;=\u0026thinsp;2), lung metastases (n\u0026thinsp;=\u0026thinsp;1), and inguinal lymph node metastases (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e \u003cp\u003ePeri- and postoperative complications were reported in only five of 12 studies.\u003csup\u003e20\u0026ndash;22,24,27\u003c/sup\u003e Four of these studies provided the number of patients experiencing any peri-and postoperative complications\u003csup\u003e20\u0026ndash;23,27\u003c/sup\u003e, with a total of 46 out of 182 patients having complications (25.3%). The most comprehensive descriptions were reported by Ayhan et al.\u003csup\u003e20\u003c/sup\u003e, Bristow et al.\u003csup\u003e21\u003c/sup\u003e, and Moller et al.\u003csup\u003e27\u003c/sup\u003e, with complication rates of 40.5% (n\u0026thinsp;=\u0026thinsp;15), 51.6% (n\u0026thinsp;=\u0026thinsp;16), and 23% (n\u0026thinsp;=\u0026thinsp;12) respectively. The latter study revealed that the rate of complications did not differ between patients who underwent complete/optimal or incomplete CRS (p-value\u0026thinsp;=\u0026thinsp;0.33). Among the reported complications, two were fatal (0.5% of 430 patients in total), one patient died due to pulmonary embolism and the other due to small bowel obstruction followed by sepsis.\u003csup\u003e20,21\u003c/sup\u003e The five studies collectively documented 21 patients with major or severe complications (5% of 430 patients), including: myocardial infarction, gastrointestinal haemorrhage, anastomotic gastrointestinal leak, cerebrovascular accident, thrombosis, and pulmonary embolism. Fourteen patients experienced mild complications according to the authors (3% of 430 patients).\u003c/p\u003e \u003cp\u003eThe majority of patients (n\u0026thinsp;=\u0026thinsp;575, 75% of total study population) received chemotherapy. In two studies it was separately reported that four patients had received neo-adjuvant chemotherapy\u003csup\u003e25,30\u003c/sup\u003e, in the remaining studies neo-adjuvant or adjuvant chemotherapy was not separately mentioned. The adjuvant chemotherapy treatment regimens differed among studies. Platinum-based chemotherapy (carboplatin or cisplatin) was the only agent or combined with paclitaxel. Other frequently administered chemotherapy agents were doxorubicin) or cyclophosphamide. Less common chemotherapy regimens included agents such as docetaxel, epirubicine, ifosfamide, irinotecan, vinorelbine, and 5-fluorouracil.\u003c/p\u003e \u003cp\u003eAdjuvant radiotherapy was given in almost all studies to a small proportion of the patients (n\u0026thinsp;=\u0026thinsp;155, 20%), and consisted of external beam radiotherapy in the majority of the patients or vaginal brachytherapy or both.\u003csup\u003e20\u0026ndash;27,29,30\u003c/sup\u003e In four studies, a total of 66 patients (9%) received hormonal treatment as adjuvant therapy.\u003csup\u003e23,27,29\u0026ndash;31\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSurvival\u003c/h2\u003e \u003cp\u003eAll included studies reported on OS data and ten studies found a significant advantage of complete and/or optimal CRS compared to incomplete CRS in patients with primary stage IV EC (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003csup\u003e20\u0026ndash;26,28,29,31\u003c/sup\u003e Only three studies reported the OS separately for complete, optimal, and incomplete CRS.\u003csup\u003e20,24,26\u003c/sup\u003e In these three studies, OS was longer for patients who had complete CRS (48, 48, and 18 months) compared to patients with incomplete CRS (10, 14, and 7 months). Patients with optimal CRS had intermediate OS times which were closer to those of incomplete CRS in two out of three of the studies (13, 23, and 17 months). Ayhan et al.\u003csup\u003e20\u003c/sup\u003e and McEachron et al.\u003csup\u003e26\u003c/sup\u003e provided p-values that compared complete vs. optimal CRS. In the first study, the p-value was 0.001 (OS of 48 months after complete CRS and 13 months after optimal CRS), whilst for the study of McEachron et al.\u003csup\u003e26\u003c/sup\u003e the p-value was 0.67 (OS of 18 months after complete CRS and 17 months after optimal CRS). Both of these studies found a significant benefit of complete/optimal CRS vs. incomplete CRS (both \u0026lt;\u0026thinsp;0.001). Shih et al.\u003csup\u003e29\u003c/sup\u003e reported a significant difference (p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in OS among patients who underwent complete CRS (42 months) vs. optimal/incomplete CRS (19 months) vs. irresectable (2.2 months). In seven studies, the results of patients with complete and optimal CRS were combined and compared to incomplete CRS.\u003csup\u003e21\u0026ndash;23,25,27,28,31\u003c/sup\u003e The complete/optimal CRS patients had an OS that ranged from 15 to 57 months, which was significantly better than after incomplete CRS (6\u0026ndash;13 months), in all but two studies.\u003csup\u003e27,30\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFive studies\u003csup\u003e21,25\u0026ndash;28\u003c/sup\u003e focused solely on patients with serous EC. Despite that OS seemed substantially shorter in these studies, four out of five studies demonstrated a significant OS benefit of complete/optimal CRS compared to incomplete CRS.\u003csup\u003e21,25,26,28\u003c/sup\u003e McEachron et al.\u003csup\u003e26\u003c/sup\u003e reported an OS of 18 months for patients who had complete CRS, 17 months for optimal CRS, and 7 months for patients after incomplete CRS (p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the remaining three studies\u003csup\u003e21,25,28\u003c/sup\u003e, results of patients with complete/optimal CRS showed an OS ranging from 15 to 31 months, compared to 8 to 13 months after incomplete CRS.\u003c/p\u003e \u003cp\u003eTwo studies reported on OS after CRS in patients with extra-abdominal metastases.\u003csup\u003e24,31\u003c/sup\u003e Both showed a benefit of complete/optimal CRS regardless of their extra-abdominal metastases. In the study of Ueda et al.\u003csup\u003e31\u003c/sup\u003e, patients with extra-abdominal metastases had an OS of 57 months after complete/optimal CRS (residual disease\u0026thinsp;\u0026le;\u0026thinsp;2cm), compared to 6 months after incomplete CRS (p-value\u0026thinsp;=\u0026thinsp;0.0016). Similarly, Eto et al.\u003csup\u003e24\u003c/sup\u003e reported an OS after a complete CRS of 58 months vs. 11 months after optimal and incomplete CRS (p-value\u0026thinsp;=\u0026thinsp;0.0012).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOverall survival after cytoreductive surgery\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003eOverall survival in months\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy, year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eTotal study population\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eComplete CRS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eOptimal CRS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eIncomplete CRS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003ep-value univariate\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eanalysis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003ep-value multivariate analysis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAyhan, 2002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003cp\u003eand \u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBristow, 2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBristow, 2001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChi, 1997\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEto, 2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLee, 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMcEachron, 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003cp\u003eand\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.001***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoller, 2004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatsavas, 2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShih, 2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTanioka, 2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUeda, 2010 - I cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUeda, 2010 \u0026ndash; E cohort\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eDefinition of abbreviations: CRS\u0026thinsp;=\u0026thinsp;cytoreductive surgery, NR\u0026thinsp;=\u0026thinsp;not reported, I cohort\u0026thinsp;=\u0026thinsp;patients with\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eintra-abdominal metastasis only, E cohort\u0026thinsp;=\u0026thinsp;patients with extra-abdominal metastasis\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e* First p-value for complete CRS vs. optimal CRS, second p-value for complete/optimal CRS vs. incomplete CRS\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e** Compared to optimal vs. incomplete vs. irresectable\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*** Compared complete vs. optimal/incomplete vs. irresectable, median OS of patients which were irresectable is not reported in the table\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eMeta-analysis\u003c/h2\u003e \u003cp\u003eThe meta-analysis included nine eligible studies that all reported OS data on primary stage IV EC patients who underwent complete/optimal CRS vs. incomplete CRS.\u003csup\u003e20\u0026ndash;22,24\u0026minus;28,31\u003c/sup\u003e Ueda et al.\u003csup\u003e31\u003c/sup\u003e provided the data on the OS for patients with intra-abdominal metastasis only and patients with additional extra-abdominal metastasis separately. Therefore, the data from this study were included in the meta-analysis as two separate cohorts of one study. Five studies reported a HR with 95%CI of OS for complete/optimal vs. incomplete CRS\u003csup\u003e21,24\u0026ndash;26,31\u003c/sup\u003e, while for the remaining four studies\u003csup\u003e20,22,27,28\u003c/sup\u003e the HR was imputed by the method outlined by Tierney et al.\u003csup\u003e19\u003c/sup\u003e (Appendix C).\u003c/p\u003e \u003cp\u003eThe meta-analysis showed that complete/optimal CRS was associated with a significant better OS, compared to incomplete CRS in patients with primary stage IV EC (pooled HR 0.38, 95% CI 0.21\u0026ndash;0.69) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the studies included in our meta-analysis, the study by Eto et al.\u003csup\u003e24\u003c/sup\u003e carries the most weight in the meta-analysis because it has the largest population. This study, along with the study conducted by Moller et al.\u003csup\u003e27\u003c/sup\u003e showed the least favourable effect of complete/optimal CRS. Both patient groups in the study conducted by Ueda et al.\u003csup\u003e31\u003c/sup\u003e (intra-abdominal disease only (n\u0026thinsp;=\u0026thinsp;15), and extra-abdominal disease (n\u0026thinsp;=\u0026thinsp;15)) had a significant benefit of complete/optimal CRS.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSensitivity analysis showed that the estimate of the pooled HR was robust against study effects (see Appendix D). There was significant heterogeneity between studies (I\u003csup\u003e2\u003c/sup\u003e of 76.7%, Q test p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The funnel plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e) shows substantial asymmetry favouring small positive studies, which indicates publication bias towards a beneficial effect of complete/optimal CRS, compared to incomplete CRS. This was confirmed by the test for asymmetry (p\u0026thinsp;=\u0026thinsp;0.0014).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe aim of this systematic review and meta-analysis was to determine the survival benefit of CRS in patients with primary stage IV EC. Through a comprehensive search across five databases, we included twelve studies. Ten studies showed a favourable effect on OS of complete/optimal CRS compared to incomplete CRS. Meta-analysis showed a pooled HR of 0.38 (95% CI 0.28\u0026ndash;0.69, p\u0026thinsp;=\u0026thinsp;0.0016) in favour of complete/optimal CRS. Three studies provided OS data for complete CRS vs. optimal vs. incomplete CRS and one for complete CRS vs. incomplete CRS. Three of them reported an OS of more than 40 months after complete CRS compared to 13\u0026ndash;23 months after optimal and 7\u0026ndash;14 months after incomplete CRS. Our results highlight the value of complete/optimal CRS, applying the same paradigm of high-stage ovarian cancer for EC.\u003csup\u003e7\u003c/sup\u003e Current guidelines cautiously recommend CRS in women with advanced EC if complete resection is deemed feasible.\u003csup\u003e4\u0026ndash;6\u003c/sup\u003e However, reluctance among clinicians remains, due to the challenges of CRS in patients with stage IV EC which are also opposed in our study.\u003c/p\u003e \u003cp\u003ePrimary stage IV EC comprises a heterogeneous patient population due to several factors, firstly due to the presence of extra-abdominal metastases in some patients with stage IV EC. In our review, the majority of the patients had intra-abdominal metastasis only, however details on intra-abdominal localization were scarcely provided by the included studies. The significance of differentiation between pelvic, abdominal, and extra-abdominal metastases is demonstrated in the study by Height et al.\u003csup\u003e32\u003c/sup\u003e These authors applied the updated 2023 FIGO stage for endometrial cancer\u003csup\u003e33\u003c/sup\u003e, which classifies pelvic metastases as stage III and extra-abdominal metastases as stage IVC. Their findings revealed a significant prolonged OS among patients with stage III under the updated classification, while these patients were classified as stage IV in the FIGO 2009 system. Furthermore, current guidelines do not specify whether CRS should be attempted in the presence of extra-abdominal disease. Within our review, three of the seven studies that included patients with extra-abdominal disease provided information regarding the treatment of these metastases. These studies documented the surgical removal in some patients with extra-abdominal metastases located in the lungs, liver, supraclavicular and inguinal lymph nodes, umbilicus/skin, and breast. On the contrary, surgical removal of bone and brain metastases was not performed. Additionally, in one study (Eto et al.\u003csup\u003e24\u003c/sup\u003e) radiotherapy was administered for extra-abdominal metastases. The majority of this cohort with extra-abdominal metastases had metastasis localized in a single anatomical region. These authors, together with Ueda et al.\u003csup\u003e31\u003c/sup\u003e reported a significant longer OS in patients who underwent complete or optimal CRS, regardless of the presence of extra-abdominal metastases. Guo et al.\u003csup\u003e34\u003c/sup\u003e have demonstrated a survival benefit after the surgical removal of lung, bone, or multiple organ metastasis. In contrast, surgical and/or radio therapeutic treatment of brain metastases does not seem to lead to a survival benefit.\u003csup\u003e34,35\u003c/sup\u003e Consequently, considering the findings of our and the abovementioned studies, we oppose the notion that complete/optimal CRS provides a benefit even if extra-abdominal disease is present, particularly if is the extra-abdominal metastasis is localized in a single anatomical region other than the brain.\u003c/p\u003e \u003cp\u003eAdditionally, the histologic subtype of EC introduces heterogeneity in patients with primary stage IV EC. Consequently, certain studies have focused on patients with a specific histological subtype, including only patients with endometroid EC or only patients with serous EC. Serous EC, characterized by its high-grade nature and aggressiveness, is more frequently detected in advanced stages of the disease.\u003csup\u003e36,37\u003c/sup\u003e This is also reflected in the number of patients with serous EC in our population (42%), despite the overall incidence of serous EC across all stages of EC being only 10%.\u003csup\u003e4,38\u003c/sup\u003e It has been suggested that less aggressive tumours are better suited for complete resection, implying that observed survival benefit may also be attributed to the histological characteristics of the tumour rather than solely the surgical intervention itself.\u003csup\u003e20,23,31\u003c/sup\u003e In our review five studies included patients with serous EC only, and four reported a significant advantage in OS after complete or optimal CRS compared to incomplete CRS. These findings demonstrate that CRS can be advantageous for both endometroid and serous stage IV EC patients.\u003c/p\u003e \u003cp\u003eLastly, due to patient heterogeneity it is not feasible to establish a uniform recommendation. Patients with EC typically exhibit characteristics such as advanced age, frailty, and potential comorbidities. These factors contribute to possible prolonged post-surgical recovery and an increased risk of peri- and postoperative complications and mortality\u003csup\u003e26\u003c/sup\u003e, particularly when extensive surgical procedures, including bowel resection, are needed for complete/optimal CRS. Notably, in our review, a considerable proportion of patients (40\u0026ndash;47%) had macroscopic residual disease larger than 1 or 2 cm following CRS. Unfortunately, the studies included in our review provided limited information on peri- and postoperative complications. However, when reported, a notable percentage of patients experienced complications, with rates ranging from 23\u0026ndash;51.6%. Furthermore, there are two reported patients with fatal surgery-related complications. Objective tools such as frailty assessment questionnaires like the G8 questionnaire\u003csup\u003e39\u003c/sup\u003e and WHO performance status can help predict post-surgical morbidity rates. Of the studies in our review, Bristow et al.\u003csup\u003e22\u003c/sup\u003e identified age and a good performance status, in addition to complete/optimal CRS, as significant predictors of survival. Eto et al.\u003csup\u003e24\u003c/sup\u003e further supported this notion, finding that patients with a good performance score and limited metastases were more likely suitable candidates for complete CRS. In conclusion, the treatment of elderly, frail women with primary stage IV EC poses additional challenges, requiring a delicate balance between the risk of complications and the potential survival benefits, where the focus should not be solely on age but also on physical health and patients\u0026rsquo; preferences.\u003c/p\u003e \u003cp\u003eWe observed variations in the definition of optimal CRS among the studies included in our systematic review and meta-analysis. While most studies defined optimal CRS as \u0026le;\u0026thinsp;1cm residual disease, some studies used a less strict criterion of \u0026le;\u0026thinsp;2cm residual disease. Despite the difference in cut-off values, both optimal CRS definitions were associated with improved survival outcomes. Importantly, the survival benefit was superior in patients who underwent complete CRS compared to patients who underwent with optimal CRS. In our study cohort, a significant proportion (40 to 47%) still had residual macroscopic disease exceeding 1 or 2 cm following surgery. This emphasizes the importance of accurate pre-operative imaging and the need for innovative tools and techniques to maximize the chances of achieving complete CRS. Based on our findings, we recommend a thorough pre-operative assessment to determine the feasibility of complete CRS and only perform surgery if complete CRS appears achievable. In patients in whom complete CRS is not feasible during surgery, efforts should be made to achieve optimal CRS. Residual disease\u0026thinsp;\u0026le;\u0026thinsp;1cm is more effectively managed through adjuvant radiotherapy or systemic therapy, emphasizing the importance of striving for the best possible surgical outcome.\u003c/p\u003e \u003cp\u003eThis study and two previously published systematic review and meta-analyses\u003csup\u003e14\u0026ndash;16\u003c/sup\u003e have investigated the benefit of complete and/or optimal CRS in patients with advanced stage EC. The most recent study, a systematic review by Capozzi et al.\u003csup\u003e16\u003c/sup\u003e has investigated the optimal management for stage IVB EC and stated that determining the optimal treatment for these patients remains complex due to the lack of comprehensive evidence. Regarding the role of CRS in management for these patients the authors, similar to our perspective, conclude after the systematic review that optimal CRS remains crucial, however this effect is not quantified in a meta-analysis. The systematic review and meta-analysis by Albright et al.\u003csup\u003e14\u003c/sup\u003e, included studies on patients with both stage III and stage IV EC. Thirty-four studies were selected, which included a total of 1329 patients. Eleven of these studies were also included in our meta-analysis. The studies not included in our analysis focused on stage III EC, or did not report the survival data of patients with stage IV EC separately. To impute the HR of studies that were only reporting on median survival, Albright et al.\u003csup\u003e14\u003c/sup\u003e calculated the HR by dividing the median survival in the two groups, rather than taking the whole survival curves into account as recommended by Tierney et al.\u003csup\u003e19\u003c/sup\u003e. The estimated effect of complete/optimal CRS was similar to our meta-analysis. This does, however, not imply that the results presented in the meta-analysis of Albright et al.\u003csup\u003e18\u003c/sup\u003e can be extrapolated to patients with primary stage IV EC because patients with stage III EC are more often treated with emphasis on curative treatment, in contrast to patients with stage IV EC. In 2010, Barlin et al.\u003csup\u003e15\u003c/sup\u003e conducted a meta-analysis to determine prognostic factors for OS in patients with stage III and IV and recurrent EC. The authors selected 14 studies, including a total of 672 patients, of which 157 had recurrent EC. Their analysis also showed that complete CRS was significantly associated with a longer OS (9.3 months increase, range 0.1\u0026ndash;18.5, p\u0026thinsp;=\u0026thinsp;0.04). In their analysis, optimal CRS also positively impacted on OS (16 months increase, range \u0026minus;\u0026thinsp;0.7\u0026ndash;32.7) compared to incomplete CRS, though this was on the verge of significance (p\u0026thinsp;=\u0026thinsp;0.05). Hence, both meta-analyses concluded, in line with our meta-analysis, that complete CRS and optimal CRS are associated with improved survival outcomes.\u003c/p\u003e \u003cp\u003eFuture studies should prospectively investigate the effect of CRS in patients with primary stage IV EC on survival, morbidity and quality of life. Recording details on pre-operative imaging, surgical decision-making, and the extent of surgery might shed light on the predictability of achieving complete CRS, for example with the frailty assessment questionnaires.\u003csup\u003e39\u003c/sup\u003e Moreover, the heterogeneity resulting from the intra- or extra-abdominal localization of metastases can be more effectively classified through the incorporation of the updated 2023 FIGO stage for endometrial cancer.\u003csup\u003e33\u003c/sup\u003e Additionally, the role of the molecular classification\u003csup\u003e40\u003c/sup\u003e, both prognostic impact and predictive for completeness of CRS should be investigated. In stage I-III EC, the different molecular EC classes are known to have a distinct prognosis and respond differently to adjuvant chemotherapy and radiotherapy.\u003csup\u003e41\u0026ndash;43\u003c/sup\u003e Besides one study in recurrent EC, which showed prognostic significance\u003csup\u003e44\u003c/sup\u003e, the value of molecularly classifying advanced EC has not been explored. Given the rarity of primary stage IV EC, a multi-center, international prospective study is most likely needed.\u003c/p\u003e \u003cp\u003eTo our knowledge, this study stands out as the sole systematic review and meta-analysis that specifically focuses on CRS in patients diagnosed with primary stage IV EC. The comprehensive analysis of the available literature presented here is particularly valuable, as the heterogeneity within the stage IV EC patient group is substantial, which often leads to reluctance in considering CRS. We conducted a comprehensive and systematic search across five databases to ensure the inclusion of all relevant studies that reported on survival outcomes after CRS in patients with primary stage IV EC. There was optimal use of the available data by advanced imputation techniques and performed state-of-the-art statistical analyses. The aim was to investigate the role of complete CRS in primary stage IV EC. However, due to limitations in the available data from the included studies, we could only investigate the effect of complete/optimal CRS versus incomplete CRS.\u003c/p\u003e \u003cp\u003eThe quality of every meta-analysis depends on the quality of the original studies that are pooled. Here, only relatively small, retrospective studies were available, which are hampered by selection bias, registration bias, and confounding by indication. In addition, our analysis showed that there is significant publication bias in this field, in favour of small studies showing a positive impact of complete/optimal CRS on survival. Hence, the estimated benefit of complete/optimal CRS might be overestimated. Another limitation is the substantial heterogeneity between the included studies. This causes additional uncertainty in the pooled estimate of the HR that is not fully addressed by the 95% confidence interval.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePrimary stage IV EC is a rare and heterogeneous disease which is associated with a dismal prognosis. This systematic review and meta-analysis provides an overview of current evidence on the value of CRS and shows a benefit in OS in patients who underwent complete/optimal CRS, with a few of the included studies indicating a superior effect of complete compared to optimal CRS. This benefit seems also present in patients with extra-abdominal disease, and irrespective of the histological subtype of EC. These findings support the consideration of CRS in all patients with primary stage IV EC if achieving complete resection is deemed feasible. It is, however, crucial to take the harms and benefits of this extensive treatment into account and to adopt shared-decision making in these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE. N.B. Pham\u003c/strong\u003e: data curation, formal analysis, investigation, methodology, resources, visualization, writing - original draft, and writing - review \u0026amp; editing\u003cstrong\u003e; N. Horeweg\u003c/strong\u003e: formal analysis, investigation, methodology, Resources, Software, validation, visualization, writing - review \u0026amp; editing. \u003cstrong\u003eJ. van der Marel\u003c/strong\u003e: conceptualization, investigation, methodology, writing - review \u0026amp; editing; \u003cstrong\u003eL.S. Nooij\u003c/strong\u003e: conceptualization, investigation, methodology, supervision, writing - review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearch data are stored in an institutional repository and can be shared upon request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interest related to this work.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) received no specific funding for this work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCreasman WT, Odicino F, Maisonneuve P, et al. 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Nov 2012;127(2):338-44. doi:S0090-8258(12)00697-X [pii] 10.1016/j.ygyno.2012.08.012\u003c/li\u003e\n \u003cli\u003eLee LJ, Demaria R, Berkowitz R, Matulonis U, Viswanathan AN. Clinical predictors of long-term survival for stage IVB uterine papillary serous carcinoma confined to the abdomen. \u003cem\u003eGynecol Oncol\u003c/em\u003e. Jan 2014;132(1):65-9. doi:S0090-8258(13)01284-5 [pii] 10.1016/j.ygyno.2013.10.035\u003c/li\u003e\n \u003cli\u003eMcEachron J, Zhou N, Hastings V, et al. Optimal cytoreduction followed by chemoradiation in stage IVB uterine serous carcinoma. \u003cem\u003eCancer Treat Res Commun\u003c/em\u003e. Sep 2 2022;33:100631. doi:S2468-2942(22)00122-8 [pii] 10.1016/j.ctarc.2022.100631\u003c/li\u003e\n \u003cli\u003eMoller KA, Gehrig PA, Van Le L, Secord AA, Schorge J. The role of optimal debulking in advanced stage serous carcinoma of the uterus. \u003cem\u003eGynecol Oncol\u003c/em\u003e. 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Endometrial carcinoma with extra-abdominal metastasis: improved prognosis following cytoreductive surgery. \u003cem\u003eAnn Surg Oncol\u003c/em\u003e. Apr 2010;17(4):1111-7. doi:10.1245/s10434-009-0892-8\u003c/li\u003e\n \u003cli\u003eHaight PJ, Riedinger CJ, Backes FJ, O\u0026apos;Malley DM, Cosgrove CM. The right time for change: A report on the heterogeneity of IVB endometrial cancer and improved risk-stratification provided by new 2023 FIGO staging criteria. \u003cem\u003eGynecol Oncol\u003c/em\u003e. Aug 2023;175:32-40. doi:S0090-8258(23)00322-0 [pii] 10.1016/j.ygyno.2023.05.069\u003c/li\u003e\n \u003cli\u003eBerek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023. \u003cem\u003eInt J Gynaecol Obstet\u003c/em\u003e. Aug 2023;162(2):383-394. doi:10.1002/ijgo.14923\u003c/li\u003e\n \u003cli\u003eGuo J, Cui X, Zhang X, Qian H, Duan H, Zhang Y. 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Endometrial cancer. \u003cem\u003eLancet\u003c/em\u003e. Aug 6-12 2005;366(9484):491-505. doi:S0140-6736(05)67063-8 [pii] 10.1016/S0140-6736(05)67063-8\u003c/li\u003e\n \u003cli\u003eSagae S, Susumu N, Viswanathan AN, et al. Gynecologic Cancer InterGroup (GCIG) consensus review for uterine serous carcinoma. \u003cem\u003eInt J Gynecol Cancer\u003c/em\u003e. Nov 2014;24(9 Suppl 3):S83-9. doi:00009577-201411003-00017 [pii] 10.1097/IGC.0000000000000264\u003c/li\u003e\n \u003cli\u003eAnic K, Flohr F, Schmidt MW, et al. Frailty assessment tools predict perioperative outcome in elderly patients with endometrial cancer better than age or BMI alone: a retrospective observational cohort study. \u003cem\u003eJ Cancer Res Clin Oncol\u003c/em\u003e. Apr 2023;149(4):1551-1560. doi:10.1007/s00432-022-04038-6 [pii] 4038 [pii] 10.1007/s00432-022-04038-6\u003c/li\u003e\n \u003cli\u003eCancer Genome Atlas Research N, Kandoth C, Schultz N, et al. 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Mar 1 2017;123(5):802-813. doi:10.1002/cncr.30496\u003c/li\u003e\n \u003cli\u003eHoreweg N, Nout RA, Jurgenliemk-Schulz IM, et al.\u0026nbsp;Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer.\u0026nbsp;\u003cem\u003eJ Clin Oncol\u003c/em\u003e. Jul 24 2023:JCO2300062. doi:10.1200/JCO.23.00062\u003c/li\u003e\n \u003cli\u003eSiegenthaler F, Lindemann K, Epstein E, et al.\u0026nbsp;Time to first recurrence, pattern of recurrence, and survival after recurrence in endometrial cancer according to the molecular classification. \u003cem\u003eGynecol Oncol\u003c/em\u003e. May 2022;165(2):230-238. doi:S0090-8258(22)00143-3 [pii] 10.1016/j.ygyno.2022.02.024\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bjc-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BJC Reports](https://www.springer.com/journal/44276) ","snPcode":"44276","submissionUrl":"https://submission.springernature.com/new-submission/44276/3","title":"BJC Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3951101/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3951101/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eBackground\u003c/span\u003e. This systematic review and meta-analysis aimed to investigate the survival outcomes following cytoreductive surgery (CRS) in patients with primary stage IV endometrial cancer (EC). The role of CRS in this context is debatable, given the limited evidence from large studies and the inherent heterogeneity among patients with stage IV EC.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMethods\u003c/span\u003e. We systematically searched the Cochrane Library, Embase, MEDLINE/PubMed, and Web of Science for original studies reporting survival outcomes of primary stage IV EC after complete, optimal, and incomplete CRS. Pooled hazard ratios (HRs) for overall survival (OS) per CRS outcome were calculated using a random-effects model. Heterogeneity was assessed using the I2 and the Q-test.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eResults.\u003c/span\u003e Twelve studies, including 748 patients, were analysed. 187 patients underwent complete CRS, and 146 patients optimal CRS. Ten studies reported a significant OS benefit after complete (18\u0026ndash;48 months) and optimal CRS (13\u0026ndash;34 months) compared to incomplete CRS (7\u0026ndash;19 months). A benefit was also observed in patients with serous EC or extra- abdominal metastasis. Meta-analysis showed improved OS after complete/optimal vs. incomplete CRS (HR\u0026thinsp;=\u0026thinsp;0.38, 95% CI 0.21\u0026ndash;0.69, p\u0026thinsp;=\u0026thinsp;0.0016). Heterogeneity was substantial between studies (I2\u0026thinsp;=\u0026thinsp;76.7%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eConclusion\u003c/span\u003e. Complete/optimal CRS results in an OS benefit for patients with primary stage IV EC, including serous EC or extra-abdominal metastasis.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePROSPERO registration\u003c/b\u003e. CRD42022302968 on May 10th, 2022.\u003c/p\u003e","manuscriptTitle":"Survival benefit of cytoreductive surgery in patients with primary stage IV endometrial cancer: a systematic review \u0026amp; meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-15 15:53:17","doi":"10.21203/rs.3.rs-3951101/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-19T19:21:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-18T11:56:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-04-15T12:03:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"185f7207-4b8e-48e5-a1fc-7d916cf79841","date":"2024-04-07T08:42:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"635f2723-2de2-4183-b29a-dcc1daf7ec4a","date":"2024-04-07T08:37:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9224f807-52c8-4d66-8d85-837cbcf3deca","date":"2024-03-20T22:42:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"829d4474-500f-40f5-aec2-f79201e0b018","date":"2024-02-27T22:03:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-27T20:40:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-20T19:55:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-13T12:54:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BJC Reports","date":"2024-02-12T13:30:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bjc-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BJC Reports](https://www.springer.com/journal/44276) ","snPcode":"44276","submissionUrl":"https://submission.springernature.com/new-submission/44276/3","title":"BJC Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5a6f7f9f-f681-4e52-a70f-d4c74dfb8eb0","owner":[],"postedDate":"February 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-07-20T19:39:02+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-15 15:53:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3951101","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3951101","identity":"rs-3951101","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}