ESMO-ESGO-ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up

ESMO-ESGO-ESTRO Consensus guidelines ESMO–ESGO–ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up q Nicoletta Colombo a, ⇑ , Carien Creutzberg b , Frederic Amant c,d , Tjalling Bosse e , Antonio González-Martín f,g , Jonathan Ledermann h , Christian Marth i , Remi Nout j , Denis Querleu k,l , Mansoor Raza Mirza m , Cristiana Sessa n , The ESMO–ESGO–ESTRO Endometrial Consensus Conference Working Group 1 a Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; b Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; c Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium; d Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; e Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; f Medical Oncology Department, GEICO, Madrid, Spain; g MD Anderson Cancer Center, Madrid, Spain; h Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; i Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; j Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; k Department of Surgery, Institut Bergonié, Bordeaux, France; l Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Canada; m Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; and n Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland article info Article history: Received 16 October 2015 Accepted 18 November 2015 Available online 9 December 2015 Keywords: Endometrial neoplasms Practice guideline Consensus Treatment Adjuvant Surgery abstract The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11–13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically-relevant questions about endometrial cancer relating to the following four areas: Prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article. Ó2015 The Authors. Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 117 (2015) 559–581 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/). Key message This ESMO–ESGO–ESTRO consensus conference manuscript was compiled by a multidisciplinary panel of 40 experts. It addresses clinically-relevant questions regarding prevention, screening, surgery, adjuvant therapy and management of advanced/recurrent endometrial cancer, and complements the ESMO clinical practice guidelines. Recommendations provided are accompanied by relevant supporting evidence. Introduction Endometrial cancer is the most common gynaecological cancer in developed countries. The number of newly diagnosed cases in Europe was nearly 100,000 in 2012, with an age standardised incidence of 13.6 per 100,000 women. Cumulative risk of a diagnosis of endometrial cancer is 1.71% [1]. More than 90% of cases of endometrial cancer occur in women >50 years of age, with a median age at diagnosis of 63 years. However, 4% of women with endometrial cancer are younger than 40 years old [2], many of whom still wish to retain their fertility. The majority of endometrial cancers are diagnosed early (80% in stage I), with five-year survival rates of over 95%. However, fiveyear survival rates are much lower if there is regional spread or distant disease (68% and 17%, respectively) [3]. Historically, endometrial carcinoma has been classified into two main clinicopathological and molecular types: Type I is the much http://dx.doi.org/10.1016/j.radonc.2015.11.013 0167-8140/Ó2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). q These Guidelines were developed by the European Society for Medical Oncology (ESMO), the European Society of Gynaecological Oncology (ESGO), and the European SocieTy of Radiotherapy and Oncology (ESTRO), and are published jointly in the Annals of Oncology, the International Journal of Gynecological Cancer and Radiotherapy & Oncology. The three societies nominated participants who attended the consensus conference and co-authored the final manuscript. ⇑ Correspondence to: Prof. Nicoletta Colombo, ESMO Guidelines Committee, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland. E-mail address: [email protected]. 1 See Appendix for members of the ESMO–ESGO–ESTRO Endometrial Consensus Conference Working Group. Radiotherapy and Oncology 117 (2015) 559–581 Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: www.thegreenjournal.com more common endometrioid adenocarcinoma (80–90%) and Type II comprises non-endometrioid subtypes such as serous, clear cell and undifferentiated carcinomas, as well as carcinosarcoma/ malignant-mixed Müllerian tumour (10–20%) [4]. Molecular data in support of this dichotomous classification have become an integral component of pathologic evaluation, as type I carcinomas are preferentially associated with genetic alterations in PTEN, KRAS, CTNNB1 and PIK3CA and MLH1 promoter hypermethylation, whereas serous carcinomas prototypically harbour TP53 mutations. However, this dualistic model has limitations as considerable molecular heterogeneity exists; for example, 25% of high grade endometrioid carcinomas express mutated TP53 and behave like serous carcinomas [5]. Extensive work performed by The Cancer Genome Atlas (TCGA) Research Network has significantly improved our understanding of the molecular landscape of endometrial cancer, introducing not 2, but 4 molecular subtypes including: (1) POLE (ultramutated) tumours, (2) microsatellite unstable tumours, (3) copy-number high tumours with mostly TP53 mutations and (4) remaining group without these alterations [6]. Hereditary endometrial adenocarcinomas are mostly seen in families with hereditary non-polyposis colon cancer (HNPCC, Lynch syndrome [LS]). Although the majority of endometrial carcinomas related to LS are Type I cancers, the proportion of Type II cancers seems to be higher than in the case of sporadic endometrial carcinoma [7]. Although the majority of cases of endometrial cancer are diagnosed at an early stage, differences in patient characteristics and histopathological features of the disease impact both on patient prognosis and the recommended treatment approach. Given the large body of literature available that addresses the management of endometrial cancer, the aim of this consensus conference was to produce multidisciplinary evidence-based guidelines on selected clinically-relevant questions in order to complement the already-available European Society for Medical Oncology (ESMO) Clinical Practice Guidelines (CPG) for the diagnosis, treatment and follow-up of patients with endometrial cancer [8]. Methods In 2014, ESMO decided to update the clinical recommendations for endometrial cancer using a consensus conference approach. The consensus panel comprised 40 experts in the management of endometrial cancer, and included representation from the European SocieTy for Radiotherapy & Oncology (ESTRO), the European Society of Gynaecological Oncology (ESGO) and ESMO. Each panel member was assigned to one of four working groups, with a working group chair and co-chair appointed for each group. Three consensus conference chairs (N. Colombo, C. Creutzberg, C. Sessa) were also appointed. Each working group was assigned a subject area as follows: 1. Prevention and screening of endometrial cancer (Chair: F. Amant; Co-Chair: T. Bosse). 2. Surgery (Chair: C Marth; Co-Chair: D. Querleu). 3. Adjuvant treatment (Chair: R. Nout; Co-Chair: M.R. Mirza). 4. Advanced and recurrent disease (Chair: J. Ledermann; Co-Chair: A. González-Martín). The consensus conference was held on 11–13 December 2014 in Milan, Italy. Before this consensus conference, three clinicallyrelevant questions were identified for each subject area/working group, giving a total of 12 clinically-relevant questions as follows: 1. Which surveillance should be used for asymptomatic women? 2. What work-up and management scheme should be undertaken for fertility preserving therapy in patients with atypical hyperplasia (AH)/endometrial intraepithelial neoplasia (EIN) and grade 1 endometrioid endometrial cancer (EEC)? 3. Which (molecular) markers can help distinguish (pre)- cancerous lesions from benign mimics? 4. How does the medical condition influence surgical treatment? 5. What are the indications for and to what extent is lymphadenectomy indicated in the surgical management of endometrial cancer? 6. How radical should the surgery be in different stages and pathological subtypes of endometrial cancer? 7. What is the current best definition of risk groups for adjuvant therapy? 8. What are the best evidence-based adjuvant treatment strategies for patients with lowand intermediate-risk endometrial cancer? 9. What are the best evidence-based adjuvant treatment strategies for patients with high-risk endometrial cancer? 10. Does surgery or radiotherapy (RT) have a role in advanced or recurrent endometrial cancer? 11. What are the optimal systemic therapies for advanced/ recurrent disease? 12. What are the most promising targeted agents and which study designs should be used to evaluate their clinical benefit? Each working group was responsible for reviewing the relevant literature in order to draft preliminary recommendations relating to each of their assigned questions. No systematic literature search was undertaken. During the conference, in parallel sessions, the four working groups discussed and reached agreement on recommendations relating to each of their assigned questions. Recommendations from each group were then presented to the entire panel of experts, where they were discussed and modified as required. An adapted version of the ‘Infectious Diseases Society of America-United States Public Health Service Grading System’ was used (Table 1 [9]) to define the level of evidence and strength of each recommendation proposed by the group. Finally, a vote was conducted to determine the level of agreement among the expert panel for each of the recommendations. Panel members were allowed to abstain from voting in cases where they either had insufficient expertise to agree/disagree with the recommendation or if they had a conflict of interest that could be considered as influencing their vote. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article, and a summary of all recommendations is included in supplementary Table S1. However, these additional recommendations for specific clinical situations should be read in conjunction with the ESMO CPG for the diagnosis, treatment and follow-up of patients with endometrial cancer [8]. Results Prevention and screening of endometrial cancer Risk factors for endometrial cancer Most patients with endometrial cancer have an identifiable source of excess oestrogen and typically display a characteristic clinical profile comprising a high body mass index (BMI) that is considered as overweight (BMI 25–30) or obese (BMI 30), often with other components of metabolic syndrome (e.g. hypertension, diabetes). The evidence that greater body fatness (reflected by BMI, 560 Endometrial cancer consensus conference guidelines measures of abdominal girth and adult weight gain) is a cause of endometrial cancer is convincing. Glycaemic load is probably a cause of endometrial cancer, while the evidence suggesting that sedentary habits (marked by sitting time) and adult attained height are causes of endometrial cancer is limited [10]. High BMI correlates with good prognostic features of endometrial cancer, including low tumour grade, endometrioid histology and presentation at early stage. In a small subset of patients, the pathogenesis is related to mismatch repair abnormality and LS. Tumours associated with mismatch repair abnormalities and LS appear to be distinct, with worse prognostic factors and worse clinical outcome [11]. According to a recent meta-analysis involving six studies and 3132 cancer cases, relative risk (RR) for developing endometrial cancer in women with metabolic syndrome is 1.89 (95% confidence interval [CI] 1.34–2.67, P= <0.001). According to individual components of metabolic syndrome, obesity is associated with the greatest increase in RR of 2.21 (P= <0.001) [12]. The strength of association between obesity and cancer risk increases with increasing BMI: RR for overweight is 1.32 (95% CI 1.16–1.50) and for obesity is 2.54 (95% CI 2.11–3.06) [13]. Other components of the metabolic syndrome linked to endometrial cancer include hypertension, with a RR of 1.81 (P= 0.024) [12] or an odds ratio (OR) of 1.77 (1.34–2.34) [14]. Hypertriglyceridaemia has a weaker but still significant association (RR 1.17, P< 0.001) [12]. Diabetes mellitus, in particular type II, has long been held as an independent risk factor for endometrial cancer, with an approximate doubling of risk (OR 2.1; 95% CI 1.40–3.41), [14]. However, the fact that people with type II diabetes mellitus (T2DM) tend to be obese is a confounding factor, and a recent epidemiological study from the United States questioned the independent role of T2DM as a risk factor for endometrial cancer [15]. Nulliparity and infertility are also classical risk factors for endometrial cancer. Among the causes of infertility, polycystic ovarian syndrome (PCOS) seems to be the most important, with an almost 3-fold increase in risk (OR 2.79–2.89) [16]. However, as with diabetes, obesity seems to be a confounding factor, and the BMI-adjusted OR is lower (2.2; 95% CI 0.9–5.7) [17]. Other risk factors for endometrial cancer include unopposed oestrogen therapy, oestrogen-producing tumours and early menarche/late menopause. Unopposed oestrogen therapy increases the risk for endometrial cancer 10to 30-fold if treatment continues 5 years or more [18]. Oestrogen-producing tumours, or ovarian granulosa, and theca cell tumours carry an increased risk for endometrial cancer, with up to 20% of women with these tumours reported as having a simultaneous endometrial cancer [19]. Both early menarche and late menopause are associated with a 2-fold increased risk for endometrial cancer. The RR is 2.4 for women <12 vs P15 years [20] and is 1.8 for women P55 vs <50 years [21]. Studies of women with breast cancer taking tamoxifen with therapeutic or preventive intent have shown that the RR of developing endometrial cancer is 2.53 times higher than that of an age matched population. This risk differs depending on menopausal status. Premenopausal women treated with tamoxifen have no known increased risk of endometrial cancer, while this risk in postmenopausal women is 4.0 (95% CI 1.70–10.90) [22]. The level of risk of endometrial cancer is also dose and time dependent. LS or HNPCC is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair genes. Women with mutations in MLH1, MSH2, MSH6 or PMS2 have up to a 40–60% lifetime risk of developing both endometrial and colorectal cancers, as well as a 9–12% lifetime risk of developing ovarian cancer [23]. Screening and prevention of endometrial cancer Most cases of endometrial cancer cannot be prevented, but reducing the risk factors and introducing protective factors into the lifestyle whenever possible, may lower the risk of developing this disease. All women should be told about the risks and symptoms of endometrial cancer and be strongly encouraged to engage in regular physical activity (exercise) and adopt an active lifestyle which can help to attain and maintain a healthy weight as well as lowering the risk of other risk factors for endometrial cancer such as high blood pressure and diabetes. The use of combined oral contraceptives is significantly associated with decrease in endometrial cancer in ever users, a benefit that is greater with increasing duration of use. 1. Which surveillance should be used for asymptomatic women? Women with average risk for endometrial cancer There is no indication that population-based screening has a role in the early detection of endometrial cancer among women who are at average endometrial cancer risk and have no symptoms. There is also no standard or routine screening test for endometrial cancer. Screening of asymptomatic women for endometrial carcinoma has in general been recommended only for those with LS [24,25]. There is no evidence that screening by ultrasonography (e.g. endovaginal or transvaginal ultrasound) reduces mortality from endometrial cancer. Moreover, cohort studies indicate that screening asymptomatic women will result in unnecessary additional biopsies because of false-positive test results. Risks associated with falsepositive tests include anxiety and complications from biopsies [26]. At the time of menopause, women should be strongly encouraged to report any vaginal bleeding, discharge or spotting to their doctor to ensure they receive appropriate treatment of any precancerous disorders of the endometrium. Recommendation 1.1. There is no evidence for endometrial cancer screening in the general population Level of evidence: II Strength of recommendation: A Consensus: 100% yes (37 voters) Table 1 Levels of evidence and grades of recommendation. Levels of evidence I Evidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of wellconducted randomised trials without heterogeneity II Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity III Prospective cohort studies IV Retrospective cohort studies or case–control studies V Studies without control group, case reports, experts opinions Grades of recommendation A Strong evidence for efficacy with a substantial clinical benefit, strongly recommended B Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, ...), optional D Moderate evidence against efficacy or for adverse outcome, generally not recommended E Strong evidence against efficacy or for adverse outcome, never recommended By permission of the Infectious Diseases Society of America-United States Public Health Service Grading System [9]. N. Colombo et al. / Radiotherapy and Oncology 117 (2015) 559–581 561 Women at increased risk for endometrial cancer Women at increased risk for endometrial cancer due to a history of unopposed oestrogen therapy, late menopause, tamoxifen therapy, nulliparity, infertility or failure to ovulate, obesity, diabetes or hypertension should be informed of the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians. Asymptomatic women with risk factors for endometrial cancer who have endometrial thickening and other positive findings on ultrasound, such as increased vascularity, inhomogeneity of the endometrium, particulate fluid or thickened endometrium over 11 mm should be managed on a case-by-case basis. The potential benefits, risks and limitations of testing for early endometrial cancer should be explained in order to ensure informed decisionmaking about testing. Premenopausal women treated with tamoxifen do not require additional monitoring beyond routine gynaecological care. Postmenopausal women taking tamoxifen should be informed about symptoms of endometrial hyperplasia or cancer [27]. Although findings from a recently published meta-analysis have verified the efficacy of the levonorgestrel intrauterine device (LNGIUD) in preventing de novo polyps in breast cancer patients treated with tamoxifen, there was insufficient evidence to ascertain whether the LNG-IUD was associated with any benefit in reducing the incidence of precancerous or cancerous lesions [28]. Recommendation 1.2. Unopposed oestrogen treatment should not be started or should be discontinued in women with a uterus in situ Level of evidence: III Strength of recommendation: A Consensus: 100% yes (37 voters) Recommendation 1.3. Routine surveillance in asymptomatic women with obesity, PCOS, diabetes mellitus, infertility, nulliparity or late menopause is not recommended Level of evidence: III Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 1.4. For women with adult granulosa cell tumour, if hysterectomy has not been performed, endometrial sampling is recommended. If this shows no evidence of (pre)malignancy, no further screening for endometrial malignancies is required Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 1.5. In patients with epithelial ovarian cancer undergoing fertility sparing treatment, endometrial sampling is recommended at the time of diagnosis Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 1.6. Routine screening for endometrial cancer in asymptomatic tamoxifen users is not recommended Level of evidence: III Strength of recommendation: B Consensus: 94.6% (35) yes, 5.4% (2) abstain (37 voters) Women with high risk for endometrial cancer Women with a high risk for endometrial cancer include known carriers of HNPCC-associated genetic mutations, those who have a substantial likelihood of being a mutation carrier (i.e. a mutation is known to be present in the family), and women without genetic testing results but who are from families with a suspected autosomal dominant predisposition to colon cancer. Findings from a prospective observational cohort study of women with LS opting for endometrial cancer screening and who underwent annual outpatient hysteroscopy and endometrial sampling (OHES) suggest that in women with LS, annual OHES is acceptable and has high diagnostic accuracy in screening for endometrial cancer and atypical endometrial hyperplasia (AEH) [29]. However, larger international studies are needed for confirmation. Women with an HNPCC-associated mutation or with a substantial likelihood of having an HNPCC-associated mutation should be informed of the potential benefits, risks and limitations of testing for early endometrial cancer; they should also be informed that the recommendation for screening is based on expert opinion in the absence of definitive scientific evidence. Although there is insufficient evidence to endorse annual screening for endometrial cancer in this group, annual screening beginning at age 35 is recommended due to the high risk of endometrial cancer and the potentially life-threatening nature of this disease. As screening will be of limited efficacy in gynaecological cancers (endometrial and ovarian), once the family is completed, particularly by age 35–40 years, careful consideration must be given to the option of prophylactic hysterectomy and bilateral salpingo-oophorectomy [30]. In women with LS, the following options are available: Annual screening beginning at age 35 (recommended). Regular hysteroscopy and endometrial biopsies or hysterectomy (current options). The application of local progesterone using the LNG-IUD. Treatment of premalignant disease (AEH, EIN). Hysterectomy and bilateral oophorectomy. Evaluating the likelihood of a patient having a gynaecological cancer predisposition syndrome enables the physician to provide individualised assessments of cancer risk, as well as the opportunity to offer tailored screening and prevention strategies such as surveillance, chemoprevention and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Recommendation 1.7. Surveillance of the endometrium by gynaecological examination, transvaginal ultrasound and aspiration biopsy starting from the age of 35 years (annually until hysterectomy) should be offered to all LS mutation carriers Level of evidence: IV Strength of recommendation: B Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters) Recommendation 1.8. Prophylactic surgery (hysterectomy and bilateral salpingo-oophorectomy), preferably using a minimally invasive approach, should be discussed at the age of 40 as an option for LS mutation carriers to prevent endometrial and ovarian cancer. All pros and cons of prophylactic surgery must be discussed Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) 562 Endometrial cancer consensus conference guidelines 2. What work-up and management scheme should be undertaken for fertility preserving therapy in patients with AH/ EIN and grade 1 EEC? Work-up for fertility preserving therapy The diagnosis of endometrial carcinoma in young women of childbearing age is rare. Indeed, only 4% of patients with endometrial carcinoma are less than 40 years of age [2]. Younger and premenopausal women with endometrial carcinoma seem to have a better prognosis than older patients, with increased rates of early stage and low grade disease reported [2,31,32]. The standard approach for the management of endometrial cancer in young women of childbearing age is hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy. Although this is a highly effective approach, carrying a 5-year survival rate of 93%, it also results in a permanent loss of reproductive potential. Conservative management of endometrial carcinoma is based on medical treatment with oral progestins. The most important issues when considering a conservative management approach are the assessment of clinical and pathological characteristics of the tumour and selection of the appropriate medical intervention. A conservative management approach could be considered in patients with a histological diagnosis of grade 1 endometrial carcinoma (or premalignant disease such as AH) [31]. The optimal method to obtain these histologic characteristics is dilatation and curettage (D&C) [33]; this procedure is superior to pipelle biopsy in terms of accuracy of the tumour grade [34]. The histological diagnosis should be reviewed by an expert pathologist to improve the accuracy of histological assessment (endometrial carcinoma or AH) and the reliability of tumour grading [35], whereas the initial stage should be confirmed by enhanced pelvic magnetic resonance imaging (MRI) to exclude overt myometrial invasion, as well as adnexal or pelvic node involvement [36]. Patients should be informed that this is a nonstandard approach and they should be willing to accept close follow-up during and after the treatment. They should also be informed of the need for future hysterectomy in case of failure of the treatment and/or after pregnancies. Recommendation 2.1. Patients with AH/EIN or grade 1 endometrioid endometrial cancer requesting fertility preserving therapy must be referred to specialised centres Level of evidence: V Strength of recommendation: A Consensus: 100% yes (37 voters) Recommendation 2.2. In these patients, D&C with or without hysteroscopy must be performed Level of evidence: IV Strength of recommendation: A Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters) Recommendation 2.3. AH/EIN or grade 1 EEC must be confirmed/diagnosed by a specialist gynaecopathologist Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (37 voters) Recommendation 2.4. Pelvic MRI should be performed to exclude overt myometrial invasion and adnexal involvement. Expert ultrasound can be considered as an alternative Level of evidence: III Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 2.5. Patients must be informed that fertilitysparing treatment is a non-standard treatment and the pros and cons must be discussed. Patients should be willing to accept close follow-up and be informed of the need for future hysterectomy Level of evidence: V Strength of recommendation: A Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters) Management schemes for fertility-preserving therapy Conservative medical treatment for endometrial cancer is based on progestins with medroxyprogesterone acetate (MPA; 400– 600 mg/day) or megestrol acetate (MA; 160–320 mg/day) [33]. Few papers have addressed the use of LNG-IUD but preliminary data using such treatment (added to gonadotropin-releasing hormone [GnRH] analogues) seem to demonstrate similar remission and recurrence rates as oral progestins [37]. Assessment of response must be performed at 6 months with a new D&C and imaging [38]. Response rates associated with the conservative management of endometrial carcinoma are around 75% [39,40], but recurrence rates are 30–40% [39,41,42]. Standard surgery with hysterectomy should be proposed to non-responders while maintenance treatment for a further 6 months can be considered in responders who wish to delay pregnancy [33]. Although progesterone receptor (PgR) status is a reliable predictive factor for disease remission, a routine check is not recommended since 50% of PgR negative patients will respond to treatment [43]. Pregnancy is associated with a reduced risk for endometrial cancer recurrence [40]. Findings from recent meta-analyses showed that the pooled live birth rate among women receiving fertility-preserving treatment for endometrial cancer was 28%, and reached 39% when assisted reproduction technology was used [39,44]. Thus, for patients achieving a complete response at 6 months, conception must be encouraged and these patients should be referred to a fertility clinic. For patients with disease recurrence after an initial response, hysterectomy should be proposed as the first option. Moreover, given the high rate of recurrence, after completion of childbearing (or after the age of potential pregnancy), standard treatment with hysterectomy and salpingo-oophorectomy is recommended. Preservation of the ovaries can be considered in selected cases, depending on the patient’s age and genetic risk factors. Recommendation 2.6. For patients undergoing fertilitypreserving therapy, MPA (400–600 mg/day) or MA (160–320 mg/- day) is the recommended treatment. However, treatment with LNG-IUD with or without GnRH-analogues can also be considered Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 2.7. In order to assess response, D&C, hysteroscopy and imaging at 6 months must be performed. If no response is achieved after 6 months, standard surgical treatment should be performed Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 2.8. In case of complete response, conception must be encouraged and referral to a fertility clinic is recommended Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) N. Colombo et al. / Radiotherapy and Oncology 117 (2015) 559–581 563 Recommendation 2.9. Maintenance treatment should be considered in responders who wish to delay pregnancy Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 2.10. Patients not undergoing hysterectomy should be re-evaluated clinically every 6 months Level of evidence: IV Strength of recommendation: B Consensus: 97.3% (36) yes, 2.7% (1) abstain (37 voters) Recommendation 2.11. After completion of childbearing, a hysterectomy and salpingo-oophorectomy should be recommended. The preservation of the ovaries can be considered depending on age and genetic risk factors Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) 3. Which (molecular) markers can help distinguish (pre)cancerous lesions from benign mimics? Differential diagnosis between benign uterine lesions and endometrial (pre)carcinomas is based mainly on morphological criteria but may be supported by additional immunohistochemical (IHC) markers and molecular alterations in problematic cases [45]. Currently, AH/EIN is the preferred terminology of the precursor lesion of the most common type of endometrial carcinoma, endometrioid carcinoma, including its variants. Recommendation 3.1. In case of uncertainty low threshold referral to a specialised gynaecopathologist is recommended Level of evidence: V Strength of recommendation: A Consensus: 100% yes (37 voters) The differential diagnosis of AH/EIN includes, in particular, endometrial hyperplasia without atypia, but also includes other mimics, such as glandular and stromal breakdown, focal glandular crowding and epithelial metaplasias (e.g. hypersecretory changes). Loss of PTEN expression, mostly by mutation, and loss of PAX-2 by downregulation [46–48], are the only immunohistochemical markers that have been sufficiently studied and can be used on curettage material. Loss of PTEN occurs in 40–50% of AH/EIN cases, whereas loss of PAX-2 occurs in 70% of AH/EIN, and a joint loss of PTEN and PAX-2 occurs in around 30% of AH/EIN [49–51]. Recommendation 3.2. PTEN and PAX-2 IHC is recommended to distinguish AH/EIN from benign mimics. Other markers that can be used in this context are MLH1 and ARID1a by IHC Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Another histological entity that may arise in the differential diagnosis of AH/EIN is the rare atypical polypoid adenomyoma (APA), for which there are no IHC stains with practical value. Recommendation 3.3. IHC is not recommended to distinguish APA from AH/EIN Level of evidence: V Strength of recommendation: B Consensus: 100% yes (37 voters) The putative precursor of serous carcinoma, serous endometrial intraepithelial carcinoma (SEIC), is considered a non-invasive cancer rather than a precancer since it may be associated with extensive extrauterine disease [9]. Molecular alterations of serous carcinoma are already present in SEIC, which is especially true for p53 expression [52–54]. A completely negative immunoreactive pattern for p53 (‘all or null’) is considered a surrogate for p53 mutation, and is present in almost all SEIC and invasive serous carcinomas [55]. Recommendation 3.4. p53 by IHC is recommended to distinguish SEIC from its mimics Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (37 voters) In selected cases of endometrial cancer, clinical and radiological work-up may not be conclusive about the endometrial origin of the uterine tumour. In addition, endocervical, ovarian and endometrial adenocarcinomas may show histopathological overlap. Several IHC markers have been proposed for these differential diagnoses, but these markers lack sensitivity or specificity to be used as single markers. When endocervical origin is considered, the use of a panel of markers, including carcinoembryonic antigen (CEA), vimentin, oestrogen receptor (ER) and p16 (as surrogate for human papilloma virus [HPV]), is recommended [56]. In case of p16 positivity, the staining pattern should be taken into account. Diffuse p16 staining is frequently seen in serous, clear cell and mucinous carcinoma endometrial cancers [57,58]. In cases of scanty tissue with serous carcinoma, an ovarian origin of the serous carcinoma should be considered. The most discriminatory marker for this differential diagnosis is Wilms tumour 1 gene (WT-1) [59], which is expressed in 80–100% of high-grade serous carcinomas of the ovary [60,61] compared with 7–20% in serous endometrial carcinomas [62,63]. In general, the expression profile should be interpreted in the context of the morphological subtype. An individual approach, with close correlation between clinical presentation and morphological subtype, is therefore recommended. Recommendation 3.5. A panel of markers must be used in cases where endocervical cancer is suspected. This panel should include at least ER, vimentin, CEA and p16 by IHC, and needs to be assessed in the histologic and clinical context. In addition, HPV analysis can be considered Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 3.6. WT-1 by IHC is the recommended marker to determine the origin of serous cancer Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (37 voters) Recommendation 3.7. Morphology (and not IHC) should be used to distinguish AH/EIN from EEC Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (37 voters) Surgery 4. How does the medical condition influence surgical treatment? Mandatory pre-operative work-up The consensus is based on current clinical practice. Family history is usually taken to identify risk factors associated with LS, 564 Endometrial cancer consensus conference guidelines including endometrial cancer, colon cancer and other cancers belonging to the Lynch spectrum. General assessment and, if appropriate, geriatric assessment are required in patients with comorbidities and elderly patients, respectively, in order to adapt the surgical strategy. Indeed, endometrial cancer is frequently associated with obesity, hypertension and diabetes and, in some patients, the extent of surgery or staging that is theoretically required may not be feasible. In such cases, a benefit-risk assessment of surgery may lead to an individualised decision to perform a ‘non-standard’ surgery or a limited staging procedure. Pelvic examination and pelvic ultrasonography are mandatory components of clinical staging of endometrial cancer in order to establish a tentative International Federation of Gynecology and Obstetrics (FIGO) staging before definitive pathology. In addition to being the first imaging technique used to evaluate abnormal uterine bleeding, ultrasonography, preferably specialised ultrasonography [64], offers the possibility of evaluating the size of the tumour, ruling out ovarian disease, and assessing myometrial invasion and cervical stromal involvement [65]. Pre-operative pathological information is crucial for establishing the surgical plan. First, all patients with a risk of cancer, particularly patients with postmenopausal bleeding and a hyperplastic endometrium at ultrasound, should be investigated with endometrial biopsy or curettage in order to (1) avoid uterine morcellation, which poses a risk of spreading unsuspected cancerous tissue, notably endometrial carcinomas or sarcomas, beyond the uterus and may make the pathological assessment of myometrial invasion extremely difficult; and (2) prevent the discovery of an unexpected malignancy after inadequate surgery (subtotal hysterectomy and/or preservation of the ovaries in a postmenopausal patient, incomplete staging). Second, as grading of EEC has a significant prognostic impact [66] and various histotypes of endometrial cancer harbour different natural histories, the primary therapeutic strategy must be adapted to the information provided by a pre-operative pathological examination, despite the fact that discrepancies between pre-operative evaluation and final pathology exist [67]. The final therapeutic strategy should be adapted according to the information available before surgery, taking into account the tentative stage (apparent stage I or more advanced stage), grade (of endometrioid tumours; grade 1–3 or a binary system) and histotype (endometrioid versus non-endometrioid tumour). Recommendation 4.1. Mandatory work-up must include: Family history; general assessment and inventory of comorbidities; geriatric assessment, if appropriate; clinical examination, including pelvic examination; transvaginal or transrectal ultrasound; and complete pathology assessment (histotype and grade) of an endometrial biopsy or curettage specimen Level of evidence: V Strength of recommendation: A Consensus: 100% yes (37 voters) Recommendation 4.2. Extent of surgery should be adapted to the medical condition of the patient Level of evidence: V Strength of recommendation: A Consensus: 100% yes (37 voters) Optional pre-operative work-up Imaging Additional imaging is considered according to the clinical situation. Computed tomography (CT) scan and/or positron emission tomography (PET)-CT are options in clinically advanced endometrial cancer. In apparent stage I endometrial cancer, MRI may be useful to complete information regarding myometrial invasion [65]. However, this applies only in institutions where the indication for lymph node dissection (LND) is tailored according to the stratification of patients into low-, intermediateand high-risk groups. In this setting, specialised ultrasonography and/or intra-operative pathological examination of the uterus may also be considered [68]. Recommendation 4.3. In clinical stage I, grade 1 and 2: At least one of the three following tools should be used to assess myometrial invasion if LND is considered: Expert ultrasound and/or MRI and/or intra-operative pathological examination Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (37 voters) Recommendation 4.4. Other imaging methods (thoracic, abdominal and pelvic CT scan, MRI, PET scan or ultrasound) should be considered to assess ovarian, nodal, peritoneal or metastatic disease Level of evidence: IV Strength of recommendation: C Consensus: 94.6% (35) yes, 2.7% (1) abstain, 2.7% (1) no (37 voters) Serum tumour markers There is evidence that the serum tumour markers cancer antigen 125 (CA-125) and, more recently, human epididymis protein 4, are significantly correlated with histological grade, stage, lymph node metastases, myometrial invasion and cervical involvement [69–71]. However, the appropriate cut-off has not been established and evidence that serum marker assessment is clinically useful is lacking. Recommendation 4.5. There is no evidence for the clinical usefulness of serum tumour markers, including CA-125 Level of evidence: IV Strength of recommendation: B Consensus: 91.9% (34) yes, 5.4% (2) abstain, 2.7% (1) no (37 voters) Surgical management of apparent stage I endometrial cancer With the exception of patients managed conservatively, extrafascial total hysterectomy without colpectomy is the mainstay of management for patients with endometrial cancer. The rationale for the additional removal of the adnexae is to prevent ovarian cancer and rule out ovarian metastases. In premenopausal patients, however, ovarian preservation may be discussed in selected cases. Younger patients with endometrial cancer often have early stage, low grade tumours. Thus, to avoid the shortterm and long-term consequences of surgical menopause, there is a rationale for ovarian preservation in young women. Several retrospective studies have recently provided evidence that ovarian preservation has no statistically significant impact on the overall survival (OS) of young patients with early-stage endometrial cancer [72]. However, extreme care must be taken to rule out synchronous concomitant ovarian malignancy. Recommendation 4.6. Standard surgery is total hysterectomy with bilateral salpingo-oophorectomy without vaginal cuff Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (37 voters) Recommendation 4.7. Ovarian preservation can be considered in patients younger than 45 years old with grade 1 EEC with myometrial invasion <50% and no obvious ovarian or other extrauterine disease N. Colombo et al. / Radiotherapy and Oncology 117 (2015) 559–581 565 Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 4.8. In cases of ovarian preservation, salpingectomy is recommended Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Recommendation 4.9. Ovarian preservation is not recommended for patients with cancer family history involving ovarian cancer risk (e.g. BRCA mutation, LS, etc.). Genetic counselling/testing should be offered Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (37 voters) Minimally invasive surgical techniques Hysterectomy and bilateral salpingo-oophorectomy can be carried out using the open, laparoscopic or vaginal approach. The largest randomised trial comparing laparoscopy to laparotomy is the LAP2 study [73], which was designed to compare laparoscopy versus laparotomy for comprehensive surgical staging and management of stage I–IIA uterine cancer, including hysterectomy, salpingo-oophorectomy, pelvic cytology and pelvic and para-aortic lymphadenectomy. In this trial, patients were randomly assigned to laparoscopy (n= 1696) or open laparotomy (n= 920). A significantly longer operative time was reported for the laparoscopy group compared with the laparotomy group (204 vs 130 minutes, respectively). Intra-operative complication rates were similar between groups. However, laparoscopy was associated with significantly fewer moderate to severe postoperative adverse events (14% vs 21%) and a lower frequency of hospitalisations of more than 2 days (52% vs 94%) than laparotomy. Although pelvic and para-aortic lymph nodes were not removed in 8% and 4% of patients in the laparoscopy and laparotomy groups, respectively (P< 0.0001), there was no difference in the overall detection of advanced stage disease between the two groups. The major shortcoming of this trial is the high conversion rate related to its multicentric design. Indeed, 25.8% of patients assigned to the laparoscopic group were converted to laparotomy, with a statement of ‘poor visibility’ reported in 14.6% of cases, reflecting the learning curve of some investigators, particularly for LND. In contrast, a conversion rate of 10.8%, with poor visibility recorded as the main factor in 4.9% of cases, was reported in a Dutch randomised trial in which no lymphadenectomy was performed [74]. However, as further training or the use of robotic assistance would likely have resulted in even better results with laparoscopic surgery, this high conversion rate reported in LAP2 does not weaken the authors’ conclusions, and this trial provides evidence that laparoscopic surgical staging for uterine cancer results in fewer complications and shorter hospital stay. According to a meta-analysis of data from eight randomised controlled trials (RCTs) conducted by Zullo et al. [75], intraoperative complication rates were not different between laparoscopy and laparotomy (RR 1.25; 95% CI 0.99–1.56) with no significant heterogeneity across the studies. Estimated blood loss and haemoglobin or haematocrit changes were consistently less after laparoscopy in the six studies where this was reported. Operative time was higher by 34–74 min in the laparoscopy group. The authors also found a significant advantage of laparoscopy over laparotomy in terms of post-operative complications (RR 0.71; 95% CI 0.63–0.79) with significant heterogeneity across the studies. Aortic dissection can also be achieved in obese patients using an extraperitoneal laparoscopic approach [76]. Taken together, these findings provide definitive evidence of the short-term benefit and cost-effectiveness of laparoscopic hysterectomy in patients with gynaecological cancer. This includes patients with comorbidities, obesity or advanced age. Regarding comorbidity, Tozzi et al. [77] found that the surgical technique is the only significant parameter associated with complication rate, regardless of risk group, stressing the fact that patients with serious comorbidities benefit most from laparoscopy. The issue of advanced age has also been addressed in the gynaecological oncology literature. Siesto et al. [78] reported outcomes from a series of 48 patients aged >65 years who had undergone laparoscopic surgery for endometrial cancer. Outcomes from this group were comparable to younger patients in terms of operative time, blood loss, need for blood transfusions, nodal count and intra-operative and postoperative complications. The authors conclude that in the absence of absolute anaesthesia contraindications, laparoscopy is feasible and safe in older women with endometrial cancer. However, as cancer in older women was more frequently upstaged than in younger women, they state that comprehensive surgical staging should be offered, regardless of age, to avoid understaging and to optimise treatment strategies. Six randomised trials comparing outcomes after laparotomy versus laparoscopy are currently available, four of which have been includedina published metanalysis [79].However,only two ofthese four trials reported data for OS, disease-free survival and cancerrelated survival. Based on the availability of new data, this metaanalysis was subsequently updated by Palomba et al. in 2009 [80] to include a third trial reporting these long-termoutcomes, resulting in a sample of 359 patients. No significant heterogeneity was observed among these trials and there was no significant adverse effect of a laparoscopic approach on the OS, disease-free survival or cancer-related survival (OR 0.96, 0.95 and 0.91, respectively). Long-term outcomes of the randomised controlled LAP2 trial were published in 2012 [81]. The primary endpoint was noninferiority of the recurrence-free interval. Non-inferiority was defined as no more than a 40% increase in the risk of recurrence with laparoscopy compared with laparotomy. The estimated hazard ratio (HR) for recurrence-free survival with laparoscopy versus laparotomy was 1.14 (90% CI 0.92–1.46).Actual recurrence rates were substantially lower than anticipated; the estimated 3-year recurrence rate was 11.4% with laparoscopy and 10.2% with laparotomy, and the estimated 5-year OS was almost identical in both arms (89.8%). Recommendation 4.10. Minimally invasive surgery is recommended in the surgical management of low-and intermediaterisk endometrial cancer Level of evidence: I Strength of recommendation: A Consensus: 100% yes (37 voters) In a retrospective, multi-institutional trial of patients with high grade endometrial cancer, outcomes of 191 patients who underwent laparotomy were compared with 192 patients who underwent minimal invasive surgery. In this trial, women with high grade endometrial cancer staged by minimally invasive techniques experienced fewer complications and similar survival outcomes compared with those staged by laparotomy [82]. Recommendation 4.11. Minimally invasive surgery can be considered in the management of high-risk endometrial cancer Level of evidence: IV Strength of recommendation: C Consensus: 100% yes (37 voters) 566 Endometrial cancer consensus conference guidelines Alternative approaches for patients unsuitable for standard surgical therapy Although advances in surgical techniques, anaesthesiology and peri-operative management mean that the vast majority of patients with endometrial cancer are amenable to standard surgical therapy, a small proportion of patients are still medically unfit for laparoscopic surgery or laparotomy. However, these patients can still be managed either surgically by vaginal hysterectomy, whenever possible, with bilateral salpingo-oophorectomy, or by definitive RT, combining external beam radiation therapy (EBRT) and brachytherapy, or by hormonal treatment. In addition, vaginal hysterectomy is an acceptable minimally invasive surgical option in some low-risk patients who do not need LND (see Section 4). Recommendation 4.12. Vaginal hysterectomy with salpingooophorectomy can be considered in patients unfit for the recommended surgery and in selected patients with low-risk endometrial cancer Level of evidence: IV Strength of recommendation: C Consensus: 100% yes (37 voters) Recommendation 4.13. In medically unfit patients, RT or hormone treatment can be considered Level of evidence: IV Strength of recommendation: C Consensus: 100% yes (37 voters) 5. What are the indications for and to what extent is lymphadenectomy indicated in the surgical management of endometrial cancer? Surgical staging in apparent stage I EEC Collection of peritoneal cytology was included as a staging procedure in earlier recommendations, but it is no longer considered mandatory. However, since retrospective studies indicate that positive peritoneal cytology has prognostic value, collection of this information could be considered, especially in patients with tumours of non-endometrioid histology [83,84]. Recommendation 5.1. Peritoneal cytology is no longer considered mandatory for staging Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (37 voters) Lymphadenectomy Lymphadenectomy is an integral part of the comprehensive surgical staging of endometrial cancer. However, the role of lymphadenectomy in early endometrial cancer is unclear and controversy remains regarding the indications for, the anatomic extent of, and the therapeutic value of lymphadenectomy in the management of the disease. The definition of an adequate lymphadenectomy has not been standardised: Current approaches include pelvic lymphadenectomy, para-aortic lymphadenectomy to the inferior mesenteric artery (IMA) and para-aortic lymphadenectomy up to the renal vessels. Lymph node counts have become a marker for adequacy of lymph node evaluation in a variety of solid tumour disease sites. In endometrial cancer, two retrospective reviews have shown that patients had improved survival when at least 10 to 12 lymph nodes were removed during lymphadenectomy [85,86]. Lymph node counts therefore provide a surrogate way of measuring the adequacy of a LND and, as such, more than 10 nodes should be removed [87,88]. Sampling of lymph nodes has a low sensitivity in endometrial cancer [89]. Indeed, it has been shown that para-aortic nodes may be positive in the absence of positive pelvic nodes [90,91], suggesting that para-aortic lymph nodes should be removed in cases where a lymphadenectomy is indicated. In the Mayo Clinic experience of 281 patients with endometrial cancer who underwent lymphadenectomy, 22% of patients with high-risk disease had lymph node metastases: 51% had both positive pelvic and para-aortic nodes, 33% had positive pelvic lymph nodes only, and 16% had isolated para-aortic lymphadenopathy [92]. As the majority (77%) of patients with para-aortic lymph node involvement had metastases above the IMA, para-aortic lymphadenectomy up to the renal vessels is recommended. The concept of sentinel lymph node (SLN) dissection (SLND) was first developed in cervical cancer as a tool to select patients most suitable for surgical management. In lowand intermediate-risk endometrial cancer, the rationale is different as the need for SLND is controversial. However, SLND could represent a compromise between no dissection (leaving a small proportion of node positive patients) and full dissection (adding a useless procedure for the majority of node-negative patients). In addition, ultrastaging of the SLNs detects micrometastases otherwise undiagnosed by conventional histology, even in patients considered at low risk, on the basis of grade and depth myometrial invasion [93]. However, these large series only use the cervix as the injection site. The question of alternative injection sites in the endometrium or uterine fundus, which are anatomically more logical, is still a topic for investigation. Injection under hysteroscopic, ultrasound, laparoscopic or open guidance in patients with endometrial cancer has been addressed, without evidence of benefit of the more demanding and less practical modalities.Nevertheless, evidence is accumulating that the SLND may be useful in the management of endometrial cancers [94]. Recommendation 5.2. If a lymphadenectomy is performed, systematic removal of pelvic and para-aortic nodes up to the level of the renal veins should be considered Level of evidence: IV Strength of recommendation: B Consensus: 91.9% (34) yes, 2.7% (1) abstain, 5.4% (2) no (37 voters) Recommendation 5.3. SLND is still experimental, but large series suggest that it is feasible. SLND increases the detection of lymph nodes with small metastases and isolated tumour cells; however, the importance of these findings is unclear Level of evidence: IV Strength of recommendation: D Consensus: 100% yes (37 voters) Indications for lymphadenectomy Although the therapeutic effect of lymphadenectomy is unclear, it is an integral part of comprehensive staging. The advantages of comprehensive surgical staging are a better definition of prognosis and appropriate triage of patients for adjuvant therapy. Data from two RCTs do not support the therapeutic benefit of lymphadenectomy in early stage endometrial cancer. BenedettiPanici et al. randomised 514 women with clinical stage I endometrial cancer to either systematic pelvic lymphadenectomy or no LND and found no improvement in disease-free survival or OS between the two groups [95]. Similarly, the ASTEC trial, which included 1408 patients with stage I endometrial cancer who were randomised to receive surgical staging with or without pelvic lymphadenectomy, failed to show a beneficial effect of N. Colombo et al. / Radiotherapy and Oncology 117 (2015) 559–581 567 distant sites. There is currently no evidence to suggest that modern techniques of image-guided brachytherapy and intensitymodulated RT (IMRT) are superior to conventional approaches, although a single institution retrospective study of RT (EBRT predominantly using an IMRT technique followed by image-guided high dose rate [HDR] brachytherapy) for vaginal recurrence has also reported high tumour control rates [172]. Recommendation 10.5. RT with curative intent is indicated in patients with isolated vaginal relapse after surgery Level of evidence: III Strength of recommendation: A Consensus: 100% yes (34 voters) Chemotherapy with RT for recurrence RT can be considered for patients with vaginal or pelvic nodal recurrence. Improvements in RT techniques allow for better means of localised treatment, or possibly retreatment of patients who have previously received RT. Whether chemotherapy has an additional benefit is unclear. The ongoing randomised phase II GOG0238 (NCT00492778) trial is comparing pelvic irradiation of 45 Gy in 25 fractions plus either brachytherapy or external beam boost with the same schedule plus concomitant cisplatin (40 mg/ m 2 weekly) in women with vaginal/pelvic relapse who have not received prior RT. Recommendation 10.6. For vaginal or pelvic nodal recurrence, chemotherapy with RT could be considered in patients with highrisk features for systemic relapse Level of evidence: IV Strength of recommendation: C Consensus: 97.1% (33) yes, 2.9% (1) abstain (34 voters) Combined approaches to recurrence and re-irradiation The use of systemic therapy or surgery prior to RT for vaginal or pelvic node recurrence could be considered in certain patients with more bulky disease. As the techniques for image-guided RT have improved, there are situations where re-irradiation can be considered, although evidence from clinical trials is lacking. Recommendation 10.7. Use of systemic therapy or surgery prior to RT for vaginal or pelvic node recurrence could be considered in certain patients Level of evidence: V Strength of recommendation: C Consensus: 100% yes (34 voters) Recommendation 10.8. Re-irradiation could be considered in highly selected patients using specialised techniques Level of evidence: V Strength of recommendation: C Consensus: 100% yes (34 voters) Palliative RT RT can be effectively used to palliate symptoms such as bleeding, bone metastases or painful nodal recurrence. No randomised trials have been conducted comparing RT with palliative chemotherapy. Recommendation 10.9. RT is indicated for palliation of symptoms related to local recurrence or systemic disease Level of evidence: IV Strength of recommendation: A Consensus: 100% yes (34 voters) Radical RT for primary endometrial cancer RT can be used as a primary treatment in patients with unresectable disease, or where there are medical contraindications to surgery [173,174]. Treatment involves intrauterine brachytherapy alone or in combination with EBRT. Image guided brachytherapy may improve outcomes [175]. Two year local control rates of more than 90% can be achieved for medically inoperable stage I disease. Recommendation 10.10. RT may be indicated for primary tumours that are unresectable, or where surgery cannot be performed or is contraindicated for medical reasons Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (34 voters) 11. What are the optimal systemic therapies for advanced/ recurrent disease? The majority of patients with advanced or recurrent disease will be candidates for systemic palliative therapy. The choice between hormonal treatment and chemotherapy relies on several factors, including histopathological and clinical features of the individual patient. Hormonal therapy: Which patient and when? Hormonal therapy is indicated for patients with advanced or recurrent endometrial cancer and endometrioid histology. This statement is based on several clinical trials that have shown clinical activity with a favourable toxicity profile [176,177]. Recommendation 11.1. Hormone therapy is indicated in advanced or recurrent EEC Level of evidence: II Strength of recommendation: A Consensus: 100% yes (34 voters) Response to hormonal therapy is quite variable, and a number of pathological factors contributing to this variation have been identified. For example, hormonal therapy is more likely to be effective in grade 1 or 2 endometrioid tumours. In a large clinical trial of MPA, the response rate was 37% for grade 1, 23% for grade 2 and 9% for grade 3 tumours [176]. Others have reported similar findings [177]. Patients with hormone receptor positive disease have also been shown to have a higher chance of responding to endocrine therapy. In a randomised trial, the response rate observed in patients with ER and PgR positive disease was around 25% and 37%, respectively, but was only 7–8% in patients with ER/ PgR negative disease [176,177]. Based on these results, it seems that positivity of ER and/or PgR could be a predictive factor of response to endocrine therapy and so should be determined before initiating hormonal therapy. Recommendation 11.2. Hormone therapy is more likely to be effective in grade 1 or 2 endometrioid tumours Level of evidence: IV Strength of recommendation: B Consensus: 100% yes (34 voters) Recommendation 11.3. Hormone receptor status should be determined before hormone therapy is initiated, as it is more likely to be effective in patients with positive PgR and ER status Level of evidence: III Strength of recommendation: B Consensus: 97.1% (33) yes, 2.9% (1) abstain (34 voters) 574 Endometrial cancer consensus conference guidelines Biopsy of recurrent disease can be considered, since there may be differences in hormone receptor status in the primary and metastatic tumour. In a prospective collection of 686 primary endometrial tumours and 171 metastatic lesions, loss of PgR expression increased with disease progression, with 23% of primary tumours and 76% of metastatic lesions demonstrating PgR loss [178]. Recommendation 11.4. Biopsy of recurrent disease could be considered as there may be differences in hormone receptor status in the primary and metastatic tumour Level of evidence: III Strength of recommendation: C Consensus: 100% yes (34 voters) Hormone therapy is the preferred front-line systemic therapy for patients with hormone receptor positive grade 1 or 2 tumours in the absence of rapidly progressive disease, as it provides an excellent benefit/risk ratio and convenient toxicity profile. However, patients with visceral involvement and rapidly progressive disease are not candidates for hormone therapy as it is not usually associated with a rapid response. Recommendation 11.5. Hormone therapy is the preferred frontline systemic therapy for patients with hormone receptor positive tumours – grade 1 or 2 and without rapidly progressive disease Level of evidence: V Strength of recommendation: A Consensus: 100% yes (34 voters) The progestogens, MPA 200 mg or MA 160 mg, are generally recommended. They have shown clear activity for the front-line treatment of non-selected patients with recurrent or persistent endometrioid tumours not suitable for surgery or RT, with response rates of around 25% and PFS times of 3 months [176,179]. Data from a randomised trial comparing low (200 mg/- day) versus high (1000 mg/day) dose MPA in 299 patients with advanced or recurrent endometrial carcinoma showed that lowdose MPA was more active than the high dose in terms of response rate (25% vs 15%, respectively) and OS (11.0 vs 7.0 months, respectively) [176]. Recommendation 11.6. Progestogens (e.g. MPA 200 mg or MA 160 mg) are generally recommended Level of evidence: III Strength of recommendation: A Consensus: 100% yes (34 voters) Other endocrine therapies have also demonstrated activity in phase II trials among patients with advanced or recurrent endometrial cancer, with tamoxifen, anastrozole and fulvestrant all associated with response rates of approximately 10% [180–182]. Interestingly, patients included in the anastrozole trial had not received prior progestin therapy [182]. The combination of tamoxifen and MPA is associated with response rates and PFS similar to MPA alone [183,184]. Recommendation 11.7. Other hormonal agents to consider after progestins include tamoxifen, fulvestrant and aromatase inhibitors Level of evidence: III Strength of recommendation: C Consensus: 100% yes (34 voters) Chemotherapy: Is there any standard of care? Endometrial cancer is a relatively chemo-sensitive disease, with anthracyclines, platinum-based drugs and taxanes shown to be the most active agents. Two clinical trials showed that the combination of cisplatin and doxorubicin was more active than doxorubicin alone in terms of response rate (43–41% vs 17–25%) but with no benefit in terms of OS [185,186]. The combination also resulted in a higher incidence of grade 3–4 myelotoxicity and nausea/ vomiting. In another GOG trial, conducted in patients with measurable FIGO III–IV endometrial cancer, the addition of paclitaxel to cisplatin and doxorubicin was associated with a higher response rate and PFS than cisplatin and doxorubicin alone (objective response rate [ORR]: 57% vs 34%, respectively, P< 0.01; median PFS: 8.3 vs 5.3 months, respectively, P< 0.01), and a small but significant improvement in OS (median 15.3 vs 12.3 months, respectively, P= 0.037) [187]. However, toxicity, especially peripheral neuropathy, was significantly higher (grade 2–3: 39% vs 5%, respectively). For this reason, it has not been widely adopted as a standard of care. Finally, GOG209 was a randomised, non-inferiority trial that compared the combination of paclitaxel 160 mg/m 2 , cisplatin 60 mg/m 2 and doxorubicin 50 mg/m 2 (TAP) with paclitaxel 175 mg/m 2 and carboplatin AUC 6 (TC), both administered every 3 weeks. A total of 1305 patients were included in this trial, and preliminary data (not yet fully published) indicate a similar response rate (51.3% vs 51.2%) and PFS (median 13.5 vs 13.3 months) [188]. The median OS (primary study endpoint) was 40.3 months for TAP and 36.5 months for TC, which met the criteria of non-inferiority. TC had a more favourable toxicity profile than TAP in this trial, with fewer patients discontinuing therapy due to toxicity (12% vs 18%). In addition, TC can be administered in the outpatient setting whereas TAP is given in the inpatient setting in most countries. This aspect may be important in terms of logistical, financial and quality of life considerations in the palliative setting. Recommendation 11.8. The standard of care is 6 cycles of threeweekly carboplatin and paclitaxel. This is based on the preliminary communication of a randomised trial showing similar efficacy and less toxicity compared to cisplatin/doxorubicin/paclitaxel Level of evidence: I Strength of recommendation: A Consensus: 100% yes (34 voters) Evidence supporting the use of second line chemotherapy after platinum-containing therapy in patients with endometrial cancer is limited, especially in cases where the treatment-free interval following first line chemotherapy is less than 6–12 months. Although various regimens have been evaluated in this setting [189–192],no randomised trials have been published. Therefore, no specific regimen can be recommended as a standard of care for second line chemotherapy. Recommendation 11.9. There is no standard of care for second line chemotherapy Level of evidence: V Strength of recommendation: C Consensus: 100% yes (34 voters) 12. What are the most promising targeted agents and which study designs should be used to evaluate their clinical benefit? Potentially ‘druggable’ molecular alterations in endometrial cancer According to the WHO classification of endometrial carcinoma, there are seven different types of tumours; however, endometrioid carcinoma, grade 3 and serous carcinomas account for the vast majority of aggressive tumours. Molecular genetic alterations involved in the development of endometrioid cancers differ from those of serous tumours and this must be taken into account when N. Colombo et al. / Radiotherapy and Oncology 117 (2015) 559–581 575 designing clinical trials to evaluate the efficacy of molecular targeted agents. Over the last fifteen years, it has been demonstrated that endometrial cancer shows microsatellite instability (MSI) and mutations in PTEN, PIK3CA and KRAS, and that beta-catenin genes are the most common molecular abnormalities in endometrioid carcinomas, whereas serous tumours have alterations of p53 and loss of heterozygosity on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin, and C-erbB2) [193]. Recently, the TCGA Research Network performed an integrated genomic characterisation of endometrial carcinoma [5]. The PI3K/AKT pathway is one of the most frequently altered signalling pathways in endometrioid tumours, often resulting from mutations in PTEN, PIK3CA and PIK3RI [194]. Of particular interest is the downstream effector, mammalian target of rapamycin (mTOR), and inhibitors of mTOR are now undergoing evaluation in clinical trials. The RAS-RAF-MEK-ERK signalling pathway also plays an important role in these tumours, with frequent mutations in KRAS, but also inactivation of tumour suppressors such as RASF1A [195,196]. Fibroblast growth factor-2 (FGFR2) is mutated in 10–14% of endometrioid tumours and is a target for receptor tyrosine kinase inhibitors [197]. Angiogenesis also plays a role in endometrial tumourigenesis [198]. In addition, tumour homologous recombination and mismatch repair deficiencies are seen in endometrioid tumours, the latter of which is particularly associated with LS, and these pathways could be interesting targets. Although there are a large number of specific gene abnormalities and aberrant signalling pathways that appear to be promising targets, the frequency of each abnormality is small and this presents a challenge to evaluating therapies in clinical trials [199]. Examples include known tumour markers such L1CAM, Anexin 2, other tyrosine kinase receptors (insulin-like growth factor receptor [IGFR], epidermal growth factor receptor [EGFR]), and signalling pathways involved in epithelial to mesenchymal transition (transforming growth factor-beta [TGF-b], wnt) or stem cell-ness (Notch). PI3K/PTEN/AKT/mTOR pathway, PTEN, MAPK-KRAS, angiogenesis (especially FGFR2 and vascular endothelial growth factor [VEGF]/VEGF receptor [VEGFR]), ER/PR and homologous recombination deficiency (HRD)/MSI are altered in endometrial cancer, and the relevance of these potential targets should be studied in clinical trials with targeted agents. Recommendation 12.1. PI3K/PTEN/AKT/mTOR pathway, PTEN, RAS-MAPK, angiogenesis (especially FGFR2 and VEGF/VEGFR), ER/PgR and HRD/MSI are altered in endometrial cancer and their relevance should be studied in clinical trials with targeted agents Level of evidence: III Strength of recommendation: B Consensus: 100% yes (34 voters) New agents in recurrent or metastatic endometrial cancer The benefit of standard chemotherapy and hormonal therapies is usually modest and of short duration. Currently, several different targeted therapies are undergoing clinical evaluation but none are currently licensed for use. EGFR, human epidermal growth factor receptor-2 (HER2), mTOR and VEGFR inhibitors have been tested in phase I and II trials, with modest response rates [200–203]. However, since this consensus conference was held, findings from two randomised phase II trials evaluating the addition of bevacizumab to TC in advanced or recurrent endometrial cancer suggest that this might be a promising approach worthy of further evaluation in phase III clinical trials [204,205]. GOG-86P was a 3-arm trial evaluating the addition of bevacizumab, temsirolimus or ixabepilone to first line TC in 349 patients with advanced or recurrent endometrial cancer [204]. No differences in PFS were seen when the three arms were compared with historical data for TC from GOG 209 [188]. However, bevacizumab appeared superior when the median OS results were compared with these historical control data (34.0 vs 22.7 months, P< 0.039). In the MITO END-2 trial, which included 108 patients with advanced or recurrent endometrial cancer who had received 0 or 1 prior lines of chemotherapy, bevacizumab was added to 6–8 cycles of TC and then continued as maintenance therapy. This approach resulted in a significant improvement in median PFS (13 vs 8.7 months, P= 0.036) and a numerical increase in median OS (23.5 vs 18 months, P= 0.24), although these OS data are not yet mature [205]. Despite these promising results, few clinical trials of new targeted therapies are molecularly driven [206] and the prevalence of potential targets in metastatic lesions has been studied less than in primary tumours [178]. Taken together, these findings suggest that PI3 Kinase, mTOR and angiogenesis inhibitors are the most promising classes of drugs to investigate in endometrial cancer [207], and progress in this area is likely to be faster if studies are biomarker driven with biopsy at entry. Recommendation 12.2. Drugs targeting PI3K/mTOR pathway signalling and angiogenesis have shown modest activity but no agent has been approved for clinical use, and further biomarker driven studies are warranted Level of evidence: III Strength of recommendation: A Consensus: 100% yes (34 voters) Clinical trial design While clinical trial endpoints such as OS and PFS are desirable, it may not be possible to make progress unless novel trial design and endpoints are used. There should be better selection of patients, using a more systematic approach to integration of biomarkers as well as earlier characterisation and standardisation of diagnostic imaging and biomarker assessments. Tumour response to biological agents may not occur to the same degree as with chemotherapy and alternative early endpoints, such as the percentage of patients free from progression at 18 weeks [208], have been used. Trial designs that include different gynaecological cancers of the same histotype should also be considered, an approach that is being taken in in the ongoing phase III GOG0261 trial of paclitaxel plus carboplatin versus paclitaxel plus ifosfamide in patients with different types of gynaecological carcinosarcomas (NCT00954174), and a randomised phase II trial of nintedanib versus chemotherapy in patients with recurrent clear cell carcinoma of the ovary or endometrium (EudraCT 2013-002109-73). There is also an argument for not being too selective, as the presence of a specific biomarker target may not be reflective of the probability of response. In a recent analysis of phase II studies of mTOR inhibitors, there was no correlation between response and the presence of mutations in the PI3K-AKT pathway [209], a result that could be explained by a variety of reasons, including the presence of multiple mutations, cross-talk in the signalling pathways involved, and the lack of re-biopsy samples to discount discordance between the tumour mutation profile at diagnosis versus recurrence. Setting up individual trials is both costly and timeconsuming, although adaptive phase II/III trials may offer some advantages [210]. Alternative strategies such as the ‘basket’ approach, which includes all patients subdivided by specific histological or molecular cohorts under the umbrella of a single trial, may be the most efficient way forward [211]. Such trials should also incorporate novel endpoints and the design would be strengthened by the inclusion of sequential and repeated assessments of biomarkers. 576 Endometrial cancer consensus conference guidelines Recommendation 12.3. Clinical trial designs for new, targeted therapy: 1: Basket studies with multiple cohorts related to histological subtypes and/or molecular alterations are considered a priority 2: Biomarker driven clinical trials with biopsy at entry and sequential biopsies in trials with molecular endpoints are recommended 3: PFS or PFS at a defined time-point are the preferred primary endpoints for early phase trials 4: OS is the preferred primary endpoint in phase III trials, unless crossover is planned or expected Level of evidence: V Strength of recommendation: A Consensus: 100% yes (34 voters) Funding All costs relating to the consensus conference were covered from the European Society for Medical Oncology central funds. There was no external funding of the event or manuscript production. Disclosures Frederic Amant (senior investigator for the Research Fund Flanders [FWO]), Nicoletta Colombo (consultancy – Roche, Astra Zeneca), Luis Chiva de Agustín (speaker for Roche and Takeda), Günter Emons (research grants from Aeterna Zentaris and Astra Zeneca), Christian Kurzeder (research funding from Roche, speaker for Roche), Fabrice Lécuru (research grants from Intuitive Surgicals, advisory board for Roche), Jonathan Ledermann (advisory boards for AstraZeneca, Clovis Oncology, Merck/MSD, Bayer, Oxigene), Helga Salvesen (pending intellectual property rights for some aspects relating to STMN/pSTMN1 as a prognostic marker for endometrial cancer [US 127962,946(HS) and US 147155,412 (HS)]). All remaining authors have declared no conflicts of interest. Acknowledgements The authors thank Jennifer Lamarre, Claire Bramley, Matthew Wallace, Aude Galli and all ESMO staff for their support throughout the whole consensus process. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript. This support was funded by ESMO. Appendix ESMO–ESGO–ESTRO Endometrial Consensus Conference Working Group Miguel Abal, Translational Medical Oncology (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Santiago de Compostela, Spain; Ozden Altundag, Department of Medical Oncology, Basßkent University Hospital, Ankara, Turkey; Frederic Amant, Department of Gynecological Oncology, University Hospital Leuven, Leuven, Belgium and Center for Gynecological Oncology Amsterdam (CGOA), Antoni van Leeuwenhoek, Amsterdam, The Netherlands; Susana Banerjee, Gynaecology Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Tjalling Bosse, Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; Antonio Casado, EORTC Gynecological tumor group, Hospital Universitario San Carlos, Madrid, Spain; Luis Chiva de Agustín, MD Anderson Cancer Center, Madrid, Spain and University of Texas, USA; David Cibula, Department of Obstetrics and Gynecology, Charles University, Prague, Czech Republic; Nicoletta Colombo, Division of Medical Gynecologic Oncology, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy; Carien Creutzberg, Department of Radiation Oncology, Leiden University Medical Center, Leiden, The Netherlands; Josep-María del Campo, Division of Medical Oncology, Vall d’Hebron Institute of Oncology, Barcelona, Spain; Günter Emons, Department of Obstetrics & Gynecology, GeorgAugust-Universität Göttingen, Frauenklinik, Göttingen, Germany; Frédéric Goffin, Department of Gynecologic Oncology, CHU Liège, Site Hôpital de la Citadelle, Liège, Belgium; Antonio GonzálezMartín, Medical Oncology Department, GEICO and MD Anderson Cancer Center, Madrid, Spain; Stefano Greggi, Department of Gynecologic Oncology, National Cancer Institute of Naples, Naples, Italy; Christine Haie-Meder, Radiation Oncology Department, Brachytherapy Service, Gustave Roussy Hospital, Villejuif, France; Dionyssios Katsaros, Department of Gynecologic Oncology, Azienda Ospedaliero-Universitaria Città della Salute, Sant’Anna Hospital and University of Turin, Turin, Italy; Vesna Kesic, Medical Faculty, University of Belgrade and Department of Obstetrics and Gynecology, Clinical Center of Serbia, Belgrade, Serbia; Christian Kurzeder, Department of Gynaecology and Gynaecologic Oncology, Kliniken Essen-Mitte, Essen, Germany; Sigurd Lax, Department of Pathology, Hospital Graz West, Graz, Austria; Fabrice Lécuru, Service de Chirurgie Gynécologique et Cancérologique, Hôpital Européen Georges Pompidou, Paris, France; Jonathan Ledermann, Department of Oncology and Cancer Trials, UCL Cancer Institute, London, United Kingdom; Tally Levy, Division of Gynecologic Oncology, Wolfson Medical Center, Tel-Aviv University, Holon, Israel; Domenica Lorusso, Department of Gynecologic Oncology, Fondazione ‘‘IRCCS” National Cancer Institute of Milan, Milan, Italy; Johanna Mäenpää, Department of Obstetrics and Gynecology, University of Tampere and Tampere University Hospital, Tampere, Finland; Christian Marth, Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; Xavier Matias-Guiu, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, Lleida, Spain; Philippe Morice, Gynaecological Surgery Department, Institut Gustave Roussy, Villejuif, France; Hans W. Nijman, Department of Gynaecologic Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Remi Nout, Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands; Melanie Powell, Department of Clinical Oncology, Barts Health NHS Trust, St Bartholomew’s Hospital, West Smithfield, London, United Kingdom; Denis Querleu, Department of Surgery, Institut Bergonié, Bordeaux, France and Gynecology and Obstetrics Department, McGill University Health Centre, Montreal, Quebec, Canada; Mansoor R. Mirza, Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Nick Reed, Department of Clinical Oncology, Beatson Oncology Centre, Gartnavel General Hospital, Glasgow, United Kingdom; Alexandros Rodolakis, First Department of Obstetrics and Gynecology, Athens University, Alexandra Hospital, Athens, Greece; Helga Salvesen, Department of Clinical Science, Haukeland University Hospital, Bergen, Norway; Jalid Sehouli, Department of Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany; Cristiana Sessa, Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland; Alexandra Taylor, Gynaecology Unit and Radiotherapy Department, The Royal Marsden NHS Foundation Trust, London, United Kingdom; Anneke Westermann, Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands; Alain G. 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