Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

•This ESMO Clinical Practice Guideline provides key recommendations for managing epithelial ovarian cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.•Treatment and management algorithms for early and advanced disease, as well as recurrent disease, are provided.•ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for treatment choices including targeted therapies.•The multidisciplinary expert author group stems from different institutions and countries in Europe, Asia and the USA. Epithelial ovarian cancer (EOC) represents a heterogeneous spectrum of disease entities at a clinical, pathological and molecular level. Ovarian cancer is the second most lethal gynaecological malignancy worldwide behind cervical cancer and the first in developed countries, with ∼200 000 women dying globally in 2020.1Sung H. Ferlay J. Siegel R.L. et al.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2021; 71: 209-249Crossref PubMed Scopus (41097) Google Scholar A study of epidemiological trends from 1990 to 2019 showed that highly developed regions had the highest burden and mortality.2Yi M. Li T. Niu M. et al.Epidemiological trends of women’s cancers from 1990 to 2019 at the global, regional, and national levels: a population-based study.Biomark Res. 2021; 9: 55Crossref PubMed Scopus (46) Google Scholar Infertility or nulliparity, estrogen hormone treatment and obesity have been reported as risk factors for EOC and could account for the rising incidence of the disease in developed countries.3Wentzensen N. Poole E.M. Trabert B. et al.Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium.J Clin Oncol. 2016; 34: 2888-2898Crossref PubMed Google Scholar Oral contraceptive use, especially over longer periods, and breastfeeding can reduce incidence.4Karlsson T. Johansson T. Höglund J. et al.Time-dependent effects of oral contraceptive use on breast, ovarian, and endometrial cancers.Cancer Res. 2020; 81: 1153-1162Crossref PubMed Scopus (27) Google Scholar A recent large study revealed significant heterogeneity of associations for 14 EOC risk factors across histological subtypes.3Wentzensen N. Poole E.M. Trabert B. et al.Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium.J Clin Oncol. 2016; 34: 2888-2898Crossref PubMed Google Scholar Higher parity, younger age at menopause and tubal ligation were most strongly associated with reduced risk in endometrioid carcinomas (ECs) and clear-cell carcinomas (CCCs), while endometriosis was associated with an increased risk in both EOC subtypes.3Wentzensen N. Poole E.M. Trabert B. et al.Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium.J Clin Oncol. 2016; 34: 2888-2898Crossref PubMed Google Scholar Serous and poorly differentiated carcinomas had modest associations with parity and menopausal hormonal therapy use and stronger associations with a family history of ovarian cancer.3Wentzensen N. Poole E.M. Trabert B. et al.Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium.J Clin Oncol. 2016; 34: 2888-2898Crossref PubMed Google Scholar Deleterious germline BRCA1/2 mutations (gBRCA1/2-muts) are associated with a 16%-65% increased risk of EOC, predominantly of high-grade serous histology.5Tan D.S.P. Rothermundt C. Thomas K. et al.“BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations.J Clin Oncol. 2008; 26: 5530-5536Crossref PubMed Scopus (407) Google Scholar Women with mutations in mismatch repair genes (Lynch syndrome) have a 10%-12% lifetime risk of developing EOC, which tends to be of either EC or CCC subtype.6Ketabi Z. Bartuma K. Bernstein I. et al.Ovarian cancer linked to lynch syndrome typically presents as early-onset, non-serous epithelial tumors.Gynecol Oncol. 2011; 121: 462-465Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar There is currently no reliable screening method for ovarian cancer. Most women are diagnosed based on symptoms, with the majority presenting at an advanced stage. Recognised symptoms include abdominal/pelvic pain, constipation, diarrhoea, urinary frequency, vaginal bleeding, abdominal distension and fatigue. In advanced disease, ascites and abdominal masses lead to bloating, nausea, anorexia, dyspepsia and early satiety. Extension of disease into the pleural cavities can produce effusions and respiratory symptoms. The standard work-up for patients suspected of having EOC should include detailed history and clinical examination with relevant laboratory and imaging tests (Table 1). Measurement of serum cancer antigen 125 (CA-125) aids diagnosis and is elevated in ∼85% of patients with advanced disease. CA-125 is less useful in early-stage disease, as it is only elevated in ∼50% of International Federation of Gynecology and Obstetrics (FIGO) stage I cases. Elevated CA-125 is not specific to ovarian cancer and may be elevated in non-gynaecological malignancies and benign conditions (e.g. endometriosis and ovarian cysts).7Charkhchi P. Cybulski C. Gronwald J. et al.CA125 and ovarian cancer: a comprehensive review.Cancers. 2020; 12: 3730Crossref PubMed Scopus (112) Google ScholarTable 1Diagnosis of EOCWork-up if EOC is suspected•Detailed history and clinical examination•Serum CA-125•Serum CEA and CA 19-9, in the case of MC, and endoscopy, if either or both are elevated•Transabdominal and transvaginal US by expert examiner•CT of thorax, abdomen and pelvis•Pathological examination of adequate tumour sample from diagnostic biopsy or surgical specimen•Cytological assessment of pleural effusion if presentCA 19-9, carbohydrate antigen 19-9; CA-125, cancer antigen 125; CEA, carcinoembryonic antigen; CT, computed tomography; EOC, epithelial ovarian cancer; MC, mucinous carcinoma; US, ultrasound. Open table in a new tab CA 19-9, carbohydrate antigen 19-9; CA-125, cancer antigen 125; CEA, carcinoembryonic antigen; CT, computed tomography; EOC, epithelial ovarian cancer; MC, mucinous carcinoma; US, ultrasound. Measuring serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 levels in addition to CA-125 may help distinguish primary mucinous ovarian tumours from a gastrointestinal metastasis. In this scenario, endoscopies should be considered, especially if the CA-125/CEA ratio is ≤25/1.8Timmerman D. Planchamp F. Bourne T. et al.ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors.Int J Gynecol Cancer. 2021; 31: 961-982Crossref PubMed Scopus (44) Google Scholar Initial imaging should comprise pelvic ultrasound (US; transabdominal and/or transvaginal) and computed tomography (CT) of the thorax, abdomen and pelvis to complete clinical staging and aid surgical planning. US-based diagnostic models [International Ovarian Tumor Analysis (IOTA) Simple Rules risk model or IOTA Assessment of Different NEoplasias in the adneXa (ADNEX) model] are preferable to CA-125, the human epididymis protein 4 (HE4) or the Risk of Ovarian Malignancy Algorithm, as they are superior in distinguishing between benign and malignant ovarian tumours and performed better than the Risk of Malignancy Index in a randomised controlled trial (RCT).8Timmerman D. Planchamp F. Bourne T. et al.ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors.Int J Gynecol Cancer. 2021; 31: 961-982Crossref PubMed Scopus (44) Google Scholar A definitive diagnosis of ovarian cancer requires pathological examination by an expert pathologist of tumour samples from either a diagnostic biopsy or, preferably, a surgical specimen. An adequate amount of tissue, particularly if neoadjuvant chemotherapy (ChT) is planned, allows genetic tumour testing for therapeutic stratification. If a complete pathological response is achieved, sufficient viable tumour tissue may be unavailable for genetic testing following interval cytoreductive surgery (ICS). Cytological assessment of ascites (in early-stage disease) and of pleural fluid (if present and safely assessable) is required to complete staging. EOC represents the majority (∼90%) of ovarian malignancies. The 2020 World Health Organization (WHO) classification based on histopathology, immunohistochemistry (IHC) and molecular analysis recognises at least five distinct subtypes of malignant EOC: high-grade serous carcinoma (HGSC; 70% of cases), EC (10%), CCC (6%-10%), low-grade serous carcinoma (LGSC; 5%) and mucinous carcinoma (MC; 3%-4%), along with other rare entities including mesonephric-like carcinoma, mixed-cell tumour, malignant Brenner tumour, carcinosarcoma and undifferentiated carcinoma.9WHO Classification of Tumours Editorial BoardFemale Genital Tumours: WHO Classification of Tumours. IARC, Lyon, France2020Google Scholar Each subtype represents a distinct disease entity with a different site of origin, pathogenesis, clinical features and prognosis. The complexity of subclassification and its effect on personalised treatment choice underline the importance of histological tumour typing by an expert gynaecological pathologist. Details of the molecular features of HGSC, EC, CCC, LGSC and MC are provided in the Supplementary Material Section 1, available at https://doi.org/10.1016/j.annonc.2023.07.011. IHC staining patterns and molecular features of the different subtypes are summarised in Table 2. Certain genomic or molecular alterations, such as BRCA1/2-mut or homologous recombination deficiency (HRD), are helpful in predicting the magnitude of benefit of targeted therapy with poly (ADP-ribose) polymerase inhibitors (PARPis) in high-grade tumours.10Miller R.E. Leary A. Scott C.L. et al.ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer.Ann Oncol. 2020; 31: 1606-1622Abstract Full Text Full Text PDF PubMed Scopus (176) Google ScholarTable 2Pathology and molecular biology of EOC subtypesHGSCECCCCLGSCMCIHC stainingp53AbnormalAbnormal/normalNormalNormalNormalp16+−−WT-1+−−+−ER+/−+−+−PAX8+++−Vimentin+HNF1β+CDX2+Molecular alterations (decreasing prevalence from top to bottom)TP53CTNNB1ARID1AKRASCDKN2ABRCA1/2ARID1API3KCABRAFKRASHRDPTENPTENRAFHER2KRASMSI/dMMRTP53 (high-grade EC)MSI/dMMRCCC, clear-cell carcinoma; CDX2, homeobox protein CDX-2; dMMR, mismatch repair deficiency; EC, endometrioid carcinoma; EOC, epithelial ovarian cancer; ER, estrogen receptor; HGSC, high-grade serous carcinoma; HNF1β, hepatocyte nuclear factor-1β; HRD, homologous recombination deficiency; IHC, immunohistochemistry; LGSC, low-grade serous carcinoma; MC, mucinous carcinoma; MSI, microsatellite instability; PAX8, paired box gene 8; WT-1, Wilms tumour 1. Open table in a new tab CCC, clear-cell carcinoma; CDX2, homeobox protein CDX-2; dMMR, mismatch repair deficiency; EC, endometrioid carcinoma; EOC, epithelial ovarian cancer; ER, estrogen receptor; HGSC, high-grade serous carcinoma; HNF1β, hepatocyte nuclear factor-1β; HRD, homologous recombination deficiency; IHC, immunohistochemistry; LGSC, low-grade serous carcinoma; MC, mucinous carcinoma; MSI, microsatellite instability; PAX8, paired box gene 8; WT-1, Wilms tumour 1. •If EOC is suspected, diagnostic work-up should include serum CA-125 measurement, pelvic US by an expert examiner and CT scan of the thorax, abdomen and pelvis [III, A].•Pathological diagnosis should be made according to the 2020 WHO classification by an expert gynaecological pathologist [IV, A].•All patients with high-grade ovarian cancer should be tested for germline and/or somatic BRCA1/2-muts at diagnosis [I, A].•Testing for HRD is recommended in advanced high-grade cancers [I, A]. All patients with ovarian cancer should be surgically staged according to the revised 2014 FIGO staging system for EOC (Table 3).11Mutch D.G. Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer.Gynecol Oncol. 2014; 133: 401-404Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar The histotype and primary site (i.e. ovary, fallopian tube or peritoneum) of the tumour should be established and recorded as part of routine staging for treatment planning.Table 3FIGO staging system for EOC11Mutch D.G. Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer.Gynecol Oncol. 2014; 133: 401-404Abstract Full Text Full Text PDF PubMed Scopus (246) Google ScholarEOC, epithelial ovarian cancer; FIGO, International Federation of Gynecology and Obstetrics.Stage I: Tumour confined to ovaries or fallopian tube(s)IATumour limited to one ovary (capsule intact) or fallopian tube, without tumour on ovarian or fallopian tube surface and without malignant cells in the ascites or peritoneal washingsIBTumour limited to both ovaries (capsules intact) or fallopian tubes, without tumour on ovarian or fallopian tube surface and without malignant cells in the ascites or peritoneal washingsICTumour limited to one or both ovaries or fallopian tubes, with any of the following: IC1 Surgical spill IC2 Capsule ruptured before surgery or tumour on ovarian or fallopian tube surface IC3 Malignant cells in the ascites or peritoneal washingsStage II: Tumour involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or primary peritoneal cancerIIAExtension and/or implants on uterus and/or fallopian tubes and/or ovariesIIBExtension to other pelvic intraperitoneal tissuesStage III: Tumour involves one or both ovaries or fallopian tubes or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodesIIIA1Positive retroperitoneal lymph nodes only (cytologically or histologically proven): IIIA1(i) Metastasis ≤10 mm in greatest dimension IIIA1(ii) Metastasis >10 mm in greatest dimensionIIIA2Microscopic extra-pelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodesIIIBMacroscopic peritoneal metastasis beyond the pelvis ≤2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodesIIICMacroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumour to capsule of liver and spleen without parenchymal involvement of either organ)Stage IV: Distant metastasis excluding peritoneal metastasesIVAPleural effusion with positive cytologyIVBParenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)Reprinted from Mutch DG, et al.11Mutch D.G. Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer.Gynecol Oncol. 2014; 133: 401-404Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar with permission from Elsevier. Open table in a new tab Reprinted from Mutch DG, et al.11Mutch D.G. Prat J. 2014 FIGO staging for ovarian, fallopian tube and peritoneal cancer.Gynecol Oncol. 2014; 133: 401-404Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar with permission from Elsevier. There is a strong prognostic link between the degree of post-operative residual disease and patient survival.12du Bois A. Reuss A. Pujade-Lauraine E. et al.Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials.Cancer. 2009; 115: 1234-1244Crossref PubMed Scopus (1179) Google Scholar Preoperative imaging can help predict the likelihood of suboptimal cytoreductive surgery.13Jeong S.Y. Kim T.J. Park B.K. Epithelial ovarian cancer: a review of preoperative imaging features indicating suboptimal surgery.J Gynecol Oncol. 2020; 31: e57Crossref PubMed Scopus (2) Google Scholar Extension of tumour from the omentum to the spleen or liver surface (stage IIIC) should be differentiated from isolated liver or spleen parenchymal metastases (stage IVB). CT and positron emission tomography (PET)–CT imaging have been shown to underestimate bowel or mesenteric involvement compared with surgical exploration.14Dromain C. Leboulleux S. Auperin A. et al.Staging of peritoneal carcinomatosis: enhanced CT vs. PET/CT.Abdom Imaging. 2007; 33: 87-93Crossref Scopus (164) Google Scholar Diffusion-weighted magnetic resonance imaging may have better sensitivity than CT for detecting involvement of surgically critical tumour sites including mesenteric root infiltration, small bowel and colon carcinomatosis.15Michielsen K. Dresen R. Vanslembrouck R. et al.Diagnostic value of whole body diffusion-weighted MRI compared to computed tomography for pre-operative assessment of patients suspected for ovarian cancer.Eur J Cancer. 2017; 83: 88-98Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar When the disease appears suitable for cytoreduction as assessed by imaging, and there are no surgical or medical contraindications, surgical staging (through midline laparotomy or initial laparoscopy) should be carried out to explore the extent of the disease in the abdomino-peritoneal cavity and assess the likelihood of achieving optimal cytoreduction (no gross visible residual disease or complete resection). •The revised 2014 FIGO staging system for EOC should be used [I, A]. Figure 1 provides a treatment algorithm for the management of FIGO stage I-II EOC. Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2023.07.011, provides a summary of the benefit of adjuvant systemic therapy for FIGO stage I-II EOC. The aim of surgery for early EOC is complete resection of the tumour and to undertake adequate staging, including:•Midline laparotomy•Inspection and palpation of the whole abdominal cavity•Peritoneal washing with cytological examination•Biopsies from all visible lesions and all abdominal fields•Bilateral salpingo-oophorectomy•Hysterectomy•Omentectomy•Appendicectomy in MC•Systematic pelvic and para-aortic lymphadenectomy Whether a laparoscopic approach is a safe alternative to midline laparotomy is being debated, but as prospective trials are lacking and the risk of capsule rupture increases,16Matsuo K. Huang Y. Matsuzaki S. et al.Minimally invasive surgery and risk of capsule rupture for women with early-stage ovarian cancer.JAMA Oncol. 2020; 6: 1110-1113Crossref PubMed Scopus (35) Google Scholar midline laparotomy remains the standard procedure. Surgical staging will provide prognostic information and define whether ChT is needed. The availability of an intra-operative frozen section to identify a malignant epithelial cancer may allow the appropriate surgical staging to be done without the need for a second operative procedure. Depending on the histological grade and subtype, ≤60% of patients with apparent early EOC will be upstaged after comprehensive surgical staging, which can impact progression-free survival (PFS) and overall survival (OS).17Grabowski J.P. Harter P. Buhrmann C. et al.Re-operation outcome in patients referred to a gynecologic oncology center with presumed ovarian cancer FIGO I-IIIA after sub-standard initial surgery.Surg Oncol. 2012; 21: 31-35Crossref PubMed Scopus (0) Google Scholar,18Trimbos B. Timmers P. Pecorelli S. et al.Surgical staging and treatment of early ovarian cancer: long-term analysis from a randomized trial.J Natl Cancer Inst. 2010; 102: 982-987Crossref PubMed Scopus (127) Google Scholar Systematic pelvic and para-aortic lymphadenectomy for staging purposes is recommended for high-grade histologies. The rate of lymph node metastases in patients with low-grade EC or expansile MC is <1%.19Heitz F. Harter P. Ataseven B. et al.Stage- and histologic subtype-dependent frequency of lymph node metastases in patients with epithelial ovarian cancer undergoing systematic pelvic and paraaortic lymphadenectomy.Ann Surg Oncol. 2018; 25: 2053-2059Crossref PubMed Scopus (32) Google Scholar Therefore, lymphadenectomy could be omitted in patients with these subtypes and with radiologically and clinically negative nodes. Further information on the role of lymphadenectomy in stage I EOC is provided in the Supplementary Material Section 2, available at https://doi.org/10.1016/j.annonc.2023.07.011. Fertility-sparing surgery can be considered in young patients, but always after full discussion with the patient about potential risks. Patients with any stage IA histotype or stage IC1-2 with unilateral ovarian involvement and favourable histology (i.e. low-grade tumours) would be amenable to contralateral ovary and uterus preservation, in combination with the other recommended surgical staging procedures.20Fruscio R. Corso S. Ceppi L. et al.Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series.Ann Oncol. 2013; 24: 138-144Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Adjuvant platinum-based ChT significantly prolongs OS and PFS in patients with early-stage EOC, as demonstrated in the joint analysis of ACTION and ICON1 trials and a Cochrane systematic review.21Trimbos J.B. Parmar M. Vergote I. et al.International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma.J Natl Cancer Inst. 2003; 95: 105-112Crossref PubMed Google Scholar, 22Collinson F. Qian W. Fossati R. et al.Optimal treatment of early-stage ovarian cancer.Ann Oncol. 2014; 25: 1165-1171Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 23Lawrie T.A. Winter-Roach B.A. Heus P. et al.Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer.Cochrane Database Syst Rev. 2015; 2015: CD004706PubMed Google Scholar An updated analysis showed the benefit of adjuvant ChT largely depended on histological subtype (see Figure 1 and Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2023.07.011).22Collinson F. Qian W. Fossati R. et al.Optimal treatment of early-stage ovarian cancer.Ann Oncol. 2014; 25: 1165-1171Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar A large Surveillance, Epidemiology and End Results series of stage I EC demonstrated no improvement in grade 1-2 EC.24Oseledchyk A. Leitao Jr., M.M. Konner J. et al.Adjuvant chemotherapy in patients with stage I endometrioid or clear cell ovarian cancer in the platinum era: a Surveillance, Epidemiology, and End Results Cohort Study, 2000-2013.Ann Oncol. 2017; 28: 2985-2993Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar In CCC, retrospective studies of an Asian population did not identify any benefit with adjuvant ChT for early-stage disease (stage IA-IC1).25Mizuno M. Kajiyama H. Shibata K. et al.Adjuvant chemotherapy for stage I ovarian clear cell carcinoma: is it necessary for stage IA?.Int J Gynecol Cancer. 2012; 22: 1143-1149Crossref PubMed Scopus (31) Google Scholar In stage I MC, adjuvant ChT may be avoided for either expansile subtype or grade 1 infiltrative based on the excellent prognosis.26Gouy S. Saidani M. Maulard A. et al.Staging surgery in early-stage ovarian mucinous tumors according to expansile and infiltrative types.Gynecol Oncol Rep. 2017; 22: 21-25Crossref PubMed Scopus (28) Google Scholar The standard adjuvant ChT consists of six cycles of platinum-based ChT. A Gynecologic Oncology Group (GOG) trial comparing three versus six cycles of adjuvant paclitaxel–carboplatin did not identify a significant reduction in recurrence risk with longer treatment, but additional toxicity occurred.27Bell J. Brady M.F. Young R.C. et al.Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study.Gynecol Oncol. 2006; 102: 432-439Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar Only serous carcinoma seems to benefit from longer adjuvant therapy compared with non-serous tumours.28Chan J.K. Tian C. Fleming G.F. et al.The potential benefit of 6 vs. 3 cycles of chemotherapy in subsets of women with early-stage high-risk epithelial ovarian cancer: an exploratory analysis of a Gynecologic Oncology Group study.Gynecol Oncol. 2010; 116: 301-306Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar The optimal ChT regimen (platinum alone or a platinum-based combination) is not completely resolved.22Collinson F. Qian W. Fossati R. et al.Optimal treatment of early-stage ovarian cancer.Ann Oncol. 2014; 25: 1165-1171Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar •Surgical staging is recommended in presumed early-stage ovarian cancer for classification and recommendation of optimal systemic therapy [III, A].•Adjuvant ChT in early-stage ovarian cancer is generally recommended for FIGO stage I-IIB (see exceptions below) [II, A], either paclitaxel–carboplatin [I, B] or carboplatin (six cycles) alone [I, A].•For patients receiving paclitaxel–carboplatin, a minimum of three cycles are recommended except for HGSC/high-grade EC or any stage IC-II regardless of histotype, for which six cycles are suggested [II, B].•The benefit of adjuvant ChT is uncertain and can be considered as optional [III, C] for:oLGSC stage IB-ICoCCC stage IA-IC1oLow-grade EC stage IB-ICoExpansile MC stage ICoInfiltrative MC stage IA•Adjuvant ChT is not recommended in completely staged patients with LGSC stage IA, low-grade EC stage IA or expansile MC stage IA-IB [II, E]. In advanced EOC, surgery aims to achieve a complete or optimal cytoreduction, defined as total macroscopic tumour clearance with no residual visible disease, since this has been shown to significantly increase OS and PFS.12du Bois A. Reuss A. Pujade-Lauraine E. et al.Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials.Cancer. 2009; 115: 1234-1244Crossref PubMed Scopus (1179) Google Scholar This needs maximal surgical effort and may require intestinal resection, diaphragmatic and peritoneal stripping, splenectomy and removal of bulky para-aortic lymph nodes and, in some cases, extra-abdominal disease.29Ataseven B. Chiva L.M. Harter P. et al.FIGO stage IV epithelial ovarian, fallopian tube and peritoneal cancer revisited.Gynecol Oncol. 2016; 142: 597-607Abstract Full Text Full Text PDF PubMed Google Scholar An increasing body of evidence suggests that surgical expertise and specialist training result in improvements in the rate of complete cytoreduction. Thus, patients with advanced disease are advised to undergo surgery in specialised centres with adequate infrastructure and trained teams.30Fotopoulou C. Concin N. Planchamp F. et al.Quality indicators for advanced ovarian cancer surgery from the European Society of Gynaecological Oncology (ESGO): 2020 update.Int J Gynecol Cancer. 2020; 30: 436-440Crossref PubMed Scopus (52) Google Scholar Patients with macroscopic complete resection and clinically negative nodes do not benefit from systematic lymphadenectomy, which unnecessarily increases the rate of post-operative complications and mortality.31Harter P. Sehouli J. Lorusso D. et al.A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms.N Engl J Med. 2019; 380: 822-832Crossref PubMed Scopus (318) Google Scholar The timing of surgical cytoreduction in relation to ChT is still debated. The gold standard in patients with stage III-IV disease is primary cytoreductive surgery (PCS), if physically able to undergo surgery and complete resection seems achievable, followed by systemic treatment (Figure 2). PCS is also recommended in patients with less chemosensitive subtypes (e.g. MC or LGSC), even if uncertainty about achieving complete resection exists and a small residual tumour (<1 cm) is likely to remain.32Colombo N. Sessa C. du Bois A. et al.ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.Ann Oncol. 2019; 30: 672-705Abstract Full Text Full Text PDF PubMed Scopus (599) Google Scholar Prospective trials have shown that three cycles of platinum-based neoadjuvant ChT (NACT) followed by ICS and completion of ChT was not inferior to PCS followed by ChT in patients with advanced bulky stage IIIC or IV disease, for whom complete resection at primary surgery is unlikely or extensive surgery is not tolerable due to frailty or other significant comorbidities.33Vergote I. Tropé C.G. Amant F. et al.Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.N Engl J Med. 2010; 363: 943-953Crossref PubMed Scopus (1876) Google Scholar,34Kehoe S. Hook J. Nankivell M. et al.Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial.Lancet. 2015; 386: 249-257Abstract Full Text Full Text PDF PubMed Scopus (935) Google Scholar In all neoadjuvant trials, however, the PFS and OS were lower than in primary surgery trials. Due to the limitations of randomised NACT trials, it is not yet determined whether NACT and ICS could be an option for patients for whom complete resection at primary surgery seems feasible. This is being addressed in the TRUST/ENGOT-OV33/Arbeitsgemeinschaft Gynäkologische Onkologie (AGO)-OVAR