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

Abstract

The estimated number of new ovarian cancer cases in Europe in 2012 was 65 538 with 42 704 deaths [1.EUCAN Cancer Factsheets: Ovary http://eu-cancer.iarc.fr/EUCAN/CancerOne.aspx?Cancer=27&Gender=2 (11 July 2013, date last accessed).Google Scholar]. There is variation in the incidence rate across the continent with a higher incidence in northern European countries. In the USA, there were ∼20 400 newly diagnosed cases and 14 400 deaths in 2009 [2.U.S. Cancer Statistics Working Group United States Cancer Statistics: 1999–2009 Incidence and Mortality Web-based Report. Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute, Atlanta (GA)2013http://www.cdc.gov/uscsGoogle Scholar]. Ovarian cancer is the fifth most common type of cancer in women and the fourth most common cause of cancer death in women. The estimated lifetime risk for a woman developing ovarian cancer is about 1 in 54. Ovarian cancer is predominantly a disease of older, postmenopausal women with the majority (>80%) of cases being diagnosed in women over 50 years. The exact cause of ovarian cancer remains unknown but many associated risk factors have been identified. A woman's reproductive history appears to contribute significantly to her lifetime risk of ovarian cancer. Those women who have had multiple pregnancies have a lower risk than those with fewer pregnancies, who in turn have a lower risk than nulliparous women. Early menarche and late menopause also seem to contribute to a greater risk of ovarian cancer, while use of the oral contraceptive pill, tubal ligation, breastfeeding and suppression of ovulation offer protection against ovarian cancer. All of these risk factors point to ovulation being correlated with the development of ovarian cancer. Further risk factors are obesity and possibly the use of talcum powder. Family history plays a very important role in the development of ovarian cancer, although in a recent study 44% patients with high-grade serous ovarian cancer and a germline BRCA mutation did not report a family history of cancer [3.Alsop K. Fereday S. Meldrum C. et al.BRCA Mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.J Clin Oncol. 2012; 30: 2654-2663Crossref PubMed Scopus (874) Google Scholar]. Women with a first-degree relative have more than a twofold increase in risk of ovarian cancer compared with women with no family history. However, only 10% of ovarian cancer cases have an identifiable genetic mutation, e.g. the known susceptibility genes BRCA 1 and BRCA 2. An inherited BRCA 1 mutation confers a 15%–45% lifetime risk of developing ovarian cancer and ≤85% risk of developing breast cancer. A BRCA 2 mutation increases the lifetime risk of ovarian cancer to 10%–20% and breast cancer risk of ≤85%. Women with hereditary ovarian cancer tend to develop the disease ∼10 years earlier than women with non-hereditary ovarian cancer. There are no clear guidelines for referral of ovarian cancer patients for testing. Referral is made on the basis of a family history and ethnic background. The importance of identifying BRCA mutations has increased as, in addition to risk-reducing surgery and surveillance for breast cancer in the patient and in family members, there are new treatments emerging specifically for BRCA-related cancers. The majority of cases of ovarian cancer are of epithelial origin (∼90%). The World Health Organisation histological typing of epithelial ovarian tumours recognises the following distinct subtypes [4.Scully R.E. Sobin L.H. Serov S.F. Histological Typing of Ovarian Tumours. Springer, Berlin,Heidelberg, New York1999Crossref Google Scholar]:•serous•endometrioid•clear cell•mucinous•Brenner (transitional cell)•mixed epithelial tumours•undifferentiated•unclassified Clinical trials have demonstrated that the subtype has prognostic importance [5.Mackay H.J. Brady M.F. Oza A.M. et al.Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial ovarian cancer.Int J Gynecol Cancer. 2010; 20: 945-952Crossref PubMed Scopus (207) Google Scholar] [I]. Grade is an additional prognostic determinant and a number of grading systems currently exist which are derived from reviewing the following tumour characteristics: architectural features, mitotic counts and nuclear atypia. Based on these, a grade of 1–3 is most commonly assigned [6.Shimizu Y. Kamoi S. Amada S. et al.Toward the development of a universal grading system for ovarian epithelial carcinoma: testing of a proposed system in a series of 461 patients with uniform treatment and follow-up.Cancer. 1998; 82: 893-901Crossref PubMed Scopus (214) Google Scholar]. There is no single universally accepted grading system. Some use a two-tier staging [7.Bodurka D.C. Deavers M.T. Tian C. et al.Reclassification of serous ovarian carcinoma by a 2-tier system: a Gynecologic Oncology Group Study.Cancer. 2012; 118: 3087-3094Crossref PubMed Scopus (117) Google Scholar]; moreover, it is being recognised increasingly that different grading systems for different histological subtypes should be employed. The complexity of subclassification below and its affect on treatment choice underline the importance of the role of an expert in gynaecological pathology in typing tumours. Invasive serous carcinomas are the most common histological type accounting for up to ∼80% of advanced ovarian cancers. In recent years, convincing data have been presented that high-grade serous and low-grade serous ovarian cancers are two distinct disease entities [8.Vang R. Shih I.-M. Kurman R.J. Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems.Adv Anat Pathol. 2009; 16: 267-282Crossref PubMed Scopus (417) Google Scholar, 9.Bonome T. Lee J.Y. Park D.C. et al.Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary.Cancer Res. 2005; 65: 10602-10612Crossref PubMed Scopus (268) Google Scholar]. Tumours with mild to moderate cytologic atypia and low mitotic rates are classified as low-grade, whereas patients with severe cytologic atypia and high mitotic rates are considered high-grade serous tumours. There are also distinct mutations present in each type, and the cell of origin may also be different, as discussed in the next section. Clinically, women with low-grade serous tumours, which account for ∼10% of serous cancers tend to present at a younger age and have a longer survival compared with women with high-grade tumours [10.Diaz-Padilla I. Malpica A.L. Minig L. et al.Ovarian low-grade serous carcinoma: a comprehensive update.Gynecol Oncol. 2012; 126: 279-285Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. There is an increasing realisation that low-grade serous tumours do not respond to traditional chemotherapy regimens [11.Schmeler K.M. Sun C.C. Bodurka D.C. et al.Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum.Gynecol Oncol. 2008; 108: 510-514Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar] and that alternative approaches are required particularly for the treatment of recurrent tumours. The majority of endometrioid ovarian cancers are usually early stage (stage 1) and low grade. The prevalence of endometrioid ovarian cancers has decreased in recent years, likely due to better pathological diagnosis, and currently they account for ∼10% of ovarian cancers. Endometriosis and in particular endometriotic cysts have been implicated as putative precursor lesions to endometrioid ovarian cancer. ARID1A mutations have been detected in endometriotic cysts and in endometrioid ovarian cancer, suggesting a causative role [12.Wiegand K.C. Shah S.P. Al-Agha O.M. et al.ARID1A mutations in endometriosis-associated ovarian carcinomas.N Engl J Med. 2010; 363: 1532-1543Crossref PubMed Scopus (1247) Google Scholar]. Clear-cell cancers account for ∼5% of ovarian cancers, although the incidence varies worldwide. Japanese women develop clear-cell ovarian cancers more commonly. The prognosis for stage 1 clear-cell cancers is relatively good. However, advanced stage clear-cell cancers have a worse prognosis than serous ovarian cancers as the tumours tend to be resistant to the standard chemotherapeutic agents used in ovarian cancer. Clear-cell cancers are also strongly associated with endometriosis and a significant proportion carry ARID1A mutations [12.Wiegand K.C. Shah S.P. Al-Agha O.M. et al.ARID1A mutations in endometriosis-associated ovarian carcinomas.N Engl J Med. 2010; 363: 1532-1543Crossref PubMed Scopus (1247) Google Scholar]. Primary ovarian transitional carcinomas are rare but carcinomas with transitional features are quite common. The majority of the latter are variants of high-grade serous carcinomas and exhibit WT1 positivity. Mixed carcinomas are diagnosed when a tumour consists of more than one histological type and the minor component forms >10%. Undifferentiated carcinomas are rare and are likely to represent one end of the high-grade serous spectrum [13.McCluggage W.G. Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis.Pathology. 2011; 43: 420-432Abstract Full Text PDF PubMed Scopus (359) Google Scholar]. Borderline tumours comprise about 10%–15% of ovarian tumours and do not fit into the category of benign or malignant. As most ovarian tumours are serous in origin, borderline serous tumours are the most common type but borderline mucinous and endometrioid tumours also occur. Borderline serous tumours form part of the spectrum of low-grade serous cancers. They are managed primarily by surgery and respond poorly to chemotherapy. Ovarian cancer is recognised as a heterogeneous disease, and in the last few years a dualistic model for the pathogenesis of this disease has emerged which divides epithelial tumours into type 1 and type 2 ovarian carcinomas. This classification is not intended to replace histological subtypes but provides a parallel terminology pertaining to the broad mechanism of cancer development [13.McCluggage W.G. Morphological subtypes of ovarian carcinoma: a review with emphasis on new developments and pathogenesis.Pathology. 2011; 43: 420-432Abstract Full Text PDF PubMed Scopus (359) Google Scholar]. Type 1 cancers tend to be low-grade and indolent tumours and include low-grade serous, endometrioid, mucinous, clear-cell and malignant Brenner tumours. These tumours are characterised by mutations of KRAS, BRAF, ERBB2, PTEN, PIK3CA and ARID1A and are relatively genetically stable. These mutations occur early in the evolution of type 1 ovarian tumours and are also observed in borderline tumours and endometriosis. A stepwise sequence of tumour development is now well recognised from benign precursor lesions (e.g. borderline tumour) to malignant lesions in type 1 cancers. Conversely, there is no clear precursor lesion for type 2 cancers. These are high-grade, aggressive tumours comprising high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumours and undifferentiated tumours. Type 2 tumours are very frequently associated with TP53 mutations, and one landmark study found that 97% of high-grade serous cancers were associated with a TP53 mutation. Approximately 20% of these tumours also carried a BRCA1/2 mutation due to a combination of germline and somatic mutations [14.Bell D. Berchuck A. Birrer M. et al.Integrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615Crossref PubMed Scopus (5436) Google Scholar]. In recent years, accumulating evidence has shown that the majority of high-grade serous ovarian and peritoneal tumours originate in the fimbria of the fallopian tube (serous tubal intraepithelial carcinoma) [15.Vang R. Shih I.-M. Kurman R.J. Fallopian tube precursors of ovarian low- and high-grade serous neoplasms.Histopathology. 2013; 62: 44-58Crossref PubMed Scopus (210) Google Scholar, 16.Carlson J.W. Miron A. Jarboe E.A. et al.Serous tubal intraepithelial carcinoma: its potential role in primary peritoneal serous carcinoma and serous cancer prevention.J Clin Oncol. 2008; 26: 4160-4165Crossref PubMed Scopus (272) Google Scholar]. These malignant cells then metastasise to the ovaries and the peritoneal cavity. Patients with ovarian cancer confined to the ovary may have few or no symptoms, making clinical diagnosis of early ovarian cancer more difficult. Symptoms are most commonly seen with advanced disease. Recognised symptoms of all stages include abdominal or pelvic pain, constipation, diarrhoea, urinary frequency, vaginal bleeding, abdominal distension and fatigue. In advanced ovarian cancer, ascites and abdominal masses lead to increased abdominal girth, bloating, nausea, anorexia, dyspepsia and early satiety. Extension of disease across the diaphragm to the pleural cavities can produce pleural effusions and the development of respiratory symptoms. Patients may become aware of an abdominal or nodal mass either in the inguinal region, axillae or the supraclavicular fossa. Following a full clinical assessment, measurement of serum CA 125 is routinely used to aid diagnosis. However, its utility to detect early disease is questionable as it is elevated only in about 50% of patients with the International Federation of Gynecology and Obstetrics (FIGO) stage I disease. In advanced disease, CA 125 is elevated in about 85% of patients. It is not specific for ovarian cancer and raised CA 125 levels may be found in non-gynaecological malignancies (e.g. breast, lung, colon and pancreatic cancer) and benign disease (e.g. endometriosis, pelvic inflammatory disease and ovarian cysts). Serum carcinoembryonic antigen (CEA) and CA 19–9 levels are sometimes measured in situations where it is unclear whether an ovarian mass is of gastrointestinal origin, or a primary mucinous ovarian tumour. Similarly, in these situations, colonoscopy and/or gastroscopy are sometimes considered, particularly when CA 125/CEA ratio is ≤25. Ultrasonography of the abdomen and pelvis is usually the first imaging investigation recommended for women in whom ovarian cancer is suspected. Transvaginal ultrasonography has improved the visualisation of ovarian structures, thus improving the differentiation of malignant versus benign conditions [17.Lerner J.P. Timor-Tritsch I.E. Federman A. Abramovich G. Transvaginal ultrasonographic characterization of ovarian masses with an improved, weighted scoring system.Am J Obstet Gynecol. 1994; 170: 81-85Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar]. A number of morphological variables have been identified as being strongly associated with ovarian cancer. The presence of a large lesion, multi-locular cysts, solid papillary projections, irregular internal septations and ascites are highly suggestive of ovarian cancer. A ‘risk of malignancy’ index can be calculated from clinical factors, ultrasound and CA 125 and can be used to refer patients to a specialist gynaecological oncology team. Computed tomography (CT) scans are routinely used to determine the extent of disease and to aid in surgical planning. Imaging of the chest with CT or chest X-ray should be done to look for pleural effusions and disease above the diaphragm. A pleural effusion cannot be regarded as malignant and indicative of FIGO stage IV disease without confirmation of positive cytology. Magnetic resonance imaging (MRI) scans do not form part of routine investigations. FIGO staging remains the most powerful indicator of prognosis (see Table 1). Although surgically defined, preoperative assessment with cross-sectional imaging (CT or MRI) is essential as it guides surgery and the pathway of intervention. Given the variation in histological subtypes and evolving different patterns of care, reliance on a cytological diagnosis should be avoided and a histological diagnosis should be obtained if at all possible. Primary surgery remains the most common and preferred approach, but where this is deemed not feasible, an image-guided or laparoscopic biopsy should be carried out.Table 1Staging of cancer of the ovaryStage IGrowth limited to the ovaries IAGrowth limited to one ovary; no ascites present containing malignant cells. No tumour on the external surface; capsule intact IBGrowth limited to both ovaries; no ascites present containing malignant cells. No tumour on the external surfaces; capsules intact ICaIn order to evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know whether rupture of the capsule was spontaneous, or caused by the surgeon and whether the source of malignant cells detected was peritoneal washings or ascites.Tumour either stage IA or IB, but with tumour on surface of one or both ovaries, or with capsule ruptured, or with ascites present containing malignant cells, or with positive peritoneal washingsStage IIGrowth involving one or both ovaries with pelvic extension IIAExtension and/or metastases to the uterus and/or tubes IIBExtension to other pelvic tissues IICaIn order to evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know whether rupture of the capsule was spontaneous, or caused by the surgeon and whether the source of malignant cells detected was peritoneal washings or ascites.Tumour either stage IIA or IIB, but with tumour on surface of one or both ovaries, or with capsule(s) ruptured, or with ascites present containing malignant cells, or with positive peritoneal washingsStage IIITumour involving one or both ovaries with histologically confirmed peritoneal implants outside the pelvis and/or positive regional lymph nodes. Superficial liver metastases equal stage III. Tumour is limited to the true pelvis, but with histologically proven malignant extension to small bowel or omentum IIIATumour grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces, or histologically proven extension to small bowel or mesentery IIIBTumour of one or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative IIICPeritoneal metastasis beyond the pelvis >2 cm in diameter and/or positive regional lymph nodesStage IVGrowth involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytology to allot a case to stage IV. Parenchymal liver metastasis equals stage IVReprinted from the International Journal of Gynecology and Obstetrics [57.Rustin G.J. van der Burg M.E. on behalf of MRC and EORTC collaborators A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials).J Clin Oncol (Meeting Abstracts). 2009; 27: 1Crossref Google Scholar]. Copyright 2006, with permission from Elsevier.a In order to evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know whether rupture of the capsule was spontaneous, or caused by the surgeon and whether the source of malignant cells detected was peritoneal washings or ascites. Open table in a new tab Reprinted from the International Journal of Gynecology and Obstetrics [57.Rustin G.J. van der Burg M.E. on behalf of MRC and EORTC collaborators A randomized trial in ovarian cancer (OC) of early treatment of relapse based on CA125 level alone versus delayed treatment based on conventional clinical indicators (MRC OV05/EORTC 55955 trials).J Clin Oncol (Meeting Abstracts). 2009; 27: 1Crossref Google Scholar]. Copyright 2006, with permission from Elsevier. The aim of surgery for early ovarian cancer is to resect the tumour and to undertake adequate staging. This will provide prognostic information and will define whether chemotherapy is needed. The diagnosis may be made preoperatively, but sometimes a tumour is an incidental finding. The availability of a frozen section to identify a malignant epithelial cancer may allow the necessary surgical staging to be done, without the need for a second operative procedure. Accurate surgical staging is important as it may unmask occult advanced disease. Depending on the histological grade and subtype, ≤30% of the patients with apparently early epithelial ovarian cancer will be upstaged after comprehensive surgical staging [18.Garcia-Soto A.E. Boren T. Wingo S.N. et al.Is comprehensive surgical staging needed for thorough evaluation of early-stage ovarian carcinoma?.Am J Obstet Gynecol. 2012; 206 (–): 242.e241-242.e245Abstract Full Text Full Text PDF Scopus (30) Google Scholar, 19.Timmers P.J. Zwinderman A.H. Coens C. et al.Understanding the problem of inadequately staging early ovarian cancer.Eur J Cancer. 2010; 46: 880-884Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. Cass et al. showed that, in 96 patients with grade 3 tumours and gross disease confined to one ovary, 15% had microscopically positive lymph nodes [20.Cass I. Li A.J. Runowicz C.D. et al.Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas.Gynecol Oncol. 2001; 80: 56-61Abstract Full Text PDF PubMed Scopus (105) Google Scholar]. Among these patients, 50% had positive pelvic nodes, 36% had positive para-aortic node and both were positive in 14% of the cases. Maggioni et al. reported on a prospective randomised trial of systematic lymphadenectomy in patients with ovarian cancer macroscopically confined to the pelvis. Positive nodes were detected in 22% of patients undergoing systematic lymphadenectomy, compared with only 9% of patients who underwent merely a sampling (P = 0.007). Although a trend for improved progression-free survival (PFS) and overall survival (OS) was observed for the lymphadenectomy group when compared with the control group, the study lacked the statistical power to be conclusive in this respect [21.Maggioni A. Benedetti Panici P. Dell'Anna T. et al.Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis.Br J Cancer. 2006; 95: 699-704Crossref PubMed Scopus (229) Google Scholar]. Thus, there is currently no evidence to suggest that lymphadenectomy per se improves survival. Bulky lymph nodes should be resected in an effort to remove all visible residual disease. Adequate, non-fertility-sparing surgery should consist of peritoneal washings, ideally taken before manipulation of the tumour, bilateral salpingo-oophorectomy, hysterectomy, multiple peritoneal biopsies of all abdominal fields, at least infracolic omentectomy, appendectomy in case of mucinous histology and pelvic and para-aortic lymph node dissection up to the renal veins. When young women are affected, fertility-sparing surgery could be considered in early-stage disease, but always after thoroughly informing the patient about the potential risks. Patients with stage IA or stage IC with unilateral ovarian involvement and favourable histology, that is mucinous, serous, endometrioid or mixed histology and grade 1 or 2, would be amenable to organ-preserving surgery, but only in combination with complete surgical staging. This would include a lymphadenectomy to exclude more advanced disease. In large retrospective analyses, women with G3 disease or stage IC with clear-cell histology had a higher risk of recurrence. However, this increased risk is mainly related to a higher incidence of extraovarian spread observed in grade 3 tumours, rather than to a higher relapse rate in the preserved ovary [22.Fruscio 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 (114) Google Scholar]. Therefore, these patients should be carefully informed about their prognosis to enable them to make a personalised and thorough choice. In advanced epithelial ovarian cancer, the aim is complete cytoreduction of all macroscopic visible disease, since this has been shown to be associated with a significantly increased OS and PFS [23.du 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: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO).Cancer. 2009; 115: 1234-1244Crossref PubMed Scopus (1112) Google Scholar, 24.van der Burg M.E. van Lent M. Buyse M. et al.The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer.N Engl J Med. 1995; 332: 629-634Crossref PubMed Scopus (733) Google Scholar, 25.Vergote 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 (1773) Google Scholar]. In order to achieve this, a maximal surgical effort is required, including intestinal resection, peritoneal stripping, diaphragmatic resection, removal of bulky para-aortic lymph nodes and splenectomy. There is an increasing body of evidence that suggests specialist training and surgical expertise results in improvements in the rate of cytoreduction, with no increase in morbidity as a result of this process [26.Aletti G.D. Dowdy S.C. Gostout B.S. et al.Quality improvement in the surgical approach to advanced ovarian cancer: the Mayo Clinic experience.J Am Coll Surg. 2009; 208: 614-620Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar]. Thus, women with advanced disease are advised to undergo surgery in specialised centres with adequate infrastructure and training [B]. Optimal cytoreduction is defined as total macroscopic tumour clearance with no residual visible disease. A recent meta-analysis evaluating the surgical outcome of more than 3120 patients showed that residual tumour is a more powerful prognostic determinant than FIGO stage; patients with suboptimally debulked stage IIB–IIIB tumours had a worse outcome that those with completely debulked stage IIIC tumours [23.du 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: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les Etudes des Cancers de l'Ovaire (GINECO).Cancer. 2009; 115: 1234-1244Crossref PubMed Scopus (1112) Google Scholar]. The value of systematic pelvic and para-aortic lymphadenectomy in advanced disease remains controversial. A retrospective analysis of more than 1900 patients found that lymphadenectomy was associated with a prolonged survival in patients with no gross residual disease [27.du Bois A. Reuss A. Harter P. et al.Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials.J Clin Oncol. 2010; 28: 1733-1739Crossref PubMed Scopus (135) Google Scholar]. However, a prospective randomised trial of lymphadenectomy versus removal of bulky nodes in patients with <2 cm residual tumour showed an improvement in PFS but not OS for the lymphadenectomy group [28.Panici P.B. Maggioni A. Hacker N. et al.Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial.J Natl Cancer Inst. 2005; 97: 560-566Crossref PubMed Scopus (390) Google Scholar]. A large multi-centre, prospectively randomised trial of lymphadenectomy in this group of patients just completed accrual (LION Trial, AGO-OVAR OP.3 [NCT00712218]). Until the results of such trials become available, systematic lymphadenectomy should not be regarded as a standard procedure. Currently, the removal of bulky lymph nodes is carried out as part of an attempt to achieve maximum cytoreduction. The timing of surgical cytoreduction in relation to chemotherapy is still debated. A large prospective trial showed [25.Vergote 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 (1773) Google Scholar] that in advanced bulky stage IIIC or IV disease, three cycles of platinum-based neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy [I, A]. Surgical morbidity had a non-significant trend to be lower in the neoadjuvant arm. As a result of these data, the use of primary chemotherapy with interval surgery is becoming more widely accepted and is offered to patients with poor performance status at presentation, low albumin levels and in those with very extensive tumour dissemination. Validation of the results of this approach may come from further trials that are ongoing. The place of secondary interval debulking surgery after primary surgery with suboptimal cytoreduction and three cycles of chemotherapy is less clear. Improved survival following secondary surgery was seen in the European Organisation for Research and Treatment of Cancer (EORTC) trial [24.va