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1 Current Obstetrics & Gynaecology (2006) 16, ARTICLE IN PRESS Available at journal homepage: Ovarian cancer S.B. Decruze, J.M. Kirwan Department of Gynaecological Oncology, Liverpool Women s Hospital, Liverpool, UK KEYWORDS Ovarian cancer; UKCTOCS; Cancer network; Multidisciplinary teams; CHORUS; Intraperitoneal chemotherapy Summary Over 6000 cases of ovarian cancer are diagnosed in the UK every year. Most women present with advanced disease. The overall 5-year survival is 26%. Only 5 10% of cases are hereditary and genetic testing can be offered in high-risk families. Screening with CA125 and transvaginal ultrasonography in the general population is currently being investigated in the UKCTOCS study. The treatment of ovarian cancer depends on the stage of disease. Suspected cases should be managed by a multidisciplinary team. Optimal staging and cytoreductive surgery should be performed by a gynaecological oncologist. In advanced disease adjuvant chemotherapy with platinum and paclitaxel is the treatment of choice. New approaches to the treatment of ovarian cancer include fertility sparing surgery, neoadjuvant chemotherapy followed by debulking surgery, and intraperitoneal chemotherapy. & 2006 Elsevier Ltd. All rights reserved. Introduction Ovarian cancer is the fourth most common cancer in women following breast, bowel and lung cancer. Over 6000 new cases are diagnosed in the UK per annum and of all the gynaecological cancers, ovarian cancer has the highest mortality. Five-year survival rate in the UK is 26% (Eurocare Study, 1995). The disease occurs predominantly in older post-menopausal women and its peak incidence is in the over 70s. Most cases present at an advanced stage of disease. The lifetime risk of a woman developing ovarian cancer is 1 in 108. Approximately 5 10% of cases are hereditary. Currently there is no proven effective screening method for ovarian cancer, however, the UK Collaborative Trial of Ovarian Cancer Screening, (UKCTOCS) is currently in the process of addressing this. Standard treatment for Corresponding author. Tel.: address: bridgetdecruze@hotmail.com (S.B. Decruze). advanced ovarian cancer includes primary cytoreductive surgery followed by platinum-based chemotherapy. Histopathologic classification Different ovarian tumours are classified on the basis of their cell or tissue of origin. It is believed that neoplasms are derived from undifferentiated cells in mature tissues which retain the same potentiality for differentiation as is possessed by the embryonic cells that are the precursors of that tissue. Table 1 lists the histopathological classification. Genetic factors Family history is the strongest risk factor for ovarian cancer, however, only 5 10% of all epithelial ovarian cancers are hereditary. There are three clinical genetic manifestations: site specific ovarian cancer, breast and ovarian cancer /$ - see front matter & 2006 Elsevier Ltd. All rights reserved. doi: /j.curobgyn

2 162 S.B. Decruze, J.M. Kirwan Table 1 Histological classification of ovarian neoplasms. 1. Neoplasm derived from coelomic epithelium 3. Neoplasm derived from specialized gonadal stroma Serous tumour Granulosa-theca cell tumours Mucinous tumour J Granulosa tumour Endometrioid tumour J Thecoma Mesonephroid (clear cell) tumour Brenner tumour undifferentiated carcinoma Sertoli Leydig tumours Carcinosarcoma and mixed mesodermal tumour J Arrhenoblastoma J Sertoli tumour Gynandroblastoma Lipid cell tumours 2. Neoplasms derived from germ cells 4. Neoplasms derived from non-specific mesenchyme Teratoma Fibroma, haemangioma, leiomyoma, lipoma J Mature teratoma Lymphoma Solid adult teratoma Sarcoma Dermoid cyst Struma ovarii 5. Neoplasms metastatic to the ovary Malignant neoplasms secondarily arising from Gastrointestinal tract (Krukenberg) mature cystic teratoma Breast Immature teratoma (partially differentiated Endometrium teratoma) Lymphoma Dysgerminoma Embryonal carcinoma Endodermal sinus tumour Choriocarcinoma Gonadoblastoma syndromes, and hereditary nonpolyposis colorectal cancer (HNPCC, Lynch II). The first two are associated with mutations in the BRCA 1 and BRCA 2 tumour suppressor genes being present in 90% of hereditary cases. HNPCC is associated with alterations in the DNA mismatch repair genes, predominantly hmlh 1 and hmsh 2, and account for the remaining hereditary ovarian cancer cases. Ovarian cancers due to BRCA mutations occur in younger women with higher grade or advanced serous carcinomas. However, BRCA mutations do not seem to have a role with mucinous or borderline ovarian cancer. The cumulative lifetime risk of ovarian cancer is 40 50% for a BRCA 1 mutation and 20 30% for a BRCA 2 mutation. In view of this significant increased risk these women are offered prophylactic oophorectomy once their family is complete. Women who carry the HNPCC mutation have a cumulative lifetime risk of ovarian cancer of more than 12%. These women also develop ovarian cancer at a younger age, but it tends to be a lower grade, typically well to moderately differentiated carcinomas. Annual follow-up is recommended for these women with regular ultrasound and hysteroscopy. Prophylactic surgery includes hysterectomy along with oophorectomy. Clinical cancer genetic services offer screening across most of the UK for these familial factors in high-risk families, however, pick up of mutations remain low. Screening As most women present with advanced disease, there is an urgent need to find an effective screening programme for early detection, preferably when the cancer is confined to the ovaries and prognosis is most favourable. Strategies for screening include pelvic examination, the use of the tumour markers and transvaginal ultrasonography (TVS). CA125 is a tumour-associated antigen that is elevated in 80 85% of epithelial ovarian cancers. In non-epithelial ovarian cancers it can remain in the normal range until extensive spread of the disease has occurred. CA125 is generally elevated in any condition that causes inflammation of the mesothelial surfaces. It therefore lacks the sensitivity and specificity to detect ovarian cancer alone. Van Nagell et al. used TVS in asymptomatic postmenopausal women as a screening tool for ovarian cancer and found TVS used for screening had a sensitivity of 81%, positive predictive value (PPV) of 9.4% and specificity of 98.9%. Jacobs et al. reported improved detection rates using CA125 followed by TVS. In women screened for 1 year, 41 women screened positive and 11 cases of ovarian cancer were identified. In the women who screened negative there were eight cases of ovarian cancer that later presented. Combining CA125 and TVS gave an improved

3 Ovarian cancer 163 sensitivity of 78.6%, PPV of 26.8% and specificity of 99.9%. Currently one of the largest randomised controlled trials (RCTs) in the UK, UKCTOCS is in progress. This study has recruited post-menopausal women to detect the real efficacy of ovarian cancer screening with CA125 and TVS and should provide long-term follow-up data. Until the results of UKCTOCS are available, screening in women at low risk of developing ovarian cancer cannot be recommended. For those with a strong family history or a proven gene mutation annual screening for CA125 and TVS can be offered. These women should be fully counselled about the limitations of the tests, anxiety and possible unnecessary surgery they may encounter. There is no evidence at present that screening this high-risk group actually reduces mortality. Alongside the UKCTOCS a similar study is underway in women with family history of ovarian cancer. The UK Familial Ovarian Cancer Study (UKFOCS) should be able to provide evidence of the value of screening in this group for the future. Symptoms A Scottish report from 1997 addressed the difficulties in improving outcomes of ovarian cancer as Fighting the silent killer. Whereas other gynaecological cancers have initial presenting symptoms ovarian cancer gives rise to vague symptoms. By the time symptoms are apparent the disease has progressed to an advanced stage and usually presents with non-specific symptoms so that patients are referred to other specialities for investigation. Investigation In view of the insidious nature of this disease any woman suspected of having ovarian cancer should have prompt investigations. The most valuable investigation for women presenting with non-specific symptoms is a pelvic examination to palpate for obvious pelvic pathology. Failing this imaging of the pelvis with ultrasonography should be arranged. If a pelvic mass is confirmed then serum CA125 should be measured. Jacobs et al. devised a risk of malignancy index (RMI), which is an effective discriminator between cancer and benign lesions. To calculate the RMI three criteria are used, menopausal status (M), ultrasound findings (U) and serum CA125. Ultrasound reports are scored 1 point for each of the following criteria: (1) multilocular cyst, (2) evidence of solid areas, (3) evidence of metastases, (4) presence of ascites, (5) bilateral lesions. RMI ¼ U M CA125, where U ¼ 0 for ultrasound score 0, U ¼ 1 for ultrasound score of 1, U ¼ 3 for ultrasound score of 2 5, M ¼ 1 if premenopausal, M ¼ 3 if post-menopausal. Using an RMI cut-off level of 200, the sensitivity is 85% and the specificity is 97%, appropriate referral to a cancer centre can be arranged. The cancer network Since the Calman Hine report (1995) there have been significant changes to the provision of cancer care in the UK. Any patient suspected of having cancer is seen urgently within 2 weeks in a diagnostic centre and once cancer is confirmed definitive treatment should be commenced within 62 days. Most diagnostic centres will calculate the RMI and triage the patient accordingly, where patients with low RMI can be treated in the local cancer unit and those with high RMI are treated in the regional cancer centre. The high-risk cases are discussed at the MDT meeting to determine the most appropriate treatment. The MDT at the cancer centre deals with less common or advanced gynaecological cancers. All ovarian cancers should be managed at the cancer centre where there are at least two gynaecological oncologists, radiotherapy specialist, chemotherapy specialist, radiologist, histopathologist, cytopathologist and clinical nurse specialist. There is evidence that management in a MDT clinic has lead to more appropriate treatment and resulted in improved survival for women with ovarian cancer. Clinical nurse specialists play a vital role in the team supporting the cancer patient through her treatment. Staging Accurate staging of ovarian cancer is performed on a surgical and pathological basis. Staging by The International Federation of Gynaecological Oncology (FIGO) is listed in Table 2. Accurate staging allows an accurate prognosis to be provided and is essential for determining the correct treatment strategy for an individual patient. Five-year survival rates by stage are listed in Table 3. Surgery The main role of surgery in ovarian cancer is for diagnostic, curative or staging purposes. However, there are few proper surgical RCTs in ovarian cancer. Classically, surgical staging requires a vertical incision, cytology of ascitic fluid or peritoneal washings, any encapsulated masses removed intact, all intestinal and peritoneal surfaces examined and biopsies taken from suspicious areas, followed by total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO) and omentectomy. Aggressive tumour resection should be attempted with optimal debulking defined as the presence of no tumour nodule greater than 1 cm in diameter left in situ. The reduction in tumour load is associated with improved survival by improving the effect of adjuvant treatment (chemotherapy or radiotherapy), however, it is unknown whether this debulking really improves outcome or is merely associated with chemosensitivity in those tumours that are amenable to debulking. Ozols et al. found that at second-look laparotomy after platinum plus paclitaxel chemotherapy, patients with optimal cytoreduction had a progression-free survival of 22 months compared with 18 months over those with suboptimal cytoreduction. Clear benefit has been proven when a patient receives initial surgical management for suspected ovarian cancer by

4 164 S.B. Decruze, J.M. Kirwan Table 2 Stage FIGO staging of ovarian cancer. Description I Ia Ib Ic Growth confined to ovaries Growth limited to one ovary, no ascites present containing malignant cells, no tumour on external surface, capsule intact Growth limited to both ovaries, no ascites present containing malignant cells, no tumour on external surfaces, capsule intact Tumour stage Ia or Ib but with tumour on the surface on one or both ovaries, or with capsule ruptured, or with ascites present with malignant cells, or positive peritoneal washings II IIa IIb IIc III IIIa IIIb IIIc IV Growth involving one or both ovaries Extension and/or metastases to uterus and/or fallopian tubes Extension to other pelvic tissues Tumour stage IIa or IIb 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 washings Tumour involving one or both ovaries with peritoneal implants outside pelvis and/or retroperitoneal or inguinal nodes, superficial liver metastases, tumour is limited to true pelvis but with histologically verified malignant extension to small bowel or omentum Tumour grossly limited to the true pelvis with positive nodes with microscopic seedlings of abdominal peritoneal surfaces Tumour one or both ovaries, peritoneal implants no greater than 2 cm in diameter, nodes negative Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes Growth involving one or both ovaries with distant metastasis. Includes liver parenchymal metastasis and/or pleural effusion with positive cytology Table 3 Cancer Research UK ovarian cancer statistics and prognosis. Stage Survival (%) I 90 II III IV 5 14 a gynaecological oncologist and this is the basis of centralisation of cancer treatment in the UK. For advanced disease the standard treatment remains maximal primary cytoreductive surgery followed by combination chemotherapy. There is anecdotal evidence that more patients are receiving chemotherapy before radical surgery than standard management. This may be suitable for patients who have co-morbid factors that could make extensive surgery unsafe, however, at present the evidence base for this approach is limited. Interval debulking surgery (IDS) is defined as an operation performed after a short course of chemotherapy, usually three cycles. One European trial on IDS has demonstrated a survival advantage in women who responded to chemotherapy and who underwent interval cytoreduction. A more recent, GOG 152 (Gynaecologic Oncology Group) trial reported no such survival benefit. Although similar in design, there were significant differences in the patient populations. In the GOG trial all patients had primary optimal debulking surgery by a gynaecological oncologist. Further IDS only seems to confer an advantage in those patients who had initial surgery performed by a general gynaecologist or general surgeon. Retrospective studies have shown that neoadjuvant chemotherapy followed by surgery does not seem to worsen prognosis compared with primary debulking surgery followed by chemotherapy. This seems a promising approach for future treatment for advanced ovarian cancer and is the rationale for the CHORUS trial and EORTC-GOG/NCI Canada RCTs currently in progress. Between 50% and 80% of late-stage ovarian cancer patients have metastasis in the lymph nodes. Some gynaeoncologists have routinely performed retroperitoneal lymphadenectomy as part of surgical debulking. However, there are additional risks inherent to the surgery, such as increased post-operative complications, longer operating time, and greater blood loss. A recent study by Benneti et al., which spanned 12 years, involved 13 centres, accrued 427 eligible patients, and had a long median follow-up (68.4 months) was negative. All advanced ovarian cancer patients underwent optimal surgical debulking (96% had residual disease o1 cm), including removal of clinically suspicious lymph nodes 41 cm. They were then randomly assigned to systematic lymphadenectomy or not. After surgery, 88% of patients received platinum-based chemotherapy. The authors found a progression-free survival advantage of 5 7 months with systematic lymphadenectomy, but no overall survival advantage to the procedure. They conclude that systematic lymphadenectomy is not part of front-line maximal surgical debulking in the management of advanced ovarian cancer. Secondary debulking surgery has a limited place in management and should only be considered in patients

5 Ovarian cancer 165 who had complete initial response to chemotherapy with a long treatment-free interval, usually over 12 months and in the presence of resectable disease. Unfortunately no survival advantage has been demonstrated following such surgery. Chemotherapy For optimally staged grade I stage I ovarian cancer adjuvant treatment is not required. The International Collaboration Ovarian Neoplasm (ICON) 1 and Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) trials showed a 7% survival benefit at 5 years in medium to high-risk stage I ovarian cancer patients using platinum-based chemotherapy. The majority of women are offered chemotherapy following primary debulking surgery. The Advanced Ovarian Cancer Trialists Group performed a meta-analysis of chemotherapy in advanced disease, which confirmed the superiority of platinum agents compared with non-platinum agents. This meta-analysis was before the widespread use of taxanes. After confirmation of the effectiveness of platinum-based chemotherapy, large randomised trials were performed of platinum in combination with paclitaxel. Three major studies, GOG 111, GOG 132 and OV 10, all confirmed that both progression-free survival and overall survival were prolonged in the platinum paclitaxel groups. However, ICON 3 did not show any evidence of overall survival advantage in the platinum paclitaxel group. Much debate continues with regard to the correct interpretation of the results of these studies but the standard chemotherapy regimen for advanced ovarian cancer is now a combination of platinum and paclitaxel. Treatment is still tailored to the individual where risk of toxicity should be carefully considered. Carboplatin causes less nephrotoxicity and neurotoxicity (paraesthesia, hearing loss) than cisplatin, but nausea, allergic hypersensitivity reactions, gastrointestinal and haematological adverse effects remain problems. Paclitaxel commonly causes alopecia, nausea, diarrhoea, mucositis, hypersensitivity and neurological side effects. With combination treatment the toxicity profile is worse, and so there remains a role for single-agent carboplatin for frail or elderly patients. Despite improvements in treatment for ovarian cancer, many patients develop recurrent disease within 3 years of diagnosis. For these patients further chemotherapy remains an option, and patients may either be retreated with platinum or in selected cases paclitaxel. Alternative drugs for second-line treatment include liposomal doxorubicin or topotecan. Patients who were platinum-sensitive to firstline treatment (defined as disease-free for 6 months) can be given further carboplatin therapy. The ICON 4 study compared platinum versus platinum plus paclitaxel and showed a 2-year survival advantage of 7% in the combined treatment arm. ICON 4 did, however, show the toxicity profile was higher, particularly neurotoxicity in the combined treatment arm. Intraperitoneal chemotherapy Intraperitoneal (IP) chemotherapy is particularly appealing to oncologists at it delivers the drug directly to the tumour, especially as ovarian cancer commonly remains confined to the IP cavity. Furthermore pharmacokinetic studies suggest an advantage to the prolonged exposure of the drug to the tumour. However, there are treatment complexities limiting widespread adoption, arising primarily from the presence of an IP catheter, which may lead to short-term potentially severe or life-threatening toxicities, including infection, haemorrhage, bowel perforation and obstruction and pain. Indeed the majority of trials report an increase in severe toxicity with the majority of patients unable to complete the full number of cycles. There have been several RCTs of IP chemotherapy, and although it has been demonstrated that the regimens that included IP cisplatin led to improved outcomes, the toxicity of this approach has precluded widespread acceptance of this modality. The NCI have recently released their second clinical announcement in 6 years based on these large RCTs. It coincides with the publication of GOG-172. This trial of 429 women with optimally debulked stage III ovarian cancer demonstrated that patients who receive IP chemotherapy had a median survival of 16 months longer than patients receiving intravenous chemotherapy. The IP group fared better, although less completed the planned treatments. As expected toxicity was much higher in the IP group but quality of life questionnaires at 1 year were similar between the two groups apart from continued abdominal parethesia in the IP group. The new data confirm that IP therapy can provide improved outcomes for patients with small-volume or no visible residual disease and an intact peritoneal cavity. Candidates for IP therapy include those in whom complete surgical resection has been achieved and to whom a multidisciplinary team providing safe catheter management is available. IP chemotherapy, however, is complicated and requires a full understanding of the risks and benefits associated with its delivery. Epithelial cancer of low malignant potential (borderline tumour) Borderline tumours constitute 15% of all epithelial ovarian cancers. They tend to affect younger women and have generally a very good prognosis. After an agreed consensus for their diagnosis, pathologists are now increasingly identifying these tumours. Borderline tumours of the ovary can resemble benign tumours macroscopically but histologically there are epithelial changes that suggest malignancy such as multilayering, irregular budding, cellular atypia and mitotic activity, but without any evidence of stromal invasion. Extensive sectioning of the tumour is necessary to exclude any foci of truly invasive disease. Seventy-five percent are stage I at diagnosis and have an excellent prognosis with 10-year survival of about 95%. Surgical staging and optimal cytoreduction is the mainstay of treatment. For women with stage I disease who still wish to preserve fertility, conservative surgery with unilateral oophorectomy can be performed provided the contralateral ovary appears healthy. For all other patients a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be performed for maximal cytoreduction. In more advanced disease adjuvant chemotherapy can be avoided provided invasive implants are excluded. The only

6 166 S.B. Decruze, J.M. Kirwan role for adjuvant chemotherapy is in the presence of rapidly progressive disease. For patients with borderline ovarian tumour with recurrent disease, especially after a long disease-free interval, further surgical debulking may be indicated. If one ovary has been conserved then follow-up should include annual TVS. Non-epithelial ovarian cancers Germ cell tumours These tumours arise from the primitive germ cells of the embryonic gonad. They represent only a small proportion of ovarian cancers. They are most commonly diagnosed in young women presenting with an abdominal mass. Before advances in chemotherapy they were aggressive tumours with poor prognosis, but nowadays with newer chemotherapy regimes they are highly curable. Classification of germ cell tumour is important for prognostication and for treatment with chemotherapy. Dysgerminoma is chemotherapy and radiotherapy sensitive and endodermal sinus tumour and choriocarcinoma are the most aggressive cancers. In view of the effectiveness of chemotherapy even with advanced disease, surgical intervention should be minimal and radiotherapy avoided. As most patients are young, fertility-sparing surgery is performed. This involves a laparotomy, removal of the tumour and biopsies from suspicious areas. With minimal cytoreduction and conservation of the other ovary and uterus fertility can be preserved. The recommended chemotherapy regime for germ cell tumours is etoposide, cisplatin with or without bleomycin. Patients with stage I grade I immature teratoma or mature teratoma do not require chemotherapy if adequately staged. All other higher stage and higher grade tumours should receive post-operative chemotherapy. These patients should be followed up with monitoring of the tumour markers: human gonadotrophin (HCG), alpha-feto protein (AFP) and lactate dehydrogenase (LDH). Ninety percent of relapse in these patients occurs within 1 2 years after primary diagnosis. Granulosa cell tumour Granulosa cell tumours of the ovary account for 70% of sexcord stromal tumours. They represent 3 5% of all ovarian cancers. There are two forms, juvenile and adult, the former presents with precocious puberty and the latter with post-menopausal bleeding. In both forms there are high levels of oestrogen production. They tend to be slow growing and recur late. The stage at diagnosis seems to be the most important prognostic factor. Surgical staging and adequate cytoreduction is the mainstay of treatment. In younger patients fertility-sparing surgery should be the aim. Granulosa cell tumours of the ovary are only moderately sensitive to chemotherapy or radiotherapy, but these modalities may be considered in advanced disease. Repeated surgery is performed for further recurrences. Hence close observation is necessary to detect recurrence early for further successful cytoreduction. Serum inhibin has been investigated as a potential tumour marker for this type of malignancy but its sensitivity and specificity are yet to be proven. Sarcoma of the ovary This is a rare tumour, but important to differentiate from other ovarian tumours as it has such a poor prognosis. There are two types of sarcoma, mixed mullerian tumours (MMT), which contain both carcinomatous and sarcomatous components and pure sarcomas. Patients with early stage disease tend to have a survival advantage to those with advanced disease. The mainstay of treatment is surgical staging and optimal cytoreduction followed by post-operative platinumbased chemotherapy. The overall prognosis is poor. Followup for relapse is performed clinically. Lymphoma of the ovary Primary lymphoma of the ovary is rare. Lymphoma involving the ovary usually presents as part of a systemic disease. Fifty percent of normal ovaries have benign lymphoid tissue and so primary ovarian lymphoma is possible from malignant transformation of these benign aggregates. This diagnosis can only be made with the absolute exclusion of systemic lymphoma and involves excisional biopsy of the tumour followed by appropriate fixation to allow accurate subclassification. Once diagnosed treatment requires systemic chemotherapy based on histological subtype. These cases should be managed and followed up by haemato-oncologists. Prognosis is usually good. Practice points Use risk of malignancy index (RMI) in setting of ovarian cysts. Adequate staging possible with fertilitysparing surgery in young women. Referral to gynaecological oncology multidisciplinary team in Cancer Center. Role of interval debulking surgery yet to be determined. Standard treatment remains primary surgery and platinum-based chemotherapy. Further reading 1. Berrino F, Sant M, Verdecchia A, et al., editors. Survival of cancer patients in Europe: the EUROCARE study. Lyon: International Agency for Research on Cancer; Prat J, Ribe A, Gallardo A. Hereditary ovarian cancer. Hum Pathol 2005;36: Van Nagell JR, DePriest PD, Reedy MB, Gallion HH, Ueland FR, Pavlik EJ, et al. The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecol Oncol 2000;77: Jacobs I, Davies AP, Bridges J, Stabile I, Fay T, Lower A, et al. Prevalence screening for ovarian cancer in postmenopausal

7 Ovarian cancer 167 women by CA125 measurement and ultrasonography. BMJ 1993;306: Kirwan JMJ, Tincello DG, Herod JJO, Frost O, Kingston RE. Effect of delays in primary care referral on survival of women with epithelial ovarian cancer: retrospective audit. BMJ 2002;324: Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy index incorporating CA125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. BJOG 1990;97: Junor EJ, Hole DJ, Gillis CR. Management of ovarian cancer: referral to a multidisciplinary team matters. Br J Cancer 1994;70: Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era; a meta-analysis. J Clin Oncol 2002;20: Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and palclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynaecologic Oncology Group study. J Clin Oncol 2003;21: Giede KC, Kieser K, Dodge J, Rosen B. Who should operate on patients with ovarian cancer? An evidence-based review. Gynecol Oncol 2005;99: Vergote I, De Brabanter J, Fyles A, et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001;357: Trimbos JB, Parmar M, Vergote I, et al. European organisation for research and treatment of cancer collaborators-adjuvant chemotherapy in ovarian neoplasm. International collaborative ovarian neoplasm trial and adjuvant chemotherapy in ovarian neoplasm trial: two parallel randomised phase III trials of adjuvant chemotherapy in patients with early stage ovarian carcinoma. J Natl Cancer Inst 2003;95: van de Burg ME, 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 Organisation for Research and Treatment of Cancer. N Engl J Med 1995;332: Rose PG, Nerenstone N, Brady M, et al. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351: Benedetti Panici P, 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: Advanced Ovarian Cancer Trialists Group. Chemotherapy in advanced ovarian cancer (Cochrane review). In: Cochrane library, p ICON collaborators. ICON 2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. International Collaborative Ovarian Neoplasm Study. Lancet 1998;352: McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: Muggia FM, Braly PS, Brady MF, et al. Phase III randomised study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2000;180: Piccart MJ, Bertelsen K, James K, et al. Randomised intergroup trial of cisplatin paclitaxel versus cisplatin cyclophosphamide in women with advanced epithelial ovarian cancer: three-tear results. J Natl Cancer Inst 2000;92: International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON 3 randomised trial. Lancet 2002;360: Ovarian cancer (advanced) paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan (review) (No. 91) NICE. 23. Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinumbased chemotherapy in women with relapsed ovarian cancer: the ICON 4/AGO-OVAR: 2.2 trial. Lancet 2003;361: