Epidemiology

Carcinoma of the ovary is a common tumour affecting 7116 women in the United Kingdom in 2011 and leading to the death of 4272 women (Table 19.1). The average age at which the disease occurs is 63 years.

Pathogenesis

There are three main types of ovarian cancer: epithelial (representing 90% of patients), germ cell (5%) and sex cord–gonadal stromal tumours (5%) (Figure 19.1). By far the most common pathological subtype of ovarian cancer is epithelial, and this chapter concentrates virtually exclusively upon ovarian epithelial malignancy.

The relatively uncommon ovarian germ cell tumours originate from embryonic germ cells and resemble testicular germ cell tumours in their histology, tumour marker production, treatment and good prognosis. The four most common histological types are:

• dysgerminoma (resembling seminoma in men)
  
• immature teratoma
  
• yolk sac tumours (also named endodermal sinus tumours)
  
• mixed tumours

Sex cord–stromal tumours arise from stromal elements in ovaries and generally are indolent tumours with favourable prognoses. Most are granulosa cell tumours that secrete inhibin, which can be used as a tumour marker, and oestradiol that is responsible for postmenopausal bleeding which is the most common presentation. Less common sex cord–stromal tumours are thecomas and fibromas which originate from gonadal stromal cells. Most thecomas secrete oestrogens, but some produce androgens causing hirsutism and virilization.

The pathogenesis of epithelial ovarian cancer includes hereditary predisposition and environmental factors particularly relating to the total lifetime number of ovulatory cycles. There is a familial association between breast and ovarian cancers. This relates to germline mutations in the BRCA1 and BRCA2 genes, which are associated with a risk approaching 60–80% of developing ovarian cancer. The prevalence of BRCA mutations is about 1 in 500; however; in some populations such as in the Ashkenazi Jews, it is 1 in 40. The Ashkenazis represent about 75% of Jews, total around 11 million worldwide and included Sigmund Freud, Albert Einstein, Gustav Mahler and Franz Kafka. The lifetime risk of ovarian cancer in a woman carrying a BRCA1 mutation is 40% and a BRCA2 mutation is 10–20%. Ovarian cancer is also a feature of Lynch syndrome (hereditary non-polyposis colon cancer (HNPCC)) and Peutz–Jeghers syndrome (see Table 2.3).

Early menarche, late menopause and nulliparity are all associated with a higher risk of ovarian cancer. Similarly the oral contraceptive pill reduces the risk of ovarian cancer. There is controversy as to other associated risk factors for the development of ovarian cancer, especially postmenopausal hormone replacement therapy (HRT). For example, long-term oestrogen replacement therapy may be associated with the development of these tumours, and in one prospective study of over 31,000 postmenopausal women, the increased risk for the development of ovarian cancer was 1.7-fold. This effect may be diminished with combined oestrogen–progesterone HRT. The UK Million Women Study suggests that risk was only increased in current HRT users and that this risk only became significant after 7 or more years of HRT.

Screening

Presentation

The specialist should see the patient in an outpatient clinic and take a full clinical history and examine the patient. The examination should include a pelvic assessment. If the patient is thought clinically to have ovarian cancer, the investigations organized should include a full blood count, routine biochemistry, chest X-ray, a pelvic ultrasound and an abdominal and pelvic CT scan, together with measurement of serum levels of CA-125 (Figures 19.2, 19.3 and 19.4).

Ovarian cancer secretes CA-125, which is a glycoprotein. Approximately 80% of patients with advanced ovarian cancer have elevated CA-125 levels in the blood. Raised CA-125 levels may also occur in patients with almost any gynaecological, pancreatic, breast, colon, lung or hepatocellular tumour. CA-125 levels also are elevated in a number of benign conditions including endometriosis, pancreatitis, pelvic inflammatory disease and peritonitis. So, a raised CA-125 level is not sufficient for a diagnosis of ovarian cancer, but changing levels may be used to monitor treatment and in follow-up after treatment.

If the tumour is operable, the patient should then be booked for a laparotomy. Surgery should be undertaken in specialist centres by a surgical gynaecological oncologist. At operation, the abdominal contents are examined and, where possible, tumour debulking should be undertaken. This should include removal of the omentum, ovaries, fallopian tubes and uterus, with excision of all visible peritoneal deposits (total abdominal hysterectomy with bilateral salpingo-oophorectomy and omentectomy). The aim of surgery is to remove as much tumour as possible, optimally reducing the maximum diameter of any tumour deposit to 1 cm or less. Effective cytoreductive surgery is the most significant correlate for survival.

Staging and grading

Ninety per cent of ovarian cancers are epithelial tumours. The classification of tumours is given in Table 19.2.

An attempt should be made to stage the patient’s tumour. The staging used is the FIGO classification, which is as follows:

• Stage 1: growth limited to the ovaries
  
  
  
  • Stage 1A: one ovary, no malignant ascites
    
  • Stage 1B: both ovaries, no malignant ascites
    
  • Stage 1C: tumour on ovarian surface or capsular rupture or ascites positive for malignant cell (Figure 19.6)
  
  
• Stage 2: growth involving one or both ovaries with pelvic extension
  
• Stage 3: growth involving one or both ovaries with peritoneal implants or superficial liver metastases or abdominopelvic lymph node involvement (Figure 19.7)
  
• Stage 4: tumour metastazing to liver parenchyma, pleura or other visceral metastatic sites

Treatment

For patients with advanced ovarian cancer it was thought during the early 1990s that single-agent therapy carboplatin was just as effective as combination treatments in terms of overall survival, although it was thought that there might be a minor advantage in terms of initial response rates and response duration to combination programmes. In the late 1990s, fashions changed again and treatment involved the use of combination therapy. There was evidence from randomized studies that combination therapy with cisplatin and paclitaxel had the highest response rates and in two high-profile studies showed superiority over another platinum-based regimen in terms of disease-free result and overall survival. In this century, treatment recommendations have come full circle, and in the ICON 3 study, a large trial conducted in the United Kingdom and Italy, single-agent carboplatin was not shown to be inferior to carboplatin and paclitaxel together. Ovarian cancer is, however, a highly heterogeneous condition of many entities, and current advice from the National Institute for Health and Clinical Excellence (NICE) is that the patient and oncologist should discuss whether better benefit might be obtained from single-agent carboplatin or carboplatin and paclitaxel on a case-by-case basis.

At relapse patients are divided into those with platinum-sensitive disease and those with platinum refractory disease on the basis of a platinum-free interval of greater or less than 6 months. Those with platinum-sensitive relapses are usually retreated with a platinum-based chemotherapy regimen. The management of those with refractory disease requires the introduction of new lines of chemotherapy. Agents such as pegylated liposomal doxorubicin, gemcitabine, topotecan, pemetrexed, trabectedin, oxaliplatin and ixabepilone have been shown to be effective. Chemotherapy resistance is one of the major features of patients with end-stage ovarian cancer, and this may be due to clonal evolution with gains of chromosomal material on the chromosomes 1 and 17 and losses at chromosome 3.

Patients with relapsed ovarian cancer are commonly troubled by recurrent pelvic and abdominal disease that obstructs bowel and kidneys and causes ascites (Figure 19.7). The treatment of recurrence involves a combined approach between oncologists, surgeons and interventional radiologists in order to provide the patient with good quality of life. Interventions may include further attempts at cytoreductive surgery, the formation of stomas, renal stenting and the use of agents such as octreotide to relieve intestinal obstruction. In what seems to be a rehearsal of treatments investigated in the 1980’s peritoneal chemotherapy appears to be undergoing a resurgence.

However, the explosion of targeted biotherapies informed by the results of the Human Genome Project is beginning to find its way into ovarian cancer clinical trials. The main target under consideration currently is vascular endothelial growth factor (VEGF) and its receptor and poly-ADP ribose phosphorylase (PARP) an enzyme involved in repairing single strand breaks in DNA. These molecules are targeted in ovarian cancer by small molecular weight inhibitors (nibs) and monoclonal antibodies (mabs). In the case of VEGF, both the monoclonal antibody bevacizumab that binds VEGF and the kinase inhibitor cediranib that inhibits VEGF receptors 1, 2 and 3 have shown promise in ovarian cancer. For patients with BRCA mutation associated cancers including ovarian cancer, olaparib, a PARP inhibitor, has been shown to be effective. It would seem that if there is to be a bright future for these modern novel agents then it is most likely to be in combination with conventional chemotherapy.

Non-epithelial ovarian cancer (germ cell tumours and sex cord–stromal tumours) is treated initially, where possible, by surgery. The procedures may range from oophorectomy to extensive tumour debulking. In relapse, or where a patient has presented with gross metastatic disease, treatment for non-epithelial ovarian cancers may involve similar chemotherapy programmes to those used for testicular cancer. Occasional responses are seen to hormonal therapy, using luteinizing hormone-releasing hormone (LHRH) agonists for those patients with ovarian malignancies secreting sex steroids.

Prognosis

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