Elsevier

The Lancet

Volume 384, Issue 9951, 11–17 October 2014, Pages 1376-1388
The Lancet

Seminar
Ovarian cancer

https://doi.org/10.1016/S0140-6736(13)62146-7Get rights and content

Summary

Epithelial ovarian cancer is the commonest cause of gynaecological cancer-associated death. The disease typically presents in postmenopausal women, with a few months of abdominal pain and distension. Most women have advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage III), for which the standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although this treatment can be curative for most patients with early stage disease, most women with advanced disease will develop many episodes of recurrent disease with progressively shorter disease-free intervals. These episodes culminate in chemoresistance and ultimately bowel obstruction, the most frequent cause of death. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Targeted treatments such as antiangiogenic drugs or poly (ADP-ribose) polymerase inhibitors offer potential for improved survival. The efficacy of screening, designed to detect the disease at an earlier and curable stage remains unproven, with key results expected in 2015.

Introduction

Epithelial ovarian cancer is the fourth commonest cause of female cancer death in the developed world. The reason for the high death rate is the late presentation in most cases, meaning that the disease is widely metastatic within the abdomen. Although with modern management, a significant proportion of women attain complete response, most of those who present with advanced disease will develop recurrence within 18 months. For some patients, the tumour remains sensitive to periodic retreatment with platinum-based chemotherapy, becoming relatively chronic and free of debilitating symptoms until chemoresistance restricts further treatment options.

The management of epithelial ovarian cancer needs expertise in surgery, chemotherapy, imaging, histopathology, and palliation; specialist multidisciplinary teamwork is essential to achieve optimum outcomes. The histopathology of epithelial ovarian tumours is heterogeneous and each epithelial ovarian cancer subtype harbours genetic mutations that are being assessed for their potential to predict the efficacy of molecularly targeted treatments. With an overall survival at diagnosis of roughly 40% and the continuing development of new treatments, the medium-term outlook for women with ovarian cancer is far better than it was.

This Seminar focuses on epithelial ovarian cancer rather than the much rarer germ cell, sex cord, or stromal tumours. We describe clinical management and the emerging role of targeted treatment based on knowledge of the molecular pathology and consideration of the prospects for effective screening.

Section snippets

Epidemiology and genetics

Every year 220 000 women develop epithelial ovarian cancer worldwide.1 In the UK, 7000 women develop the cancer (of whom 4200 die every year);2 in the USA, 22 500 women develop the disease (of whom 14 000 die every year).3 The age-standardised incidence of the disease4 has been estimated at 9·4 per 100 000 population in more developed areas, and five per 100 000 population elsewhere.5 In the UK the lifetime risk of developing ovarian cancer is about one in 60. The median age of patients

Histopathology and molecular pathology

Histological interpretation of resected tissue can be complex and needs specialist input. Figure 1 shows the major epithelial ovarian cancer histotypes. The notion of ovarian cancer description and diagnosis is changing, from one disease with several epithelial subtypes to several distinct diseases22, 23, 24 (figure 2). Almost 10 years ago, a new classification was proposed that separated ovarian cancers into type I and II tumours.26 Type I tumours were low grade; some (endometrioid, mucinous,

Presentation

Ovarian cancer typically presents with 3–4 months of abdominal pain or distension,35 which might be mistakenly attributed to irritable bowel syndrome.36 The UK National Institute for Health and Clinical Excellence (NICE) has recommended that patients who develop symptoms like irritable bowel syndrome, especially those older than 50 years, should undergo measurement of serum cancer antigen 125 (CA-125) concentrations as a secondary screen.37 If symptoms persist in the absence of raised CA-125

Primary disease

Women with germline BRCA1 or BRCA2 mutations have a 40–60% lifetime risk of epithelial ovarian cancer.6, 38 For women in whom fertility is no longer an issue, risk-reducing salpingo-oophorectomy is the most protective strategy.39 Younger women can opt for annual screening by pelvic ultrasound, though this has not been shown to reduce the risk of developing epithelial ovarian cancer.

Ovarian cancer typically presents to general practitioners or gynaecologists, but because of the diverse symptoms

Recurrent disease

Recurrence can be detected in several ways. The earliest indication of recurrent disease might be a doubling in CA-125 concentration70 above the upper limit of normal, with neither radiological nor clinical evidence of disease. Although not routinely used in follow up, a CT scan can detect an asymptomatic recurrence or relapse might present with symptoms and a clinically detectable mass. Further treatment should be initiated on the basis of the clinical features, radiological findings, and the

BRCA gene mutations, BRCAness, and poly (ADP-ribose) polymerase inhibitors

About 15% of (mostly serous) ovarian cancers are associated with germline mutations of the BRCA1 or BRCA2 genes and up to 25% of unselected high-grade serous cancers harbour mutations in BRCA1 or BRCA2. The BRCA genes are needed for normal repair of double-stranded DNA damage through homologous recombination. Recent evidence has shown that homologous recombination deficiency might occur in up to 50% of sporadic high-grade serous cancers due to germline or somatic BRCA gene mutation, epigenetic

Endocrine treatment, hormone replacement therapy, and bone density

Historically, the oestrogen receptor has been detected in roughly 60% of ovarian cancer samples, but the disease is not responsive to oestrogen and only occasionally responsive to endocrine agents such as tamoxifen114 or letrozole.115, 116 These drugs might be more useful in low-grade disease where cytotoxic agents yield a low response rate.117 While expression of oestrogen receptor is not predictive of efficacy to the degree seen in breast cancer, some centres identify oestrogen receptor

Prognosis

The prognosis of ovarian cancer is associated with performance status, FIGO stage, and the volume of residual disease after initial debulking surgery. Recent data have suggested that thrombocytosis is associated with advanced stage and shortened survival.120 Survival from the disease varies between and within countries. Although survival figures are potentially confounded by the quality of data collected, in the UK, 5 year survival seems to have steadily improved,121 which is most likely due to

Future perspectives

The efficacy of cytotoxic treatment has been improved by the introduction of dose-dense treatments, and is being assessed in first-line trials. VEGF pathway inhibitors improve the response rate when added to traditional cytotoxic regimens and prolong disease control when given as one drug maintenance treatment. However, VEGF pathway inhibitors are probably not being used optimally. Maintenance treatment almost certainly needs longer treatment, perhaps until or even beyond progression; the

Search strategy and selection criteria

We searched the Cochrane Library and PubMed for relevant randomised trials and other high-quality studies (eg, systematic reviews and meta-analyses) published in English between Jan 1, 2000, and Sept 1, 2013, with the terms “ovarian cancer”, “chemotherapy”, “surgery”, “VEGF”, “BRCA”, and “genetics”. We also included widely cited older publications that we judged to have important references. We also searched references from relevant articles identified by our search strategy.

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