Description of the condition
In postmenopausal women epithelial ovarian cancer (EOC) is one of the most frequent malignancies in developed countries. According to the definition of the European Union it has to be categorised as an 'orphan disease' (EU Parliament 1999), however with an age-standardised incidence rate of 12.6 (per 100,000 population) and more than 44,000 cases per year, it is the sixth commonest cause of cancer among women in Europe (EUCAN 2013; Ferlay 2013), and the fifth most common in the UK (Cancer Research UK 2014). Furthermore, with a mortality rate of 7.4 (per 100,000 population) it is the most lethal gynaecological malignancy, ahead of breast or uterine cancer (EUCAN 2013; Ferlay 2013; Pavlik 2013). One reason for this high mortality is the lack of early or specific symptoms pointing to EOC and the concomitant late cancer diagnosis. Affected women complain of non-specific symptoms, such as persistent abdominal distension, pelvic or back pain, loss of appetite or increased urinary frequency (Bankhead 2005; Goff 2012; Hippisley-Cox 2012; NICE 2011). As these symptoms occur mostly when the ovarian cancer has spread from the ovaries into the abdomen (Aletti 2007), 70% to 80% of women are diagnosed at an advanced disease stage, with tumour spread into the abdominal organs or beyond the abdominal cavity (International Federation of Gynecology and Obstetrics (FIGO) stage III to IV) (Baldwin 2012; Hippisley-Cox 2012; Jelovac 2011; Maringe 2012). Therefore, the prognosis for advanced-stage disease is poor and the case-fatality rate is high (five-year survival rate: 20% to 35% or lower) (Baldwin 2012; Carlson 1994; Jacobs 2004; Jemal 2009; Slomski 2012; Whitehouse 2003), compared to early-stage diagnoses where the cancer is confined to the ovaries (FIGO stage I) or to the pelvis (FIGO stage II) (five-year survival rate: up to 95%) (Baldwin 2012; Bell 2006; Jemal 2009; Maringe 2012; van Nagell 2011; Whitehouse 2003). On average the five-year survival rate in developed countries is greater than 40% (Baldwin 2012; Berrino 2007; Cancer Research UK 2014; Jemal 2009; Whitehouse 2003). This variation in the prognosis demonstrates the importance of early-stage detection in order to improve the outcome and to reduce premature EOC-specific mortality.
In order to find suitable and reliable screening methods, those women at increased risk of EOC due to genetic factors need to be distinguished from women who are at average risk. While the general population have a life-time risk of developing an ovarian malignancy of 1.2% to 1.4% (US data) (Jelovac 2011; van Nagell 2012), the life-time risk of women with known genetic mutations (e.g. BRCA 1/2, HNPCC) or a strong family history of EOC is 12% to 60% (Antoniou 2003; Bell 1998; Ford 1998; Jelovac 2011; King 2003). As the effect of any screening measure could vary between these average-risk and high-risk women, it may be necessary to design different screening strategies for each risk group and to evaluate these separately. In addition, the pathogenesis and prevalence of the most frequent EOC types could influence the choice of screening measures or screening intervals, particularly as screening aims to identify the tumours at an early stage, with confinement to the ovaries. For some time there has been broad consensus that this malignancy has its origin in the ovaries. However, new theories suggest that there are two subgroups of EOC, which differ in the site and natural history of their origin: low-grade type 1 tumours and high-grade type 2 tumours. The slow-growing type 1 tumours evolve from intra-ovarian lesions (i.e. borderline tumours) and are confined to the ovaries at detection, with a good prognosis. In contrast, recent data suggest that type 2 tumours may arise from intra-epithelial lesions outside the ovary (e.g. in the fallopian tubes). This type of tumour is characterised by rapid growth with immediate access to the intra-abdominal cavity, therefore the prognosis of affected women differs vastly from prognosis of women with type 1 tumours (Hong 2013; Kurman 2008b; Shih 2004). It is possible that the high percentage of type 2 tumours (probably 75% of all EOC) has a negative impact on the effectiveness of available screening measures in decreasing EOC-specific mortality. Future screening tools might include the assessment of the tumour volume by transvaginal sonography and novel target-orientated genetic tests or biomarkers in order to improve early detection rates of both tumour types (Kurman 2008a; Kurman 2010; Shih 2004).
Description of the intervention
Various methods may currently be used to screen asymptomatic women, including physical examination, transvaginal sonography and serum tumour markers (e.g. cancer antigen 125 (CA-125) and human epididymis protein 4 (HE 4)) (Aletti 2007; Gentry-Maharaj 2012; Kyrgiou 2006).
Transvaginal sonography was first described as a screening method in 1989 by Higgins and colleagues (Higgins 1989). Prior to this, ultrasound scanning was mostly performed transabdominally (Higgins 1989). Transvaginal sonography uses a 5 MHz to 7.5 MHz ultrasound probe to examine the ovarian morphology and to measure the size of the ovaries in three dimensions, in order to compute the volume of the ovaries (van Nagell 2012). Due to the reduction in ovarian size in women after the age of 30 and the decrease in ovarian activity in women after their last menstruation, there are different upper limits for normal ovarian size in pre- (20 cm³) and postmenopausal women (10 cm³) (Pavlik 2000). Transvaginal sonography enables the detection of adnexal masses, as well as a first assessment of the individual risk of malignancy, by examining these suspicious masses in terms of the ovarian shape, internal structure and the morphological characteristics (e.g. visible solid or cystic components, existing ascites, non-uniform ovarian echogenicity) (Manegold 2013; Menon 2009). If the ovary volume exceeds these thresholds, or if there is at least one morphological reference relating to a malignant lesion, further diagnostic evaluations (e.g. magnetic resonance tomography, laparoscopy) are indicated.
The ability of transvaginal sonography to distinguish accurately between EOC and non-malignant ovarian abnormalities was demonstrated in a large prospective observational study in asymptomatic women aged 50 years and over, and in women above 25 years with a family history of EOC (van Nagell 2011). In this study, regardless of the cancer stage, a sensitivity of 86.4% and specificity of 98.8% was achieved by transvaginal sonography by using different threshold values of the ovarian volume depending on the menopausal status. These data may support the suitability of transvaginal sonography as a screening tool.
Cancer antigen CA-125
The cancer antigen CA-125, a high molecular glycoprotein, is the most used and described blood serum marker, which can rise to high concentrations in women with EOC. Bast 1983 showed that serum levels of CA-125 higher than 35 U/ml can be found in more than 80% of women with a confirmed diagnosis of EOC. As serum CA-125 levels above the threshold of 35 U/ml can also be the consequence of other conditions, such as inflammation of the peritoneum, endometriosis, benign cysts or non-gynaecological malignancies, there is a significant risk of false-positive screening results (Gentry-Maharaj 2012; Medeiros 2009; Whitehouse 2003). In one quantitative systematic review (Medeiros 2009), with 17 included studies, the diagnostic accuracy of CA-125 (threshold: 35 U/ml) was high in surgically confirmed EOC patients. The pooled sensitivity of 80% and the pooled specificity of 75% showed (despite high heterogeneity) an acceptable capability to discriminate between malignant or borderline lesions versus benign lesions of the ovaries.
The current clinical practice guideline from the National Institute for Health and Care Excellence (NICE) recommends that in cases with clinical symptoms, such as persistent abdominal bloating, pelvic/abdominal pain or other complaints, serum levels of CA-125 are measured. If this marker exceeds the cut-off value of 35 U/ml, a transvaginal sonographic examination is indicated (NICE 2011). While the NICE clinical practice guideline does not explicitly cover population-based screening measures, the statement from the US Preventive Service Task Force in 2012 (Moyer 2012), as well as the clinical practice guideline from the German Cancer Society (DKG) in 2013 (DKG 2013), do not recommend EOC screening in asymptomatic women.
How the intervention might work
Screening aims to identify a disorder at the earliest possible opportunity and disease stage, where early treatment can improve outcome. EOC screening should diagnose ovarian cancer at an earlier stage, before clinical signs or noticeable symptoms are noticed (Figure 1), ideally when the tumour is confined to the ovaries and potentially curable (Cho 2009; Kurman 2010). However, screening may only identify disease at an earlier time point, without improving the stage or natural history of the disease, by finding disease in an asymptomatic or subclinical stage, thereby reducing the lag time from disease development to diagnosis, without making any impact on true survival.
Transvaginal sonography and serum tumour markers, as well as other screening measures, have to fulfil important requirements. Apart from a high level of acceptability and diagnostic accuracy, every screening procedure should be easy, rapid and inexpensive to perform, and have minimal associated adverse effects and inter-observer variation (Hulka 1988; van Nagell 2012). In addition, a screening procedure has to be able to discriminate clearly and reliably between (seemingly healthy) women who would benefit from early therapeutical intervention, and those who would not (Gates 2003). These benefits could be manifold, besides a possible increase in survival, due to the use of effective therapy an early stage, and could increase quality of life due to the use of less aggressive therapy. Healthy women could also benefit from an accurate (negative) test as their fears could be allayed (Adriaensen 2013).
All screening methods have an associated risk of false-positive diagnosis of the condition. For EOC the rate of this 'screening over-diagnosis' seems to be higher with transvaginal sonography (1.2% to 2.5%) than with serum CA-125 testing (Nelson 2004; Schnell 2011). In turn, this could result in the use of unnecessary diagnostic and therapeutic procedures (e.g. surgery or chemotherapy (Morrison 2012)) and corresponding mental or physical harm, or both. Beyond the sensitivity and specificity of the screening measures, due to the relatively low prevalence of EOC there is basically a higher risk of low positive predictive values (Gates 2003) and of a higher rate of false-positive EOC diagnoses in actually healthy women. Alternatively, there is also a risk of false-negative screening results, which could falsely reassure women and delay the necessary early-stage therapy by disregarding specific symptoms (Gates 2003). Both aspects threaten the utilisation of screening measures and should be evaluated in order to balance the risks, harms and benefits of each measure (Nelson 2004; Wegwarth 2013; Woolf 2012).
Why it is important to do this review
Due to the importance of early-stage detection of ovarian malignancies there is an urgent need for a systematic and high-level evaluation of the evidence for EOC screening measures. Owing to the poor prognosis of late-diagnosed EOC, it is necessary to appraise these screening measures, beyond their technical properties and their diagnostic accuracy, with respect to patient-relevant outcomes, such as cancer-specific or all-cause mortality. There are a small number of randomised controlled trials (RCTs), however, there is currently no systematic review of the evidence that evaluates the suitability and patient-relevant features of screening methods such as transvaginal sonography.
In 2011, the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, with more than 78,000 participants, presented their first results as one of the few RCTs in this area (Andriole 2012). In addition, the results of the ongoing United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), with a study population of more than 200,000 women, are expected in 2015 (Menon 2009). The findings of these two large studies and possibly of additional RCTs, which could result from the systematic literature search, will allow for a high-level, evidence-based assessment of the benefits and of possible harms of transvaginal sonography or other EOC screening measures.