In the UK, ovarian cancer is the 5th most common cancer after breast, bowel, lung and uterine cancers. Two hundred and four thousand cases are diagnosed annually worldwide with incidences highest in the USA and Northern Europe and lowest in Africa and Asia. In the UK, ovarian cancer affects approximately 6,600 women annually (125 women weekly) of which the majority are over the age of 65 and have already been through the menopausal stage (Cancer Research UK, 2009).
Figure 1: Graph illustrating the number of incidence diagnosed with ovarian cancer as age increases per 100,000 populations (Cancer Research UK 2009)
Around 4300 women die of ovarian cancer per year in the UK, however over the last thirty years the mortality rates in younger women has decreased while in over 65s the mortality rates have risen. This may be explained by younger women being more likely to be diagnosed at an earlier stage.
The survival rates for ovarian cancer are higher the earlier diagnosis is carried out. Research has shown that around 40% of women that are diagnosed with ovarian cancer tend to survive for at least five years (survival rate) [Cancer Research UK 2009].
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Ovarian cancer can be categorised into three groups namely stromal ovarian cancer, germ cell ovarian cancer and the most common type, epithelial ovarian cancer. Epithelial ovarian cancer accounts for 70-80% of all ovarian cancers and develops from a formation of cells that surround the germinal epithelium (outside of the ovary). It mainly affects women in post- menopausal stage but it can also affect younger women.
There is no definite cause for ovarian cancer; however it is thought that several factors increase its risk. Studies have shown that an increase in age and the presence of gene mutations such as BRCA1 and BRCA2 are the highest risk factors for developing ovarian cancer (ref). Other risk factors include infertility, use of hormone replacement therapy (HRT), increased us of talc (as found in baby powder), family history and previous cancers such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and smoking amongst other.
Ovarian cancer is referred to as a "silent killer" because its symptoms are vague in its early stages and also its symptoms are very similar to those of other conditions such as pre-menstrual syndrome (PMS), often presenting with abdominal pain and swelling, uterine bleeding and gastrointestinal and urinary tract complaints (Pearse and Behrman 1954). This has therefore led to an increased interest in the research for effective screening for ovarian cancer. It is because of this that only approximately 70% of women with ovarian cancer are diagnosed with advanced ovarian cancer, thus survival is only about 20-30% (emedicine 2009). According to Kobayashi, H. et al (2008), the increased survival advantage for patients diagnosed with early stage disease might have an impact on disease mortality and may improve survival.
AVAILABLE SCREENING TESTS
In the UK, there is no routine screening for ovarian cancer, however cancer screening trials are underway to try and detect the cancer before the presentation of symptoms, thus helping in reducing a person's chance of dying from the disease (National Cancer Institute, 2009).
Screening tests that are currently used are transvaginal ultrasound (also known as ultrasonography, USS) and blood tests for serum cancer antigen (CA) 125 assay.
Transvaginal ultrasound (TVS) is an imaging method that provides detailed images of the ovary and of any malignancies within the pelvis. Higgens, R. (1989) and Von Nagell, J. (1991) stated that this method of screening is not only easy to perform but it is well accepted by the patients and portrays a strong interobserver interpreter agreement.
Serum CA125 on the other hand is a glycoprotein that has been found to be released by cancerous cells into the bloodstream (Jacob, I and Bast, R. 1989). It has also been found to be released in other gynaecological conditions such as benign ovarian cyst and during normal body functioning such as menstrual cycle and even in pregnancy. (Pittaway and Fayez 1987; Jacobs and Bast 1989). Most women have a raised serum CA125 level; therefore a cut- off level of between 30-35 units per millilitre (U/ml) is used to suggest that there is an abnormality (Cancer Research UK). This technique is not entirely reliable due to the fact that CA125 is also released during normal body functioning.
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However recently, two screening strategies involving these two methods have become apparent. These include TVS which is the primary screening test and the combination of the blood test for serum CA125 with TVS (now known as multimodal screening, MMS), which is the secondary test (Jacobs, I. 2003)
Various studies that have shown that a combination of the two methods (multimodal screening) can detect ovarian cancer in asymptomatic women (UKCTOCS 2008) and subsequently increase the sensitivity and specificity of the screening test hence resulting in an increase in the survival rate (Jacob, I. et al 1988, Jacob, I. Skates, S. et al 1999),
One such study was conducted between 2001 and 2005 by primary care trusts (PCTs) across the UK and revealed that in 90% of their participant population (202 638 postmenopausal women) cancer was detected using the MMS method, while 75% using the USS method (emedicine 2009). It was therefore concluded that MMS had a significantly better specificity and positive predictive value compared to that of USS (Jacobs, I 2003; emedicine 2009). Another study includes the largest and currently ongoing United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which was designed in 2001 by Ian Jacobs.
This study involves 200,000 postmenopausal women randomised into three groups: 'ultrasound screening' group, 'multimodal screening' group and 'control' group (patients who will not be screened). This clinical trial aims to study the effects of ovarian cancer screening on the mortality rate. It will also be addressing issues such as target population, compliance, and health economics, physical and psychological morbidity of screening (Jacobs, I. 2003). Other ongoing studies include the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS), NIH PLCO study and the USA Cancer Genetics Network Study.
Unfortunately, despite all the research taking place there continues to be lack of data and information on the screening available, primarily due to the low prevalence of ovarian cancer. There is also limited knowledge and understanding known about the molecular and biological events involved in ovarian carcinogenesis which limits the ability to detect ovarian cancer in its early stages. Furthermore uncertainties regarding the impact of screening on mortality and issues surrounding the quality of life still exist. The implications of health economics of screening also remain unclear (Jacob, I. 2003). This study will therefore be evaluating and comparing the effectiveness of the two screening strategies and assessing and comparing the cost effectiveness in implementing routine screening. The findings will contribute to the evidence already available regarding the effectiveness and cost of the two screening stategies.
The attitudes and satisfaction of the key stakeholders is an important part of the evaluation. The theory of change (logic frame model) approach will be used to clearly outline the aim of the study, the outcomes and the assumptions to the stakeholders. Stakeholders value theories of change as part of the planning and evaluation of a program, as it clearly shows and clarifies in a simplified manner, both short term and long term goals, how they can be reached and what will be used to measure to progress as the study proceeds (www.theoryofchange)
In this case the stakeholders will include the women who will be participating in screening, the General Practitioners (GPs) who will be providing the patient records, health professionals carrying out the screening, histopathology and haematology laboratories to test biopsy and blood results respectively, pathologists interpreting results, Primary Care Trust (PCT) NHS, Cancer Research UK, Office of National Statistics and Cancer Registry (UKCTOCS), commissioners and various funders and sponsers.
AIM OF THE STUDY
The aim of the study is to determine the effectiveness and cost- effectiveness of MMS compared to USS in women aged between the ages of 45 and 74 years (postmenopausal women).
Determine the effectiveness of MMS for ovarian cancer screening (by specificity, sensitivity)
Determine the effectiveness of USS for ovarian cancer screening (by sensitivity and specificity)
Determine the cost associated with USS and MMS
Determine the cost effectiveness of MMS and USS
A two-arm randomised controlled trial (RCT) will be carried out to compare the effectiveness and cost effectivessness of multimodal screening (MMS, whereby screening with serum CA125 is the primary test and ultrascan is the secondary test) with transvaginal ultrascan (USS). This design will be used as a result of the limitations of bias and being that it is the gold standard in intervention studies. Randomisation will ensure that all the participants will have equal chance of being allocated to each group thus ensuring that the baseline characteristics of both groups are identical. Due to the fact that the participants will know what they are receiving in terms of MMS or USS the possibility of blinding will be limited. The assessors will also not be blinded due to the nature of the study.
PARTICIPATION AND SETTINGS
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Participants will comprise of female aged between 50 and 75 years, whose records will be accessed from NHS database and GP records.
Women must be ordinarily resident in the UK
They must be aged between 50 and 75 years as women in this group are at higher risk of ovarian cancer
They must be postmenopausal (This restriction is important as postmenopausal (i) are at a higher risk of ovarian cancer compared to other ages (ii) pre-menopausal women are more likely to have benign conditions such as ovarian cysts or likely to be taking hormone replacement therapy, which could result in false positives)
They must have more than one year of amenorrhoea
No history of ovarian cancer
No bilateral oophorectomy
They must not have been known to have any current malignancies (incase they may have had previous malignancies, they should have received their last treatment more than a year before commencement of the screening and they must not show any evidence of recurrence of the disease)
History of bilateral oophorectomy
Presence of malignancy or evidence that it is likely to recur
Previous history of ovarian cancer
Previously participated in other ovarian cancer screening trials
Ethical approval will be obtained before starting the study and enrolling participants from the NHS Research Ethics Committee because of the use of NHS patients' records and data and also because of the use of NHS facilities. This is done so as to abide by the ethical code surrounding screening and also to protect the dignity, rights and safety of the participants.
Taking into account inclusion and exclusion criteria, participants will be recruited from NHS centres and GP surgeries involved in the clinical trial. All eligible participants will be sent a package including information about the study, eligibility criteria and an invitation letter by post to participate in the study. A consent form will also be attached to the invitation letter. Those willing to participate will reply with a short slip through a prepaid envelope or via email. They will then be contacted by telephone (for further verification) so as to obtain verbal consent before proceeding.
Participants who have consented both verbally and in writing to take part in the study will be randomised. However before randomisation core baseline data would need to be collected. Participants will be invited for an interview where they will be required to fill in a questionnaire. They will be questioned on their age, marital status, parity, smoking history, use of hormone replacement therapy, family history of cancer
Baseline serum sample and baseline diagnostic images and volume of ovaries will be required from all participants so as to provide a means of checking the comparability of the participants at baseline. The questionnaires will be kept confidential from those assessing the participants, thus blinding them to minimise observer bias when interpreting results. A simple randomisation will be used to allocate the participants into two arms of the MMS group and the USS group. Equal numbers of participants will be allocated into each group so as to maximise the study power.
The intervention will include two screening tests; blood test for serum CA125 and transvaginal ultrasound. Collectively termed as Multimodal Screening (MMS).
Blood test for serum CA125
Blood tests will be carried out by phlebotomists and at the end of the day the blood samples will be transported to a specially designated haematology laboratory where they will be stored overnight. On the following day, blood samples will be centrifuged individually to separate the serum. Enzyme-linked immunosorbent assay (ELISA), a widely used diagnostic tool will be used to detect for the presence of CA125 using monoclonal antibodies. The normal measurement range for CA125 was taken as 30-35U/ml
This will be conducted by a radiologist, who will insert a small thin ultrascan probe into the vagina thus allowing for better viewing and quality of ovaries (christenhs). Ovarian morphology will be categorised as:
Normal: This is whereby the ovary is smooth and of uniform hypoechogenicity, with no apparent abnormalities seen. A diameter of less than 4cm is considered normal.
Simple cyst: This is whereby abnormalities are slightly visible. Anechoic cyst is present with no septa or papillary projections and the ovary is slightly greater than 4cm.
Complex case: This is where there is visible pelvic abnormalities with irregular ovarian echogenicity and ovaries evidently greater than 4cm .(Japan study)
Multimodal screening group
Serum CA125 will be interpreted using the Risk of Ovarian Cancer (ROC) algorithm as the primary screening test and TVS as the second screening test. ROC is determined by serum CA125 values and woman's age specific incidence of ovarian cancer. It also provides a single figure that gives information about the risk of change in CA125 levels.
Once the participants have been screened using either the MMS or USS strategies, a second phase test will be performed so as to further confirm the results of the first phase tests (MMS or USS). This test will involve the aspiration of fluid from the tumour using a fine needle and guided by a CT scan. The needle will be directed into the tumour through the skin and the fluid aspirated and sent off to the histopathology laboratory.
The outcome in this study will be the number of cases of ovarian cancer that are correctly diagnosed. This will be measured by the number of participants that are identified as having either a true positive result or a true negative result, which will therefore determine the effectiveness of the MMS and the USS and also compare the cost effectiveness of the two strategies.
To determine the effectiveness of MMS and USS, the sensitivity and specificity will be measured. Sensitivity can be defined as the proportion of participants who have the disease and when tested results are positive. This therefore means that a high sensitivity will correctly diagnose a high proportion of participants that truely have ovarian cancer (true positives). Specificity on the other hand, is the proportion of participants who do not have the disease and when tested results are negative. This means that a high specificity will give few positive results in those without ovarian cancer (true negatives) (Hulley S.2007).
Sensitivity and specificity can further determine the likelihood that people with positive results have the disease or those with a negative result do not have the disease. This is referred to as positive and negative predictive values respectively.
The table below illustrates a summary of the test results:
False positive (b)
False negative (c)
True negative (d)
a + c
Figure 2: Table illustrating the summary of test results.
From the table (figure 3) it can be seen that sensitivity will be calculated using the formulae; a/ (a+c). Specificity on the other hand will be calculated using; d/ (b+d). The positive and negative predictive values will be calculated using formulae a/ (a+b) and d/ (c+d) respectively.
To further evaluate the diagnostic performance and accuracy of the two screening strategies, the Receiver Operating Characteristic (ROC) curve will be used. The ROC is determined by the investigator who selects several cutoff points and thus determines the sensitivity and specificity at each point (Hulley,S 2007). The sensitivity will be plotted on the y-axis and specificity on the x-axis (see figure 4 below).
The closer the ROC plot is to the upper left corner, the higher the accuracy and performance of the test (Zweig et al 1993, Hulley 2007)
Figure 3: Receiver Operating Characteristic curve for good tests. (MedCalc, 2010)
As diagnosis for ovarian cancer is difficult and due to the fact that it has a low prevalence, a test that is highly specific is essential to accurately diagnose ovarian cancer. It is difficult to achieve a balance between sensitivity and specificity thus to overcome further confirmatory tests (i.e. biopsy) will be required to further accurately diagnose ovarian cancer. The problem with this is that there will be an increase in costs and possibly interpretation, as will be seen later in the study.
It is important to choose an appropriate evaluation technique depending on the study design so as to effectively assess the quality of the study. For the purpose of this study, quality assessment will be performed using the RE-AIM evaluation model. This model is made up of 5 factors namely reach, efficacy, adoption, implementation and maintenance (Glasgow, R. 1999) who stated that the model emphasises reach and representativeness of both participants and settings. It also discusses the implications and the contributions of the study to public health as a whole.
Glasgow, R. (1999) also states that RE-AIM model can be appropriately used to evaluate RCTs, as is the case in this study. RE-AIM will also provide a framework as to whether the study is of economic substance and whether it is sustainable. It also applies it to real-life situations thus giving an indication of what is to be expected in reality and is also compatible with evidence based medicine.
According to Drummond et al (2005), the availability of good quality data on the effectiveness of programme or treatments being assessed is important to the cost effectiveness of the study. A design model
The cost that will be involved in this study will include the cost of MMS and cost of the USS.
Cost of MMS
Materials for blood test for serum CA125 include:
Tourniquet/ constricting band
Materials required for TVS
Cover to protect participants dignity
POTENTIAL LIMITATIONS OF THE STUDY
As there is no routine screening for ovarian cancer, there is no gold standard hence the use of confirmatory tests (in this case biopsy)