In the UK, ovarian malignant neoplastic disease is the fifth most common malignant neoplastic disease after chest, intestine, lung and uterine malignant neoplastic diseases.
Two hundred and four 1000 instances are diagnosed yearly world-wide with incidences highest in the USA and Northern Europe and lowest in Africa and Asia. In the UK, ovarian malignant neoplastic disease affects about 6,600 adult females yearly ( 125 adult females hebdomadally ) of which the bulk are over the age of 65 and have already been through the menopausal phase ( Cancer Research UK, 2009 ) .Figure 1: Graph exemplifying the figure of incidence diagnosed with ovarian malignant neoplastic disease as age additions per 100,000 populations ( Cancer Research UK 2009 )Around 4300 adult females dice of ovarian malignant neoplastic disease per twelvemonth in the UK, nevertheless over the last 30 old ages the mortality rates in younger adult females has decreased while in over 65s the mortality rates have risen. This may be explained by younger adult females being more likely to be diagnosed at an earlier phase.The endurance rates for ovarian malignant neoplastic disease are higher the earlier diagnosing is carried out. Research has shown that around 40 % of adult females that are diagnosed with ovarian malignant neoplastic disease tend to last for at least five old ages ( survival rate ) [ Cancer Research UK 2009 ] .
Ovarian malignant neoplastic disease can be categorised into three groups viz. stromal ovarian malignant neoplastic disease, germ cell ovarian malignant neoplastic disease and the most common type, epithelial ovarian malignant neoplastic disease. Epithelial ovarian malignant neoplastic disease histories for 70-80 % of all ovarian malignant neoplastic diseases and develops from a formation of cells that surround the originative epithelial tissue ( outside of the ovary ) . It chiefly affects adult females in post- menopausal phase but it can besides impact younger adult females.There is no definite cause for ovarian malignant neoplastic disease ; nevertheless it is thought that several factors increase its hazard. Surveies have shown that an addition in age and the presence of cistron mutants such as BRCA1 and BRCA2 are the highest hazard factors for developing ovarian malignant neoplastic disease ( ref ) . Other hazard factors include sterility, usage of endocrine replacing therapy ( HRT ) , increased us of talc ( as found in babe pulverization ) , household history and old malignant neoplastic diseases such as Hereditary Non-Polyposis Colorectal Cancer ( HNPCC ) and smoking amongst other.
Ovarian malignant neoplastic disease is referred to as a “ soundless slayer ” because its symptoms are obscure in its early phases and besides its symptoms are really similar to those of other conditions such as pre-menstrual syndrome ( PMS ) , frequently showing with abdominal hurting and puffiness, uterine hemorrhage and GI and urinary piece of land ailments ( Pearse and Behrman 1954 ) . This has hence led to an increased involvement in the research for effectual showing for ovarian malignant neoplastic disease. It is because of this that merely about 70 % of adult females with ovarian malignant neoplastic disease are diagnosed with advanced ovarian malignant neoplastic disease, therefore endurance is merely approximately 20-30 % ( emedicine 2009 ) . Harmonizing to Kobayashi, H. et Al ( 2008 ) , the increased endurance advantage for patients diagnosed with early phase disease might hold an impact on disease mortality and may better endurance.
AVAILABLE Screening TESTS
In the UK, there is no everyday showing for ovarian malignant neoplastic disease, nevertheless malignant neoplastic disease showing tests are afoot to seek and observe the malignant neoplastic disease before the presentation of symptoms, therefore assisting in cut downing a individual ‘s opportunity of deceasing from the disease ( National Cancer Institute, 2009 ) .
Screening trials that are presently used are transvaginal ultrasound ( besides known as echography, USS ) and blood trials for serum malignant neoplastic disease antigen ( CA ) 125 check.Transvaginal ultrasound ( TVS ) is an imaging method that provides elaborate images of the ovary and of any malignances within the pelvic girdle. Higgens, R. ( 1989 ) and Von Nagell, J.
( 1991 ) stated that this method of testing is non merely easy to execute but it is good accepted by the patients and portrays a strong interobserver translator understanding.Serum CA125 on the other manus is a glycoprotein that has been found to be released by cancerous cells into the blood stream ( Jacob, I and Bast, R. 1989 ) .
It has besides been found to be released in other gynecological conditions such as benign ovarian cyst and during normal organic structure working such as catamenial rhythm and even in gestation. ( Pittaway and Fayez 1987 ; Jacobs and Bast 1989 ) . Most adult females have a raised serum CA125 degree ; hence a cut- off degree of between 30-35 units per milliliter ( U/ml ) is used to propose that there is an abnormalcy ( Cancer Research UK ) . This technique is non wholly dependable due to the fact that CA125 is besides released during normal organic structure operation.However late, two showing schemes affecting these two methods have become evident. These include TVS which is the primary screening trial and the combination of the blood trial for serum CA125 with TVS ( now known as multimodal showing, MMS ) , which is the secondary trial ( Jacobs, I. 2003 )Assorted surveies that have shown that a combination of the two methods ( multimodal showing ) can observe ovarian malignant neoplastic disease in symptomless adult females ( UKCTOCS 2008 ) and later increase the sensitiveness and specificity of the testing trial hence ensuing in an addition in the endurance rate ( Jacob, I. et al 1988, Jacob, I.
Skates, S. et al 1999 ) ,One such survey was conducted between 2001 and 2005 by primary attention trusts ( PCTs ) across the UK and revealed that in 90 % of their participant population ( 202 638 postmenopausal adult females ) malignant neoplastic disease was detected utilizing the MMS method, while 75 % utilizing the USS method ( emedicine 2009 ) . It was hence concluded that MMS had a significantly better specificity and positive prognostic value compared to that of USS ( Jacobs, I 2003 ; emedicine 2009 ) . Another survey includes the largest and presently ongoing United Kingdom Collaborative Trial of Ovarian Cancer Screening ( UKCTOCS ) , which was designed in 2001 by Ian Jacobs.This survey involves 200,000 postmenopausal adult females randomised into three groups: ‘ultrasound testing ‘ group, ‘multimodal testing ‘ group and ‘control ‘ group ( patients who will non be screened ) . This clinical test purposes to analyze the effects of ovarian malignant neoplastic disease testing on the mortality rate.
It will besides be turn toing issues such as mark population, conformity, and wellness economic sciences, physical and psychological morbidity of testing ( Jacobs, I. 2003 ) . Other on-going surveies include the United Kingdom Familial Ovarian Cancer Screening Study ( UKFOCSS ) , NIH PLCO survey and the USA Cancer Genetics Network Study.Unfortunately, despite all the research taking topographic point at that place continues to be deficiency of informations and information on the showing available, chiefly due to the low prevalence of ovarian malignant neoplastic disease. There is besides limited cognition and understanding known about the molecular and biological events involved in ovarian carcinogenesis which limits the ability to observe ovarian malignant neoplastic disease in its early phases. Furthermore uncertainnesss sing the impact of testing on mortality and issues environing the quality of life still exist. The deductions of wellness economic sciences of testing besides remain ill-defined ( Jacob, I.
2003 ) . This survey will hence be measuring and comparing the effectivity of the two showing schemes and measuring and comparing the cost effectivity in implementing everyday showing. The findings will lend to the grounds already available sing the effectivity and cost of the two showing stategies.
The attitudes and satisfaction of the cardinal stakeholders is an of import portion of the rating. The theory of alteration ( logic frame theoretical account ) attack will be used to clearly sketch the purpose of the survey, the results and the premises to the stakeholders. Stakeholders value theories of alteration as portion of the planning and rating of a plan, as it clearly shows and clarifies in a simplified mode, both short term and long term ends, how they can be reached and what will be used to mensurate to come on as the survey returns ( www.theoryofchange )In this instance the stakeholders will include the adult females who will be take parting in showing, the General Practitioners ( GPs ) who will be supplying the patient records, wellness professionals transporting out the showing, histopathology and hematology research labs to prove biopsy and blood consequences severally, diagnosticians construing consequences, Primary Care Trust ( PCT ) NHS, Cancer Research UK, Office of National Statistics and Cancer Registry ( UKCTOCS ) , commissioners and assorted funders and sponsers.
AIM OF THE STUDY
The purpose of the survey is to find the effectivity and cost- effectivity of MMS compared to USS in adult females aged between the ages of 45 and 74 old ages ( postmenopausal adult females ) .
Determine the effectivity of MMS for ovarian malignant neoplastic disease showing ( by specificity, sensitiveness )Determine the effectivity of USS for ovarian malignant neoplastic disease showing ( by sensitiveness and specificity )Determine the cost associated with USS and MMSDetermine the cost effectivity of MMS and USS
A two-arm randomised controlled test ( RCT ) will be carried out to compare the effectivity and cost effectivessness of multimodal showing ( MMS, whereby testing with serum CA125 is the primary trial and ultrascan is the secondary trial ) with transvaginal ultrascan ( USS ) . This design will be used as a consequence of the restrictions of prejudice and being that it is the gilded criterion in intercession surveies.
Randomisation will guarantee that all the participants will hold equal opportunity of being allocated to each group therefore guaranting that the baseline features of both groups are indistinguishable. Due to the fact that the participants will cognize what they are having in footings of MMS or USS the possibility of blinding will be limited. The assessors will besides non be blinded due to the nature of the survey.
Engagement AND SETTINGS
Participants will consist of female aged between 50 and 75 old ages, whose records will be accessed from NHS database and GP records.
Womans must be normally occupant in the UKThey must be aged between 50 and 75 old ages as adult females in this group are at higher hazard of ovarian malignant neoplastic diseaseThey must be postmenopausal ( This limitation is of import as postmenopausal ( I ) are at a higher hazard of ovarian malignant neoplastic disease compared to other ages ( two ) pre-menopausal adult females are more likely to hold benign conditions such as ovarian cysts or likely to be taking hormone replacing therapy, which could ensue in false positives )They must hold more than one twelvemonth of amenorrheaNo history of ovarian malignant neoplastic diseaseNo bilateral ovariectomyThey must non hold been known to hold any current malignances ( incase they may hold had old malignances, they should hold received their last intervention more than a twelvemonth before beginning of the showing and they must non demo any grounds of return of the disease )
History of bilateral ovariectomyPresence of malignance or grounds that it is likely to repeatPrevious history of ovarian malignant neoplastic diseasePreviously participated in other ovarian malignant neoplastic disease showing tests
Ethical blessing will be obtained before get downing the survey and inscribing participants from the NHS Research Ethics Committee because of the usage of NHS patients ‘ records and informations and besides because of the usage of NHS installations. This is done so as to stay by the ethical codification environing showing and besides to protect the self-respect, rights and safety of the participants.
Taking into history inclusion and exclusion standards, participants will be recruited from NHS Centres and GP surgeries involved in the clinical test. All eligible participants will be sent a bundle including information about the survey, eligibility standards and an invitation missive by station to take part in the survey.
A consent signifier will besides be attached to the invitation missive. Those willing to take part will answer with a short faux pas through a postpaid envelope or via electronic mail. They will so be contacted by telephone ( for farther confirmation ) so as to obtain verbal consent before proceeding.
Participants who have consented both verbally and in composing to take portion in the survey will be randomised. However before randomization nucleus baseline informations would necessitate to be collected.
Participants will be invited for an interview where they will be required to make full in a questionnaire. They will be questioned on their age, matrimonial position, para, smoking history, usage of endocrine replacing therapy, household history of malignant neoplastic diseaseBaseline serum sample and baseline diagnostic images and volume of ovaries will be required from all participants so as to supply a agency of look intoing the comparison of the participants at baseline. The questionnaires will be kept confidential from those measuring the participants, therefore blinding them to understate observer prejudice when construing consequences. A simple randomization will be used to apportion the participants into two weaponries of the MMS group and the USS group. Equal Numberss of participants will be allocated into each group so as to maximize the survey power.
The intercession will include two testing trials ; blood trial for serum CA125 and transvaginal ultrasound. Jointly termed as Multimodal Screening ( MMS ) .
Blood trial for serum CA125
Blood trials will be carried out by phlebotomists and at the terminal of the twenty-four hours the blood samples will be transported to a specially designated hematology research lab where they will be stored nightlong. On the undermentioned twenty-four hours, blood samples will be centrifuged separately to divide the serum. Enzyme-linked immunosorbent check ( ELISA ) , a widely used diagnostic tool will be used to observe for the presence of CA125 utilizing monoclonal antibodies. The normal measuring scope for CA125 was taken as 30-35U/ml
This will be conducted by a radiotherapist, who will infix a little thin ultrascan investigation into the vagina therefore leting for better screening and quality of ovaries ( christenhs ) . Ovarian morphology will be categorised as:Normal: This is whereby the ovary is smooth and of unvarying hypoechogenicity, with no evident abnormalcies seen. A diameter of less than 4cm is considered normal.
Simple cyst: This is whereby abnormalcies are somewhat seeable. Anechoic cyst is present with no septa or papillose projections and the ovary is somewhat greater than 4cm.Complex instance: This is where there is seeable pelvic abnormalcies with irregular ovarian echogenicity and ovaries obviously greater than 4cm.
( Japan survey )
Multimodal testing group
Serum CA125 will be interpreted utilizing the Hazard of Ovarian Cancer ( ROC ) algorithm as the primary screening trial and TVS as the 2nd screening trial. ROC is determined by serum CA125 values and adult female ‘s age specific incidence of ovarian malignant neoplastic disease. It besides provides a individual figure that gives information about the hazard of alteration in CA125 degrees.
Once the participants have been screened utilizing either the MMS or USS schemes, a 2nd stage trial will be performed so as to farther corroborate the consequences of the first stage trials ( MMS or USS ) .
This trial will affect the aspiration of fluid from the tumor utilizing a all right acerate leaf and guided by a CT scan. The acerate leaf will be directed into the tumor through the tegument and the fluid aspirated and sent away to the histopathology research lab.
The result in this survey will be the figure of instances of ovarian malignant neoplastic disease that are right diagnosed. This will be measured by the figure of participants that are identified as holding either a true positive consequence or a true negative consequence, which will therefore find the effectivity of the MMS and the USS and besides compare the cost effectivity of the two schemes.
To find the effectivity of MMS and USS, the sensitiveness and specificity will be measured. Sensitivity can be defined as the proportion of participants who have the disease and when tested consequences are positive. This therefore means that a high sensitiveness will right name a high proportion of participants that truely have ovarian malignant neoplastic disease ( true positives ) . Specificity on the other manus, is the proportion of participants who do non hold the disease and when tested consequences are negative. This means that a high specificity will give few positive consequences in those without ovarian malignant neoplastic disease ( true negatives ) ( Hulley S.2007 ) .Sensitivity and specificity can farther find the likeliness that people with positive consequences have the disease or those with a negative consequence do non hold the disease. This is referred to as positive and negative prognostic values severally.
The tabular array below illustrates a sum-up of the trial consequences:Screening trialGold criterionDiseaseNo diseaseEntirePositiveTrue positive( a )False positive ( B )a+bNegativeFalse negative ( degree Celsius )True negative ( vitamin D )c+dEntirea + degree Celsiusb+dFigure 2: Table exemplifying the sum-up of trial consequences.From the tabular array ( figure 3 ) it can be seen that sensitiveness will be calculated utilizing the expression ; a/ ( a+c ) . Specificity on the other manus will be calculated utilizing ; d/ ( b+d ) .
The positive and negative predictive values will be calculated utilizing formulae a/ ( a+b ) and d/ ( c+d ) severally.To further measure the diagnostic public presentation and truth of the two showing schemes, the Receiver Operating Characteristic ( ROC ) curve will be used. The ROC is determined by the research worker who selects several cutoff points and therefore determines the sensitiveness and specificity at each point ( Hulley, S 2007 ) . The sensitiveness will be plotted on the y-axis and specificity on the x-axis ( see figure 4 below ) .The closer the ROC secret plan is to the upper left corner, the higher the truth and public presentation of the trial ( Zweig et al 1993, Hulley 2007 )Figure 3: Receiver Operating Characteristic curve for good trials. ( MedCalc, 2010 )As diagnosing for ovarian malignant neoplastic disease is hard and due to the fact that it has a low prevalence, a trial that is extremely specific is indispensable to accurately name ovarian malignant neoplastic disease.
It is hard to accomplish a balance between sensitiveness and specificity therefore to get the better of farther confirmatory trials ( i.e. biopsy ) will be required to further accurately diagnose ovarian malignant neoplastic disease. The job with this is that there will be an addition in costs and perchance reading, as will be seen subsequently in the survey.
It is of import to take an appropriate rating technique depending on the survey design so as to efficaciously measure the quality of the survey. For the intent of this survey, quality appraisal will be performed utilizing the RE-AIM rating theoretical account. This theoretical account is made up of 5 factors viz.
reach, efficaciousness, acceptance, execution and care ( Glasgow, R. 1999 ) who stated that the theoretical account emphasises range and representativeness of both participants and scenes. It besides discusses the deductions and the parts of the survey to public wellness as a whole.
Glasgow, R. ( 1999 ) besides states that RE-AIM theoretical account can be suitably used to measure RCTs, as is the instance in this survey. RE-AIM will besides supply a model as to whether the survey is of economic substance and whether it is sustainable. It besides applies it to real-life state of affairss therefore giving an indicant of what is to be expected in world and is besides compatible with grounds based medical specialty.
Harmonizing to Drummond et Al ( 2005 ) , the handiness of good quality informations on the effectivity of programme or interventions being assessed is of import to the cost effectivity of the survey.
A design theoretical accountThe cost that will be involved in this survey will include the cost of MMS and cost of the USS.
Cost of MMS
Materials for blood trial for serum CA125 include:PanpipesAcerate leafsAlcoholCotton woolPlaster tapeTourniquet/ compressing setCannulaMaterials required for TVSDoppler scanKY jellyScreen to protect participants self-respect
POTENTIAL LIMITATIONS OF THE STUDY
As there is no everyday showing for ovarian malignant neoplastic disease, there is no gilded criterion hence the usage of confirmatory trials ( in this instance biopsy )