A Cluster-Randomised, Parallel Group, Controlled Intervention Study Of
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Downloaded from http://bmjopen.bmj.com/ on November 15, 2015 - Published by group.bmj.com Open Access Protocol A cluster-randomised, parallel group, controlled intervention study of genetic prostate cancer risk assessment and use of PSA tests in general practice—the ProCaRis study: study protocol Pia Kirkegaard,1 Peter Vedsted,1 Adrian Edwards,2 Morten Fenger-Grøn,1 Flemming Bro1 To cite: Kirkegaard P, ABSTRACT et al ARTICLE SUMMARY Vedsted P, Edwards A, . Introduction: Unsystematic screening for prostate A cluster-randomised, parallel cancer (PCa) is common, causing a high number of group, controlled intervention Article focus false-positive results. Valid instruments for assessment study of genetic prostate The objectives of this study are cancer risk assessment and of individual risk of PCa have been called for. ▪ To evaluate the impact on the use of prostate- use of PSA tests in general A DNA-based genetic test has been tested specific antigen (PSA) tests of introducing practice—the ProCaRis retrospectively. The clinical use of this test needs genetic prostate cancer (PCa) risk assessment in study: study protocol. BMJ further investigation. The primary objective is to general practice. Open 2013;3:e002452. evaluate the impact on the use of prostate-specific ▪ To evaluate PCa-related patient experiences. doi:10.1136/bmjopen-2012- antigen (PSA) tests of introducing genetic PCa risk ▪ To explore sociocultural aspects of genetic PCa 002452 assessment in general practice. The secondary risk assessment in patients at high PCa risk. objectives are to evaluate PCa-related patient ▸ Prepublication history for experiences, and to explore sociocultural aspects Key messages this paper are available of genetic risk assessment in patients at high PCa risk. ▪ Use of PSA tests in unsystematic screening for online. To view these files Methods and analysis: The study is a cluster- PCa increases the risk of overdiagnosis and over- please visit the journal online randomised, controlled intervention study with practice treatment of indolent cancers. Valid instruments (http://dx.doi.org/10.1136/ as the unit of randomisation. We expect 140 practices for individual PCa risk assessment have been bmjopen-2012-002452). to accept participation and include a total of 1244 called for. ▪ Retrospective studies of genetic PCa risk assess- Received 21 December 2012 patients in 4 months. Patients requesting a PSA test in ment have shown promising results in stratifying Revised 23 January 2013 the intervention group practices will be offered a Accepted 24 January 2013 genetic PCa risk assessment. Patients requesting a high-risk and low-risk individuals. PSA test in the control group practices will be handled ▪ Use of genetic PCa risk assessment may reduce This final article is available according to current guidelines. Data will be collected the number of low-risk individuals who get for use under the terms of from registers, patient questionnaires and interviews. screened unsystematically. the Creative Commons Quantitative data will be analysed according to Attribution Non-Commercial intention-to-treat principles. Baseline characteristics will 2.0 Licence; see be compared between groups. Longitudinal analyses http://bmjopen.bmj.com will include time in risk, and multivariable analysis will BACKGROUND be conducted to evaluate the influence of general Prostate cancer (PCa) is the most common cancer type among men in Europe.1 The 1Research Unit for General practitioner and patient-specific variables on future PSA Practice & Research Centre testing. Interview data will be transcribed verbatim and strongest risk factors are old age, positive 2 for Cancer Diagnosis in analysed from a social-constructivist perspective. family history and black race. PCa is asso- Primary Care—Aarhus Ethics and dissemination: Consent will be obtained ciated with increased production of the University, Aarhus C, from patients who can withdraw from the study at any serum marker prostate-specific antigen Denmark time. The study provides data to the ongoing (PSA). The preferred method for early detec- 2School of Medicine, conceptual and ethical discussions about genetic risk tion of PCa in older men with a family history Cochrane Institute of Primary assessment and classification of low-risk and high-risk Care and Public Health, of PCa is the PSA test, although the method is individuals. The intervention model might be applicable Cardiff University, Cardiff, UK imprecise.34Nearly 1055 men need to to other screening areas regarding risk of cancer with undergo PSA screening and 37 PCa cases Correspondence to identified genetic components, for example, colon cancer. The study is registered at the ClinicalTrials.gov need to be detected in order to prevent one Dr Pia Kirkegaard; 5 [email protected], (Identifier: NCT01739062). death from PCa. Treatment options include [email protected] surgery, radiotherapy and hormone therapy, Kirkegaard P, Vedsted P, Edwards A, et al. BMJ Open 2013;3:e002452. doi:10.1136/bmjopen-2012-002452 1 Downloaded from http://bmjopen.bmj.com/ on November 15, 2015 - Published by group.bmj.com Genetic risk assessment for prostate cancer PSA screening is recommended only for men with a ARTICLE SUMMARY minimum of two close relatives with PCa, which approxi- mates a lifetime risk of 33% of being diagnosed with Strengths and limitations of this study 8 ▪ The study adds a genetic component to an already existing PCa. In spite of this, up to 26% of all tests requested in ‘ risk assessment tool for PCa which employs family history general practice can be categorised as preceded by taking.8 Thus, we expect to see an increase in the proportion normal’, meaning tests which are performed within of patients stratified to high risk, and a reduction in the 2 years after a normal test. Tests in this category may indi- number of patients stratified to low risk who get proceeded by cate unsystematic screening.9 normal PSA test. If, on the contrary, patients stratified to low By now, scientific advancement in genome-wide associ- risk continue to request preceded by normal PSA tests, the ation studies has identified more than 40 genetic var- overall consequence might be an unwanted increase in the iants for PCa risk, the so-called single nucleotide use of PSA tests. We expect, however, to see a decrease in polymorphisms (SNPs). The individual risk of PCa accu- the number of low-risk patients requesting a preceded by mulates with the increasing number of these variants. normal PSA test because the genetic risk assessment may work as a decision support for unsure patients who are not at The risk is doubled if a patient has familial disposition high risk according to the conventional risk assessment tool as well. In retrospective studies, non-genetic risk predic- with family history taking. tion models were compared to risk prediction models ▪ Screening for cancer has dominated the health policy debate containing both non-genetic factors and SNP analyses. for several years.75758Recent studies have shown the limited The genetic models had a significantly higher specificity – effects of general screening for PCa.451359New national than the non-genetic models.10 12 It has been argued guidelines for screening with PSA tests in men with familial that genetic PCa risk assessment could reduce the use of disposition are likely to be introduced during the study period. PSA tests, saving it for patients at high risk of PCa.11 13 14 A more restrictive guideline may reduce the effect of introdu- This genetic PCa risk assessment tool needs further cing genetic risk assessment on the use of PSA, compared investigation in a clinical setting. between the intervention group and the control group. Previous studies have indicated that men are inter- ▪ The study provides the opportunity to study cancer risk per- – ested in receiving genetic PCa risk assessments.15 18 ception in male patients who have been under-represented in ’ the literature about cancer risk perception.33 60 In this way, Men s reactions to information about PCa family history fi the study may contribute to the ongoing conceptual and have shown no signi cant long-term psychological dis- 18–22 ethical discussions about genetic risk assessment and classifi- tress, but the studies remain small and inconclusive. cation of high-risk individuals.47 61–64 There is a vast literature on female-specific genetic ▪ The project is based on the present Danish recommendation cancer risk assessment and its consequences for clinical – to PSA test only men who have two close relatives with PCa, practice and female patient behaviour.23 28 Few studies which approximates a lifetime risk of 33%. A certain propor- about male carriers of the BRCA1/2 gene associated – tion of those recommended not to have a PSA test will be with breast cancer have been conducted.29 32 Studies in diagnosed at a later stage with PCa, and a PSA test might related fields have shown a gendered difference in have led to an earlier diagnosis. In this project, we aim to health-related behaviour and perception of risk, indicat- detect men who may benefit from systematic PSA tests. We ing that men more than women worry about maintain a cut-off point of 33% lifetime risk before a patient is fl recommended screening with PSA tests. This means that 10% health-related risks that in uence work life and sexual 33–38 fi of those with a normal PSA will be recommended to have the life. Thus, male-speci c genetic cancer risk assess- test done, whereas none of those with a normal PSA today are ment is likely to be influenced by sociocultural contexts currently recommended to be tested, unless they have two or not described in the current literature. more close relatives with PCa. We know very little about the The main study hypothesis is that genetic information benefits and disadvantages for this group of joining a screen- about low risk of PCa can reduce the number of patients ing programme.