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Early diagnosis and treatment of prostate cancer: observational studies in the National Prostate Cancer Register of Sweden and the Västerbotten Intervention Project
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Tidig diagnostik och behandling av prostatacancer  : observationsstudier i Nationella Prostatacancerregistret och Västerbottens interventionsprojekt (Swedish)
Abstract [en]

Prostate-specific antigen (PSA) testing has caused a steep increase in the incidence of prostate cancer, especially the incidence of localised low risk disease. In order to decrease the overdiagnosis accompanied by PSA testing, analysis of inherited genetic variants have been suggested as potential tools for clinical assessment of disease risk. With the aim of minimizing overtreatment and postpone side-effects of curative treatment for low risk prostate cancer, active surveillance, a treatment strategy with initial surveillance and deferred radical prostatectomy at the time of progression has evolved. 

The aim of this thesis was to study the validity of PSA (paper I) and inherited genetic variants (paper II) for early diagnosis of prostate cancer, to assess the extent of PSA testing in Sweden (paper III), and to study the safety of deferred radical prostatectomy in localised low to intermediate risk prostate cancer (paper IV).

The study designs were i) case-control studies nested within the Västerbotten intervention project (paper I and II), ii) observational study in the Cancer Register of Sweden (paper III), and iii) observational study in the NPCR Follow-up study (paper IV).

PSA had a high validity in predicting a prostate cancer diagnosis with an area under the receiver operating characteristics (ROC) curve of 0.86 (95% CI, 0.84 to 0.88). A combined test, including PSA, the ratio of free to total PSA, and 33 single nucleotide polymorphisms (SNPs) in a genetic risk score, increased the area under curve to 0.87 (95% CI, 0.85 to 0.89). The estimated uptake of PSA testing among men aged 55 to 69 years increased from zero to 56% between 1997 and 2007 and there were large variations in the uptake of PSA testing between counties in Sweden. After a median follow-up time of eight years there was no significant difference in presence of any one or more adverse pathology features or prostate cancer specific mortality after primary compared to deferred radical prostatectomy in localised low to intermediate risk prostate cancer.

Results from these studies indicate that PSA and the hitherto identified SNPs are not suitable biomarkers in single-test prostate cancer screening. It is possible to estimate the uptake of PSA testing on a population level. Initial surveillance and deferred radical prostatectomy represent a feasible treatment strategy in localised low to intermediate risk prostate cancer.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2011. , 58 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1397
Keyword [en]
Prostate cancer, prostate-specific antigen, single nucleotide polymorphism
National Category
Urology and Nephrology
Research subject
Urology
Identifiers
URN: urn:nbn:se:umu:diva-42843ISBN: 978-91-7459-134-7OAI: oai:DiVA.org:umu-42843DiVA: diva2:411904
Public defence
2011-05-13, Sal E04, Byggnad 6E, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-04-21 Created: 2011-04-14 Last updated: 2011-04-21Bibliographically approved
List of papers
1. Prostate specific antigen for early detection of prostate cancer: longitudinal study
Open this publication in new window or tab >>Prostate specific antigen for early detection of prostate cancer: longitudinal study
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2009 (English)In: BMJ (Clinical research ed.), ISSN 1468-5833, Vol. 339, b3537- p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To evaluate if prostate specific antigen test attains validity standards required for screening in view of recent prostate cancer screening trial results.

DESIGN: Case-control study nested in longitudinal cohort.

SETTING: Västerbotten Intervention Project cohort, Umeå, Sweden.

PARTICIPANTS: 540 cases and 1034 controls matched for age and date of blood draw.

MAIN OUTCOME MEASURE: Validity of prostate specific antigen for prediction of subsequent prostate cancer diagnosis by record linkage to cancer registry.

RESULTS: Blood samples were drawn on average 7.1 (SD 3.7) years before diagnosis. The area under the curve for prostate specific antigen was 0.84 (95% confidence interval 0.82 to 0.86). At prostate specific antigen cut-off values of 3, 4, and 5 ng/ml, sensitivity estimates were 59%, 44%, and 33%, and specificity estimates were 87%, 92%, and 95%. The positive likelihood ratio commonly considered to "rule in disease" is 10; in this study the positive likelihood ratios were 4.5, 5.5, and 6.4 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. The negative likelihood ratio commonly considered to "rule out disease" is 0.1; in this study the negative likelihood ratios were 0.47, 0.61, and 0.70 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. For a cut-off of 1.0 ng/ml, the negative likelihood ratio was 0.08.

CONCLUSIONS: No single cut-off value for prostate specific antigen concentration attained likelihood ratios formally required for a screening test. Prostate specific antigen concentrations below 1.0 ng/ml virtually ruled out a prostate cancer diagnosis during the follow-up. Additional biomarkers for early detection of prostate cancer are needed before population based screening for prostate cancer should be introduced.

National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-26272 (URN)10.1136/bmj.b3537 (DOI)000270231800002 ()19778969 (PubMedID)
Available from: 2009-10-02 Created: 2009-10-02 Last updated: 2016-03-07Bibliographically approved
2. Combining 33 genetic variants with prostate-specific antigen for prediction of prostate cancer: longitudinal study
Open this publication in new window or tab >>Combining 33 genetic variants with prostate-specific antigen for prediction of prostate cancer: longitudinal study
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2012 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 1, 129-137 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate if a genetic risk score including 33 common genetic variants improves prediction of prostate cancer when added to measures of prostate-specific antigen (PSA). We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort (NSHDC), a prospective cohort in northern Sweden. A total of 520 cases and 988 controls matched for age, and date of blood draw were identified by linkage between the regional cancer register and the NSHDC. Receiver operating characteristic curves with area under curve (AUC) estimates were used as measures of prostate cancer prediction. The AUC for the genetic risk score was 64.3% [95% confidence interval (CI) = 61.4-67.2], and the AUC for total PSA and the ratio of free to total PSA was 86.2% (95% CI = 84.4-88.1). A model including the genetic risk score, total PSA and the ratio of free to total PSA increased the AUC to 87.2% (95% CI = 85.4-89.0, p difference = 0.002). The addition of a genetic risk score to PSA resulted in a marginal improvement in prostate cancer prediction that would not seem useful for clinical risk assessment.

Keyword
early detection, prostate cancer, prostate-specific antigen, single-nucleotide polymorphism
National Category
Urology and Nephrology
Research subject
Urology
Identifiers
urn:nbn:se:umu:diva-43005 (URN)10.1002/ijc.25986 (DOI)000297851300014 ()21328341 (PubMedID)
Available from: 2011-04-15 Created: 2011-04-15 Last updated: 2016-03-07Bibliographically approved
3. Uptake of prostate-specific antigen testing for early prostate cancer detection in Sweden
Open this publication in new window or tab >>Uptake of prostate-specific antigen testing for early prostate cancer detection in Sweden
2011 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 8, 1881-1888 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to estimate uptake of PSA testing in an entire country, including time trends and geographical differences. Data from the Swedish Cancer Register on prostate cancer incidence between 1980 and 2007 and published data from the Gothenburg branch of the European Randomized Study of Screening for Prostate Cancer (ERSPC), a population-based PSA screening study, were used in a multiplicative model of changes in incidence of prostate cancer as a proxy for uptake of PSA testing in all 24 Swedish counties. The estimated PSA testing in any one year, irrespective of previous years' exposure, reached a peak of 12% of all men in 2004 and decreased thereafter to 6% in 2007 and varied between 5% and 20% between counties. Under the assumption that men who underwent PSA testing were previously unexposed to PSA testing, the cumulated uptake of PSA testing in men aged 55-69 years in Sweden increased from zero in 1997 to 56% in 2007. This study shows that it is possible to estimate uptake of PSA testing in the population from the prostate cancer incidence pattern. There were large geographical variations in uptake of PSA testing despite a uniform health care system in Sweden and there was a substantial increase in the uptake of PSA testing during the study period, despite that there were no national recommendations for PSA-based prostate cancer screening.

Place, publisher, year, edition, pages
Geneve: International union against cancer, 2011
Keyword
early detection, prostate cancer, prostate-specific antigen
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-40917 (URN)10.1002/ijc.25846 (DOI)21154740 (PubMedID)
Available from: 2011-03-14 Created: 2011-03-14 Last updated: 2011-09-19Bibliographically approved
4. Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden follow-up study
Open this publication in new window or tab >>Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden follow-up study
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2010 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 184, no 4, 1322-1327 p.Article in journal (Refereed) Published
Abstract [en]

Purpose We assessed outcomes in terms of adverse pathology and prostate cancer specific mortality in men who underwent primary or deferred radical prostatectomy.

Materials and Methods In the National Prostate Cancer Register of Sweden Follow-Up Study men 70 years old or younger at diagnosis with localized low to intermediate risk prostate cancer diagnosed from 1997 to 2002 were identified. Outcome in terms of adverse pathology, namely upgrading of Gleason score, positive surgical margins and extraprostatic extension, as well as prostate cancer specific mortality, was assessed in 2,344 men who underwent primary radical prostatectomy and 222 who underwent deferred radical prostatectomy after an initial period of surveillance.

Results Upgrading of Gleason score in surgical specimens vs core biopsies was less frequent after primary (25%) vs deferred radical prostatectomy (38%), p <0.001. There was no significant difference in the percentage of men who underwent primary vs deferred radical prostatectomy for positive surgical margins (33% vs 24%) or extraprostatic extension (27% vs 25%), and there was no difference in any 1 or more of the 3 adverse pathology features (55% vs 56%). After a median followup of 8 years 0.7% of men in the primary radical prostatectomy group and 0.9% in the deferred radical prostatectomy group had died of prostate cancer.

Conclusions There was no significant difference in the presence of any 1 or more adverse pathology features or in prostate cancer specific mortality after primary compared to deferred radical prostatectomy. However, longer followup is needed to conclusively evaluate the role of deferred radical prostatectomy.

Place, publisher, year, edition, pages
Elsevier, 2010
Keyword
prostatectomy, prostatic neoplasm
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-42197 (URN)10.1016/j.juro.2010.06.008 (DOI)000282615400027 ()20723940 (PubMedID)
Available from: 2011-04-06 Created: 2011-04-06 Last updated: 2011-05-11Bibliographically approved

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