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Prostate Cancer; Metabolic Risk Factors, Drug Utilisation, Adverse Drug Reactions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Increased possibilities during the last decades for early detection of prostate cancer have sparked research on preventable or treatable risk factors and on improvements in therapy. Treatments of the disease still entail significant side effects potentially affecting men during the rest of their lives. The studies of the present thesis concern different aspects of prostate cancer from etiological risk factors and factors influencing treatment to an improved methodology for the detection of treatment side effects.

Papers I, II, both based in the population based cohort ULSAM (Uppsala Longitudinal Study of Adult Men), investigate possible risk factors of prostate cancer with options for intervention: selenium levels and the metabolic syndrome. The phenomenon of competing risk of death from other causes than prostate cancer and its impact on and importance for choice of statistical methods is also exemplified and discussed for the first time in prostate cancer research.

-Smokers with low selenium status have an increased future risk of later development of prostate cancer. Influence of genetic variability appears plausible.

-The metabolic syndrome and especially its increased waist circumference component are associated with later development of prostate cancer – taking competing risks of death from other causes into account.

Papers III and IV using pharmacoepidemiological methods investigate aspects of drug utilisation in prostate cancer using nationwide and international databases. In Paper III factors influencing anti-androgen use in prostate cancer are investigated, both from a prescriber- and patient perspective.  The age and disease risk group of the patient, unsupported scientifically, influence both the prescribers’ choice of dose and the patients’ adherence to treatment.

-Adherence, not previously investigated in male cancer patients, was considerably higher than reported for adjuvant breast cancer treatment. Subgroups of men suitable for intervention to increase adherence were identified.

Paper IV, investigates the feasibility of improving an established method for screening large adverse drug reactions databases, the proportional reporting ratio (PRR), this by using restricted sub-databases according to treatment area (TA), introducing the concept of PRR-TA.

-The PRR-TA method increases the signal-noise relationship of analyses; a finding highly relevant for possibly conserving manual resources in Pharmacovigilance work in a drug-authority setting.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 115 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 870
Keyword [en]
Prostate cancer, Epidemiology, Pharmacoepidemiology, Metabolic Syndrome, Selenium, Smoking, hOGG1, MnSOD, Competing Risk, Adherence, Persistance, Medical Possession Ratio, MPR, Signal Detection, PRR, proportional reporting ratio, ULSAM, PcBaSE, EudraVigilance, SPDR, Swedish Prescribe Drug Registry, NPCR, National Prostate Cancer Registry, SDR, Signal, disproportionality analysis, PRR-TA, EudraVigilance
National Category
Surgery
Research subject
Epidemiology; Urology; Oncology; Geriatrics
Identifiers
URN: urn:nbn:se:uu:diva-194297ISBN: 978-91-554-8609-9 (print)OAI: oai:DiVA.org:uu-194297DiVA: diva2:608354
Public defence
2013-04-25, Universitetshuset, Biskopsgatan 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-03-26 Created: 2013-02-12 Last updated: 2013-06-27
List of papers
1. Serum levels of selenium and smoking habits at age 50 influence long term prostate cancer risk; a 34 year ULSAM follow-up
Open this publication in new window or tab >>Serum levels of selenium and smoking habits at age 50 influence long term prostate cancer risk; a 34 year ULSAM follow-up
2011 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, 431- p.Article in journal (Refereed) Published
Abstract [en]

Background: Serum selenium level (s-Se) has been associated with prostate cancer (PrCa) risk. We investigated the relation between s-Se, smoking and non-screening detected PrCa and explored if polymorphisms in two DNA repair genes: OGG1 and MnSOD, influenced any effect of s-Se.

Methods: ULSAM, a population based Swedish male cohort (n = 2322) investigated at age 50 for s-Se and s-Se influencing factors: serum cholesterol, erythrocyte sedimentation rate and smoking habits. At age 71 a subcohort, (n = 1005) was genotyped for OGG1 and MnSOD polymorphisms.

Results: In a 34-year-follow-up, national registries identified 208 PrCa cases further confirmed in medical records. Participants with s-Se in the upper tertile had a non-significantly lower risk of PrCa. Smokers with s-Se in the two lower tertiles (<= 80 mu g/L) experienced a higher cumulative incidence of PrCa than smokers in the high selenium tertile (Hazard Ratio 2.39; 95% CI: 1.09-5.25). A high tertile selenium level in combination with non-wt rs125701 of the OGG1 gene in combination with smoking status or rs4880 related variation of MnSOD gene appeared to protect from PrCa.

Conclusions: S-Se levels and smoking habits influence long-term risk of PrCa. Smoking as a risk factor for PrCa in men with low s-Se is relevant to explore further. Exploratory analyses of variations in OGG1 and MnSOD genes indicate that hypotheses about patterns of exposure to selenium and smoking combined with data on genetic variation in genes involved in DNA repair can be valuable to pursue.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-161467 (URN)10.1186/1471-2407-11-431 (DOI)000296103400001 ()21982398 (PubMedID)
Available from: 2011-11-14 Created: 2011-11-14 Last updated: 2017-12-08Bibliographically approved
2. The Metabolic Syndrome and the Risk of Prostate Cancer under Competing Risks of Death from Other Causes
Open this publication in new window or tab >>The Metabolic Syndrome and the Risk of Prostate Cancer under Competing Risks of Death from Other Causes
Show others...
2010 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 8, 2088-2096 p.Article in journal (Refereed) Published
Abstract [en]

Background:

Associations between metabolic syndrome (MetS) components and prostate cancer development have not been studied comprehensively; results have been divergent. Using the National Cholesterol Education Program Adult Treatment panel III (NCEP) and International Diabetes Federation (IDF) definitions of the MetS, we investigated such associations taking competing risks of death into consideration.

Methods:

In the prospective Uppsala Longitudinal Study of Adult Men of 2,322 Caucasian men with 34 years of follow-up baseline, MetS measurements at age 50 years were used. Cumulative incidence of prostate cancer and death with/without the MetS were calculated. Competing risk of dying was taken into account by calculating the conditional probability of prostate cancer with/without the MetS.

Results:

Two hundred and thirty-seven prostate cancers were identified. Prostate cancer probability by age 80 years with baseline MetS compared with without MetS was nonsignificantly higher [5.2 percent units (confidence interval (CI), -0.8% to 11.3%; NCEP); 2.7 percent units (CI, -2.7% to 8.0%; IDF)]; cumulative incidence proportions of death was significantly higher [19.3 percent units (CI, 13.4-25.3%; NCEP); 15.3 percent units (CI, 9.5-21.1%; IDF)]; and conditional probability of prostate cancer considering death from other causes was significantly higher [7.3 percent-units (CI, 0.2-14.5%); odds ratio of 1.64 (CI, 1.03-2.23; NCEP)] and nonsignificantly higher [5.0 percent-units (CI, -1.6% to 11.6%); odds ratio of 1.43 (CI, 0.89-1.90; IDF].

Conclusions:

The MetS by the NCEP definition is associated with prostate cancer, taking the competing risk of early death from other causes into account. Impact: The results further highlight the public health effect of the increasing prevalence of MetS and the importance of considering competing risks when studying risk factors for cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-135608 (URN)10.1158/1055-9965.EPI-10-0112 (DOI)000280675000023 ()20647401 (PubMedID)
Available from: 2010-12-07 Created: 2010-12-07 Last updated: 2013-04-02Bibliographically approved
3. Anti-androgen prescribing patterns, patient treatment adherence and influencing factors: results from the nationwide PCBaSe Sweden
Open this publication in new window or tab >>Anti-androgen prescribing patterns, patient treatment adherence and influencing factors: results from the nationwide PCBaSe Sweden
Show others...
2012 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 12, 1619-1630 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

Adherence has not been studied in male oncology populations. The aim of this study on both the prescriber and user perspectives in prostate cancer treatment was to analyse real-life prescribing patterns of anti-androgens (AA), primarily bicalutamide, and factors influencing the patients' adherence to treatment.

METHODS:

A nationwide clinical cohort of incident prostate cancer, PCBaSe, was linked to the Swedish Prescribed Drug Register. Men with a planned first line monotherapy AA treatment were identified; dosages and extent of off-label treatment were investigated. Cumulative incidence proportions for reasons for drug discontinuation were calculated. Factors potentially influencing adherence were explored using the medical possession ratio based on the individual prescribed daily dose.

RESULTS:

First line monotherapy AA was planned in 4.4 % of all incident cases and in 2.1 % of low risk disease cases. Among 1,406 men prescribed bicalutamide, 1,109 (79 %) received the approved daily dose of 150 mg. Discontinuation reasons differed with disease severity. Off-label, low-dose prescription associated with age above 75 years and disease categorised as low risk was noted in 297 men (21 %). Sixty percent of the men adhered well, i.e. to ≥80 %. Age above 75 years and less severe disease were both negatively associated with adherence.

CONCLUSIONS:

Patient age and tumour risk group influenced the prescriber's choice of dose, pointing to important issues for critical reflection. Possible over-treatment was noted in low risk disease. Interventions to increase adherence in older men and in men with less severe disease are worth considering after critically reviewing the appropriateness of the treatment indication, especially in the latter case.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-181552 (URN)10.1007/s00228-012-1290-x (DOI)000310999700006 ()22562608 (PubMedID)
Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2017-12-07Bibliographically approved
4. Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area
Open this publication in new window or tab >>Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area
2014 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 5, 627-635 p.Article in journal (Refereed) Published
Abstract [en]

Disproportionality screening analysis is acknowledged as a tool for performing signal detection in databases of adverse drug reactions (ADRs), e.g., in the European Union (EU) Drug Authority setting. The purpose of this study was to explore the possibility of decreasing false-positive signals of disproportionate reporting (SDR) by calculating the proportional reporting ratio (PRR)-by-therapeutic area (TA), while still maintaining the ability to detect relevant SDRs. In the EudraVigilance (EV) Database, output from PRR calculated with a restricted TA comparator background was compared in detail to output from conventional authority-setting PRR calculations for four drugs: bicalutamide, abiraterone, metformin, and vildagliptin, within the TAs of prostate gland disease and type 2 diabetes mellitus. ADR reports per investigated drug ranged from 2,400 to 50,000. The PRR-TA's ability to detect true-positive SDRs (as acknowledged in approved labeling) was increased compared to the conventional PRR, and performed 8-31 % better than a recently proposed stricter EU-SDR definition. The PRR-TA removed false SDRs confounded by disease or disease spill-over by up to 63 %, while retaining/increasing the number of unclassified SDRs relevant for manual validation, and thereby improving the ratio between confounded SDRs (i.e., noise) and unclassified SDRs for all investigated drugs (possible signals). The performance of the PRR was improved by background restriction with the PRR-TA method; the number of false-positive SDRs decreased, and the ability to detect true-positive SDRs increased, improving the signal-to-noise ratio. Further development and validation of the method is needed within other TAs and databases, and for disproportionality analysis methods.

Keyword
Signal detection, disproportionality analysis, PRR, proportional reporting ratio, prostate cancer, type 2 diabetes mellitus, PRR-TA, adverse drig reactions, ADR, SDR, signals of disproportionate reporting, signal, noise
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology
Identifiers
urn:nbn:se:uu:diva-195805 (URN)10.1007/s00228-014-1658-1 (DOI)000334422700015 ()
Available from: 2013-02-27 Created: 2013-02-27 Last updated: 2017-12-06Bibliographically approved

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