Prostate Cancer; Metabolic Risk Factors, Drug Utilisation, Adverse

116 Pages·2013·1.84 MB·English

by  Birgitta Grundmark

Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 870
Prostate Cancer; Metabolic
Risk Factors, Drug Utilisation,
Adverse Drug Reactions
BIRGITTA GRUNDMARK
ACTA
UNIVERSITATIS
ISSN 1651-6206
UPSALIENSIS
ISBN 978-91-554-8609-9
UPPSALA
urn:nbn:se:uu:diva-194297
2013
Dissertation presented at Uppsala University to be publicly examined in Universitetshuset,
Biskopsgatan 3, Uppsala, Thursday, April 25, 2013 at 09:00 for the degree of Doctor of
Philosophy (Faculty of Medicine). The examination will be conducted in Swedish.
Abstract
Grundmark, B. 2013. Prostate Cancer; Metabolic Risk Factors, Drug Utilisation,
Adverse Drug Reactions. Acta Universitatis Upsaliensis. Digital Comprehensive
Summaries of Uppsala Dissertations from the Faculty of Medicine 870. 115 pp. Uppsala.
ISBN 978-91-554-8609-9.
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.
Keywords: 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
Birgitta Grundmark, Uppsala University, Department of Surgical Sciences, Akademiska
sjukhuset, SE-751 85 Uppsala, Sweden. Department of Public Health and Caring Sciences,
Geriatrics, Box 609, SE-751 25 Uppsala, Sweden.
© Birgitta Grundmark 2013
ISSN 1651-6206
ISBN 978-91-554-8609-9
urn:nbn:se:uu:diva-194297 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-194297)
”Jag vill inte klaga;
jag har faktiskt upptäckt Atlantis.”

Wisława Szymborska ur Lovsång till drömmarna
Department of Surgical Sciences
Uppsala University

Supervisor:
Professor Lars Holmberg
Co-supervisor:
Associate Professor Björn Zethelius
Statistician:
Dr Hans Garmo

Opponent:
Professor Gunnar Engström
Lund University
List of Papers
This thesis is based on the following Papers, which are referred to in the text
by their Roman numerals.

I Serum levels of selenium and smoking
habits at age 50 influence long term pros-
tate cancer risk, a 34 year ULSAM follow-
up.
BMC Cancer. 2011 Oct 7;11:431

II The metabolic syndrome and the risk of
prostate cancer under competing risks of
death from other causes.
Cancer Epidemiol Biomarkers Prev. 2010
Aug;19(8):2088-96

III Anti-androgen prescribing patterns, patient
treatment adherence and influencing fac-
tors, results from the nationwide PCBaSe
Sweden.
Eur J Clin Pharmacol. 2012
Dec;68(12):1619-30

IV Reducing the noise in signal detection of
adverse drug reactions by standardizing the
background: analyses of Proportional Rate
Ratios-by-therapeutic area. Manuscript
Reprints were made with permission from the respective publishers.
I Open access license agreement
II © Cancer Epidemiology Biomarkers and Prevention (American Association for Cancer
Research)
III© Springer

Contents
Introduction...................................................................................................13
Epidemiological trends in Prostate Cancer..............................................13
Clinical presentation, diagnosis, grading, staging and risk
classification:............................................................................................14
Risk factors for Prostate Cancer (Papers I, II)..........................................15
Age.......................................................................................................15
Hereditary factors, ethnicity, geographic and genetic variation..........16
Oxidative stress, endogenous factors...................................................17
Oxidative stress, exogenous factors.....................................................18
The Metabolic syndrome.....................................................................19
Smoking, false protectivity, competing risk........................................20
Drug utilisation and Pharmacovigilance (Papers III, IV).........................21
Prostate Cancer treatment....................................................................21
Hormonal treatment.............................................................................22
Anti-androgens....................................................................................22
Prescribing patterns.............................................................................22
Treatment adherence............................................................................23
Pharmacovigilance...............................................................................23
Approval of drugs, benefit/risk evaluation..........................................23
Efficacy vs. effectiveness, the risk of harm in trials vs. in real life.....24
Spontaneous Reporting for Signal Detection.......................................24
Pharmacovigilance signal....................................................................25
Signal detection methods, the PRR:....................................................25
Aims of the thesis..........................................................................................28
Overall aim...............................................................................................28
Specific aims............................................................................................28
Material and Methods, Papers I, II................................................................29
The ULSAM cohort:............................................................................29
Investigations at baseline.....................................................................30
Investigation at age 71.........................................................................31
The Metabolic syndrome, definitions:.................................................31
Follow up and outcome definitions Paper I, II....................................32
Statistical analysis methods:................................................................33
Material and Methods, Paper III...................................................................34
PCBaSe Sweden, National Prostate Cancer Register (NPCR)............34
Study population..................................................................................34
Bicalutamide indication, treatment guidelines.....................................35
Risk classification................................................................................35
Follow-up and outcome definitions, statistical analysis methods........35
Adherence calculations........................................................................37
Material and Methods Paper IV....................................................................39
Proportional Reporting Ratios, PRR, thresholds.................................40
PRR by therapeutic area......................................................................40
Results Paper I..............................................................................................43
Baseline measurements and Prostate Cancer risk................................44
Smoking and Selenium: early death competing with Prostate Cancer..46
Influence of genotype?........................................................................47
Results Paper II.............................................................................................49
Baseline measurements and relative risk of Prostate Cancer...............49
Analysing cumulatively.......................................................................51
Results Paper III............................................................................................57
Prescribing pattern, dosage influencing factors:..................................58
The more severe the disease, the lower the treatment persistence.......60
Reasons for treatment discontinuation vary with disease severity......60
Adherence to bicalutamide treatment..................................................61
Results Paper IV...........................................................................................64
Conventional PRR calculations using the SDR3 and SDR5
thresholds.............................................................................................64
PRR calculations by restricting the background of comparison,
detection of acknowledged ADRs in SPCs = true positive SDRs.......65
Detection of SDRs not acknowledged as ADRs in the SPCs..............67
Discussion and Conclusions, Papers I, II......................................................70
“Clinically relevant” prostate cancer...................................................70
Screening detected vs. non-screening detected prostate cancer...........70
The role of selenium............................................................................72
The role of smoking- competing risk...................................................72
The role of genetic variation, OGG1, MnSOD....................................73
Attempting prevention of prostate cancer by selenium
supplementation...................................................................................74
Risk of harm vs. chance of benefit of supplementation- more is not
always better........................................................................................75
Prevention of Prostate Cancer, is it really relevant?............................76
Better chance of success in high risk populations?..............................76
Other Prostate Cancer prevention attempts.........................................77
The role of the Metabolic Syndrome or its components......................77
The metabolic syndrome and competing risk......................................78
Reverse the Metabolic Syndrome and prevent Prostate Cancer?........79
The Metabolic Syndrome, its Raison d’être........................................79
What happened since Paper II.............................................................80
Type 2 Diabetes Mellitus - does it really protect from Prostate
Cancer?................................................................................................81
Competing risk - does it matter in the screening age of Prostate
Cancer?................................................................................................81
Discussion and Conclusions, Paper III.........................................................83
Treatment in relation to guidelines......................................................83
Persistence...........................................................................................84
Off-label use........................................................................................84
On adherence to prescribed treatment.................................................84
On measuring adherence......................................................................85
Adhering to guidelines and approved indication.................................86
Awareness of adherence to improve effectiveness of oral cancer
treatment..............................................................................................86
Adherence affects effectiveness..........................................................87
Recent comments on methods for measuring adherence.....................87
Future...................................................................................................87
Discussion and Conclusions Paper IV..........................................................88
Comparison with literature..................................................................89
Strengths and weaknesses of the PRR-TA..........................................90
Clinical implications............................................................................91
Unanswered questions and future research specified..........................91
Conclusions.........................................................................................91
Tack!.............................................................................................................93
References:....................................................................................................95