Clinically Significant Prostate Cancer: Biological and ...

Clinically Significant Prostate Cancer: Biological and Epidemiological Observations to

Improve Cancer-Free and Survival Metrics

by

Christopher J.D. Wallis, M.D.

A thesis submitted in conformity with the requirements for the Degree of Doctor of Philosophy (Clinical Epidemiology and Health Care Research),

Institute of Health Policy, Management, & Evaluation, University of Toronto

? Copyright by Christopher J.D. Wallis, 2017

Issues following prostate cancer treatment

Clinically Significant Prostate Cancer: Biological and Epidemiological Observations to

Improve Cancer-Free and Survival Metrics

Christopher J.D. Wallis, M.D. Degree of Doctor of Philosophy (Clinical Epidemiology and Health Care Research)

Institute of Health Policy, Management, & Evaluation, University of Toronto 2017

ABSTRACT

Background: Due to very high disease-specific survival following prostate cancer treatment, disease progression (metastasis) and treatment-related complications may significantly affect a patient's life trajectory. Using distinct epidemiologic methodologies, this thesis sought to (1) identify novel microRNA predictors of metastasis following radical prostatectomy; (2) examine the association between local treatment modality (surgery or radiotherapy) and androgen deprivation therapy (ADT) on non-prostate cancer mortality; and (3) study the association between radiotherapy for prostate cancer and secondary malignancies. Methods: We conducted a matched-case control study of 38 patients who underwent radical prostatectomy using bootstrapping with automated backward selection to identify miRNA sequences which were significantly associated with metastasis. To examine the association between treatment modality and non-prostate cancer mortality, we performed a propensity-score matched, population-based retrospective cohort study of 10,786 men treated for non-metastatic prostate cancer in Ontario between 2002 and 2009. We used the Fine and Gray method with generalized estimating equation survival models with a sandwich variance estimator to calculate the sub-distribution hazard ratio of treatment effect, accounting for ADT exposure in a time-

ii

Issues following prostate cancer treatment varying manner. To assess the association between radiotherapy for prostate cancer and the development of secondary cancers, we performed a systematic review and meta-analysis utilizing random-effects models and Mantel-Haenszel weighting. Results: We identified a panel of five microRNA which were associated with metastasis following surgery (AUC 89.5%, 95% CI 79.5-99.5). Treatment with radiotherapy was independently associated with an increased risk of non-prostate cancer mortality (HR 1.57, 95% CI 1.35-1.83) though ADT exposure was not (p = 0.26 - 0.87 depending on analytic strategy). Radiotherapy was associated with an increased risk of bladder (aHR 1.67, 95% CI 1.55-1.80), colorectal (aHR 1.79, 95% CI 1.34-2.38) and rectal cancers (aHR 1.79, 95% CI 1.34-2.38) but not hematological (aHR 1.64, 95% CI 0.90-2.99) or lung (aHR 1.45, 95% CI 0.70-3.01) cancers. Conclusions: Varied epidemiologic techniques may be used to characterise outcomes following prostate cancer treatment. These data may inform patients and physicians when making decisions regarding prostate cancer treatment choice.

iii

Issues following prostate cancer treatment

ACKNOWLEDGEMENTS

This dissertation is the result of the contributions of many people who have fostered and encouraged my interest in research, advised and assisted me as I've undertaken this work, and supported me throughout.

First and foremost, to my wife Julie, whose patience, support, encouragement, and love has been invaluable and truly life changing. You set an example that I endeavour to follow. Thank you.

To my parents, who fostered my curiosity from a young age, endured the unending questions which resulted, and supported my education and efforts throughout.

To Dr. Robert Nam, whose support and mentorship have helped to shape me as a physician and researcher.

To Drs. Arun Seth, Calvin Law, and Girish Kulkarni, who gave generously of their time and expertise in guiding the design and conduct of this dissertation.

To Drs. Raj Satkunasivam, James Byrne, and Alaina Garbens, wonderful friends and colleagues who have enriched my research experience and helped me grow as a researcher and person.

Finally, to Refik Sakin and Deepit Bhatia, to whom I am indebted for research and analytic support during this process.

iv

Issues following prostate cancer treatment

TABLE OF CONTENTS

Acknowledgements....................................................................................................................... iv Table of contents............................................................................................................................ v List of Tables ................................................................................................................................ ix List of Figures............................................................................................................................... xi List of Appendices ...................................................................................................................... xiii

1.1 Study rationale ..................................................................................................................... 1 1.2 Study objectives ................................................................................................................... 2 Chapter 2: Background .................................................................................................................. 3 2.1 Prostate cancer epidemiology .............................................................................................. 3 2.2 Prostate cancer carcinogenesis and risk factors ................................................................... 3

2.2.1 Demographic factors ..................................................................................................... 3 2.2.2 Diet and lifestyle ........................................................................................................... 5 2.2.3 Medication..................................................................................................................... 6 2.2.4 Inflammation ................................................................................................................. 6 2.2.5 Genetic factors............................................................................................................... 7 2.2.6 MicroRNA (miRNA) .................................................................................................. 10 2.3 Prognostic factors............................................................................................................... 15 2.3.1 General considerations regarding prognostic factors in oncology .............................. 15 2.3.2 Prognostic factors in prostate cancer........................................................................... 17 2.4 An overview of prostate cancer identification and treatment ............................................ 25 2.4.1 Prostate cancer screening ............................................................................................ 25 2.4.2 Prostate cancer diagnosis............................................................................................. 27 2.4.3 Prostate cancer treatment............................................................................................. 27 2.5 Outcomes following prostate cancer treatment.................................................................. 32 2.5.1 Oncologic outcomes .................................................................................................... 32 2.5.2 Functional outcomes.................................................................................................... 38 2.6 Thesis overview ................................................................................................................. 45 Chapter 3: Identification of a novel microRNA panel associated with metastasis following radical prostatectomy for prostate cancer .................................................................................... 46 3.1 Abstract .............................................................................................................................. 46

v

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download