Prostate cancer : aspects of screening and prognostic factors

Abstract

Prostate cancer is the most common malignancy among Swedish men. Each year approx. 2 500 men die from the disease constituting almost 1/5 of all cancer death among men. Screening for prostate cancer has not been recommended in Sweden but PSA-testing is despite that commonly used. With high diagnostic activity more men are diagnosed with early stage prostate cancer, increasing the risk of over treatment. There is a strong need for better prognostic markers of prostate cancer. The aim of this thesis was to evaluate an early prostate cancer screening study and to assess different possible prognostic factors of prostate cancer.

In 1988, all men aged between 55-70 years living in the catchment area of Stockholm South Hospital were identified (26 602). 2 400 of them were randomly selected and invited to participate in a single intervention prostate cancer screening study. 1 782 men accepted, and were examined with DRE, TRUS and PSA analysis. 65 cases of prostate cancer were detected. Study I is based on a 15-year follow up of the screening study. There was no significant difference in the risk of dying from prostate cancer between the source population and the invited group. The risk of dying from other diseases was however significantly increased among the non-attendees, with an IRR of 1.89 (95% CI 1.65-2.16), compared to the attendees.

In study II we evaluated the pre-diagnostic serum values of testosterone, dihydrotestosterone and SHBG influence on prostate cancer survival. Of the 65 men with screening detected prostate cancer, 41 died during follow up. 17 died of prostate cancer. Having a DHT value above median were associated with lower risk of dying from prostate cancer with a HR of = 0.24 (95% CI 0.08-0.75). We speculate that high DHT values lead to increased stimulation of the ERbeta-receptor which has antiproliferative properties.

Study III assesses suPAR as a prognostic marker of prostate cancer and longevity. We measured the serum level of two different forms of suPAR among 375 men of the screening cohort. Among these we included 63 of the screening detected prostate cancer cases. Neither suPAR (I-III) nor suPAR (II-III) were associated with prostate cancer mortality after adjustment for other prognostic factors. Both suPAR-forms were however associated with decreased overall survival with HR 2.26 (95% CI 1.17-4.35) for one unit increase of suPAR (I-III). The increase of overall survival was especially due to an increase in the risk of dying from cardiovascular disease. One unit increase of SuPAR (I-III) had a HR of 6.44 (95% CI 2.16-19.18).

Study IV Since low DHT level was associated with higher risk of prostate cancer death in study II, we wanted to explore if treatment with drugs lowering the DHT level (5-alpha-reductase inhibitors) would influence the risk of dying from PC. We used a prescription database to identify men prescribed 5-alpha-reductase inhibitors before diagnosis of prostate cancer. To compensate for lead time bias we also included men prescribed alpha-adrenoceptor antagonist for comparison. Treatment with 5-alpha-reductase inhibitors did not increase the risk of prostate cancer death (HR 0.94 (95% CI 0.77-1.16). However, treatment with alpha-adrenoceptor antagonist did significantly reduce the risk with HR 0.82 (95% CI 0.70-0.96). We also analyzed the risk of being diagnosed with metastasized prostate cancer with DDD of medicine as exposure variable. The OR for having metastasized disease at diagnosis was 1.14 (95% 1.01-1.29) per 100 DDD of finasteride treatment.