Low Risk Prostate Cancer and Active Surveillance

The first part of this thesis comprises an introduction to prostate cancer and screening (chapter 1). The European Randomized study of Screening for Prostate Cancer (ERSPC) has shown an effect of screening on prostate cancer mortality in favor of the screening population, however, controversies remain. One of the most important side-effects of screening is overdiagnosis with subsequent overtreatment, which has led to the introduction of active surveillance as an alternative to the radical treatment of prostate cancer (chapter 2). With active surveillance, patients with supposedly low-risk tumors receive expectant management and are strictly followed over time. In case of reclassification to higher risk or signs of true disease progression, the patient will switch to deferred radical treatment. Because active surveillance is a relatively new management strategy, its feasibility and the short-term outcomes are the main focus of this thesis (chapter 3). The second part of this thesis focuses on low-risk prostate cancer. In chapter 4 the main findings of the ERSPC are described and the controversial points in prostate cancer screening are discussed, as well as how these issues should be dealt with. Overdiagnosis and overtreatment are indicated as major worries, but less aggressive screening methods, risk modifying calculators and the use of active surveillance can decrease the impact of these side-effects and, if applied, will lead to a better risk-benefit ratio in screening. In chapter 5, it is shown that the risk of developing prostate cancer, aggressive prostate cancer and prostate cancer death in men with initial PSA values <3.0 ng/ml in the Rotterdam screening arm of the ERSPC increased with higher initial PSA levels. However, prostate cancer mortality in this cohort was relatively low, compared to men with initial levels >3.0 ng/ml (11-fold higher) and compared to the risk of other causes of death (150-fold higher). Especially men with PSA <1.0 ng/ml at first screen had a minimal risk to die from prostate cancer during an 11 year period. This finding supports the idea to prolong the screening interval to at least 8 years in this group. The overall outcomes of this study contribute to risk stratification and individual management of men in PSA-based screening programs. The long-term feasibility of expectant management as a proxy for active surveillance in contemporary practice is assessed in chapter 6 by evaluating outcomes of men with screen-detected localized prostate cancer who initially elected to withhold radical treatment for either low- or intermediate-risk disease. Although intermediate-risk men, by definition, had more unfavorable disease characteristics at diagnosis, their 10-year disease-specific survival rates did not differ from the low-risk group. The overall outcomes were favorable with a 98.4% disease-specific survival rate for the overall cohort, while radical treatment was avoided in a majority of cases. These results support the feasibility for active surveillance on the longer-term and even show that selected patients with intermediate-risk disease might profit from this strategy. In part three, chapter 7, an effort is made to calculate correction factors based on autopsy data for the use of the prostate cancer risk calculator in contemporary practice. The original risk calculator is based on sextant biopsies, while nowadays often more biopsy cores are taken. Adjustments correcting for this increase would lead to a more accurate prediction of the probability of indolent cancer. Correction factors for 12 and 18-core schemes were calculated; however, the small number of patients and the lack of validation hamper implementation of the results and reinforce the need for further study. Part four shows the results of the Prostate Cancer Research International: Active Surveillance (PRIAS) trial. Chapter 8 focuses on the outcome of the routinely obtained 1-year repeat biopsies and identifying prognosticators for unfavorable results. Risk reclassification to higher risk was found in 163 out of 757 (21.5%) repeat biopsies. The outcome was found to be significantly associated with the number of positive cores (2 vs. 1) and PSA density at diagnosis, as well as PSA doubling time at the time of repeat biopsy. Though reclassification is quite common and more likely due to misclassification than to actual disease progression, the relatively high rate emphasizes the difficulty of patient selection and the need for continued evaluation in active surveillance. Results of this study show that clinical features at baseline and during follow-up can be used in risk stratification of men for the prediction of unfavorable features at repeat biopsy. Radical prostatectomy results after initial active surveillance are described in chapter 9. The majority of men showed organ-confined disease and favorable Gleason grading (<3+4) in a majority of cases. Nevertheless, 29% (49/167) were found to have an unfavorable radical prostatectomy outcome. Since median time to surgery was quite short (1.3 years), it is likely that that most of the cases with unfavorable outcome were misclassified at diagnosis. More than 75% of this cohort switched to surgery based on a protocol recommendation, which may, at least in part, explain the relatively high rate of unfavorable findings due to the self-selection of men who start on active surveillance and receive surgery because of reclassification during follow-up. These results again show the importance of improvement in patient selection for active surveillance. Chapter 10 gives an up-to-date overview of the PRIAS study. Short-term data confirm the feasibility of active surveillance in the reduction of overtreatment and the use of a web-based tool to facilitate worldwide inclusion of patients. Clinical characteristics at baseline and PSA kinetics are again shown to be predictive for reclassification, as well as for switching to deferred treatment. The active therapy-free survival after 2 and 4 years was found to be 77.3% and 67.7%, respectively. The disease-specific survival rate was 100%, but follow-up is still too short to draw definitive conclusions. Finally, in chapter 11, an overview is presented of key issues in active surveillance that need to be tackled and emerging technologies and markers that will hopefully lead to optimization of patient selection and care in the near future. The fifth part of this thesis summarizes and discusses the key findings of the studies described in all previous chapters and puts them into perspective (chapter 12). The rationale for active surveillance and the feasibility of this strategy are discussed in more detail. An overview of contemporary active surveillance trials is presented and the areas of improvement are indicated. Eventually, a balance needs to be found between maximizing the number of patients who can avoid treatment and minimizing the number of aggressive prostate cancer missed. The improvement of screening strategies and developments in the technologies for radical treatment in the future might lead to decreased rates of overdiagnosis and virtual disappearance of side-effects, which in turn would reduce the need for active surveillance as an alternative to radical treatment. Until then, research aimed at improving active surveillance strategies will continue and we will carry on providing the best care available today to our patients.

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