Bul, M.

Low Risk Prostate Cancer and Active Surveillance (Doctoral Thesis)

2013-05-14T00:00:00Z

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.

Efficacy versus effectiveness study design within the European screening trial for prostate cancer: Consequences for cancer incidence, overall mortality and cancer-specific mortality (Article)

2012-09-01T00:00:00Z

Objective: To assess the impact of different study designs on outcome data within the European Randomized Study of Screening for Prostate Cancer (ERSPC). Methods: Observed data from the Gothenburg centre (effectiveness trial with upfront randomization before informed consent) and the Rotterdam centre (efficacy trial with randomization after informed consent) were compared with expected data, which were retrieved from national cancer registries and life tables. Endpoints were 11-year cumulative prostate cancer (PC) incidence, overall mortality and PC-specific mortality. Results: In Gothenburg, the 11-year PC incidence was higher than predicted (5.8%) in both the intervention (12.4%) and control arms (7.3%). The observed overall mortality was higher than predicted (15.9%) in both the intervention (17.8%) and control arms (18.5%). The observed PC-specific mortality in the intervention arm was 0.56% versus 0.83% in the control arm, while the expected mortality was 0.83%. In Rotterdam, the observed PC incidence in the intervention arm (10.4%) was higher than expected (4.4%). The incidence in the control arm was 4.6%. The observed overall mortality was lower than expected: 13.6% in the intervention arm and 14.0% in the control arm versus an expected mortality of 16.1%. The observed PC-specific mortality was lower than expected (0.65%) in both the intervention (0.27%) and control arms (0.41%). Conclusions: Our results suggest that an efficacy trial with informed consent prior to randomization may have introduced a 'healthy screenee bias'. Therefore, an effectiveness trial with consent after randomization may more accurately estimate the PC-specific mortality reduction if population-based screening is introduced.

Prediction of prostate cancer risk: The role of prostate volume and digital rectal examination in the ERSPC risk calculators (Article)

2012-03-01T00:00:00Z

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators (RCs) are validated tools for prostate cancer (PCa) risk assessment and include prostate volume (PV) data from transrectal ultrasound (TRUS). Objective: Develop and validate an RC based on digital rectal examination (DRE) that circumvents the need for TRUS but still includes information on PV. Design, setting, and participants: For development of the DRE-based RC, we studied the original ERSPC Rotterdam RC population including 3624 men (885 PCa cases) and 2896 men (547 PCa cases) detected at first and repeat screening 4 yr later, respectively. A validation cohort consisted of 322 men, screened in 2010-2011 as participants in ERSPC Rotterdam. Measurements: Data on TRUS-assessed PV in the development cohorts were re-coded into three categories (25, 40, and 60 cm3) to assess the loss of information by categorization of volume information. New RCs including PSA, DRE, and PV categories (DRE-based RC) were developed for men with and without a previous negative biopsy to predict overall and clinically significant PCa (high-grade [HG] PCa) defined as T stage >T2b and/or Gleason score ≥7. Predictive accuracy was quantified by the area under the receiver operating curve. We compared performance with the Prostate Cancer Prevention Trial (PCPT) RC in the validation study. Results and limitations: Areas under the curve (AUC) of prostate-specific antigen (PSA) alone, PSA and DRE, the DRE-based RC, and the original ERSPC RC to predict PCa at initial biopsy were 0.69, 0.73, 0.77, and 0.79, respectively. The corresponding AUCs for predicting HG PCa were higher (0.74, 0.82, 0.85, and 0.86). Similar results were seen in men previously biopsied and in the validation cohort. The DRE-based RC outperformed the PCPT RC (AUC 0.69 vs 0.59; p = 0.0001) and a model based on PSA and DRE only (AUC 0.69 vs 0.63; p = 0.0075) in the relatively small validation cohort. Further validation is required. Conclusions: An RC should contain volume estimates based either on TRUS or DRE. Replacing TRUS measurements by DRE estimates may enhance implementation in the daily practice of urologists and general practitioners.

Towards an optimal interval for prostate cancer screening (Article)

2012-01-01T00:00:00Z

Background: The rate of decrease in advanced cancers is an estimate for determining prostate cancer (PCa) screening program effectiveness. Objective: Assess the effectiveness of PCa screening programs using a 2- or 4-yr screening interval. Design, setting, and participants: Men aged 55-64 yr were participants at two centers of the European Randomized Study of Screening for Prostate Cancer: Gothenburg, Sweden (2-yr screening interval, n = 4202), and Rotterdam, the Netherlands (4-yr screening interval, n = 13 301). We followed participants until the date of PCa, the date of death, or the last follow-up at December 31, 2008, or up to a maximum of 12 yr after initial screening. Potentially life-threatening (advanced) cancer was defined as cancer with at least one of following characteristics: clinical stage ≥T3a, M1, or N1; serum prostate-specific antigen (PSA) >20.0 ng/ml; or Gleason score ≥8 at biopsy. Intervention: We compared the proportional total (advanced) cancer incidence (screen-detected and interval cases), defined as the ratio of the observed number of (advanced) cancers to the expected numbers of (advanced) cancers based on the control arm of the study. Measurements: The proportional cancer incidence from the second screening round until the end of observation was compared using a 2- or 4-yr screening interval. Results and limitations: From screening round 2 until the end of observation, the proportional cancer incidence was 3.64 in Gothenburg and 3.08 in Rotterdam (relative risk [RR]: 1.18; 95% confidence interval [CI], 1.04-1.33; p = 0.009). The proportional advanced cancer incidence was 0.40 in Gothenburg and 0.69 in Rotterdam (RR: 0.57; 95% CI, 0.33-0.99; p = 0.048); the RR for detection of low-risk PCa was 1.46 (95% CI, 1.25-1.71; p < 0.001). This study was limited by the assumption that PSA testing in the control arm was similar in both centers. Conclusions: A 2-yr screening interval significantly reduced the incidence of advanced PCa; however, the 2-yr interval increased the overall risk of being diagnosed with (low-risk) PCa compared with a 4-yr interval in men aged 55-64 yr. Individualized screening algorithms must be improved to provide the strategy for this issue.

Re: Disease-specific survival of men with prostate cancer detected during the screening interval: Results of the european randomized study of screening for prostate cancerrotterdam after 11 years of follow-up (Article)

2011-11-01T00:00:00Z

Disease-specific survival of men with prostate cancer detected during the screening interval: Results of the European Randomized Study of Screening for Prostate Cancer-Rotterdam after 11 years of follow-up (Article)

2011-08-01T00:00:00Z

Background: In a screening program, interval cancers are cancers diagnosed between two screening visits. Objective: To assess the disease-specific survival (DSS) of men with prostate cancer (PCa) detected during the screening interval. Design, setting, and participants: Within the European Randomized Study of Screening for Prostate Cancer section Rotterdam, 42 376 men identified from population registries (55-74 yr of age) were randomized to a screening or control arm. The median follow-up was 11 yr. Intervention: Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant biopsy. The screening interval was 4 yr. Measurements: The disease-specific mortality of men with interval cancers was compared with that of men with PCa in the control arm; the secondary end point was overall mortality. An independent committee determined the causes of death. Results and limitations: In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, the corresponding numbers were 1149 and 128, respectively. When comparing men with interval cancer to men with PCa in the control arm, no statistically significant difference in disease-specific mortality (hazard ratio [HR]:1.12; 95% confidence interval [CI], 0.53-2.36; p = 0.77) and overall mortality (HR: 0.98; 95% CI, 0.68-1.38; p = 0.90) was found, adjusted for age, prognostic factors, and treatment modality. The follow-up is too limited to address the difference in DSS stratified for screening interval. Conclusions: In the setting of population-based PCa screening at 4-yr intervals, the DSS of men with interval cancer seems to be similar to that of men with PCa in the control arm. Given that interval cancers contribute significantly to PCa mortality, further benefit in DSS in the screening arm may be achieved by decreasing the occurrence of interval cancer. However, the balance between mortality reduction and overdiagnosis should be preserved. Trial registration: ISRCTN49127736.

Disease-specific survival of men with prostate cancer detected during the screening interval: Results of the European Randomized Study of Screening for Prostate Cancer-Rotterdam after 11 years of follow-up (Article)

2011-08-01T00:00:00Z

Screening for prostate cancer-The controversy continues, but can it be resolved? (Article)

2011-06-01T00:00:00Z

Background. In 2009, the European Randomized Study of Screening for Prostate Cancer (ERSPC) was one of two studies to report interim data on the effect of screening for prostate cancer (PC) on the disease specific mortality. Contradictory results caused considerable discussion and misunderstanding in secondary literature. Methods. This document is based on a non systematic review of recent evidence for and against screening for PC, specifically considering three recently published randomized screening trials [1â€"3]. Results. The ERSPC data are based on a core age group of 162 387 men, aged 55â€"69 years, who were identified through population registries in seven European countries. Men were randomized between a screening group that received screening at an average of once every four years and a control group. After a median follow-up of nine years, a reduction in the rate of death from PC by 20% was shown which increased to 31% after adjusting for non-compliance and contamination. Overdetection and subsequent overtreatment (with a number needed to treat (NNT) of 48) are considered to be the major down sides of screening. The recently published 14-year results have shown that these down sides strongly depend on the duration of follow-up. In response to the outcomes of the ERSPC, several points of discussion have been brought up by various authors concerning the usefulness of screening considering benefits, harms and costs, the methodology of the ERSPC and the interpretation of its outcomes. Important issues to address regarding PC screening are addressed. Conclusions. This paper sheds a light on the controversial points of the ERSPC as well as on the priority issues of PC screening. On July 2, 2010 the Swedish section of ERSPC (Göteborg screening trial) published their results with a median follow-up of 14 years. With longer follow-up the data confirm the trend seen in improvement of PC mortality and suggest much more favorable future outcomes also with respect to the NNT to prevent one PC death.

Identifying and characterizing "escapes"-men who develop metastases or die from prostate cancer despite screening (ERSPC, section Rotterdam) (Article)

2011-04-06T00:00:00Z

We aim to identify and characterize "escapes," men who developed metastasis and/or died from prostate cancer (PCa) despite screening, in the framework of the novel international ESCAPE-project. With this knowledge, the ultimate goal is to improve screening strategy. In this article, we focus on the study cohort of the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. In all, 21,210 men were randomized to the screening arm of whom 19,950 were actually screened. The screening interval was 4 years. Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant prostate biopsy. The follow-up was complete until January 1, 2009. Of 19,950 screened men, 2,317 were diagnosed with PCa. Of these cancers 1,946 were detected in a screening round and 371 during an interval. The median follow-up was 11.1 years for the whole cohort and 7.3 years for men diagnosed with PCa. In total, we identified 168 escapes among 2,317 cancers (7.3%) within our screening cohort of 19,950 men (0.8%). More than half of these escapes were found in the initial screening round (94 of 168). Possible mechanisms behind escaping are nonattending, inadequate screening tests, the relative long screening interval, the age cut-off at 75 years, and undertreatment. International cooperation is crucial to compare the escapes of our cohort with other study groups participating in the ESCAPE-project which have different, more aggressive screening strategies. Subsequently, we can achieve improvements of the current screening algorithm, which hopefully will further decrease PCa-specific mortality without increasing overdiagnosis and overtreatment. Copyright

Prostate Cancer Incidence and Disease-Specific Survival of Men with Initial Prostate-Specific Antigen Less Than 3.0 ng/ml Who Are Participating in ERSPC Rotterdam (Article)

2011-04-01T00:00:00Z

Background: The European Randomised Study of Screening for Prostate Cancer (ERSPC) applies a prostate-specific antigen (PSA) cut-off value ≥3.0 ng/ml as an indication for lateralised sextant biopsy. Objective: To analyse the incidence and disease-specific mortality for prostate cancer (PCa) in men with an initial PSA <3.0 ng/ml. Design, setting and participants: From November 1993 to December 1999, a total of 42 376 men identified from population registries in the Rotterdam region (55-74 yr of age) were randomised to an intervention or control arm. A total of 19 950 men were screened during the first screening round. Intervention: A PSA <3.0 ng/ml was below the biopsy threshold. PCa cases were identified at rescreens every 4 yr or as interval cancers. Measurements: Distribution of incidence, aggressiveness, and disease-specific mortality of PCa per PSA range was measured. Causes of death were evaluated by an independent committee, and follow-up was complete until 31 December 2008. Results and limitations: From 1993 to 2008, 915 PCa cases were diagnosed in 15 758 men (5.8%) with an initial PSA <3.0 ng/ml and a median age of 62.3 yr. Median overall follow-up was 11 yr. PCa incidence increased significantly with higher initial PSA levels. Aggressive PCa (clinical stage ≥T2c, Gleason score ≥8, PSA >20 ng/ml, positive lymph nodes, or metastases at diagnosis) was detected in 66 of 733 screen-detected PCa cases (9.0%) and 72 of 182 interval-detected PCa cases (39.6%). Twenty-three PCa deaths occurred in the total population (0.15%), with an increasing risk of PCa mortality in men with higher initial PSA values. Conclusions: The risk of PCa, aggressive PCa and PCa mortality in a screening population with initial PSA <3.0 ng/ml increases significantly with higher initial PSA levels. These results contribute to the risk stratification and individual management of men in PSA-based screening programmes.