Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed ...serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.
Abstract Background The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with ...prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality. Design, setting, and participants Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis. Outcome measurements and statistical analysis Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis. Results and limitations In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03–2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16–1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89–1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52–0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller. Conclusions The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr. Patient summary The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer.
Abstract Background Until now the therapeutic value of lymphadenectomy for renal-cell carcinoma has remained controversial. Several studies attempting to solve this controversy have been published, ...but none of them were set up as prospective randomized trials. Objective To assess whether a complete lymph-node dissection in conjunction with a radical nephrectomy for renal-cell cancer is more effective than a radical nephrectomy alone. Design, setting, and participants In 1988, the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group started a randomized phase 3 trial comparing radical nephrectomy with a complete lymphadenectomy to radical nephrectomy alone. After the renal-cell carcinoma was judged to be N0M0 and resectable, patients were randomly selected prior to surgery to undergo either a radical nephrectomy with a complete lymph-node dissection or to undergo a radical nephrectomy alone. Postoperatively all patients were followed for progression of disease and mortality. Intervention All patients underwent a radical nephrectomy with or without a complete lymph-node dissection. Measurements All patients were postoperatively evaluated for time-to-progression, overall survival, and progression-free survival. Time-to-event curves were estimated based on the Kaplan-Meier method and compared using a two-sided log-rank test. Results and limitations Of the 772 patients selected for randomization, 40 were not eligible for the study. 383 patients were randomly selected to receive a complete lymph-node dissection together with a radical nephrectomy, and 389 patients were randomly selected to undergo a radical nephrectomy alone. The complication rate did not differ significantly between the two groups. Complete lymph-node dissections in 346 patients revealed an absence of lymph-node metastases in 332 patients. The study revealed no significant differences in overall survival, time to progression of disease, or progression-free survival between the two study groups. Conclusions This study shows that, after proper preoperative staging, the incidence of unsuspected lymph-node metastases is low (4.0%) and that, notwithstanding a possible relationship to this low incidence rate, no survival advantage of a complete lymph-node dissection in conjunction with a radical nephrectomy could be demonstrated.
Abstract Background Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. Objective To assess the effect of screening for PCa on the incidence of ...metastatic disease in a randomized trial. Design, setting, and participants Data were available for 76 813 men aged 55–69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. Intervention Regular screening based on serum PSA measurements was offered to 36 270 men randomized to the screening arm, while no screening was provided to the 40 543 men in the control arm. Outcome measurements and statistical analysis The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. Results and limitations After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively ( p < 0.001). This finding translated into a relative reduction of 30% (hazard ratio HR: 0.70; 95% confidence interval CI, 0.60–0.82; p = 0.001) in the intention-to-screen analysis and a 42% ( p = 0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41–0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. Conclusions PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.
Abstract 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.
The randomized controlled European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 studied the effect of radiotherapy after prostatectomy in patients with adverse risk factors. ...Review pathology data of specimens from participants in this trial were analyzed to identify which factors predict increased benefit from adjuvant radiotherapy.
After prostatectomy, 1,005 patients with stage pT3 and/or positive surgical margins were randomly assigned to a wait-and-see (n = 503) and an adjuvant radiotherapy (60 Gy conventional irradiation) arm (n = 502). Pathologic review data were available for 552 patients from 11 participating centers. The interaction between the review pathology characteristics and treatment benefit was assessed by log-rank test for heterogeneity (P < .05).
Margin status assessed by review pathology was the strongest predictor of prolonged biochemical disease-free survival with immediate postoperative radiotherapy (heterogeneity, P < .01): by year 5, immediate postoperative irradiation could prevent 291 events/1,000 patients with positive margins versus 88 events/1,000 patients with negative margins. The hazard ratio for immediate irradiation was 0.38 (95% CI, 0.26 to 0.54) and 0.88 (95% CI, 0.53 to 1.46) in the groups with positive and negative margins, respectively. We could not identify a significant impact of the positive margin localization.
Provided careful pathology of the prostatectomy is performed, our results suggest that immediate postoperative radiotherapy might not be recommended for prostate cancer patients with negative surgical margins. These findings require validation on an independent data set.
Study Type – Therapy (outcomes)
Level of Evidence 2b
What's known on the subject? and What does the study add?
Active surveillance aims to reduce overtreatment by selecting patients with low risk ...prostate cancer (PCa) based on favourable disease characteristics. However, most studies on active surveillance do not have long‐term results available; in particular, data on patients with intermediate risk disease are lacking.
Our findings demonstrate that withholding radical treatment in men with low or intermediate risk screen‐detected localized PCa leads to a substantial delay or even avoidance of radical treatment in a majority of men. Favourable disease‐specific outcomes confirm the feasibility of active surveillance for low risk PCa and also support a role for active surveillance in selected patients with intermediate risk PCa.
OBJECTIVE
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To assess the longer‐term feasibility of active surveillance, we aimed to evaluate outcomes of patients with screen‐detected localized prostate cancer (PCa) who initially elected to withhold radical treatment for either low or intermediate risk disease.
PATIENTS AND METHODS
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All men underwent screening for PCa in the Rotterdam and Helsinki arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC); eligible men were diagnosed with PCa prior to the establishment of the ERSPC‐affiliated Prostate Cancer Research International: Active Surveillance (PRIAS) study (1994–2007) and were initially expectantly managed in the absence of a fixed follow‐up protocol.
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Low risk PCa was defined as clinical stage T1/T2, PSA ≤ 10 ng/mL, PSA density < 0.2 ng/mL/mL, Gleason ≤ 6 and maximum two positive biopsy cores, whereas PSA 10–20 ng/mL, Gleason score 7 and three positive biopsy cores were considered intermediate risk features.
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Disease‐specific, overall and treatment‐free survival were analysed using the Kaplan–Meier and competing risks methods.
RESULTS
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In all, 509 patients with PCa were eligible, of whom 381 were considered low risk and 128 intermediate risk.
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During a median follow‐up of 7.4 years, a total of 221 patients (43.4%) switched to deferred treatment after a median of 2.6 years.
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The calculated 10‐year disease‐specific survival rates were 99.1% and 96.1% for low and intermediate risk patients, respectively (P= 0.44), and for overall survival 79.0% and 64.5%, respectively (P= 0.003).
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Competing risks analysis showed similar results.
CONCLUSIONS
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Withholding radical treatment in men with low to intermediate risk screen‐detected PCa leads to a substantial delay or even avoidance of radical treatment and its potential side‐effects in a majority of patients.
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Disease‐specific outcomes at 7.4 years of follow‐up are favourable in low as well as intermediate risk patients.
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This confirms the feasibility of active surveillance according to contemporary criteria, and also suggests a potential role for active surveillance in selected men with intermediate risk features.
Abstract Context More than half the male population aged >50 yr have histologic evidence of benign prostatic hyperplasia (BPH), while prostate cancer (PCa) is among the most common male cancers ...according to recent registry data. Understanding the aetiologies of both conditions is crucial to reduce the resulting burden of mortality and morbidity. Objective This review aims to examine the available data on the epidemiology, pathology, risk factors, and genetic markers involved in BPH and PCa; to discuss their clinical implications for management of both conditions; and to discuss their implications for PCa prevention. Our primary objective was to clarify the relationship between BPH and PCa by bringing together evidence from diverse areas of research. Evidence acquisition The primary source of data was PubMed, which was searched using Boolean strategies and by scanning lists of related articles. We also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses. Evidence synthesis Accumulating evidence suggests that BPH and PCa share important anatomic, pathologic, and genetic links in addition to the well-established epidemiologic association between these conditions. We also found data that suggest interactions between apparently diverse factors, such as dihydrotestosterone levels and inflammation. Recent publications support the hypothesis that both BPH and PCa are part of the metabolic syndrome, while inflammation is emerging as a major contributor to the development of both BPH and PCa. Although many of the findings are preliminary and require further research, they offer new insight into the mechanisms of disease underlying the development of BPH and PCa. Conclusions Available data suggest that epidemiologic and pathologic links exist between BPH and PCa. Evidence of links between the conditions and contributory factors may offer common preventative strategies for BPH and PCa and common therapeutic approaches to their management.
The USPSTF's grade D recommendation contradicts the common view that PSA screening saves lives by reducing the risk of death from prostate cancer. Decisions about screening should be made by informed ...patients and their clinicians, weighing particular risk factors.
On October 11, 2011, the U.S. Preventive Services Task Force (USPSTF) issued a draft report on prostate specific antigen (PSA)–based screening for prostate cancer, giving it a grade D recommendation. Grade D means that “the USPSTF recommends against the service” because it has concluded that “there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.”
This recommendation contradicts the view that PSA-based screening saves lives by reducing the risk of death from prostate cancer. The task force acknowledges that “clinical decisions involve more considerations than evidence alone” and that “clinicians . . .
Summary Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer ...opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.
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