Ramiro Castro

Is There Evidence of a Relationship between Benign Prostatic Hyperplasia and Prostate Cancer? Findings of a Literature Review

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.

Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management

Benign prostatic hyperplasia (BPH) is a complex disease that is progressive in many men. BPH is commonly associated with bothersome lower urinary tract symptoms; progressive disease can also result in complications such as acute urinary retention (AUR) and BPH‐related surgery. It is therefore important to identify men at increased risk of BPH progression to optimise therapy. Several factors are associated with progression, including age and prostate volume (PV). Serum prostate‐specific antigen level is closely correlated with PV, making it useful for determining the risk of BPH progression. Medical therapy is the most frequently used treatment for BPH. 5‐alpha‐reductase inhibitors impact the underlying disease and decrease PV; this results in improved symptoms, urinary flow and quality of life, and a reduced risk of AUR and BPH‐related surgery. Alpha‐blockers achieve rapid symptom relief but do not reduce the overall risk of AUR or BPH‐related surgery, presumably because they have no effect on PV. Combination therapy provides greater and more durable benefits than either monotherapy and is a recommended option in treatment guidelines. The Combination of Avodart® and Tamsulosin (CombAT) study is currently evaluating the combination of dutasteride with tamsulosin over 4 years in a population of men at increased risk of BPH progression. A preplanned 2‐year analysis has shown sustained symptom improvement with combination therapy, significantly greater than with either monotherapy. CombAT is also the first study to show benefit in improving BPH symptoms for combination therapy over the alpha‐blocker, tamsulosin, from 9 months of treatment.

The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT study.

BACKGROUND Knowledge of baseline factors that influence outcomes for men with benign prostatic hyperplasia (BPH) receiving medical therapy may help to improve outcomes and cost effectiveness. OBJECTIVES To examine the influence of baseline parameters on changes in International Prostate Symptom Score (IPSS) and maximum urinary flow rate (Q(max)) in men with BPH receiving dutasteride, tamsulosin, or a combination of the two using 2-yr Combination of Avodart and Tamsulosin (CombAT) study data. DESIGN, SETTING, AND PARTICIPANTS CombAT is an ongoing, 4-yr, multicentre, randomised, double-blind study in 4844 men aged >or=50 yr with clinical diagnosis of BPH, IPSS >or=12, prostate volume >or=30 cm(3), prostate-specific antigen (PSA) 1.5-10 ng/ml, and Q(max) >5 and <or=15 ml/s with minimum voided volume >or=125 ml. INTERVENTION Daily tamsulosin 0.4 mg, dutasteride 0.5 mg, or the combination. MEASUREMENTS Post hoc analyses of mean IPSS and Q(max) changes from baseline by treatment group and by baseline prostate volume, PSA, age, body mass index (BMI), IPSS, IPSS quality of life (QoL) score, BPH Impact Index score, Q(max), and previous BPH medical therapy. RESULTS AND LIMITATIONS Combination therapy was more effective than either monotherapy after 24 mo in improving IPSS in all baseline subgroups, with benefit onset varying by baseline prostate volume. Combination therapy was also more effective in improving Q(max) versus tamsulosin in all subgroups and versus dutasteride in 10 of 18 subgroups. At 24 mo, dutasteride monotherapy resulted in significantly greater IPSS improvements versus tamsulosin in men with lower age, worse symptoms, worse QoL, less bother, higher BMI, greater Q(max), higher prostate volume, and higher PSA at baseline. Post hoc analyses, the lack of placebo control, and the exclusion of men with unsuccessful medical BPH treatment are study limitations. CONCLUSIONS Combination therapy with tamsulosin and dutasteride affords the greatest and the most rapid symptomatic benefit among men with higher baseline prostate volume and is effective regardless of previous BPH medical therapy. Dutasteride monotherapy is more effective than tamsulosin in men with higher baseline prostate volume or PSA and worse symptoms.

The Effect of Dutasteride on the Usefulness of Prostate Specific Antigen for the Diagnosis of High Grade and Clinically Relevant Prostate Cancer in Men With a Previous Negative Biopsy: Results From the REDUCE Study

PURPOSE We assessed whether dutasteride enhances the usefulness of total prostate specific antigen for diagnosing clinically significant prostate cancer. MATERIALS AND METHODS The 4-year REDUCE study evaluated the efficacy and safety of 0.5 mg dutasteride daily for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative prostate biopsy. Specificity, sensitivity, and positive and negative predictive values of prostate specific antigen for the diagnosis of prostate cancer were assessed. RESULTS Final prostate specific antigen before biopsy and change from month 6 to final prostate specific antigen performed better for the diagnosis of Gleason score 7-10 tumors in men who received dutasteride vs placebo as assessed by the area under the ROC curves (0.700 vs 0.650, p = 0.0491; and 0.699 vs 0.593, p = 0.0001, respectively). Increases in prostate specific antigen were associated with a higher likelihood of biopsy detectable, Gleason score 7-10 and clinically significant (modified Epstein criteria) prostate cancer. Percentage decreases in prostate specific antigen from baseline to month 6 in the dutasteride arm did not predict prostate cancer overall or Gleason score 7-10 cancer. CONCLUSIONS In men with a previously negative prostate biopsy, prostate specific antigen performed better during the 4-year study as a marker of prostate cancer in men who received dutasteride vs placebo. The degree of prostate specific antigen increase after 6 months was a better indicator of clinically significant cancer in the dutasteride arm than in the placebo arm. Conversely, the initial decrease in prostate specific antigen in men taking dutasteride did not predict the likelihood of prostate cancer.

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: Lessons from the REDUCE study

Study Type – Prognostic (RCT)

Dutasteride Treatment Over 2 Years Delays Prostate-specific Antigen Progression in Patients with Biochemical Failure After Radical Therapy for Prostate Cancer: Results from the Randomised, Placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS)

BACKGROUND Rising prostate-specific antigen (PSA) levels after radical therapy are indicative of recurrent or residual prostate cancer (PCa). This biochemical recurrence typically predates clinically detectable metastatic disease by several years. Management of patients with biochemical recurrence is controversial. OBJECTIVE To assess the effect of dutasteride on progression of PCa in patients with biochemical failure after radical therapy. DESIGN, SETTING, AND PARTICIPANTS Randomised, double-blind, placebo-controlled trial in 294 men from 64 centres across 9 European countries. INTERVENTION The 5α-reductase inhibitor, dutasteride. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was time to PSA doubling from start of randomised treatment, analysed by log-rank test stratified by previous therapy and investigative-site cluster. Secondary end points included time to disease progression and the proportion of subjects with disease progression. RESULTS AND LIMITATIONS Of the 294 subjects randomised (147 in each treatment group), 187 (64%) completed 24 mo of treatment and 107 discontinued treatment prematurely (71 [48%] of the placebo group, 36 [24%] of the dutasteride group). Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment (p<0.001); the relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35-76.90) for the overall study period. Dutasteride also significantly delayed disease progression (which included PSA- and non-PSA-related outcomes) compared with placebo (p<0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53-75.09). The incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal were similar between the treatment groups. A limitation was that investigators were not blinded to PSA levels during the study. CONCLUSIONS Dutasteride delayed the biochemical progression of PCa in patients with biochemical failure after radical therapy for clinically localised disease. The safety and tolerability of dutasteride were generally consistent with previous experience. CLINICAL TRIAL REGISTRY ClinicalTrials.gov, NCT00558363.

Influence of baseline variables on changes in International Prostate Symptom Score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms: 4-year results of the CombAT study.

To examine, using post hoc analysis, the influence of baseline variables on changes in international prostate symptom score (IPSS), maximum urinary flow rate (Qmax) and IPSS quality of life (QoL) in patients with moderate‐to‐severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with either the α‐blocker tamsulosin or the dual 5‐alpha reductase inhibitor dutasteride, alone or in combination, as part of the 4‐year Combination of Avodart and Tamsulosin (CombAT) study.

Can benign prostatic hyperplasia be identified in the primary care setting using only simple tests? Results of the Diagnosis IMprovement in PrimAry Care Trial.

Aims:  Diagnosis IMprovement in PrimAry Care Trial (D‐IMPACT) was a prospective, multicentre epidemiological study in three European countries to identify the optimal subset of simple tests applied in primary care to diagnose benign prostatic hyperplasia (BPH) in men who spontaneously present with lower urinary tract symptoms (LUTS).

Predictors of pathological progression among men with localized prostate cancer undergoing active surveillance: a sub-analysis of the REDEEM study.

PURPOSE We identify risk factors for pathological progression among men on active surveillance in the REDEEM (REduction by Dutasteride of clinical progression Events in Expectant Management trial). MATERIALS AND METHODS REDEEM was a 3-year, randomized, double-blind study of patients in 65 North American academic centers. Eligible men were 48 to 82 years old, with low risk prostate cancer (T1c-T2a), Gleason score 6 or less, 3 or fewer cores positive, tumor less than 50% of any 1 core, serum prostate specific antigen 11 ng/ml or less, life expectancy greater than 5 years and undergoing active surveillance. Entry biopsies (10 cores or more) were required. The analysis included 276 patients with 1 biopsy or more after the start of study treatment. Patients received dutasteride 0.5 mg per day or placebo for 3 years. Time to pathological progression (volume [4 or more cores positive or 50% or greater of 1 core] or grade progression [Gleason score 7 or greater]) in a post-baseline biopsy (not preceded by therapeutic intervention), and baseline variables were analyzed using a Cox proportional hazard model. RESULTS In total 94 of 276 patients with a post-baseline biopsy (34.1%) had pathological progression, 54 (19.6%) had volume progression only, 19 (6.9%) had grade progression only and 21 (7.6%) had both types of progression. Older age (HR 1.05, 95% CI 1.01-1.08, p=0.009) and higher prostate specific antigen density (HR 1.06, 95% CI 1.04-1.09, p<0.001) were associated with pathological progression. Post-baseline prostate specific antigen identified grade, but not volume progression in patients treated with placebo and dutasteride. CONCLUSIONS Older age and higher prostate specific antigen density were independent predictors of pathological progression. Post-baseline measurements as predictors of pathological progression could not be established. Further studies are needed to evaluate the role of dutasteride and establish better markers of pathological progression in active surveillance.

Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study

To describe the Avodart after Radical Therapy for prostate cancer Study (ARTS), investigating the use of dutasteride (a dual 5α‐reductase inhibitor that suppresses intraprostatic dihydrotestosterone, reduces tumour volume and improves other markers of tumour regression in prostate cancer) to prevent or delay disease progression in patients with biochemical recurrence after therapy with curative intent.