The effects of 5alpha-reductase inhibitors on the natural history, detection and grading of prostate cancer: current state of knowledge

PURPOSE: The Prostate Cancer Prevention Trial (PCPT) showed that the 5alpha-reductase inhibitor (5ARI) finasteride significantly decreased the 7-year period prevalence of prostate cancer vs placebo. However, Gleason score 7-10 tumors were significantly more common in the finasteride vs the placebo group. We considered data on the effects of 5ARIs on prostate cancer natural history and detection. MATERIALS AND METHODS: A detailed review was performed of the literature identified from the MEDLINE database examining the effects of 5ARIs on prostate cancer prevalence and tumor histopathology. RESULTS: In PCPT there were fewer biopsies performed for cause in the finasteride vs the placebo group and the proportion of high grade tumors in the treatment groups did not diverge with time. Given that finasteride has an effect on prostate specific antigen and prostate volume, which are key factors in triggering prostate biopsies, they may be significant confounders of Gleason score results. Prostate shrinkage in the finasteride treated group may minimize biopsy sampling error. Furthermore, histological studies have shown that 5ARIs have a significant effect on prostate architecture, which can make the interpretation of prostate specimens in men treated with 5ARIs difficult. Further evaluation of PCPT findings will help determine the true nature of these observations. CONCLUSIONS: 5ARIs decrease the risk of prostate cancer but also alter the detection of disease through effects on prostate specific antigen, and prostate volume and histology. The weight of evidence suggests an artifactual effect of finasteride on Gleason grading in the PCPT. The role of 5ARIs for prostate cancer chemoprevention needs further examination before it can be considered for wide recommendation.     

The interpretation of serum prostate specific antigen in men receiving 5alpha-reductase inhibitors: a review and clinical recommendations

PURPOSE: We reviewed the effects of 5alpha-reductase inhibitors on prostate specific antigen and clarified the adjustments that should be made to compensate for these effects to ensure that the usefulness of prostate specific antigen for detecting prostate cancer is maintained. MATERIALS AND METHODS: We reviewed articles published in the scientific literature with relevance to the effects of 5alpha-reductase inhibitors on the usefulness of prostate specific antigen for detecting prostate cancer. RESULTS: A total serum prostate specific antigen of 4.0 ng/ml has traditionally been used as the threshold for triggering prostate biopsy. However, clinical trials of finasteride and dutasteride have shown that 5alpha-reductase inhibitors decrease serum prostate specific antigen in patients with and without prostate cancer. To compensate, the doubling rule has been applied in clinical trials and clinical practice. However, doubling serum prostate specific antigen may overestimate actual prostate specific antigen in some patients receiving 5alpha-reductase inhibitors for up to 6 to 9 months, accurately estimate prostate specific antigen from 1 to 3 years and underestimate it thereafter. An increase in prostate specific antigen of 0.3 ng/ml from nadir as a trigger for biopsy maintains 71% sensitivity for prostate cancer in men receiving dutasteride with 60% specificity, similar to the 4.0 ng/ml prostate specific antigen cutoff using placebo. CONCLUSIONS: We propose that a prostate specific antigen increase from nadir of 0.3 ng/ml or greater could represent an alternative to the doubling rule for monitoring prostate specific antigen in patients on 5alpha-reductase inhibitors. The prostate specific antigen increase from nadir appears to be a more accurate cancer indicator than a doubled value in some patients.     

Improved prediction of disease relapse after radical prostatectomy through a panel of preoperative blood-based biomarkers.

PURPOSE: The preoperative blood levels of biomarkers may allow accurate identification of patients who are likely to fail radical prostatectomy as a first-line therapy for localized prostate cancer, thereby allowing more efficient delivery of neoadjuvant and adjuvant therapy. The aim of this study was to determine the added value of biomarkers relative to established predictors of biochemical recurrence, such as clinical stage, biopsy Gleason sum, and preoperative prostate-specific antigen. EXPERIMENTAL DESIGN: The preoperative plasma levels of transforming growth factor-beta1 (TGF-beta1), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), vascular endothelial growth factor (VEGF), vascular cell adhesion molecule-1 (VCAM-1), endoglin, urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor were measured with the use of commercially available enzyme immunoassays in 423 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostate cancer. Multivariable models were used to explore the gain in the predictive accuracy of the models. This predictive accuracy was quantified by the concordance index statistic and was validated with 200 bootstrap resamples. RESULTS: In standard multivariable analyses, TGF-beta1 (P < 0.001), sIL-6R (P < 0.001), IL-6 (P < 0.001), VCAM-1 (P < 0.001), VEGF (P = 0.008), endoglin (P = 0.002), and uPA (P < 0.001) were associated with biochemical recurrence. The multivariable model containing standard clinical variables alone had an accuracy of 71.6%. The addition of TGF-beta1, sIL-6R, IL-6, VCAM-1, VEGF, endoglin, and uPA increased the predictive accuracy by 15% to 86.6% (P < 0.001) and showed excellent calibration. CONCLUSIONS: A nomogram based on these biomarkers improves the accuracy of standard predictive models and could help counsel patients about their risk of biochemical recurrence following radical prostatectomy.     

Long-term patient survival after cystectomy for regional metastatic transitional cell carcinoma of the bladder

The records of 280 patients who underwent pelvic lymphadenectomy and radical cystectomy for transitional cell carcinoma of the bladder between 1971 and 1986 were reviewed. A total of 42 patients had either 1 (stage pN1) or more than 1 (stage pN2) positive lymph nodes (20 and 22 patients, respectively). The over-all 3-year survival rate for patients with positive lymph nodes was 27%, and it was 30 and 18.5% for stages pN1 and pN2 disease, respectively. Kaplan-Meier survival curves revealed a sustained survival advantage for stage pN1 over pN2 disease for the first 3 years (p less than 0.05) but the difference was not significant at 5 years of followup. Eleven patients with negative lymph nodes but local extension of tumor into the prostatic stroma and/or ducts had a 5-year survival rate of 36%, which equaled the survival of 49 stage pT3b,pN0 cancer patients in the same series. Surgical mortality for the entire population of 280 patients was 2.1% and there was no increase in mortality or morbidity among the node positive patients. Based on the findings of improved survival of stages pN1 and pT3b,N0 cancer patients compared to stage pN2 cancer patients, the tumor, nodes and metastasis classification offers more specific prognostic information than does a single designation of Jewett stage D disease.     

The progression of benign prostatic hyperplasia: examining the evidence and determining the risk

BACKGROUND: Benign prostatic hyperplasia (BPH) is often associated with enlargement of the prostate gland, lower urinary tract symptoms, decreased urinary flow and a reduced quality of life. Furthermore, if the symptoms associated with BPH are left untreated, serious complications, such as acute urinary retention, may ensue. Evidence is emerging from long-term clinical studies to suggest that BPH is a progressive disease, with some patients progressing much more rapidly than others. OBJECTIVE: This article aims to explore the natural history of BPH progression from a molecular, pathological and clinical perspective, with emphasis on the key clinical evidence to support the progressive nature of this disease. How our increased understanding of the disease and of the risk factors for BPH progression might be applied to improve current management practices are also discussed. CONCLUSION: Strategies to identify patients most at risk and guidelines directed towards long-term management, in addition to short-term treatment, may be useful in helping to prevent BPH progression.     

Efficacy and safety of once-daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a randomized, placebo-controlled trial

Objectives. To assess the efficacy and safety, and determine the optimal dosage, of a once-daily (OD) formulation of the clinically uroselective alpha₁-blocker, alfuzosin, in patients with lower urinary tract symptoms and symptomatic benign prostatic hyperplasia.Methods. Five hundred thirty-six patients were randomized to receive alfuzosin (10 mg OD or 15 mg OD), without initial dose titration, or placebo in a 3-month double-blind trial conducted in North America. The primary efficacy criteria were improvement in symptoms (International Prostate Symptom Score) and peak urinary flow rate.Results. Alfuzosin was significantly more effective than placebo in improving the symptoms and peak urinary flow rate from the first follow-up visit (day 28). The mean change in the International Prostate Symptom Score from baseline at endpoint was −3.6 and −3.4 with alfuzosin 10 mg and 15 mg, respectively, compared with −1.6 with placebo (alfuzosin 10 mg versus placebo, P = 0.001; alfuzosin 15 mg versus placebo, P = 0.004). The median increase in the peak urinary flow rate was +1.1 mL/s and +1.0 mL/s with alfuzosin 10 mg and 15 mg, respectively, compared with 0.0 mL/s with placebo (P = 0.0006 versus placebo for both dose groups). The patients’ quality of life also significantly improved with both alfuzosin doses. Overall, alfuzosin at both doses was well tolerated. The incidence of orthostatic hypotension as determined by systematic blood pressure measurements with both doses of alfuzosin was similar to placebo. No clinically relevant ejaculation disorders were observed with alfuzosin.Conclusions. Alfuzosin 10 mg OD, administered without dose titration, provides effective relief from the symptoms of benign prostatic hyperplasia with no additional benefit from a 15-mg dose. It is well tolerated from a cardiovascular viewpoint and is not associated with abnormal ejaculation.     

Association of overactive bladder and C-reactive protein levels. Results from the Boston Area Community Health (BACH) Survey

Study Type – Aetiology (cohort) Level of Evidence 3a What's known on the subject? and What does the study add? Evidence of chronic inflammation in benign prostatic hyperplasia suggests a role of inflammation in the development of lower urinary tract symptoms. However, few studies have investigated the association of inflammation and overactive bladder in both men and women. Results of this population‐based study show a consistent association of increased C‐reactive protein levels with overactive bladder in both men and women. These results support the hypothesized role of inflammation in the development of overactive bladder.

OBJECTIVE

• ? To investigate the association between overactive bladder (OAB) and C‐reactive protein (CRP) in a population‐based sample of men and women.

SUBJECTS AND METHODS

• ? Epidemiological survey of urological symptoms among men and women aged 30–79 years. A multi‐stage stratified cluster design was used to randomly sample 5503 adults from the city of Boston. Analyses were conducted on 1898 men and 1854 women with available CRP levels.
• ? The International Continence Society defines OAB as ‘Urgency with or without urge incontinence, usually with frequency and nocturia.’ OAB was defined as: (1) urgency, (2) urgency with frequency, and (3) urgency with frequency and nocturia.
• ? Odds ratios (OR) and 95% confidence intervals (95% CI) of the CRP and OAB association were estimated using logistic regression.

RESULTS

• ? Prevalence of OAB increased with CRP levels in both men and women.
• ? In men, adjusted ORs (95% CI) per log₁₀(CRP) levels were 1.90 (1.26–2.86) with OAB defined as urgency, 1.65 (1.06–2.58) with OAB defined as urgency and frequency, and 1.92 (1.13–3.28) with OAB defined as urgency, frequency and nocturia.
• ? The association was more modest in women with ORs (95% CI) of 1.53 (1.07–2.18) for OAB as defined urgency, 1.51 (1.02–2.23) for OAB defined as urgency and frequency, and 1.34 (0.85–2.12) for OAB defined as urgency, frequency and nocturia.

CONCLUSIONS

• ? Results show a consistent association of increasing CRP levels and OAB among both men and women.
• ? These results support our hypothesis for the role of inflammation in the development of OAB and a possible role for anti‐inflammatory agents in its treatment.

     

Ultrasonography of the kidney

Summary Office-based renal sonography provides the urologist with cost-effective and noninvasive means of imaging the upper urinary tract. A majority of transrectal sonography units currently on the market can be easily adapted to transabdominal use by the purchase of one additional transducer. This enables the urologist to rule out hydronephrosis sonographically and to follow patients with known upper-tract disease who have previously undergone radiographic studies. In contrast, the differential diagnosis of upper-tract mass lesions requires a much more advanced level of training and experience. For patients at low risk of developing renal tumor, e.g., patients with BPH, renal ultrasound should replace contrast-enhanced imaging studies.