Karen M. Jones

Radical Prostatectomy versus Observation for Localized Prostate Cancer

BACKGROUND The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. RESULTS During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. CONCLUSIONS Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.).

Benign Prostatic Hyperplasia Specific Health Status Measures in Clinical Research: How Much Change in the American Urological Association Symptom Index and the Benign Prostatic Hyperplasia Impact Index is Perceptible to Patients?

PURPOSE We assessed the relationship between changes in scores for the American Urological Association (AUA) symptom index and benign prostatic hyperplasia (BPH) impact index with patient global ratings of improvement in a large Veterans Affairs trial comparing different pharmacological therapies for BPH. MATERIALS AND METHODS The primary analyses compared absolute score changes from baseline with global ratings of improvement at 13 weeks for 1,218 men. RESULTS Subjects who rated themselves as being slightly improved had a mean decrease in AUA symptom index and BPH impact index scores of 3.1 and 0.4 points, respectively. However, the baseline scores strongly influenced this relationship. CONCLUSIONS These data provide guidance for investigators using the AUA symptom index and BPH impact index as outcome measures.

The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer ☆

BACKGROUND Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. Ninety percent of men with prostate cancer are over aged 60 years, diagnosed by early detection with the prostate specific antigen (PSA) blood test and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting surgery to remove the prostate gland (radical prostatectomy), external beam radiation therapy and interstitial radiation therapy (brachytherapy) and androgen deprivation. Little is known about the relative effectiveness and harms of treatments due to the paucity of randomized controlled trials. The VA/NCI/AHRQ Cooperative Studies Program Study #407: Prostate cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy to watchful waiting in men with clinically localized prostate cancer. METHODS We describe the study rationale, design, recruitment methods and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy versus watchful waiting conducted in Scandinavia. RESULTS We screened 13,022 men with prostate cancer at 52 United States medical centers for potential enrollment. From these, 5023 met initial age, comorbidity and disease eligibility criteria and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African-American. Approximately 85% reported they were fully active. The median prostate specific antigen (PSA) was 7.8 ng/mL (mean 10.2 ng/mL). In three-fourths of men the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade and tumor stage, approximately 43% had low risk, 36% had medium risk and 20% had high-risk prostate cancer. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the U.S. and quite different from men in the Scandinavian trial. CONCLUSIONS PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared to watchful waiting for men with predominately PSA detected clinically localized prostate cancer.

THE IMPACT OF MEDICAL THERAPY ON BOTHER DUE TO SYMPTOMS, QUALITY OF LIFE AND GLOBAL OUTCOME, AND FACTORS PREDICTING RESPONSE

PURPOSE We determine the effect of placebo, finasteride, terazosin and a combination of drugs on bother due to symptoms, quality of life and patient perception of improvement, and identify baseline clinical factors that predict clinical response to medical therapy. MATERIALS AND METHODS A total of 1,229 subjects with clinical benign prostatic hyperplasia (BPH) were randomized to 1 year of placebo, finasteride, terazosin or drug combination. The primary outcome measures were American Urological Association (AUA) symptom score and peak flow rate. Relevant secondary outcome measures were symptom problem score, BPH impact score and global rating of improvement. RESULTS Group mean differences in symptom problem and BPH impact scores between the finasteride versus placebo, and terazosin versus combination groups were not statistically or clinically significant. Group mean differences in all outcome measures were highly statistically significant between the terazosin and finasteride, and combination and finasteride groups. The percentage of subjects who rated improvement as marked or moderate with placebo, finasteride, terazosin and combination was 39, 44, 61 and 65%, respectively. In the subsets of men in the placebo, finasteride, terazosin and combination groups with prostates greater than 50 cm.3 group mean decrease from baseline in AUA symptom score was -2.5, -3.6, -6 and -7, group mean increase in peak flow rate was 0.6, 2.7, 3.6 and 3.7 ml. per second, group mean decrease in symptom problem score was -2.2, - 1.9, -3.1 and -4.5, and group mean decrease in BPH impact score was -0.6, -0.3, -1.1 and -1.5, respectively. A correlational analysis failed to show a significant relationship between baseline prostate volume and treatment response to finasteride. There was a significant but weak relationship between change in AUA symptom score and peak flow rate in the finasteride and combination groups. The symptom responses with terazosin were independent of baseline peak flow rate. CONCLUSIONS In men with clinical BPH finasteride and placebo are equally effective, while terazosin and combination are significantly more effective. In men with clinical BPH and large prostates the advantage of finasteride over placebo in terms of symptom reduction, impact on bother due to symptoms and quality of life is small at best, while the advantage of terazosin and combination over finasteride and placebo is highly significant. Baseline prostate volume was not a predictor of response to finasteride in the overall study population. On the basis of our results alpha1 blockers, such as terazosin, should be first line medical treatment for BPH.

Follow-up of Prostatectomy versus Observation for Early Prostate Cancer

BACKGROUND We previously found no significant differences in mortality between men who underwent surgery for localized prostate cancer and those who were treated with observation only. Uncertainty persists regarding nonfatal health outcomes and long‐term mortality. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer to radical prostatectomy or observation. We extended follow‐up through August 2014 for our primary outcome, all‐cause mortality, and the main secondary outcome, prostate‐cancer mortality. We describe disease progression, treatments received, and patient‐reported outcomes through January 2010 (original follow‐up). RESULTS During 19.5 years of follow‐up (median, 12.7 years), death occurred in 223 of 364 men (61.3%) assigned to surgery and in 245 of 367 (66.8%) assigned to observation (absolute difference in risk, 5.5 percentage points; 95% confidence interval [CI], ‐1.5 to 12.4; hazard ratio, 0.84; 95% CI, 0.70 to 1.01; P=0.06). Death attributed to prostate cancer or treatment occurred in 27 men (7.4%) assigned to surgery and in 42 men (11.4%) assigned to observation (absolute difference in risk, 4.0 percentage points; 95% CI, ‐0.2 to 8.3; hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P=0.06). Surgery may have been associated with lower all‐cause mortality than observation among men with intermediate‐risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8 to 25.6) but not among those with low‐risk disease (absolute difference, 0.7 percentage points; 95% CI, ‐10.5 to 11.8) or high‐risk disease (absolute difference, 2.3 percentage points; 95% CI, ‐11.5 to 16.1) (P=0.08 for interaction). Treatment for disease progression was less frequent with surgery than with observation (absolute difference, 26.2 percentage points; 95% CI, 19.0 to 32.9); treatment was primarily for asymptomatic, local, or biochemical (prostate‐specific antigen) progression. Urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation through 10 years. Disease‐related or treatment‐related limitations in activities of daily living were greater with surgery than with observation through 2 years. CONCLUSIONS After nearly 20 years of follow‐up among men with localized prostate cancer, surgery was not associated with significantly lower all‐cause or prostate‐cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. (Funded by the Department of Veterans Affairs and others; PIVOT ClinicalTrials.gov number, NCT00007644.)

The mechanism of adverse events associated with terazosin : An analysis of the veterans affairs cooperative study

PURPOSE We determined the mechanism of adverse events associated with alpha1-blockers for treating benign prostatic hyperplasia (BPH). MATERIALS AND METHODS We randomized 1,229 men with clinical BPH at 31 Veterans Affairs medical centers into equal treatment groups, including those who received placebo, terazosin, finasteride, and combined terazosin and finasteride therapy, respectively. Adverse events were captured at all study visits during our 1-year study. Our current review of adverse events is limited to patients randomized to the placebo and terazosin groups. We compared the incidence of orthostatic blood pressure change, postural symptoms and orthostatic hypotension in men who were normotensive and hypertensive at baseline, respectively. We also determined the association of changes in systolic blood pressure with the incidence of treatment related adverse events. RESULTS The treatment related rates of dizziness, asthenia, postural hypotension and syncope were 19%, 6%, 6% and 1%, respectively. Of these adverse events only postural hypotension was associated with orthostatic blood pressure changes. The incidence of asthenia, dizziness and postural hypotension was not significantly greater in patients with a systolic blood pressure decrease of 5 or greater and less than 5 mm. Hg, respectively. CONCLUSIONS Dizziness and asthenia are not associated with changes in blood pressure, suggesting that these treatment related adverse events associated with alpha1-blockers are not related to vascular events. Designing a subtype selective alpha1 antagonist that has less effect on blood pressure may not result in marked improvement in tolerability over commercially available alpha1-blockers.

Effect of finasteride and/or terazosin on serum PSA: Results of VA cooperative study #359†

Medical management of benign prostatic hyperplasia (BPH) giving rise to lower urinary tract symptomatology (LUTS) has emerged as the mainstay for first‐line therapy. Prostate‐specific antigen (PSA) is the most important method of detecting prostate carcinoma. The effect of finasteride on PSA has been widely reported. Little data exist with respect to alpha‐adrenergic blocking therapy in men treated for BPH. In the present investigation we set out to evaluate the effect of these two forms of therapy.

FILLING AND VOIDING SYMPTOMS IN THE AMERICAN UROLOGICAL ASSOCIATION SYMPTOM INDEX: THE VALUE OF THEIR DISTINCTION IN A VETERANS AFFAIRS RANDOMIZED TRIAL OF MEDICAL THERAPY IN MEN WITH A CLINICAL DIAGNOSIS OF BENIGN PROSTATIC HYPERPLASIA

PURPOSE We used data from a large Veterans Affairs trial of medical therapy for men with benign prostatic hyperplasia to evaluate the value of calculating separate filling and voiding subscores of the American Urological Association (AUA) symptom index. MATERIALS AND METHODS We performed factor analysis to assess the psychometric validity of separating the 7 items of the AUA symptom index into filling and voiding subsets. To assess the clinical usefulness of calculating these subscores we correlated them against baseline measurements of symptom interference as well as urodynamic and anatomical measures of disease severity, and used them for predicting the response to medical therapy. RESULTS Factor analysis confirmed the psychometric validity of separating the AUA symptom index into a 3-item filling and a 4-item voiding subscale. However, calculating filling and voiding subscores did not result in differential correlations with measures of disease interference or severity. It also did not enable us to predict a better symptomatic or uroflowmetry response to medical therapy. CONCLUSIONS Calculating separate filling and voiding subscores of the AUA symptom index is psychometrically valid but not clinically useful.

Ascertaining cause of death among men in the Prostate Cancer Intervention Versus Observation Trial

Background The Prostate Cancer Intervention Versus Observation Trial (PIVOT) randomized 731 men with localized prostate cancer to radical prostatectomy or observation. Purpose We describe the methods and results for cause-of-death assignments in PIVOT, and compare them to alternative strategies for ascertaining prostate cancer–specific mortality, as well as to the methods and results in the similar Scandinavian Prostate Cancer Group Study 4 (SPCG-4) trial. Methods Three PIVOT Endpoints Committee members, blinded to randomized treatment assignments, reviewed medical records and death certificates when available to assign a cause of death using a primary and a secondary adjudication question. Initial disagreements were resolved through discussion. The level of initial agreement among committee members was examined, as well as guesses at randomized treatment assignments for a convenience sample of cases. Final cause of death determinations were compared to death certificates. Results Complete agreement on cause of death by all three committee members before any discussion was achieved in 200/354 (56%) cases on the primary and 209/354 (59%) cases on the secondary. However, complete agreement on the primary rose to 306/354 (86%) when ‘definite’ and ‘probably’ categories were collapsed, as planned a priori. The three committee members’ proportions of correct guesses of randomized treatment assignment were 82/121 (68%), 113/148 (76%), and 99/134 (74%). Using the committee’s final adjudications as a gold standard, death certificates had suboptimal sensitivities, specificities, or predictive values depending on how they were used to determine cause of death. Limitations There was no separate ‘gold standard’ by which to judge the accuracy of the final endpoints committee adjudications, and useful death certificates could not be obtained on about a third of PIVOT participants who died. Conclusions The low level of initial agreement on cause of death among endpoint committee members and the potential for biased determinations due to partial unblinding to treatment assignment raise methodologic concerns about using prostate cancer mortality as an endpoint in clinical trials like PIVOT.

The Fluctuation of Nocturia in Men with Lower Urinary Tract Symptoms Allocated to Placebo during a 12-Month Randomized, Controlled Trial

PURPOSE We determined the fluctuation of nocturia in a 12-month period in men with lower urinary tract symptoms. MATERIALS AND METHODS Men with lower urinary tract symptoms were allocated to the placebo arm of the United States Department of Veterans Affairs Cooperative Studies Program Benign Prostatic Hyperplasia Study. Reported nocturia frequency using the American Urological Association Symptom Index was collected at 6 time points (2, 4, 13, 26, 39 and 52 weeks). Repeat measurements of nocturia during a 1-year period were analyzed using a generalized mixed linear model. RESULTS Of the 305 men allocated to the placebo group 256 participants (84%) gave answers for all 6 time points. In the entire sample the mean nocturia count did not significantly vary from baseline (week 2) after adjusting for covariates (p = 0.542). However, there was considerable fluctuation in nocturia during 1 year. Of the 93 men with 3 or 4 episodes at baseline 47% had improvement and 12% had worsening at 1 year. Of the 184 men who reported 2 or greater nocturia episodes at baseline 15% reported 0 or 1 at 52 weeks. Depending on the case definition during followup the probability of nocturia progression varied between 8% and 54% while nocturia regression varied between 2% and 33%. CONCLUSIONS Using repeat questionnaire based assessments we observed considerable fluctuation in nocturia. However, overall there was no significant increase in prevalence in a 1-year period. These findings may be reassuring to providers and patients who elect to delay interventions for nocturia.