Gary J. Miller

Bio: Gary J. Miller is an academic researcher from Anschutz Medical Campus. The author has contributed to research in topics: Prostate cancer & Prostate. The author has an hindex of 44, co-authored 97 publications receiving 12436 citations. Previous affiliations of Gary J. Miller include University of Colorado Hospital & University of Colorado Denver.

The Influence of Finasteride on the Development of Prostate Cancer

Abstract: background Androgens are involved in the development of prostate cancer. Finasteride, an inhibitor of 5 a -reductase, inhibits the conversion of testosterone to dihydrotestosterone, the primary androgen in the prostate, and may reduce the risk of prostate cancer. methods In the Prostate Cancer Prevention Trial, we randomly assigned 18,882 men 55 years of age or older with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3.0 ng per milliliter or lower to treatment with finasteride (5 mg per day) or placebo for seven years. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng per milliliter or if the digital rectal examination was abnormal. It was anticipated that 60 percent of participants would have prostate cancer diagnosed during the study or would undergo biopsy at the end of the study. The primary end point was the prevalence of prostate cancer during the seven years of the study. results Prostate cancer was detected in 803 of the 4368 men in the finasteride group who had data for the final analysis (18.4 percent) and 1147 of the 4692 men in the placebo group who had such data (24.4 percent), for a 24.8 percent reduction in prevalence over the seven-year period (95 percent confidence interval, 18.6 to 30.6 percent; P<0.001). Tumors of Gleason grade 7, 8, 9, or 10 were more common in the finasteride group (280 of 757 tumors [37.0 percent], or 6.4 percent of the 4368 men included in the final analysis) than in the placebo group (237 of 1068 tumors [22.2 percent], P<0.001 for the comparison between groups; or 5.1 percent of the 4692 men included in the final analysis, P=0.005 for the comparison between groups). Sexual side effects were more common in finasteride-treated men, whereas urinary symptoms were more common in men receiving placebo. conclusions Finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer.

The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia.

Abstract: background Benign prostatic hyperplasia is commonly treated with alpha-adrenergic–receptor antagonists (alpha-blockers) or 5 a -reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. methods We conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia. results The risk of overall clinical progression — defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection — was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P =0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. conclusions Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.

Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial.

Abstract: ContextDespite a stage-shift to earlier cancer stages and lower tumor volumes for prostate cancer, pathologically advanced disease is detected at radical prostatectomy in 38% to 52% of patients. However, the optimal management of these patients after radical prostatectomy is unknown.ObjectiveTo determine whether adjuvant radiotherapy improves metastasis-free survival in patients with stage pT3 N0 M0 prostate cancer.Design, Setting, and PatientsRandomized, prospective, multi-institutional, US clinical trial with enrollment between August 15, 1988, and January 1, 1997 (with database frozen for statistical analysis on September 21, 2005). Patients were 425 men with pathologically advanced prostate cancer who had undergone radical prostatectomy.InterventionMen were randomly assigned to receive 60 to 64 Gy of external beam radiotherapy delivered to the prostatic fossa (n = 214) or usual care plus observation (n = 211).Main Outcome MeasuresPrimary outcome was metastasis-free survival, defined as time to first occurrence of metastatic disease or death due to any cause. Secondary outcomes included prostate-specific antigen (PSA) relapse, recurrence-free survival, overall survival, freedom from hormonal therapy, and postoperative complications.ResultsAmong the 425 men, median follow-up was 10.6 years (interquartile range, 9.2-12.7 years). For metastasis-free survival, 76 (35.5%) of 214 men in the adjuvant radiotherapy group were diagnosed with metastatic disease or died (median metastasis-free estimate, 14.7 years), compared with 91 (43.1%) of 211 (median metastasis-free estimate, 13.2 years) of those in the observation group (hazard ratio [HR], 0.75; 95% CI, 0.55-1.02; P = .06). There were no significant between-group differences for overall survival (71 deaths, median survival of 14.7 years for radiotherapy vs 83 deaths, median survival of 13.8 years for observation; HR, 0.80; 95% CI, 0.58-1.09; P = .16). PSA relapse (median PSA relapse–free survival, 10.3 years for radiotherapy vs 3.1 years for observation; HR, 0.43; 95% CI, 0.31-0.58; P<.001) and disease recurrence (median recurrence-free survival, 13.8 years for radiotherapy vs 9.9 years for observation; HR, 0.62; 95% CI, 0.46-0.82; P = .001) were both significantly reduced with radiotherapy. Adverse effects were more common with radiotherapy vs observation (23.8% vs 11.9%), including rectal complications (3.3% vs 0%), urethral strictures (17.8% vs 9.5%), and total urinary incontinence (6.5% vs 2.8%).ConclusionsIn men who had undergone radical prostatectomy for pathologically advanced prostate cancer, adjuvant radiotherapy resulted in significantly reduced risk of PSA relapse and disease recurrence, although the improvements in metastasis-free survival and overall survival were not statistically significant.Trial Registrationclinicaltrials.gov Identifier: NCT00394511

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer

Abstract: Background Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. Methods We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. Results Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of tox...

Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

Abstract: Background Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. Methods In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. Results In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P = 0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P = 0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P = 0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. Conclusions The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer

Abstract: background Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormoneindependent prostate cancer. methods We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. results Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. conclusions The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

Natural history of progression after PSA elevation following radical prostatectomy.

Abstract: Context In men who develop an elevated serum prostate-specific antigen level (PSA) after having undergone a radical prostatectomy, the natural history of progression to distant metastases and death due to prostate cancer is unknown. Objective To characterize the time course of disease progression in men with biochemical recurrence after radical prostatectomy. Design A retrospective review of a large surgical series with median (SD) follow-up of 5.3 (3.7) years (range, 0.5-15 years) between April 1982 and April 1997. SettingAn urban academic tertiary referral institution.Patients A total of 1997 men undergoing radical prostatectomy, by a single surgeon, for clinically localized prostate cancer. None received neoadjuvant therapy, and none had received adjuvant hormonal therapy prior to documented distant metastases. Main Outcome Measures After surgery, men were followed up with PSA assays and digital rectal examinations every 3 months for the first year, semiannually for the second year, and annually thereafter. A detectable serum PSA level of at least 0.2 ng/mL was evidence of biochemical recurrence. Distant metastases were diagnosed by radionuclide bone scan, chest radiograph, or other body imaging, which was performed at the time of biochemical recurrence and annually thereafter. Results The actuarial metastasis-free survival for all 1997 men was 82% (95% confidence interval, 76%-88%) at 15 years after surgery. Of the 1997 men, 315 (15%) developed biochemical PSA level elevation. Eleven of these underwent early hormone therapy after the recurrence and are not included in the study. Of the remaining 304 men, 103 (34%) developed metastatic disease within the study period. The median actuarial time to metastases was 8 years from the time of PSA level elevation. In survival analysis, time to biochemical progression (P<.001), Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease. An algorithm combining these parameters was constructed to stratify men into risk groups. Once men developed metastatic disease, the median actuarial time to death was 5 years. The time interval from surgery to the appearance of metastatic disease was predictive of time until death (P<.02). Conclusions Several clinical parameters help predict the outcomes of men with PSA elevation after radical prostatectomy. These data may be useful in the design of clinical trials, the identification of men for enrollment into experimental protocols, and counseling men regarding the timing of administration of adjuvant therapies.

Hsp70 chaperones: cellular functions and molecular mechanism.

Abstract: Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.