Bryan J. Donnelly

Absolute Prostate-Specific Antigen Value After Androgen Deprivation Is a Strong Independent Predictor of Survival in New Metastatic Prostate Cancer: Data From Southwest Oncology Group Trial 9346 (INT-0162)

PURPOSE To establish whether absolute prostate-specific antigen (PSA) value after androgen deprivation (AD) is prognostic in metastatic (D2) prostate cancer (PCa). PATIENTS AND METHODS D2 PCa patients with baseline PSA of at least 5 ng/mL received 7 months induction AD. Patients achieving PSA of 4.0 ng/mL or less on months 6 and 7 are randomly assigned to continuous versus intermittent AD on month 8. Eligibility for this analysis required a prestudy PSA with at least two subsequent PSAs and that patients be registered at least 1 year before analysis date. Survival was defined as time to death after 7 months of AD. Associations were evaluated by proportional hazards regression models. RESULTS One thousand one hundred thirty four of 1,345 eligible patients achieved a PSA of 4 ng/mL or less. At end of induction, 965 patients maintained PSA of 4 or less and 604 had a PSA of 0.2 ng/mL or less. After controlling for prognostic factors, patients with a PSA of 4 or less to more than 0.2 ng/mL had less than one third the risk of death (ROD) as those with a PSA of more than 4 ng/mL (P < .001). Patients with PSA of 0.2 ng/mL or less had less than one fifth the ROD as patients with a PSA of more than 4 ng/mL (P < .001) and had significantly better survival than those with PSA of more than 0.2 to 4 ng/mL or less (P < .001). Median survival was 13 months for patients with a PSA of more than 4 ng/mL, 44 months for patients with PSA of more than 0.2 to 4 ng/mL or less, and 75 months for patients with PSA of 0.2 ng/mL or less. CONCLUSION A PSA of 4 ng/mL or less after 7 months of AD is a strong predictor of survival. This data should be used to tailor future trial design for D2 prostate cancer.

Intermittent versus Continuous Androgen Deprivation in Prostate Cancer

BACKGROUND Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. METHODS Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. RESULTS A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. CONCLUSIONS Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).

Salvage Prostate Cryoablation: Initial Results From the Cryo On-Line Data Registry

PURPOSE We report contemporary outcomes of salvage cryoablation at a large number of centers which have participated in the COLD (Cryo On-Line Data) Registry. MATERIALS AND METHODS A secure online database was developed to collect data for patients undergoing prostate cryoablation. Kaplan-Meier analysis was performed with biochemical failure defined using the American Society of Therapeutic Radiology and Oncology, and the Phoenix definitions. RESULTS Data from 279 patients who had undergone salvage cryoablation were entered. Average patient age was 70.0 +/- 7.1 years. Pretreatment prostate specific antigen was 7.6 +/- 8.2 ng/ml and Gleason score was 7.5 +/- 1.1 (median 7). Patients were followed for 21.6 +/- 24.9 months and 47 were followed longer than 5 years. The 5-year actuarial biochemical disease-free rates were 58.9% +/- 5.7% (American Society of Therapeutic Radiology and Oncology) and 54.5% +/- 4.9% (Phoenix). As predicted based on the preservation of some prostatic tissue, 83% +/- 3.5% of patients had a detectable prostate specific antigen 0.2 ng/ml or greater at 5 years. Positive biopsies were observed in 15 of the 46 patients (32.6%) who underwent prostate biopsy after salvage cryotherapy. The incontinence rate (requiring pad use) was 4.4%. The rectal fistula rate was 1.2% and 3.2% of patients underwent transurethral prostate resection to remove sloughed tissue. CONCLUSIONS Biochemical and local control rates support the use of salvage cryoablation for localized recurrence following failed radiation therapy. Efforts to continue to minimize these complications and to improve disease control in patients with persistent cancer following definitive radiotherapy should continue.

Prospective trial of cryosurgical ablation of the prostate: five-year results

OBJECTIVES To determine in a prospective pilot study the safety and efficacy of cryosurgical ablation for localized prostate carcinoma. METHODS A total of 87 cryosurgical procedures were performed on 76 consecutive patients between December 1994 and February 1998. All patients had histologically proved adenocarcinoma of the prostate, with prostate-specific antigen (PSA) readings of less than 30 ng/mL. Clinical evaluations, PSA determinations, and patient self-reported quality-of-life questionnaires (functional assessment of cancer treatment-prostate; FACT-P) were used to determine biochemical and clinical disease-free status and complications. Patients had a mean follow-up of 50 months (minimum 36). RESULTS Follow-up biopsies were performed in 73 patients, and 72 were negative for malignancy after one or more treatments. Ten patients required two treatments and 1 patient required three treatments. The 5-year overall and cancer-specific survival rate was 89% (95% confidence interval, 83% to 97%) and 98.6% (95% confidence interval, 96% to 100%), respectively. The undetectable PSA rate (less than 0.3 ng/mL) for low-risk patients (n = 13) was 60% at 5 years; for moderate-risk patients (n = 23), it was 77%, and for high-risk patients (n = 40), 48%. The corresponding percentage of patients with a PSA level less than 1.0 ng/mL at 5 years was 75%, 89%, and 76%. Sloughing occurred in 3 patients (3.9%), incontinence in 1 (1.3%), and testicular abscess in 1 (1.3%). At 3 years, 18 (47%) of 38 patients capable of unassisted intercourse at the time of cryosurgery had resumed sexual intercourse, 5 spontaneously and 13 with sildenafil or prostaglandin. CONCLUSIONS The results of this prospective evaluation show cryosurgery to be both a safe and an effective option in the treatment of localized prostate cancer.

Prostate-Specific Antigen Progression Predicts Overall Survival in Patients With Metastatic Prostate Cancer: Data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916

PURPOSE Prostate-specific antigen progression (PSA-P) is an indicator of progression in hormone-sensitive (HS) and castration-resistant (CR) prostate cancer (PC). We evaluated different definitions of PSA-P as predictors of overall survival (OS). PATIENTS AND METHODS A total of 1,078 patients with HSPC who were on hormones (Southwest Oncology Group [SWOG] trial 9346 [S9346]) and 597 patients with CRPC who were treated with chemotherapy (SWOG trial 9916 [S9916]) were eligible for this analysis. PSA-P definitions tested included the following: PSA Working Group, Prostate Cancer Working Group (PCWG 2008), and other definitions. A time-varying approach analyzed associations between PSA-P at any time and OS. A landmark analysis examined the relationship between PSA-P status at 7 months for S9346, or 3 months for S9916, and subsequent OS. RESULTS In the time-varying analysis, both working groups definitions were strongly associated with OS (P < .001) in both study settings. In patients enrolled onto S9346, both definitions predicted a 2.4-fold increased risk of death (ROD) and a greater than four-fold increased ROD if PSA-P occurred in the first 7 months. In S9916, they predicted a 40% increase in ROD and a two-fold increase in ROD if PSA-P occurred at 3 months. In landmark analyses of patients on S9346 by using the PCWG 2008 definition of PSA-P, median subsequent OS was 10 months versus 44 months in patients who did or did not have PSA-P by 7 months, respectively; in S9916, data were 11 months versus 18 months for patients who did or did not have PSA-P by 3 months, respectively. CONCLUSION PSA-P, defined as an increase of > or = 25% greater than the nadir and an absolute increase of at least 2 or 5 ng/mL, predicts OS in HSPC and CRPC and may be a suitable end point for phase II studies in these settings.

Whole Gland Primary Prostate Cryoablation: Initial Results From the Cryo On-Line Data Registry

PURPOSE We report the largest data set to date to our knowledge regarding outcomes for primary whole gland prostate cryoablation. MATERIALS AND METHODS The COLD (Cryo On-Line Data) Registry consists of case report forms obtaining pretreatment and posttreatment information for patients undergoing whole gland prostate cryoablation. A total of 1,198 patients were stratified into low, intermediate and high risk groups. Biochemical success was defined according to the traditional American Society for Therapeutic Radiology and Oncology definition (3 increases) and the newer (Phoenix) definition (nadir +2). Biopsy was performed at physician discretion but most commonly for cause if a patient had an increasing or suspicious prostate specific antigen. RESULTS Average patient age was 69.8 +/- 7.5 years. Pretreatment prostate specific antigen was 9.6 +/- 8.6 ng/ml and median Gleason sum was 7 (range 4 to 10). Patients were followed for 24.4 +/- 25.9 months with 136 having minimum 5-year data. The 5-year biochemical disease-free status for the entire population was 77.1% +/- 2.1% (American Society for Therapeutic Radiology and Oncology) and 72.9% +/- 2.1% (Phoenix). Five-year American Society for Therapeutic Radiology and Oncology biochemical disease-free status was 84.7% +/- 4.5%, 73.4% +/- 4.3% and 75.3% +/- 3.7% for the low, moderate and high risk groups, respectively. Using the Phoenix definition the biochemical disease-free status was 91.1% +/- 2.9%, 78.5% +/- 3.6% and 62.2% +/- 4.9%, respectively. As predicted based on intentional preservation of some prostatic tissue, 72.5 +/- 1.8% had a detectable prostate specific antigen 0.2 ng/ml or greater at 5 years. Biopsy after cryotherapy was positive during empiric without cause biopsy in 30 of 207 patients (14.5%), and the highly selected group biopsied based on suspicion of treatment failure due to abnormal or increasing prostate specific antigen had positive results in 38.0% (49 of 129). The rectal fistula rate was 0.4% and incontinence was 4.8% with 2.9% of patients using pads. Intercourse was reported by 25.2% but only 8.8% without pharmaceutical or device assistance. CONCLUSIONS Whole gland cryoablation, practiced in a spectrum of academic and community users, maintains efficacy and morbidity similar to that of single center reports.

A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer

Localized prostate cancer can be treated several different ways, but head‐to‐head comparisons of treatments are infrequent. The authors of this report conducted a randomized, unblinded, noninferiority trial to compare cryoablation with external beam radiotherapy in these patients.

A model for the time dependent three-dimensional thermal distribution within iceballs surrounding multiple cryoprobes

A time dependent three-dimensional finite difference model of iceball formation about multiple cryoprobes has been developed and compared to experimental data. Realistic three-dimensional probe geometry is specified and the number of cryoprobes, the cryoprobe cooling rates, and the locations of the probes are arbitrary inputs by the user. The simulation accounts for observed longitudinal thermal gradients along the cryoprobe tips. Thermal histories for several points around commercially available cryoprobes have been predicted within experimental error for one, three, and five probe configurations. The simulation can be used to generate isotherms within the iceball at arbitrary times. Volumes enclosed by the iceball and any isotherms may also be computed to give the ablative ratio, a measure of the iceballs killing efficiency. This ratio was calculated as the volume enclosed by a critical isotherm divided by the total volume of the iceball for assumed critical temperatures of -20 and -40 degrees C. The ablative ratio for a single probe is a continuously decreasing function of time but when multiple probe configurations are used the ablative ratio increases to a maximum and then essentially plateaus. Maximum values of 0.44 and 0.55 were observed for three and five probe configurations, respectively, with an assumed critical temperature of -20 degrees C. Assuming a critical temperature of -40 degrees C, maximum ablative ratios of 0.21 and 0.3 for three and five probe configurations, respectively, were observed.

The evolution and state of modern technology for prostate cryosurgery

Cryosurgery is the in situ ablation of a target tissue by application of extreme cold temperature. The ability of cryosurgery to ablate tissue is unquestioned. It is the controlled application of a cryoinjury in a manner to minimize morbidity that is problematic. Prostate cryosurgery is complicated by the proximity of the prostate to adjacent structures that are sensitive to a freeze injury, namely the urethra, rectal wall, and neurovascular bundles. Several recent technological advances have led to the development of an effective treatment protocol with acceptable morbidity. These include the advent of real-time transrectal ultrasound, cryomachines with almost instant freeze-thaw control through the use of the Joule-Thompson effect, and warming catheters to effectively preserve the integrity of the urethra and external sphincter. Further, temperature monitoring at the posterior margin of the prostate sometimes combined with an injection of saline solution into Denonvilliers fascia has reduced the occurrence of urethrorectal fistula formation to 0% to 0.5% in modern series. We review the key innovations of prostate cryosurgery that differentiate this state-of-the-art procedure from that used by early investigators to even that of the early 1990s. Potential future innovations, specifically related to image guidance of the procedure, are also addressed.

Quality of life and sexuality of men with prostate cancer 3 years after cryosurgery

The current study was designed to describe the long-term life quality and sexuality of men enrolled in a phase 2 clinical trial of cryosurgery for the treatment of localized prostate cancer. A total of 75 men were administered the Functional Assessment of Cancer Treatment-Prostate (FACT-P) before treatment and after treatment at 6 weeks, and at 3, 6, 12, 24, and 36 months. Additionally, these men completed a Sexuality Follow-Up Questionnaire (SFQ) 3 years after cryosurgery. By 12 months after cryosurgery, most FACT-P subscales had returned to pretreatment levels. Quality of life remained stable over the subsequent 2 years. The only exception to this general trend was persistent impairment in measures of social/family well-being. At 36 months, 13% (5 of 38) of patients had regained erectile functioning, and an additional 34% (13 of 38) of patients were sexually active with the help of aids. The 3-year quality-of-life outcomes support the renewed interest in cryosurgery. No late complications were observed. Whereas improvements in erectile function were observed between years 1 and 3 for some patients, most continue to experience erectile dysfunction. For these patients, aids are an important adjunct to the treatment of their erectile dysfunction.