Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Minimally invasive options to treat low-risk prostate cancer are more desirable than radical therapy. Technological improvements in cryotherapy have increased its use, and long-term data on its efficacy are emerging. In this review, we discuss contemporary data on cryotherapy with specific focus on studies using the newest technology. RECENT FINDINGS/RESULTS:With respect to biochemical recurrence rates, cryotherapy appears to be as effective for low-risk prostate cancer as other treatment modalities. The definition of recurrence remains problematic, though contemporary studies are more consistently using both the American Society for Therapeutic Radiation Oncology and Phoenix criteria. Erectile dysfunction rates are universally high after whole-gland cryoablation, but incontinence and urethrorectal fistula rates appear to be low with third-generation cryo systems. Focal cryotherapy has encouraging short-term efficacy in terms of biochemical disease-free survival rate for unifocal disease, and rates of erectile dysfunction are dramatically lower than those seen with whole-gland cryoablation. SUMMARY/CONCLUSIONS:Cryosurgery has a promising role in primary and salvage treatment of select prostate cancer patients. Focal cryotherapy for unilateral disease offers the added benefit of minimal adverse effects. Long-term data are emerging to support cryosurgery, and large multicenter databases have been developed to answer questions regarding optimal treatment outcomes and patterns.

Stage migration has led to an increased incidence of localized and low-risk prostate cancer. Intermediate-term data are emerging on the efficacy of cryotherapy, but direct comparison to other therapeutic modalities is difficult as the parameters for recurrence are not well defined. Studies using the American Society for Therapeutic Radiation and Oncology and the Phoenix (nadir plus 2) criteria for biochemical recurrence show that primary cryotherapy appears to be comparable for low-risk prostate cancer as other treatment modalities. In addition, health-related quality-of-life measures have improved with the most recent third-generation systems demonstrating low incontinence and urethrorectal fistula rates. Erectile dysfunction is high with whole gland ablation, but focal therapy may reduce these rates while still ablating unilateral cancerous tissue. Prostate cryotherapy for localized prostate cancer is an evolving but viable therapeutic option. Long-term data are still needed to establish a definitive role for cryosurgery in prostate cancer treatment.

Subjects diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN) at biopsy are at increased risk for developing prostate cancer (CaP). A prospective clinical trial was done to determine the safety and tolerability of a novel herbal amalgam, Zyflamend (New Chapter, Inc., Brattleboro, VT), with various dietary supplements in subjects with HGPIN. Men ages 40 to 75 years with HGPIN were eligible. Subjects were evaluated for 18 months. Every 3 months, standard blood chemistries and prostate-specific antigen (PSA) were monitored. Rebiopsy was done every 6 months. Tissue was evaluated for HGPIN or CaP and stained for cyclooxygenase-2, nuclear factor kappaB (NF-kappaB), interleukin-6, and thromboxane. Twenty-three subjects were evaluable. The median age was 64.1 years (range 46-75 years), and the mean (+/- SD) PSA level was 6.13 +/- 3.56 ng/mL. Side effects, when present, were mild and gastrointestinal in nature. There were no reported serious adverse events or toxicities. No significant changes in blood chemistries, testosterone, or cardiac function were noted. Forty-eight percent of subjects demonstrated a 25 to 50% decrease in PSA after 18 months. Of subjects who had the 18-month biopsy, 60% (9 of 15) had benign tissue, 26.7% (4 of 15) had HGPIN in one core, and 13.3% (2 of 15) had CaP at 18 months. A reduction in serum C-reactive protein was observed (95% confidence interval [CI] 0.7-1.7, p = .045). Immunoreactive staining demonstrated a reduction in NF-kappaB in the 18-month samples (95% CI 0.8-3.0, p = .017). Zyflamend alone and in combination with various dietary supplements is associated with minimal toxicity and no serious adverse events when administered orally for 18 months. Further studies are warranted to evaluate these agents in patients who are at risk for CaP.

Bark extracts from the Amazonian rain forest tree Geissospermum vellosii (pao pereira), enriched in alpha-carboline alkaloids have significant anticancer activities in certain preclinical models. Because of the predominance of prostate cancer as a cause of cancer-related morbidity and mortality for men of Western countries, we preclinically tested the in vitro and in vivo effects of a pao pereira extract against a prototypical human prostate cancer cell line, LNCaP. When added to cultured LNCaP cells, pao pereira extract significantly suppressed cell growth in a dose-dependent fashion and induced apoptosis. Immunodeficient mice heterotopically xenografted with LNCaP cells were gavaged daily with pao pereira extract or vehicle control over 6 weeks. Tumor growth was suppressed by up to 80% in some groups compared with tumors in vehicle-treated mice. However, we observed a striking U-shaped dose-response curve in which the highest dose tested (50 mg/kg/d) was much less effective in inducing tumor cell apoptosis and in reducing tumor cell proliferation and xenograft growth compared with lower doses (10 or 20 mg/kg/d). Although this study supports the idea that a pao pereira bark extract has activity against human prostate cancer, our in vivo results suggest that its potential effectiveness in prostate cancer treatment may be limited to a narrow dose range.

PURPOSE/OBJECTIVE:We report the largest data set to date to our knowledge regarding outcomes for primary whole gland prostate cryoablation. MATERIALS AND METHODS/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.

PURPOSE/OBJECTIVE: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/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.