Prospective Outcome Analysis of the Safety and Efficacy of Partial and Complete Cryoablation in Organ-confined Prostate Cancer.

OBJECTIVE: To determine the rate of complications and change in International Prostate Symptom Score and Sexual Health Inventory for Men scores following cryotherapy treatment of low- and intermediate-risk prostate cancer. The secondary end points were the change in prostate-specific antigen post cryotherapy and biopsy-proven recurrence. MATERIALS AND METHODS: Enrollment occurred from 2007 to 2015 to assess long-term complications of cryotherapy. A prostate biopsy was performed at 1 year or in the event of biochemical failure. Subjects were staged and graded by standard 12- to 14-core transrectal ultrasound (TRUS) biopsy. A subset of subjects underwent additional 3-dimensional mapping biopsy if the cancer was suspected to be downgraded. Analyses of functional outcomes were stratified into focal and nonfocal treatments. RESULTS: The study consisted of 393 men with low- and intermediate-risk prostate cancer, aged 44-89 years. Patient IPSS scores improved significantly in the nonfocal treatment strata at all time points and after 1 year in the focal strata with a median drop at 1 year of 4 points (P <.001). No significant difference was detected for a change in preprocedural SHIM score in either treatment strata after 2 years (P >.7). Eighty-two patients (20.9%) had a rise in prostate-specific antigen resulting in biochemical failure. Seventy patients had detected recurrence for an overall recurrence rate of 20.4% in 343 patients. A total of 109 patients (27.7%) reported urinary retention and urgency post cryotherapy, with 15.3% requiring catheterization for up to 3 weeks. Thirty-seven patients (9.4%) experienced urethral meatal stricture, and 36 patients (9.2%) reported unresolved new-onset erectile dysfunction. CONCLUSION: Complication rates, most significantly erectile dysfunction, are decreased in this study compared with those previously reported in the literature for cryotherapy for prostate cancer.

Targeted focal therapy for the management of organ confined prostate cancer.

PURPOSE: Patients currently diagnosed with low risk prostate cancer are often overtreated and experience complications, resulting in detriment to quality of life. Targeted focal therapy is a minimally invasive procedure designed to ablate tumor foci while minimizing collateral damage to maintain quality of life. MATERIALS AND METHODS: This institutional review board approved, prospective study was done to assess the safety and efficacy of targeted focal therapy using cryotherapy in men 40 to 85 years old diagnosed with low risk, organ confined prostate cancer at our institution between 2006 and 2009. Low risk, organ confined prostate cancer was defined as Gleason score 7 or less (3 + 4) on transrectal ultrasound biopsy, tumor burden 50% or less and prostate specific antigen less than 10 ng/dl. Patients were evaluated for eligibility after undergoing 3-dimensional mapping biopsy. Median followup was 28 months (IQR 26-31). RESULTS: A total of 62 men with low risk disease met study inclusion criteria. At 1 year biopsy was negative in 50 of 62 patients (81%). All 12 men who tested positive on repeat biopsy had a Gleason score of 3 + 3 = 6 with 1 or 2 positive cores. The median prostate specific antigen change was a 3.0 ng/dl decrease (p <0.01). The median American Urological Association symptom score change was a 1.5-point decrease (p <0.01). No significant change was observed in Sexual Health Inventory for Men score (p = 0.6). No urinary incontinence episodes and no severe side effects were noted. CONCLUSIONS: Targeted focal therapy in carefully selected patients provides a feasible, practical option for treating low risk prostate cancer with minimal impact on quality of life.

Moving Forward the State of the Art in Prostate Cancer Treatment: Targeted Focal Therapy.

INTRODUCTION: The diagnosis and treatment of prostate cancer have changed dramatically in the prostate specific antigen era. We are now faced with the clinical dilemma of over diagnosis and overtreatment. Targeted focal therapy offers a potential middle ground between the binary choices of active surveillance and the whole gland treatments of radical prostatectomy or radiotherapy. METHODS: A PubMed® search was performed using the terms "targeted focal therapy," "focal therapy," "hemiablation" and "transperineal mapping biopsy" to locate studies and reviews published after 2000 pertaining to targeted focal therapy of the prostate. Key articles were selected and included in this review, which covers the practical aspects of targeted focal therapy for prostate cancer. RESULTS: Three international, multidisciplinary consensus statements were located which provide best practice for patient selection in ongoing and future trials of targeted focal therapy. Other studies located for the review elaborate on the best techniques to properly stage a case of histologically confirmed prostate cancer under consideration for focal therapy and summarize outcomes reported to date in the literature. CONCLUSIONS: Phase I and II studies of targeted focal therapy for prostate cancer have demonstrated safety and efficacy. With improved imaging and standardized patient selection criteria, phase III study is under way, perhaps setting the stage for a new era of prostate cancer therapy for many individuals.

Clinical-pathologic correlation between transperineal mapping biopsies of the prostate and three-dimensional reconstruction of prostatectomy specimens.

BACKGROUND: Extended transrectal ultrasound guided biopsies (TRUSB) of the prostate may not accurately convey true morphometric information and Gleason score (GS) of prostate cancer (PCa) and the clinical use of template-guided (5-mm grid) transperineal mapping biopsies (TPMBs) remains controversial. METHODS: We correlated the clinical-pathologic results of 1,403 TPMB cores obtained from 25 men diagnosed with PCa with 64 cancer lesions found in their corresponding radical prostatectomy (RP) specimens. Special computer models of three-dimensional, whole-mounted radical prostatectomy (3D-WMRP) specimens were generated and used as gold standard to determine tumor morphometric data. Between-sample rates of upgrade and downgrade (highest GS and a novel cumulative GS) and upstage and downstage (laterality) were determined. Lesions ≥ 0.5 cm(3) or GS ≥ 7 were considered clinically significant. RESULTS: From 64 separate 3D-WMRP lesions, 25 had significant volume (mean 1.13 cm(3)) and 39 were insignificant (mean 0.09 cm(3)) (P < 0.0001); 18/64 lesions were missed by TPMB, but only one was clinically significant with GS-8 (0.02 cm(3)). When comparing the cumulative GS of TPMB versus RP, 72% (n = 18) had identical scores, 12% (n = 3) were upgraded, and only 16% (n = 4) were downgraded. Laterality of TPMB and RP was strongly correlated, 80% same laterality, 4% were up-staged, and 16% down-staged. CONCLUSIONS: Our clinical-pathology correlation showed very high accuracy of TPMB with a 5-mm grid template to detect clinically significant PCa lesions as compared with 3D-WMRP, providing physicians and patients with a reliable assessment of grade and stage of disease and the opportunity to choose the most appropriate therapeutic options.

Current Challenges in Prostate Cancer Management and the Rationale behind Targeted Focal Therapy.

Among men, prostate cancer has a high prevalence, with relatively lower cancer-specific mortality risk compared to lung and colon cancer. Prostate-specific antigen (PSA) screening has increased prostate cancer awareness since its implementation as a screening tool almost 25 years ago, but, due to the largely indolent course of this disease and the unspecific nature of the PSA test, increased incidence has largely been associated with cancers that would not go on to cause death (clinically insignificant), leading to an overdiagnosis challenge and an ensuing overtreatment consequences. The overtreatment problem is exacerbated by the high risk of side effects that current treatment techniques have, putting patients' quality of life at risk with little or no survival benefit. The goals of this paper are to evaluate the rise, prevalence, and impact of the overdiagnosis and ensuing overtreatment problems, as well as highlight potential solutions. In this effort, a review of major epidemiological and screening studies, cancer statistics from the advent of prostate-specific antigen screening to the present, and reports on patient concerns and treatment outcomes was conducted to present the dominant factors that underlie current challenges in prostate cancer treatment and illuminate potential solutions.

The insults of illicit drug use on male fertility.

One-third of infertile couples may have a male factor present. Illicit drug use can be an important cause of male factor infertility and includes use of anabolic-androgenic steroids, marijuana, opioid narcotics, cocaine, and methamphetamines. The use of these illicit drugs is common in the United States, with a yearly prevalence rate for any drug consistently higher in males compared with females. We aim to provide a review of recent literature on the prevalence and effects of illicit drug use on male fertility and to aid health professionals when counseling infertile men whose social history suggests illicit drug use. Anabolic-androgenic steroids, marijuana, cocaine, methamphetamines, and opioid narcotics all negatively impact male fertility, and adverse effects have been reported on the hypothalamic-pituitary-testicular axis, sperm function, and testicular structure. The use of illicit drugs is prevalent in our society and likely adversely impacting the fertility of men who abuse drugs.

The value of second-opinion pathology diagnoses on prostate biopsies from patients referred for management of prostate cancer.

Gleason score (GS) (sum of primary plus secondary grades) is used to predict patients' clinical outcome and to customize treatment strategies for prostate cancer (PC). However, due in part to pathologist misreading, there is significant discrepancy of GS between needle-core biopsies (NCB) and radical prostatectomy specimens. We assessed the requirement for re-evaluating NCB diagnosed by outside pathologists in patients referred to our institution for management of PC. In 100 patients, we reviewed both their original "outside" and second-opinion ("in-house") diagnoses of the same NCB specimens, and compared them with the diagnoses of the whole-mount radical prostatectomy (WMRP) specimens (gold standard for analysis). We found that both outside and in-house biopsy GS vary significantly from the WMRP diagnoses, with GS undergrading substantially predominating above overgrading. Statistical analysis demonstrated that the main diagnostic discrepancy was in the differentiation between primary and secondary Gleason grades (mainly 3 and 4) and that outside NCB GS was significantly less accurate with respect to the WMRP specimens than the in-house NCB GS. In addition, in a different cohort of 65 NCB cases, we found that in 5 out of 11 patients, outside pathologists failed to report the presence of extraprostatic extension, an important feature for diagnosis of a higher pathology stage (pT3a). Since histopathological evaluation is a critical factor for appropriate treatment selection, we recommend that a re-evaluation by in-house urologic pathologists should be performed in all outside NCB specimens before patients are admitted for treatment in any given institution.

Methods of developing UWIN, the modified American Urological Association symptom score.

PURPOSE: The American Urological Association symptom score instrument is widely used to assess lower urinary tract symptom severity in men. We describe the methods used to develop a shorter form of the American Urological Association symptom score that may provide symptom score assessment with minimal compromise in accuracy. MATERIALS AND METHODS: Complete American Urological Association symptom score data were collected on 8,731 men who attended Prostate Cancer Awareness Week in 2003 or 2004. Correlation analysis and area under the ROCs were used to determine the best reduced index and cutoff points in scores for the severity categories of mild, moderate and severe. RESULTS: The number of responses in the original 7 American Urological Association symptom score items was lowered from 6 to 4 and for the bothersome index it was lowered from 7 to 3. Four of the original 7 items were retained. Cronbach's α was 0.851 for the symptom score items in our data. The combination of items with the best joint correlation to the American Urological Association symptom score and bothersome score was UWIN (urgency, weak stream, incomplete emptying and nocturia). The correlation of UWIN with the American Urological Association symptom score was 0.938. The correlation of UWIN bother to the American Urological Association bothersome score was 0.638. The ROC for the mild, moderate and severe UWIN categories compared to the categorized American Urological Association symptom score was 0.96, 0.97 and 0.99, respectively. CONCLUSIONS: The UWIN instrument may potentially be a valuable tool to assess American Urological Association symptom score severity and bother. Clinical validation of this instrument is indicated in a prospective comparative study.

Validation of the modified American Urological Association symptom score.

PURPOSE: We created a shorter version of the American Urological Association symptom score, called UWIN (urgency, weak stream, incomplete emptying and nocturia). MATERIALS AND METHODS: Participants in Prostate Cancer Awareness Week from 2006 and 2007 were administered the regular American Urological Association symptom score and UWIN. A total of 278 participants completed each questionnaire. Total scores of each participant for the American Urological Association symptom score (range 0 to 35) and UWIN (range 0 to 12) were evaluated using Spearman's correlation coefficients and Bland-Altman plots to determine the level of agreement between the 2 questionnaires. RESULTS: The correlation between the total American Urological Association symptom score (range 0 to 35) and the total UWIN score (range 0 to 12) was 0.913 (p<0.0001). The correlation between the quality of life question on the American Urological Association symptom score and UWIN was 0.821 using the Spearman correlation coefficient (p<0.0001). A second analysis performed using Bland-Altman plots showed good agreement between the American Urological Association symptom score and UWIN. Overall, respondents tended to have slightly higher UWIN total scores than their American Urological Association symptom scores. CONCLUSIONS: This study validates that the UWIN questionnaire can be used in place of the American Urological Association symptom score. The UWIN questionnaire will lessen the burden on the respondent, broaden the applicability of the instrument and make collecting data as efficient and effective as possible.

The role of 3-dimensional mapping biopsy in decision making for treatment of apparent early stage prostate cancer.

PURPOSE: We determined the impact of a grid based, transperineal 3-dimensional mapping biopsy on decision making for primary management of early stage prostate cancer. MATERIALS AND METHODS: We prospectively performed 3-dimensional mapping biopsy on 180 consecutive men who presented to our clinic between 2006 and 2009 with early stage, organ confined prostate cancer based on transrectal ultrasound guided 10 to 12-core biopsy, and on 35 with prior negative transrectal ultrasound biopsies. RESULTS: At presentation median patient age was 60.5 years (range 43 to 77), median prostate specific antigen was 4.8 ng/ml (range 0.5 to 72.4) and median prostate volume was 35 cc (range 9 to 95). The median number of cores acquired by transrectal ultrasound and 3-dimensional mapping biopsy was 12 and 56, and the median number of positive cores was 1 and 2, respectively. We documented Gleason score upgrade in 49 of 180 cases (27.2%) and up-stage in 82 (45.6%). The incidence of urinary retention catheter requirement of greater than 48 hours was 3.2% and the incidence of transient orthostatic hypotension was 5%. No urinary tract infections were documented. A total of 38 men received radical extirpative therapy, 11 radiation and 45 cryotherapy while 60 enrolled in a targeted focal therapy study, 44 entered active surveillance and 5 underwent other focal investigational treatments. Post-mapping data on 12 men were not available for analysis. CONCLUSIONS: Three-dimensional mapping biopsy revealed that a significant portion of men initially diagnosed with apparently low risk disease harbored clinically significant cancers requiring more aggressive therapy. The technique also enabled a number of men with low risk disease to elect surveillance or another less morbid option.

The effect of short-term dutasteride intake in early-stage prostate cancer: analysis of 148 patients who underwent three-dimensional prostate mapping biopsy.

OBJECTIVES: The effect of dutasteride on existing prostate cancer volume is largely unknown. In this study, we assessed the impact of dutasteride on tumor burden and Gleason score. METHODS: A retrospective review of patients from our institution was performed, examining men interested in surveillance for prostate cancer, who underwent transperineal three-dimensional mapping (TP-3DM) biopsy within 3-6 months after their initial cancer diagnosis. The criteria to qualify for TP-3DM biopsy included prostate-specific antigen < 10 ng/mL, Gleason score ≤ 7, ≤ 2 positive cores out of 12. There were 2 cohorts of men--those who took dutasteride daily before the TP-3DM biopsy and those who did not receive any 5ARIs. Upstaging of prostate cancer diagnosis was defined as an increase in one or more positive cores or a change from unilateral to bilateral disease. RESULTS: From 2006-2008, a cohort of 148 men underwent TP-3DM biopsy of the prostate. Ninety-one men received a treatment regime of dutasteride at least 3 months before TP-3DM biopsy. Fifty-seven men did not receive dutasteride or any other 5ARI. Approximately 74% of men who did not take dutasteride were upstaged and/or upgraded compared with 49.4% of men who received dutasteride (P = .0038). CONCLUSIONS: We observed a 24.3% decrease in the proportion of upstaging and/or upgrading of prostate cancer in men who received dutasteride at least 3 months before 3D prostate TP-3DM biopsy. Thus, the effect of dutasteride on prostate cancer may have implications for its potential use as a secondary chemoprevention agent.

Photodynamic therapy for treatment of solid tumors--potential and technical challenges.

Photodynamic therapy (PDT) involves the administration of photosensitizer followed by local illumination with visible light of specific wavelength(s). In the presence of oxygen molecules, the light illumination of photosensitizer can lead to a series of photochemical reactions and consequently the generation of cytotoxic species. The quantity and location of PDT-induced cytotoxic species determine the nature and consequence of PDT. Much progress has been seen in both basic research and clinical application in recent years. Although the majority of approved PDT clinical protocols have primarily been used for the treatment of superficial lesions of both malignant and non-malignant diseases, interstitial PDT for the ablation of deep-seated solid tumors are now being investigated worldwide. The complexity of the geometry and non-homogeneity of solid tumor pose a great challenge on the implementation of minimally invasive interstitial PDT and the estimation of PDT dosimetry. This review will discuss the recent progress and technical challenges of various forms of interstitial PDT for the treatment of parenchymal and/or stromal tissues of solid tumors.

Emerging role of HIFU as a noninvasive ablative method to treat localized prostate cancer.

The use of high-intensity focused ultrasound (HIFU) as a method for ablation of a localized tumor growth is not new. Several attempts have been made to apply the principles of HIFU to the treatment of pelvic, brain, and gastrointestinal tumors. However, only in the past decade has our understanding of the basic principles of HIFU allowed us to further exploit its application as a radical and truly noninvasive, intent-to-treat, ablative method for treating organ-confined prostate cancer. Prostate cancer remains an elusive disease, with many questions surrounding its natural history and the selection of appropriate patients for treatment yet to be answered. HIFU may play a crucial role in our search for an efficacious and safe primary treatment for localized prostate cancer. Its noninvasive and unlimited repeatability potential is appealing and unique; however, long-term results from controlled studies are needed before we embrace this new technology. Furthermore, a better understanding of HIFU's clinical limitations is vital before this treatment modality can be recommended to patients who are not involved in well-designed clinical studies. This review summarizes current knowledge about the basic principles of HIFU and its reported efficacy and morbidity in clinical series published since 2000.

The effect of Tookad-mediated photodynamic ablation of the prostate gland on adjacent tissues--in vivo study in a canine model.

Photodynamic therapy (PDT) mediated with vascular acting photosensitizer Tookad (Pd-bacteriopheophorbide) was investigated as an alternative modality for treating prostate cancer. Photodynamic effects on the prostate gland and its adjacent tissues were evaluated in a canine model. Interstitial prostate PDT was performed by irradiating individual lobes with a cylindrical diffuser fiber at various drug/light doses. The sensitivity of the adjacent tissues to Tookad PDT was determined by directly irradiating the surface of the bladder, colon, abdominal muscle and pelvic plexus with a microlens fiber at various drug/light doses. The prostate and adjacent tissues were harvested one-week after the treatment and subjected to histopathological examination. PDT-induced prostate lesions were characterized by marked hemorrhagic necrosis. The bladder, colon, abdominal muscle and pelvic plexus appeared to be sensitive to PDT although the Tookad PDT-induced responses in these tissues were minimal compared to that of the prostate gland at the same dose levels. Nevertheless, the protection of the adjacent tissues should be taken into consideration during the total prostate ablation process due to their sensitivity to PDT. The sensitivity of the prostatic urethra is worth further investigation. Direct intraurethral irradiation might provide an ideal means to determine the sensitivity of the prostatic urethra and might lead to transurethral PDT protocols for the management of benign prostatic hyperplasia (BHP).

The current use and future trends of focal surgical therapy in the management of localized prostate cancer.

The current treatment algorithms for management of localized prostate cancer are mainly extirpative in nature. Treatment varies from expectant management to radical prostatectomy or radiation therapy. However, the ever-increasing emphasis on achieving the best survival benefit while better preserving quality of life, coupled with the introduction of new, safer, and efficacious minimally invasive ablative technologies, has led to the increased popularity of minimally invasive treatment (MIT). MIT refers to the use of a wide range of techniques for local target ablation of the prostate gland with minimal damage to the surrounding tissue. Currently these include cryotherapy and high-intensity focused ultrasound. However, other experimental technologies such as photodynamic therapy, interstitial prostate brachytherapy, and microwave and radiofrequency interstitial tumor ablation are also currently under investigation in early clinical trials. To date, the overall interim results for these relatively new modalities of treatment appear comparable to those for surgical and radiation therapies. However, randomized, controlled studies are needed to support use of these modalities as an alternative to surgery and radiation. In this review, we will address the current rationale for and knowledge of MIT with regard to its safety and efficacy in the treatment of localized prostate cancer. In addition, we will discuss future promising tools in MIT such as photodynamic therapy and the target focal therapy approach as a new trend for the treatment of organ-confined low-volume disease.