Dai, C., V. Ganesan, J. Zabell, Y. A. Nyame, N. Almassi, D. J. Greene, D. Hettel, C. Reichard, S. C. Haywood, H. Arora, et al., "Impact of 5α-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features.", The Journal of urology, vol. 199, issue 2, pp. 445-452, 2018. Abstract

PURPOSE: We determined the effect of 5α-reductase inhibitors on disease reclassification in men with prostate cancer optimally selected for active surveillance.

MATERIALS AND METHODS: In this retrospective review we identified 635 patients on active surveillance between 2002 and 2015. Patients with favorable cancer features on repeat biopsy, defined as absent Gleason upgrading, were included in the cohort. Patients were stratified by those who did or did not receive finasteride or dutasteride within 1 year of diagnosis. The primary end point was grade reclassification, defined as any increase in Gleason score or predominant Gleason pattern on subsequent biopsy. This was assessed by multivariable Cox proportional hazards regression analysis.

RESULTS: At diagnosis 371 patients met study inclusion criteria, of whom 70 (19%) were started on 5α-reductase inhibitors within 12 months. Median time on active surveillance was 53 vs 35 months in men on vs not on 5α-reductase inhibitors (p <0.01). Men on 5α-reductase inhibitors received them for a median of 23 months (IQR 6-37). On actuarial analysis there was no significant difference in grade reclassification for 5α-reductase inhibitor use in patients overall or in the very low/low risk subset. The overall percent of patients who experienced grade reclassification was similar at 13% vs 14% (p = 0.75). After adjusting for baseline clinicopathological features 5α-reductase inhibitors were not significantly associated with grade reclassification (HR 0.80, 95% CI 0.31-1.80, p = 0.62). Furthermore, no difference in adverse features on radical prostatectomy specimens was observed in treated patients (p = 0.36).

CONCLUSIONS: Among our cohort of men on active surveillance 5α-reductase inhibitor use was not associated with a significant difference in grade reclassification with time.

Elshafei, A., K. J. Tay, O. Kara, E. Malkoc, Y. Nyame, H. Arora, A. Hatem, S. A. Patel, F. Lugnani, T. J. Polascik, et al., "Associations Between Prostate Volume and Oncologic Outcomes in Men Undergoing Focal Cryoablation of the Prostate.", Clinical genitourinary cancer, vol. 16, issue 2, pp. e477-e482, 2018. Abstract

INTRODUCTION: The purpose of this study was to assess the relationship of total prostate volume (TPV) and oncologic outcomes following focal prostate cryoablation.

MATERIALS AND METHODS: A query of the Cryo On-Line Database (COLD) registry for men who underwent primary focal prostate cryoablation revealed 829 patients with complete data. The impact of TPV on oncologic outcomes including progression-free survival (PFS) and post-cryoablation biopsy outcome was assessed using Kaplan-Meier curves and Cox and logistic regression models.

RESULTS: The median follow-up time was 25.2 months (interquartile range [IQR], 12.7-48.2 months). The median age at time of treatment was 68 years (IQR, 63-74 years) with median prostate-specific antigen (PSA) 5.6 ng/mL (IQR, 4.4-7.5 ng/mL), and median TPV 35 mL (IQR, 26.5-46 mL). PFS was achieved in 83.2%, with positive post-cryoablation biopsy detected in 81 (35.7%) of 228 patients. Higher TPV was associated with higher biochemical progression (BP) using the Phoenix definition (39 vs. 34.5 mL; P = .003) and was an independent predictor of BP (hazard ratio, 1.01; P = .02). Conversely, men who had a positive post-cryoablation biopsy had significantly smaller median TPV on univariate and multivariate analyses (31 vs. 39 mL; P < .001), (odds ratio, 0.97; P = .001), respectively. Higher median pretreatment PSA density was associated with higher BP (0.18 vs. 0.16; P = .005) and positive post-cryoablation biopsy rates (0.2 vs. 0.16; P = .003).

CONCLUSION: Prostate volume has contradictory effects on BP and post-cryoablation biopsy outcome in men who underwent primary focal prostate cryoablation. Remnant viable tissue in larger prostates continues to produce more PSA over time, which may impact BP. This may raise the need to develop a new definition for oncologic success following focal gland therapy rather than the American Society for Radiation Oncology (ASTRO) and Phoenix definitions.

Aminsharifi, A., T. J. Polascik, A. Schulman, K. J. Tay, G. Jibara, C. Sze, E. Tsivian, A. Elshafei, and S. J. Jones, "Predictors of Rectourethral Fistula Formation After Primary Whole-Gland Cryoablation for Prostate Cancer: Results from the Cryo On-Line Database Registry.", Journal of endourology, vol. 32, issue 9, pp. 791-796, 2018. Abstract

PURPOSE: To define the incidence and risk factors associated with rectourethral fistula (RUF) formation following primary whole-gland cryosurgery using a multicenter centralized registry.

PATIENTS AND METHODS: The Cryo On-Line Data (COLD) registry was queried for men undergoing primary whole-gland cryotherapy between 1990 and 2014 who developed a RUF. Patient factors and disease parameters were correlated with RUF using chi-square and the t-test. Variables with p < 0.25 were entered into a binary logistic regression with stepwise backward elimination to determine the factors associated with RUF formation.

RESULTS: A total of 4102 men underwent primary whole-gland cryotherapy in the COLD registry at the time of analysis. Postoperative RUF was documented in 50 out of 4102 cases (1.2%). Patients with RUF had similar demographic data, prostate volume, preoperative prostate-specific antigen level, and clinical stage in comparison to those without fistula. On both univariate and multivariate analyses, postoperative urinary retention (odds ratio [OR]: 6.30; confidence interval [95% CI] 3.43-11.58, p < 0.001), preoperative Gleason score of ≥7 (OR: 1.92; 95% CI 1.08-3.43, p = 0.027), and preoperative incontinence (OR: 2.95; 95% CI 1.12-7.76, p = 0.028) were the most significant risk factors associated with RUF formation.

CONCLUSION: Primary whole-gland cryotherapy for prostate cancer is associated with a historically low rate (1.2%) of postoperative RUF formation. The rate decreased further to 0.55% over the last several years, suggesting better patient selection and technical improvement. Postoperative urinary retention, Gleason score ≥7, and preoperative urinary incontinence were the key demographic, clinical, and pathologic features associated with RUF formation in this study.

Aminsharifi, A., T. J. Polascik, M. Tsivian, A. Schulman, E. Tsivian, K. J. Tay, A. Elshafei, and S. J. Jones, "Does Any Racial Disparity Exist in Oncologic Outcomes After Primary Cryotherapy for Prostate Cancer? A Matched-pair Comparative Analysis of the Cryo On-Line Data Registry.", Clinical genitourinary cancer, vol. 16, issue 5, pp. e1073-e1076, 2018. Abstract

BACKGROUND: African-American (AA) men have the greatest incidence of and disease-specific mortality from prostate cancer of any racial group. Although encouraging oncologic and functional outcomes have been reported with prostate cancer cryotherapy, little is known about how ethnicity can potentially affect the oncologic outcomes of primary cryotherapy. We report the oncologic outcomes of primary cryotherapy in AA patients through a matched-pair analysis.

PATIENTS AND METHODS: A 1:2 (AA to non-AA) cohort of patients was designed using the Cryo-On-Line Data Registry. The 2 arms were matched for patient age, prostate-specific antigen level, Gleason score, and prostate volume. The oncologic outcome was defined in terms of the biochemical recurrence (BCR) rates after primary cryoablation using Phoenix criteria. The results of "for-cause" post-treatment biopsies and the BCR-free survival rates were also analyzed between the 2 groups.

RESULTS: The 1:2 cohort of AA and non-AA men in the present study included 109 and 218 men, respectively. Their median age (69 vs. 71 years; P = .71), median prostate-specific antigen level (6.5 vs. 6.8 ng/mL; P = .95), median prostate volume (32 vs. 30 cm; P = .31), Gleason score distribution (P = .97), and prostate cancer risk group (P = .12) were similar statistically. The median postoperative follow-up period was also comparable between the 2 groups (AA, 32 months vs. non-AA, 27 months; P = .52). The BCR rates were similar between the AA and non-AA men (14% vs. 17%; P = .52). Likewise, the rate of positive "for-cause" prostate biopsy findings was similar between the 2 groups (AA vs. non-AA, 25% vs. 36%; P = .44). Furthermore, the 5-year biochemical relapse-free survival rates were comparable for the AA and non-AA patients (74% vs. 71%; P = .37).

CONCLUSION: When matched for tumor characteristics, cryotherapy as a treatment modality for primary, clinically localized prostate cancer offers men of African-American descent similar oncologic outcomes to those of non-AA men.

Tay, K. J., T. J. Polascik, A. Elshafei, M. L. Cher, R. W. Given, V. Mouraviev, A. E. Ross, and S. J. Jones, "Primary Cryotherapy for High-Grade Clinically Localized Prostate Cancer: Oncologic and Functional Outcomes from the COLD Registry.", Journal of endourology, vol. 30, issue 1, pp. 43-8, 2016 Jan. Abstract

OBJECTIVE: To evaluate the oncological and functional outcomes of primary cryotherapy in men with clinically localized, high-grade prostate cancer.

SUBJECTS AND METHODS: We included all men with biopsy Gleason score ≥8, localized (cT1-2) disease with a serum prostate-specific antigen (PSA) ≤50 ng/mL from the Cryo On-Line Data (COLD) registry. The primary outcome was biochemical progression free survival (BPFS) as defined by the Phoenix criteria (nadir PSA +2 ng/mL). Secondary outcomes of continence (defined as strictly no leak) and potency (able to have intercourse) were patient reported. Factors influencing BPFS were evaluated individually using Kaplan Meier and in a multivariate model using Cox regression.

RESULTS: Altogether, 300 men were included for analysis. The median follow-up was 18.2 months (mean 28.4) and median BPFS was 69.8 months. Based on Kaplan-Meier analysis, the estimated 2- and 5-year BPFS rate was 77.2% and 59.1%, respectively. Neoadjuvant hormonal therapy was administered to 41% of men and this tended to occur in men with larger prostates, likely as a technical consideration for downsizing before cryosurgery. At multivariate analysis, the presence of Gleason score 9 or 10 (Hazard Ratio [HR] 1.9) and a posttreatment PSA nadir of ≥0.4 ng/mL (HR 5.7) were the only significant variables associated with biochemical progression using Cox regression. Complete continence was noted in 90.5% of men and potency in 17% of men at the 12-month follow-up. The incidence of rectourethral fistulae and urinary retention requiring intervention beyond temporary catheterization was 1.3% and 3.3%, respectively.

CONCLUSION: Primary cryotherapy appears to be effective and safe in the community setting for high-grade, clinically localized prostate cancer in the short term.

Elshafei, A., Y. Nyame, O. Kara, A. Badawy, I. Amujiogu, K. Fareed, E. Klein, and S. J. Jones, "More Favorable Pathological Outcomes in Men with Low Risk Prostate Cancer Diagnosed on Repeat versus Initial Transrectal Ultrasound Guided Prostate Biopsy.", The Journal of urology, vol. 195, issue 6, pp. 1767-72, 2016 Jun. Abstract

PURPOSE: We assessed the pathological outcomes after radical prostatectomy in men with favorable risk prostate cancer diagnosed on first/initial biopsy compared to those of men who were diagnosed on a subsequent/repeat prostate biopsy.

MATERIALS AND METHODS: We identified 422 patients who met National Comprehensive Cancer Network® very low (199) and low risk (223) prostate cancer definitions who instead underwent radical prostatectomy. In each risk category we compared adverse pathological outcomes, defined as Gleason score upgrading, extraprostatic extension, seminal vesicle invasion and positive surgical margins, between men diagnosed on initial prostate biopsy vs repeat/subsequent prostate biopsy after a negative biopsy(-ies).

RESULTS: There were no significant differences in the baseline clinical and demographic characteristics between the groups. However, men who were diagnosed on initial prostate biopsy demonstrated a higher median maximum cancer percent per single core (p <0.001) and higher median percent of positive cores (p <0.001). Compared to repeat/subsequent prostate biopsy, men diagnosed on initial prostate biopsy had a higher Gleason score upgrade (7 or greater) (57.7% vs 42.1%, p=0.005) and extraprostatic extension (14.1% vs 5.4%, p=0.01). On stratified analysis comparing initial prostate biopsy to repeat/subsequent prostate biopsy, very low risk disease was associated with Gleason score upgrade (49.3% vs 31.8%, p=0.02) and low risk disease demonstrated higher rates of extraprostatic extension (19.9% vs 6.0%, p=0.02).

CONCLUSIONS: The likelihood of adverse pathological outcomes at radical prostatectomy is lower in men diagnosed with favorable risk prostate cancer on repeat/subsequent prostate biopsy than in men diagnosed on initial prostate biopsy, and may represent an important consideration in risk stratifying cases of favorable risk prostate cancer.

Kovac, E., A. Elshafei, K. J. Tay, M. Mendez, T. J. Polascik, and S. J. Jones, "Five-Year Biochemical Progression-Free Survival Following Salvage Whole-Gland Prostate Cryoablation: Defining Success with Nadir Prostate-Specific Antigen.", Journal of endourology, vol. 30, issue 6, pp. 624-31, 2016 Jun. Abstract

BACKGROUND AND OBJECTIVES: Salvage prostate cryoablation is an effective treatment for patients with localized prostate cancer relapse following primary radiotherapy. The postsalvage prostate-specific antigen (PSA) nadir that best predicts long-term biochemical progression-free survival (bPFS) is not yet defined. We sought to determine what nadir PSA best predicted success following salvage whole-gland cryoablation.

PATIENTS AND METHODS: We retrospectively reviewed a cohort of 486 hormone-naive patients who underwent salvage whole-gland cryoablation from the Cryo On-Line Database (COLD). Studied variables were age, race, initial PSA, presalvage prostate-specific antigen (psPSA), initial Gleason score, Gleason score at presalvage biopsy, clinical stage, and follow-up PSA values. Kaplan-Meier (KM) analysis was used to calculate 5-year bPFS using the Phoenix criteria. Hazard ratio and relative risk were also analyzed. Differences among the KM estimates, at 5 years, were calculated using the log-rank test.

RESULTS: Using group thresholds, KM analysis identified nadir PSA less than or greater than 0.4 ng/mL as the nadir PSA threshold, with the greatest difference in bPFS. The KM estimated 5-year bPFS was 75.5% and 22.1% for nadir PSA <0.4 and ≥0.4 ng/mL, respectively. Stratified by psPSA, the KM estimated 5-year bPFS comparing patients with PSA nadir <0.4 vs ≥0.4 ng/mL was 78.5% and 17.9% (p < 0.0001) for psPSA <4 ng/mL, 77.1% and 15.7% (p < 0.0001) for psPSA 4-10 ng/mL, and 77.8% and 16.8% (p < 0.0001) for psPSA >10 ng/mL, respectively.

CONCLUSION: The best objective indicator of biochemical success following whole-gland salvage cryoablation of the prostate is PSA nadir <0.4 ng/mL.

Greene, D. J., A. Elshafei, Y. A. Nyame, O. Kara, E. Malkoc, T. Gao, and S. J. Jones, "External validation of a PCA-3-based nomogram for predicting prostate cancer and high-grade cancer on initial prostate biopsy.", The Prostate, vol. 76, issue 11, pp. 1019-23, 2016 Aug. Abstract

INTRODUCTION: The aim of this study was to externally validate a previously developed PCA3-based nomogram for the prediction of prostate cancer (PCa) and high-grade (intermediate and/or high-grade) prostate cancer (HGPCa) at the time of initial prostate biopsy.

METHODS: A retrospective review was performed on a cohort of 336 men from a large urban academic medical center. All men had serum PSA <20 ng/ml and underwent initial transrectal ultrasound-guided prostate biopsy with at least 10 cores sampling for suspicious exam and/or elevated PSA. Covariates were collected for the nomogram and included age, ethnicity, family history (FH) of PCa, PSA at diagnosis, PCA3, total prostate volume (TPV), and abnormal finding on digital rectal exam (DRE). These variables were used to test the accuracy (concordance index) and calibration of a previously published PCA3 nomogram.

RESULTS: Biopsy confirms PCa and HGPCa in 51.0% and 30.4% of validation patients, respectively. This differed from the original cohort in that it had significantly more PCa and HGPCA (51% vs. 44%, P = 0.019; and 30.4% vs. 19.1%, P < 0.001). Despite the differences in PCa detection the concordance index was 75% and 77% for overall PCa and HGPCa, respectively. Calibration for overall PCa was good.

CONCLUSIONS: This represents the first external validation of a PCA3-based prostate cancer predictive nomogram in a North American population. Prostate 76:1019-1023, 2016. © 2016 Wiley Periodicals, Inc.

Greene, D. J., A. Elshafei, Y. A. Nyame, O. Kara, E. Malkoc, T. Gao, and S. J. Jones, "External validation of a PCA-3-based nomogram for predicting prostate cancer and high-grade cancer on initial prostate biopsy.", The Prostate, vol. 76, issue 11, pp. 1019-23, 2016 Aug. Abstract

INTRODUCTION: The aim of this study was to externally validate a previously developed PCA3-based nomogram for the prediction of prostate cancer (PCa) and high-grade (intermediate and/or high-grade) prostate cancer (HGPCa) at the time of initial prostate biopsy.

METHODS: A retrospective review was performed on a cohort of 336 men from a large urban academic medical center. All men had serum PSA <20 ng/ml and underwent initial transrectal ultrasound-guided prostate biopsy with at least 10 cores sampling for suspicious exam and/or elevated PSA. Covariates were collected for the nomogram and included age, ethnicity, family history (FH) of PCa, PSA at diagnosis, PCA3, total prostate volume (TPV), and abnormal finding on digital rectal exam (DRE). These variables were used to test the accuracy (concordance index) and calibration of a previously published PCA3 nomogram.

RESULTS: Biopsy confirms PCa and HGPCa in 51.0% and 30.4% of validation patients, respectively. This differed from the original cohort in that it had significantly more PCa and HGPCA (51% vs. 44%, P = 0.019; and 30.4% vs. 19.1%, P < 0.001). Despite the differences in PCa detection the concordance index was 75% and 77% for overall PCa and HGPCa, respectively. Calibration for overall PCa was good.

CONCLUSIONS: This represents the first external validation of a PCA3-based prostate cancer predictive nomogram in a North American population. Prostate 76:1019-1023, 2016. © 2016 Wiley Periodicals, Inc.

Kara, O., A. Elshafei, Y. A. Nyame, B. Akdogan, E. Malkoc, T. Gao, M. Altan, B. Citamak, E. Mammadov, F. Dursun, et al., "The nomogram conundrum: a demonstration of why a prostate cancer risk model in Turkish men underestimates prostate cancer risk in the USA.", International urology and nephrology, vol. 48, issue 10, pp. 1623-9, 2016 Oct. Abstract

PURPOSE: The utility of a nomogram is based on the patient population it is designed for-and their inherent properties and biases. Our aim was to demonstrate the variability in predictive model accuracy and utility between different populations.

METHODS: Our model is based on 761 men who underwent initial TRUS biopsy at a single institution in Turkey. Patients were included if they had at least 10 cores on biopsy and PSA level <20 ng/ml. Multivariable logistic regression models were used to develop a new nomogram. External validity was tested with two different cohorts one from another institution in Turkey (N = 136) and cohort from USA (N = 2242).

RESULTS: Prostate cancer (PCa) and high-grade PCa was diagnosed in 249/761 (32.7 %) and 101/761 (13.3 %) patients from Ankara, Turkey, respectively. Predictors of PCa were age (p < 0.0001, OR 2.11), PSA (p = 0.044, OR 1.44), PV (p < 0.0001, OR 0.38), %fPSA (p = 0.016, OR 0.72), and abnormal DRE (p < 0.0001, OR 2.05). The predictive accuracy (c-index) of our nomogram was 73 %. C-indices of 71 and 70 % were recorded in external validation cohorts from Turkey and the USA, respectively. Virtually ideal calibration was recorded for the internal validated predictive model, and good calibration was recorded when applied to the Istanbul cohort. However, the model/nomogram underestimates PCa risk in the US cohort.

CONCLUSION: This is the first nomogram predicting the risk of PCa at initial biopsy in a Turkish population and provides a good risk estimation tool with good predictive accuracy and calibration in the Turkish populations. However, our study demonstrates the poor transferability of predictive tools to widely different populations.