Aquablation Therapy in Large Prostates (80-150 mL) for Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Final WATER II 5-Year Clinical Trial Results.

PURPOSE: We report 5-year safety and efficacy outcomes of the Aquablation procedure for the treatment of men with symptomatic benign prostatic hyperplasia and large-volume prostate glands. MATERIALS AND METHODS: A total of 101 men with moderate to severe benign prostatic hyperplasia symptoms and prostate volumes between 80 and 150 mL underwent a robotic-assisted Aquablation procedure in a prospective multicenter international trial (NCT03123250). Herein we report the final 5-year results. RESULTS: The study successfully met its safety and efficacy performance goal, which was based upon transurethral resection of the prostate outcomes typically done in smaller prostates, at 3 months. Mean prostate volume was 107 mL (range 80-150) at baseline. Patient symptoms showed a significant improvement where the mean (SD) International Prostate Symptom Score of 22.6 (6.4) at baseline to 6.8 (4.6) at 5 years, resulting in a change score of 15.9 (7.7, P < .001). Uroflowmetry measurements also demonstrated improvement where the mean maximum urinary flow rate increased from 8.6 (SD 3.4) to 17.1 (9.8) mL/s at 5 years, resulting in a change score of 9.2 (11.1) mL/s at 5 years (P < .001). A regression analysis evaluating change in PSA as a function of baseline PSA across all time points out to 5 years resulted in a 50% reduction. A prespecified subgroup analysis using a baseline prostate volume cutoff of 100 mL showed no difference in efficacy outcomes through 5 years. Freedom from a secondary benign prostatic hyperplasia procedure at 5 years was 96.3% based on Kaplan-Meier. CONCLUSIONS: At 5-years of prospective follow-up, the Aquablation procedure was shown to be safe with durable efficacy and low rates of retreatment in men with large prostates (80-150 mL).

WATER vs WATER II 3-Year Update: Comparing Aquablation Therapy for Benign Prostatic Hyperplasia in 30-80 cc and 80-150 cc Prostates.

OBJECTIVE: To compare the outcomes of Aquablation for small-to-moderate (30-80cc) prostates with the outcomes for large (80-150 cc) prostates at 3-year follow up. METHODS: WATER is a prospective, double-blind, multicenter, international clinical trial comparing the safety and efficacy of Aquablation and TURP in the treatment of LUTS/BPH in men 45-80 year with a prostate of 30cc-80cc. WATER II is a prospective, multicenter, single-arm international clinical trial of Aquablation in men with a prostate of 80cc-150cc. We compare 36-mo outcomes amongst 116 WATER and 101 WATER II study subjects undergoing Aquablation. RESULTS: International Prostate Symptom Score (IPSS) scores improved from 22.9 and 23.2 at baseline in WATER and WATER II, respectively, to 8.0 and 6.5 at 36-month, with 36-mo reductions of 14.4 and 16.3 points, respectively (P = .247). At baseline, urinary flow rate (Qmax) was 9.4 and 8.7 cc/sec in WATER and WATER II, improving to 20.6 and 18.5 cc/sec, respectively (P = .552) at 36-mo. Improvements in both IPSS and Qmax were immediate and sustained throughout follow-up. At 3 year, 98% and 94% of treated patients were BPH medication-free in WATER and WATER II, respectively (P = .038). At 3yr, 96% and 97% of treated patients were free from surgical retreatment in WATER and WATER II, respectively (P = .613). CONCLUSIONS: Three-year follow-up demonstrates that Aquablation therapy leads to sustained outcomes, few irreversible complications, and low retreatment rates for the treatment of LUTS/BPH independently of prostate volume.

Aquablation for benign prostatic hyperplasia in large prostates (80-150 mL): 6-month results from the WATER II trial.

OBJECTIVE: To present 6-month safety and effectiveness data from a multicentre prospective study of aquablation in men with lower urinary tract symptoms (LUTS) attributable to benign prostatic hyperplasia (BPH) with prostate volumes between 80 and 150 mL. METHODS: Between September and December 2017, 101 men with LUTSattributable to BPHwere prospectively enrolled at 16 centres in Canada and the USA. RESULTS: The mean prostate volume was 107 mL. The mean length of hospital stay after the aquablation procedure was 1.6 days (range: same day to 6 days). The primary safety endpoint (Clavien-Dindo grade 2 or higher or any grade 1 event resulting in persistent disability) at 3 months occurred in 45.5% of men, which met the study design goal of < 65% (P < 0.001). At 6 months, 22% of the patients had experienced a Clavien-Dindo grade 2, 14% a grade 3 and 5% a grade 4 adverse event. Bleeding complications requiring intervention and/or transfusion were recorded in eight patients prior to discharge and in six patients after discharge. The mean International Prostate Symptom Score improved from 23.2 ± 6.3 at baseline to 6.7 ± 5.1 at 3 months, meeting the study's primary efficacy endpoint goal (P < 0.001). The maximum urinary flow rate increased from 8.7 to 18.8 mL/s (P < 0.001) and post-void residual urine volume decreased from 131 at baseline to 47 at 6 months (P < 0.0001). At 6 months, prostate-specific antigen concentration reduced from 7.1 ± 5.9 ng/mL at baseline to 4.0 ± 3.9 ng/mL, a 44% reduction. CONCLUSIONS: Aquablation is safe and effective in treating men with larger prostates (80-150 mL), without significant increase in procedure or resection time.

Prevention of Prostate Tumor Development by Stimulation of Antitumor Immunity Using a Standardized Herbal Extract (Deep Immune®) in TRAMP Mice.

Low-risk prostate cancer (PCa) does not require immediate treatment, but PCa progression after years of active surveillance will need the treatment. This study was to test the efficacy of immunostimulant Deep Immune (DI) in controlling PCa progression. DI is an extract of eight different medicinal herbs. In vitro activity of DI was determined by phagocytosis activation using flow cytometric analysis of fluorescence-labeled latex bead uptake, expression of immune-modulating 84 genes using PCRarray, and tumor killing using coculturing with immune cells. Anti-PCa activity of DI in vivo was examined in male TRAMP mice. In vitro DI stimulated phagocytosis and expression of a panel of inflammatory mediators (C4b, CXCL3, lymphotoxin, NOS2, TLR1, TNF, and TNFSF14) in cultured macrophages and increased tumor killing of both macrophages and TRAMP mouse splenocytes. Daily intake of this herbal product significantly suppressed the tumor size (P = 0.0368) with lower histopathologic scores (P = 0.0364) in TRAMP mice, which were associated with an increase in both splenocyte cytotoxicity against tumor cells and numbers of CD8 T cells, macrophages, and dendritic cells in the spleens in vivo. In conclusion, daily intake of DI prevents PCa progression in TRAMP mice, suggesting the possible effectiveness of the immunostimulant herbal products on prevention of PCa progression after diagnosis of low-risk PCa.

Identifying intermediate-risk candidates for active surveillance of prostate cancer.

PURPOSE: Although already established for very-low and low-risk (LR) prostate cancer (PCa), controversy remains around offering active surveillance (AS) to men with intermediate-risk (IR) PCa. As IR represents a broad spectrum of disease biology, there is a critical need to define eligibility criteria that will enable both patient and physician to accept AS as the best balance of competing risks. In this study, we aimed to identify predictors of progression to enable optimal patient selection. MATERIALS AND METHODS: In our AS cohort, men were assigned to risk categories according to the National Comprehensive Cancer Network (NCCN favorable and NCCN unfavorable) and the CAPRA classifications. Clinical, biochemical and pathological characteristics, progression to definitive invasive treatment, and pathologic progression on follow-up biopsies were compared among these groups. A multivariate Cox regression model was used to identify independent predictors of progression on AS. RESULTS: AS was the initial management option for 651 men, including 144 with IR PCa. During the median follow-up of 4.5 years (range: 0.6-19.1), 259 patients (39.7%) underwent definitive treatment. Further, 5- and 10-year predicted rates of intervention for IR patients were 50% and 66%, respectively. Treatment rates were no different between the NCCN LR and NCCN IR groups, but were higher in CAPRA IR compared to CAPRA LR groups (P = 0.025). NCCN unfavorable IR patients had a twofold increased risk of definitive intervention compared to favorable IR (hazard ratio [HR] = 2.07; 95% CI: 1.17-3.65; P = 0.01). In the entire cohort, the percentage of biopsy cores positive (continuous variable; P = 0.006) and ISUP grade 2 or higher on initial biopsy (P = 0.027) were independent predictors of cessation of AS on multivariate analysis. In the intermediate group, only the percentage of positive biopsy cores was an independent predictor (P = 0.021) of AS cessation. Only 1 IR patient developed metastatic disease (0.7%). Actuarial overall survival at 5 and 10 years was 98.6% and 94.1%, respectively. There were 2 PCa deaths at 18.7 and 19.1 years of follow-up. CONCLUSION: In all AS, increasing percentage of core involvement and presence of Gleason pattern 4 are predictors of increased risk of progression. For IR patients, the NCCN favorable criteria and CAPRA score predict those more likely to remain on AS.

Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma.

Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC.