Introduction

The prevalence of lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH) increases significantly with age, with some data suggesting up to 90% of men in their eighth decade of life suffering from this condition [1, 2]. While LUTS/BPH is often not life threatening, it can have a significant impact on quality of life and, when left untreated, may lead to serious complications such as infections, calculus formation, bleeding, urinary retention, and deterioration of renal function [2].

Management options for LUTS/BPH associated with prostates of small to moderate volume are numerous and include oral medications, in-office procedures, and more traditional transurethral resection and laser endoscopic procedures, with varying success rates [2]. For men with significantly enlarged prostates, many of these options are neither safe nor efficacious and not recommended per AUA guidelines [3, 4]. One alternative is to proceed with simple open prostatectomy, but this requires abdominal access and is associated with considerable bleeding as well as longer hospitalization stay and catheterization time rates [5,6,7]. Another alternative is GreenLight XPS (Boston Scientific, Marlborough, MA, USA) photoselective vaporization (PVP), but this has been associated with significant retreatment rates and need for conversion to transurethral resection due to intra-operative bleeding [8, 9]. Finally, Holmium enucleation of the prostate (HoLEP) has emerged as a reasonable approach for larger prostates, but has not been widely adopted, mostly due to its significant learning curve [10, 11].

More recently, Aquablation (PROCEPT BioRobotics, Inc.), a robotically executed, surgeon-guided, ultrasound-imaging aided, waterjet treatment has become available as a potential option for the management of LUTS/BPH [12, 13]. In a randomized, double-blinded trial of Aquablation vs. transurethral resection of prostate (TURP) in men with 30–80 cc prostates (WATER trial), Aquablation demonstrated non-inferior symptom relief as compared to TURP, but with a lower risk of sexual dysfunction [14]. Notably, Aquablation was associated with a more pronounced symptom relief benefit in a subgroup of larger (50–80 cc) prostates.

These results served as the impetus for the WATER II trial, a single-arm prospective, multicenter, international clinical trial of Aquablation for the surgical treatment of LUTS/BPH associated with large prostate volumes (80–150 cc). Data demonstrating 1-month feasibility and safety were recently published [15]. In this manuscript, we present longer 3-month safety and efficacy data from the cohort of American men included in the WATER II trial.

Methods

Trial design and participants

WATER II (NCT03123250) is a prospective, multicenter, international clinical trial of Aquablation for the surgical treatment of LUTS/BPH in men 45 to 80 years of age with a prostate volume between 80 and 150 cc as measured by transrectal ultrasound. Participants were required to have a baseline International Prostate Symptom Score (IPSS) ≥ 12, and a maximum urinary flow rate (Qmax) < 15 mL/s, a serum creatinine < 2 mg/dL, a history of inadequate or failed response to medical therapy and mental capability and willingness to participate in the study. Men were excluded if they had body mass index ≥ 42, a history of prostate or bladder cancer, clinically significant bladder calculus or bladder diverticulum, active infection, previous urinary tract surgery, urinary catheter use daily for 90 or more consecutive days, chronic pelvic pain, urethral stricture, meatal stenosis or bladder neck contracture, use of anticholinergic agents specifically for bladder problems, and other general conditions that could prevent adequate study follow-up. Patients were not excluded for prior prostate surgery or if in retention unless the catheter was in place for more than 90 days. Only patients from the United States were included in this analysis. The study was performed with Institutional Review Board approval from each participating institution and all participants provided informed consent using study-specific forms prior to any test that went beyond standard care.

Study parameters

At baseline, subjects completed IPSS as well as several validated questionnaires (Incontinence Severity Index, Pain Intensity Scale, International Index of Erectile Function (IIEF-5), the Male Sexual Health Questionnaire (MSHQ-EjD), uroflowmetry and post-void residual (PVR) volume measurements, and underwent standard laboratory blood assessment. Questionnaires, uroflowmetry, PVR and laboratory tests were also required at postoperative visits at 1 and 3 months.

Aquablation was performed using the AquaBeam System (PROCEPT BioRobotics, Redwood City, California, USA), as described previously [14]. Following the Aquablation treatment, the bladder was thoroughly irrigated to remove residual prostate tissue and blood clots that tend to accumulate during resection. Hemostasis was achieved using tissue tamponade with a low-pressure Foley balloon catheter, which was inflated with 40–80 cc of saline either at the bladder neck or within the prostatic fossa with adequate traction using TRUS guidance.

Data study and monitoring

Study data were entered into an electronic data capture system by site coordinators, were monitored, and source-verified. Physician surveys were collected on paper and entered into a separate database. Adverse events were collected throughout follow-up and evaluated by an independent clinical events committee. A data monitoring committee reviewed safety data periodically.

Statistical analysis

A standard statistical approach was used for analysis that used the Students’ t-test for continuous variables and Fisher’s test for ordinal/binary variables. All statistical analysis was performed using R [16]. p-value ≤ 0.05 was considered statistically significant. Additional analysis, such as a US only cohort, was allowed per protocol.

Results

Procedural outcomes

Of 92 screened patients, 82 subjects who met inclusion and exclusion criteria were enrolled at 13 US sites between September and December 2017. Of those, 79 subjects completed the 3-month follow-up visit. Of the three missed visits, one subject withdrew consent, one subject missed the visit due to holiday schedule, and one subject missed the visit due to adverse event recovery. Baseline characteristics are summarized in Table 1. Mean age was 67.9 ± 6.5 years and mean baseline IPSS score was 23.7 points ± 6.4. Study procedures were performed under general anesthesia in 18% and spinal anesthesia in 82% of patients. Prostate volume ranged from 80–150 cc (consistent with study eligibility criteria) with a mean volume of 108 ± 21.1 cc. A middle lobe was present in 82% of cases with an average protrusion distance of 1.9 cm ± 0.81. Table 1 summarizes the baseline characteristics.

Table 1 Baseline characteristics (n = 82)
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Mean operative time, defined as handpiece placement until final urinary catheter placement, was 38.2 ± 14.4 min. The mean Aquablation resection time was 7.7 ± 3.3 min. The number of men requiring a single pass, 2 passes, and greater than 2 passes of resection were 35%, 54%, and 11%, respectively (Table 2).

Table 2 Procedure characteristics
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Postoperatively, a urethral catheter balloon placed in the bladder under mild tension was used for hemostasis in 98% of cases. The duration and degree of traction were at the surgeon’s discretion, based on urine color and clinical status postoperatively. None of the patients in this cohort necessitated post-Aquablation cautery for hemostasis. The average length of stay following the procedure was 1.6 ± 1.04 days. The average duration to final catheter removal was 4.3 ± 3.8. Re-catheterization occurred in 11% of patients following a successful voiding trial. Hemoglobin levels decreased from a mean of 14.9 ± 1.4 g/dL at baseline to 11.8 ± 2.2 g/dL postoperatively (p < 0.0001).

Clinical end-points

Mean pre-, 1 month and 3 months post-treatment IPSS scores were 23.7 ± 6.4, 11.8 ± 6.5, and 7.1 ± 5.1, p < 0.05. Mean pre-, 1 month and 3 months post-treatment IPSS QOL scores were 4.6 ± 1, 2.7 ± 1.9, and 1.9 ± 1.7, p < 0.05. Mean pre-, 1 month and 3 months post-treatment Qmax were 9.2 ± 3.3 ml/s, 15.2 ± 8.2 ml/s, and 19.5 ± 13.0 ml/s, p < 0.05. Mean pre-, 1 month and 3 months post-treatment PVR’s were 120.6 ± 119.1 cc, 46.6 ± 51.6 cc, and 50.6 ± 61.6 cc, p < 0.05. Outcomes are summarized in Table 3 and Fig. 1.

Table 3 Efficacy outcomes
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Fig. 1
figure 1

One- and 3-month functional outcomes following Aquablation in 82 men with LUTS/BPH and large prostates, a IPSS, b IPSS QOL, c Qmax, d PVR. *Denotes statistical significance compared to baseline. + + denotes statistical significance compared to 1 month

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Treatment-related adverse events

The CD grade 2 or higher event rate at 3 months was 34.1% (Table 4). The CD grade 1 persistent events consisted of ejaculatory dysfunction (11%), incontinence (6%), and erectile dysfunction (0%).

Table 4 ComplicationsPlease check and confirm if table 4 legend is ok.Please refer the PDF
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Discussion

In this prospective multicenter clinical trial of 82 American men with moderate-to-severe LUTS/BPH and large prostates volumes (80–150 cc), Aquablation demonstrated safety and significant clinical improvements in all urinary parameters (IPSS, IPSS QOL, Qmax, and PVR) at 3 months post-treatment.

In the multicenter, randomized WATER trial, Aquablation notably demonstrated superior functional outcomes and acceptable safety as compared to TURP in patients with larger prostates of 50–80 cc [14]. These results prompted the initiation of the WATER II trial for even larger prostates of 80–150 cc. The recently published 1 month study aimed to assess the safety profile of Aquablation in this patient cohort [15]. In this group, grade 2, 3, 4 CD complications were recorded in 19%, 11%, and 5%, respectively, and bleeding complications were recorded in 9.9% of patients. In this extended American follow-up, grade 2 or higher CD complications were 34% showing very little change from the 1 month safety results. Of note, no additional bleeding was reported. While these rates are slightly higher than CD2 + grade complications reported in WATER (20%), they do compare favorably to those reported with open prostatectomy for larger prostates [6, 17]. While reports suggest that PVP may be associated with lower transfusion rates, it is worth noting the high associated rates of conversion to TURP for control of hemostasis [8, 18, 19]. None of the patients in this cohort required transurethral cautery for hematuria, with the only postoperative hemostatic strategy used being balloon traction therapy. Finally, while HoLEP has been associated with lower bleeding/transfusion rates than the currently presented Aquablation data, it is associated with a considerable learning cure, and the need for post-enucleation tissue morcellation with its potential morbidity [10, 20, 21].

As has been reported with other surgical interventions for large prostates, there was initial transient combined mixed and urge urinary incontinence reported in 8% of patients at 1 month following Aquablation, but this decreased to 6% by 3 months, and should continue to improve over time with further bladder recovery [15]. None of the patients in this cohort experienced worsening erectile function, as per IIEF-5, while 11% reported anejaculation. This is in stark contrast to other surgical options demonstrating up to 40–100% ejaculatory dysfunction rates [22, 23].

This study is the first to provide functional outcomes related to Aquablation for larger prostates. The 3-month data provided herein are comparable to those observed with Aquablation in the WATER trial with smaller prostates, providing further evidence to the generalizability of this intervention, regardless of prostate size [14]. Changes in IPSS, IPSS QoL, Qmax, and PVR at 3 months in this study were −16.6 points, −2.7 points, + 10.8 mL/s and −72.0 cc, as compared to −17.0 points, −3.5 points, + 10.9 mL/s and –55.0 cc, respectively at 6 months in the WATER trial. The IPSS score improvement in this study compares favorably to that reported in large studies with HoLEP (−14.4 points) and PVP (−13.0 points), but inferiorly to that seen with simple prostatectomy (−23.2 points) [18, 24, 25]. Similarly, Qmax improvements with Aquablation in this study compared well with HoLEP ( + 11.2 mL/s) but were slightly inferior to simple prostatectomy ( + 13–20 mL/s) [18, 24]. Considering, however, that these results were obtained 6 months after simple prostatectomy and the continued improvements in IPSS and Qmax at 1 then 3 months with Aquablation, it will be important to compare outcomes at 6 months.

One major advantage of Aquablation over other surgical interventions is the significantly shorter operative time needed (38 min vs. 93–236 min for other interventions) [15]. Furthermore, while the mean prostate volume in this study was 108 cc, as compared to 54 cc in the WATER trial, the total operative time was only increased by 5 min, a surrogate of homogeneity of length of intervention regardless of prostate size. Another major advantage is the short hospital stay needed following Aquablation (mean 1.6 days) in this study as compared to other surgical interventions for larger prostates (1.2–11.9 days) [15].

One of the major limitations of the WATER II trial is that it is a single-arm Aquablation study without any control group, be it placebo or any other well recognized treatment modality for large prostates. Another notable limitation is the small population sample. Considering the strong randomized data obtained from the WATER trial, however, we feel that this analysis is sufficient to further demonstrate safety and efficacy of Aquablation in a subset of patients with large prostates. Furthermore, standardized reporting of events categorized by CD is not routinely reported in other BPH studies for large prostates. Finally, while the duration of follow-up of this cohort is short, it does allow us to demonstrate exciting early functional post-treatment improvements. Longer term data regarding efficacy and safety are necessary to further validate Aquablation as a durable treatment option for men with bothersome LUTS/BPH and large prostates.

Conclusions

In a 3-month U.S. cohort analysis, Aquablation appears to provide a strong surgical alternative in patients with LUTS/BPH due to larger prostate volumes with good functional outcomes, and relatively short operative time and length of hospital stay, and acceptable complication and transfusion rates. Results in this cohort demonstrate similar outcomes to those observed in the overall study population.