Comprehensive Evaluation of Focal Therapy Complications in Prostate Cancer: A Standardized Methodology

Abstract

Purpose:

Today, up to one-third of newly diagnosed prostate cancer (PCa) cases may be suitable for focal treatment. The lack of data about the toxicity profiles of lesion-targeting therapies, however, has made it difficult to compare treatment modalities. The aim of the present study was to evaluate comprehensively the incidence, severity, and timing of onset of complications for PCa patients undergoing focal high-intensity focused ultrasound (HIFU) and focal cryosurgical ablation of the prostate (CSAP).

Materials and Methods:

A total of 336 patients were included who underwent focal HIFU or focal CSAP as a primary treatment for PCa between January 2009 and December 2017. Mean follow-up was 11 months (standard deviation: 3.0). All complications were captured and graded according to severity, and classified by timing of onset. Univariate and multivariate analysis was performed to identify predictors of the most common side effects.

Results:

There were 98 complications in 79/210 patients (38%) undergoing focal HIFU and 34 complications in 27/126 patients (21%) undergoing focal CSAP. In terms of severity, 95% of the complications of focal HIFU and 91% of the complications of focal CSAP were minor. Most complications presented in the early postoperative period. On multivariate analysis, subtotal HIFU was associated with acute urinary retention (AUR), while a smaller prostate size and longer catheterization time with dysuria. In CSAP patients, longer catheterization time was associated with AUR and urethral sloughing. The main limitation is the nonrandomized and retrospective nature.

Conclusions:

Focal HIFU and focal CSAP provide a tolerable toxicity, with primarily minor complications presenting in the early postoperative period.

Introduction

Prostate cancer (PCa) is the second-most common oncologic diagnosis facing senior men, with an estimated 1.1 million diagnoses worldwide annually.¹ Treatment with curative intent provides good oncologic results, although damage to the surrounding tissue, compromising functional outcomes, remains a significant drawback.^2,3 In the last decade, PCa diagnosis has dramatically shifted toward low-risk, organ-confined disease; as a result, technology has advanced significantly, with minimally invasive modalities garnering huge interest in PCa care. High-intensity focused ultrasound (HIFU) and cryosurgical ablation of the prostate (CSAP) have developed as minimally invasive procedures with the aim of providing equivalent oncologic safety to open procedures, but with a reduced side effect profile.⁴ More recent modifications in more precise, lesion-targeted ablation have been proposed for PCa patients, with the intention of decreasing treatment toxicity to the minimum possible. However, we still lack data about the toxicity profile of targeting smaller regions of the prostate, making it difficult to compare treatment modalities.⁵ The aim of our study was to define comprehensively the incidence, severity, and timing of onset of complications for patients undergoing focal HIFU and focal CSAP as the primary treatment for localized PCa.

Materials and Methods

Population

The present study relied on a retrospective database of treatment-naive PCa patients who underwent focal HIFU or focal CSAP as a primary treatment for localized disease at a single, high-volume European center between January 2009 and December 2017. Patients who had undergone previous PCa treatment or androgen-deprivation therapy were excluded from the study. Concomitant α-blocker therapy or previous transurethral resection of the prostate (TURP) was not considered an exclusion criterion. Prebiopsy MRI was performed on all patients, and PCa diagnosis was confirmed by systematic and targeted transperineal mapping biopsies. Typically, twelve cores were taken in systematic biopsies, and three cores of each target lesion. Slight technique variations were allowed in large-sized prostates, large-sized target lesions, or previously negative biopsies. Patients with prostate volume more than 50 cc and no lower urinary tract symptoms (LUTS) or patients with smaller prostate size but with LUTS were indicated with α-blocker therapy preoperatively.

Focal treatment was considered a targeted destruction of PCa lesions in a specific area of the prostate within a 10 mm safety margin, sparing the rest of the prostate and nearby tissue. A single dose of antibiotic prophylaxis was used in the operating room immediately before the procedure. Post-therapy treatment with α-blockers was recommended in most cases for CSAP and in HIFU patients with no preoperative TURP. All patients were followed up by the same physicians at the outpatient clinic. All data were collected retrospectively from postoperative medical records up to 1 year after the surgery, including in the inpatient and outpatient setting.

Focal HIFU

Patients underwent transrectal focal HIFU using Ablatherm HIFU^® device (EDAP TMS, Lyon, France) between January 2009 and June 2015, and Focal One^® device (EDAP TMS) starting from June 2015. The patient was positioned in the right-hand side lateral decubitus position and bladder catheterization was performed. A transrectal probe was inserted and prostatic ultrasound scanning with MRI/US fusion was initiated. The area to be treated was located and lesion planning was performed, maintaining a 6 mm safety distance from the sphincter. During the treatment, the surgeon continuously monitored the ablation process and was able to stop and replan the targeted area if necessary (only Focal One technology). At the end of the procedure a contrast-enhanced US was performed to evaluate the ablation zone. The bladder catheter was removed within 24 to 72 hours, depending on the degree of postoperative hematuria.

Focal CSAP

Focal CSAP was carried out with the Precise™ cryoablation system (Galil Medical, Inc., Arden Hills, MN) between January 2009 and January 2014, and from January 2014 to the present, Endocare technology (Irvine, CA) has been deployed. Before the CSAP procedure, a urethral warmer was inserted. Cryoprobes were placed via a transperineal approach under ultrasound guidance in a specific PCa lesion. The maximum distance between the needles was 18 mm, while the minimum safe distance from the urethra was 8 mm. Temperature sensors were inserted at Denonvillier's fascia and PCa lesion. A double freeze–thaw cycle was carried out to achieve less than or equal to −40.0°C within the specific PCa lesion and to maintain ≥0.0°C in the Denonvillier's fascia. The bladder catheter was removed within 24 to 72 hours, depending on the degree of postoperative hematuria.

Outcomes

The outcome of the study was new onset of unanticipated complications, defined as any deviation from the ideal postoperative course that was not inherent in the procedure. All complications were graded according to the modified Clavien–Dindo classification system.⁶ According to the timing of onset, all complications were classified as follows: early (onset: ≤30 days), intermediate (onset: 31–90 days), or late (onset: >90 days). Sequelae of the ablative therapy (i.e., erectile dysfunction, urinary incontinence) and PCa recurrence were not considered complications.

Covariates

Data collected and analyzed in the univariate and multivariate analysis included type of focal treatment, volume of the ablation zone, age, body mass index (BMI), prostate-specific antigen (PSA) level, 2014 International Society of Urological Pathology (ISUP) group, prostate size, previous TURP, American Society of Anesthesiologists (ASA) physical status score, Charlson comorbidity index (CCI) score, bladder catheterization time, and α-blocker therapy. To standardize the reporting and to facilitate comparison with other treatment modalities, we sought to apply the standards set forth by Martin et al.⁷ and 10 of 10 criteria were fulfilled in our study.

Statistical analyses

Statistical analyses as well as reporting and interpretation of the results were conducted according to the established guidelines.⁸ Continuous variables are expressed as mean ± standard deviation (SD), unless otherwise specified. Data for categorical variables are presented as frequencies and percentages. We checked continuous variables for normal distribution by Shapiro–Wilk statistics and compared them by using the t-test when normally distributed, or the Mann–Whitney test for non-normally distributed variables. We used Pearson's χ² and Fisher exact tests for comparison of categoric variables, as appropriate. We used multivariable Cox proportional hazards analysis with forward stepwise variable selection to assess significant predictors of the most common complications. Hazards ratio with 95% confidence interval was calculated. All statistical tests were performed using SPSS software (IBM Corp., Armonk, NY); p-value <0.050 was considered statistically significant.

Results

Overall, 336 patients with localized PCa were included: 210 patients (62%) treated with focal HIFU and 126 (38%) treated with focal CSAP. In the HIFU arm, 9 of 210 patients (4.3%) underwent subtotal ablation (i.e., treated more than half of the prostate), while 201 of 210 patients (95.7%) underwent hemi/lesion-targeting ablation, where at least half of the prostate was spared. In the CSAP arm, all patients were treated in a hemi/lesion-targeting ablation manner.

The mean age of patients in our study was 67 years (SD: 7.1). The population was generally healthy, with ASA score ≤2 in 179 of 192 patients (93%) in the HIFU arm and 100 of 103 patients (97%) in the CSAP arm, and CCI score ≤2 in 96 of 204 patients (47%) in the HIFU arm and 52 of 126 patients (41%) in the CSAP arm (all p > 0.050). In the HIFU cohort, 49 of 204 patients (24%) were on antiaggregation therapy, while 16 of 204 patients (7.8%) were on anticoagulation therapy. In the CSAP cohort, 26 of 126 patients (21%) and 6 of 126 patients (4.8%) patients, respectively, were undergoing antiaggregation and anticoagulation therapy (all p > 0.050). According to demographic (age, BMI, comorbidities) and clinical characteristics (PSA, 2014 ISUP group, prostate size), the HIFU and CSAP cohorts were homogeneous (all p > 0.050).

In the HIFU group, 50 of 210 patients underwent TURP up to 1 year preoperatively, while just 1 of 126 patients in the CSAP group had undergone previous TURP (p < 0.001). Postoperative treatment with α-blockers was prescribed to 122 of 210 patients (58%) in the HIFU group, while 118 of 126 patients (94%) in the CSAP cohort were using α-blocker therapy (p < 0.001). Mean time of bladder catheterization after the treatment was 2.4 days (SD: 1.0) and 1.9 days (SD: 0.5) in the HIFU and CSAP arms, respectively (p < 0.001). Mean follow-up was 11 months (SD: 3.0). A total of 282 of 336 patients (84%) reached follow-up to 1 year: 165 of 210 patients (79%) in the HIFU arm and 117 of 126 patients (93%) in the CSAP arm. The clinical characteristics are presented in Table 1. In the HIFU subgroups (subtotal vs hemi/lesion-targeting ablation), the patients did not differ in any of the demographic or clinical parameters (p > 0.050), except that the bladder catheterization time was significantly longer in patients undergoing subtotal ablation, with a mean of 3.1 days (SD: 1.8) vs 2.3 days (SD: 0.9), respectively (p < 0.001).

Table 1.

Preoperative and Postoperative Clinical Parameters Stratified by Treatment Modality

Parameter	All patients (n = 336)	Focal HIFU (n = 210)	Focal CSAP (n = 126)	p
Preoperative clinical parameters
Age, years
Mean (SD)	67 (7.1)	68 (7.2)	66 (6.9)	0.667
BMI
Mean (SD)	26 (3.2)	26 (3.2)	26 (3.4)	0.906
PSA, ng/cc
Mean (SD)	7.4 (2.9)	7.4 (2.7)	7.3 (3.1)	0.576
2014 ISUP group, n (%)
Grade I	244 (73)	150 (71)	94 (75)	0.696
Grade II	86 (26)	55 (26)	31 (25)
Grade III	5 (1.5)	4 (1.9)	1 (0.8)
Grade IV	1 (0.3)	1 (0.5)	0
Grade V	0	0	0
Prostate size, cc ^a
Mean (SD)	42 (13)	40 (13)	46 (14)	0.058
Previous TURP, n (%)	51 (15)	50 (24)	1 (0.8)	<0.001
ASA score, n (%)^b
1	94 (32)	59 (31)	35 (34)	0.356
2	185 (63)	120 (63)	65 (63)
3	16 (5.4)	13 (6.8)	3 (2.9)
Charlson comorbidity score, n (%)^c
0	2 (0.6)	2 (1.0)	0 (0)	0.088
1	34 (10)	20 (9.8)	14 (11)
2	112 (34)	74 (36)	38 (30)
3	116 (35)	60 (29)	56 (44)
4	40 (12)	27 (13)	13 (10)
≥5	26 (7.9)	21 (10)	5 (4.0)
Postoperative clinical parameters
Bladder catheterization, days
Mean (SD)	2.2 (0.8)	2.4 (1.0)	1.9 (0.5)	<0.001
α-Blocker therapy, n (%)	240 (71)	122 (58)	118 (94)	<0.001

Prostate size missing in 6 HIFU and 15 CSAP patients.

ASA score missing in 18 HIFU and 23 CSAP patients.

Charlson comorbidity score missing in six HIFU patients.

ASA = American Society of Anesthesiologists; BMI = body mass index; CSAP = cryosurgical ablation of the prostate; HIFU = high-intensity focused ultrasound; ISUP = International Society for Urological Pathology; PSA = prostate-specific antigen; SD = standard deviation; TURP = transurethral resection of the prostate.

We recorded 132 complications in 106 patients, resulting in an overall complication rate of 32% for focal ablative therapies. Ninety-eight complications were identified in 79 of 210 patients in the HIFU group and 34 complications in 27 of 126 patients in the CSAP group, with an overall complication rate for each treatment modality of 38% and 21%, respectively (p = 0.002). The most common treatment-related adverse event in the HIFU arm was acute urinary retention (AUR; 17%), followed by urethral sloughing (8.1%), urinary tract infection (UTI; 8.1%), and acute infective epididymitis (AIE; 3.0%). Two of 36 AUR cases (5.6%) required TURP 1 month after the procedure, while the majority were treated with temporary bladder catheterization and α-blocker therapy. In the CSAP group, the most common complications were AUR (7.1%); testicular, perineal, or anal pain (3.2%); and UTI (3.2%). No case with AUR required any kind of surgical intervention. Despite AUR and UTI being the most commonly acquired complications, noticeably AUR, urethral sloughing, and infective complications were the most common issues in HIFU patients (p < 0.050), while testicular, perineal, and anal pain in CSAP cases (p = 0.048). Iatrogenic urethral stricture disease was rare in both treatment modalities (4 of 210 HIFU patients [1.9%] and 1 of 126 CSAP patients [0.8%; p = 0.414]). Table 2 summarizes the incidences of complications. Analyzing the two HIFU subgroups (subtotal vs hemi/lesion-targeting ablation), we recorded 10 complications in 7 of 9 patients undergoing subtotal HIFU and 88 complications in 72 of 201 patients undergoing hemi/lesion-targeting ablation. Therefore, the overall complication rate for subtotal HIFU was as high as 78%, while the rate for hemi/lesion-targeting ablation was significantly lower at 36% (p = 0.011). The incidences of complications in the HIFU subgroups are detailed in Table 3.

Table 2.

Incidence of Complications in High-Intensity Focused Ultrasound and Cryosurgical Ablation of the Prostate Groups

Complication	All patients (n = 336), % (n)	HIFU (n = 210), % (n)	CSAP (n = 126), % (n)	p ^*
Lower urinary tract symptoms
Dysuria w/o infection	2.7 (9)	3.8 (8)	0.8 (1)	0.097
Urethral sloughing/visible hematuria	6.3 (21)	8.1 (17)	3.2 (4)	0.054
Acute urinary retention	13 (45)	17 (36)	7.1 (9)	0.009
Urethral stricture	1.5 (5)	1.9 (4)	0.8 (1)	0.415
Hemorrhage
Hematospermia	1.2 (4)	1.4 (3)	0.8 (1)	0.603
Penis/scrotum/perineum hematoma	0.6 (2)	0 (0)	1.6 (2)	0.067
Infections
Urinary tract infection	6.3 (21)	8.1 (17)	3.2 (4)	0.071
Acute infective epididymitis	3.0 (10)	4.8 (10)	0 (0)	0.013
Perineal abscess	0.6 (2)	0 (0)	1.6 (2)	0.067
Hydronephrosis/renal colic	0.3 (1)	0 (0)	0.8 (1)	0.196
Acute renal insufficiency	0.3 (1)	0.5 (1)	0 (0)	0.438
Penis/scrotum edema	0.3 (1)	0 (0)	0.8 (1)	0.196
Testicular/perineal/anal pain	1.5 (5)	0.5 (1)	3.2 (4)	0.048
Fistula	0.3 (1)	0 (0)	0.8 (1)	0.196
Other
Hypotension	0.9 (3)	0.5 (1)	1.6 (2)	0.295
Allergic reaction	0.3 (1)	0 (0)	0.8 (1)	0.196
In total	32 (106)	38 (79)	21 (27)	0.002

The p-values are used for comparison of incidence of complications across HIFU and CSAP.

w/o = without.

Table 3.

Incidence of Complications in High-Intensity Focused Ultrasound Subgroups

Complication	HIFU (n = 210), % (n)	Hemi/lesion-targeting HIFU (n = 201), % (n)	Subtotal HIFU (n = 9), % (n)	p ^*
Lower urinary tract symptoms
Dysuria w/o infection	3.8 (8)	3.5 (7)	11 (1)	0.242
Urethral sloughing/visible hematuria	8.1 (17)	8.5 (17)	0 (0)	0.363
Acute urinary retention	17 (36)	15 (31)	56 (5)	0.002
Urethral stricture	1.9 (4)	1.5 (3)	11 (1)	0.039
Hemorrhage
Hematospermia	1.4 (3)	1.5 (3)	0 (0)	0.712
Penis/scrotum/perineum hematoma	0 (0)	0 (0)	0 (0)	n/a
Infections
Urinary tract infection	8.1 (17)	7.5 (15)	22 (2)	0.112
Acute infective epididymitis	4.8 (10)	4.5 (9)	11 (1)	0.361
Perineal abscess	0 (0)	0 (0)	0 (0)	n/a
Hydronephrosis/renal colic	0 (0)	0 (0)	0 (0)	n/a
Acute renal insufficiency	0.5 (1)	0.5 (1)	0 (0)	0.832
Penis/scrotum edema	0 (0)	0 (0)	0 (0)	n/a
Testicular/perineal/anal pain	0.5 (1)	0.5 (1)	0 (0)	0.832
Fistula	0 (0)	0 (0)	0 (0)	n/a
Other
Hypotension	0.5 (1)	0.5 (1)	0 (0)	0.832
Allergic reaction	0 (0)	0 (0)	0 (0)	n/a
In total	38 (79)	36 (72)	78 (7)	0.011

The p-values are used for comparison of incidence of complications across HIFU subgroups.

On univariate analysis, clinical characteristics such as age, 2014 ISUP group, previous TURP, ASA score, CCI index, and α-blocker therapy did not reveal any statistically significant difference with respect to any kind of complication in patients undergoing HIFU, but increasing BMI was associated with AIE (p = 0.009), smaller prostate size was associated with dysuria (p = 0.038) and urethral stricture (p = 0.008), longer catheterization time was associated with dysuria (p = 0.005) and UTI (p = 0.003), and subtotal HIFU was associated with AUR (p = 0.002) and urethral stricture (p = 0.039). On univariate analysis in the CSAP arm using the same demographic and clinical parameters, we observed no statistically significant differences with any kind of side effect, except that longer bladder catheterization time was associated with AUR (p < 0.001). We performed multivariate analysis to identify significant predictors of the most common complications in both treatment modalities. Analyzing the HIFU cohort by using Cox regression analysis and forward stepwise entering of covariates, subtotal HIFU was the only independent predictor of AUR (p = 0.003), while BMI showed a significant prognostic value for AIE (p = 0.015). Prostate size and bladder catheterization time were significant predictors of dysuria (p = 0.030 and 0.047, respectively). Analyzing the CSAP cohort in the same manner, bladder catheterization time was revealed as a prognostic factor for AUR (p = 0.014). Urethral sloughing was associated with α-blocker therapy (p = 0.004) and bladder catheterization time (p = 0.049). The results of the multivariate analysis are presented in Table 4.

Table 4.

Predictors of Complications in Both Treatment Modalities

	Hazards ratio (95% CI)	p
Focal HIFU
Acute urinary retention
Subtotal HIFU	7.78 (1.96–30.80)	0.003
Acute infective epididymitis
BMI	1.26 (1.05–1.52)	0.015
Dysuria
Prostate size	0.91 (0.83–0.99)	0.030
Bladder catheterization time	2.20 (1.01–4.78)	0.047
Focal CSAP
Acute urinary retention
Bladder catheterization time	5.32 (1.41–20.01)	0.014
Urethral sloughing
α-Blocker therapy	0.03 (0.01–0.31)	0.004
Bladder catheterization time	5.04 (1.01–25.23)	0.049

CI = confidence interval.

In terms of severity according to the Clavien–Dindo classification system, 93 of 98 complications (95%) in the focal HIFU arm and 31 of 34 complications (91%) in the focal CSAP arm were classified as minor (grades I–II), not requiring any surgical intervention. In contrast, 5 of 98 complications (5.1%) in the focal HIFU cases and 3 of 34 complications (8.8%) in the focal CSAP cases were classified as major (grades III–V). In comparing the treatment modalities by severity of complications, no statistically significant difference was observed (p = 0.275). The frequency of the severity grades of complications is presented in Table 5. The readmission rate was 12 of 210 (5.7%) for patients undergoing focal HIFU and 4 of 126 (3.2%) for focal CSAP (p = 0.290). Similarly, reintervention rates did not differ between treatment modalities: 6 of 210 patients (2.9%) in the HIFU group and 2 of 126 patients (1.6%) in the CSAP group (p = 0.460). Most complications (83 [85%] in HIFU and 30 [88%] in CSAP) presented in the early postoperative period, while just 15 complications (15%) in the HIFU group and 4 complications (12%) in the CSAP group were recorded in the intermediate postoperative period, with no complications in the late period. No treatment-related deaths were registered during the follow-up period.

Table 5.

Frequency of Severity Grade of Complications Stratified by Treatment Modality

Complication	Clavien–Dindo grading system							In total
Complication	I	II	III-a	III-b	IV-a	IV-b	V	In total
Dysuria w/o infection, n
HIFU	4	4						8
CSAP	1							1
Urethral sloughing/visible hematuria, n
HIFU	13	4						17
CSAP	4							4
Acute urinary retention, n
HIFU		34	1	1				36
CSAP		9						9
Urethral stricture, n
HIFU		2		2				4
CSAP				1				1
Hematospermia, n
HIFU	3							3
CSAP	1							1
Penis/scrotum/perineum hematoma, n
HIFU								0
CSAP	2							2
Urinary tract infection, n
HIFU		17						17
CSAP		4						4
Acute infective epididymitis, n
HIFU		10						10
CSAP								0
Perineal abscess, n
HIFU								0
CSAP		2						2
Hydronephrosis/renal colic, n
HIFU								0
CSAP	1							1
Acute renal insufficiency, n
HIFU		1						1
CSAP								0
Penis/scrotum edema, n
HIFU								0
CSAP	1							1
Testicular/perineal/anal pain, n
HIFU	1							1
CSAP	4							4
Fistula, n
HIFU								0
CSAP				1				1
Hypotension, n
HIFU					1			1
CSAP		1			1			2
Allergic reaction, n
HIFU								0
CSAP		1						1
In total, n (%)
HIFU	21 (21)	72 (74)	1 (1.0)	3 (3.0)	1 (1.0)	0 (0)	0 (0)	98 (100)
CSAP	14 (41)	17 (50)	0 (0)	2 (6.0)	1 (3.0)	0 (0)	0 (0)	34 (100)

Treatment of grades III–V complications: acute urinary retention—suprapubic catheterization and transurethral resection of the prostate; urethral stricture—urethrotomy and urethroplasty; fistula—reconstructive surgery; hypotension—intensive care unit management.

Discussion

Literature evidence of focal therapy in patients with primary PCa is limited because of the recent introduction of these lesion-targeted techniques into clinical practice. The goal of focal therapy is to achieve oncologic outcomes at least equivalent to the standard of care while preserving genitourinary function and resulting in fewer complications. According to our data, both treatment modalities offer an acceptable safety profile, with >91% of minor complications not requiring any kind of intervention. According to our series, the most common complications in both treatment modalities are similar, although focal HIFU has higher rates of AUR and infectious complications and patients undergoing CSAP more commonly suffer from pain.

As reported in the literature, the most common complications of focal HIFU are AUR (2.4%–23.8%), dysuria (16.1%–22.0%), AIE (7.6%), hematuria (39.0%), urethral sloughing (6.7%–43.0%), urethral stricture (2.4%–4.0%), and UTI (6.0%–18.0%).^9

–15 Our study revealed a slightly higher rate (17.0%) of AUR than reported in the majority of the studies, except in the prospective trial by Barret and colleagues¹⁴; comparable results for AIE, urethral sloughing, urethral stricture, and UTI; but a lower rate of dysuria (without infection; 3.8%). A few studies in the literature report a limited number of complications associated with focal CSAP therapy—namely, AUR (0.5%–15.0%), cavernous corpus necrosis (2.1%), fistula (0.1%–2.1%), hematuria (2.0%), pelvic pain (2.0%), urethral stricture (2.1%), and UTI (3.8%).^{14

–21} Our series revealed the same complications with comparable rates, but a broader side effect profile.

The reported rate of complications may differ between the studies, what was clearly shown in a systematic review.¹⁵ The different rates of complications may be attributed to different treatment protocols used in clinical practise. In the study by Ahmed and colleagues, the rate of AUR was significantly lower (2.4%), while it was the major issue in our cohort.¹¹ However, all the patients in the latter study underwent a suprapubic bladder catheterization immediately before the procedure for a mean of 8.5 days, while none of our patients had a suprapubic catheter preoperatively.¹¹ There is also a variety in the size of ablation zone between different authors. Some differences may also be explained by our large and homogenous cohort, analyzed using a standardized methodology. Reporting on complication frequency rather than the number of patients is mandatory because some patients may have multiple complications of varying severities. Standard classification and severity grading are also essential and could result in a high risk of bias if not performed correctly.

On multivariate analysis, adjusting for other determinants, subtotal HIFU was associated with higher incidences of AUR, while a smaller prostate size and longer bladder catheterization time were associated with post-HIFU dysuria. Multivariate analysis in patients undergoing focal CSAP revealed an association between longer bladder catheterization time and AUR and urethral sloughing. It was not possible to identify the precise size of focal ablation in patients undergoing CSAP, so in addition to assuming that bladder catheterization time, urethral sloughing, and AUR could be determined by the volume of ablation zone, there is the possibility of indirect association among these three parameters. Urethral sloughing was also associated with α-blocker therapy, where slight but significant improvement was observed.

Most complications (85% for HIFU and 88% for CSAP) presented in the early postoperative period. Therefore, patients should be followed more closely during the 1st month postoperatively, when the risk of complications is highest. The complications that occurred in the intermediate postoperative period were UTI, AIE, AUR, acute renal insufficiency, urethral stricture, and perineal abscess. In the follow-up period, about 39% of patients undergoing focal therapy will face treatment failure or PCa recurrence in the spared prostate tissue (unpublished data), and hence, part of the patients will be retreated. It should be noted that retreatment in the future may be associated with higher risk of side effects.

The main limitation of our study is its nonrandomized and retrospective nature. First, the nonrandomized design prevents comparison of data across different treatment modalities. Also, we have adopted treatment strategies across the time line and generally moved toward lesion-only ablation. Second, regarding missing information on documentation, it was not possible to capture the precise volume of the ablation zone, so some patients were missing information about comorbidities and antiaggregation and anticoagulation therapy. Third, it is possible that some complications were not recorded because they occurred elsewhere and were not reported to our institution. Fourth, 21% of the HIFU and 7.1% of the CSAP patients were followed <1 year, which could also provide a risk of bias in comparing treatment modalities. Fifth, some type of complications (i.e., fistula, stricture) may present later than 1 year after the procedure and so were not identified in our study. Nevertheless, the strength of the present study is that it is the largest series of focal HIFU reporting complications comprehensively based on a standardized methodology.

Conclusions

These two commonly used ablative modalities provide tolerable results in terms of genitourinary toxicity and are certainly more favorable than the respective whole-gland therapies. If the outcomes that we report are reproducible in larger prospective studies, with survival efficacy and functional outcomes at least equivalent to radical treatment, then focal therapy could become the standard of care for carefully selected PCa patients.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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