This nonrandomized controlled trial investigates the efficacy and safety of high-frequency electroporation therapy in the treatment of localized prostate cancer.
Key Points
Question
What is efficacy and safety of high-frequency irreversible electroporation (H-FIRE) in the treatment of localized prostate cancer?
Findings
In this nonrandomized controlled trial, 109 patients from 4 centers received H-FIRE treatment; among the 100 patients who underwent biopsy at 6 months, the 6-month clinically significant prostate cancer rate was 6.0%. Superiority criteria vs the historical control of 20% was achieved.
Meaning
The rate of 6-month clinically significant prostate cancer with H-FIRE ablation was lower than the historical control using other energy platforms and had a minimal effect on functional outcomes.
Abstract
Importance
Focal therapy of prostate cancer must balance the oncologic outcome and functional outcome. High-frequency irreversible electroporation (H-FIRE) can destroy cancer cells while selectively preserving surrounding nerves and blood vessels, but no clinical trials have been conducted, to our knowledge.
Objective
To evaluate the efficacy and safety of H-FIRE in the treatment of localized prostate cancer (PCa).
Design, Setting, and Participants
This was a single-group, objective performance criteria, nonrandomized controlled trial. Recruitment began on May 2, 2018, and ended March 27, 2019. The follow-up duration was 6 months. This was a multicenter trial conducted at 4 tertiary teaching hospitals in China. Patients with low or intermediate risk of biochemical recurrence of localized and locally advanced PCa were eligible. Key inclusion criteria were serum prostate-specific antigen (PSA) level less than 20 ng/mL, clinical stage of T2c or less, and Gleason score of 7 or less. Data were analyzed from January 20 to February 20, 2021.
Intervention
H-FIRE ablation of all lesions identified with biopsy.
Main Outcomes and Measures
The primary end point was 6-month clinically significant PCa (csPCa), which was defined as any biopsy core with Gleason score of greater than or equal to 7, or Gleason score of 6 plus maximum cancer core length of greater than 3 mm or an increase from the original cancer burden. Secondary outcomes were calculated in patients who actually received H-FIRE treatment.
Results
A total of 117 patients (median [IQR] age, 67 [62-73] years) were recruited from 4 centers, and 109 patients (27 [24.8%] low risk and 82 [75.2%] intermediate risk) actually received H-FIRE. Median (IQR) PSA level was 9.0 (6.0-12.7) ng/mL. Among the 100 patients who underwent biopsy at 6 months, the 6-month csPCa rate was 6.0% (95% CI, 2.2%-12.6%; P < .001; 1 in the treatment zone and 5 outside the treatment zone). Superiority criteria vs the historical control of 20% was achieved. PCa was detected in 14 patients, with a Gleason score of 7 in 2 patients and 6 in the remaining 12 patients. At 6 months, median (IQR) PSA level was 1.08 (0.4-3.2) ng/mL, median (IQR) International Prostate Symptom Score was 4.5 (2.0-9.5), and median (IQR) International Index of Erectile Function 5 score was 2.0 (0.5-12.5). Superiority vs the 20% historical control was also met in the subgroup analysis that only included the 57 patients with Gleason score of 7 at baseline (3.5% 6-month csPCa; 95% CI, 0.4%-12.1%).
Conclusions and Relevance
The rate of 6-month csPCa with H-FIRE ablation was lower than the historical control using other energy platforms.
Trial Registration
ClinicalTrials.gov Identifier: NCT03838432
Introduction
For localized prostate cancer (PCa), radiotherapy and radical prostatectomy can achieve maximum oncologic benefits but are associated with incontinence, bowel dysfunction, and sexual dysfunction.1 To balance oncologic outcomes and the effect on quality of life, active surveillance is recommended for patients with relatively low risk of biochemical recurrence of localized and locally advanced PCa.2 Focal therapy is an alternative that provides some degree of oncologic control while largely preserving urinary and erectile function.3 A variety of energy platforms exist for focal therapy, including high-intensity focused ultrasound (HIFU), cryotherapy, laser, and photodynamic therapy.4 These methods are generally associated with relatively high tumor residue and retreatment rate. For example, retreatment rate after HIFU therapy is as high as 20%.5 Extending the ablation area could reduce the residue rate but increases the complication rate.6
Irreversible electroporation (IRE) is a new energy platform for focal therapy that can destroy tumor cells without producing thermal heat and thus produces minimal damage to nearby healthy tissues.7 A major limitation of the first-generation IRE includes muscle contraction and electrode movement, mostly attributable to the electric field sinks (ie, redistribution of electric fields owing to the presence of blood vessels and consequently reduced electric field strength in proximity to large blood vessels and in areas with clustered vessel structures).8 Accordingly, tumor residue rate after IRE in patients with localized PCa could be as high as 40%.9 Recurrence rate has been reported to range from 5% to 100% among different trials.8
High-frequency IRE (H-FIRE) could mitigate electric field sinks caused by impedance changes.10 Better ablation and less muscle contraction have been shown with H-FIRE in animal experiments.11 We recently completed a phase 1 trial and demonstrated benign safety profile of H-FIRE in human participants.12 The trial also established critical parametric requirements needed for sufficient ablation. We have now completed a multicenter, single-group, objective performance criteria, nonrandomized controlled trial of H-FIRE in patients with localized PCa.
Methods
This trial was conducted at 4 medical centers in China during a period from May 2, 2018, to March 27, 2019. The initial plan included 5 centers, but one never recruited any patients. Trial protocol was approved by the ethics committees of all participating centers and registered on ClinicalTrials.gov (Supplement 1). This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines. Written informed consent was obtained from all study participants. Patients with low- or intermediate-risk PCa, as defined by the National Comprehensive Cancer Network risk classification, were eligible. PCa was verified by template-guided mapping biopsy or targeted plus template-guided mapping biopsy. Other inclusion criteria included the following: (1) participants aged 40 to 85 years; (2) serum prostate-specific antigen (PSA) level less than 20 ng/mL (to convert to micrograms per liter, multiply by 1); (3) clinical stage of T2c or less (defined based on digital rectal examination); and (4) Gleason score of 7 or less. The exclusion criteria included the following: (1) prior radical prostatectomy, hormonal therapy, or radiotherapy; (2) prostatic calculus greater than 5 mm; (3) history of epilepsy; (4) cardiac pacemaker or any metal implant between L1 and midfemur level; and (5) any other malignant tumor.
All participants underwent 1.5- or 3.0-T multiparametric magnetic resonance imaging (mpMRI) with pelvic phased-array coils to map the lesions (Figure 1). The sequences included T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast-enhanced imaging. Images were evaluated and scored by an experienced radiologist according to the Prostate Imaging Reporting and Data System (PI-RADS).13 Prostate biopsy was performed via the perineum and included a cognitive-fusion targeted biopsy (ie, 3 cores each for lesions with PI-RADS score of 3 or more), followed by a 12- to 20-region systematic template-guided biopsy. Those who had negative MRI findings underwent template-guided biopsy only. The template-guide biopsy region varied slightly across the 4 participating centers but remained identical within each center throughout the trial period.
Figure 1. Electrode Needle Placement and Typical Case.
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H-FIRE was performed using a composite steep-pulse therapeutic apparatus (Remedicine Co) under general anesthesia with full muscle paralysis. Electrode needles were placed into the target lesion through a 5-mm brachytherapy template grid under the guidance of a biplanar transrectal ultrasound probe (Figure 1). One electrode needle was placed at the center of each targeted lesion; 3 or 4 were placed 0.5 to 2.0 cm from the center of each lesion.
Follow-up was planned at 1 week, 1 month, 3 months, and 6 months after H-FIRE ablation and consisted of serum PSA level and clinical assessment using the International Prostate Symptom Score (IPSS), International Index of Erectile Function 5 (IIEF-5), and diaper usage. MRI was conducted at 1 and 6 months (Figure 1). Prostate biopsy (cognitive-fusion targeted biopsy with 3 cores for each ablation area followed by regional systematic template-guided biopsy plus targeted biopsy for suspected lesions based on mpMRI) was conducted at 6 months.
The primary outcome was clinically significant PCa (csPCa), defined as any biopsy core with a Gleason score of 7 or more or a Gleason score of 6 plus maximum cancer core length of greater than 3 mm or an increase from the original cancer burden.14 The rate of csPCa in the ablation zone was included as a secondary outcome. Biochemical recurrence was defined as PSA level of greater than 2 ng/mL over the nadir. Adverse events (AEs) were reported using the Clavien-Dindo classification system. Urinary tract infection was defined as the presence of large amount of white blood cells in the urine, dysuria, or fever, plus response to antibiotic treatment, and did not require pathogen identification. We also assessed the shortest distance from the ablation needle to neurovascular bundle, urethra, and rectum using intraoperative ultrasound images.
Statistical Analysis
Sample size calculation was based on the following assumptions: (1) the 6-month rate of csPCa of 20% for historical control with focal therapy14 and 9% in patients receiving H-FIRE treatment and (2) 80% power and α level of 0.025 (1-sided). The 9% 6-month csPCa rate was a conservative estimate based on 7.2% to 10.0% 6-month out-field csPCa5,15,16 and no in-field csPCa, as previously reported.12 The calculation yielded 87 participants. Because the csPCa was diagnosed using an invasive biopsy, a dropout rate of 20% at 6 months was assumed, and the final sample size was set at 110 participants.
Analysis of the 6-month csPCa was conducted in patients who received a 6-month biopsy. Superiority was defined by the upper limit of the 95% CI less than 20%. A worst-scenario sensitivity test, in which participants who did not undergo 6-month biopsy were imputed as having csPCa, was conducted to test the robustness of the main findings. The 6-month csPCa was also examined in a subgroup analysis that included only patients with Gleason score at the baseline. Categorical variables are presented as frequency (percentage). For binary efficacy and safety outcomes, 95% CIs were calculated based on Clopper-Pearson exact method. Continuous variables are presented as mean (SD) if they followed normal distribution or as median (IQR) if not. Paired continuous variables were analyzed using t test or Wilcoxon signed rank test, as appropriate. The PSA level, IPSS, and IIEF-5 score are presented as median (IQR). Median change from baseline and corresponding 95% CIs were estimated using quantile regression.
To analyze the association between ablation ratio and treatment effects (efficacy and AEs), participants were divided into 3 groups based on ablation ratio (<50%, 50%-75%, and >75%), as determined by ITK-SNAP software, version 3.8.0 (Paul A. Yushkevish). Differences in 6-month csPCa, IPSS, and IEFF-5 score among the 3 groups were assessed using χ2 test or Fisher exact test for categorical variables; analysis of variance or Kruskal-Wallis test was used for continuous variables, as appropriate. P values were 1-sided, and the cutoff for statistical significance was .05. All statistical analyses were conducted from January 20 to February 20, 2021, using SAS, version 9.4 (SAS Institute).
Results
From May 2, 2018, to March 27, 2019, a total of 117 patients were enrolled in this study (median [IQR] age, 67 [62-73] years) (Figure 2), and 109 patients actually received H-FIRE ablation (Table 1). Based on the National Comprehensive Cancer Network risk classification, the risk for biochemical recurrence of locally advanced PCa was low in 27 patients (24.8%) patients and intermediate in 82 patients (75.2%). The median (IQR) serum PSA level was 9.0 (6.0-12.7) ng/mL. Median (IQR) number of biopsy cores was 20.0 (19.5-23.0). Median (IQR) number of positive biopsy cores was 3 (1-4). Gleason score was 4 + 3 = 7 in 17 patients (15.6%), 3 + 4 = 7 in 45 patients (41.3%), and 3 + 3 = 6 in the remaining 47 patients (43.1%). The PI-RADS was 3 or higher in 85 patients (78.0%; PI-RADS 3: 24 patients [28.2%]; PI-RADS 4: 52 patients [61.2%]; PI-RADS 5: 9 patients [10.6%]). Median (IQR) time from the start of surgery to indwelling catheter placement was 93 (75-115) minutes. The median (IQR) anesthesia time was 125 (100-140) minutes. Mean (SD) catheterization time was 15.2 (10.0) days. The shortest median (IQR) distance from the ablation needle was 6.7 (5.0-10.0) cm to neurovascular bundle, 6.4 (5.1-7.9) cm to urethra, and 5.9 (4.3-7.9) cm to rectum.
Figure 2. Patient Flow Diagram.
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Table 1. Baseline Characteristics of the Patients Undergoing High-Frequency Irreversible Electroporation (N = 109).
| Characteristics | Description |
|---|---|
| Age, mean (SD), y | 67 (8) |
| Body mass index, mean (SD)a | 24.1 (2.9) |
| Prostate volume, mean (SD), mL | 38.1 (17.1) |
| Prostate-specific antigen, median (IQR), ng/mL | 9.0 (6.0-12.7) |
| Prostate-specific antigen density, mean (SD), ng/mL/g | 0.3 (0.2) |
| No. of cores taken, median (IQR) | 20.0 (19.5-23.0) |
| Positive cores, median (IQR) | 3.0 (1.0-4.0) |
| MRI PI-RADS, No. (%) | |
| 1-2 | 24 (22.0) |
| 3-5 | 85 (78.0) |
| Biopsy Gleason Score, No. (%) | |
| 3 + 3 | 47 (43.1) |
| 3 + 4 | 45 (41.3) |
| 4 + 3 | 17 (15.6) |
| Clinical stage, No. (%)b | |
| T1c | 32 (29.4) |
| T2a | 62 (56.9) |
| T2b | 6 (5.5) |
| T2c | 9 (8.3) |
| NCCN risk category, No. (%) | |
| Low | 27 (24.8) |
| Intermediate | 82 (75.2) |
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Abbreviations: MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PI-RADS, Prostate Imaging–Reporting and Data System.
SI conversion factor: To convert prostate-specific antigen to μg/L, multiply by 1.
a
Calculated as weight in kilograms divided by height in meters squared.
b
Clinical stages indicate the following: T1c, tumor identified by needle biopsy (eg, elevated prostate-specific antigen); T2a, tumor involves one-half of 1 lobe but not both lobes; T2b, tumor involves more than half of 1 lobe but not both lobes; T2c, tumor involves both lobes.
Efficacy
In the 100 patients with 6-month biopsy, there were 6 csPCa, including 1 in the treatment zone and 5 outside the treatment zone. The rate of csPCa was 6.0% (95% CI, 2.2%-12.6%) (Table 2). The upper limit of 95% CI was less than 20%, and 1-sided P was < .001. In the worst-scenario sensitivity analysis, in which the csPCa was assumed in the 6 patients without 6-month biopsy, the 6-month csPCa rate was 11.0% (95% CI, 5.8%-18.4%). Superiority vs the 20% historical control was also met in the subgroup analysis that only included the 57 patients with a Gleason score of 7 at the baseline (3.5% 6-month csPCa; 95% CI, 0.4%-12.1%; P < .001). PCa was detected in 14 patients (14.0%; 95% CI, 7.9%-22.4%). Gleason score was 4 + 3 in 2 patients; 1 patient refused further treatment, and the other underwent radical prostatectomy. In the remaining 12 patients with Gleason score at 3 + 3, 1 patient underwent radical prostatectomy, and another underwent second H-FIRE treatment. The patient who had 4 + 3 Gleason score but refused further treatment was lost to follow-up. All other patients were under active surveillance at the time of article preparation.
Table 2. Efficacy and Safety Outcomes in Patients Undergoing High-Frequency Irreversible Electroporation.
| Outcomes | No. | % (95% CI) |
|---|---|---|
| 6-mo Biopsy (n = 100) | ||
| Median No. of cores | 14 | NA |
| Clinically significant prostate cancer | 6 | 6 (2.2 to 12.6) |
| Any cancer | 14 | 14 (7.9 to 22.4) |
| Gleason score | ||
| 3 + 3 | 12 | 12 (6.4 to 20.0) |
| 4 + 3 | 2 | 2 (0.2 to 7.0) |
| Complications (n = 109) | ||
| No. of patients | 29 | 26.6 (18.6 to 35.9) |
| No. of events | 41 | 37.6 (28.5 to 47.4) |
| Clavien-Dindo gradea | ||
| I | 33 | 30.3 (21.8 to 39.8) |
| II | 7 | 6.4 (2.6 to 12.8) |
| III | 1 | 0.9 (0 to 5.0) |
| Type | ||
| Abnormal white blood cell in urine | 26 | 23.9 (16.2 to 33.0) |
| Epididymitis | 5 | 4.6 (1.5 to 10.4) |
| Prolonged gross hematuria | 4 | 3.7 (1.0 to 9.1) |
| Urinary retention | 3 | 2.8 (0.6 to 7.8) |
| Urinary tract infection | 2 | 1.8 (0.2 to 6.5) |
| Bladder stone | 1 | 0.9 (0 to 5.0) |
| Other 6-mo assessments (n = 100) | ||
| PSA, ng/mL | 1.08 (0.4 to 3.2)b | –6.4 (–7.7 to –5.1)c |
| IPSS | 4.50 (2.0 to 7.0)b | –4.0 (–6.1 to –1.9)c |
| IIEF-5 | 2.00 (0.5 to 12.5)b | 0 (–0.2 to 0.2)c |
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Abbreviations: IIEF-5, International Index of Erectile Function 5; IPSS, International Prostate Symptom Score; NA, not applicable; PSA, prostate-specific antigen.
SI conversion factor: To convert prostate-specific antigen to μg/L, multiply by 1.
a
Clavien-Dindo grades are as follows: I, any deviation from the normal postoperative course without the need for pharmacologic treatment or surgical, endoscopic, and radiologic interventions; II, requiring pharmacologic treatment with drugs other than those allowed for grade I complications; III, requiring surgical, endoscopic, or radiologic intervention.
b
Median (IQR).
c
Change from baseline.
PSA level, IPSS, and IIEF-5 score are summarized in Table 2. The median (IQR) PSA level was 9.0 (6.0-12.7) ng/mL at the baseline and 1.1 (0.4-3.2) ng/mL at 6 months. Median (IQR) nadir PSA level was 1.0 (0.3-2.6) ng/mL. Biochemical recurrence occurred in 5 patients (all at 6 months). Median (IQR) IPSS was 9.0 (4.0-15.0) at baseline and 4.5 (2.0-9.5) at 6 months. Median (IQR) IIEF-5 score was 2.0 (1.0-18.0) at baseline and 2.0 (0.5-12.5) at 6 months.
Diaper-free rate was 99.1% (108 of 109 patients) at baseline and 98% (98 of 100 patients) at 6 months. Of the 100 patients with 6-month follow-up, percentage change in IPSS from baseline to 6 months was 50.0%, and only 9 patients (9%; 95% CI, 4.2%-16.4%) experienced emergent sexual dysfunction (IIEF-5 >7 at the baseline and ≤7 at 6 months).
Safety
No intraoperative complications were reported. During the 6-month follow-up, a total of 41 complications occurred in 29 patients. The overall complication rate was 37.6% (95% CI, 28.5%-47.4%) (Table 2). The most common complication was elevated white blood cell level in urine (23.9%; 26 of 109 patients), followed by epididymitis (4.6%; 5 of 109 patients), prolonged gross hematuria (3.7%; 4 of 109 patients), urinary retention (2.8%; 3 of 109 patients), urinary tract infection (1.8%; 2 of 109 patients), and bladder stones (0.9%; 1 of 109 patients). A Clavien-Dindo classification grade III complication occurred in 1 patient (0.9%; bladder stone composed of mostly tissue debris). No urethrorectal fistula was reported. Other clinically significant events that were deemed to be not associated with the H-FIRE treatment included acute coronary syndrome (1 [0.9%]), myocardial infarction (2 [1.8%]), gastric cancer (1 [0.9%]), obstructive jaundice (1 [0.9%] caused by hepatic cyst), and proliferative lymphadenopathy (1 [0.9%]).
Association Between Ablation Ratio and Outcomes
Patients with lower ablation ratio (<50%, 50%-75%, and >75%) had higher rate of 6-month csPCa (ratio <50%, 4 of 22 [18.2%]; 50%-75%, 2 of 55 [3.6%]; >75%, 0%; P = .04), but comparable IPSS and IIEF-5 score (eTable in Supplement 2). A linear regression analysis showed that ablation ratio was not correlated with the change of either IPSS or IIEF-5 score at 6 months relative to the baseline (Figure 3).
Figure 3. Association Between Ablation Rate and Functional Outcomes.
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Discussion
In this nonrandomized controlled trial, the 6-month rate of csPCa after H-FIRE treatment was 6.0%, meeting the predefined superiority vs historical control of 20%. Lower 6-month csPCa rate was also supported by the results of a worst-scenario sensitivity analysis, in which the 6-month rate of csPCa was 11.0%. Superiority vs the 20% historical control was also met in the subgroup analysis that only included the 57 patients with Gleason score of 7 at the baseline. A total of 41 complications were reported in 29 patients. At the 6-month follow-up, mean reduction in IPSS was 43% relative to the baseline, and only 9.0% of the participants had emergent sexual dysfunction. No patient developed urethrorectal fistula. All together, these results indicated superior oncologic control and minimal effect on functional outcomes.
Among the 6 cases of csPCa, only 1 was inside the treatment zone, suggesting the reliability of H-FIRE. In contrast, reported in-field recurrence rate was 1.7% to 26.0% for cryotherapy, 6.0% to 100% for HIFU, 8.0% to 38.0% for laser ablation, and 17.0% to 33.0% for photodynamic therapy,4 mostly likely attributable to the heat sedimentation effect (ie, heat loss caused by blood flow through tumors or major peripheral blood vessels).17 In-field recurrence rate after conventional IRE has been reported at 9.8% to 38.9%.15,16,18,19,20 Limited efficacy of conventional IRE is primarily attributable to electric field sinks, namely, the redistribution of electric fields owing to the presence of blood vessels and consequently reduced electric field strength in proximity to large blood vessels and in areas with clustered vessel structures.8 H-FIRE minimizes electric field sinks associated with IRE21 and thus could achieve more complete ablation throughout the target area.
Out-field recurrence rate is affected by the size of the ablation area. The index lesion22 may or may not represent the culprit lesion because of the multifocal feature of prostate cancer4 and the less than 100% sensitivity with all currently available diagnostic systems.23 Consequently, a larger area of ablation with thermal energy platform is associated with better oncologic outcomes and lower rate of repeat therapy.24 Unfortunately, a larger ablation area is also associated with higher rate of incontinence and sexual dysfunction owing to damage of the neurovascular bundle.6,25 Recommended safe distance is 3 mm for HIFU26 and 5 mm for cryotherapy.25 Despite such a precaution, hemiablation with HIFU is associated with 2% incontinence and 21% sexual dysfunction,27 whereas hemiablation with cryotherapy is associated with 17% incontinence and 54% sexual dysfunction.25 In the current study, the rate of out-field csPCa was 5.0%, likely driven by the relatively large ablation ratio (62.6%). Despite the large ablation ratio, the rate of incontinence and sexual dysfunction was 1% and 9%, respectively.
Another important finding in the current study was the significant correlation of higher ablation ratio with lower residual tumor but not IPSS or IIEF-5 score, supporting the minimal damage to important structures (eg, blood vessels and nerves) by H-FIRE. Also, despite the 62.6% mean ablation ratio (range, 23.8%-100%) in this trial, the negative effect on IPSS and IIEF-5 score was minimal, again supporting the safety of H-FIRE.
Accurate preoperative tumor assessment is critical to achieve satisfactory oncologic outcomes. Improved detection rate has been shown with template-guided biopsy,28,29 as well as mpMRI-based targeted biopsy.23,30 The low 6-month PCa rate in the current study could be attributed to the combined use of template-guided biopsy and mpMRI-based targeted biopsy in addition to the use of H-FIRE.
Limitations
A major limitation of the current study was the use of a historical control rather than including a parallel control group. The assumption of 20% csPCa rate for the control in the experimental design was based on previous studies using thermal energy platform, but the rate differed widely in these studies. Also, improvement in preoperative assessment (the use of template-guided biopsy and mpMRI-based targeted biopsy) may have produced bias that favored the H-FIRE treatment in the current study. Further, the sample size was relatively small. Trials that compare H-FIRE with thermal energy platform directly using a larger sample size are needed to verify our preliminary findings.
Conclusions
Focal therapy of prostate cancer must balance the oncologic outcome and functional outcome. Results of this nonrandomized controlled trial showed encouraging efficacy and minimal effect on functional outcomes in patients receiving extensive focal ablation with H-FIRE for localized PCa. Future trials with larger sample sizes that compare H-FIRE directly with a thermal energy platform should be performed.
Supplement 1.
Trial Protocol
Click here for additional data file. (1.8MB, pdf)
Supplement 2.
eTable. Relationship Between Ablation Ratio and Outcome Factors
Click here for additional data file. (166.4KB, pdf)
Supplement 3.
Data Sharing Statement
Click here for additional data file. (12.9KB, pdf)
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplement 1.
Trial Protocol
Click here for additional data file. (1.8MB, pdf)
Supplement 2.
eTable. Relationship Between Ablation Ratio and Outcome Factors
Click here for additional data file. (166.4KB, pdf)
Supplement 3.
Data Sharing Statement
Click here for additional data file. (12.9KB, pdf)
