Interventional procedure overview of focal therapy using high-intensity focused ultrasound for localised prostate cancer
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Summary of key evidence on focal therapy using HIFU for localised prostate cancer
Study 1 Bakavicius A (2022)
Study type | Systematic review |
Country | Not reported for individual studies |
Recruitment period | Studies published from 2010 to 2020 |
Study population and number | n=20 studies, 4,209 people in total (fewer reported for outcomes) People with treatment-naïve localised prostate cancer who had focal HIFU as primary treatment |
Age and sex | Not reported for individual studies; 100% male |
Patient selection criteria | Inclusion criteria:
Exclusion criteria: Review articles, case reports, congress abstracts, studies reporting whole-gland ablation or procedures performed in a salvage setting. |
Technique | All people had transrectal focal HIFU using 1 of 3 devices: Sonablate 500 (SonaCare Medical LLC; 8 studies and 2786 people), Ablatherm Fusion (EDAP TMS; 8 studies and 778 people), and Focal One (EDAP TMS; 6 studies and 679 people). Four studies used a 6 mm safety margin from the apex of the prostate to preserve sphincter functionality and maintain continence, 1 used 3 mm and 1 used 10 mm. TURP was done in 6 of 20 studies, typically 6 to 12 months preoperatively. ADT was done in 2 studies. |
Follow up | Ranged from 3 to 73 months |
Conflict of interest/source of funding | Conflict of interest: The authors declared no conflict of interest. Source of funding: One author reports a grant from the European Urological Scholarship Programme. |
Analysis
Study design issues: This systematic review summarises the available evidence on focal HIFU for prostate cancer. The systematic review was conducted according to the Cochrane handbook and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Only the MEDLINE database was searched, possibly leading to the identification of fewer studies. Twenty studies were included in the final analysis, including 1 RCT (that reported no functional or oncological outcomes), 10 prospective development studies, and 9 retrospective case series. No bias assessment was conducted. Outcomes included:
Technical aspects of focal HIFU therapy, oncologic and functional outcomes, complications, and management of disease recurrence.
Study population issues: All studies used focal HIFU in a primary treatment setting – studies reporting on salvage therapy were excluded. Most studies included people in low and intermediate prostate cancer risk groups (based on modified D'Amico classification system).
Key efficacy findings
Oncological outcomes
Number of people analysed: 16 studies, n=3,440
PSA nadir
Median time to reach PSA nadir ranged from 3 to 12 months postoperatively (6 studies)
Median PSA reduction was 53% to 84% (10 studies)
Infield recurrence
Clinically significant infield recurrence was detected in 5% to 22% of people (9 studies)
Any prostate cancer in the HIFU field was detected in 10% to 37% of people (7 studies)
Out-of-field progression
Clinically significant out-of-field progression was detected in 2% to 29% of people (7 studies)
Any prostate cancer out of the HIFU field was detected in 8% to 35% of people (6 studies)
Author, years | Study design | People, N | Follow up, months | Infield recurrence, % | Out-of-field progression, % | ||
|---|---|---|---|---|---|---|---|
Any | Clinically significant | Any | Clinically significant | ||||
Ahmed HU et al. (2015) Eur Urol. 68:927-36 | Prospective development study | 56 | 12 | 34.6 | 15.4 | 7.7 | 3.8 |
Dickinson L et al. (2017) Urol Oncol. 35:30.e9-30.e15 | Prospective development study | 118 | 12 | 36.9 | 18.9 | – | – |
Feijoo ER et al. (2016) Eur Urol. 69:214-20. | Prospective development study | 67 | 12 | 16.4a | – | 10.4a | – |
Guillaumier S et al. (2018) Eur Urol. 74:422-9 | Prospective development study | 625 | 56 | 18.0 | – | 12.2 | – |
Rischmann P et al. (2017) Eur Urol. 71:267-73 | Prospective development study | 111 | 30 | 13.9 | 5.0 | 20.8 | 6.9 |
van Velthoven R et al. (2016) Prostate Cancer Prostatic Dis. 19:79-83. | Prospective development study | 50 | 35 | 6.0b | – | 10.0b | – |
Ganzer R et al. (2018) J Urol. 199:983-9. | Prospective development study | 51 | 17 | 26.5 | 8.2 | 34.7 | 2.0 |
Mortezavi A et al. (2019) J Urol. 202:717-24. | Prospective development study | 75 | 6 | – | 20.6 | – | 29.4 |
Albisinni S et al. (2017) J Endourol. 31:14-9 | Retrospective cases series | 55 | 36 | 12.7b | 9.1b | 21.8b | – |
Tourinho-Barbosa RR et al. (2020) J Urol. 203:320-30 | Retrospective cases series | 190 | 37 | 30.0 | – | 16.8 | – |
Stabile A et al. (2019) BJU Int. 24:431-440 | Retrospective cases series | 1032 | 36 | 31.5 | |||
Johnston MJ et al. (2019) Urology 133:175-81 | Retrospective cases series | 107 | 30 | 28.0 | |||
Bass R et al. (2019) J Urol. 201:113-9 | Retrospective cases series | 150 | 24 | – | 12.7 | – | 12.0 |
Annoot A et al. (2019) World J Urol. 37:261-8. | Retrospective cases series | 55 | 33 | – | 21.8 | – | 5.5 |
Huber PM et al. (2020) J Urol. 203:734-42. | Retrospective cases series | 598 | – | 35.1c | |||
Abreu AL et al. (2020) J Urol. 204:741-7. | Retrospective cases series | 100 | 18 | 10.0 | 8.0 | 23.0 | 10.0 |
In some studies control biopsies were performed not routinely per-protocol and (a) based on scheduled clinical visits without postoperative mpMRI, (b) on PSA kinetics only, as well as (c) triggered only when a suspicious lesion on postoperative mpMRI was detected or PSA rising was observed.
Quality of life
Number of people analysed: 2 studies, n=131
There was no deterioration in QoL on the FACT-P questionnaire (2 studies).
Retreatment
Number of people analysed: 13 studies, n=2,657
Infield recurrence: 5% to 11% of people had a second focal HIFU (2 studies).
Out-of-field progression: 2% to 13% of people had a second focal HIFU (4 studies).
Not specified disease location: 4% to 19% of people had a second focal HIFU (7 studies).
Other retreatments:
Salvage focal cryotherapy: 1% of people (1 study).
Salvage whole-gland HIFU: 0.4% to 10% of people (3 studies).
Salvage radical prostatectomy: 1% to 22% of people (10 studies).
Salvage EBRT with or without ADT: 0.9% to 8% of people (9 studies).
ADT only: 0.2% to 6% of people (6 studies).
Key safety findings
Complications
Number of people analysed: 13 studies, n=1,870
Overall, 13% to 41% of people who had focal HIFU experienced some type of complication (12 studies).
The most common treatment-related adverse events included:
Acute urinary retention (7% to 27% of people) (8 studies)
Urethral sloughing (7% to 43%) (4 studies)
UTI (5% to 18%) (8 studies)
Acute infective epididymitis (2% to 8%) (2 studies)
Fistula (0.3% to 3%) (2 studies)
Iatrogenic urethral stricture disease (2% to 4%) (3 studies)
Most complications (85% to 100%) presented up to 3 months after the procedure (3 studies).
Complications were mostly minor (80% to 100%; Clavien–Dindo grade I-II) and did not require any surgical intervention (9 studies).
Ablation volume and inclusion of the urethra were identified as the main predictors for postoperative complications.
Functional outcomes
Number of people analysed: 13 studies, n=2,057
Urinary continence
Incontinence was defined as the use of any pad in 9 studies or more than 1 pad per day in 2 studies.
3 months postoperatively: 86% to 98% reported to be totally continent (3 studies).
6 months postoperatively: 90% to 98% reported to be totally continent (6 studies).
12 months postoperatively: 93% to 97% reported to be totally continent (6 studies).
IPSS: IPSS remained unchanged during the first 6 months postoperatively (3 studies).
ICSmaleSF: No changes in ICSmaleSF score were detected for 85% of people 3 months after the procedure (1 study), although the same improvement from baseline was observed 12 months after focal therapy in another study.
EPIC urinary domain: the incontinence score showed initial deterioration, although 6 months after the procedure, the score had returned to baseline (1 study) and remained high at 2 (97% continent) and 3 years (98% continent) afterwards (1 study).
Erectile function
Erectile dysfunction was defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual intercourse.
6 months postoperatively: 69% to 80% had retained sufficient erections for sexual intercourse (2 studies), and these rates remained stable (5 studies) or improved slightly (1 study) within the next 2 years.
IIEF:
15-question IIEF questionnaire initially decreased by 23 points in 1 study, with a gradual recovery during the early postoperative phase, 6 months after the procedure, the total score was still inferior by 17 points compared with baseline. In another study, 88% of people had normal erectile function at 12 months.
5 question IIEF: 1 study reported no deterioration in erectile function, while 2 other studies reported that 52% to 70% of people retained the same preoperative values on the IIEF-5 after the procedure. One study reported erectile dysfunction rates after a second focal HIFU, where retreatment was associated with a 7% increased erectile dysfunction rate.
Study 2 He Y (2020)
Study type | Systematic review and meta-analysis (of complications) |
Country | Belgium (1 study), Canada (1 study), France (3 studies), Germany (1 study), Switzerland (1 study), UK (2 studies) |
Recruitment period | Study publication dates range from 2016 to 2019 |
Study population and number | Partial-gland ablation evidence: n=9 studies, 1,698 people People with prostate cancer who had whole-gland or partial-gland HIFU as primary treatment. |
Age and sex | Means ranged from 45 to 81; 100% male |
Patient selection criteria | Inclusion criteria:
Exclusion criteria: Recurrent prostate cancer, HIFU as salvage therapy, reviews, conference or poster presentation, editorial commentaries, overlapping cohorts, or fewer than 50 people included. |
Technique | Hemiablation was the most common technique used by the included studies. |
Follow up | Ranged from 12 to 39 months |
Conflict of interest/source of funding | Conflict of interest: The authors declared that they have no conflict of interest. Source of funding: The authors report the receipt of several grants from academic and public sources. |
Analysis
Study design issues: This systematic review and meta-analysis summarises the outcomes of primary treatment with partial-gland and whole-gland HIFU for prostate cancer. Meta-analyses were only conducted on complications; efficacy outcomes are less comprehensively described than in Bakavicius (2022) and are not described in this overview. The methods of the meta-analysis are not well described.
Incidence of complications after HIFU were compared between partial-gland and whole-gland. p<0.05 was considered statistically significant.
Other issues: Forest plots generated by the meta-analysis appear to be in the wrong format. The plots describe the pooled rate of complications but are formatted as risk difference between experimental and control arms.
Key efficacy findings
Meta-analyses were only conducted on complications; efficacy outcomes are less comprehensively described than in Bakavicius (2022) and are not described in this overview.
Key safety findings
Complications and functional outcomes
Urinary incontinence
Number of people analysed: 5 studies, n=469
The pooled incontinence rate for focal HIFU was 2% with no heterogeneity (I2=0%).
There was a statistically significantly lower incidence of incontinence with focal HIFU versus whole-gland HIFU (2% vs. 10%; p<0.001; whole-gland HIFU meta-analysis based on 13 studies).
Erectile dysfunction
Number of people analysed: 6 studies, n=536
The pooled erectile dysfunction rate for focal HIFU was 21% with moderate heterogeneity (I2=62%).
There was a statistically significantly lower incidence of erectile dysfunction with focal HIFU versus whole-gland HIFU (21% vs. 44%; p<0.001; whole-gland HIFU meta-analysis based on 8 studies).
Urinary retention
Number of people analysed: 5 studies, 429 people
The pooled urinary retention rate for focal HIFU was 9% with no heterogeneity (I2=0%).
There was no statistically significant difference in incidence of urinary retention with focal HIFU versus whole-gland HIFU (9% vs. 11%; p=0.945; whole-gland HIFU meta-analysis based on 5 studies).
Urinary obstruction
Number of people analysed: 5 studies, n=386
Urinary infection
Number of people analysed: 4 studies, n=279
The pooled urinary infection rate for focal HIFU was 11% with moderate heterogeneity (I2=67%).
There was a statistically significantly higher incidence of urinary infection with focal HIFU versus whole-gland HIFU (11% vs. 7%; p=0.001; whole-gland HIFU meta-analysis based on 4 studies).
Study 3 Khoo CC (2020)
Study type | Systematic review |
Country | Not reported for individual studies. |
Recruitment period | Study publication dates ranged from 2012 to 2017 |
Study population and number | n=3 studies, 237 people People with radiorecurrent prostate cancer who had focal HIFU salvage therapy |
Age and sex | Means ranged from 68.8 to 70.5; 100% male |
Patient selection criteria | Inclusion criteria:
Exclusion criteria: whole-gland ablation, review articles, unpublished studies, case reports, letters, bulletins, comments, conference abstracts, small series (n<10), duplicates, and studies with follow-up articles. |
Technique | Treatment strategies varied, and included quadrant-, hemi- and index lesion ablation (with residual cancer left untreated). |
Follow up | Ranged from 16.3 to 35 months. |
Conflict of interest/source of funding | Conflict of interest: The authors declare various grants, some of which were from manufacturers of HIFU devices. Source of funding: The authors declared that no funding was received. |
Analysis
Study design issues: This systematic review summarises the evidence on the use of focal HIFU as a salvage therapy in people with radiorecurrent prostate cancer. Reporting of the review followed the PRISMA statement. A quality assessment was conducted using the Methodological Index for Non-Randomized Studies instrument. Using this instrument, the 3 studies identified for HIFU scored 12, 12, and 13 out of 16, respectively. Outcomes included:
BDFS, rates of metastases, second-line therapies, and adverse events.
Key efficacy findings
Number of people analysed: 3 studies, n=237
BDFS: BDFS at the end of follow up or 3 years ranged from 0% to 67%. One study split people by whether they had achieved a PSA nadir of <0.5 ng/mL; those that did had higher BDFS rates.
Metastasis rates ranged from 5 to 12.5%.
Conversion to second-line therapy was only reported in 1 study and was 8%.
Author | n | Mean age (years) | Median pre-salvage PSA (ng/mL) | Median follow up (months) | Biochemical disease-free survival | Metastasis | Conversion to second-line salvage therapies |
|---|---|---|---|---|---|---|---|
Ahmed HU et al. (2012) Cancer 118:4148-55 | 39 | 70.5 | 4.6 | 17 | PSA nadir <0.5 ng/mL: 1 year: 86% 2 years: 75% 3 years: 63% PSA nadir ≥0.5 ng/mL: 1 year: 55% 2 years: 24% 3 years: 0% | 5% | n.a. |
Baco E et al. (2014) BJU 114:532-40 | 48 | 68.8 | na | 16.3 | End of follow-up: 67% | 12.5% | n.a. |
Kanthabalan A et al. (2017) BJU Int 120:246-56. | 150 | 69.8 | 5.5 | 35 | 3 years: 48% | 6% | 8.0% (sRP: 3, EBRT of spinal metastatic disease: 1, irreversible electroporation: 1, sCT: 1, chemotherapy: 4, other drug treatments: 2) |
Key safety findings
Complications
Number of people analysed: 3 studies, n=237
Reported complications included:
Rectourethral fistula (2% to 3.6%; 2 studies)
Bladder neck stenosis (8.0%; 1 study)
Pubic bone osteitis (0.7% to 4.2%; 2 studies)
Functional outcomes
Number of people analysed: 2 studies, n=189
Incontinence rates:
One study reported a pad-free, leak-free continence rate of 64% and the pad-free rate was 87% at last follow up.
The other study reported a pad-free rate of 87.5% at 2 years and 67.6% of people drip-free continent at baseline remained drip-free.
Erectile dysfunction:
One study reported worsening IIEF5 scores from a pre-procedure median of 18 to 13 at 6 months.
The other study reported a minor decline in median IIEF5 scores from 15 to 13.
Study 4 Reddy D (2022)
Study type | Prospective, multicentre registry analysis – the HEAT registry |
Country | UK |
Recruitment period | 2005 to 2020 |
Study population and number | n=1,379 People with non-metastatic prostate cancer who were treated using focal HIFU |
Age and sex | Median 66; 100% male |
Patient selection criteria | People with Gleason score of 6 to 9 prostate cancer and radiological stage up to T3bN0M0 were offered focal therapy. |
Technique | Focal HIFU using the Sonablate (500 and 3G) device (Sonacare Inc., Charlotte, NC, USA). Quadrant was the most used ablative pattern (62%), with hemiablation (35%), and hockey-stick ablation (3%) less common. Up to 2 focal HIFU treatments were permitted (differences in functional outcome between 1 and 2 treatments are provided in Lovegrove 2020; study 5). |
Follow up | Overall: median 32 months (interquartile range [IQR] 17 to 58 months) For people with more than 5-year follow up: median 82 months (IQR 72 to 94 months) |
Conflict of interest/source of funding | Conflict of interest: Authors report various industry and governmental grants. Source of funding: The HEAT registry is funded by Sonacare, the manufacturer of a HIFU device. |
Analysis
Follow-up issues: The median follow up was 32 months in all people. In 325 people with more than 5 years of follow up, the median follow up was 82 months.
Study design issues: This study was an analysis of the HEAT registry and reported cancer control outcomes. Functional outcomes are reported in Lovegrove (2020; study 5). People suitable for focal HIFU were prospectively and consecutively entered into the registry. Recommended follow up included 3 to 6 monthly PSA follow up in the 1st year and 6-monthly thereafter, with MRI at 6 to 12 months. Outcomes included:
Primary: FFS, with failure defined as evidence of cancer requiring whole-gland salvage treatment or 3rd focal therapy treatment, systemic treatment, development of prostate cancer metastases, or prostate cancer-specific death.
Secondary: any retreatment-free survival, salvage whole-gland and systemic treatment-free survival, ADT-free survival, metastasis-free and prostate cancer-specific survival, OS, and adverse events and complications.
The Kaplan–Meier method was used to calculate survival outcomes.
Study population issues: Most people were D'Amico risk level intermediate (65%), followed by high (28%). Pretreatment T-stage was most commonly T2 (74%), and Gleason score was most commonly 3 + 4 = 7 (62%). A total of 13 people (0.9%) had neoadjuvant or cytoreductive ADT.
Key efficacy findings
Cancer control outcomes
Number of people analysed: 1,379
FFS at 7 years was 69% (95% CI 64% to 74%).
By D'Amico risk class, FFS at 7 years was:
Low risk cancers 88% (95% CI 77% to 99%)
Intermediate risk cancers 68% (95% CI 62% to 75%)
High risk cancers 65% (95% CI 56% to 74%)
Salvage whole-gland or systemic treatment-free survival at 7 years was 75% (95% CI 71% to 80%).
132 people had salvage local whole-gland or systemic treatment.
53 people transitioned to salvage radical prostatectomy and 39 had salvage radiotherapy or brachytherapy.
Metastasis-free and prostate cancer-specific survival at 7 years were 100% (95% CI 99% to 100%).
There were 20 deaths in the study period; the OS at 7 years was 97% (95% CI 96% to 99%).
Kaplan–Meier estimate, % (95% CI) | 1-year | 2-year | 3-year | 4-year | 5-year | 6-year | 7-year |
|---|---|---|---|---|---|---|---|
Failure-free survival | 100 (100 to 100) | 96 (95 to 98) | 93 (91 to 95) | 88 (85 to 90) | 82 (79 to 86) | 75 (71 to 79) | 69 (64 to 74) |
By D'Amico risk class | |||||||
Low | 100 (100 to 100) | 99 (96 to 100) | 99 (96 to 100) | 94 (88 to 100) | 91 (84 to 100) | 91 (84 to 100) | 88 (77 to 99) |
Intermediate | 100 (100 to 100) | 97 (96 to 98) | 93 (91 to 95) | 88 (85 to 91) | 83 (79 to 87) | 75 (70 to 81) | 68 (62 to 75) |
High | 100 (99 to 100) | 95 (93 to 97) | 91 (88 to 94) | 85 (81 to 90) | 79 (73 to 85) | 69 (62 to 78) | 65 (56 to 74) |
Salvage or systemic treatment-free survival | 100 (100 to 100) | 97 (96 to 98) | 93 (91 to 95) | 89 (86 to 91) | 85 (83 to 88) | 80 (77 to 84) | 75 (71 to 80) |
By D'Amico risk class | |||||||
Low | 100 (100 to 100) | 99 (96 to 100) | 99 (96 to 100) | 99 (96 to 100) | 99 (96 to 100) | 99 (96 to 100) | 95 (87 to 100) |
Intermediate | 100 (100 to 100) | 97 (96 to 99) | 94 (91 to 96) | 89 (86 to 92) | 84 (80 to 88) | 79 (74 to 84) | 73 (67 to 80) |
High | 100 (99 to 100) | 95 (93 to 98) | 91 (87 to 94) | 86 (82 to 91) | 84 (79 to 89) | 78 (71 to 85) | 73 (65 to 82) |
Key safety findings
Complications
Number of people analysed: 1,379
There were a total of 83/1379 (6.0%) postoperative complications.
The rate of complications with Clavien–Dindo score >2 was 0.5% (7/1,379).
Most common complications were:
UTIs, n=52 (3.8%)
Epididymitis, n=11 (0.8%)
Urinary retention, n=10 (0.7%)
Rectourethral fistulae, n=2 (0.1%)
Incomplete focal treatment due to movement, n=1
Study 5 Lovegrove CE (2020)
Study type | Prospective, multicentre registry analysis – the HEAT registry |
Country | UK |
Recruitment period | 2005 to 2016 |
Study population and number | n=420 People with non-metastatic prostate cancer who were treated using 1 (cohort 1; n=355) or 2 (cohort 2; n=65) focal HIFU treatments |
Age and sex | 66.4 (cohort 1)/65.6 (cohort 2); 100% male |
Patient selection criteria | Inclusion criteria: Gleason 7 or high-volume Gleason 6 disease with maximum cancer core length of more than 4 mm, stage T1c radiological T3aN0M0 disease, and PSA level of 20 ng/mL or less. However, some people with disease characteristics outside of these criteria chose to have focal HIFU. Exclusion criteria: previous use of whole-gland therapy. |
Technique | As per Reddy (2022; study 4). A second focal HIFU procedure was permitted in the protocol as part of the focal therapy intervention for residual or recurrent disease detected during follow up. |
Follow up | Cohort 1: median 64.9 months (IQR 41.9 to 78.9 months) Cohort 2: median 72.5 months (IQR 65.8 to 91.0 months) |
Conflict of interest/source of funding | Conflict of interest: One author reports consultancy fees for Sonacare, the manufacturer of a HIFU device. Source of funding: Not reported, though Reddy (2022) notes that the HEAT registry is funded by Sonacare. |
Analysis
Follow-up issues: A total of 821 people were entered into the HEAT registry during the recruitment period. A total of 420 people returned questionnaires and were included in this analysis: 355 people had 1 focal HIFU (cohort 1) and 65 people had 2 focal HIFUs (cohort 2).
Study design issues: This study was an analysis of the HEAT registry that reported functional outcomes and presented a comparison of outcomes between people who had 1 focal HIFU with people who had 2. Outcomes included:
Urinary continence, as measured by the IPSS and EPIC questionnaires.
Erectile function, as measured by the IIEF-5 questionnaire.
Data were collected at baseline, 1 to 2 years, and 2 to 3 years. Various tests were used to evaluate statistical significance. p<0.05 was considered statistically significant. No adjustment for multiple comparisons was made.
Study population issues: Cohorts 1 and 2 were comparable at baseline, except that cohort 2 had a higher proportion of people with T2 disease.
Key safety findings
Functional outcomes
Urinary outcomes
Number of people analysed: 355 (cohort 1), 65 (cohort 2)
There was a statistically significant decrease (implying better function) in mean IPSS from baseline to 1 to 2 years after the first focal HIFU (mean change -0.03, p=0.02).
There was no statistically significant change in mean IPSS from baseline to 2 to 3 years after the first focal HIFU, or from 1 to 2 years to 2 to 3 years after (both p>0.05).
There were no statistically significant changes in the proportion of people who were pad-free and leak-free continent after the first focal HIFU.
Cohort 2 (2 HIFUs):
There was a statistically significant decrease (implying better function) in mean IPSS from baseline to before the second focal HIFU (mean change -1.3, p=0.02).
There were statistically significant increases (implying worse function) in mean IPSS from before the second focal HIFU to 1 to 2 years after the second focal HIFU (mean change 1.4, p=0.03), and from before the second focal HIFU to 2 to 3 years after the second focal HIFU (mean change 1.2, p=0.003).
There were no other statistically significant changes in IPSS observed.
There were no statistically significant changes in the proportion of people who were pad-free and leak-free continent after the first focal HIFU.
Cohort 1 | Cohort 2 | |||
|---|---|---|---|---|
Group mean (SD) | Group mean (SD) | |||
Baseline | 9.47 (5.9) | 9.5 (6.6) | ||
1 to 2 years after 1st HIFU | 9.44 (6.3) | 7.9 (5.5) | ||
2 to 3 years after 1st HIFU | 9.6 (6.2) | 8.2 (4.8) | ||
Before 2nd HIFU | 8.2 (5.4) | |||
1 to 2 years after 2nd HIFU | 9.6 (5.8) | |||
2 to 3 years after 2nd HIFU | 9.5 (5.5) | |||
Change in mean | p-value | Change in mean | p-value | |
Baseline vs. 1 to 2 years after 1 HIFU | -0.03 | 0.02 | ||
Baseline vs. 2 to 3 years after 1 HIFU | 0.1 | 0.8 | ||
1 to 2 years after 1 HIFU vs. 2 to 3 years after 1 HIFU | 0.2 | 0.2 | ||
Baseline vs. before 2nd HIFU | -1.3 | 0.02 | ||
Baseline vs. 1 to 2 years after 2nd HIFU | 0.1 | 0.36 | ||
Baseline vs. 2 to 3 years after 2nd HIFU | 0.0 | 0.37 | ||
Before 2nd HIFU vs. 1 to 2 years after 2nd HIFU | 1.4 | 0.03 | ||
Before 2nd HIFU vs. 2 to 3 years after 2nd HIFU | 1.2 | 0.003 | ||
1 to 2 years after 2nd HIFU vs. 2 to 3 years after 2nd HIFU | -0.1 | 0.06 | ||
Pad-free continent proportions | % | p-value vs. baseline | % | p-value vs. baseline/ before 2nd HIFU |
Baseline | 98.6 | - | 100 | - |
1 to 2 years after 1st HIFU | 94.8 | 0.07 | 100 | >0.05 |
2 to 3 years after 1st HIFU | 95.3 | 0.2 | 100 | >0.05 |
Before 2nd HIFU | 100 | >0.05 | ||
1 to 2 years after 2nd HIFU | 98.2 | >0.05 | ||
2 to 3 years after 2nd HIFU | 97.4 | >0.05 | ||
Leak-free continent proportions | % | p-value vs. baseline | % | p-value vs. baseline/ before 2nd HIFU |
Baseline | 77.9 | - | 72.1 | - |
1 to 2 years after 1st HIFU | 72.8 | 0.06 | 66.7 | >0.05 |
2 to 3 years after 1st HIFU | 73.5 | 0.5 | 80.6 | >0.05 |
Before 2nd HIFU | 72.9 | >0.05 | ||
1 to 2 years after 2nd HIFU | 71.4 | >0.05 | ||
2 to 3 years after 2nd HIFU | 78.9 | >0.05 | ||
Erectile function outcomes
Number of people analysed: 355 (cohort 1), 65 (cohort 2)
Cohort 1 (1 HIFU):
There was a statistically significant decrease (implying worse function) in EF score from baseline to 1 to 2 years after the first focal HIFU (mean change -0.4, p=0.02).
There was no statistically significant change in the proportion of people reporting erectile dysfunction (a score of 0 or 1 on question 2 of the IIEF) after the first focal HIFU.
Cohort 2 (2 HIFUs):
There were statistically significant decreases (implying worse function) in EF score from baseline to 1 to 2 years and 2 to 3 years after the second focal HIFU (mean change -0.8, p=0.005, and -1.1, p=0.008, respectively).
There was no statistically significant change in the proportion of people reporting erectile dysfunction (a score of 0 or 1 on question 2 of the IIEF) after the first or second focal HIFU.
EF score | Cohort 1 | Cohort 2 | ||
|---|---|---|---|---|
Group mean (SD) | Group mean (SD) | |||
Baseline | 3.9 (1.3) | 4.1 (1.3) | ||
1 to 2 years after 1st HIFU | 3.5 (1.6) | 3.3 (1.5) | ||
2 to 3 years after 1st HIFU | 3.8 (1.5) | 3.6 (1.3) | ||
Before 2nd HIFU | 3.5 (1.4) | |||
1 to 2 years after 2nd HIFU | 3.3 (1.7) | |||
2 to 3 years after 2nd HIFU | 3.0 (1.4) | |||
Change in mean | p-value | Change in mean | p-value | |
Baseline vs. 1 to 2 years after 1 HIFU | -0.4 | 0.02 | ||
Baseline vs. 2 to 3 years after 1 HIFU | -0.2 | 0.6 | ||
1 to 2 years after 1 HIFU vs. 2 to 3 years after 1 HIFU | 0.3 | 0.2 | ||
Baseline vs. before 2nd HIFU | -0.6 | 0.2 | ||
Baseline vs. 1 to 2 years after 2nd HIFU | -0.8 | 0.005 | ||
Baseline vs. 2 to 3 years after 2nd HIFU | -1.1 | 0.008 | ||
Before 2nd HIFU vs. 1 to 2 years after 2nd HIFU | -0.2 | 0.6 | ||
Before 2nd HIFU vs. 2 to 3 years after 2nd HIFU | -0.5 | 0.1 | ||
1 to 2 years after 2nd HIFU vs. 2 to 3 years after 2nd HIFU | -0.3 | 0.6 | ||
Erectile dysfunction proportions | % | p-value vs. baseline | % | p-value vs. baseline/ before 2nd HIFU |
Baseline | 9.9 | - | 5.9 | - |
1 to 2 years after 1st HIFU | 20.8 | 0.08 | 19.5 | >0.05 |
2 to 3 years after 1st HIFU | 18.3 | NR | 3.7 | >0.05 |
Before 2nd HIFU | 12.8 | >0.05 | ||
1 to 2 years after 2nd HIFU | 30.6 | >0.05 | ||
2 to 3 years after 2nd HIFU | 19.0 | >0.05 | ||
Study 6 van Son MJ (2021)
Study type | Propensity score weighted analysis – focal HIFU data from the HEAT registry |
Country | UK (radiotherapy, prostatectomy, focal HIFU, focal cryotherapy data) and the Netherlands (brachytherapy data) |
Recruitment period | 2005 to 2018 (focal therapy data); 2007 to 2018 (radical therapy data) |
Study population and number |
|
Age and sex | Not reported; 100% male |
Patient selection criteria | Inclusion criteria: PSA less than 20 ng/mL, ≤Gleason 4+3=7 and T-stage T2c or lower (National Comprehensive Cancer Network low to intermediaterisk) Exclusion criteria: history of previous prostate cancer treatment. |
Technique | Focal HIFU (Sonablate, Sonacare) was offered to people with peripheral or posterior tumours or those anteriorly based in which the anterior-posterior height was 3.5 cm or less. |
Follow up | Focal therapy group: median 62 months (IQR 42 to 83 months) |
Conflict of interest/source of funding | Conflict of interest: Authors report various grants and fees, some of which are from Sonacare, the manufacturer of a HIFU device. Source of funding: Not reported. |
Analysis
Study design issues: This propensity score matched analysis compared the outcomes of focal versus radical therapy. People were identified from 5 different registries. The radical radiotherapy registry was retrospective; the others were prospective. Missing data were imputed with single imputation. Identified people were assigned a propensity score based on age, PSA, Gleason score, maximum cancer core length, T-stage, and year of treatment. People were then weighted to correct for imbalances between treatment groups, with more weights applied to people with equal probabilities of assignment to either treatment group. The purpose of this weighting is to reduce the effect of non-random assignment to treatments in observational research. That is, people in the focal therapy group and the radical therapy group may differ in baseline characteristics other than assignment to treatment. These differences may influence the estimate of treatment effect in each group. Outcomes included:
Primary: FFS, a composite endpoint of (1) need for local salvage treatment, (2) development of metastatic disease, (3) use of systemic treatment (ADT or chemotherapy) or (4) progression to a watchful waiting strategy.
Secondary: OS.
Two-way analyses (focal therapy versus radical therapy) and three-way analyses (focal therapy versus radiotherapy versus prostatectomy) were performed. For all three-way analyses, p<0.017 was considered statistically significant (Bonferroni correction). For all two-way comparisons, p<0.05 was considered statistically significant. The Kaplan–Meier method was used to analyse survival over time.
Key efficacy findings
Number of people analysed: Focal therapy, n=530 (of which focal HIFU, n=419); radical therapy, n=830
Two-way analysis:
There was no statistically significant difference in FFS at 6 years between focal and radical therapy groups (p=0.10).
People treated with focal therapy had a statistically significantly higher OS at 6 years than people treated with radical therapy (97.5% vs. 93.4%, p=0.02).
There were no statistically significant differences between the groups in treatment failure or overall mortality (both p>0.05).
Three-way analysis:
There was a statistically significant difference in FFS at 6 years between the 3 groups (p<0.001).
Treatment failure was statistically significantly more likely in both LRP and focal therapy groups compared to EBRT (both p<0.001).
Overall mortality was statistically significantly less likely in the focal therapy group than the EBRT group (HR 0.29, 95% CI 0.11 to 0.76, p=0.008).
There was no statistically significant difference in overall mortality between the focal therapy and radical prostatectomy groups.
Two-way analysis | Focal therapy, % (95% CI) | Radical therapy, % (95% CI) | p-value | |||
|---|---|---|---|---|---|---|
FFS at 6 years | 72.8 (66.8 to 79.8) | 80.3 (73.9 to 87.3) | 0.10 | |||
OS at 6 years | 97.5 (94.0 to 99.9) | 93.4 (90.1 to 95.2) | 0.02 | |||
HR (95% CI) | SE | p-value | ||||
Treatment failure, focal vs. radical | 1.29 (0.96–1.75) | 0.15 | 0.10 | |||
Overall mortality, focal vs. radical | 0.49 (0.22–1.09) | 0.41 | 0.08 | |||
Three-way analysis | Focal therapy | EBRT | LRP | p-value | ||
FFS at 6 years | 74.4 (68.4 to 81.5) | 87.4 (79.9 to 93.9) | 73.9 (68 to 80.9) | <0.001 | ||
OS at 6 years | 97.5 (94.9 to 100) | 92.3 (83.5 to 95.8) | 95.3 (88.9 to 98.3) | 0.05 | ||
HR (95% CI) | SE | p-value | ||||
Treatment failure | ||||||
LRP vs. EBRT | 2.41 (1.44 to 4.05) | 0.26 | 0.0005 | |||
FT vs. EBRT | 2.24 (1.4 to 3.64) | 0.25 | 0.0002 | |||
FT vs. LRP | 0.93 (0.65 to 1.33) | 0.18 | 0.69 | |||
Overall mortality | ||||||
LRP vs. EBRT | 0.54 (0.23 to 1.29) | 0.44 | 0.17 | |||
FT vs. EBRT | 0.29 (0.11 to 0.76) | 0.48 | 0.008 | |||
FT vs. LRP | 0.54 (0.19 to 1.52) | 0.53 | 0.24 | |||
Study 7 Stabile A (2019)
Study type | Two-centre, retrospective case series |
Country | UK |
Recruitment period | 2005 to 2017 |
Study population and number | n=1032 People with low or intermediate risk prostate cancer who received focal HIFU |
Age and sex | Median 65; 100% male |
Patient selection criteria | Inclusion criteria: consecutive people who had focal HIFU for low or intermediate risk prostate cancer. |
Technique | Transrectal focal HIFU (Sonablate 500; Sonacare Inc). Focal ablation was most common (70.7%) with hemiablation less common (29.3%). |
Follow up | Median 36 months (IQR 14 to 64 months) |
Conflict of interest/source of funding | Conflict of interest: The authors report various grants and fees, including from Sonacare, the manufacturer of a focal HIFU device. Source of funding: Not reported. |
Analysis
Study design issues: This two-centre, retrospective case series presented the outcomes of focal HIFU in a large cohort. Consecutive people were enrolled to a prospective registry; the data were then analysed retrospectively. During follow up, PSA was assessed every 3 to 4 months and an MRI was offered at 6 or 12 months. Later MRIs were offered between 1 and 3 years, with additional scans based on PSA levels. Follow up biopsies were offered to a subset of people who were involved in other studies or where there was a concern. Outcomes included:
Oncological outcomes including:
OS
Retreatment-free survival
Radical treatment-free survival, defined as radical prostatectomy, external-beam radiotherapy and other whole-gland therapies
Biopsy FFS, defined as the presence of clinically significant prostate cancer at post-treatment biopsy.
Kaplan–Meier curves were plotted to assess survival. Multivariable regression was used to assess the predictors of 5-year retreatment. All tests were 2-sided with p<0.05 considered statistically significant.
Study population issues: Most people had Gleason score of 3 + 4 (63%) and T2 stage (78%).
Key efficacy findings
Oncological outcomes
Number of people analysed: 1,032
At 96 months, OS was 96.6%, biopsy FFS was 54.0%, retreatment-free survival was 45.8%, and radical treatment-free survival was 80.8%.
Predictors of 5-year retreatment included:
Year of surgery, odds ratio (OR) 0.77 (95% CI 0.67 to 0.89, p<0.001), suggesting a learning curve
PSA, OR 1.07 (95% CI 1.01 to 1.12, p=0.015)
T2 or T3 stage prostate cancer (compared to T1), OR 3.75 (95% CI 1.63 to 9.82, p=0.003) and OR 5.0 (95% CI 1.9 to 14.9, p=0.002), respectively.
Follow up (months) | Outcome (%) | |||
|---|---|---|---|---|
Overall survival | Biopsy FFS | Retreatment-free survival | Radical treatment-free survival | |
12 | 99.3 | 93.5 | 97.5 | 99.8 |
24 | 99.1 | 83.8 | 85.0 | 97.6 |
60 | 97.3 | 63.6 | 58.9 | 90.6 |
96 | 96.6 | 54.0 | 45.8 | 80.8 |
Retreatments
Number of people analysed: 1,032
Throughout the follow up period, 271 people were retreated (26.3%).
Retreatments included:
Focal HIFU, n=193
Focal cryotherapy, n=12
EBRT, n= 9
Radical prostatectomy, n=30
Whole-gland HIFU, n=4
ADT, n=20
Other, n=3
Key safety findings
Safety findings were not reported.
Study 8 Byun S-S (2022)
Study type | Single-centre, retrospective cohort study |
Country | South Korea |
Recruitment period | 2018 to 2020 |
Study population and number | n=206 (152 partial-gland HIFU and 54 whole-gland HIFU) People who had partial- or whole-gland HIFU for localised prostate cancer |
Age and sex | Median 68; 100% male |
Patient selection criteria | Inclusion criteria: all people who had HIFU for localised prostate cancer during the study period. |
Technique | HIFU was performed using the Focal One device (Edaps TMS, France). Whole-gland ablation was defined as ablation of all the prostate; partial-gland ablation was defined as hemiablation and subtotal ablation. Transurethral prostatectomy (TURP) was performed before HIFU in all people. |
Follow up | Median 12 months (IQR 7 to 17 months) |
Conflict of interest/source of funding | Conflict of interest: The authors declare that they have no conflicts of interest. Source of funding: This work was supported by institutional grant from university research fund. |
Analysis
Follow up issues: Incontinence and erectile function were assessed at every follow up visit. Prostatic biopsy was recommended at the 12-month follow up. At 12 months follow up, biopsy results were available for 27 whole-gland and 59 partial-gland ablation people. The reasons for loss to follow up are not reported.
Study design issues: This retrospective cohort study compared the outcomes of partial-gland and whole-gland ablation for treating localised prostate cancer. People were identified retrospectively from a prospectively maintained registry. Outcomes included:
Primary outcomes were not defined.
Other listed outcomes:
Urinary continence, using the EPIC-CP, with incontinence was defined based on pad usage.
Erectile function, using the IIEF-5, with normal erectile function was defined as an IIEF-5 score of 22 or more.
Cancer control, assessed through biopsy.
Kaplan–Meier analyses were performed to assess survival. All statistical tests were 2-sided, and p<0.05 was considered statistically significant. There was no adjustment for multiple comparisons.
Study population issues: There were several statistically significant differences in baseline characteristics between the whole-gland and partial-gland ablation groups, including:
Age: Partial-gland ablation people were younger (p=0.033)
Risk and severity: Partial-gland ablation people had lower D'Amico risk classification (p=0.015), Gleason score (p=0.023), and T-stage (p=0.032)
Tumour characteristics: Partial-gland ablation people had fewer positive cores (p<0.001) and a small median maximal tumour length (p=0.01)
Key efficacy findings
Oncological outcomes
Number of people analysed: 59 (partial-gland ablation), 27 (whole-gland ablation)
There were no statistically significant differences in positive biopsies between the whole-gland and partial-gland ablation groups.
Oncological outcomes summary
Outcomes at 12 months after HIFU | Whole-gland ablation (n=27) | Partial-gland ablation (n=59) | p-value |
|---|---|---|---|
Any positive biopsy | 8 (29.6%) | 16 (27.1%) | 0.713 |
Infield positive | 8 (29.6%) | 2 (3.4%) | |
Outfield positive | 0 | 10 (16.9%) | |
Both positive | 0 | 4 (6.8%) | |
Clinically significant cancer positive biopsy | 5 (18.5%) | 9 (15.3%) | NR |
Infield positive | 5 (18.5%) | 2 (3.4%) | |
Outfield positive | 0 | 5 (8.5%) | |
Both positive | 0 | 2 (3.4%) |
Key safety findings
Complications
Number of people analysed: 152 (partial-gland ablation), 54 (whole-gland ablation)
The postoperative complication rate was statistically significantly higher in the whole-gland ablation group compared to the partial-gland ablation group (66.7% vs. 37.5%, p=0.023).
Whole-gland ablation (n=54) | Partial-gland ablation (n=152) | p-value | |
|---|---|---|---|
Complications by grade | 46 (66.7%) | 57 (37.5%) | 0.023 |
None | 18 (33.3%) | 95 (62.5%) | |
Grade I | 13 (24.1%) | 23 (15.1%) | |
Grade II | 0 (0%) | 0 (0%) | |
Grade III | 23 (42.6%) | 34 (22.4%) | |
Grade IV | 0 (0%) | 0 (0%) | |
Type of complications | 0.476 | ||
Urinary retention | 10 (18.5%) | 16 (10.5%) | |
Bladder outlet obstruction Of who required endoscopic surgery | 19 (35.2%) 19 (35.2%) | 24 (15.8%) 24 (15.8%) | 0.005 |
Urinary tract infection | 1 (1.9%) | 3 (2.0%) | |
Bleeding | 3 (5.6%) | 8 (5.2%) | |
Bladder stone | 2 (3.7%) | 1 (0.7%) | |
Incontinence (any pad usage) | 6 (11.1%) | 12 (7.9%) | |
Incontinence (pad ≥ 2/day) | 2 (3.7%) | 4 (2.6%) | 0.661 |
Functional outcomes
Number of people analysed: 152 (partial-gland ablation), 54 (whole-gland ablation)
In Kaplan–Meier analysis, the partial-gland ablation group recovered continence statistically significantly faster than the whole-gland ablation group (p=0.047).
There was no statistically significant difference in the recovery of erectile function between the groups (p=0.317).
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