High-intensity focused ultrasound strategies for treating prostate cancer

Abstract

Prostate cancer (PCa) is a significant health concern globally, necessitating effective treatment options. Typical treatment methods for early stage, particularly localized PCa, encompass radical procedures, such as radical prostatectomy (RP) and radiotherapy (RT), and nonradical focal therapy (FT). FT is a focused approach mainly used for treating small lesions limited to a specific zone of the prostate. Its objective is to achieve cancer control when minimizing damage to benign tissue. High-intensity focused ultrasound (HIFU) is one of the most used modalities in FT for the management of PCa. The progress in HIFU technology showcases continuous advancements, offering clinicians a variety of strategies to cater to diverse patient requirements. The advancements include the development of transrectal and transurethral HIFU machines that offer enhanced treatment distances, magnetic resonance imaging (MRI) fusion capabilities, real-time monitoring, and precise ablation. These improvements contribute to increased treatment effectiveness and better outcomes for patients. This narrative review aims to summarize the use of HIFU technology and its evolution, offering diverse options to clinicians, and explores the safety, effectiveness, and quality of different HIFU strategies, such as whole-gland ablation, hemigland ablation, and focal ablation. We conclude that nonwhole-gland HIFU offers similar cancer control with better short-term functional outcomes and fewer complications compared to whole-gland ablation. Combining HIFU with transurethral resection of the prostate (TURP) improves urinary function and reduces catheterization time. Focal ablation and hemigland ablation show promise in achieving cancer control when preserving continence and potency.

INTRODUCTION

Prostate cancer (PCa) is a prevalent malignancy affecting men worldwide, particularly in aging populations.1,2,3 It is estimated that PCa is the second most diagnosed cancer and the fifth leading cause of cancer-related deaths among men globally, highlighting the significance of effective treatment options for this disease.3,4 Standard treatment approaches for early stage, mainly localized PCa, include radical treatments, such as radical prostatectomy (RP),5,6 radiotherapy (RT),6,7 and nonradical focal therapy (FT).8,9 FT is a targeted approach primarily employed for small tumors confined to a specific area of the prostate, aiming to achieve cancer control when minimizing harm to benign tissue.10

Significant advancements have been made in high-intensity focused ultrasound (HIFU) machines. Sonacare Inc. (Charlotte, NC, USA) has developed the Sonablate® HIFU, a transrectal device with a treatment distance of approximately 3.5 cm. Sonacare Inc. also offers the Sonafuse™-MIM Symphony™, an optional choice that incorporates magnetic resonance imaging (MRI) fusion for enhanced precision.

EDAP TMS (Vaulx-en-Velin, France) provides the Ablatherm® Fusion Robotic HIFU, along with the recently introduced Focal One®. The Focal One® offers a treatment distance of 4.0 cm, showcasing advanced capabilities for precise and targeted treatment.

Insightec (Tirat Carmel, Israel) has developed the ExAblate™ real-time MRI-guided HIFU machine, which stands out for its real-time temperature monitoring and immediate confirmation of treatment outcomes. The clinical team can optimize treatment results by monitoring the procedure in real time using thermometry data. Additionally, a contrast image is used at the end of treatment to confirm successful delivery.

There is also another transurethral real-time MRI-guided HIFU machine. Profound Medical Corp (Mississauga, ON, Canada) offers the TULSA-PRO® with a treatment distance of 3.0 cm from the urethra that provides enhanced accuracy and control during the ablation process facilitated by real-time MRI.

These advancements in HIFU technology demonstrate the ongoing progress in the field, providing clinicians with a diverse range of options to meet different patient needs. The development of transrectal and transurethral HIFU machines with improved treatment distances, MRI fusion capabilities, real-time monitoring, and precise ablation improves treatment efficacy and patient outcomes.

In previous studies,8,11,12 the focus was primarily on reporting and comparing the functional outcomes of FT to other treatments such as active surveillance and robot-assisted laparoscopic prostatectomy. Additionally, these studies also aimed to compare the effectiveness of different modalities employed in FT.13,14 Among the various modalities utilized in FT, HIFU has gained significant attention as a minimally invasive treatment option for PCa. It involves the precise application of focused ultrasound waves to the prostate gland, generating high-intensity energy at a focal point.15,16 This focused energy results in thermal ablation of the targeted tissue, destroying cancer cells.17 The energy source utilized in this process involves the conversion of ultrasonic waves into heat, reaching a temperature of 65°C. The primary mechanism of action is attributed to acoustic cavitation and coagulative necrosis. The predominant method employed is the utilization of a transrectal probe under the guidance of transrectal ultrasound (TRUS) imaging.18

The use of HIFU in PCa management was initially reported in 1996, primarily focusing on whole-gland ablation.19 In that study, they have evaluated the efficacy of transrectal focused ultrasound on localized PCa. This approach was intended for patients who either declined or were not eligible for RP, providing an alternative treatment option. In that study, only 14 patients who were unsuitable for surgery were treated and a satisfactory local control with 50% negative biopsy was observed. In more recent years, a large cohort of men (n=1032) treated with HIFU revealed that 54% of the cohort remained free from clinically significant PCa upon follow-up biopsy (only done in men with a suspicion on MRI or unexplained prostate-specific antigen [PSA] rise) after 8 years of treatment. Furthermore, 81% of patients avoided radical treatment at 8 years, with or without receiving another session of FT.20

However, more research needs to be conducted to compare the efficacy of different strategies of HIFU for PCa treatment. Previously published articles have examined the safety and efficacy of these strategies, including standalone HIFU treatment or followed by transurethral resection of the prostate (TURP),21 focal or hemigland ablation using HIFU in PCa,20,22,23,24 as well as nonwhole-gland HIFU versus whole-gland HIFU,25,26 and MRI/real-time ultrasound image fusion-guided HIFU.4 Therefore, we aim to conduct a narrative review to demonstrate these strategies’ relative safety, effectiveness, and quality. This review aims to assist health-care providers in gaining a better understanding of the outcomes associated with these treatment options to guide clinical decision-making.

HIFU STRATEGIES FOR PCA TREATMENT

HIFU has emerged as a prominent modality for the FT of localized PCa. The treatment can be performed through ablation of the entire prostate (whole-gland ablation), ablation of half of the prostate (hemigland ablation), or the targeting of specific cancerous lesions (focal ablation). Clinical study has evaluated the efficacy and safety of HIFU in various treatment approaches, including whole-gland ablation,27 hemigland ablation, and the role of MRI-guided imaging.

Whole-gland ablation versus nonwhole-gland ablation

Lei et al.25 conducted a study to compare the oncological and functional outcomes in localized PCa patients between nonwhole-gland ablation and whole-gland ablation therapy. In that study, 25 patients underwent nonwhole-gland ablation and 61 patients received whole-gland ablation. No significant differences were observed in the two groups regarding histological results, biochemical disease-free survival (BDFS), PSA nadir, and suspicious lesions in multiparametric MRI (mpMRI). However, the nonwhole-gland ablation group exhibited lower (mean ± standard deviation [s.d.]: 8.64 ± 3.63 vs 10.85 ± 6.10) International Prostate Symptom Score (IPSS) at 1 month, and a longer time (mean ± s.d.: 5.04 ± 2.07 months vs 3.83 ± 1.65 months) to PSA nadir, along with a lower temporary urine retention rate (20.0% vs 44.3%) and a lower complication rate (4.0% vs 26.2%), particularly regarding urethral strictures, than those in the whole-gland ablation group, respectively. Meanwhile, the pad-free and leakage-free rates and International Index of Erectile Function-5 (IIEF-5) scores were comparable between the two groups.

TURP immediately after HIFU

Several studies compared whole-gland HIFU treatment with and without TURP in the management of PCa. In 2010, Sumitomo et al.21 evaluated the long-term outcomes of HIFU followed by TURP for PCa. This retrospective study included 65 PCa patients who underwent HIFU alone and 64 patients who underwent TURP immediately after HIFU. Both catheterization time (P<0.0001) and posttreatment IPSS at 6 months, 12 months, and 24 months after treatment differed significantly between groups (P<0.001). Sixteen cases (24.6%) of urethral strictures were observed in patients who underwent HIFU treatment alone, while seven cases (10.9%) were reported in patients who received TURP thereafter. Among the patients in the whole-gland HIFU-only group, bladder neck contracture occurred in 11 cases (68.8%), whereas in the HIFU+TURP group, there were only two cases with urethral stricture (28.6%). Multiple logistic regression analyses demonstrated that the resection volume of TURP was a significant factor in preventing urethral stricture (P=0.02). This study indicated that the combination of whole-gland HIFU with a subsequent TURP procedure improved posttreatment urinary function with reduced bladder neck contracture or urethral stricture.

In 2013, Baumunk et al.28 reported the comparison results of 96 patients who had received HIFU treatment alone or HIFU+TURP with standard therapies (RP, external beam radiation therapy, and brachytherapy). The 4-year BDFS after HIFU and HIFU+TURP is comparable to that of the standard radical treatment. The erectile function was sustainably affected, whereas postoperative micturition and quality of life were not affected by either HIFU or HIFU+TURP. These results are limited by the small sample size and the short follow-up period.

Pan et al.29 have conducted a meta-analysis to report functional and oncologic outcomes of combining whole-gland HIFU with TURP in 1861 patients, including 1388 men with low- to intermediate-risk PCa and 473 men with high-risk PCa. HIFU with TURP might have potential advantages of decreasing catheterization time and urinary retention rates related to urethral stricture. Therefore, the combination treatment of whole-gland HIFU with TURP improved postoperative recovery and reduced urethral complications compared with HIFU alone.

A systematic review was done by Bossier et al.30 in patients with HIFU or HIFU+TURP. The matched pairs were discriminated against whether they had received HIFU treatment alone or HIFU+TURP. The results demonstrated that neither HIFU only nor HIFU+TURP showed an impact on postoperative micturition and erectile function. There was no measurable change in quality of life after the treatment. HIFU alone may achieve the similar postoperative micturition, erectile function, and quality of life compared to HIFU+TURP.

HIFU for local recurrence after RT

Whole-gland salvage HIFU (S-HIFU) has demonstrated effective oncologic outcomes for patients experiencing local recurrence after external-beam radiotherapy (EBRT) failure.

Song et al.31 conducted a study to assess the oncologic outcomes and postoperative complications in this patient population. The study included 13 patients with a median age of 68 (range: 60–76) years. The patients were followed up for a median period of 44.5 months after S-HIFU. The overall biochemical recurrence (BCR)-free rate was 53.8%. It reported a relatively high rate of complications (38.5%) requiring intervention, including bladder neck stenosis, urethral stricture, and stress urinary incontinence.

Crouzet et al.32 conducted a clinical trial including 418 patients with a mean follow-up of 3.5 years. Overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) were assessed. Adverse events and quality of life status were reported. The OS, CSS, and MFS rates at 7 years were 72%, 82%, and 81%, respectively. Complication rates decreased after the introduction of specific post-RT parameters: incontinence (grade II or III) from 32% to 19% (P=0.002), bladder outlet obstruction or stenosis from 30% to 15% (P=0.003), and rectourethral fistula decreased from 9% to 0.6% (P<0.001). The study concluded that S-HIFU should be initiated early following EBRT failure.

HEMIGLAND ABLATION

The use of HIFU in treating localized PCa has evolved, with different approaches being developed to optimize treatment outcomes and reduce side effects. Whole-gland treatment has been traditionally used but can result in a higher rate of side effects such as bladder neck stenosis and erectile dysfunction. In recent years, hemigland ablation has been more commonly performed.33 Hemigland treatment was proposed to reduce the risk of side effects when achieving reasonable cancer control. The lesion(s) must be confined to one lobe of the prostate. However, concerns remain regarding the risk of cancer recurrence in the untreated portion of the prostate gland.

Several studies have focused on investigating the oncologic and functional outcomes of hemigland ablation in PCa. The assessment of oncologic outcomes involved negative biopsies and PSA measurements, while functional outcomes were evaluated using validated genitourinary symptom questionnaires.

In 2016, Feijoo et al.34 demonstrated the feasibility of achieving acceptable cancer control with fewer complications through hemigland ablation of the affected lobe. The study included 67 patients, with a median PSA of 6.1 ng ml⁻¹. At the 12-month point, 56 out of 67 patients had a negative biopsy in the treated lobe. All patients maintained continence for 3 months, and 11 out of 21 preoperatively potent patients maintained potency. Complications included 8% Clavien–Dindo grade 2 events and 2.8% grade 3 events.

Abreu et al.35 focused on reporting the outcomes of hemigland ablation as a primary treatment for localized PCa. Before and after ablation, the median IIEF-5 and IPSS scores were 22 vs 21 (P=0.99) and 9 vs 6 (P=0.005), respectively. Minor complications were observed in 13% of patients, while no major complications, rectal fistula, or deaths occurred. At the 2-year follow-up, radical treatment was avoided in 91% of men. Based on short-term results, HIFU demonstrates safety, excellent preservation of potency and continence, and satisfactory control of PCa. Ganzer et al.36 demonstrated the results of hemigland ablation in 51 men (out of 54) who completed 12-month or longer follow-up. The follow-up duration (mean ± s.d.) was 17.4 ± 4.5 months. PSA levels (mean ± s.d.) decreased significantly from 6.2 ± 2.0 ng ml⁻¹ to 2.9 ± 1.9 ng ml⁻¹ at 12 months. At the 12-month biopsy, 13 patients (26.5%) tested positive for any PCa, while only 4 patients (8.2%) had clinically significant PCa out of the 49 patients evaluated. The sensitivity of posttreatment mpMRI for clinically significant PCa was limited to 25%. Salvage treatment was administered to 10 patients (19.6%) in total. Among the 30 potent men before the procedure, 21 maintained their potency. There were no reported cases of de novo incontinence. Postoperatively, there was no significant change in quality of life, anxiety, or depression.

In 2014, Baco et al.37 conducted a multicenter study that reported the oncologic and functional outcomes of salvage hemigland ablation in patients with unilateral radio-recurrent PCa, with a total of 48 patients enrolled. The study revealed a disease progression rate of 33%, with 4 cases of local recurrence in the untreated lobe, 4 cases of bilateral recurrence, and 6 cases of metastasis. The occurrence rate of severe incontinence was 8%, with 17% of patients requiring one pad per day and 75% being pad-free. The IPSS and IIEF-5 scores (mean ± s.d.) decreased from 8.6 ± 5.1 to 7.01 ± 5.6 and from 11.2 ± 8.6 to 7.0 ± 5.8 before and after ablation, respectively. The EORTC QLQ-C30 scores (mean ± s.d.) before and after ablation were 35.7 ± 8.6 and 36.8 ± 8.6, respectively.

Focal ablation versus hemigland ablation

Stabile et al.20 conducted the first comparative study on the rate of additional treatment after follow-up in a cohort of over 1000 men who underwent primary ablation. The patients underwent either an entire ablation of one prostatic lobe (hemigland ablation) or the ablation of the index lesion only. In this study, 71% of patients underwent focal ablation and 29% underwent hemigland ablation (15% of these patients underwent a hemigland ablation that crossed the midline of the prostatic gland). It demonstrated that focal ablation for PCa is a feasible therapeutic strategy, with acceptable survival and oncological results and a reduction in the 5-year retreatment rates over the last decade. It is important to note that as the extent of treatment increases, the functional outcomes tend to resemble those observed in whole-gland therapies, such as RP or RT. Therefore, for effective patient counseling and treatment planning, it is crucial to have a clear understanding of the extent of FT treatment.

HIFU WITH MRI-GUIDED IMAGING

The utilization of MRI-guided imaging in HIFU treatment has been used to enhance treatment accuracy and improve outcomes. The traditional method involves transrectal HIFU, where the ultrasound waves are delivered through the rectum. This approach has been widely used and extensively researched, providing valuable insights into its effectiveness and safety.

On the other hand, a more recent and increasingly prominent approach is transurethral HIFU. Transurethral HIFU offers advantages including more precise ablation, enhanced visualization and targeting of the treatment area with real-time MRI, MRI-based temperature monitoring, and immediate posttreatment assessment. Both transrectal and transurethral HIFU with MRI guidance have shown promise in advancing the field of HIFU therapy.

In 2022, Ehdaie et al.38 performed a multicenter study in patients with intermediate-risk PCa using real-time transurethral HIFU and showed that 89 of 101 patients had no evidence of grade group 2 or higher PCa in the treated area at 24 months. There were no treatment-related deaths identifying that MRI-guided focused ultrasound FT is safe and treats grade group 2 or 3 PCa effectively.

In 2021, Galgano et al.39 conducted a comprehensive review on the novel treatment modality of high-intensity transurethral directional ultrasound ablation (TULSA), which has shown promising early results for both whole-gland ablation and focal ablation.

Furthermore, a systematic review by Dora et al.40 explored the efficacy, functional outcomes, and safety of MRI-guided transurethral ultrasound ablation. The findings indicated that TULSA is a safe and effective alternative to conventional treatments for prostate tissue ablation in men with primary PCa. Additionally, TULSA has demonstrated the ability to provide effective relief of urinary symptoms when treating PCa in a single, low-morbidity procedure. It is important to note that further research and clinical studies are necessary to validate and expand upon these initial findings. However, the emerging evidence supports the potential of TULSA as an effective and well-tolerated treatment option for PCa patients.

DISCUSSION

HIFU has emerged as an alternative treatment option for localized PCa. It offers flexibility in terms of treatment extent, with options such as whole-gland, hemigland, or focal ablation being utilized in low- to intermediate-risk PCa cases (Table 1).

Table 1.

Study design, ablation gland, and types of ablation included

Study	Patient (n)	Ablation gland	Median follow-up time (month)	Type of ablation
Lei et al.25 2019	86	Whole or nonwhole	12	Transrectal
Baumunk et al.28 2013	96	Whole or whole + TURP	36	Transrectal
Baco et al.37 2014	48	Hemi	16.3	Transrectal
Feijoo et al.34 2016	71	Hemi	12	Transrectal
Abreu et al.35 2020	100	Hemi	20	Transrectal
Ganzer et al.36 2018	54	Hemi	12	Transrectal
Stabile et al.20 2019	1032	Focal or hemi	36	Transrectal
Sumitomo et al.21 2010	65	Whole + TURP	24	Transrectal
Byun et al.26 2022	206	Whole or nonwhole	12	Transrectal
Song et al.31 2014	13	Whole	44.5	Transrectal
Crouzet et al.27 2014	1002	Whole	76.8	Transrectal
Crouzet et al.32 2017	418	Whole	42	Transrectal
Reddy et al.41 2022	1379	Whole	32	Transrectal
Ghai et al.42 2018	8	Focal	6	Real-time MRI, transurethral
Ehdaie et al.38 2022	101	Whole	24	Real-time MRI, transurethral

MRI: magnetic resonance imaging; TURP: transurethral resection of the prostate

The morbidities associated with HIFU treatment are correlated with the extent of treatment. Focal ablation, which aims to treat cancer with minimal morbidity, has gained popularity in recent years. As a result, hemigland or focal ablations have become more commonly performed procedures.

Despite the differing extents of treatment, the oncological outcomes of various strategies appear to be similar. Reddy et al.41 showed a multi-institute 15-year experience of 1379 men with nonmetastatic PCa, with a median follow-up of 32 months. HIFU in carefully selected patients with clinically significant intermediate- or high-risk PCa has good cancer control in the medium term.

When analyzing the outcomes, several aspects require further investigation. First, more evidence is needed regarding erectile function and the ability to engage in successful penetrative sexual activity after HIFU treatment. Additionally, oncological outcomes necessitate longer follow-up time and larger sample size in comparative studies to obtain more comprehensive and reliable results. Randomized controlled trials like arm A of the Comparative Healthcare Research Outcomes of Novel Surgery (CHRONOS) trial (NCT04049747) are ongoing, with the aim to assess oncological control comparing focal treatment (including HIFU and cryotherapy) and radical treatments (PR or RT).

CONCLUSION

Comparing whole-gland ablation and nonwhole-gland ablation techniques suggests that nonwhole-gland HIFU may offer similar oncological control when having better short-term functional outcomes and lower complication rates. The combination of HIFU with TURP has shown potential benefits in terms of urinary function and catheterization time. Focal ablation and hemigland ablation are alternative approaches that have shown promise in achieving cancer control when preserving continence and potency.

AUTHOR CONTRIBUTIONS

XW carried out the literature screening and drafted and revised the manuscript. YW carried out literature screening and drafted the manuscript. CFN and CHY revised the manuscript. PKFC conceived the study, reviewed, and helped revise the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.