High-intensity focused ultrasound is a method that focuses ultrasound to heat/ablate target tissues without injuring surrounding structures.

Prostate Cancer

Prostate cancer, accounting for 33 % of all male cancers, is the 2nd leading cause of cancer death in men, exceeded only by lung cancer. The disease is histologically evident in as many as 34 % of men during their 5th decade of life and in up to 70 % of men aged 80 years old and older.

Staging of prostate cancer entails the size of the tumor, if lymph nodes are affected, if the tumor has metastasized, and the appropriate course of treatment.

Table: Staging of Prostate Cancer Stage Effects of Cancer

Stage I (A)

Prostate cancer can not be felt by digital rectal examination, causes no symptoms, and is only in the prostate, usually found incidentally in a prostatectomy specimen when surgery is done for benign prostatic hyperplasia

Stage II (B)

Cancer confined to the prostate gland found by needle biopsy done for an elevated prostate-specific antigen (PSA) level or after rectal examination reveals a mass in the prostate

Stage III (C)

Cancer cells have spread outside the capsule of the prostate to tissues around the prostate (e.g., seminal vesicles) Stage IV (D) Cancer cells have metastasized to lymph nodes or to organs and tissues (e.g., the bone, liver, or lungs)

Another staging system for prostate cancer is known as the TNM system, which separately evaluates the tumor (T), lymph nodes (N) and metastases (M).

Table: T (Tumor) Staging: Stage Effects of Tumor T1 The tumor is too small to be seen on scans or felt during examination of the prostate (it has been discovered by needle biopsy) T2 The tumor is completely inside the prostate gland T3 The tumor has broken through the capsule of the prostate gland T4 The tumor has spread into other body organs Table: N (Lymph Node) Staging: Stage Effects of Lymph Node N0 No cancer cells found in any lymph nodes N1 One positive lymph node smaller than 2 cm across N2 More than 1 positive lymph node; or one that is between 2 cm and 5 cm across N3 Any positive lymph node that is bigger than 5 cm across Table: M (Metastases) Staging: Stage Effects of Metastases M0 No cancer spread outside the pelvis M1 Cancer has spread outside the pelvis

The American Urological Association (AUA)'s Prostate Cancer Clinical Guideline Update Panel (Thompson et al, 2007) stated that standard options for the management of clinically localized prostate cancer include watchful waiting and active surveillance, interstitial prostate brachytherapy, external beam radio-therapy (EBRT), radical prostatectomy, as well as primary hormonal therapy. Other treatment modalities entailed cryotherapy, high-intensity focused ultrasound (HIFU), and combinations of treatments (e.g., EBRT and interstitial prostate bracytherapy). However, the Panel did not include the other treatment options in the analysis and recommendations because of a combination of factors (e.g., limited published experience and short-term follow-up).

High-intensity focused ultrasound (HIFU) is the delivery of targeted high-intensity ultrasound that rapidly elevates the temperature in a precise focal zone. The increased tissue temperature is suggested to kill excess prostate tissue.

Dubinsky and co-workers (2008) noted that although a great deal about HIFU physics is understood, its clinical applications are currently limited, and multiple trials are underway worldwide to determine its effectiveness. In this regard, HIFU has been studied for the treatment of patients with prostate cancer. This non-invasive approach destroys malignant cells by creating intense heat of 80 to 100

^°

C with highly focused transrectal ultrasonic beams. Gardner and Koch (2005) stated that continued technological advances combined with well-designed clinical trials could allow HIFU to become part of the armamentarium against prostate cancer. Konstantinos (2005), in a review on prostate cancer in the elderly, noted that other treatment options under development include cryotherapy and HIFU.

Pickles et al (2005) performed an evidence-based review of published papers in the English language on the use of HIFU for prostate cancer. Only case series have been published; there were no randomized studies. These investigators stated that the quality of evidence was poor, with no reports having longer follow-up than a mean of 2 years, with median follow-ups substantially shorter. Effectiveness outcomes were thus premature and preclude assessment. Toxicity varied substantially with impotence rates 44 % to 61 %, grade 2 to 3 incontinence 0 % to 14 %, and rectal fistulae 0.7 % to 3.2 %. There were limited data on the use of HIFU as salvage therapy after radiation failure. There were no data on the toxicity of subsequent standard curative therapies after HIFU. The authors concluded that in view of the lack of effectiveness outcomes, and in the presence of significant toxicity, HIFU should only be offered within a research setting.

Uchida et al (2006) assessed the biochemical disease-free survival (DFS) rates, predictors of clinical outcome and morbidity in patients with localized prostate cancer treated with HIFU. A total of 181 consecutive patients underwent HIFU with the use of Sonablate (Focus Surgery, Indianapolis, IN). Biochemical recurrence was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel. The median age and pre-treatment PSA level were 70 years (range of 44 to 88) and 9.76 ng/ml (range of 3.39 to 89.60). A total of 95 patients (52 %) were treated with neoadjuvant hormones. The median follow-up period for all patients was 18.0 months (range of 4 to 68). The biochemical DFS rates at 1, 3 and 5 years in all patients were 84 %, 80 % and 78 %, respectively. The biochemical DFS rates at 3 years for patients with pre-treatment PSA less than 10 ng/ml, 10.01 to 20.0 ng/ml and more than 20.0 ng/ml were 94 %, 75 % and 35 %, respectively (p < 0.0001). Multi-variate analysis identified pre-treatment PSA (p < 0.0001) as an independent predictor of relapse. The authors concluded that HIFU therapy appeared to be a safe and effective minimally invasive therapy for patients with localized prostate cancer, especially those with a pre-treatment PSA level less than 20 ng/ml.

Eggener et al (2007) explained the rationale for and concerns about focal therapy for low-risk prostate cancer, and reviewed potential methods of delivery. The authors concluded that early detection of prostate cancer has led to concerns that while many cancers now diagnosed pose too little a threat for radical therapy, many men are reluctant to accept watchful waiting or active surveillance. Several emerging technologies seem capable of focal destruction of prostate tissue with minimal morbidity. The authors encouraged the investigation of focal therapy in select men with low-risk prostate cancer in prospective clinical trials that carefully document safety, functional outcomes and cancer control.

In a phase I/II clinical trial, Koch et al (2007) examined the safety and potential effectiveness of transrectally delivered HIFU for the full gland ablation of previously untreated localized prostate cancer. A total of 20 patients underwent 1 to 3 HIFU treatments of the prostate. The primary outcome was safety and the secondary outcomes were PSA, prostate biopsy and quality of life (QOL) measures. A total of 19 patients had complete follow-up. Serious adverse events related to treatment were limited, with the most common adverse event being transient urinary retention of more than 30 days in only 10 % of patients. Rectal injury occurred in 1 patient. With 1 to 3 treatments, 42 % of the patients achieved PSA less than 0.5 ng/ml and a negative prostate biopsy. The authors concluded that HIFU in patients with previously untreated prostate cancer is generally well-tolerated and has the potential to completely ablate the prostate gland. With further refinement of the optimal treatment dose and technique, this technology has the potential to be an effective form of therapy for localized prostate cancer.

Illing and Chapman (2007) noted that transrectal HIFU for prostate cancer is a promising technique with medium-term oncological results broadly comparable to standard therapies. It is the only form of therapy which is non-invasive and does not utilize ionizing radiation. This is an exciting field undergoing rapid developments, both in the technology and the way in which prostate cancer is managed. Lynch and Loeb (2007) stated that HIFU has emerged in the past decade as a new addition to the arsenal of therapeutic options for prostate cancer. Clinical studies have investigated its use as a treatment for clinically localized disease and as salvage therapy in the setting of failure after EBRT. The authors stated that additional studies with long-term follow-up are needed to further evaluate cancer control and QOL outcomes of this new modality.

Huang and associates (2007) noted that for patients with biopsy-proven recurrent cancer confined to the prostate, local salvage therapy may be a potentially curative treatment option. Most men, however, do not undergo local salvage therapy owing to difficulties in diagnosis as well as concerns over treatment-related complications in the salvage setting. Recently, improvements in technique and technology have substantially reduced the morbidity associated with locally ablative therapies, resulting in an increased interest in the use of minimally invasive therapies such as brachytherapy, cryotherapy, and HIFU in the salvage setting. Although these treatments are well-tolerated, concerns remain over incomplete and inadequate treatment with locally ablative therapies. The authors stated that more studies are needed to appropriately select candidates for salvage ablative therapies and to determine the long-term oncological effectiveness of these treatments.

Marberger (2007) stated that energy-based ablative techniques are of growing interest for today's heterogeneous spectrum of prostate cancer. At present, primary HIFU appears to be a valid alternative to active surveillance protocols in low-risk cancers; and to standard therapy in older patients. Morbidity is low, although post-operative impotence occurs frequently. Cryoablation has higher morbidity, even with third-generation conformal technology. With radio-recurrent cancer the potential radiation damage of the rectal wall renders transrectal HIFU more hazardous. Third-generation cryoablation seems to give better cancer control with lower morbidity in this situation. Unfortunately, long-term outcome data from controlled trials are not available. The author concluded that these minimally invasive techniques are not magic bullets, and patients must be informed accordingly. Focal ablation of the prostate segment with the index cancer would minimize morbidity and therefore appears highly appealing. Its success depends on correct localization of the lesion. Until this is achieved with sufficient reliability by appropriate biopsy or imaging techniques, focal ablation for the treatment of prostate cancer remains strictly experimental.

Lledo García et al (2007) assessed the current state of HIFU as therapeutical option of prostate cancer. These investigators noted that this technique is usually being indicated in Europe as treatment of many cases of either primary or relapsed prostate cancer following radiotherapy. Although some reports suggested that HIFU is very effective as treatment for low and medium risk localized prostate cancer, no randomized series comparing this technique with conventional therapies have been presented yet. They also found vast disparity in criteria to define DFS rendering interpretation of results difficult. The authors concluded that experience of some groups in HIFU is highly promising. Local tumor destruction is evident both in primary and relapsed cases of prostate cancer. However, randomized controlled studies with long-term follow-up are necessary to measure benefits in global survival and QOL. Comparisons must also be made with conventional techniques, and a uniform definition of DFS is necessary.

Barqawi and Crawford (2008) stated that the use of HIFU as a method for ablation of a localized tumor growth is not new. Several attempts have been made to apply the principles of HIFU to the treatment of pelvic, brain, and gastrointestinal tumors. However, only in the past decade has the understanding of the basic principles of HIFU allowed researchers to further exploit its application as a radical and truly non-invasive, intent-to-treat, ablative method for treating organ-confined prostate cancer. The authors stated that HIFU may play a crucial role in the search for a safe and effective primary treatment for localized prostate cancer. Its non-invasive and unlimited repeatability potential is appealing and unique; however, long-term results from controlled studies are needed. In addition, a better understanding of HIFU's clinical limitations is vital before this treatment modality can be recommended to patients who are not involved in well-designed clinical studies.

Rebillard et al (2008) discussed the safety and effectiveness of HIFU in patients with prostate cancer. These investigators searched Medline and Embase for clinical studies evaluating the safety and effectiveness of HIFU in prostate cancer (July 2007). In addition, abstracts presented at the 2005 to 2007 annual meetings of the European Association of Urology and AUA were screened. In all, 37 articles and abstracts were selected. As the data on HIFU as salvage therapy were limited, the authors focused on HIFU as primary therapy. Studies consisted of case series only. Included patients were approximately 70 years old with T1-T2 N0M0 disease, Gleason Score less than or equal to 7, a PSA level of less than or equal to 28 ng/ml and a prostate volume of less than or equal to 40 ml. Negative biopsy rates with the Ablatherm device were 64 % to 93 %, and a PSA nadir of less than or equal to 0.5 ng/ml was achieved in 55 % to 84 % of patients. The 5-year actuarial DFS rates were 60 % to 70 %. The most common complications were stress urinary incontinence, urinary tract infection, urethral/bladder neck stenosis or strictures, and erectile dysfunction. For the Ablatherm device, the rate of complications has been significantly reduced over the years, due to technical improvements in the device as well as the use of transurethral resection of the prostate before HIFU. The authors concluded that HIFU as primary therapy for prostate cancer is indicated in older patients (greater than or equal to 70 years) with T1-T2 N0M0 disease, a Gleason score of less than 7, a PSA level of less than 15 ng/ml and a prostate volume of less than 40 ml. In these patients HIFU achieved short-term cancer control, as shown by a high percentage of negative biopsies and significantly reduced PSA levels. The median-term survival data also appeared promising, but long-term follow-up studies are needed to further evaluate cancer-specific and overall survival rates before the indications for primary therapy can be expanded.

Thuroff and Chaussy (2008) stated that reports describing results of HIFU for prostate cancer are mainly based on single-center, prospective, clinical trials. The latest published results suggest that HIFU is a valuable option for well-differentiated and moderately-differentiated tumors, as well as for local recurrence after EBRT. The authors noted that HIFU in locally recurrent cancer after surgery, as well as adjuvant HIFU for local debulking in locally advanced or metastatic disease, shows promising results for reducing local disease-induced morbidity and for delay of progression.

Poissonnier and colleagues (2008) ascertained the effectiveness and adverse effects of HIFU for the treatment of local recurrence of prostate cancer after exclusive EBRT. A total of 72 patients with histologically and biologically documented local recurrence after radiotherapy were treated by HIFU. The mean age was 68.27 +/- 5.93 years, and mean PSA was 6.64 +/- 7.26 ng/ml. A total of 30 patients were treated according to standard parameters and 42 according to specific parameters. The 2005 ASTRO criteria, specific for salvage therapy (Phoenix consensus), were used to define recurrence. Progression-free survival (PFS) was calculated by the Kaplan-Meier method. Mean follow-up was 39 +/- 28 months. The rate of negative biopsy was 80 % and the median nadir PSA was 0.10 ng/ml. Specific survival was 94 % at 3 years and 90 % at 5 years, and PFS was 50 % at 3 years and 44 % at 5 years. The rate of urinary incontinence was 44 % (grade 1: 12 %, grade 2/3: 32 %) and the rate of urethral stricture or bladder neck stenosis was 30 %. The use of specific parameters reduced the incidence of severe incontinence (19 % versus 50 %, p = 0.005) and stenosis (24 % versus 40 %). The authors concluded that treatment with HIFU achieved a 5-year PFS of 44 %, but patients must be clearly informed about the high rate of adverse effects.

Muto et al (2008) evaluated the feasibility and effectivenerss of HIFU for localized prostate cancer. A total of 70 patients received HIFU using Sonablate(R) 500 were included in this study. In patients whose cancer was confined to only one lobe by multi-regional biopsies, total peripheral zone and a half portion of transitional zone were ablated (focal therapy). Otherwise, patients received whole organ ablation (whole therapy). Scheduled biopsies were performed at 6 and 12 months after treatment. Pre- and post-HIFU serum testosterone levels were measured. The 2-year biochemical DFS rates in patients at low-, intermediate- and high-risk were 85.9 %, 50.9 % and 0 %, respectively, (p = 0.0028). After 12 months, 81.6 % (40/49) of patients were biopsy negative; 84.4 % in patients who received whole therapy, whereas 76.5 % in those with focal therapy. The 2-year biochemical DFS rates for the patients at low- and intermediate-risk was 90.9 % and 49.9 %, respectively, in patients with whole therapy, whereas 83.3 % and 53.6 % in patients with focal therapy. In patients without neoadjuvant androgen deprivation, serum testosterone levels continuously decreased after whole therapy, whereas no changes were observed in those with focal therapy. Patients whose follow-up biopsies were positive tended to have significantly higher changes in PSA levels than biopsy-negative patients. The authors concluded that in patients with low-risk prostate cancer, HIFU monotherapy resulted in comparable immediate cancer control with other modalities. In particular, focal therapy might offer a feasible minimally invasive therapeutic option, which maintained serum testosterone level. To the authors' knowledge, this is the first report that whole, but not focal, therapy affects the serum testosterone level.

Zacharakis et al (2008) examined the use of HIFU as a salvage therapy in men with localized prostate cancer recurrence following EBRT. A review of 31 cases treated using the Sonablate(R) 500 HIFU device was carried out. All men had presumed organ-confined, histologically confirmed recurrent prostate cancer following EBRT. The mean (range) age was 65 (57 to 80) years with a mean pre-operative PSA level of 7.73 (0.20 to 20) ng/ml. Patients were followed for a mean (range) of 7.4 (3 to 24) months. Side effects included stricture or intervention for necrotic tissue in 11 of the 31 patients (36 %), urinary tract infection or dysuria syndrome in 8 (26 %), and urinary incontinence in 2 (7 %). Recto-urethral fistula occurred in 2 men, although 1 was due to patient movement as a consequence of inadequate anesthesia, so the "true" rate was 3 %. Half of the patients had PSA levels of less than 0.2 ng/ml at the last follow-up. Three patients had metastatic disease while another 2 had only local, histologically confirmed, failure. A further 4 patients had evidence of biochemical failure only. Overall, 71 % had no evidence of disease following salvage HIFU. The authors concluded that salvage HIFU is a minimally invasive day-case procedure that can achieve low PSA nadirs and good cancer control in the short-term, with comparable morbidity to other forms of salvage treatment. However, the issue of accurate staging at the time of recurrence is still problematic, as a proportion of these men will harbor microscopic metastases undetected by conventional staging investigations.

Sumitomo et al (2008) examined if combining short-term neoadjuvant androgen deprivation therapy (NADT) with HIFU had a significant benefit in a large population of men with non-metastatic prostate cancer. These researchers evaluated the records of 530 patients whose PSA level at diagnosis was 30 ng/ml or less and whose follow-up period was not less than 12 months, at 7 investigational sites. A total of 270 patients had received NADT (within 6 months), and 260 had not. The primary outcome measure was DFS according to the combined criteria satisfying the Phoenix definition (less than nadir + 2), negative prostate biopsy, and no findings of distant metastasis after the last HIFU treatment. The significance of the differences of values or the distributions of each parameter between two groups was evaluated with a Mann-Whitney U test, unpaired t test, or chi-square test, and a multi-variate Cox proportional hazards model was used to evaluate the prognostic relevance of pre-operative parameters. Statistical analyses showed that the NADT group had worse disease (higher PSA and risk group) than the HIFU-only group. Variables shown by multi-variate analyses to be significant prognostic parameters were pre-treatment PSA level, clinical stage, and no use of NADT. Short-term NADT significantly improved the 3-year DFS rate of patients with intermediate-risk and high-risk prostate cancer. During follow-up the frequencies of complications did not differ significantly with or without NADT. The authors concluded that these findings suggested that combining short-term NADT with HIFU treatment is of significant clinical benefit to intermediate-risk and high-risk prostate cancer patients without increasing the likelihood of complications.

Misrai et al (2008) assessed the long-term oncological results of HIFU as a primary and single treatment for clinically localized prostate cancer. A total of 119 patients underwent HIFU as first-line treatment and were retrospectively reviewed. They were stratified according to risk groups proposed by D'Amico. No patient had undergone previous hormonal therapy. Patients' PSA level was monitored at 3, 6, 12, 18, 24 months and then yearly. According to the latest ASTRO criteria, failure was defined by a PSA rise of 2 ng/ml or more above the PSA nadir. The biochemical-free survival rate (BFSR) was calculated. Mean patient age was 68 +/- 7.8 years (46 to 83). Mean follow-up was 3.9 years (1 to 6.8). Overall, 52 patients (43.7 %) experienced a biochemical recurrence which included 26, 23 and 3 patients in the low-, intermediate- and high-risk groups, respectively. In uni-variate and multi-variate analyses, there was a statistical association between pre-operative PSA value greater than 10, a nadir PSA value greater than 1 and the risk of biochemical recurrence (p < 0.05). The 5-year BFSR rate was 30 % with no statistical difference between low- and intermediate-risk patients. None of the 119 patients died of prostate cancer. The authors concluded that HIFU therapy provides efficient oncological control only in patients with low-risk prostate cancer. However, these findings could be used to improve the selection of patients who are potential candidates for HIFU therapy.

Blana and colleagues (2008) evaluated the long-term effectiveness of HIFU therapy for patients with localized prostate cancer. Patients included in this multi-center analysis had T1-T2 N0M0 prostate cancer, a PSA of less than 15 ng/ml, and a Gleason score of less than or equal to 7, and were treated with prototypes or first-generation Ablatherm HIFU devices. The Phoenix definition of biochemical failure was used (PSA nadir + 2). Treatment failure was defined as: biochemical failure or positive biopsy. A total of 140 patients with a mean (standard deviation [SD]) age 69.1 years (6.6) were included. Mean (SD) follow-up was 6.4 years (1.1). Control prostate biopsies were negative in 86.4 % of patients. Median PSA nadir of 0.16 ng/ml (range of 0.0 to 9.1) was achieved at a mean (SD) of 4.9 months (5.2). A PSA nadir of less than or equal to 0.5 ng/ml was recorded in 68.4 % of patients. The actuarial biochemical failure-free survival rates (SR) at 5 and 7 years were 77 % and 69 %, respectively. The actuarial disease-free SR at 5 and 7 years were 66 % and 59 %, respectively. The authors concluded that these findings demonstrated the effective long-term cancer control achieved with HIFU in patients with low- or intermediate-risk localized prostate cancer.

The American College of Radiology Expert Panel on Radiation Oncology-Prostate Work Group's guideline on locally advanced (high-risk) prostate cancer (Lee et al, 2006) did not mention the use of HIFU in the list of treatment options. Furthermore, National Comprehensive Cancer Network's guideline on prostate cancer does not include HIFU among the therapeutic options for localized prostate cancer (NCCN, 2008). The Agency for Healthcare Research and Quality's guideline on treatments for clinically localized prostate cancer (Wilt et al, 2008) does not cover some newer treatments (e.g., cryotherapy, HIFU, and laparoscopic or robotic-assisted prostatectomy) for which there is little research about comparative effectiveness. The American Urological Association lists active surveillance, radiotherapy as well as radical prostatectomy as options for the management of patients with clinically localized prostate cancer. It does not mention the use of HIFU (Dahm et al, 2008). Guidelines on management of prostate cancer from the National Institute for Health and Clinical Excellence (NICE, 2008) state that HIFU for prostate cancer is "not recommended other than in the context of clinical trials." Guidelines on treatment of prostate cancer from the Spanish National Health Service (2008) conclude that HIFU is an experimental treatment for prostate cancer. Other systematic evidence reviews have reached similar conclusions about the experimental status of HIFU for prostate cancer (Pichon-Riviere et al, 2008; Dussault, 2008). Furthermore, HIFU for prostate cancer has not been approved for use in the United States.

Cordeiro et al (2012) provided an up-to-date review of the available literature on HIFU as a definitive treatment of prostate cancer. A systematic literature search was conducted using MEDLINE and EMBASE via Ovid databases (January 2000 to December 2011) to identify studies on HIFU for treatment of prostate cancer. Only English-language and human-based full manuscripts that reported on case series studies with more than 50 participants, patient characteristics, efficacy and safety data were included. No randomized controlled trials (RCTs) were identified by the literature search. These investigators identified 31 uncontrolled studies that examined the efficacy of HIFU as primary treatment and 2 studies that examined the efficacy of HIFU as salvage treatment. Most treated patients had localised prostate cancer (stage T1-T2); Gleason scores of 2 to 10 and mean prostate specific antigen (PSA) values of 4.6 to 12.7 ng/ml. The mean age range of the patients was 64.1 to 72 years. The mean follow-up ranged from 6.4 to 76.8 months. Negative biopsy rates ranged from 35 to 95 %; PSA nadirs ranged from 0.04 to 1.8 ng/ml. The 5-year DFS rates ranged from 61.2 to 95 %; 7- and 8-year DFS rates ranged from 69 to 84 %. The most common complications associated with the HIFU procedure as the primary treatment included: urinary retention (less than 1 to 20 %); urinary tract infections (1.8 to 47.9 %); stress or urinary incontinence (less than 1 to 34.3 %); and erectile dysfunction (20 to 81.6 %). Recto-urethral fistula was reported in less than 2 % of patients. Treatment-related morbidity appeared to be reduced by the combination of transurethral resection (TURP) of the prostate and HIFU. The authors concluded that novel therapeutic methods have emerged in recent years as "focal" treatment alternatives, in which cancer foci could be eradicated by greatly reducing the associated side-effects of radical treatment. High-intensity focused ultrasound seems to result in short- to medium-term cancer control, with a low rate of complications comparable with those of established therapies. However, longer-term follow-up studies are needed to evaluate cancer-specific and overall survival. If available promising results on HIFU for definitive treatment of prostate cancer are confirmed in future prospective trials, focal therapy could start to challenge the current standard of care.

In a retrospective single-center study, Pfeiffer and colleagues (2012) reported cancer control results after a single application of HIFU in patients with localized prostate cancer (PCa), stratified by tumor recurrence risk according to D'Amico risk classification. These investigators analyzed the outcomes of patients with localized PCa who were treated with curative intent between December 2002 and October 2006 using an Ablatherm HIFU device. Transurethral resection of the prostate or adenomectomy were performed before HIFU to down-size large prostate glands. Oncological failure was determined by the occurrence of biochemical relapse, positive biopsy and/or metastasis. Biochemical relapse was defined as a PSA nadir +1.2 ng/ml (Stuttgart definition), or as a rise in PSA level to greater than or equal to 0.5 ng/ml if PSA doubling time was less than or equal to 6 months. Kaplan-Meier analysis was performed for survival estimates. A total of 191 consecutive patients were included in the study. The median (range) patient age was 69.7 (51 to 82) years, and 38, 34 and 28 % of these patients were in the low-, intermediate- and high-risk groups, respectively. The median (range) follow-up was 52.8 (0.2 to 79.8) months. At 5 years, overall and cancer-specific survival rates were 86.3 % and 98.4 %, respectively. Stratified by risk group, negative biopsy rates were 84.2 %, 63.6 %, and 67.5 % (p = 0.032), 5-year biochemical-free survival rates were 84.8 %, 64.9 % and 54.9 % (p < 0.01), and 5-year DFS rates were 81.7 %, 53.2 % and 51.2 % (p < 0.01), respectively. The authors concluded that single-session HIFU is recommended as a curative approach in elderly patients with low-risk PCa. Patients at higher risk of tumor progression should be counseled regarding the likely need for salvage therapy, including repeat HIFU.

Komura et al (2012) evaluated the oncologic results of HIFU as treatment for clinically PCa. A total of 180 patients with clinically PCa underwent HIFU and were retrospectively reviewed. Of those 171 patients primarily treated with HIFU were included in the analysis. They were stratified by prostatic volume, neoadjuvant hormonal ablation (NHA), and post-treatment PSA nadir; PSA level was monitored every month during the first 6 months after the treatment and every 3 months thereafter. According to the latest Phoenix criteria, biochemical failure was defined by a PSA rise of 2 ng/ml or more above the PSA nadir. Seventy-six (44.4 %) patients were offered pre-operative NHA in median duration of 3 months (inter-quartile range [IQR]: 3 to 5.75). Pre-operative TURP was performed in 56 (32.7 %) patients having the calcification within the prostate. Mean patient age was 68.3 +/- 7.0. The median follow-up time was 43 months (IQR: 30 to 55). According to D'amico risk groups 52 (30.4 %) patients were identified with low-risk, 47 (27.5 %) patients with intermediate-risk, and 72 (42.1 %) with high-risk. The overall and cancer-specific survival rates at 5 years were 98.8 % and 100 %, respectively. The metastasis-free survival rate at 5 years was 99.4 %. No significant differences were seen in biochemical failure-free survival when stratified according to pre-operative prostatic volume and administration of pre-operative NHA (p = 0.931 and p = 0.712, respectively). Regardless of NHA administration, patients with smaller PSA nadir (0.2 ng/ml) achieved better biochemical failure-free survival ratio. The authors concluded that HIFU therapy provided sufficient oncologic control only in patients with low-risk prostate cancer. However, these data could be used to improve the selection of patients who are potential candidates for HIFU therapy.

Uddin et al (2012) described the use of the Sonablate 500 HIFU system in the salvage setting of PCa recurrence after EBRT. An evaluation was performed of a consecutive group of men with biochemical failure after EBRT with histologically proven local recurrence and bone-scan and pelvic magnetic resonance imaging (MRI) to exclude macroscopic metastases, and who chose to have whole-gland salvage HIFU (Sonablate 500) at 2 centers (3 expert HIFU surgeons at each center). The modified Clavien system was used to categorize adverse events and validated questionnaires for functional outcomes. Progression following HIFU treatment was defined as ASTRO-Phoenix criteria (PSA greater than nadir+2 ng/ml) and/or a positive biopsy and/or start of hormone therapy. A total of 84 men underwent whole-gland salvage HIFU (2004 to 2009). Median age, pre-treatment serum PSA, and biopsy Gleason score was 68 years (range of 64 to 72 years), 4.3 ng/ml (range of 1.9 to 7.9 ng/ml), and 7 (range of 6 to 7), respectively. Mean follow-up was 19.8 months (range of 3.0 to 35.1 months). After salvage HIFU, 62 % of the men were pad-free and leak-free. Mean International Index of Erectile Function-5 point score fell from 8.8 to 4.7 (p < .001). International Prostate Symptoms Score and RAND-SF36 scores were not affected. Two men developed recto-urethral fistulae after 1 salvage procedure. A further 2 fistulae occurred in the 6 men undergoing a second salvage HIFU. Intervention for bladder outlet obstruction was needed in 20 % (17 of 84 patients). If PSA non-responders were included, 1- and 2-year PFS rates were 59 % (50 of 84 patients) and 43 % (36 of 84 patients), respectively. If PSA non-responders were excluded, 1- and 2-year PFS rates were 62 % (48 of 77 patients) and 48 % (37 of 77 patients), respectively. The authors concluded that salvage whole-gland HIFU is a high-risk procedure. Although its use in early cancer control is promising, strategies to better identify metastatic disease prior to salvage therapy and reduce local toxicity are needed to improve on this.

In a pilot study, Asimakopoulos et al (2012) examined HIFU as salvage first-line treatment for palpable, TRUS-evidenced, biopsy-proven locally recurrent prostate cancer (CaP) after radical prostatectomy (RP). A total of 19 patients with palpable, TRUS-evidenced, biopsy-proven local recurrence of CaP after RP, unwilling to undergo salvage radiotherapy (SRT), underwent HIFU as a single-session procedure. Pre-, intra-, and post-operative data including early and late complications, and oncologic outcomes (PSA nadir, biochemical recurrence (BCR)-free survival, and need of secondary adjuvant treatment) were prospectively evaluated. Success was defined as PSA nadir less than or equal to 0.1 ng/ml obtained within 3 months from HIFU. In case of PSA nadir greater than 0.1 ng/ml or PSA increase greater than or equal to 1 ng/ml above the PSA nadir, a biopsy of the treated lesion was performed, and if negative, maximum androgen blockade (MAB) was adopted. In case of positive biopsy, RT was performed. Failure was defined as use of secondary adjuvant treatment (MAB or RT). Median follow-up was 48 months. All cases were performed as overnight procedure. No case of urethra-rectal fistula or anastomotic stricture was observed. Two cases of acute urinary retention were resolved with prolonged urethral catheterization. Four cases of stress urinary incontinence were observed; 2 (mild incontinence) were resolved after pelvic floor exercises within 6 months, while 2 cases of severe incontinence required surgical minimally invasive treatment; 17/19 patients (89.5 %) were classified as success. Two patients failed to show a PSA nadir of less than 0.1 ng/ml. During follow-up, 8/17 patients (47 %) were classified as failure, with consequent total rate of failures 10/19 (52.6 %). A statistically significant difference was observed in pre-HIFU median PSA (2 versus 5.45 ng/ml, respectively, p = 0.013) and Gleason score of the RP specimen (p = 0.01) between the success and failure group. The authors concluded that salvage first-line HIFU for palpable, TRUS-evidenced, biopsy-proven local recurrence of CaP is a feasible, minimally invasive day-case procedure, with an acceptable morbidity profile. It seems to have a good cancer control in the short- and mid-term. Patients with lower pre-HIFU PSA level and favorable pathologic Gleason score presented better oncologic outcomes. They stated that a prospective randomized trial with an adequate recruitment and follow-up is necessary to confirm these preliminary oncologic results.

Dickinson et al (2013) described the study design of an investigator-led United Kingdom multi-center, single-arm trial using HIFU to deliver focal therapy for men with localized prostate cancer. A total of 140 men with histologically proven localized low or intermediate risk prostate cancer (PSA less than 15, Gleason less than or equal to 7, less than or equal to T2cN0M0) will undergo precise characterization of the prostate using a combination of multi-parametric MRI (mpMRI) and trans-perineal template prostate mapping (TPM) biopsies. Unilateral dominant tumors, the so-called index lesion, will be eligible for treatment provided the contra-lateral side is free of “clinically significant” disease (as defined by Gleason greater than or equal to 7 or maximum cancer core length greater than or equal to 4 mm). Patients will receive focal therapy using HIFU (Sonablate 500 ^® ). Treatment effect will be assessed by targeted biopsies of the treated area and TPM biopsies at 36 months. Primary outcome is the absence of clinically significant disease based on 36-month post-treatment TPM biopsies. Secondary outcomes address

genito-urinary function using validated patient questionnaires (IPSS, IPSS-QoL, International Index of Erectile Function (IIEF)-15, EPIC-Urinary, EPIC-Bowel, FACT-P, EQ-5D),

the predictive validity of imaging, and

risk factors for treatment failure.

The authors concluded that INDEX will be the first multi-center, medium-term follow-up trial to evaluate the outcomes of a tissue preserving strategy for men with localized prostate cancer using the TPM-ablate-TPM strategy.

An UpToDate review on “Initial approach to low-risk clinically localized prostate cancer” (Klein, 2013) states that “The role of ablation with cryotherapy or HIFU as an alternative to radical prostatectomy or RT remains uncertain. Potential advantages in men with localized disease include the ability to destroy cancer cells using a relatively noninvasive procedure. As such, these procedures are associated with minimal blood loss and pain. There is also a more rapid posttreatment convalescence. Whether the long-term outcomes are equivalent to those with definitive surgery or RT is uncertain however. Additional experience and longer follow-up are required to compare the rate of disease control and side effects profiles with other treatment modalities”.

The National Institute for Health and Care Excellence’s clinical practice guideline on “Prostate cancer: Diagnosis and treatment” (NUCE, 2014) listed HIFU and cryotherapy (as part of clinical trials) as therapeutic options for the prostate cancer.

In a systematic review, Ramsay et al (2015) determined the relative clinical effectiveness and cost-effectiveness of ablative therapies compared with RP, EBRT and active surveillance (AS) for primary treatment of localized prostate cancer, and compared with RP for salvage treatment of localized prostate cancer which has recurred after initial treatment with EBRT. MEDLINE (1946 to week 3 of March 2013), MEDLINE In-Process & Other Non-Indexed Citations (March 29, 2013), EMBASE (1974 to week 13 of 2013), Bioscience Information Service (BIOSIS) (1956 to April 1, 2013), Science Citation Index (1970 to April 1, 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2013), Cochrane Database of Systematic Reviews (CDSR) (issue 3, 2013), Database of Abstracts of Reviews of Effects (DARE) (inception to March 2013) and Health Technology Assessment (HTA) (inception to March 2013) databases were searched. Costs were obtained from NHS sources. Evidence was drawn from RCTs and non-RCTs; and from case series for the ablative procedures only, in people with localized prostate cancer. For primary therapy, the ablative therapies were cryotherapy, HIFU, brachytherapy and other ablative therapies. The comparators were AS, RP and EBRT. For salvage therapy, the ablative therapies were cryotherapy and HIFU. The comparator was RP. Outcomes were cancer related, adverse effects (functional and procedural) and quality of life. Two reviewers extracted data and carried out quality assessment. Meta-analysis used a Bayesian indirect mixed-treatment comparison. Data were incorporated into an individual simulation Markov model to estimate cost-effectiveness. The searches identified 121 studies for inclusion in the review of patients undergoing primary treatment and 9 studies for the review of salvage treatment. Cryotherapy [3,995 patients; 14 case series, 1 RCT and 4 non-randomized comparative studies (NRCSs)], HIFU (4,000 patients; 20 case series, 1 NRCS) and brachytherapy (26,129 patients; 2 RCTs, 38 NRCSs) studies provided limited data for meta-analyses. All studies were considered at high risk of bias. There was no robust evidence that mortality (4-year survival 93 % for cryotherapy, 99 % for HIFU, 91 % for EBRT) or other cancer-specific outcomes differed between treatments. For functional and quality-of-life outcomes, the paucity of data prevented any definitive conclusions from being made, although data on incontinence rates and erectile dysfunction for all ablative procedures were generally numerically lower than for non-ablative procedures. The safety profiles were comparable with existing treatments. Studies reporting the use of focal cryotherapy suggested that incontinence rates may be better than for whole-gland treatment. Data on AS, salvage treatment and other ablative therapies were too limited. The cost-effectiveness analysis confirmed the uncertainty from the clinical review and that there is no technology which appears superior, on the basis of current evidence, in terms of average cost-effectiveness. The probabilistic sensitivity analyses suggest that a number of ablative techniques are worthy of further research. The authors concluded that these findings indicated that there is insufficient evidence to form any clear recommendations on the use of ablative therapies in order to influence current clinical practice. They stated that research efforts in the use of ablative therapies in the management of prostate cancer should now be concentrated on the performance of RCTs and the generation of standardized outcomes.

In an assessment for the Belgian Health Care Knowledge Centre (KCE), Veereman et al (2015) systematically evaluated the evidence on the efficacy and side effects of HIFU in the primary treatment of localized prostate cancer. The authors performed a critical review and appraisal of Medline (Ovid), PreMedline, Embase, and Cochrane Database of Systematic Reviews publications on HIFU up to May 2013. One systematic review and 18 primary studies, all case series, were eligible. Outcomes were summarized and evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Low-quality evidence suggested an OS rate after Ablatherm HIFU ranging from 80 % to 89 % for greater than 5 years. The prostate cancer survival rate ranges from 97 % to 99 % for greater than 5 years. The effect of HIFU on quality of life remains undetermined. Erectile dysfunction was the most frequent adverse event reported from zero but up to 74 % of patients. Adverse events affecting the urinary tract occurred in 0.7 % to 31 % of patients, bladder outlet obstruction in 4 % to 51.5 %, and they were more frequent in patients who had transurethral resection of the prostate the same day or within 2 days of HIFU. Outcomes vary for low- and high-risk categories. The asssessment concluded that good quality evidence on the efficacy of HIFU treatment for localised prostate cancer is lacking. The authors concluded that the quality of the evidence was very low because the information is based on a series of patients who received HIFU treatment with no comparison with active surveillance or radical treatment. Case series suggested an overall survival rate up to 89 % and a prostate cancer survival rate up to 99 % after 5 years, but these numbers vary according to the patient's risk category. Longer term and effects on quality of life are unknown.

Golan et al (2017) conducted a systematic review of HIFU for prostate cancer following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using a combination of MeSH terms, free text search and examination of relevant bibliographies using MEDLINE and Embase from the inception of each database through October 10, 2016. The authors excluded studies describing exclusively whole gland ablation, case reports and series where treatment was followed by immediate resection. A total of 13 studies that enrolled 543 patients were included. Of the studies 11 were performed in the primary setting and 2 in the salvage setting. Median followup ranged from 6 months to 10.6 years. Rates of posttreatment erectile dysfunction and urinary incontinence ranged from 0% to 48% and 0% to 50%, respectively, with definitions varying by study. Overall there were 254 reported complications. Marked heterogeneity between studies limited the ability to pool results regarding functional and oncologic outcomes. A total of 76 patients (14%) subsequently received further oncologic treatment. The authors concluded that early evidence suggests that partial gland ablation is a safe treatment option for men with localized disease. Longer term data are needed to evaluate oncologic efficacy and functional outcomes, and will aid in identifying the optimal candidates for therapy. Standardization of outcomes definitions will allow for better comparison between studies and among treatment modalities.

Abreu et al (2020) reported short-term outcomes of hemi-gland HIFU ablation as primary treatment for localized PCa in the U.S. A total of 100 consecutive men underwent hemi-gland HIFU (December 2015 to December 2019). Primary endpoint was treatment failure, defined as grade Group 2 or greater on follow-up prostate biopsy, radical treatment, systemic therapy, metastases or PCa specific mortality. IIEF, IPSS and 90-day complications were also reported. At study entry patients had very low (8 %), low (20 %), intermediate favorable (50 %), intermediate unfavorable (17 %) and high (5 %) risk PCa. Median follow-up was 20 months. The 2-year survival free from treatment failure, grade Group 2 or greater recurrence, repeat focal HIFU and radical treatment was 73 %, 76 %, 90 % and 91 %, respectively. Bilateral PCa at diagnosis was the sole predictor for grade Group 2 or greater recurrence (p = 0.03). Of men who underwent post-treatment biopsy (n = 58), 10 had in-field and 8 out-of-field grade Group 2 or greater positive biopsy. Continence (0 pad) was maintained in 100 % of patients. Median IIEF-5 and IPSS scores before versus after hemi-gland HIFU were 22 versus 21 (p = 0.99) and 9 versus 6 (p = 0.005), respectively. Minor and major complications occurred in 13 % and 0 % of patients. No patient had rectal fistula or died. The authors concluded that short-term results of focal HIFU indicated safety, excellent potency and continence preservation, and adequate short-term PCa control. Radical treatment was avoided in 91 % of men at 2 years. Men with bilateral PCa at diagnosis have increased risk for grade Group 2 or greater recurrence. To the authors’ knowledge, this was the initial and largest U.S. series of focal HIFU as primary treatment for PCa.

The updated AUA guidelines on “Clinically localized prostate cancer” (2022) noted that “Currently, the Panel believes that ablation may be considered in select, appropriately informed patients (with clinical trial enrollment prioritized). Patients being considered for ablation should have intermediate-risk prostate cancer, as data supporting treatment of high-risk disease with ablation are lacking, while patients with low-risk cancers should be preferentially managed with active surveillance. Patients considering ablation should be counseled regarding side effects and recurrence risk and should be followed post-ablation with PSA, DRE, MRI, and biopsy tailored to their specific health and cancer characteristics”.

Furthermore, on October 27, 2022, the National Government Services (NGS) stated that “Based on the comments we received at our Open Meeting on 10/20/2022, National Government Services has decided to retire the Proposed LCD DL38262 Salvage High-intensity Focused Ultrasound (HIFU) Treatment in Prostate Cancer (PCa). Additionally, L38262, the current active LCD, will also be retired, effective 10/20/2022”.

Radio-Recurrent Prostate Cancer

Ingrosso et al (2020) noted that different non-surgical therapeutic strategies can be adopted for intra-prostatic relapse of PCa after primary RT, including re-irradiation (with brachytherapy [BT] or EBRT), HIFU, and cryotherapy. The main issues to consider when choosing non-surgical salvage local therapies are local tumor control and significant genito-urinary toxicity. These researchers conducted a systematic review and meta-analysis on the role of non-surgical salvage modalities in patients with radio-recurrent PCa and associated clinical outcomes and toxicity profiles. They performed a critical review of the Medline, Scopus, and ClinicalKey databases from January 1, 2000 through February 1, 2018 according to the Preferred Reporting Items and Meta-Analyses (PRISMA) statement. To assess the overall quality of the literature reviewed, these investigators used a modified Delphi tool for case-series studies. A total of 64 case-series studies were included, corresponding to a cohort of 5,585 patients. The modified Delphi checklist evidenced high methodological quality overall (mean quality score of 80.6 %). Biochemical control rates were lowest for patients treated with HIFU (58 %, 95 % CI: 47 % to 68 %) and highest for patients treated with BT (69 %, 95 % CI: 62 % to 76 %) and EBRT (69 %, 95 % CI: 53 % to 83 %). The lowest prevalence of incontinence was for patients treated with BT (3 %, 95 % CI: 0 % to -6 %; I2 = 63.4 %) and the highest was among patients treated with HIFU (28 %, 95 % CI: 19 % to 38 %; I2 = 89.7 %). The authors concluded that non-surgical therapeutic options, especially BT, showed good outcomes in terms of biochemical control and tolerability in the local recurrence setting.

In a prospective, cohort, multi-center study, Schmid et al (2020) examined focal therapy using HIFU for the treatment of localized PCa; they analyzed the safety and complications of this procedure. This trial included patients who suffered from low-to-intermediate risk localized PCa with no prior treatment. After tumor identification on multi-parametric MRI and in prostate biopsy, the lesions were treated with HIFU observing a safety margin of 8 to 10 mm; AEs after 30 and 90 days, as well as the required interventions were assessed and stratified for treatment localizations. Of the 98 men included in the study in 2 European centers, 35 (35.7 %) experienced AEs in the first 30 days after HIFU intervention with Clavien-Dindo grade of less than or equal to II: 15 pts (15.3 %) had a post-operative urinary tract infection and 26 patients (26.5 %) a urinary retention; 4 patients (4.1 %) underwent subsequent intervention (Clavien-Dindo grade IIIa/b). The number of late post-operative complications occurring between 30 and 90 days after intervention was low (2.0 %). The highest complication rate was associated with tumors located at the anterior base (50.0 %). The inclusion of the urethra in the ablation zone led to AEs in 20 out of 41 cases (48.8 %) and represented a significant risk factor for complications within 30 days (OR = 2.53; 95 % CI: 1.08 to 5.96; p = 0.033). The authors concluded that focal therapy of PCa lesions with a robotic HIFU-probe was safe and rendered an acceptable rate of minor early AEs. The inclusion of the urethra in the ablation zone led to an increase in early complications and should be avoided whenever possible.

In a multi-center study (2005 to 2016), Lovegrove et al (2020) examined change in functional outcomes after 2nd focal-HIFU compared to 1 focal-HIFU treatment. A total of 821 men underwent focal-HIFU for localized non-metastatic PCa. PROMS on IPSS, pad usage and erectile function (EF-score) were prospectively collected for up to 3 years. Inclusion criteria were men who had completed at least 1 follow-up questionnaire. The primary outcome was comparison of change in functional outcomes between baseline and follow-up after 1 focal-HIFU or 2nd focal-HIFU using IPSS, EPIC and IIEF questionnaires. Of 821 men, 654 had 1 focal-HIFU and 167 had a 2nd focal-HIFU; 355 (54.3 %) men undergoing 1 focal-HIFU and 65 (38.9 %) having 2nd focal-HIFU returned follow-up questionnaires, respectively. Mean age and PSA were 66.4 and 65.6 years, and 7.9 and 8.4 ng/ml, respectively. After 1 focal-HIFU, mean change in IPSS was -0.03 (p = 0.02) and IIEF (EF-score) -0.4 (p = 0.02) at 1-2 years with no subsequent decline. Absolute rates of erectile dysfunction increased from 9.9 % to 20.8 % (p = 0.08), leak-free continence decreased from 77.9 % to 72.8 % (p = 0.06) and pad-free continence from 98.6 % to 94.8 % (p = 0.07) at 1 to 2 years, respectively. IPSS prior to 2nd focal-HIFU compared to baseline IPSS prior to 1st focal-HIFU was lower by -1.3 (p = 0.02), but mean IPSS change was +1.4 at 1 to 2 years (p = 0.03) and +1.2 at 2-3 years (p = 0.003) after 2nd focal-HIFU. Mean change in EF-score after 2nd focal-HIFU was -0.2 at 1 to 2 years (p = 0.60) and -0.5 at 2 to 3 years (p = 0.10) with 17.8 % and 6.2 % new erectile dysfunction. New pad use was 1.8 % at 1 to 2 years and 2.6 % at 2 to 3 years. The authors concluded that a 2nd focal-HIFU procedure caused minor detrimental effects in urinary and erectile function. Data can be used to counsel patients with non-metastatic PCa prior to considering HIFU therapy.

Dosanjh et al (2021) stated that HIFU is a novel therapy for PCa. Owing to a lack of long-term data, HIFU is recommended for use only in the context of research. These researchers examined the trend for HIFU use nationally and rates of strictures and fistulae. Patients undergoing HIFU for PCa between April 2007 and March 2018 were studied in an English national database (Hospital Episode Statistics). Data on complications were included for patients with a minimum of 1-year follow-up. Analysis of complications was controlled for other interventions. Descriptive analyses of HIFU rates and the incidence of strictures and fistulae were carried out. Cox and logistic regression models were built for urethral stricture incidence. A total of 2,320 HIFU treatments among 1,990 patients were identified. The median age was 67 years (IQR 61 to 72). Some 1,742 patients met the criteria for follow-up analysis. The highest-volume center performed 1,513 HIFU procedures, followed by 194 at the second highest. The number of HIFU procedures increased annually, rising from 196 to 283 per year. There were 208 patients (11.9 %) who went on to have radiotherapy and 102 (5.9%) radical prostatectomy after HIFU. Following HIFU, stricture developed in 133/1,290 patients (10.3 %) and urinary fistula in 16/1,240 (1.3 %) before any further intervention. More recent years for HIFU were associated with a lower likelihood of stricture formation (2016/2017 versus 2007/2008: hazard ratio [HR] 0.30, 95 % CI: 0.11 to 0.79; p = 0.015). Limitations included the lack of staging information and unknown rates of HIFU outside of publicly funded health care. The authors concluded that HIFU was performed at a large number of low-volume centers and complication rates did not differ from those for established therapies.

National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 4.2019) states that “At this time, the panel recommends only cryosurgery and high-intensity focused ultrasound as options for radiation therapy recurrence in the absence of metastatic diseases”. (2A Recommendation)

Central Nervous System Diseases / Disorders

Jagannathan and associates (2009) noted that the field of magnetic resonance imaging-guided HIFU surgery (MRgFUS) is a rapidly evolving one, with many potential applications in neurosurgery. These researchers discussed the historical development of the technology and its potential applications in modern neurosurgery. The evolution of MRgFUS has occurred in parallel with modern neurological surgery, and the two seemingly distinct disciplines share many of the same pioneering figures. Early studies on focused ultrasound treatment in the 1940s and 1950s demonstrated the ability to perform precise lesioning in the human brain, with a favorable risk-benefit profile. However, the need for a craniotomy, as well as the lack of sophisticated imaging technology, resulted in limited growth of HIFU for neurosurgery. More recently, technological advances have permitted the combination of HIFU along with magnetic resonance imaging guidance to provide an opportunity to effectively treat a variety of central nervous system disorders. Although challenges remain, HIFU-mediated neurosurgery may offer the ability to target and treat central nervous system conditions that were previously extremely difficult to address.

Essential tremor is a common, usually hereditary or familial, disorder of movement characterized by uncontrolled trembling of the hands and often involuntary nodding of the head and tremulousness of the voice, is exacerbated by anxiety and by activity, is not associated with Parkinson's disease or any other known disease and responds to treatment with propranolol.

In a proof-of-concept study, Lipsman et al (2013) examined the effectiveness of MR-guided focused ultrasound for the management of essential tremor (ET). This study was done in Toronto, Canada, between May, 2012, and January, 2013. A total of 4 patients with chronic and medication-resistant essential tremor were treated with MR-guided focused ultrasound to ablate tremor-mediating areas of the thalamus. Patients underwent tremor evaluation and neuroimaging at baseline and 1 month and 3 months after surgery. Outcome measures included tremor severity in the treated arm, as measured by the clinical rating scale for tremor, and treatment-related adverse events. Patients showed immediate and sustained improvements in tremor in the dominant hand. Mean reduction in tremor score of the treated hand was 89.4 % at 1 month and 81.3 % at 3 months. This reduction was accompanied by functional benefits and improvements in writing and motor tasks. One patient had post-operative paraesthesia that persisted at 3 months. Another patient developed a deep vein thrombosis, potentially related to the length of the procedure. The authors concluded that MR-guided focused ultrasound might be a safe and effective approach to generation of focal intra-cranial lesions for the management of disabling, medication-resistant essential tremor. They stated that if larger trials validate the safety and ascertain the effectiveness and durability of this new approach, it might change the way that patients with essential tremor and potentially other disorders are treated.

In an open-label, uncontrolled, pilot study, Elias et al (2013) investigated the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor. From February 2011 through December 2011, these researchers used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor. They recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor. These investigators assessed the patients' perceptions of treatment efficacy with the Quality of Life in Essential Tremor Questionnaire (ranging from 0 to 100 %, with higher scores indicating greater perceived disability). Thermal ablation of the thalamic target occurred in all patients. Adverse effects of the procedure included transient sensory, cerebellar, motor, and speech abnormalities, with persistent paresthesia in 4 patients. Scores for hand tremor improved from 20.4 at baseline to 5.2 at 12 months (p = 0.001). Total tremor scores improved from 54.9 to 24.3 (p = 0.001). Disability scores improved from 18.2 to 2.8 (p = 0.001). Quality-of-life scores improved from 37 % to 11 % (p = 0.001). The authors concluded that in this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy. They stated that large, RCTs are needed to assess the procedure's safety and effectiveness.

In a randomized controlled clinical study, Elias et al (2016) enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). The investigators included 67 patients in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort) as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively.

An editorial accompanying the study by Elias et al (2016) stated that the results are promising, particularly since this procedure, unlike traditional thalamotomy, does not require entering the cranium with a probe (Louis, 2016). The editorialist noted, however, that there are several important concerns about this study. The first is the limited follow-up period, which was 12 months. The sustained benefit at 2 years, 3 years, and 5 or more years is not known. The editorialist stated that studies with longer follow-up intervals are needed to address this issue, noting that this is particularly important because of tachyphylaxis, which is the second concern. The primary outcome measure was the score for hand tremor (on a scale ranging from 0 to 32, with higher scores indicating more severe tremor) at 3 months. The tremor score in the group that underwent focused ultrasound thalamotomy increased from 8.84 (at 1 month) to 9.55 (at 3 months) to 10.13 (at 6 months) to 10.89 (at 12 months). The increase from months 1 to 12 was 23%. Secondary outcome measures showed similar or greater increases during the 12-month follow-up period (e.g., the Clinical Rating Scale for Tremor score increased from 23.38 at 1 month to 32.38 at 12 months, which is a 38% increase). The editorialist stated that it is not clear whether this loss of efficacy, which is also seen to some extent with deep-brain stimulation, is due to disease progression or tolerance, although typical estimates of the rate of disease progression in essential tremor make the former possibility less likely. Third, the procedure did not achieve large improvements in everyone; the percentage change in tremor was less than 20% in 9 of 56 patients.

The editorialist also noted several important caveats (Louis, 2016). The first is that the procedure is a thalamotomy. Hence, it creates a fixed brain lesion. With deep-brain stimulation, there is the potential to adjust stimulator settings in order to obtain further therapeutic gains, but there is no such potential with thalamotomy. Second, the procedure is not suitable for all patients; in particular, skull thickness presents a problem in some cases. Third, the most common side effect involved altered sensation, and this deficit remained permanent in 14% of patients. The editorialist suggested a head-to-head comparison with deep-brain stimulation to facilitate the direct comparison of the two approaches.

Kim et al (2017) stated that MRgFUS is an emerging technique to treat refractory ET. These investigators presented MRgFUS as an alternative to radiofrequency (RF) thalamotomy or deep brain stimulation (DBS) for ET treatment. They retrospectively analyzed 59 patients who underwent unilateral surgery for drug-resistant ET. Treatments included RF thalamotomy (n = 17), DBS (n = 19), and MRgFUS (n = 23). The outcomes measured were tremor severity and treatment-related complications. At 1 month post-operatively, 100 % of RF thalamotomy patients, 89.5 % of DBS patients, and 91.3 % of MRgFUS patients exhibited absent/mild tremor (successful treatment); other patients exhibited partial relief. At 12 months post-operatively, treatment success for each procedure was observed in 70.6, 84.2, and 78.3 % of patients, respectively. At 1 month post-operatively, treatment-related complications had occurred in 58.8, 5.3, and 13.0 % of patients, respectively. At 12 months post-operatively, side effects persisted in 11.8, 21.1, and 4.4 % of patients, respectively. No statistical differences in treatment success were observed between treatments or over time. Complication rates differed between treatment modalities (p < 0.01) and were lowest in the MRgFUS group. The authors concluded that patients with drug-resistant ET received equivalent results from RF thalamotomy, DBS, and MRgFUS; DBS and MRgFUS resulted in fewer treatment-related complications. Moreover, they stated that further study of MRgFUS is needed to generalize the results of this study. This was a small study (n = 23 for the MRgFUS group) with short-term follow-up (12 months). (It should be noted that Chan JW (see below) is a co-author of this study).

The authors stated that this study had several drawbacks. Regarding the study design, the present work was a retrospective review of medical records over time and it was therefore limited by sample availability and the type of information collected. One of the biggest shortcomings of this study was timeline bias. These researchers could not rule out the possibility of error from their experience and technical advances, because there was a gap of over 10 years between RF thalamotomy and MRgFUS. However, to the best of their knowledge, as of early 2017 there was no ongoing or planned prospectively designed clinical trial for RF thalamotomy according to the clinical trial inventory. Despite the presence of a well-designed, noteworthy study that compared the efficacy of RF thalamotomy and DBS, these investigators needed to re-evaluate the value of lesioning procedures and compare their clinical outcomes with the advent of a new technology, namely MRgFUS.

Chang et al (2018) stated that MRgFUS has recently been investigated as a new treatment modality for ET, but the durability of the procedure has not yet been evaluated. This study reported results at a 2-year follow-up after MRgFUS thalamotomy for ET. A total of 76 patients with moderate-to-severe ET, who had not responded to at least 2 trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor; 67 of the patients continued in the open-label extension phase of the study with monitoring for 2 years; 9 patients were excluded by 2 years, for example, because of alternative therapy such as DBS (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55 % at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53 %; 8.9 ± 4.8; 70 patients) and at 2 years (56 %; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64 % at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year -- each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events (AEs) worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. The authors concluded that tremor suppression after MRgFUS thalamotomy for ET was stably maintained at 2 years. Latent or delayed complications did not develop after treatment.

The authors stated that this study had several drawbacks. First, the number of reported patients was different; 56 subjects in the previous report were compared to the 20 sham-treated patients, but in this study, the authors analyzed all 76 patients. Second, the follow-up was versus 2 years here versus 1 year previously. Third, as is characteristic with increasing duration of follow-up, there were patients who dropped-out of the study by 2 years. In total, 9 patients, many of whom had unsuccessful treatment or sub-optimal benefit, crossed-over to an alternative treatment or dropped-out or were lost to follow-up at 2 years. The exclusion of non-responders from the analysis introduced a bias and an over-estimate of the benefit in those patients that remained in the study. Nonetheless, these findings showed that for the majority of patients, the benefits of MRgFUS were immediate and that they endured for at least 2 years. The authors stated that additional follow-up are needed to determine the incidence of recurrence and the efficacy of MRgFUS over the long-term. (It should be noted that this study was supported by InSightec (Haifa, Israel), the Focused Ultrasound Foundation (Charlottesville, VA) and the Binational Industrial Research and Development (BIRD) Foundation (Israel)).

Fishman et al (2018) determined the safety profile of MRgFUS unilateral thalamotomy for ET, including frequency, and severity of AEs, including serious AEs (SAEs). Analysis of safety data for MRgFUS thalamotomy (186 patients, 5 studies). Procedure-related SAEs were very infrequent (1.6 %), without intra-cerebral hemorrhages or infections; AEs were usually transient and were commonly rated as mild (79 %) and rarely severe (1 %). As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related AEs. The authors concluded that the overall safety profile of MRgFUS thalamotomy supported its role as a new option for patients with medically refractory ET.

Guidance from the National Institute for Health and Care Excellence (NICE, 2018) concluded: "The evidence on the safety of unilateral MRI-guided focused ultrasound thalamotomy for treatment-resistant essential tremor raises no major safety concerns. However, current evidence on its efficacy is limited in quantity. Therefore, this procedure should not be used unless there are special arrangements for clinical governance, consent, and audit or research." The guidance stated that "Further research, which could include randomised controlled trials, should address patient selection, report on functional improvement and quality of life, and provide long-term follow-up data."

Gallay et al (2019) noted that since the first clinical application of the incisionless MRgFUS technology only small series of patients have been reported, and thus only extrapolations of the procedure-related risks could be offered. In this study, these investigators analyzed side-effects and targeting accuracy in 180 consecutive treatments with MRgFUS for chronic therapy-resistant idiopathic Parkinson's disease (PD), ET (n = 33), cerebellar tremor (CT), and neuropathic pain (NP), all performed in their dedicated center. A total of 180 treatments with MRgFUS for chronic therapy-resistant idiopathic PD, ET, CT, and NP were prospectively assessed for side-effects and targeting accuracy. Monitoring for later side-effects was continued for at least 3 months after the procedure in all but 1 case (0.6 %); in that single case, the patient was lost to follow-up after an uneventful early post-operative course. The surgical targets were the pallido-thalamic tract (pallido-thalamic tractotomy, n = 105), the cerebello-thalamic tract (cerebello-thalamic tractotomy, n = 50), the central lateral nucleus (central lateral thalamotomy, n = 84), the centrum medianum (centrum medianum thalamotomy, n = 12), and the globus pallidus (pallidotomy, n = 2). Cognitive testing was performed before, 1 to 2 days after, and 1 year after the procedure. The Mini-Mental State Examination (MMSE) was used for the first 29 cases and was then replaced by the Montreal Cognitive Assessment (MoCA). Lesion reconstruction and measurement of targeting accuracy were done on 2-day post-treatment MR images for each performed target. To determine targeting accuracy measurement, 234 out of the 253 lesions depicted in the 2-day post-operative MR examination could be 3D-reconstructed. The mean MoCA score was slightly improved 2 days post-operatively (p = 0.002) and remained stable at 1-year follow-up (p = 0.03). The mean MMSE score was also slightly improved 2 days post-operatively and at 1-year follow-up, but the improvement was not statistically significant (p = 0.06 and p = 0.2, respectively). The mean (± SD) accuracy was 0.32 ± 0.29 mm, 0.29 ± 0.28 mm, and 0.44 ± 0.39 mm for the mediolateral, anteroposterior, and dorso-ventral dimensions, respectively. The mean 3D accuracy was 0.73 ± 0.39 mm. As to side-effects, 14 events over 180 treatments were documented. They were classified into procedure-related (n = 4, 2.2% ), effect on neighboring structures (n = 3, 1.7 %), and disease-related (n = 7, 3.9 %). There was no bleeding. The authors concluded that the incisionless transcranial MRgFUS technology demonstrated a higher targeting accuracy and a lower side-effect profile than techniques requiring cerebral penetration. In the absence of penetration brain shift, this technique avoided the placement of a thermos-lesion away from the chosen target, thus suppressing the need for reversible therapeutic energy application. With the use of proper physiopathology-based targets, definitive therapeutic effects could be coupled with sparing of sensory, motor, and para-limbic/multi-modal thalamo-cortical functions. Clinical efficacy, not analyzed in this investigation, will ultimately rest in proper target selection and optimized thermos-lesional coverage of the target. This study had 33 patients with ET with short-term follow-up (1 year). More importantly, clinical efficacy was not addressed in this analysis.

Guidance from the National Institute for Health and Care Excellence (NICE, 2018) concluded: "Current evidence on the safety and efficacy of unilateral MRI-guided focused ultrasound thalamotomy for moderate to severe tremor in Parkinson's disease is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research." The guidance stated that "Further research, which could include randomised controlled trials, should address patient selection and report on long-term follow-up."

Park et al (2019) noted that following the emergence of magnetic resonance-guided focused ultrasound (MRgFUS) as a promising tool for movement disorder surgery, thalamotomy for essential tremor using this technique has become a useful tool based on its efficacy and lack of adverse effects. These researchers summarized the 4-year results of previous reports focusing on the durability of effectiveness of MRgFUS thalamotomy for essential tremor (ET). From October 2013 to August 2014, a total of 15 patients with intractable ET were enrolled; 12 of them completed clinical assessment through 4 years of post-operative follow-up. Tremor severity, task performance, and disability were measured using the Clinical Rating Scale of Tremor. The mean age of the 12 patients was 61.7 ± 8.1 years. Maximally delivered energy was 15,552.4 ± 6,574.1 joules. The mean number of sonications was 17.3 ± 1.6. The mean post-operative lesion volume was 82.6 ± 29.023 mm3 and in 1 year was a mean of 9.667 ± 8.573 mm3 . Four years post-operatively, improvement of the hand tremor score was 56 %, that of the disability score was 63 %, that of the postural score was 70 %, and that of the action score was 63 % compared with baseline; all improvements were significant and sustained over the 4-year period after thalamotomy. There was no permanent adverse effect throughout the 4-year follow-up period. The authors concluded that MRgFUS thalamotomy exhibited sustained clinical efficacy 4 years following the treatment of intractable ET; AEs were generally transient. These researchers stated that a large cohort of patients who have undergone MRgFUS thalamotomy with longer follow-up is needed to confirm these findings.

Liver Cancer (Primary or Metastatic)

Park et al (2009) ascertained the safety and effectiveness of HIFU in the treatment of liver metastasis from colon and stomach cancer. A total of 10 patients with liver metastasis from colon cancer and 3 from stomach cancer underwent HIFU under general anesthesia. Treatment was performed using an extra-corporeal, ultrasound-guided focused system. Complications during the study, extent of coagulative necrosis at 2-week follow-up, and evidence of tumor on further follow-up were analyzed. Patients were divided into 4 categories:

complete ablation with no evidence of recurrence on follow-up;

apparent complete ablation of target mass with new foci of disease in the target organ or distant malignancy and no local tumor progression;

local tumor progression after apparent complete ablation; and

partial ablation.

Mean follow-up period was 22 weeks in the colon cancer group and 58 weeks in the stomach cancer group. The sum of total lesion size was between 1.8 cm and 21.4 cm (mean of 8.4 cm +/- 6.7 cm) for the colon cancer group and between 1.7 and 16.3 cm (mean of 8.8 cm +/- 7.3 cm) for the stomach cancer group. In the colon cancer group, 1 patient was categorized as category (i), 1 as category (ii), 3 The authors concluded that for treating liver metastasis from colon and stomach cancer, HIFU seems safe but its effectiveness is questionable. They stated that more research is needed.

An assessment of the evidence for HIFU for liver cancer from the Catalan Agency for Health Technology Assessment and Research (CAHTA) concluded: "Based on the scientific evidence available, there is not enough information on efficacy/effectiveness, safety and cost-effectiveness of HIFU treatment in patients with liver cancer (primary or metastatic). In fact, the design and scarcity of published studies hinder a correct assessment of HIFU treatment. Thus, interventions using high intensity focused ultrasound for liver cancer treatment should be tested in randomised clinical trials, of a sufficient sample size and adequate design" (Navarro, 2008).

Ng et al (2011) evaluated the outcome of patients with hepato-cellular carcinoma (HCC) treated by HIFU in a single tertiary referral center. From October 2006 to December 2008, a total of 49 patients received HIFU for unresectable HCC. Each patient underwent a single session of HIFU with a curative intent. Treatment efficacy and survival outcome were evaluated. Clinicopathologic factors affecting the primary technique effectiveness and overall survival rates were investigated by uni-variate analysis. The median size of the treated tumors was 2.2 cm (range of 0.9 to 8 cm). The majority of patients had single tumors (n = 41, 83.6 %). Thirty-one patients (63.2 %) had artificial right pleural effusion during HIFU treatment to reduce damage to the lung and diaphragm. The hospital mortality rate was 2 % (n = 1) and the complication rate was 8.1 % (n = 4). The primary technique effectiveness rate was 79.5 % (39 of 49 patients). It increased from 66.6 % in the initial series to 89.2 % in the last 28 patients. Tumor size (greater than or equal to 3.0 cm) was the significant risk factor affecting the complete ablation rate. The 1- and 3-year overall survival rates were 87.7 % and 62. 4%, respectively. Child-Pugh liver function grading was the significant prognostic factor influencing the overall survival rate. The authors concluded that HIFU is an effective treatment modality for unresectable HCC with a high technique effectiveness rate and favorable survival outcome. The drawbacks of this study were its retrospective nature, short follow-up and small sample size. The authors stated that further studies are needed to compare the effectiveness of HIFU with other ablation modalities.

Chan and associates (2013) reported their preliminary experience of HIFU for the treatment of recurrent hepato-cellular carcinoma (HCC). Clinico-pathological data of 27 patients who received HIFU ablation and 76 patients who received radiofrequency ablation (RFA) for recurrent HCC from October 2006 to October 2009 were reviewed. Survival outcomes between the 2 groups were compared using the log-rank test. A value of p < 0.05 was considered significant. The median follow-up was 27.9 months. There was no difference in tumor size (HIFU, 1.7 cm; RFA, 1.8 cm; p = 0.28) between the 2 groups. Procedure-related morbidity rate was 7.4 % in the HIFU group and 6.5 % in the RFA group (p = 1.00). Skin burn and pleural effusion were the 2 morbidities associated with HIFU. There was no hospital mortality in the HIFU group, whereas 2 deaths occurred in the RFA group. The 1-, 2-, and 3-year DFS rates were 37.0 %, 25.9 %, and 18.5 %, respectively, for the HIFU group, and 48.6 %, 32.1 %, and 26.5 %, respectively for the RFA group (p = 0.61). The 1-, 2-, and 3-year overall survival rates were 96.3 %, 81.5 %, and 69.8 %, respectively, for the HIFU group, and 92.1 %, 76.1 %, and 64.2 %, respectively, for the RFA group (p = 0.19). The authors concluded that their preliminary experience in using HIFU for recurrent HCC is promising. They stated that further studies are needed to explore its treatment value for primary HCC.

Also, the NCCN’s clinical practice guideline on “Hepatobiliary cancers” (Version 2.2013) does not mention HIFU as a therapeutic option.

In a systematic review and meta-analysis, Hu et al (2022) examined the safety and effectiveness of HIFU combined with trans-arterial chemoembolization (TACE) for the treatment of liver cancer. The Chinese National Knowledge Infrastructure (CNKI), China Biomedical Literature Database, Cochrane Library, Medline, and Embase databases were searched using the terms "randomized controlled trial (RCT)", "liver cancer", "transarterial chemoembolization", "TACE", "high intensity focused ultrasound", "HIFU", "HIFU combined with TACE", and "efficacy analysis". Studies were included in accordance with the PICOS principle, and risk of bias was assessed in RCTs in accordance with the Cochrane Manual for Systematic Evaluation of Interventions. Rev Man 5.3 and Stata 13 were used for meta-analysis. A total of 6 RCTs (488 patients) were included in this study. Of these studies, 5 described a random allocation (RA) method, 4 described allocation sequence concealment, and 4 used a blind method for the allocation of study subjects. The results of the meta-analysis showed that the 1-year [OR =3.13, 95 % CI: 1.92 to 5.11, p < 0.00001], 2-year (OR =3.38, 95 % CI: 1.71 to 6.66, p = 0.0004), and 5-year (OR =2.15, 95 % CI: 1.02 to 4.55, p = 0.04) survival rates (SRs) of patients treated with HIFU + TACE were significantly better than those of patients treated with TACE alone. The total effective rate (TER) of patients treated with HIFU + TACE (OR = 3.61, 95 % CI: 2.14 to 6.08, p < 0.00001) was significantly better than that of patients treated with TACE alone. Compared with TACE alone, HIFU combined with TACE significantly reduced the incidence of post-operative AEs (OR = 0.57, 95 % CI: 0.34 to 9.96, p = 0.03). The authors concluded that compared with TACE alone, HIFU combined with TACE in the treatment of LC had better effectiveness, higher prognosis and survival rate, and lower incidence of AEs. However, due to the limited sample size of the study, there was some risk of bias in the findings. These investigators stated that further research is needed to confirm the findings of this study. These researchers stated that a major drawback of this study was that some of the articles showed heterogeneity, which might have affected the results.

Osteosarcoma / Bone Tumors

Li and co-workers (2009) prospectively evaluated the use of ultrasonographically guided HIFU in the salvage of limbs in patients with osteosarcoma. A total of 7 patients underwent HIFU ablation. Laboratory and radiological examinations were performed after intervention. Changes in symptoms and survival time were noted at follow-up. No severe complications were observed, and pre-existing severe pain disappeared in patients treated with HIFU. Alkaline phosphatase did not show statistically significant changes before and after HIFU treatment, although alkaline phosphatase did change 1 month and 2 months after HIFU. Complete response of the tumor was achieved in 3 patients with osteosarcoma. Partial response was achieved in another 3 patients treated with HIFU. Pulmonary metastasis was noted in only 1 patient 5 months after HIFU. The median survival time was 68 months. All patients were alive 3 years after HIFU treatment. Five patients were alive at follow-up visits after 5 years. One patient died from cachexia and infection after 4 years, another patient died of cardiac arrest attack after 4 years. Three patients died of lung dysfunction from pulmonary metastases after 5 years. The 5-year survival rate was 71.4 %. The authors concluded that HIFU ablation was a safe and feasible method of treatment of osteosarcoma which salvages the limb, but they stated that large-scale randomized clinical trials are needed for confirmation.

Chen et al (2010) evaluated the long-term follow-up results of ultrasonographically (US)-guided HIFU ablation in patients with primary bone malignancy. A total of 80 patients with a primary bone malignancy -- 60 with stage IIb disease and 20 with stage III disease (Enneking staging system) -- were treated with US-guided HIFU ablation. High-intensity focused ultrasound ablation combined with chemotherapy was performed in 62 patients with osteosarcoma, 1 patient with periosteal osteosarcoma, and 3 patients with Ewing sarcoma. The remaining 14 patients had chondrosarcoma, giant cell bone cancer, periosteal sarcoma, or an unknown malignancy and were treated with HIFU ablation only. Magnetic resonance imaging (MRI) or computed tomography (CT), and single photon emission computed tomography (SPECT) were used to assess tumor response. Cumulative survival rates were calculated by using the Kaplan-Meier method. Adverse effects were recorded. High-intensity focused ultrasound ablation guided by real-time US was performed. Follow-up images demonstrated completely ablated malignant bone tumors in 69 patients and greater than 50 % tumor ablation in the remaining 11 patients. Overall survival rates at 1, 2, 3, 4, and 5 years were 89.8 %, 72.3 %, 60.5 %, 50.5 %, and 50.5 %, respectively. Survival rates at 1, 2, 3, 4, and 5 years were 93.3 %, 82.4 %, 75.0 %, 63.7 %, and 63.7 %, respectively, in the patients with stage IIb cancer and 79.2 %, 42.2 %, 21.1 %, 15.8 %, and 15.8 %, respectively, in those with stage III disease. Among the patients with stage IIb disease, long-term survival rates were substantially improved in the 30 patients who received the full treatment -- namely, complete HIFU and full cycles of chemotherapy -- compared with the survival rates for the 24 patients who did not finish the chemotherapy cycles and the 6 patients who underwent partial ablation only. Only 5 (7 %) of the 69 patients who underwent complete ablation had local cancer recurrence during the follow-up period. A total of 40 adverse events were recorded, with 14 patients requiring surgical intervention. The authors concluded that US-guided HIFU ablation of malignant bone tumors is feasible and effective and eventually may be a component of limb-sparing techniques for patients with these cancers.

Li et al (2010) evaluate 25 patients with malignant bone tumors before and after HIFU treatment. High-intensity focused ultrasound resulted in significant improvement in biochemical markers, and no severe complications were observed. Following HIFU treatment, 21 (87.5 %) patients were completely relieved of pain, and 24 (100 %) experienced significant relief. On the basis of MRI or PET-CT, HIFU was effective: For patients with primary bone tumors, 6 (46.2 %) had a complete response, 5 (38.4 %) had a partial response, 1 (7.8 %) had a moderate response, and 1 suffered progressive disease; the response rate was 84.6 %. For patients with metastatic bone tumors, 5 (41.7 %) had complete response, 4 (33.3 %) had partial response, 1 (8.3 %) had a moderate response, 1 (8.3 %) had stable disease, and 1 suffered progressive disease; the response rate was 75.0 %. The 1-, 2-, 3-, and 5-year survival rates were 100.0 %, 84.6 %, 69.2 %, and 38.5 %, respectively, for patients with primary bone tumors and 83.3 %, 16.7 %, 0 %, and 0 %, respectively, for patients with metastatic bone tumors. The survival rates for patients with primary bone tumors were significantly better than for those with metastatic tumors. The authors concluded that HIFU safely and non-invasively ablated malignant bone tumors and relieved pain. They stated that HIFU ablation should be further investigated in larger number of patients, as it appears to be successful in the treatment of primary malignant bone tumors.

In an editorial that accompanied the afore-mentioned study by Li et al (2010), Konski (2010) stated that caution needs to be exercised in interpreting these findings because the response rates were classified by MRI or PET-CT and not pathologically. Well-designed studies comparing HIFU to cryotherapy, radiofrequency ablation, and/or external beam radiotherapy are needed to ascertain the effectiveness of HIFU in the treatment of bone metastases. The editorialist noted that HIFU may provide another treatment option for patients with primary bone tumors who are not surgical candidates or who refuse surgery, but these data need to be confirmed.

Renal Cancer

In a phase I clinical study, Klinger et al (2008) evaluated the feasibility of HIFU ablation of small renal tumours under laparoscopic control. A total of 10 kidneys with solitary renal tumors were treated with a newly developed 4.0 MHz laparoscopic HIFU probe. In the first 2 patients with 9-cm tumors, a defined marker lesion was placed before laparoscopic radical nephrectomy. In 8 patients with a mean tumor size of 22 mm (range of 11 to 40), the tumor was completely ablated as in curative intent, followed by laparoscopic partial nephrectomy in 7 tumors. One patient had post-HIFU biopsies and was followed radiologically. Specimens were studied by detailed and whole-mount histology, including NADH stains. Mean HIFU insonication time was 19 mins (range of 8 to 42), with a mean targeted volume of 10.2 cm3 (range of 9 to 23). At histological evaluation both marker lesions showed irreversible and homogeneous thermal damage within the targeted site. Of the 7 tumors treated and removed after HIFU, 4 showed complete ablation of the entire tumor. Two had a 1- to 3-mm rim of viable tissue immediately adjacent to where the HIFU probe was approximated, and 1 tumor showed a central area with about 20 % vital tissue. There were no intra- or post-operative complications related to HIFU. The authors concluded that the morbidity of laparoscopic partial nephrectomy mainly comes from the need to incise highly vascularized parenchyma. Targeted laparoscopic HIFU ablation may render this unnecessary, but further studies are needed to refine the technique.

Klatte and Marberger (2009) reviewed the current status of HIFU for the treatment of renal tumors. Application of extra-corporeal HIFU for renal tumors is well-tolerated with no serious peri-operative complications. However, the techniques available do not permit sufficient tumor destruction that can be considered as an alternative to surgical extirpation. Laparoscopic HIFU avoids problems with respiratory movement and interphases and may achieve a greater rate of tumor destruction. The authors concluded that at the current time, HIFU of renal tumors has to be considered an experimental treatment approach; and prospective evaluation of laparoscopic HIFU is needed to assess its oncologic effectiveness.

Hernández Fernández et al (2009) reviewed the mechanisms of action of HIFU as well as both experimental and clinical work related to renal tumor treatment. While most currently available experience in urological tumors with HIFU has been obtained with prostate cancer, an increasing number of studies support the efficacy and safety of this procedure for renal tumor destruction. Together with cryotherapy and radiofrequency, HIFU completes the spectrum of minimally invasive surgery in renal cancer, intended to decrease surgical morbidity while achieving similar oncological control rates. The authors concluded that it is still early to recommend this procedure for daily clinical practice. They stated that while its safety and few side effects are known, many ongoing studies intended to confirm its mid-term and long-term oncological efficacy should be completed.

Caballero et al (2010) reviewed the development, physical principles, and current status of HIFU in the treatment of renal tumors. These investigators concluded that HIFU appears to be a new option among non-invasive therapies for renal cancer in selected cases. They stated that a low complication rate has been noted, but much longer follow-up times are needed for assessment of oncological results.

The European Association of Urology’s guidelines on “Renal cell carcinoma” (Ljungberg et al, 2013) stated that other image-guided percutaneous and minimally invasive techniques (e.g., microwave ablation, laser ablation, and HIFU ablation) are experimental and are recommended only in studies.

Pancreatic Cancer

In a phase II clinical trial, Zhao et al (2010) evaluated the safety and effectiveness of concurrent gemcitabine and HIFU therapy in patients with locally advanced pancreatic cancer. Patients with localized unresectable pancreatic adenocarcinoma in the head or body of the pancreas received gemcitabine (1,000 mg/m) intravenously over 30 mins on days 1, 8, and 15, and concurrent HIFU therapy on days 1, 3, and 5. The treatment was given every 28 days. A total of 37 (94.9 %) of the 39 patients were assessable for response, and 2 cases of complete response and 15 cases of partial response were confirmed, giving an overall response rate of 43.6 % [95 % confidence interval (CI): 28.0 to 59.2 %]. The median follow-up period was 16.5 months (range of 8.0 to 28.5 months). The median time to progression and overall survival for all patients were 8.4 months (95 % CI: 5.4 to 11.2 months) and 12.6 months (95 % CI: 10.2 to 15.0 months), respectively. The estimates of overall survival at 12 and 24 months were 50.6 % (95 % CI: 36.7 to 64.5 %) and 17.1 % (95 % CI: 5.9 to 28.3 %), respectively. A total of 16.2 % of patients experienced grade 3/4 neutropenia. Grade 3 thrombocytopaenia was documented in 2 (5.4 %) patients. Grade 3 nausea/vomiting and diarrhea were observed in 3 (8.1 %), and 2 (5.4 %) patients, respectively. Grade 1 or 2 fever was detected in 70.3 % of patients. Twenty-eight patients (71.8 %) complained of abdominal pain consistent with tumor-related pain before HIFU therapy. Pain was relieved in 22 patients (78.6 %). The authors concluded that concurrent gemcitabine and HIFU is a tolerated treatment modality with promising activity in patients with previously untreated locally advanced pancreatic cancer. Further investigation is needed to ascertain the role of HIFU in the treatment of pancreatic cancer.

Li and colleagues (2014) examined the safety and effectiveness of HIFU combined with other physical therapies for the treatment of pancreatic cancer. PubMed, EMbase, the Cochrane Library (Issue 11, 2013), CBM, CNKI, and WanFang databases were systematically searched up to November 2013; RCTs and clinical controlled trials about the treatment of HIFU were included. According to the inclusion and exclusion criteria, 2 reviewers independently screened the studies, exacted the data, and assessed the quality. The meta-analysis was performed by using the RevMan 5.0 software. A total of 23 studies including 19 RCTs and 4 clinical controlled trials were included; of which 14 studies reported the safety. Results of meta-analyses showed that the survival rate at 6 months and 12 months, overall efficacy, and clinical benefit rate in HIFU plus radiation and chemotherapy group were significantly higher than those in groups treated with 3-D conformal radiation therapy (p < 0.05), gemcitabine (p < 0.05), gemcitabine plus cisplatin (p < 0.05), and gemcitabine plus 5-fluorouracil (p < 0.05). The adverse effect caused by HIFU plus other therapy was equal to those in the control group. The major HIFU-related adverse effect was skin damage and fever. The authors concluded that the current evidence suggested that the effectiveness of HIFU for pancreatic cancer was superior to other therapies. However, the poor quality of trails may reduce the reliability of outcome to some extent. They stated that the current evidence suggested that the effectiveness of HIFU for pancreatic cancer was superior to other therapies, but with poor quality. Therefore, a standard and unified criterion for the diagnosis and outcome measures of pancreatic cancer is needed, and the quality of study design and implementation should be bettered to improve the high quality of evidence for its clinical application.

In a meta-analysis, Dababou and colleagues (2017) evaluated the role of HIFU in pain palliation of advanced unresectable pancreatic adenocarcinoma. An electronic search was performed in PubMed Medline database up to the end of July 2016, for unresectable pancreatic cancer pain palliation with HIFU. Pertinent studies were identified through the PubMed search engine using the following keywords: HIFU, pancreas, pancreatic cancer, pain and palliation. Additional studies were included after manual search of the selected bibliographies. Pain palliation results reported in each study were analyzed using a logit-transformed random-effects model using the inverse variance method, with the DerSimonian-Laird estimator for τ2, and Cochran's Q test for heterogeneity among studies. The I2 was calculated to assess the percentage of the total variability in the different effect size estimates that can be attributed to heterogeneity among the true effects. A rank correlation test of funnel plot asymmetry was done to assess possible publication bias. The meta-analysis included a total number of 23 studies with 865 patients, 729 with pancreatic cancer. The population enrolled ranged from 3 patients in the smallest series, up to 61 in the largest study; τ2 (variance among studies) was 0.195, and I2 (percentage of variation among studies) was 40 % (95 % CI: 1 to 64 %); the Q test p-value was 0.026, indicating significant heterogeneity among studies. Among 639 patients treated with HIFU, 567 complained of pancreatic pain before the treatment and 459 patients experienced partial or complete pain relief after treatment. The random effects estimate of the proportion of patients with pain reduction was 0.81 (95 % CI: 0.76 to 86). The authors concluded HIFU appeared to be an effective tool for pain palliation in advanced pancreatic cancer. Studies assessing treatment in patients with pancreatic adenocarcinoma were limited by factors such as small sample sizes and heterogeneity in clinical definitions and assessments. They stated that prospective randomized and standardized studies are needed to confirm the effectiveness of HIFU in relieving pain, and to evaluate for any potential impact on tumor control and patient survival.

Stanislavova et al (2021) carried out a systematic review on the resection rate after HIFU ablation in patients with borderline resectable pancreatic cancer (BRPC) and examined the impact of this technique over the oncological results. The PubMed and Wanfang databases were searched using keywords: pancreatic cancer, HIFU ablation and high-intensity focused ultrasound. All found articles were reviewed. The systematic review was carried out according to the PRISMA guidelines. The English database search showed 109 papers, of which 3 met the inclusion criteria. The Wanfang database resulted in 110 papers; however, none met the inclusion criteria of the review. From the included studies 97 patients underwent neoadjuvant HIFU ablation ± chemotherapy; 34 patients reached resection (35.1 %). In 2 patients, residual tumor (R) classification was not reported. R0 resection rate in all reported patients was 30.5 % (29/95); and R1 resection rate was 3.2 % (3/95). The authors concluded that HIFU was safe and feasible in locally advanced and metastatic pancreatic cancer with proven down-staging and down-sizing effects. Moreover, these researchers stated that further research on the role of HIFU ablation as a neoadjuvant treatment for borderline resectable pancreatic cancer is needed.

Vulvar Dystrophy

Ruan et al (2010) evaluated the effectiveness of HIFU in the treatment of patients with non-neoplastic epithelial disorders of the vulva. These researchers reviewed 41 cases of lichen sclerosus, 38 cases of squamous cell hyperplasia, and 17 mixed cases. Biopsy specimens were assessed with light microscopy before and after treatment. Pruritus and signs of vulvar lesions were dramatically improved after HIFU treatment, without severe complications, and 90.2 % of the patients were cured or had their symptoms improved 6 months after treatment. On light microscopy, pigmentation and epithelial structures were recovered and dermal lymphocytic infiltration was reduced. The response rates were lower and complication rates higher among lichen sclerosus than among squamous cell hyperplasia cases (p < 0.05 for both). The authors concluded that treatment with HIFU may be safe and effective in cases of vulvar dystrophy. The findings of this trial need to be validated by well-desgined studies with larger number of patients and longer follow-up periods.

Thyroid Nodules

In an open, single-center, feasibility study, Esnault et al (2011) hypothesized that an optimized HIFU device could be safe and effective for ablating benign thyroid nodules without affecting neighboring structures. A total of 25 patients were treated with HIFU with real-time ultrasound imaging 2 weeks before a scheduled thyroidectomy for multi-nodular goiter. Thyroid ultrasonography imaging, thyroid function, were evaluated before and after treatment. Adverse events were carefully recorded. Each patient received HIFU for 1 thyroid nodule, solid or mixed, with mean diameter greater than or equal to 8 mm, and no suspicion of malignancy. The HIFU device was progressively adjusted with stepwise testing. One pathologist examined all removed thyroids. Three patients discontinued treatment due to pain or skin microblister. Among the remaining 22 patients, 16 showed significant changes by ultrasound. Macroscopic and histological examinations showed that all lesions were confined to the targeted nodule without affecting neighboring structures. At pathological analysis, the extent of nodule destruction ranged from 2 % to 80 %. Five out of 22 patients had over 20 % pathological lesions unmistakably attributed to HIFU. Seventeen cases had putative lesions including non-specific necrosis, hemorrhage, nodule detachment, cavitations, and cysts. Among these 17 cases, 12 had both ultrasound changes and cavitation at histology that may be expected for an HIFU effect. In the last 3 patients ablated at the highest energy level, significant ultrasound changes and complete coagulative necrosis were observed in 80 %, 78 %, and 58 % of the targeted area, respectively. There were no major complications of ablation. The authors concluded that these findings showed the potential efficacy of HIFU for human thyroid nodule ablation. Lesions were clearly visible by histology and ultrasound after high energy treatments, and safety and tolerability were good. The authors identified a power threshold for optimal necrosis of the target thyroid tissue. They stated that further studies are ongoing to assess nodule changes at longer follow-up times.

Cheong et al (2022) stated that currently there are 2 systematic reviews, as well as 1 systematic review and meta-analysis on the use of HIFU for the treatment of benign thyroid nodules. In this systematic review and meta-analysis, these investigators examined the safety and effectiveness of HIFU in the treatment of benign thyroid nodules. PubMed, Embase and Cochrane databases were searched for relevant studies from 1990 to 2021. A total of 9 studies were included in the systematic review and 6 in the meta-analysis. Pooled volume reduction rates (VRRs) at 3, 6 and 24 months after HIFU were examined. This systematic review and meta-analysis showed that pooled VRRs at 3, 6, and 24 months after HIFU were 42.14 (95 % CI: 28.66 to 55.62, I2 = 91 %), 53.51 (95 % CI: 36.78 to 70.25, I2 = 97 %) and 46.89 (95 % CI: 18.87 to 74.92, I2 = 99%), respectively. There was significant heterogeneity in the pooled VRRs at 3, 6 and 24 months after HIFU. No studies recorded complete disappearance of the nodules. Common side effects included pain, skin changes and edema. There were no major complications except for transient vocal cord paralysis and voice hoarseness (0.014 %) and transient Horner syndrome (0.5 %). The authors concluded that HIFU may be a safe and effective alternative treatment for benign thyroid nodules. Moreover, these researchers stated that larger clinical trials with longer follow-up are needed to examine the effectiveness of HIFU in the treatment of benign thyroid nodules.

The authors stated that this study had several drawbacks. First, this study may be limited by publication bias as results that suggested a benefit of HIFU were more likely to be published than those that did not. Second, the small number of studies and small sample sizes precluded the ability to adequately analyze subgroups and identify potentially important co-variates. A further meta-analysis that considers the factors that cause heterogeneity may be needed when sufficient papers have been published in the future. Moreover, different studies had different follow-up durations; therefore, direct comparisons could not be drawn. Third, many studies reported medians and their ranges only. These researchers converted those values to means and standard deviations, which may have affected the accuracy of the values. Fourth, these investigators were unable to analyze the absolute difference in nodule volumes before and after HIFU due to the heterogeneity of the baseline mean target nodule volume. Fifth, there were insufficient studies (less than 10) to evaluate funnel plot asymmetry based on Cochrane recommendations. These researchers included articles in English or were translated to English, which may have resulted in an over-estimation or under-estimation of results, given the selection bias towards populations whose studies were conducted in English.

Fractures

In a Cochrane review, Griffin et al (2012) evaluated the effects of HIFU, low-intensity ultrasound (LIUS), and extra-corporeal shockwave therapies (ECSW) as part of the treatment of acute fractures in adults. These investigators searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (December 2011), the Cochrane Central Register of Controlled Trials (in The Cochrane Library 2011, Issue 4), MEDLINE (1950 to November week 3, 2011), EMBASE (1980 to 2011 week 49), trial registers and reference lists of articles. Randomized controlled trials evaluating ultrasound treatment in the management of acute fractures in adults were selected. Studies including participants over 18 years of age with acute fractures, reporting functional outcomes, time to union, non-union, secondary procedures such as for fixation or delayed or non-union, adverse effects, pain, costs or patient adherence were included. Two authors independently extracted data from the included studies. Treatment effects were assessed using mean differences or risk ratios and, where there was substantial heterogeneity, pooled using a random-effects model. Results from "worst case" analyses, which gave more conservative estimates of treatment effects for time to fracture union, are reported in preference to those from "as reported" analyses. A total of 12 studies, involving 622 participants with 648 fractures, were included. Eight studies were randomized placebo-controlled trials, 2 studies were RCTs without placebo controls, 1 study was a quasi-randomised placebo controlled trial and the remaining study was a quasi-RCT without placebo control. Eleven trials tested LIUS and 1 trial tested ECSW. Four trials included participants with conservatively treated upper limb complete fractures and 6 trials included participants with lower limb complete fractures; these were surgically fixed in 4 trials. The remaining 2 trials reported results for conservatively treated tibial stress fractures. Very limited data from 2 complete fracture studies showed no difference between ultrasound and placebo control in functional outcome. Pooled estimates from 2 studies found LIUS did not significantly affect the time to return to training or duty in soldiers or midshipmen with stress fractures (mean difference -8.55 days, 95 % CI: -22.71 to 5.61). Based on a "worst case" analysis, which adjusted for incomplete data, pooled results from 8 heterogeneous studies showed no statistically significant reduction in time to union of complete fractures treated with LIPUS (standardised mean difference -0.47, 95 % CI: -1.14 to 0.20). This result could include a clinically important benefit or harm, and should be seen in the context of the highly significant statistical heterogeneity (I² = 90 %). This heterogeneity was not explained by the a priori subgroup analyses (upper limb versus lower limb fracture, smoking status). An additional subgroup analysis comparing conservatively and operatively treated fractures raised the possibility that LIUS may be effective in reducing healing time in conservatively managed fractures, but the test for subgroup differences did not confirm a significant difference between the subgroups. Pooled results from 8 trials reporting proportion of delayed union or non-union showed no significant difference between LIUS and control. Adverse effects directly associated with LIUS and associated devices were found to be few and minor, and compliance with treatment was generally good. One study reporting on pain scores found no difference between groups at 8 weeks. One quasi-randomized study (59 fractures) found no significant difference between ECSW and no-placebo control groups in non-union at 12 months (risk ratio 0.56, 95 % CI: 0.15 to 2.01). There was a clinically small but statistically significant difference in the visual analog scores for pain in favor of ECSW at 3-month follow-up. The only reported complication was infection, with no significant difference between the 2 groups. The authors concluded that while a potential benefit of ultrasound for the treatment of acute fractures in adults can not be ruled out, the currently available evidence from a set of clinically heterogeneous trials is insufficient to support the routine use of this intervention in clinical practice. They stated that future trials should record functional outcomes and follow-up all trial participants.

Breast Cancer

Yonetsuji and associates (2013) noted that HIFU is a promising technique for cancer treatment owing to its minimal invasiveness and safety. However, skin burn, long treatment time and incomplete ablation are main shortcomings of this method. These investigators presented a novel HIFU robotic system for breast cancer treatment. The robot has 4 rotational degrees of freedom with the workspace located in a water tank for HIFU beam imaging and ablation treatment. The HIFU transducer combined with a diagnostic 2D linear ultrasound probe was mounted on the robot end-effector, which was rotated around the HIFU focus when ablating the tumor. High intensity focused ultrasound beams were visualized by the 2D probe using beam imaging. Skin burn can be prevented or alleviated by avoiding long time insonification towards the same skin area. The time cost could be significantly reduced, as there is no need to interrupt the ablation procedure for cooling the skin. In addition, the authors stated that their proposed robot control strategies can avoid incomplete ablation. Experiments were carried out and the results showed the effectiveness of the proposed system. These preliminary findings need to be validated by well-designed studies.

In a systematic review, Peek et al (2015a) evaluated the clinical effectiveness of non-invasive HIFU ablation in the treatment of breast cancer. Medline/PubMed library databases were used to identify all studies published up to December 2013 that evaluated the role of HIFU ablation in the treatment of breast cancer. Studies were eligible if they were performed on patients with breast cancer and objectively recorded at least 1 clinical outcome measure of response (imaging, histopathological or cosmetic) to HIFU treatment. A total of 9 studies fulfilled the inclusion criteria. The absence of tumor or residual tumor after treatment was reported for 95.8 % of patients (160 of 167). No residual tumor was found in 46.2 % (55 of 119; range of 17 to 100 %), less than 10 % residual tumor in 29.4 % (35 of 119; range of 0 to 53 %), and between 10 and 90 % residual tumor in 22.7 % (27 of 119; range of 0 to 60 %). The most common complication associated with HIFU ablation was pain (40.1 %) and less frequently edema (16.8 %), skin burn (4.2 %) and pectoralis major injury (3.6 %). Magnetic resonance imaging showed an absence of contrast enhancement after treatment in 82 % of patients (31 of 38; range of 50 to 100 %), indicative of coagulative necrosis. Correlation of contrast enhancement on pre-treatment and post-treatment MRI successfully predicted the presence of residual disease. The authors concluded that HIFU treatment can induce coagulative necrosis in breast cancers. Complete ablation has not been reported consistently on histopathology and no imaging modality has been able confidently to predict the percentage of complete ablation. They stated that consistent tumor and margin necrosis with reliable follow-up imaging are needed before HIFU ablation can be evaluated within large, prospective clinical trials.

Breast Fibroadenoma

In a multi-center study, Kovatcheva et al (2015) assessed the clinical outcome and safety of US-guided HIFU in patients with breast fibroadenoma (FA). From May 2011 to February 2013, a total of 42 women with 51 FA in 1 or both breasts were selected for treatment with US-guided HIFU; 8 of 51 FA were treated twice. Patients' age ranged from 16 to 52 years (mean of 32). All patients with FA underwent core needle biopsy with histological confirmation. High-intensity focused ultrasound treatment was performed as an out-patient procedure under conscious sedation. Exclusion criteria were pregnant or lactating women, micro-calcifications within the lesion at mammogram, history of breast cancer, previous laser or radiation therapy, and breast implant in the same breast. All patients signed written informed consent. After the treatment, follow-up US with volume evaluations were performed at 2, 6, and 12 months. The FA mean baseline volume was 3.89 ml (0.34 to 19.66). At 2-month follow-up, the mean volume reduction was 33.2 % ± 19.1 % and achieved significance at 6-month (59.2 % ± 18.2 %, p < 0.001) and 12-month (72.5 % ± 16.7 %, p < 0.001) follow-up. Related side effects as superficial skin burn with blister-like aspect in 3 patients and hyper-pigmentation over the treated area in 1 patient were transient and resolved spontaneously. In 1 patient, asymptomatic subcutaneous induration persisted at the end of the study. The authors concluded that US-guided HIFU treatment is an effective non-invasive method for the treatment of breast FA and well-tolerated by the patients. They stated that these preliminary results are encouraging and showed that HIFU could be an alternative to surgery for breast FA.

Peek et al (2015b) stated that breast FA are the most common benign lesions in women. For palpable lesions, there are currently 3 standard treatment options:

reassurance (with or without follow-up),

vacuum-assisted mammotomy (VAM) or

surgical excision.

High-intensity focused ultrasound ablation has been used in the treatment of FA. The drawback of HIFU is its prolonged treatment duration. The aim of this trial is to evaluate circumferential HIFU treatment for the effective ablation of FA with a reduced treatment time. A total of 50 patients (age greater than or equal to 18 years) with symptomatic FA, visible on ultrasound (US, grade U2 benign) will be recruited. In patients greater than or equal to 25 years, cytology or histology will be performed to confirm the diagnosis of a FA. These patients will receive HIFU treatment using the US-guided Echopulse device (Theraclion Ltd., Malakoff, France) under local anesthesia. An additional 50 patients will be recruited and contacted 6 months after discharge from the breast clinic. These patients will be offered an US scan to determine the change in size of their FA. This natural change in size will be compared to the decrease in size after HIFU treatment. Secondary outcome measures include post-treatment complications, patient recorded outcome measures, mean treatment time and cost-analysis. The current trial is registered as ISRCTN76622747.

Guillez and colleagues (2018) examined the benefits and adverse effects of HIFU for the treatment for fibro-adenomas (FA). These investigators searched Medline from inception to May 2017, without any restriction. Of 20 identified abstracts, 5 primary studies met inclusion criteria. All studies reported a reduction in the size of FA treated with an increasing effect over time. Pain tolerance was most often assessed as moderate. Adverse effects of HIFU were not severe in all studies. The authors concluded that HIFU appeared to be a promising technique in the treatment of FA with a volume decrease of approximately 50 % at 6 months of therapy.

Desmoid Tumors

Avedian et al (2016) examined the potential use of HIFU in the treatment of extremity desmoid tumors. They evaluated if MR-guided HIFU can accurately ablate a pre-determined target volume within a human cadaver extremity and if MR-guided HIFU can stop progression and/or cause regression of extremity desmoid tumors? Simulated tumor volumes in 4 human cadavers, created by using plastic markers, were ablated using a commercially available focused ultrasound system. Accuracy was determined in accordance with the International Organization of Standards location error by measuring the farthest distance between the ablated tissue and the plane corresponding to the target. Between 2012 and 2014, these researchers treated 9 patients with desmoid tumors using focused ultrasound ablation. Indications for this were tumor-related symptoms or failure of conventional treatment. Of those, 5 of them were available for MRI follow-up at 12 months or longer (mean of18.2 months; range of 12 to 23). The radiographic and clinical outcomes of 5 patients who had desmoid tumors treated with focused ultrasound were prospectively recorded. Patients were assessed pre-operatively with MRI and followed at routine intervals after treatment with MRI scans and clinical examination. The ablation accuracy for the 4 cadaver extremities was 5 mm, 3 mm, 8 mm, and 8 mm. Four patients' tumors became smaller after treatment and 1 patient has slight progression at the time of last follow-up. The mean decrease in tumor size determined by MRI measurements was 36 % (95 % CI: 7 % to 66 %). No patient has received additional adjuvant systemic or local treatment. Treatment-related adverse events included first- and second-degree skin burns occurring in 4 patients, which were managed successfully without further surgery. The authors concluded that this preliminary investigation provided some evidence that MR-guided HIFU may be a feasible treatment for desmoid tumors. It may also be of use for other soft tissue neoplasms in situations in which there are limited traditional treatment options such as recurrent sarcomas. They stated that further investigation is needed to better define the indications, effectiveness, role, and long-term oncologic outcomes of focused ultrasound treatment.

Also, an UpToDate review on “Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy” (Ravi et al, 2015) lists surgery, radiation therapy and neoadjuvant systemic therapy as therapeutic options; it does not mention HIFU.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Soft tissue sarcoma” (Version 1.2015) states that “RT is generally only recommended for desmoid tumors that are in the extremity, superficial trunk, or head and neck”. It does not mention HIFU as a therapeutic option.

Hyper-Pigmentation (Pigmentary Skin Disorder)

Choi et al (2016) macroscopically and histopathologically investigated dermatological changes after HIFU at different exposure doses in a UVB-induced guinea pig model of hyper-pigmentation. These researchers applied HIFU irradiation at 0.1 and 0.2 J/cm2 to UVB-induced spotty hyper-pigmentation in guinea pig skin. The therapeutic effects of HIFU were judged based on gross appearance using photography, dermoscopy, and chromametry during a period of 3 weeks after HIFU irradiation. Histological assessments were performed using Fontana-Masson staining 1 day before and 3 weeks after HIFU irradiation. Macroscopically, UVB-induced hyper-pigmentation was significantly reduced 2 weeks after HIFU with 0.2 J/cm2 , and 3 weeks after HIFU with 0.1 J/cm2 . Histopathologically, the heavy deposition of melanin in the epidermis induced by UVB exposure was reduced 3 weeks after HIFU irradiation. The authors confirmed that HIFU has a positive effect on UVB-induced hyper-pigmentation as well as mechanical destructive activity. They suggested that HIFU may be useful as an alternative modality for human patients suffering from skin pigmentary conditions

Metastatic Bone Pain

In an observational cohort study, Huisman et al (2014) described the first experience with volumetric MR-HIFU for palliative treatment of painful bone metastases and evaluated the technique on 3 levels:

technical feasibility,

safety, and

initial effectiveness.

A total of 11 consecutive patients (7 males and 4 females; median age of 60 years; age range of 53 to 86) underwent 13 treatments for 12 bone metastases. All patients exhibited persistent metastatic bone pain refractory to the standard of care. Patients were asked to rate their worst pain on an 11-point pain scale before treatment, 3 days after treatment, and 1 month after treatment. Complications were monitored. All data were prospectively recorded in the context of routine clinical care. Response was defined as a greater than or equal to2-point decrease in pain at the treated site without increase in analgesic intake. Baseline pain scores were compared to pain scores at 3 days and 1 month using the Wilcoxon signed-rank test. For reporting, the STROBE guidelines were followed. No treatment-related major adverse events were observed. At 3 days after volumetric MR-HIFU ablation, pain scores decreased significantly (p = 0.045) and response was observed in a 6/11 (55 %) patients. At 1-month follow-up, which was available for 9 patients, pain scores decreased significantly compared to baseline (p = 0.028) and 6/9 patients obtained pain response (overall response rate 67 % (95 % CI: 35 % to 88 %)). The authors concluded that this was the first study reporting on the volumetric MR-HIFU ablation for painful bone metastases. No major treatment-related adverse events were observed during follow-up. The results of this study showed that volumetric MR-HIFU ablation for painful bone metastases is technically feasible and can induce pain relief in patients with metastatic bone pain refractory to the standard of care. They stated that future research should be aimed at standardization of the treatment procedures and treatment of larger numbers of patients to assess treatment effectiveness and comparison to the standard of care.

Hurwitz et al (2014) reported on a phase III trial to assess the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS) for palliation of pain due to bone metastases. Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher’s exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. The investigators enrolled 147 subjects, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day.

An assessment of magnetic resonance-guided focused ultrasound surgery for palliation of pain due to bone metastases (McIntosh, et al., 2015) reached the following conclusions:

there are no published studies comparing magnetic resonance guided focused ultrasound surgery (MRgFUS) with radiotherapy or other treatment alternatives for painful bone metastases;

one randomized controlled trial has compared MRgFUS with a sham control procedure in patients where radiotherapy was unsuccessful, contraindicated or declined; the trial concluded that MRgFUS was safe and effective;

there is limited published evidence on the safety of MRgFUS from small uncontrolled case series; procedure related pain is the most commonly reported adverse effect;

two ongoing randomised controlled trials comparing MRgFUS with radiotherapy were identified;

there are no published evaluations on the cost effectiveness of MRgFUS compared with radiotherapy or other treatment alternatives for painful bone metastases.

Placenta Accreta

Bay et al (2015) evaluated the safety and effectiveness of the HIFU in the treatment of placenta accreta after vaginal delivery. From September 2011 to September 2013, a total of 12 patients diagnosed with placenta accreta with stable vital signs were enrolled in this study. All patients had vaginal delivery and were treated using an ultrasound-guided HIFU treatment system. Decreased vascular index on color Doppler scanning, reduced degree of enhancement on MRI and avoided hysterectomy following treatment indicated the effectiveness of the treatment. Side effects, hemorrhage, infection, sex steroids levels, return of menses and subsequent pregnancy were also recorded to assess the safety of HIFU treatment. All patients received HIFU treatment with an average post-partum length of stay of 6.8 days and an average period of residual placenta involution of 36.9 days. These results demonstrated that HIFU treatment did not increase risk of infection and hemorrhage and no patient required hysterectomy. All patients had return of menstruation with an average delay of 80.3 days, and sex steroid levels during the middle luteal phase of the second menstrual cycle were normal. Two patients were successfully pregnant during the follow-up period. The authors concluded that the findings of this preliminary study suggested that ultrasound-guided HIFU is a non-invasive, safe and effective method to treat selected placenta accreta patients after vaginal delivery who have stable vital signs and desire fertility preservation. These preliminary findings need to be validated by well-designed studies.

Renal Sympathetic Denervation in the Treatment of Resistant Hypertension

Wang et al (2013) examined the feasibility of non-invasive renal sympathetic denervation (RSD) by using the novel approach of extracorporeal HIFU. Under the guidance of Doppler flow imaging, therapeutic ablations (250 W × 2 s) were performed by using extracorporeal HIFU on the bilateral renal nerves (36.3 ± 2.8 HIFU emissions in each animal) in a mean 27.4-min procedure in 18 healthy canines of the ablation group. Similar procedures without acoustic energy treatment were conducted in 5 canines of the sham group. The animals were killed on day 6 or 28. Blood pressure (BP), plasma noradrenaline (NA) level, and renal function were determined on days 0, 6, and 28. Pathological examinations were performed on all retrieved samples. All of the animals survived the treatment. After ablation, BP and NA significantly decreased compared with the baseline values (BP changed -15.9/-13.6 mmHg, NA changed -55.4 % [p < 0.001] 28 days after ablation]) and compared with the sham group on days 6 and 28. Ablation lesions around the renal artery adventitia were observed on day 6. A histological examination revealed the disruption of nerve fibers, necrosis of Schwann cells and neurons, and apparent denervation on day 28. No procedure-related complications were observed. The authors concluded that effective RSD was successfully achieved by using the extracorporeal HIFU method in canines. Thus, non-invasive HIFU may be further explored as an important and novel strategy for RSD.

Scope of Policy

This Clinical Policy Bulletin addresses high intensity focused ultrasound.

Medical Necessity

Aetna considers high intensity focused ultrasound (HIFU) medically necessary for radio-recurrent prostate cancer in the absence of metastatic disease.

Experimental and Investigational

Aetna considers HIFU experimental and investigational for the following indications because of insufficient evidnece of its effectiveness (not an all-inclusive list):

Abdominal wall endometriosis

Adenomyosis-related symptoms

Alzheimer’s disease

Benign prostatic hypertrophy (see

CPB 0079 - Benign Prostatic Hyperplasia

)

Breast cancer

Breast fibroadenoma

Breast fibromatosis

Central nervous system diseases/disorders (e.g., brain cancer and stroke)

Cesarean scar pregnancy

Desmoid tumors

Epilepsy

Extra-abdominal desmoid tumors

Fractures

Glaucoma

Gliomas

Graves’ disease

Gynecological tumors within the pelvis

Hepatocellular carcinoma

Hyper-pigmentation (pigmentary skin disorder)

Liver metastasis from colon and stomach cancer

Low-flow vascular malformations

Melanoma

Melasma

Metastatic bone pain

Migraines

Malignant biliary obstruction

Movement disorders (e.g., Parkinson's disease) other than essential tremor (see

CPB 0153 - Thalamotomy

)

Neuropathy/neuropathic pain

Obsessive compulsive disorder

Open-angle glaucoma

Osteoarthritis

Osteoid osteoma

Osteosarcoma/bone tumors

Pancreatic cancer

Placenta accreta

Primary hyperparathyroidism

Primary liver cancer

Renal cancer

Renal sympathetic denervation in the treatment of resistant hypertension

Thyroid nodules

Twin-twin transfusion syndrome/ twin reversed arterial perfusion (TRAP) sequence

Uterine arterio-venous malformation

Uterine leiomyomas and adenomyosis

Vulvar dystrophy.