High-Intensity Focused Ultrasound for the Treatment of Prostate Cancer: A Review.

Over the past 25 years, the average life expectancy for men has increased almost 4 years, and the age of prostate cancer detection has decreased an average of 10 years with diagnosis increasingly made at early-stage disease where curative therapy is possible. These changing trends in the age and extent of malignancy at diagnosis have revealed limitations in conventional curative therapies for prostate cancer, including a significant risk of aggressive cancer recurrence, and the risk of long-term genitourinary morbidity and its detrimental impact on patient's quality of life (QOL). Greater awareness of the shortcomings in radical prostatectomy, external radiotherapy, and brachytherapy has prompted the search for alternative curative therapies that offer comparable rates of cancer control and less treatment-related morbidity to better preserve QOL. High-intensity focused ultrasound (HIFU) possesses characteristics that make it an attractive curative therapy option. HIFU is a noninvasive approach that uses precisely delivered ultrasound energy to achieve tumor cell necrosis without radiation or surgical excision. In current urologic oncology, HIFU is used clinically in the treatment of prostate cancer and is under experimental investigation for therapeutic use in multiple malignancies. Clinical research on HIFU therapy for localized prostate cancer began in the 1990s, and there have now been ∼65,000 prostate cancer patients treated with HIFU, predominantly with the Ablatherm (EDAP TMS, Lyon, France) device. Neoadjuvant transurethral resection of the prostate has been combined with HIFU since 2000 to reduce prostate size, facilitate tissue destruction, and to minimize side effects. Advances in imaging technologies are expected to further improve the already superior efficacy and morbidity outcomes, and ongoing investigation of HIFU as a focal therapy in salvage and palliative indications is serving to expand the role of HIFU as a highly versatile noninvasive therapy for prostate cancer.

Salvage high-intensity focused ultrasound (HIFU) for locally recurrent prostate cancer after failed radiation therapy: Multi-institutional analysis of 418 patients.

OBJECTIVE: To report the oncological outcome of salvage high-intensity focused ultrasound (S-HIFU) for locally recurrent prostate cancer after external beam radiotherapy (EBRT) from a multicentre database. PATIENTS AND METHODS: This retrospective study comprises patients from nine centres with local recurrent disease after EBRT treated with S-HIFU from 1995 to 2009. The biochemical failure-free survival (bFFS) rate was based on the 'Phoenix' definition (PSA nadir + 2 ng/mL). Secondary endpoints included progression to metastasis and cancer-specific death. Kaplan-Meier analysis was performed examining overall (OS), cancer-specific (CSS) and metastasis-free survival (MFS). Adverse events and quality of life status are reported. RESULTS: In all, 418 patients with a mean (SD) follow-up of 3.5 (2.5) years were included. The mean (SD) age was 68.6 (5.8) years and the PSA level before S-HIFU was 6.8 (7.8) ng/mL. The median PSA nadir after S-HIFU was 0.19 ng/mL. The OS, CSS and MFS rates at 7 years were 72%, 82% and 81%, respectively. At 5 years the bFFS rate was 58%, 51% and 36% for pre-EBRT low-, intermediate- and high-risk patients, respectively. The 5-year bFFS rate was 67%, 42% and 22% for pre-S-HIFU PSA level ≤4, 4-10 and ≥10 ng/mL, respectively. Complication rates decreased after the introduction of specific post-RT parameters: incontinence (grade II or III) from 32% to 19% (P = 0.002); bladder outlet obstruction or stenosis from 30% to 15% (P = 0.003); recto-urethral fistula decreased from 9% to 0.6% (P < 0.001). Study limitations include being a retrospective analysis from a registry with no control group. CONCLUSION: S-HIFU for locally recurrent prostate cancer after failed EBRT is associated with 7-year CSS and MFS rates of >80% at a price of significant morbidity. S-HIFU should be initiated early following EBRT failure.

Evolution and outcomes of 3 MHz high intensity focused ultrasound therapy for localized prostate cancer during 15 years.

PURPOSE: We describe the long-term cancer control and morbidity of high intensity focused ultrasound with neoadjuvant transurethral resection of the prostate, the risk of metastatic induction by transurethral prostate resection, and the evolution of high intensity focused ultrasound application and technology with time. MATERIALS AND METHODS: A prospective Harlaching high intensity focused ultrasound database was searched for patients with primary localized prostate cancer (T1-2, N0, M0, PSA at first diagnosis less than 50 ng/ml) and followup longer than 15 months. Those patients with previous long-term androgen deprivation therapy, locally advanced prostate cancer or any therapy influencing prostate specific antigen were excluded from study. All patients were treated completely with an Ablatherm® high intensity focused ultrasound device. Evaluation was performed in aggregate, and by stratification according to cohort group, risk group (D'Amico criteria), prostate specific antigen nadir and Gleason score. The Phoenix definition was used for biochemical failure. Statistical analysis was performed using the Kaplan-Meier method, and univariate and multivariate analysis was performed using a Cox model. RESULTS: Of 704 study patients 78.5% had intermediate or high risk disease. Mean followup was 5.3 years (range 1.3 to 14). Cancer specific survival was 99%, metastasis-free survival was 95%, and 10-year salvage treatment-free rates were 98% in low risk, 72% in intermediate risk and 68% in high risk patients. Prostate specific antigen nadir and Gleason score predicted biochemical failure, and side effects were moderate. The high intensity focused ultrasound re-treatment rate has been 15% since 2005. CONCLUSIONS: Long-term followup with high intensity focused ultrasound therapy demonstrated a high overall rate of cancer specific survival and an exceptionally high rate of freedom from salvage therapy requirements in low risk patients. Advances in high intensity focused ultrasound technology and clinical practice as well as the use of neoadjuvant transurethral prostate resection allow the complete treatment of any size prostate without inducing metastasis.

High-intensity focused ultrasound (HIFU) for definitive treatment of prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Novel therapeutic methods have emerged in recent years as 'focal' treatment alternatives in which cancer foci can be eradicated and greatly reducing the associated side-effects of radical treatment. High-intensity focused ultrasound (HIFU) seems to result in a well fitted technology, which has proven short- to medium-term cancer control, with a low rate of complications comparable with those of established therapies. This is an up-to-date review of the available literature on HIFU as a definitive treatment of prostate cancer. It describes the technique in a comprehensive approach in terms of technical features, procedure, indications, and gives an overview of its historical background; finally, we present the future applications of HIFU and its development trend. OBJECTIVES: • To provide an up-to-date review of the available literature on high-intensity focused ultrasound (HIFU) as a definitive treatment of prostate cancer. • To present the technique in a comprehensive approach, comparing the available devices according to the existing evidence in terms of technical features, procedure, indications, and to give an overview of its historical background; and finally, to discuss future applications of HIFU and its development trend. MATERIALS AND METHODS: • 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 >50 participants, patient characteristics, efficacy and safety data were included. RESULTS: • No randomised controlled trials were identified by the literature search. We identified 31 uncontrolled studies that examined the efficacy of HIFU as primary treatment and two studies that examined the efficacy of HIFU as salvage treatment. • Most treated patients had localised prostate cancer (stage T1-T2); Gleason scores of 2-10 and mean prostate specific antigen (PSA) values of 4.6-12.7 ng/mL. The mean age range of the patients was 64.1-72 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 disease-free survival rates ranged from 61.2 to 95%; 7- and 8-year disease free survival rates ranged from 69 to 84%. • The most common complications associated with the HIFU procedure as the primary treatment included: urinary retention (<1-20%); urinary tract infections (1.8-47.9%); stress or urinary incontinence (<1-34.3%); and erectile dysfunction (20-81.6%). • Recto-urethral fistula was reported in <2% of patients. • Treatment-related morbidity appeared to be reduced by the combination of transurethral resection (TURP) of the prostate and HIFU. CONCLUSIONS: • 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. • HIFU 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.

Ultrasonidos de alta intensidad focalizados (HIFU) para el tratamiento local del cáncer de próstata: papel actual / Transrectal high-intensity focused ultrasound for local treatment of prostate cancer: current role

OBJETIVO: El atractivo del HIFU (High intensity focused ultradound) robotizado se basa ampliamente en la naturaleza no invasiva, extremadamente precisa de este tratamiento robótico de alta tecnología, así como su carácter limpio, sin radiación, quirúrgico y sin embargo sin sangrado. Hoy, en urología oncológica, el HIFU se utiliza clínicamente cómo una herramienta terapéutica para el tratamiento del cáncer de próstata. Su uso terapéutico en cáncer de riñón y mama se está investigando a nivel experimental.El tratamiento del cáncer de próstata localizado con HIFU transrectal ha sido investigado desde los años 90, y mientras tanto es una terapia utilizada activamente contra la enfermedad en muchos departamentos deurología en todo el mundo. Desde el 2000 el HIFU se utiliza principalmente en combinación con resección transuretral de próstata para reducir el tamaño de la glándula prostática, facilitar la destrucción efectiva del tejido y evitar los efectos secundarios. Las indicaciones paliativas y de salvación, así como el tratamiento focal del cáncer de próstata están siendo investigadas para extender el espectro de indicaciones del HIFU en el tratamiento no invasivo del cáncer de próstata(AU)

Attractivity of robotic high intensity focused ultrasound (HIFU) is based largely on the non-invasive, extremely precise nature of this high-tech robotic therapy as well as its clean, radiation free, surgical, but nevertheless, bloodless character. Today, in urological oncology, HIFU is used clinically as a therapeutic tool for the treatment of prostate cancer. Experimentally it is investigated for therapeutic use in kidney and breast cancer.Transrectal treatment of localized prostate cancer with HIFU has been under investigation since the 1990s and it is meanwhile an actively used therapy for the disease in many urological departments worldwide. Since 2000 HIFU is mostly used in combination with transurethral resection of the prostate in order to reduce prostate gland size, to facilitate effective tissue destruction and to avoid side effects. Palliative and salvage indications as well as focal therapy of prostate cancer are under investigation to extend the spectrum of HIFU indications for non invasive prostate cancer therapy(AU)

Transrectal high-intensity focused ultrasound for local treatment of prostate cancer: current role.

Attractivity of robotic high intensity focused ultrasound (HIFU) is based largely on the non-invasive, extremely precise nature of this high-tech robotic therapy as well as its clean, radiation free, surgical, but nevertheless, bloodless character. Today, in urological oncology, HIFU is used clinically as a therapeutic tool for the treatment of prostate cancer. Experimentally it is investigated for therapeutic use in kidney and breast cancer. Transrectal treatment of localized prostate cancer with HIFU has been under investigation since the 1990s and it is meanwhile an actively used therapy for the disease in many urological departments worldwide. Since 2000 HIFU is mostly used in combination with transurethral resection of the prostate in order to reduce prostate gland size, to facilitate effective tissue destruction and to avoid side effects. Palliative and salvage indications as well as focal therapy of prostate cancer are under investigation to extend the spectrum of HIFU indications for non invasive prostate cancer therapy.

Robotic high-intensity focused ultrasound for prostate cancer: what have we learned in 15 years of clinical use?

High-intensity focused ultrasound (HIFU) is an emerging, noninvasive, local treatment of prostate cancer with 15 years of clinical experience, during which about 30,000 HIFU treatments have been performed worldwide. In this paper, we review relevant publications regarding the means by which new and old prostate cancer technologies are evaluated, the outcomes of HIFU by Ablatherm (EDAP TMS, Lyon, France), and the evolution currently underway regarding how prostate cancer is diagnosed and treated. We show the potential of HIFU to be used as local therapy for men with any stage of prostate cancer and how this additional therapeutic option can fit within the future armamentarium of a sequential multimodal therapy concept.

Correlation of prostate-specific antigen nadir and biochemical failure after high-intensity focused ultrasound of localized prostate cancer based on the Stuttgart failure criteria - analysis from the @-Registry.

OBJECTIVE: •To determine if the prostate-specific antigen (PSA) nadir after high-intensity focused ultrasound (HIFU) can be used as a predictor of the biochemical disease-free survival rate (DFSR). PATIENTS AND METHODS: •Patient data were derived from the multicentre-based @-Registry, the largest registry to report outcomes in patients with localized prostate cancer after Ablatherm® HIFU. •PSA level was measured at 3-month intervals. Patients were stratified into four PSA nadir groups: group 1, ≤0.2 ng/mL; group 2, 0.21-0.5 ng/mL; group 3, 0.51-1 ng/mL; and group 4, >1 ng/mL. •Biochemical treatment failure was defined according to the Stuttgart definition (PSA nadir + 1.2 ng/mL) and the Phoenix definition (PSA nadir + 2 ng/mL). •Biopsy was performed at 3-6 months post-HIFU or if a PSA level was recorded that was considered clinically relevant. RESULTS: •The present study included 804 patients. Biochemical treatment success rates at 5 years according to the Stuttgart definition for the four PSA nadir sub-groups were as follows: 84, 64, 40 and 30% for groups 1-4, respectively. •The equivalent 5-year biochemical success rates using the Phoenix definition were 94, 74, 66 and 47%, respectively. •Significantly more patients had a negative biopsy in the lowest PSA nadir group than in the other sub-groups (91.6 vs 73.1%; P < 0.001). •The present study is limited by its retrospective nature and variations in clinical practice across participating centres. CONCLUSION: •This multicentre analysis confirms that PSA nadir after HIFU predicts biochemical DFSR in a statistically significant manner.

Robot-assisted high-intensity focused ultrasound in focal therapy of prostate cancer.

In one-third of patients, prostate cancer (PCa) is monofocal. These patients can undergo focal high-intensity focused ultrasound (HIFU) therapy of the tumor without damage to surrounding structures and not compromising uro-oncologic safety. Robot-assisted HIFU coagulates the entire targeted volume within the prostate transrectally, in one session, without direct tumor contact and without adjuvant endourologic therapy. It is performed with the patient receiving spinal anesthesia and without blood loss; negative immunologic influence can be excluded. Heat-destroyed cancer cells that act as tumor vaccination are discussed. Right now, the limitation of focal therapy is caused by the lack of diagnostic accuracy to determine multifocal stages of PCa reliably. Discussions of tumor development, triggering primary lesion monotherapy, do not overcome skepticism about leaving invisible tumor foci untreated. This explains why PCa therapy today treats always the entire gland. Furthermore, the thought that the problem could be solved "radically, once forever," ignores the fact that in all PCa therapies, local recurrence rates are between 10% and 50%. Considering the longer survival of men in industrialized countries, a structured multimodal therapy concept should be created and evaluated in studies and should replace the competition between classic therapies. Focal therapy in most cases should be the first approach in cancer therapy because it is noninvasive, has low side effects, and is a single-session therapy. It does not exclude but may delay other, more invasive therapies in cases of cancer recurrence. Focal therapy should not be misunderstood as substitution for existing classic therapies but as a therapeutic first choice in monofocal, low-aggressive PCa cases.

High-intensity focused ultrasound in the management of prostate cancer.

The treatment of localized prostate cancer with high-intensity focused ultrasound (HIFU) has been researched since the 1990s and today the treatment is an actively used therapy for the disease. HIFU works in two ways to destroy tissue, namely thermal and mechanical effects. The most recent data on the Ablatherm HIFU device come from an international registry (@-Registry) and indicate a 5-year biochemical survival rate of 85%. HIFU is commonly used in conjunction with transurethral resection of the prostate in order to reduce prostate gland size and facilitate effective tissue destruction. An additional benefit of HIFU is that it can be used as salvage therapy after radical prostatectomy and external-beam radiotherapy. A new area of research with HIFU involves focal therapy, where tumor sites within the gland are directly targeted with the objective of reducing morbidity.

High-intensity focused ultrasound for prostate cancer: comparative definitions of biochemical failure.

OBJECTIVES: To compare the specificity and sensitivity of different definitions of biochemical failure in patients treated with high-intensity focused ultrasound (HIFU) for prostate cancer, to identify the most accurate predictor of clinical failure after HIFU. PATIENTS AND METHODS: Consecutively treated patients who underwent HIFU between October 1997 and July 2006 at two centres (Lyon, France; and Regensburg, Germany) were prospectively maintained within a central database and retrospectively reviewed for this study. Clinical failure was defined as a positive prostate biopsy after treatment, radiographic evidence of lymphatic or bony metastatic disease, or salvage treatment for prostate cancer (surgery, radiation, hormonal therapy or second HIFU). The serum prostate-specific antigen (PSA) values after HIFU were assessed as a biochemical surrogate of a therapeutic success or failure. PSA threshold values, 'PSA nadir plus', PSA velocity, PSA doubling time and the American Society or Therapeutic Radiotherapy and Oncology and Phoenix definition of biochemical failure were all considered. The sensitivity, specificity, positive predictive value and negative predictive value of each biochemical definition for predicting clinical failure were determined. RESULTS: The data from 285 patients (stage

Transrectal high-intensity focused ultrasound devices: a critical appraisal of the available evidence.

Developments in the technology applied to the field of minimally invasive surgery have led to the exploration of high-intensity focused ultrasound (HIFU) for the treatment of localized prostate cancer. Extensive research and continuous evolution have resulted in two commercially available HIFU devices: the Ablatherm and the Sonablate500. These devices are conceptually the same; however, specific technical differences exist. This paper reviews the clinical outcomes obtained with these devices, evaluates the quality of the evidence from the individual trials, and provides the results of a head-to-head comparison in terms of oncologic outcomes and complication rates.

First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer.

OBJECTIVE: To evaluate the long-term efficacy of high-intensity focused ultrasound (HIFU) therapy for patients with localised prostate cancer. MATERIAL AND METHODS: Patients included in this multicentre analysis had T1-T2 NxM0 prostate cancer, a PSA<15 ng/ml, and a Gleason score (GS) < or = 7, and were treated with prototypes or first-generation Ablatherm HIFU devices between October 1997 and August 2001. The Phoenix definition of biochemical failure was used (PSA nadir+2). Treatment failure was defined as: biochemical failure or positive biopsy. RESULTS: A total of 140 patients with a mean (SD) age 69.1 yr (6.6) were included. Mean (SD) follow-up was 6.4 yr (1.1). Control prostate biopsies were negative in 86.4% of patients. Median PSA nadir of 0.16 ng/ml (range, 0.0-9.1) was achieved at a mean (SD) of 4.9 mo (5.2). A PSA nadir < or = 0.5 ng/ml was recorded in 68.4% of patients. The actuarial biochemical failure-free survival rates (SR) at 5 and 7 yr were 77% and 69%, respectively. The actuarial disease-free SR at 5 and 7 yr were 66% and 59%, respectively. CONCLUSIONS: This study demonstrates the effective long-term cancer control achieved with HIFU in patients with low- or intermediate-risk localised prostate cancer.

Technology insight: High-intensity focused ultrasound for urologic cancers.

The growing interest in high-intensity focused ultrasound (HIFU) technology is mainly due to its many potential applications as a minimally invasive therapy. It has been introduced to urologic oncology as a treatment for prostate and kidney cancers. While its application in the kidney is still at the clinical feasibility phase, HIFU technology is currently used in daily practice in Europe for the treatment of prostate cancer. Literature describing the results of HIFU for prostate cancer is mainly based on several series of patients from clinical development teams. The latest published results suggest that HIFU treatment is a valuable option for well-differentiated and moderately-differentiated tumors, as well as for local recurrence after external-beam radiation therapy.

High-intensity focused ultrasound and localized prostate cancer: efficacy results from the European multicentric study.

PURPOSE: To describe the safety and efficacy of high-intensity focused ultrasound (HIFU) for the treatment of prostate cancer as assessed in a Phase II/III prospective multicentric clinical trial. PATIENTS AND METHODS: Patients (N = 402) presenting with localized (stage T(1-2)N(0-x)M(0)) prostate cancer between 1995 and 1999 at six European sites who were not candidates for radical prostatectomy were treated with HIFU under general or spinal anesthesia. Their mean age was 69.3 +/- 7.1 (SD) years, the mean prostate volume 28.0 +/- 13.8 cc, and the mean serum prostate specific antigen (PSA) concentration 10.9 +/- 8.7 ng/mL. Nearly all (92.2%) of the patients had one to four positive biopsy samples at baseline. The Gleason scores were 2 to 4 for 13.2% of the patients, 5 to 7 for 77.5%, and 8 to 10 for 9.3%. During the follow-up, random sextant biopsies and serum PSA measurements were performed. Any positive sample in biopsies performed after the last treatment session resulted in a "HIFU failure" classification. RESULTS: The patients received a mean of 1.4 HIFU sessions. The mean follow-up duration was 407 days (quartile 1 135 days, median 321 days, quartile 3 598 days). The negative biopsy rate observed in the T1-2 primary-care population was 87.2%. These results were also stratified according to the usual disease-related risk classification, and as much as a 92.1% negative biopsy rate was observed in low-risk patients. Nadir PSA results correlated with prostate size and the clinical procedure. CONCLUSION: These short-term results obtained on a large cohort confirm that HIFU is an option to be considered for the primary treatment of localized prostate cancer.

The status of high-intensity focused ultrasound in the treatment of localized prostate cancer and the impact of a combined resection.

To decrease side effects observed after high-intensity focused ultrasound (HIFU) treatment for localized prostate cancer and to re-establish normal micturition in a patient population that often presents with concomitant prostate enlargement, the impact of a combined transurethral resection of the prostate (TURP) and HIFU has been evaluated. TURP and HIFU treatments were performed under the same spinal anesthesia. For the HIFU treatments, the Ablatherm device (EDAP SA, Lyon, France) was used. Selection criteria for HIFU treatment were localized prostate cancer, no previous treatment for prostate cancer, and prostate-specific antigen (PSA) pound 15 ng/mL at diagnosis. All patients meeting these criteria were considered for treatment and analysis. PSA nadir and stability, histology, International Prostate Specific Score (IPSS) and IPSS-quality of life, and morbidity were assessed during follow-up; 271 patients were selected: 96 in the HIFU group and 175 in the TURP plus HIFU group. A statistically significant impact was observed on catheter time (40.0 days versus 7.0 in median), incontinence (15.4% versus 6.9%), urinary infection (47.9% versus 11.4%), and the evolution of the post-treatment IPSS (8.91 versus 3.37 in average) in favor of the TURP plus HIFU group. No significant changes were observed regarding efficacy during short-term follow-up when considering a 25% retreatment rate in the HIFU group versus a 4% retreatment rate in the TURP plus HIFU group. The combination of a TURP and HIFU treatment reduces the treatment-related morbidity significantly. The patient management after a combined TURP and HIFU treatment is comparable with the management after a single TURP.