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Keywords:

  • high-intensity focused ultrasound;
  • prostatic cancer;
  • safety;
  • survival;
  • systematic review;
  • thermal ablation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

Abstract:  Recent advances in high-intensity focused ultrasound, which was developed in the 1940s as a viable thermal tissue ablation approach, have increased its popularity. High-intensity focused ultrasound is currently utilized the most in Europe and Japan, but has not yet been approved by the Food and Drug Administration, USA, for this indication. The purpose of the present report is to review the scientific foundation of high-intensity focused ultrasound technology and the clinical outcomes achieved with commercially available devices. Recently published articles were reviewed to evaluate the current status of high-intensity focused ultrasound as a primary or salvage treatment option for localized prostate cancer. Improvements in the clinical outcome as a result of technical, imaging and technological advancements are described herein. A wide range of treatment options for organ-confined prostate cancer is available. However, high-intensity focused ultrasound is an attractive choice for men willing to choose less invasive options, although establishing the efficacy of high-intensity focused ultrasound requires longer follow-up periods. Technological advances, together with cultural and economic factors, have caused a dramatic shift from traditional open, radical prostatectomy to minimally invasive techniques. High-intensity focused ultrasound is likely to play a significant role in the future of oncology practice.


Abbreviations & Acronyms
ASTRO =

American Society for Therapeutic Radiology and Oncology

BDFS =

biochemical disease-free survival

BNC =

bladder neck contracture

CT =

computed tomography

EBRT =

external beam radiation therapy

HIFU =

high-intensity focused ultrasound

MRI =

magnetic resonance imaging

PSA =

prostate-specific antigen

RPx =

radical prostatectomy

TCM =

tissue change monitor

TURP =

transurethral resection of the prostate

UTI =

urinary tract infections

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

Prostate cancer is the most frequently diagnosed cancer in men, in both the USA and Europe.1,2 It represents the second most common cause of cancer-related death in the USA and the third most common cause in Europe.1,2 The incidence of prostate cancer has increased worldwide, even in countries that have historically had a low incidence of prostate cancer, such as Japan.3 With the exponential aging of the population and the increasing life expectancy, especially in developed countries, the burden as a result of prostate cancer is expected to increase dramatically in the future.

Technological advances and their implementation in medicine have increased the treatment options in oncological urology. Established options for patients with localized prostate cancer include active surveillance, radical prostatectomy, brachytherapy, external-beam radiation, cryotherapy and hormonal therapy.4–10

Recently, however, the armamentarium for localized prostate cancer has expanded to include minimally invasive options, such as HIFU. The goal of this method is to provide similar cure rates to traditional therapies with fewer side-effects. The HIFU technique has been studied for 50 years, but recent technological developments have expanded its use for tumors of the liver, prostate and other sites.11–15 HIFU therapy is based on the delivery of the energy required to raise the tissue temperature to a cytotoxic level fast enough to prevent the tissue vasculature from having a significant effect on the extent of cell death.

Over the past 15 years, more than 30 000 prostate HIFU treatments have been carried out, mainly in Europe and Japan, but also throughout the world, including the USA (under an investigational device-exception protocol approved by the US Food and Drug Administration). In 2011, two transrectal HIFU devices became available on the market, namely Ablatherm (EDAP-TMS, Lyon, France) and Sonablate (FOCUS Surgery, Indianapolis, IN, USA), which differ significantly in technology, installed units, number of treatments carried out, scientific evaluation and publications.16–18 Since 1996, HIFU has been used for the treatment of patients with primary localized prostate cancer and salvage therapy for recurrence after radiation (Table 1).19–38 The recent use of focal therapy in specific patients with early-stage localized prostate cancer and salvage therapy in patients with recurrence of vesico-urethral anastomotic lesions after radical prostatectomy has been reported (Table 1).39–44

Table 1.  Indications of HIFU for prostate cancer
Primary HIFU:1. Whole grand treatment
2. Focal ablation
Salvage HIFU:1. Recurrence after radiation therapy
2. Recurrence at the vesico-urethral anastomotic lesion after radical prostatectomy

The present article introduces the principles of HIFU, and its history and development from a technical viewpoint. Furthermore, the clinical outcomes of current HIFU applications in the treatment of prostate cancer are reviewed.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

A MEDLINE search was carried out using the terms “HIFU” and “prostate cancer.” Only original articles were included; review articles and letters were excluded. An additional, more selective search was then carried out to identify the largest case series reported from each medical center with the purpose of eliminating population overlapping. Studies carried out on more than 30 patients were eligible for inclusion. Studies that provided clinical outcomes and treatment-related complications were sought for the present review.

The comparison methodology was based on different criteria for each category of outcomes, and it was also dependent on the available evidence. The criteria used for longer-term outcomes were the overall BDFS by ASTRO (three consecutive increases in post-treatment PSA after a nadir has been achieved), Phoenix-ASTRO (2.0 ng/mL or higher elevation from the nadir and harbored viable tumor cells as confirmed by prostate biopsy) or Stuttgart's definitions (1.2 ng/mL or higher elevation from the nadir and harbored viable tumor cells as confirmed by prostate biopsy).45–47

History

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

The first therapeutic trial of HIFU was carried out in 1942.11 The Fry brothers are credited with the first application of HIFU for the treatment of neurological disorders in humans.12 HIFU was rediscovered for the treatment of tumors in the 1990s, with the refinement of modern technologies in transducer design, mode of energy delivery and real-time imaging. Precise targeting and improved treatment follow-up techniques became available through the use of diagnostic ultrasound scanning and MRI, which paved the way to realize the full potential of HIFU treatment.

The prostate is an ideal target for HIFU because of its placement near the anus at a depth of 1–4 cm from the rectal surface and not being significantly affected by respiration movements. In the early 1990s, patients with benign prostatic hyperplasia were treated by HIFU.48–52 However, the long-term effects showed that HIFU did not have advantages over other standard treatment methods, such as transurethral resection of the prostate.53

The feasibility of HIFU for the treatment of localized prostate cancer was initially confirmed by studies on the treatment of cancerous prostates several days before radical prostatectomy.13,14 These studies helped delineate areas of coagulative necrosis in the treated areas.

HIFU principles

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

HIFU relies on the same principles as conventional ultrasound-based treatments. The time-averaged intensities of typical diagnostic ultrasound (B-mode, pulsed or continuous Doppler) can be up to 720 mW/cm2 according to US Food and Drug Administration regulations.54 In contrast, the intensity of HIFU in the focal region is several orders higher (100–10 000 W/cm2), with peak compression pressures of up to 70 MPa and peak refractional pressures of up to 20 MPa.54

Two main mechanisms are involved in HIFU ablation: a thermal effect and a mechanical effect.54–57 The thermal effect of HIFU is based on heat generation as a result of the absorption of acoustic energy with a rapid elevation of temperature in the local tissue. A tissue temperature elevation of more than 60°C for 1 s will generally lead to instantaneous and irreversible cell death through coagulation necrosis in most tissues, which is the primary mechanism for tumor cell destruction in HIFU therapy. Ultrasound beam focusing results in high intensities at a specific location within a small volume (e.g. approximately 1–3 mm in diameter and 10–17 mm in length), which minimizes the potential for thermal damage to the tissue outside the focal region.54–57 As the thermal mechanism of ultrasound is better understood and its effect is easier to control, it is preferred for tissue ablation.

Mechanical effects induced by HIFU are associated with acoustic pulses only at high intensities, including cavitations, microstreaming and radiation force. Cavitations are defined as the creation or motion of a gas cavity in an acoustic field as a result of alternating compression and expansion of tissue as an ultrasound burst propagates through it.54

Devices

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

The two commercially available devices, namely Ablatherm and Sonablate, were the therapy and imaging transducers incorporated into a treatment head mounted at the end of a transrectal probe.16–18 The existing devices have evolved, and modifications are continually being made to improve treatment accuracy, ease of use and safety. The aim of HIFU is to heat and destroy the cancerous area of the prostate by means of a probe that emits a beam of focused ultrasound. The probe has a cooling balloon around it to protect nearby areas from the high temperature. HIFU is carried out under either spinal or general anesthesia.

Although the fundamental HIFU features of both systems are identical, there are several technical differences between the two devices (Table 2).16–18 In the latest generation of the Ablatherm device, two types of transducers, namely an imaging and a treatment crystal, have been integrated into the same probe with a focal point 45 mm from the crystal. The 3.0-MHz treatment crystal creates an ablation area with a volume ranging from 1.7 × 1.7 × 19 mm (0.05 cc) to 1.7 × 1.7 × 26 mm (0.08 cc), and the 7.5-MHz imaging transducer uses real-time imaging.16,17 The A-mode ultrasound detection system together with the external ultrasound scanner used during the treatment localization phase measure the distance from the rectal wall and ensure that the patient has not moved. This automated real-time safety monitor eliminates the risk of coagulating the rectal wall and makes the procedure less operator dependent.16,17 The treatment with the Ablatherm is carried out with the patient in a right lateral decubitus position (Figs 1,2).

Table 2.  Commercially available HIFU devices for prostate cancer
ModelAblatherm Integrated ImagingSonablate 500 TCM
ManufacturerEDAP-TMS, FranceFocus Surgery, USA
Frequency (MHz)3.04.0
Focusing methodPhased array2 elements mounted back to back
Focus length (mm)4530 and 40
Image guidance (MHz)7.54.0
Probe size (mm)40 × 2230 × 22
Cycle/focus (sec)10 (5 s on/5 s off)6 s (3 s on/3 s off)
Volume/focus (mm)1.7 × 1.7 × 19–26 (0.05–0.08 cc)3 × 3 × 10 (0.09 cc) and 3 × 3 × 12 (0.11 cc)
Real time imagingYesYes
Rectal cooling systemYesYes
Rectal wall Tm measurementYesYes
3-dimentinal imageYesYes
Color Doppler systemNoYes
Safety system1. Automated movement detection system1. Reflectivity Index system
 2. Stacking system
 3. Tissue change monitoring system
Patient positionRight lateral decubitus positionSupine split leg position
image

Figure 1. Procedure setup with the Ablatherm unit. Treatment with the Ablatherm unit is carried out with the patient in a right lateral decubitus position. Courtesy of EDAP Technomed.

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image

Figure 2. Ablatherm views in the linear and sector orientation. The treatment zone covers the gland. The red circles are treated areas and green circles are to be treated. Courtesy of EDAP Technomed.

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The Sonablate device uses a single crystal for both imaging and treatment, and has two crystals that are selected by the operator according to the size of the prostate: 3.0 × 3.0 × 10 mm (0.09 cc) and 3.0 × 3.0 × 12 mm (0.11 cc) in diameter for a split beam with 30- and 40-mm focal length probes.18 An operating frequency of 4 MHz has been determined to provide both sufficient image quality and effective treatment, and it enables real-time imaging, which is used to detect patient movement. Many improvements and newly developed functions have been added to the device to shorten operation time and improve clinical outcome. The cycle was shortened from 16 s to 6 s per focus lesion. The angle was widened from 70° to 90°. Each volume was enlarged from 2.0 × 2.0 × 10 mm (0.04 cc) to 3.0 × 3.0 × 12 mm (0.11 cc). The cooling system was changed from manual to an automatic and continuous system from Sonablate 200. A color Doppler system was added to detect the neurovascular bundle. Sonablate incorporates additional safety features: reflectivity measurement, stacking and TCM systems.18 Analysis of reflected ultrasound signals and comparison with images taken before the commencement of therapy can aid in the detection of tissue changes resulting from higher temperature. If significant reflectivity index changes are observed in a region, the device will automatically pause until sufficient energy has dissipated before the therapy resumes. Stacking and TCM systems were added in Sonablate version 4 and TCM devices.18,58 The stacking system can refine the treatment plan at any time before or during the procedure. The TCM system quantifies tissue changes based on a comparison of radio frequency ultrasound pulse-echo signals at each treatment site, and can monitor the temperature of each lesion according to color change.58 The fifth generation HIFU device, Sonablate 500 TCM, has been used for treating patients with prostate cancer since 2007 (Table 2). The treatment with Sonablate is carried out with the patient in a supine, split leg position (Figs 3,4).

image

Figure 3. Procedure setup with Sonablate 500 TCM Unit. Treatment with Sonablate TCM is carried out with the patient in a supine, split leg position.

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image

Figure 4. Sonablate views in the sector and linear orientation. The red box represents the planned treatment area with the vertical red lines being the exact target. The orange, yellow and green shaded areas represent the treated areas. In the sector view, the treatment box can be accurately controlled to aim HIFU just at the lateral edge of the gland. In the linear view, the treatment box is adjusted from the apex to the base of the prostate.

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Primary HIFU in localized prostate cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

Clinical outcome

The first experience with the use of HIFU for the treatment of prostate cancer was reported in 1996 by Gelet et al.19 In that study, 14 men who had stage T1 or T2 disease and were unsuitable for radical surgery were treated with HIFU using the Ablatherm device. Half of the patients achieved a serum PSA concentration <4 ng/mL and negative prostate biopsies. However, complications, including three rectal burns, were reported in nine of the 14 patients (64%) in this pilot trial. Table 3 summarizes the largest clinical series reported and the outcomes achieved with both the Ablatherm and Sonablate HIFU devices, mainly for the primary treatment of localized prostate cancer.19–33

Table 3.  Summary of high-intensity focused ultrasound clinical outcome of focal therapy
AuthorStudy periodHIFU deviceNo. patientsInclusion criteria Stage/Gleason/PSAResponse criteria5-year BDFS (%) Total/Low/Int/HighNegative biopsy ratesFollow up (months)
  1. †71% and ‡91% of patients received combined TURP just before HIFU; §PSA < 0.5 ng/mL and negative biopsy was categorized no evidence of disease. H, HIFU only, P + H, TURP just before HIFU + HIFU, H + P, HIFU and TURP just after HIFU. Bx, biopsy; Gleason, Gleason score; High, high-risk group; Int, intermediate–risk group; Low, low-risk group; NR, not reported.

Crouzet et al.201993–2010Ablatherm803T1-2/2–10/≤50Phoenix?/82/72/6878%43 ± 33
Chaussy et al.211998–2003Ablatherm96 (H)T1-2/2–10/≤15ASTRO84/–/–/–88%19 + 12 (3–46)
175 (P + H)80/–/–/–82%11 + 6 (3–27)
Blana et al.221997–2003Ablatherm163 (P + H)T1-2/≤7/≤20Phoenix75/77/71/–93%58 ± 14 (36–103)
Vallancien et al.231999–2001Ablatherm30 (P + H)–/4−7/≤10Neg. Bx. rateNR87%20 (3–38)
Misraïet al.242001–2006Ablatherm119 (P + H)T1-2/4–8/≤25Phoenix30/–/–/–30%46 (12–82)
Lee et al.252004–2005Ablatherm58 (P + H)T1-2/2–10/<30ASTRO?/85/77/47 (1.5 y)NR14 ± 4 (6–21)
Ripert et al.262005–2010Ablatherm53T1-2/≤7/≤15Stuttgart22/–/–/–40%45 ± 16 (16–71)
Uchida et al.281999–2007Sonablate517T1-3/2–10/<50Phoenix72/84/64/4581%24 (2–88)
Sumitomo et al.292002–2010Sonablate65 (H)T1-3/2–10/<50Phoenix61/–/–/–79%83%43 (24–68)
64 (H + P)75/–/–/–37 (30–47)
Inoue et al.302003–2010Sonablate139T1-2/–/≤100Phoenix78/91/81/6191%36 (12–84)
Mearini et al.312004–2007Sonablate163T1-3/2–10/≤10Phoenix72/86/80/56 (3y)66%24 (12–41)
Fujisue et al.322004–2009Sonablate114T1-2/2–10/<50Phoenix71/–/–/–74%.42 (12–70)
Ahmed et al.332005–2007Sonablate172T1-3/–/–PSA and Bx§92/–/–/–NR12 (5–25)

Blana et al. reported a negative biopsy rate of 86.4% among 140 patients.22 Eight-year actuarial survival data were also presented; overall survival and cancer-specific survival rates were 83% and 98%, respectively. The 5-year disease-free survival rate was 66%. A total of 15% of patients required rescue adjuvant treatment. The 5-year biochemical failure-free rate was 77%. The long-term results of a European multicenter study were published in 2010 by Crouzet et al., who presented data representing 14 years of experience using the Ablatherm device at six centers across France.20 This report on 803 consecutively treated patients, which includes a minimum of 2 years of post-treatment PSA data, is the largest study on the cancer-specific outcomes of HIFU treatment to date. Nearly three-quarters of the patients included in the study underwent prostate biopsy, of which 78% had no evidence of cancer.20 Similarly, the 5- and 7-year freedom from biochemical recurrence (according to Phoenix criteria) was 83–75% for low-risk patients, 72–63% for intermediate-risk patients and 68–62% for high-risk patients.20 In contrast, Misraïet al. reported a 5-year biochemical disease-free survival rate of 30% among 119 treatment-naive patients.24 The median PSA nadir was 1.2 ng/mL and was achieved after a mean time of 12 months, which is a higher value and longer period than those reported in other studies. In most cases, the PSA nadir is reached within 6 months after HIFU treatment.19–23,27–35 Of the 84 patients who had control biopsies, 55 (65%) had positive biopsies. Although the reasons for these discrepancies are not known, they suggest that further examination of treatment and/or technical problems is necessary. In addition, Ripert et al. reported that just 22% of the patients treated with the Ablatherm device showed biochemical disease-free survival according to the Stuttgart definition (an increase in PSA level of 1.2 ng/mL above the nadir).26 In 12 of 20 patients (60%) who underwent control biopsies, the results were positive. However, this study was limited by the small population size.

The Sonablate device has been used mainly in Japan and, just recently, in the UK and Canada. The first trial using the Sonablate device was carried out by Uchida et al. in January 1999.27 In the Sonablate treatment group, midterm follow up (2–7 years) has shown that the biochemical disease-free survival rates by Phoenix criteria remain 71–78%, and the negative biopsy rate ranges from 66% to 91%.27–33 In the low-, intermediate- and high-risk groups, biochemical disease-free rates varied as follows: 84–91%, 64–81% and 45–61%, respectively. Uchida et al. published data covering 8 years of experience using Sonablate in a report on 517 consecutively treated patients, with a minimum of 2 years of post-treatment PSA data; this is the largest study of its kind.28 Nearly three-quarters of the patients included in the study underwent prostate biopsy, of which 78% had no evidence of cancer. The 5-year biochemical disease-free rate (according to Phoenix criteria) was 72%, 84% for low-risk patients, 64% for intermediate-risk patients and 45% for high-risk patients. The percentage of negative biopsies after HIFU was 81%.28

Prognostic parameters after HIFU

Many studies have shown that the PSA nadir significantly predicts the success of HIFU treatment.59,60 Uchida et al. showed unfavorable outcomes when the PSA nadir was greater than 0.2 ng/mL.59 This finding was confirmed by Ganzer et al., who reported that when the PSA nadir was below 0.2 ng/mL, the treatment failure rate was 4.5%, whereas it increased to 30.4% and 100% when the PSA nadir was 0.21–1 ng/mL and greater than 1 ng/mL, respectively.60 In most cases, the PSA nadir is reached within 6 months after the HIFU treatment, thus enabling early feedback on treatment efficacy. If an adequate PSA nadir is not attained within 6 months, HIFU is probably failing, and an additional HIFU or a change in therapy might be considered.

Contraindications

Certain relative or absolute contraindications need to be excluded before considering HIFU treatment.20,28 Accessibility is a major consideration for HIFU, because it is applied through a transrectal approach. Pathological or anatomical conditions that might impair the introduction of the probe through the anus or its displacement in the rectum are potential contraindications. Therefore, local rectal conditions should be carefully evaluated during the rectal examination, if possible, or at least by transrectal ultrasonography.

Major calcifications should be considered as possible contraindications, unless they can be removed by TURP. TURP is commonly carried out before HIFU if the patient has prostatic calcifications larger than 1.0 cm in diameter, to enable the HIFU treatment. The volume of the prostate is a major limitation with regard to the commercially available HIFU devices, but not the technology itself. Therefore, prostate volumes greater than 40 cc should be excluded because of difficult access to the anterior peripheral zone. Many options can reduce prostatic volume. The use of hormonal deprivation and TURP before HIFU can be helpful.

Complications

The most common complications associated with the HIFU procedure include urethral stricture or BNC, urinary retention, UTI, epididymitis, urinary incontinence, recto-urethral fistula and erectile dysfunction (Table 4).17,21–23,25,28–33 No significant differences in complications between the Ablatherm and Sonablate treatment groups have been reported.

Table 4.  Complications of high-intensity focused ultrasound
AuthorHIFU devicesNo. patientsUrinary retentionUS or BNCUTI or EpididymitisIncontinenceRecto-urethral fistulaErectile dysfunction
  1. †71% and ‡91% patients received combined TURP just before HIFU. High, high-risk group; Int, intermediate-risk group; Low, low-risk group; Neg. Bx. rate, negative prostate biopsy rate; NR, not reported; US, urethral stricture.

Poissonnier et al.17Ablatherm227NR13213039
Chaussy et al.21Ablatherm96 (H)NR27.147.915.4040
 175 (P + H)NR811.46.9031.8
Blana et al.22Ablatherm163 (P + H)N.R24.57.88.0044.7
Vallancien et al.23Ablatherm30 (P + H)60103032
Lee et al.25Ablatherm58 (P + H)17.26.90160NR
Uchida et al.28Sonablate51713.217.14.40.80.928.9
Sumitomo et al.29Sonablate65 (H)10.920.97.80.80.853.4
 64 (H + P)3.96.90.81.60.830.2
Inoue et al.30Sonablate13922.38.27.511.5037
Mearini et al.32Sonablate163NR150160.6NR
Fujise et al.32Sonablate11412.341.2017.5018.4
Ahmed et al.33Sonablate172NR30.27.68.1033.3

A common and usually transient complication is acute urinary retention, which has been reported in 3.9–22.3% of cases. In the immediate postoperative course, prostatic edema induced by the heating effect of the HIFU treatment increases the volume of the prostate to up to 20–30% of its initial volume. The urethra is thus compressed by the edema, which causes obstructive symptoms and subsequent urinary retention in some cases. Re-catheterization or self-catheterization is usually applied in these patients. TURP just before or after the HIFU treatment has been shown to significantly decrease the retention rate and catheterization period.21–23,25,29 Combined treatment with TURP and HIFU has been associated with similar efficacy, reduced catheter time, and significant reductions in morbidity and retreatment rates compared with HIFU alone.

Another frequent complication is urethral stricture/BNC in 0–41.2% of patients. These patients were treated with intermittent dilation, and some patients required TURP or internal urethrotomy. The use of TURP just before or after HIFU treatment has been shown to reduce the rate of urethral stricture in both Ablatherm- and Sonablate-treated patients.21–23,25,29

Urinary infection (epididymitis) was reported to occur in 0–47.9% of HIFU patients and should be treated with the appropriate antibiotics. Urinary incontinence was reported in 0.8–17.5% of patients; however, its incidence decreased with the use of the latest generation of HIFU devices, owing to a better definition of the prostate apex and technical improvements. The incidence of recto-urethral fistulas has also decreased significantly with the improvement of devices and treatment procedures. In a large series study of HIFU patients, recto-urethral fistulas were reported to occur in 0.6–0.9% of patients. In fact, most fistulas occurred in the early stages of treatment. In addition, safety features, including the continuous cooling system and rectal wall recognition, have dramatically decreased the incidence of fistulas. The rate of incidence of erectile dysfunction was reported to range from 18.4% to 53.4%, which is less than that observed with other modalities, such as radical prostatectomy or radiation therapy.21–23,25,28–33,61 Less common complications included chronic perineal pain, hematospermia and perineal edema.21–23,25,28–33 Repeat treatment with HIFU is associated with much higher complication rates than single treatments.31,62

Focal HIFU

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

Data from active surveillance studies suggest that 30% of patients require definitive treatment within 5 years for either progression or choice. Focal therapy is emerging as an alternative to active surveillance for the management of low-risk prostate cancer in carefully selected patients. The ideal patient group and an accurate method to localize cancer in the prostate are yet to be agreed on, and the optimal ablative technique is unknown. However, HIFU has enabled precision ablation to be delivered to almost millimeter accuracy.

Early studies evaluating focal therapy have reported a lower morbidity with acceptable short- to medium-term cancer control rates (Table 5).39–42 Muto et al. reported on 29 patients who underwent focal HIFU with a biochemical disease-free survival rate of 83.3% for patients at low-risk and 53.6% for patients at intermediate-risk after 2 years. The rate of negative biopsies was 76.5% at 12 months in 17 patients. The focal treatment in this series consisted of treating the entire peripheral zone of both prostate lobes and the transitional area of the diseased lobe, which is referred to as the “chair” treatment.39

Table 5.  Summary of high-intensity focused ultrasound clinical outcome of focal therapy
AuthorStudy periodHIFU deviceNo. patientsResponse criteriaTreatment typeBDFR Total/Low/IntNegative biopsy ratesFollow up (months)
  • Total peripheral zone and a half portion of transition zone. Ex, excluded; Int, intermediate -risk group; Low, low-risk group; NR, not reported.

Muto et al.392003–2006Sonablate29Phoenix ASTROChair type–/83/54 (2 years)77%32 (9–45)
El Fegoun et al.412007–2010Ablatherm12Phoenix ASTROHemi-ablation90/–/– (5 years)90%127 (90–133)
Ahmed et al.402008–2011Sonablate20NRHemi-ablationNR89%NR
Uchida et al.422007–2011Sonablate16Phoenix ASTROEx-total urethra84/–/– (5y)85%36 (10–61)

El Fegoun et al. treated 12 patients with localized prostate cancer using the Ablatherm device between 1997 and 2000. Hemi-ablation of the prostate was carried out, and recurrence-free survival was 90% at 5 years and 38% at 10 years; cancer-specific survival still remained 100%. Control biopsies at 1 year were negative in 91% (11/12) of patients.41

Armed et al. reported that return of erections sufficient for penetrative sex occurred in 95% of men (19 of 20), and 89% of men achieved the trifecta status of pad-free, leak-free continence, erections sufficient for intercourse and cancer control at 12 months.40

Recently, three eligible criteria for focal therapy were reported (Table 6), but more data from large trials on the safety and efficacy of focal therapy are required before this approach can be recommended in men with prostate cancer.63–65

Table 6.  Eligible criteria for focal therapy
 Bostwick DG et al. (2006)62Eggener SE et al. (2007)63Lecornet E et al. (2010)64
Life expectancy>5 years>5 years
Clinical elements   
 StageT1–3N0M0T1–2aN0M0T1–2N0M0
 PSA<15 ng/mL<10 ng/mL<15 ng/mL
 PSA density<0.15 ng/mL/cc
 PSA velocity<2 ng/mL/year
Prostate biopsy   
 No. cores3–D mapping≥12 coresTemplate transperineal
 Gleason scoreNo Gleason 4 or 5≤7
 Maximum tumor volume %/core(e.g. 20%)
 Maximum tumor diameter/biopsy(e.g. 7 mm)≤3 mm
 Tumor volume %/biopsy(e.g. 33%)
Image   
 Maximum tumor diameter(e.g. 12 mm)
 Maximum diameter with capsule(e.g. 10 mm)

Other minimally invasive therapies, such as cryo- or photodynamic therapy, are technically adequate for partial treatment as well, but the disadvantages of perineal, tissue and cancer perforating approaches cannot compete with the non-invasive approach of transrectal HIFU.66–68

Focal therapy appears to be a logical alternative to radical treatment and active surveillance, potentially combining cancer control and minimal morbidity. Early studies evaluating focal therapy have found a lower side-effect profile with acceptable short- to median-term cancer control rates. If these promising results are confirmed in future prospective trials, focal therapy could start to challenge the current standard of care.

Salvage HIFU after radiation therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

Men who undergo EBRT or interstitial brachytherapy for clinically localized prostate cancer have a 20–30% chance of experiencing PSA failure.69–72

Patients with biochemical recurrence after radiation therapy might experience a local recurrence, metastatic disease, or both. Ruling out distant metastases is difficult as a result of the poor sensitivity of bone scanning, abdominal CT or pelvic MRI for identifying bone and lymph node involvement. Patients thought to have localized recurrence after radiation therapy have historically been subjected to salvage radical prostatectomy, androgen ablation therapy or observation. These methods show varying degrees of success and toxicity that are aptly summarized in several recent systematic reviews.73–78 These reviews report that surgery, brachytherapy and cryotherapy showed cancer control (estimated 5-year BDFS) rates of 31–83%, 20–89% and 18–74% (1 series at 5 years, another series at 1–2 years), respectively. However, average fistula rates with these three therapies were 4.7%, 3.4% and 2.5%, respectively. UTI rates varied with the method used and were 17–67%, 0–31% and 4.3–96% for surgery, brachytherapy and cryotherapy, respectively.73–78

The use of salvage HIFU in patients with recurrence after radiation therapy has been reported (Table 7).35–37 The first report of salvage HIFU described the use of the Ablatherm device in 167 patients.34,35 Local cancer control was achieved, and negative biopsy results were reported in 122 (73%) patients with a mean (range) follow-up period of 18.1 months (range 3–121). The actual 3-year progression-free survival rates were 53%, 42% and 25% for low-, intermediate- and high-risk patients, respectively. Multivariate analysis showed that the risk ratio for intermediate- and high-risk patients, and the use of androgen-deprivation therapy were independent predictive risk factors. Recently, Zacharakis et al. reported that 71% of men treated using the Sonablate 500 HIFU device had no evidence of disease after a mean follow-up period of 7 months.36 Of those patients reaching 6- and 9-month follow ups, half achieved and maintained a PSA nadir of 0.2 ng/mL. Although 74% of men at 3 months achieved a PSA level of <0.5 ng/mL, those who did not achieve a level lower than 0.2 ng/mL experienced biochemical failure at the subsequent follow-up examination. All patients in these two series experienced recurrence after EBRT. Recently, Uchida et al. reported on the treatment of patients with recurrence after EBRT (8 patients), brachytherapy (7 patients: 6 patients using high-dose Ir192 brachytherapy and 1 using low-dose Au98 brachytherapy) or proton therapy (5 patients).37 The patients had presumed organ-confined, recurrent disease and were treated with salvage HIFU. Patients in the low- and intermediate-risk groups showed biochemical disease-free survival rates of 100% and 86%, respectively, but patients in the high-risk group showed only a 14% survival rate.37 These results show that HIFU is a good salvage treatment choice in the low- and intermediate-risk groups, in which findings are similar to those in primary cases using HIFU treatment.

Table 7.  Summary of salvage high-intensity focused ultrasound for patients with recurrence after radiation therapy
AuthorStudy periodHIFU deviceNo. patientsMedian Rd doseResponse criteriaBDFR (%) Total/Low/Int/HighNegative biopsy ratesFollow up (months)
  • Including 14 patients after external beam radiation therapy, five patients after brachytherapy and three patients after proton therapy. Rd., radiation therapy; Low, low-risk group; Int, intermediate-risk group; High, high-risk group; NR, not reported.

Murat et al.351995–2006Ablatherm16770 GyPhoenix ASTRO–/53/42/25 (3 years)73%18 (3–121)
Zacharakis et al.362005–2007Sonablate3166–70 GyNR71/–/–/–NR7 (3–24)
Uchida et al.372002–2010Sonablate2266–70 GyPhoenix ASTRO52/100/86/14 (5 years)92%24 (1–83)

Complications after salvage HIFU are reported to be much higher than after primary HIFU (Table 8).35–37 Urinary incontinence is the most frequent complication after salvage HIFU. Murat et al. reported that urinary incontinence was experienced by 49.5% of patients, and artificial urinary sphincter implantation was required in 11%.35

Table 8.  Complications of salvage high-intensity focused ultrasound for patients with recurrence after radiation therapy
AuthorHIFU devicesNo. patientsBOO or USUTI or acute epididymitisUrinary incontinence (artificial sphincter)Anal incontinenceRecto-urethral fistula
  1. BOO, bladder outlet obstruction; US, urethral stricture.

Murat et al.35Ablatherm16720–/–49.5 (11)1.23
Zacharakis et al.36Sonablate313626/3.17 (0)03
Uchida et al.37Sonablate22184.5/4.518 (0)04.5

In a Sonablate-treated group, Uchida et al. reported the occurrence of grade I urinary incontinence in 10% of patients, which is a higher rate than that found in primary cases, but lower than rates reported in other studies.37 In several studies, recto-urethral fistula was noted as a complication after salvage HIFU in 3% of the Ablatherm group and in 7% of the Sonablate group.35–37 Ahmed et al. reported that the incidence of recto-urethral fistula after salvage HIFU was higher after the failure of combined brachytherapy and EBRT.38 These rates are all higher than those found in primary HIFU. This could be attributed to poor tissue viability and poor periprostatic blood supply after previous radiation therapy, which might preclude effective tissue repair. Careful patient selection and avoidance of rectal diagnostic biopsies might also minimize this risk. Recently, Berge et al. reported on the quality of life status after salvage HIFU and suggested that the health-related quality of life outcomes after salvage HIFU therapy in patients with recurrence after radiation therapy are associated with a clinically significant reduction in urinary and sexual function.79

At present, patients with stage T1-2N0M0 organ-confined prostate cancer with a Gleason score ≤7, a PSA level ≤20 ng/mL and histologically verified recurrence of adenocarcinoma on prostate needle biopsy after radiotherapy are good candidates for salvage HIFU. In addition, eligible patients should show normal rectal anatomy and mucosa, and no evidence of metastatic disease on bone scan, CT and/or MRI.

Clearly, longer-term follow up and prospective multicenter randomized controlled trials are required to assess whether these encouraging results are truly equivalent to those observed after other salvage treatments, such as surgery, brachytherapy and cryotherapy.

Salvage HIFU for recurrence after radical prostatectomy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

RPx is the gold-standard treatment for organ-confined prostate cancer. Currently, the long-term recurrence rates after RPx are in the range of 17–29%.80,81 PSA elevation implies local recurrence, rather than occult metastasis, in the absence of identifiable metastatic disease by chest X-ray photograph, CT, MRI and/or bone scintigraphy. Early detection and treatment of local recurrence increases the possibility of cure, in addition to preventing the use of unnecessary hormonal therapy. At present, radiation therapy is widely used as a salvage therapy after RPx.82–85 However, this therapy is time-consuming and might not be tolerated by some patients with poor performance status. Two current reports describe the use of salvage HIFU after recurrence RPx (Table 9).43,44 Hayashi et al. reported the use of HIFU in four patients with biochemical failure after RPx.43 However, in this study, tumor masses were not identified by TRUS imaging, and HIFU treatments in the vesico-urethral anastomotic lesion were carried out based on PSA elevations of more than 0.2 ng/mL after RPx. The median PSA levels before and after HIFU were 0.555 ng/mL and 0.054 ng/mL, respectively. Murota et al. reported on four cases of patients with biopsy-proven local recurrence of prostrate carcinoma in the vesico-urethral anastomotic lesion after RPx.44 In all the patients on whom biopsies were carried out, HIFU was shown to cause coagulation necrosis and fibrosis at the anastomotic lesion safely and within a short treatment time. Because the HIFU procedure takes just 10–20 min under local anesthesia, patients are able to go home in a few hours. The minimally invasive nature of HIFU provides a broader opportunity for local treatment, even in patients who are not candidates for salvage radiation therapy.

Table 9.  Summary of salvage high-intensity focused ultrasound for patients with recurrence after radical prostatectomy
AuthorHIFU deviceNo. patientsPeriod after RPxSalvage Rd after RPxPSA before HIFU (ng/mL)Anastomotic site biopsy before HIFUNo. patients after HIFU (PSA <0.2 ng/mL)Negative biopsy ratesFollow up (months)
  1. G, Gleason; mo, months; ND, not determined; Rd, radiation therapy.

Hayashi et al.43Sonablate415–130 moNone0.318–0.898ND3/4 (75%)ND7–18
Murota et al.44Sonablate460–252 mo3/4 Pts4.3 (1.38–10.4)G6–92/4 (50%)3/3 (100%)18 (6–31)

The European Association of Urology guidelines defines relapse after local therapy as PSA values >0.2 ng/mL after radical prostatectomy and >2 ng/mL above the nadir after radiation therapy. Therapy for PSA relapse after radical prostatectomy includes salvage radiation therapy for PSA levels <0.5 ng/mL and salvage radical prostatectomy or cryoablation of the prostate in radiation failures is recommended.86 HIFU might be an alternative salvage therapy for patients with local recurrence after RPx. Salvage HIFU for patients with local recurrence after radical prostatectomy is feasible, even when patients have previously received salvage radiation therapy. However, a larger number of cases will be needed to further study the effectiveness of HIFU and to evaluate any possible adverse effects.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References

The currently accepted curative treatment approaches for localized prostate cancer depend on patient and tumor factors, and consist of surgery, radiotherapy and brachytherapy. Other approaches include hormonal therapy and active surveillance. Although no randomized controlled trials are underway or have been carried out to compare these options, each has evolved as a standard of care based on extended long-term patient follow up of greater than 7–10 years in well-designed prospective clinical studies.

The decision to use HIFU rather than surgery is often made on the basis of patient factors, such as patient preference, age, comorbid conditions and the availability of surgical expertise. For many reasons, HIFU appears highly attractive as a minimally invasive treatment for localized prostate cancer. HIFU treatment requires no incision or puncture, it is bloodless, can be carried out on an outpatient basis, and is repeatable. The clinical outcome of HIFU treatment has significantly improved over the years as a result of technical, imaging and device improvements.

There is a wide choice of treatments for organ-confined prostate cancer. In the case of HIFU, a longer follow-up period is needed before the efficacy of this treatment modality can be established. HIFU is an attractive choice for men willing to choose less invasive options. Technological advances, as well as cultural and economic factors, have caused a dramatic shift from traditional open, radical prostatectomy to minimally invasive techniques.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. History
  6. HIFU principles
  7. Devices
  8. Primary HIFU in localized prostate cancer
  9. Focal HIFU
  10. Salvage HIFU after radiation therapy
  11. Salvage HIFU for recurrence after radical prostatectomy
  12. Conclusions
  13. Acknowledgments
  14. Conflict of interest
  15. References