Clinical Outcome of High-Intensity Focused Ultrasound for the Treatment of Localized Prostate Cancer: 5-Years Experience

Toyoaki Uchida, Hiroshi Ohkusa, Hideyuki Yamashita, Yoshihiro Nagata Department of Urology, Tokai University Hachioji Hospital, 1838 Ishikawa-machi, Hachioji, Tokyo 192-0032, Japan

Objectives

Prostate cancer is the most common malignancy in men and second leading cause of death due to cancer in the United States. Recently, a number of alternative less invasive treatments have been developed to treat localized prostate cancer. High-intensity focused ultrasound (HIFU) is a noninvasive treatment that induces complete coagulative necrosis of a tumor at depth through the intact skin. We evaluated a biochemical diseasefree survival, predictors of clinical outcome and morbidity for localized prostate cancer treated with HIFU.

Materials and Methods

A total of 152 HIFU treatments in 132 consecutive patients with stage T1c-2bN0M localized prostate cancer have undergone using Sonablate® HIFU device (Focus Surgery, Inc., Indianapolis, IN, USA). All patients followed more than 12 months. Disease freedom was defined according to the criteria recommended by the American Society for Therapeutic Radiology and Oncology consensus definition. The median age, serum PSA and follow-up were 70 years (range 45-87), 10.5 ng/ml (range 3.39-89.6) and 17.0 months (range 3 to 63). An average treatment time was 171 minutes (range 51-390). No adjuvant therapy was given after HIFU therapy.

Results

The biochemical disease-free survival rates by Kaplan Meier curves at 1, 3 and 5 years were in 83%, 69% and 69% of the patients. The biochemical disease-free survival rates at 3 years for patients whose pretreatment PSA less than 10 ng/ml, 10.01 to 20.0, 20.01- 30.0 and more than 30 ng/ml were 88%, 67%, 61% & and 27% (logrank test, p<0.0001), respectively. The biochemical disease-free survival rates at 3 years for patients with low, intermediate and high risk group were 85%, 71% and 47% (p=0.0004), respectively. Final follow-up prostate biopsies showed 85% (112/132) of the patients to be cancer free. On multivariate analysis preoperative PSA (hazard ratio 1.061; 95%CI 1.040-1.083; p<0.0001) was a significant independent predictor of clinical outcome but age, stage, Gleason score, prostatic volume and neoadjuvant hormone therapy were not statistically significant for prognosis. Thirty-three (25%) patients developed a urethral stricture, 7 (5%) and 3 (2%) patients complained epididymitis and retrograde ejaculation. Four patients underwent transurethral resection of the prostate for prolonged urinary retention due to urethral stricture or bladder neck obstruction. One (1%) of each patient showed grade 1 incontinence for 1 month after HIFU and a rectourethral fistula. Twenty-two% (7/32) patients complained postoperative erectile dysfunction. Two of 7 erectile dysfunction patients were recovered with sildenafil citrate.

Conclusions

HIFU could noninvasively induce complete coagulative necrosis of the prostate without requiring surgical exposure or insertion of instruments into the lesion. Moreover, HIFU treatment is repeatable and, if needed, alternative options remain practicable. HIFU therapy appears to be safe and efficacious minimally invasive therapy for localized prostate cancer patients and pretreatment serum PSA was a useful predictor of clinical outcome.

High Intensity Focused Ultrasound for Prostate Cancer

Clinical Results and Technological Evolution

John C. Rewcastle, Ph.D.

Department of Radiology

University of Calgary, Alberta, Canada

Prostate cancer is responsible for 9% of cancer related death in European men (Black et al 1997) and it is estimated that each year there will be approximately 85,000 new cases of prostate cancer diagnosed in the European Union (Jensen et al 1990).

Strategies for managing prostate cancer include deferred treatment (watchful waiting), radical prostatectomy, definitive radiation therapy and hormone therapy. Deferred treatment is utilized in patients who are expected to die of causes other than prostate cancer based on the age and health of the patient and the characteristics of their disease. Hormone therapy can delay but not stop the progression of prostate cancer and is used when the cancer has spread beyond the prostate. Definitive local therapy is employed when the disease is thought to be clinically localized and has the potential of decreasing the life of patient.

There currently exists no agreement as to the ideal therapy for localized prostate cancer. Radical prostatectomy is the ideal therapy insofar as cancer control is concerned for truly localized prostate cancer. However, it is associated with significant morbidities and quality of life impact and there is no guarantee that the cancer really is completely contained within the prostate. This risk versus reward balance is unacceptable to many physicians and patients and has motivated the development of several minimally invasive therapies including brachytherapy, cryoablation and high intensity focused ultrasound (HIFU).

From the prospective of both the physician and patient the goals of a minimally invasive prostate cancer therapy are to eradicate the local disease, reduce post-operative morbidities, shorten hospital stay and quicken return to daily functions and work. They may also result in a reduction in the overall cost of treating a patient with prostate cancer. Although some of these therapies are relatively new, they are gaining popularity rather quickly and several worldwide experiences have demonstrated that may be able to achieve some or all of these goals.

Brachytherapy is associated with a very short recovery time and little postoperative morbidity. However, as some patient series mature late, onset morbidities are being observed, specifically erectile dysfunction (Raina et al 2003) and full gland cryoablation is associated with high impotence rates (Bahn et al 2002).

Among the novel prostate cancer therapies, HIFU (unique as it is), is in fact noninvasive rather than minimally invasive. It involves no incision. HIFU works by focusing and depositing a large pulse of high-energy ultrasonic waves on a single location. This increases the temperature to a point where the lipids in the cell membrane melt and proteins denature. A reproducible but small volume of ablation is created. Treatment is accomplished by systematically pulsing energy throughout the target volume at different locations until the entire tumor has been ablated. HIFU is a relatively new treatment option that has been investigated at several centers throughout the world, mainly in Europe. This article reviews and compares the published outcomes of HIFU to other prostate cancer therapies. Also, the state of the evolving HIFU technology will be assessed.

HIFU as a therapy for prostate cancer.

When a patient decides on a prostate therapy in concert with his physician several factors are considered principally, efficacy and morbidity. Establishing the efficacy of a novel therapy in relation to established therapies for prostate cancer is an exceedingly difficult task. First off, there exist no prospective, randomized, clinical trials, which compare a novel therapy to an established prostate cancer therapy. As such, one is relegated to comparing published and presented reports of similar groups of patients treated with different therapies. Although such a comparison is inherently flawed due to inevitable variability in patient population, follow-up length, definitions of biochemical disease free survival it does have merit and trends do usually emerge (Katz and Rewcastle, 2003).

Prostate cancer is a slow growing disease and five-year outcomes are generally considered minimally sufficient to definitively evaluate the efficacy of a novel therapy. There exist two such reports for HIFU. In a study of 137 stage T1-T2 patients with a mean PSA of 8.8 ng/ml Gelet et al (2003) found a negative biopsy rate of 81% and 70.1% of patients maintained no biochemical evidence of prostate caner, using the ASTRO definition of biochemical failure (3 successive rises in PSA). Blana et al (2004) treated 146 T1-2, N0, M0 patients with a mean PSA of 7.6 ng/ml and observed a disease free rate (negative biopsy and PSA < 0.4 ng/ml) of 71.5% and a negative biopsy rate of 93.4%. These results are encouraging. For comparative purposes the patient population is as described by Gelet et al could be considered to be between low and moderate risk using the standard definitions of D’Amico (i.e., D’Amico et al 2003). Table 1, modified from Katz and Rewcastle (2003), compares the 5-year biochemical disease free survival rates as published since 1992 for radical prostatectomy, cryoablation, brachytherapy, 3dimensional radiation therapy (3D-CRT) and external beam radiation therapy (XRT) with that published by Gelet et al (2003). Given the patient population, the five-year HIFU results compare favorably to all of these established therapies. It is noteworthy that the results of this patient series can be considered to be a ‘worst case scenario’ as the series includes the first patients ever to undergo HIFU as a therapy for prostate cancer. Further, many of the patients were treated with the original prototype HIFU. Subsequent reports will likely show an improved biochemical control, as proportionally more, or all, patients will have received standardized therapy with a technologically advanced HIFU device.

For in-situ ablations, biopsy provides an excellent surrogate interim therapy evaluation tool. The goal of in-situ ablations is to completely destroy a targeted tissue, in this case the prostate. If successful, subsequent biopsy should show no evidence of disease. Table 2 summarizes studies published in the last 10 years that report negative biopsy rates following brachytherapy, 3-D CRT, XRT, cryoablation and HIFU. To aid in visualization, this analysis is also presented in Figure 1. This figure is, perhaps, the most compelling case for HIFU. The ability of HIFU to locally control prostate appears to be similar if not superior to that of cryoablation, which consistently results in higher negative biopsy rates than any form of radiation therapy.

The other fundamental consideration in assessing a prostate cancer therapy is the morbidity associated with the procedure. Prostate cancer therapy is associated with urinary, rectal and sexual morbidities. Unfortunately, as with efficacy measurement, there is no consistency as to how morbidities are reported. In an attempt to be as fair and complete as possible the literature was surveyed since 1992 and summarized. Table 3 reports the rage of morbidities that have been published following radical prostatectomy, radiation therapy (regardless of delivery method), cryoablation and HIFU.

Impotence is a complicated matter. For all therapies there exists a relatively large range in the reported impotence rates following therapy. The lower end of the reported impotency rate for HIFU is 28%. Although this will need to be substantiated, it is not surprising as there is great accuracy to the geometric volume of HIFU injury that is created. Stopping the therapy abruptly at the lateral margins of the prostate may allow for treatment of only the entire prostate without ablating one or both neurovascular bundles. Any uncompromised neurovascular bundles will be completely untouched and undisturbed during the procedure. This is not possible with most other therapies in which the entire prostate is destroyed. There is manipulation during radical prostatectomy as the nerves are dissected off the prostate and interaction with scattered radiation during. The incontinence rate for HIFU appears to be lower than that of radical prostatectomy but higher than other minimally invasive therapies. This may be due to several factors including the short-term follow-up of most HIFU reports. Incontinence improves with time following prostate cancer intervention. As these data sets mature, it is expected that the incontinence rates will decrease. Rectal injury following HIFU appears to be fundamentally different in nature to that of radical prostatectomy and radiation and more akin to cryoablation. Relatively large minor rectal injury rates are observed following the former two traditional therapies occur with little or no occurrence of rectal fistula formation. First generation technical limitations of both cryoablation and HIFU resulted in initial high fistula rates but they are no longer observed in modern series. Cryoablation, during its first technological iteration was associated with significant rectal fistula formation but this rate has now dropped to < 0.5% in modern series. The fistula formation rate following HIFU has been reported from 0.5-5% with modern series consistently reporting on the low end of this range. For example, Uchida et al (2004) report a rectal injury rate using the Sonablate®500 of < 0.5%. It is expected that this low fistula rate will be further substantiated in the near future in peer-reviewed publications from multiple institutions.

In summary, there appears to be at least equivalence between the outcomes of standard therapies and those of HIFU. Specifically the results of Gelet et al (2003) and Blana et al (2004) are very encouraging and, for reasons already explained, they should represent the worst HIFU results. Subsequent publications by Gelet and others are expected to should show an improved efficacy further substantiating the role of HIFU. Regarding morbidity, the initial results yield no cause for concern when comparing to other therapies and improvements in technology in concert with procedural standardization should reduce the relatively mild morbidity profile currently observed following HIFU.

Comparison of HIFU technologies

The first commercially available HIFU machine was the Ablatherm® (Edap-Technomed, Lion, France). This is the unit used in the majority of published studies. It utilizes a single

4.0 cm focal length and HIFU crystal to deliver the therapy. Subsequently, Focus Surgery (Indianapolis, IN, USA) developed a second-generation system called the Sonablate 500® that has incorporated several technical advances including a combined therapy / imaging transducer as well as the ability to use multiple focal lengths to increase the resolution of the treatment plan and the quality of the therapy. Initial results with the Sonablate 500® are encouraging in comparison of those reported on with the Ablatherm®.

Preliminary results of HIFU for prostate cancer have measured efficacy in a relatively consistent manner. Both local control (negative biopsies) and PSA nadir measurements (less than 0.5 and 1.0 ng/ml) have been utilized as well as a combination of local control and PSA nadir < 4.0. Table 4 summarizes the patient demographics and results from results from 12 publications and presentations on HIFU. Figure 2 summarizes this data in a simple to understand form. The results observed when patients were treated with the Sonablate 500® device appear superior to those obtained using the Ablatherm® when one investigates the negative biopsy rates, PSA nadir < 1.0 and PSA nadir combined with negative biopsy. The PSA nadir < 0.5 ng/ml rates observed with the Sonablate (64-65%) fall in the middle of the range observed with the Ablatherm® (5579%) suggesting equivalence. Table 5 summarizes the differences in morbidity rates observed with the two different devices. The impotence rate of 28-30% associated with the Sonablate 500® is lower than any achieved with the Ablatherm® (45-100%). The incontinence rate of 0-2% is low in comparison to the range observed when using the Ablatherm® (1-23%). Rectal injury appears to no longer be a significant concern for HIFU. Although early series reported fistula rates as high as 5%, series using the newest technology have observed rates <0.5% for the Sonablate 500® and <0.7% for the Ablatherm®. This vast improvement is due to technical advancements. Overall the morbidity profile produced by the Sonablate appears to be superior to that found following treatment with the Ablatherm®.

One study was excluded from the comparison as it used the ASTRO definition of biochemical disease free status. It would have been appropriate to compare to other reports, all of which use PSA thresholds as definitions of biochemical failure. Uchida et al (2004) followed 85 patients for at least one year and observed that 97, 75, 33 and 0% of patients with a pre-HIFU PSA < 10, 10-20, 20-30 and >30 ng/ml, respectfully remained with no biochemical evidence of recurrence.

Although the experience with the Sonablate 500® is relatively embryonic the efficacy results are compelling with negative biopsy rates ranging form 95-100% and nadir rates equivalent or superior to those achieved with the Ablatherm® device. Further, the morbidity profile of the Sonablate 500® appears to be less severe than that associated with the Ablatherm®. This is, in fact, not surprising due to the technological advancements of the Sonablate 500®. Integrating the imaging and therapy devices to the same unit should eliminate potential inaccuracies of anatomical reference that may result during the removal of the imaging crystal and transrectal insertion of the ablation transducer. There exists no way with the Ablatherm® to verify anatomical reference points prior to treatment. Also, the use of multiple focal lengths during treatment represents a significant technological advantage of the Sonablate 500® device. This allows for an ablation zone to be created that more accurately approximates the prostate anatomy. Combined with the use of true 3-dimensional ultrasound images for the treatment planning process rather than a composite of 2-dimensional images to recreate a three dimensional image should yield a more accurate treatment plan. In concert, these technical advances should yield a better treatment with higher efficacy and lower morbidity. This in fact appears to be the case based upon review of initial results contained in this paper.

Conclusion

The ideal measure of efficacy of a prostate cancer therapy is cancer specific survival. Unfortunately, the follow-up to generate such results is on the order of 20 to 25 years. The urologic community has accepted short-term surrogate markers such as biochemical survival and biopsy results as sufficiently accurate predictors of long-term results. Those observed when HIFU technology is utilized to treat prostate cancer are encouraging at the very least and are associated with a more than acceptable morbidity profile. Research is ongoing and as more and more patients undergo this therapy it is expected that the results will improve solidifying the role of HIFU as a preferred therapy for clinically localized prostate cancer.

Table 1: Efficacy comparison published 5-year biochemical disease free rate following radical prostatectomy (RP), cryoablation (CRYO), Brachytherapy (Brachy), 3-D conformal radiation therapy (3DCRT), external beam radiation therapy (XRT) and HIFU

	RP	CRYO	Brachy	3D-CRT	XRT	HIFU
Low	76-98%	60-92%	78-89%	76-87%	81-86%	70.1-71.4%
Moderate	60-76%	61-89%	66-82%	51-58%	26-60%

Noninvasive Surgery of Prostate Tissue by High Intensity Focused Ultrasound: An Updated Report

N. T. Sanghvi², R. S. Foster¹, R. Bihrle¹, R. Casey³, T. Uchida⁴, M. H. Phillips², J. Syrus², and A. V. Zaitsev², K. W. Marich², F. J. Fry²

Introduction

Since the 1940s., High Intensity Focused Ultrasound (HIFU) has been envisioned as a potential energy modality for the noninvasive surgery of diseased tissue located deep in the body (Lynn et al., 1942; Wall et al., 1951). HIFU has many unique capabilities and qualities, some of which are described here. 1) When used with appropriate peak focal in-situ intensities, HIFU can elevate tissue temperature in the focal zone up to 80-100oC range in a very short exposure duration (1-10 s) while maintaining the intervening tissue temperature at physiologically safe levels. 2) HIFU can be applied externally and contact free to the tissues and organs that are being treated. 3) HIFU can produce sharply demarcated and predictable lesions. The size andshape of each lesion conforms to the ultrasound beam dimensions, site intensity and exposure duration (Fry et al., 1955; Coleman et al., 1985). 4) When individual lesions are combined in a matrix format, one can create a large contiguous lesion of desired size and shape (Maderbacher and Marberger 1995). 5) Since the tissue temperature is raised rapidly, blood perfusion effects are minimized during the HIFU treatment (Robinson and Lele, 1972). 6) The ultrasound energy is non-ionizing and can be applied repeatedly. 7) The HIFU procedure does not require sterile environment therefore it can be performed as an outpatient treatment.

These attractive qualities of HIFU have inspired us to pursue the application of HIFU for the treatment of benign and malignant tumors. This paper addresses the clinical application of HIFU for the treatment of benign prostatic hyperplasia (BPH) using the SB-200 device. The device was developed after extensive safety studies in the animal models, analytical computer simulations and laboratory measurements. Thereafter, under local and national regulatory approvals, several institutions under-took clinical studies to demonstrate efficacy and safety of the device. This paper summarizes the USA multi-site clinical study results that have been obtained after 24 months of HIFU treatment. In addition, the long term study results form the Male Health Centere (THMC), Ontario, Canada and Kitasato School of Medicine, Sagamihara, Japan (Kitasato-study), that utilized indwelling uretheral catheter as a source for heat sink are compared and summarized.

Method and Material

Instrumentation

Transrectal probe

The SB-200 device with a transrectal probe is shown in Fig. 1. The probe has a transducer that incorporates both the ultrasound visualization and HIFU capabilities on the same ceramic crystal operating at 4 MHz. The transducer is fabricated from modified lead titanate material (manufactured by Etalon Inc., Lebanon, IN) with two matching layers of quarter wavelength thickness. The aperture of the transducer is a curved rectangular shape of 30 x 22 mm, which is a cut out piece from a spherical disc of a fixed radius (focal length). The transducer disc is segmented into two electrically separate conducting surfaces. The center circular segment with an 11 mm diameter is used in a pulse-echo mode for imaging of the prostate. While the entire transducer surface is energized with high voltage RF energy during the HIFU treatment. Fig. 2 represents the ultrasound beam configurations during visualization and HIFU modes of operation. The probe tip is protected with a thin latex sheath and is covered with ultrasound gel for acoustic coupling to the rectal wall. The probe tip is filled with degassed circulating coupling water that keeps the rectal wall at a lower desired temperature and also cools the transducer during the treatment mode.

Imaging and therapy planning

The SB-200 provides transverse and longitudinal imaging of the prostate and displays both planes simultaneously on the video monitor as shown in Fig. 3. The mechanical scanning, (as depicted in Fig. 4) of the transducer steers the ultrasound beam during the imaging and treatment modes. The SB-200 software links these two images as shown in Fig. 3 by the trackball and cursors displayed on the images. Thus, positioning the cursor on the longitudinal image can produce a transverse image at that position; similarly, longitudinal image plane position is controlled by the cursor location on the transverse image. A 5 cm³ balloon silicon catheter (16 or 18 French, Dow Corning) is used to localize and position the bladder neck and urethra in the focal zone. The coupling water in the probe tip is used to inflate or deflate the latex rubber sheath. This water standoff aids in positioning the urethra in the focal zone and keeps the rectal wall at a fixed predetermined position from the transducer. The operator uses both transverse and longitudinal images to localize and describe the prostate tissue treatment volume. Generally, the treatment volume is selected from the verumontanum extended to 5 mm above the bladder neck. The selected treatment volume is based on the size of the prostate. This is accomplished by outlining areas in the transverse and longitudinal planes by using the computer controlled cursor of the device.

Treatment and treatment monitoring

The HIFU treatment of BPH is primarily based on thermal ablation of the prostate tissue. The ultrasound treatment dosage is based on the tissue depth (i.e. distance from rectal wall to the desired site in the prostate). The focal peak acoustic intensity, ultrasound absorption coefficient and duration of ultrasound exposure calculate the temperature rise in tissue. The required site intensity is calculated for each patient by measuring the tissue depth from the rectal wall to the focal distance and using the absorption coefficient of 0.7 dB/cm MHz. The site intensity in the range of 1260 W/cm² to 2000 W/cm² is used for 4.0 cm and 3.0 cm focal length transducers respectively. Initially, the HIFU treatment was performed with an ultrasound exposure cycle of 4 seconds ON followed by a 12 seconds OFF period. However, the recent treatment uses 4 s ON followed by a 12 s OFF duty cycle. Thus reducing the overall treatment time. During the OFF period treated tissue is imaged. This provides a feed back to the user on the position of the prostate and any changes to the tissue caused by the treatment.

Indwelling balloon catheter

A 5 cm³ balloon silicon catheter (18 French, Dow Corning) is kept in the urethra during the treatment.

Patient treatment protocol

The United States Pilot Study (USPS, n=25) was Review Board (IRB). The Kitasato study (Uchidaconducted at five sites under the Investigational et al., 1998) (n=22) was performed at the KitasatoDevice Exemption (IDE # 9110188) from the Food University School of Medicine, Sagamihara, Japanand Drug Administration of the USA, The Male under the approval of Japan Ministry of Health and Health Centre Study (TMHC, n=14) was conducted Welfare. Briefly Table 1 describes patient inclusionin Oakville, Canada under approved Investigational criteria for these studies. Patients were excluded if they had a history of prostate surgery,clinical or pathological evidence of carcinoma of the prostate or rectum or anal disease.

There were major Differences among the three protocols: For the USPS study, patients had their bladder neck and proximal urethra treated with a minimum focal intensity of 1640 Watts / cm². The treatment protocol consisted of nine lesions in the transverse plane. The treatment extended from the bladder neck to the verumontanum. The catheter used for treatment alignment was removed before treatment. In the TMHC and Kitasato studies, patients were treated with the same intensity but had the balloon catheter in-situ during the treatment. Additionally, the treatment consisted of ten lesions in the region of the bladder neck and 17 lesions in the region of the prostate tissue to increase the tissue treatment volume. In the Kitasato study more anterior portion of the prostate tissue volume was treated using two or more focal length probes. All the TMHC patients were treated as outpatients, under IV sedation and intra-prostatic injection of Lidocaine. It the Kitasato study, all patients were given epidural anesthesia.

Results

Three relevant quantitative (peak urine flow rate, ml/s) and qualitative (Symptoms and Quality of life scores) parameters to the BPH conditions were studied for the evaluation of outcome of the HIFU treatment. The patients were followed on a regular interval basis as listed in the Tables 3-5. The outcomes are also presented in the graphical forms in Fig. 5 for comparison purpose. The improvement in the symptoms and quality of life scores were statistically significant (P<0.0001) in all the three studies. The mean peak urinary flow rate improvements were statistically significant in the range of P<0.01 to P<0.001 post twelve months treatment. The complications resulting from the HIFU treatment are listed in Table 2. All complications were found to be transient and were resolved within 30 days. A total of three patients (two from USPS and one from Kitasato) were treated by TURP procedure because of insufficient improvements post HIFU treatment. There were no injuries or side effects due to HIFU treatment.

Discussion

Our group proposed the HIFU treatment of BPH in early 1986 (Sanghvi et al., 1996). The first clinical protocol for the BPH treatment was developed based on the assumption that debulking of prostatic tissue surrounding the urethra would be sufficient to relieve the patients from BPH condition. Based on that hypothesis, the Sonablate-1 (later replaced by the SB200) system was developed and human clinical studies were performed at several sites (Bihrle et al., 1993a,b; Maderbacher et al., 1994; Ebert et al., 1997; Uchida et al., 1998). These studies provided early safety and efficacy data and significant insight on HIFU interactions with prostate and the surrounding tissues. These early studies also revealed that the peak urinary flow improvements were not adequate after the HIFU treatment. Therefore it was required to debulk large volume of periurethral and central zone tissue and include the bladder neck in the treatment. To improve the efficiency of the treatment, it was necessary to remove the necrotic tissue faster from the prostate. That meant to deliver more power and mechanically disintegrate the urethra to mimic a TURP like procedure. Based on this information the treatment protocols were revised. First, more transverse lesions were placed in the prostate and the bladder neck tissues were included in the treatment (USPS). Later HIFU studies were performed by keeping the silicon catheter in the urethra during the treatment (TMHC). The catheter has higher acoustic impedance compared to tissue and reflects partial energy into the posterior part of the prostate. Thus, providing higher localized acoustic intensity at the urethra and raising tissue temperature near to vaporization. The vapor gas bubbles are trapped on the surface of the catheter. These micro gas bubbles are hyperechogenic and provide a brighter image at the site of treated tissue. In addition, the ultrasound energy absorbed by the catheter is converted into heat. The silicon material is a good thermal insulator. It retains the heat at the treatment site for a longer time thus maintaining higher base temperature of the prostate during the entire treatment. This was confirmed during in-vivo experiments in a canine model (n=20) prior to human trials. The temerpatre between the catheter surface and tissue were measured. To measure temperature in the focal zone, a bare wire 50 micrometer diameter bead tehrmocouple was attached to the catheter. The catheter was inserted in the dog prostate and imaged with SB-200. The HIFU therapy zone was selected to cover the thermocouple. Fig. 6 shows the temperature profile for the entire treatment. The tissue site near the thermocouple reached above 100o C while maintaining approximately 60o C temperature at the tissue interface during the entire treatment time. The temperature profile shows peaks and valleys as a function of sound ON/OFF cycle and the location of HIFU beam relative to the thermocouple. The highest temperature is recorded when the ultrasound beam is closest to the thermocouple.

The high safety level of HIFU has allowed users of the SB-200 device to treat larger volume of the prostatic tissue. Dr. Uchida et al. (Kitasato) treated BPH patients with two focal length probes. Initially, all patients were treated with the silicon catheter in the urethra. The appropriate focal length probe was selected to place the urethra and the bladder neck tissue in the prescribed treatment focal zone. Later the catheter was removed and a longer focal length probe was used to treat the anterior fibromuscular stroma. The Kitasato-study resulted in higher urine peak flow rates. The average peak flow rate was improved by 7 ml/s compared to about 4-5 ml/s from the other two studies. The significant aspect of the study showed that the flow rate continued to improve over time and at the end of twelve months the improvement was close to 95% compared to the base line. In addition, the average prostate volume decreased by 29% (9.4 + / – 9.4 ml, n = 12). This was due to the fact that treated prostates continued to shrink as necrotic tissues were sloughed and absorbed by the body’s scavenging system. In ten out of 12 patients, cavities were formed with new urethra in the treated prostates. These two factors, i.e. more tissue treatment and the higher temperatures generated by the indwelling catheter resulted in the desired urine flow rate improvements. All patients also attained the desired improvement in Symptoms score and Quality of life.

Conclusion

Over the last six years the non-invasive HIFU treatment of BPH has improved as more experience and knowledge has been gained from various clinical studies and continuned life science studies. The improvements in the technology have allowed us to treatpatients more aggressively and remove larger volume of prostatic tissue in shorter treatment time. The bi-plane software linkage between transverse and longitudinal planes makes the treatment planning easier and allows more accurate targeting of the tissue. The circulating cooling water keeps the rectal temperature lower than body temperature and shortens the treatment time by reducing the OFF time. The BPH patients with prostate from 30ml to 40 ml are treated in less than 45 minutes. These clinical studies prove the reliability and durability of HIFU treatment of the BPH condition. The technological changes are under way to make the HIFU device more user friendly and more effective by means of electronic beam steering and control. High-resolution ultrasound imaging and HIFU beam steering techniques will tremendously enhance in the treatment of both BPH and localized prostatic carcinoma.

Acknowledgements

The authors would like to thank the staff of the Department of Urology and Focus Surgery Inc. for their assistance during the study and in collecting the patient data.

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Footnotes

1. Department of Urology, Indiana University, Indianapolis, IN 46206, USA
2. Focus Surgery Inc., Indianapolis, IN 46226, USA
3. Male Health Centre, Ont., Canada
4. Kitasato University School of Medicine, Sagamihara, Japan