Cancer device gets OK for more tests

Charlotte company hopes to bring prostate surgery alternative to U.S.

Karen Garloch

A Charlotte company that shares ownership of a device used to treat prostate cancer in other countries has received approval to expand testing of the treatment in the United States.

The device, called Sonablate 500, uses high-intensity focused ultrasound (HIFU) as an alternative to surgery.

The treatment is approved in Japan, China and other countries, including most of Europe. But it is still considered experimental for prostate cancer in the United States and can be used here only as part of a clinical trial.

This month, the U.S. Food and Drug Administration approved the Charlotte company’s device for use in a Phase III study to determine effectiveness. The study will involve 466 patients at 24 sites, possibly one in Charlotte.

To qualify, patients must be newly diagnosed with early-stage prostate cancer that has not spread from the walnut-sized gland. Half the patients will receive HIFU, and half will receive cryosurgery, which destroys tissue by freezing it.

Patients will be followed for two years, and results could be available in three years, after which FDA approval will be sought.

“This is the last hurdle toward our goal of bringing HIFU to the United States,” said Steve Puckett Jr., chief executive of Charlotte-based U.S. HIFU. Puckett, 25, is a recent graduate of Vanderbilt University with a bachelor’s degree in history. He has the backing of his father and company founder, Steve Puckett, who also founded two hospital chains, MedCath Corp. and Hospital Partners of America, after working at Carolinas Medical Center in the 1980s.

The younger Puckett became interested in HIFU after meeting Dr. George Suarez, a Miami urologist who had investigated alternative treatments that would be less likely to cause impotence and incontinence.

HIFU delivers focused ultrasound waves to the prostate through a probe inserted into the rectum. A physician at a computer monitor controls the probe, which sends ultrasound waves through the rectal wall to produce intense heat that destroys the targeted cancerous tissue.

Puckett Jr. said HIFU patients recover more quickly than surgical patients, who remain in the hospital for two or three days and take six to eight weeks to recover. “These guys are off the table and two hours later, they’re walking around,” he said.

Suarez, who helped start U.S. HIFU, is medical director of the company and performs the treatment in other countries.

Several Charlotte-area patients have traveled to Mexico and the Dominican Republic for the treatment, and several local doctors have gone there to learn the technique.

Darrell Bunch, 50, of Fort Mill, S.C., said he chose HIFU even though his urologist recommended radical prostatectomy because he wanted to reduce the risk of becoming incontinent. “I was only 48,” Bunch said. “It was a quality-of-life issue.”

Since the treatment, his level of PSA (prostate-specific antigen) has dropped from 10 to 0.01. “You can’t get any lower than that,” he said.

“Considering what my options were, I really think I chose the best,” Bunch said. “It’s a shame that I had to go outside the country. They’ve been doing this in Europe, Germany and Japan for a long time.”

Dr. Chris Teigland, a urologist and researcher at Carolinas Medical Center, spent a weekend in Mexico this spring learning the technique and is negotiating with U.S. HIFU to be part of the Phase III study.

The treatment is “easy on the patients,” Teigland said. “One thing that’s remarkable is how quickly they bounce back.”

Teigland predicted HIFU will be approved for prostate cancer, but whether it becomes the preferred treatment for all patients remains to be seen. “I think it will be a part of the future of treatment choices for patients with prostate cancer… We need data to show us how effective it is.”

A second clinical trial of HIFU for early-stage prostate cancer is being conducted at Duke University using a second device called Ablatherm HIFU.

HIFU is also approved outside the United States for treating pancreatic, breast, liver and kidney cancer. Charlotte Realtor Barbara Tate died in July while in China, where she had traveled to receive the treatment for pancreatic cancer.

Visually directed high-intensity focused ultrasound for organ-confined prostate cancer: a proposed standard for the conduct of therapy

Prostate cancer is the most common cancer in men and the second leading cause of death from malignancy in the UK¹. The mainstay of treatment remains radical surgery or radiation therapy, but several minimally invasive treatments are now under evaluation that might prove to be of equivalent oncological effectiveness in the long term². Transrectal high-intensity focused ultrasound (HIFU) is one such treatment that has been used on an experimental and clinical basis as noninvasive therapy for clinically localized prostate cancer since the 1990s³.

HIFU relies on the physical properties of ultrasound energy. For therapeutic purposes it is focused by either an acoustic lens, bowl- shaped transducer or electronic phased array.

As ultrasound propagates through tissue, zones of high and low pressure are created. When the energy density (also known as focal intensity, measured in W/cm2) at the focus is sufficiently high (during the high-pressure phase), tissue damage can occur as a result of thermal coagulation necrosis and/or acoustic cavitation. The volume of a HIFU-generated lesion at the focal point is small (typically 10 mm long by 1–2 mm wide, in a cigar shape orientated along the long axis of the beam). If the intention is to ablate a given volume of tissue, individual lesions are placed next to each other to provide a continuous zone of necrosis.

It was shown experimentally that when mammalian tissue at the focus of a HIFU beam is raised to >60 °C for 3 s, all of the cells in that volume are rendered nonviable⁴. Thethreshold for achieving this is thought to be relatively constant among subjects⁵. Accordingly, algorithms were developed assuming certain tissue-related properties, tissue homogeneity and fixed ultrasound absorption coefficients that aim to produce thermal ablation using predefined power/time combinations at given tissue depths. In reality, the HIFU beam propagates through tissue and tissue interfaces that are characterized by natural variability, e.g. prostates vary among persons in size and in the ratio of stroma to epithelium. This will effect absorption coefficients and attenuation. Moreover, the presence of disease (cancer or no cancer) and the androgenic status of a patient are likely to add to this variability. These facts make it unlikely that an algorithm-based method of treatment will be the most likely to achieve the desired effects in most patients.

It follows therefore that some method is required for adjusting the energy to suit the unique characteristics of the prostate being treated. It is generally accepted that real-time imaging is a desirable attribute for any new minimally invasive therapy⁶, but there is debate about the best method to use. B-mode ultrasonography (US) is the only method in clinical use for monitoring HIFU therapy of the prostate, and this relies on detecting hyperechoic grey-scale changes within the treatment field. These changes are the result of both acoustic cavitation and tissue water vaporization, the latter occurring at boiling point. Grey-scale changes seen on B-mode US were correlated with histological changes within treated tissue during extracorporeal⁷ and transrectal therapy⁸, and their formation postulated for use in the control of prostate ablation⁹, but they have not been formally categorized to aid the clinician in conducting the therapy.

We describe our early experience of HIFU therapy using two distinct approaches to treatment. The first regimen was based on an estimated energy exposure, the algorithm- based approach; the second actively sought to generate grey-scale changes and to use these to guide energy exposure to the prostate. We described this type of treatment as ‘visually directed’. In addition to describing the outcomes of care associated with these two approaches, we propose a standardized nomenclature for the changes seen on B- mode US imaging during HIFU therapy for prostate cancer.

Patients and Methods

Between November 2004 and October 2005, 61 men were treated using the Sonablate500® (Focus Surgery, IN, USA) which consists of a power generator, water-cooling system (the ‘Sonachill®’), a treatment probe and a probe-positioning system (Fig. 1). The probe has two curved rectangular piezoceramic transducers with a driving frequency of 4 MHz and focal lengths of 30 and 40 mm, respectively. During treatment, these can be driven at low energy to provide real-time diagnostic US imaging or at high energy for therapeutic ablation (in situ intensity 1300–2200 W/cm2). The probe is covered by a condom through which cold (17–18 °C) degassed water circulates pumped by the Sonachill.

Thirty-four of the 61 men treated were included in this report (Fig. 2). All had prostate cancer stage =T2 (N0,M0), a PSA level of <15 ng/mL and prostate gland volumes of 1 cm diameter, as visualized by a previous TRUS. Written informed consent was obtained before treatment in all cases, and all men were followed-up for =3 months. It was necessary to exclude from the analysis men who had previously had hormone therapy, as this would confound the PSA nadir recorded after therapy.

Men were prepared before the procedure with two phosphate enemas to empty the rectum; an oral bowel preparation was used in some cases. Treatment was under general anaesthesia in all cases to reduce patient movement and discomfort. Men were placed in the lithotomy position, and the anal sphincter gently dilated. The treatment probe was introduced with a covering of ultrasound gel to couple it to the rectal mucosa, and then held in position by an articulated arm attached to the theatre table. A 16 F Foley urethral catheter was inserted under sterile technique, and a 10 mL balloon inflated to allow accurate visualization of the bladder neck and median sagittal plane.

Axial and sagittal US images were taken through the prostate using the transducer in the diagnostic mode. Treatment planning used proprietary software, which allows the prostate to be divided into ‘blocks’: anterior, middle and posterior, on both right and left sides. The software directs the transducer to move automatically so that the acoustic focus is moved sequentially through each point in the block. Each acoustic pulse ablates a volume of 3 × 3 × 10 mm, by heating the tissue to 80–98 °C almost instantaneously¹⁰, and individual lesions overlap slightly to ‘paint out’ the entire volume, using a combination of 3-s exposures (‘on’) time and 6-s pauses (‘off’) time, during which the gland was visualized with real-time US. The 4-cm focal length probe was used to treat anterior and middle blocks, and the 3-cm probe used to treat the posterior block.

The software is semi-automated, with the amount of energy applied to the prostate remaining under the control of the user. As a result, it is possible to treat the prostate in several ways. For instance, one approach uses pre-set energy exposure levels, the intensity of which depends on the part of the prostate that was being treated, and whether the treatment is a primary or salvage (after radiation) case. To a large extent, these energy exposure levels are derived from animal experiments¹¹ or as a result of outcome monitoring in case series¹². This might be termed an algorithm-based approach. Clinical series using this technique showed that the mean PSA nadirs achievable after treatment were ˜1.4 ng/mL¹³. These results are similar to those achieved by other transrectal HIFU devices that rely on the upper power limit being set without user control¹⁴.

An alternative method of managing energy exposure might involve abandoning any preset criteria to permit the maximum energy exposure deemed to be both effective and safe. This would only be possible if both therapeutic objectives of effectiveness and safety were under the control of the operator, but to a large extent they are. The site intensity at the focal point (the target zone) can be monitored using visual feedback, as evidenced by hyperechoic changes on B- mode US. It is possible to increase energy exposure to obtain these visual changes and to decrease the exposure if the changes become uncontrolled. Our hypothesis is that obtaining visual changes at the focal point can serve as a real-time feed-back to the operator that cytocidal levels of energy are being delivered to the part of the prostate being treated. Implicit in this approach are strong, and we think robust, safety considerations. By controlling the visual change at the threshold level at the focal point, the operator is as certain as possible that the energy is being deposited in the intended area. Moreover, other in-built safety features, such as the reflectivity index in the near field, place an upper boundary on energy absorption in the area abutting rectal mucosa. We termed this approach ‘visually directed’. Using this, the grey-scale changes seen on diagnostic US are actively monitored, and the power adjusted accordingly. For consensus on the types of changes seen, a semiquantitative method of analysis was developed (Appendix), which allows comparison within and between treatments. These ‘Uchida’ changes were named after Toyoaki Uchida (Professor of Urology in Tokai University Hachioji Hospital, Tokyo, Japan) who performed the preliminary clinical work on the Sonablate device.

Using visually directed treatment, the operator aims to generate grey-scale changes throughout the target tissue. During treatment, the power level (energy exposure) is constantly adjusted to achieve Uchida Grade I or II changes (Fig. 3). By obtaining these changes, the operator can control the energy in the target zone that is either on or just below the cavitation threshold. This grey- scale US feedback is also used to provide a ceiling threshold. Grade III changes occur when uncontrolled cavitation occurs in the near field; this is corrected by reducing the energy exposure. Visually directed HIFU therefore takes into account both inter- and intraprostatic differences in acoustic and thermal properties, and allows the user to respond in real-time to the therapy.

Nine men were treated using the algorithm- based protocol (group 1) and 25 men using the visually directed protocol (group 2). All patients were discharged on the day of treatment. Demographic details are given in Table 1; all patients were followed up for =3 months. After therapy, patient status and treatment-related complications were assessed at fixed intervals by visits to the clinic and by telephone consultations with a specialist nurse practitioner. All men were discharged with an indwelling urethral catheter. The PSA level was measured at 3 months after treatment to give a nadir value. Statistical analysis was used to assess the correlation of variables between groups.

Results

Table 1 shows details of the operative variables and results. The difference between the mean PSA nadirs of the groups was significant (P < 0.005). In group 2, 21 of 25 patients achieved PSA nadirs of =0.2 ng/mL at 3 months after treatment; seven patients achieved undetectable PSA values. The mean PSA nadir achieved in group 2 was 0.15 ng/ mL, vs 1.51 ng/mL in group 1.

A trial without catheter was successful at the first attempt in eight of the nine patients in group 1, and 21 of 25 in group 2 (84%). In the 3 months after HIFU, a few patients in each group required flexible cystoscopic investigation. Some also had infective complications, which are listed in Table 1.

Discussion

Visually directed HIFU for organ-confined prostate cancer can produce a low PSA nadir 3 months after the procedure. In the present patients, the mean PSA nadir was significantly lower than that using an algorithm-based protocol for treatment of similar patients, and compares favourably with both brachytherapy and cryotherapy for the treatment of organ-confined prostate cancer^15,16. In the Seattle brachytherapy series¹⁷ 72% of patients with no evidence of disease biochemically achieved PSA nadirs of <0.2 ng/mL, with the mean PSA nadir being 0.25 ng/mL. In the present study we achieved PSA nadirs of =0.2 ng/mL in 84% of patients using the visually directed method, and an undetectable PSA level in just under a third of those treated.

Clinicians familiar with TRUS will acknowledge that the characteristics of prostate glands differ between patients. Even men who have had no previous therapy can have glands of different density and with different patterns of micro- or macro- calcification. Just as the amount of pressure that is required to exert on the scalpel is based upon the real-time characteristics of the tissue it is passing through, so is the amount of energy required to cause ablation within the prostate gland.

We have given the first formal description of grey-scale US changes associated with transrectal HIFU treatment for prostate cancer (Appendix). These ‘Uchida changes’ allow a descriptive analysis of changes seen during therapy and permit a formal system of treatment to be developed, which is consistent between users but flexible according to the gland treated. Grey-scale changes seen on B-mode US have been identified in relation to ablative therapies; these have previously been termed ‘pop-corning’ in relation to HIFU treatment of the prostate, and ‘gas cloud’ formation in relation to radiofrequency ablation in the liver, but have not been quantified for use as a method of real-time feedback.

In the past, cavitation was avoided, as it was assumed to be uncontrollable, and that the risk of cavitation outside the area of interest was too great. Extensive dosimetry studies ^7,18 showed that not only are the grey-scale changes visualized on B-mode US associated with histological ablation, but that single pulses of high-intensity ultrasound can produce well circumscribed, predictable volumes of necrosis. It might be argued that, by producing cavitation, the tissue is being ‘over-treated’; in the absence of other real- time methods of detecting thermal ablation, this remains the best method of treatment monitoring. Tissue elastography¹⁹ and ultrasound thermometry²⁰ are under development but remain experimental; MRI²¹ might accurately detect temperature changes, but MRI devices are costly, do not provide feedback as instantaneously as B- mode US, and have not been used clinically in the setting of transrectal prostate HIFU.

Although presently the diagnostic TRUS uses 7 MHz probes and the 4–6 MHz centre frequency band of the Sonablate-500 is not the standard frequency for diagnostic imaging of the prostate, we have had no difficulty in using it for planning and monitoring treatment. This 4–6 MHz frequency band allows excellent visualization of the prostatic margin and grey-scale changes within the gland. Higher frequency TRUS is used in all patients before treatment, and even with the highest ultrasonic resolution the differentiation between benign and malignant prostate is still inaccurate and therefore unnecessary for the purposes of treatment²².

Despite the few patients in each group, the catheter-free rate appears equivalent between them (>80% at the first attempt) with infective complications in ˜10% of patients. This is consistent with other reports using combined prostatic resection and HIFU²³. After treatment, most patients have short-term irritative voiding symptoms as a result of the sloughing of prostatic tissue via the urethra. In the visually directed group, more patients underwent flexible cystoscopy. In all cases this was done to investigate irritative and obstructive voiding symptoms, with the result that urethral debris was cleared. The threshold for undertaking a flexible cystoscopy is now considerably higher, as most patients are taught intermittent self-catheterization before treatment, which allows the dislodging of prostatic slough with no need for formal intervention.

We assumed a relationship between the PSA nadir at 3 months and treatment outcome. Data assessing this relationship indicate that this is a justifiable association²⁴, but in that study the outcome was likelihood of disease on prostate biopsy at 6 months after treatment. Although it is logical to assume that this affects the long-term outcome, there are no long-term data to verify it at present; certainly the PSA nadir was shown to correlate with longer term outcome in the context of radical surgery and external beam radiotherapy ^25,26.

The present study represents the first reported experience of visually directed HIFU for treating organ-confined prostate cancer. We think that this is the first attempt to standardize the conduct of treatment. Standardization of therapy makes it easier to teach and makes it possible to derive quality standards. Most importantly, standardizing the intervention is the key step in health technology assessment. Once this is done it is possible to start to explore the next phase of investigation, defining the determinants of outcome. This is likely to lead to better case selection and improved conduct of therapy.

Acknowledgements

We are grateful to those at Misonix, Inc. for their ongoing financial support. Rowena Couling (Specialist Nurse Practitioner) for her help with data management and Naren Sanghvi and Focus Surgery for their scientific support.

Conflict of Interest

R. Illing is supported by a grant from Misonix; M. Emberton has acted as a paid consultant to Misonix. Source of funding: Misonix – European distributor of the Sonablate device.

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Correspondence

Rowland O. Illing, The Institute of Urology and Nephrology, University College London, London, UK. e-mail: rowland@doctors.org.uk

Abbreviations

HIFU, high-intensity focused ultrasound; US, ultrasonography.

Appendix

Uchida Changes

We devised a method of assessing grey-scale US changes seen during visually directed therapy to allow quantification and comparison in and between treatments. ‘Uchida changes’ were classified as Grades I, II and III depending on whether hyperechoic regions were identified within individual target treatment zones, became confluent between adjacent HIFU treatment exposures, or were seen migrating outside the target treatment zone, respectively. These were then subclassified into ‘a’, ‘b’ and ‘c’ depending upon whether 50% of the focal region was involved in the changes, respectively (Fig. 3). The aim was to see some form of Uchida change every second or third exposure, to confirm that treatment was taking place on or near the cavitation threshold.

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%