High intensity focused ultrasound may be superior to radiation therapy for the treatment of early stage prostate cancer

Arguing against the Proposition is Gert De Meerleer, M.D., Ph.D. Dr. Meerleer obtained his M.D. degree in 1994 and his Ph.D. in Radiation Oncology in 2000, both from Ghent University, Belgium. He currently practices as radiation oncologist and Professor at Ghent University Hospital where he is responsible for the treatment of urological and gynecological malignancies. He has published extensively in radiotherapy, especially the use of IMRT for the treatment of prostate cancer. He is an active participant in ESTRO and is currently Director of the ESTRO multidisciplinary teaching course on prostate cancer. There are many options for the treatment of localized prostate cancer, and each has its own unique risks and benefits. For early stage prostate cancer, HIFU may be superior to radiation therapy—either external beam radiation therapy (EBRT) or brachytherapy (LDR or HDR). HIFU is a minimally invasive treatment option for prostate cancer that uses either a transrectal or transurethral applicator coupled with image guidance to focus high intensity ultrasound energy in the prostate.1 At a very precise and targeted location identified using ultrasound or MRI guidance, the temperature is rapidly elevated to 55–70 °C; a lethal thermal dose which causes irreversible tissue destruction.2 MRI coupled with HIFU provides precise image guidance for these procedures as well as near real-time temperature feedback via MR-thermometry,3 making accurate destruction of prostate target tissue practical. Although HIFU remains investigational in the United States for prostate cancer, several thousand patients have been treated in trials outside of the United States.4–6 Clinical HIFU protocols typically involve ablation of the entire prostate gland and are indicated especially for nonsurgical candidates such as elderly men who are unwilling or unable to undergo radical prostatectomy or receive radiation therapy for locally advanced or recurrent disease.7 HIFU has several practical benefits as compared to RT. While both are minimally invasive procedures, HIFU can deliver a treatment in a single session. The effects of HIFU are immediate; the targeted tissue is ablated with this technique. HIFU uses nonionizing ultrasound energy, which does not suffer from the same risk of late radiation effects as with ionizing beams; thus HIFU can be repeated if needed and can be combined with EBRT.8 MR-guided HIFU provides the unique capability to perform temperature feedback and “dosimetry” in situ and imaging immediately postprocedure to verify treatment, thus providing confirmation of complete destruction of a defined target region. The superior benefits of HIFU are demonstrated by the very promising reported outcomes in the studies performed outside the United States. These report excellent biochemical control and, while side-effects (urinary stricture, retention, incontinence, impotence) are reported, they are at a rate lower than for RT.9–14 These early results, for mainly low- and intermediate-risk cancers (T1-T2 N0M0 disease, Gleason score of < 7, PSA level <15 ng/mL, and a prostate volume <40 mL),12 and for outcomes without the long, widespread clinical adoption as compared to radiation therapy, have been acceptable, but would benefit from further confirmation in prospective multicenter trials, several of which are now underway. HIFU also holds promise for focal ablation of defined regions of prostate cancer.15 Focal use of HIFU should reduce the adverse sexual, urinary, and bowel effects of whole gland ablation. New techniques under development for MRI-guided HIFU treatment enable the integration of diagnosis, planning, and treatment of localized prostate cancer using MRI and could transform the management of this disease into a minimally invasive outpatient procedure with high precision and a low-level of side effects. High-dose external beam radiotherapy has resulted in excellent biochemical control rates (BCRs) of >90% in low risk prostate cancer patients. A dose response relationship has been demonstrated in randomized phase III trials with a gain of 10%–20% when the dose was increased from 66 to 70 Gy to 74 to 78 Gy16,17 or even higher.18 When the supporters of HIFU state that it is as effective as EBRT, at least they should mention with which EBRT dose they are comparing their HIFU results. Moreover, there are no data to support such a statement and, any data there are, comes from a few research groups, making publication bias likely. Data on modern high-dose EBRT have been published by hundreds of research groups all over the world making the data concerning this treatment much more solid. A recent publication in European Urology defined the evidence to use either Ablatherm or Sonablate HIFU as primary therapy for low risk disease as “very poor.”18 BCRs at 5 years ranged between 66%–77% (Ablatherm) and 45%–84% (Sonablate). Up to 66% of the patients received neoadjuvant androgen suppression and more than 2/3 of the patients underwent transurethral resection of the prostate (TURP),19 two features that significantly influence post-treatment PSA values. Surprisingly, the need for recurrent HIFU treatment (up to four times!) was not considered as HIFU failure. Regardless, the BCR results obtained by HIFU are quite far from the 93%–98% achieved with modern high-dose EBRT and should be considered as inferior.16–18 Also, the HIFU toxicity profile does not make up for the difference in control rates. Bladder neck and urethral stricture and urinary incontinence have been reported in 2%–30% and 2%–34% respectively. Rectourethral fistulae have been reported in up to 3% of the cases. Rates for erectile dysfunction range from 20% to 50%.19 Modern EBRT technology such as IMRT performs at least as well.20,21 New generation HIFU devices have, however, been hypothesized to induce a more favorable toxicity profile.12 Only a randomized trial can compare HIFU with modern EBRT. Unfortunately, this is not likely to happen in the near future. Until then, HIFU should not be considered as a standard treatment for localized prostate cancer and can only be advocated within the framework of a well-conducted prospective study with a transparent description of the methodology (e.g., toxicity scale) and, most importantly, without violation of international standards. For example, androgen suppression has no place in the treatment of low risk disease and should be avoided.22 Dr. De Meerleer correctly states that there have been too few clinical trials to provide “high quality” evidence to fully support the use of HIFU to treat prostate cancer—so we need them. Getting this evidence has been challenging for this emerging technology, particularly in an era where institutions have invested substantial resources and technology into IMRT, brachytherapy, and robotic surgery. Dr. De Meerleer correctly identified problems with the current literature such as the lack of proper trials which compare HIFU with “modern IMRT techniques,” but there are also issues with determining if the latest image guidance and ultrasound devices have been used, which can reduce complications and ensure a thorough and complete treatment. In much of the literature cited by Dr. De Meerleer, ultrasound imaging was used to guide treatments, which has poor resolution of the prostate gland, and limited feedback of temperature rise and ablated tissue volume. Newer, MR-guided HIFU systems have emerged that provide superior imaging of soft tissue, are more reliable, and provide near real-time feedback of thermal effects and estimates of ablated tissue volume. Another “problem” reported in the literature involves the delivery of multiple treatments with HIFU. However, while a single treatment is the ideal, the option to be able to provide multiple treatments could also be a beneficial feature of HIFU relative to RT. In conclusion, I agree with Dr. De Meerleer that prospective randomized trials are the most effective way to answer questions about competing technologies for treating early stage prostate cancer. However, I also support our physician colleagues in their efforts to evaluate the rapidly evolving new technologies for image guided HIFU. Ultimately, with this preliminary work followed by well designed clinical trials, we will be able to determine the most appropriate use of HIFU in prostate cancer, as well as for other oncologic and pathologic conditions. I have read Dr. Benedict's opening statement with interest but certainly with a growing feeling of confidence in my position. The introduction focussing on technological aspects is interesting and I have nothing on which to comment. But the good part for me starts at the “results” section. He states that “The superior benefits of HIFU are demonstrated by the very promising reported outcomes….” In fact, the referred publications suggest the opposite. None of the published HIFU series can compete with the results achieved with modern external beam radiotherapy such as IMRT or modern brachytherapy. For example, for low-risk disease, the actuarial 5-year biochemical relapse-free survival (bRFS) in the cited references was 77% (Ref. 4) and 85%.9 This contrasts sharply with the >90% obtained with IMRT20 and brachytherapy.23 For intermediate-risk disease, these data were 71% (Ref. 4) and 72%.9 Again, these results do not rival the >90% bRFS obtained with IMRT20 and brachytherapy.23,24 With longer follow-up, IMRT still results in better bRFS.25 Dr. Benedict also states that urinary side-effects are less frequent than those reported with radiotherapy. One of his references,4 however, shows that over 20% of the patients required TURP during follow-up, a number that is much higher than for IMRT and brachytherapy.20,23–25 Moreover, he does not mention rectal toxicity, although up to 15% of patients might develop severe rectal toxicity after HIFU.19 Inclusion of patients in randomized controlled trials is the most valuable scientific way to go. Technological progress might improve the results. Dr. Benedict would like to thank David Schlesinger (UVa), Chris Diederich (UCSF), Rajiv Chopra (Sunnybrook Health Science Centre, Toronto, ON, Canada), Mark Emberton (UCLH/UCL Comprehensive Biomedical Research Centre, London, UK), and Joy Polefrone (FUS Foundation) for their valued contributions.

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