Emerging Role of HIFU as a Noninvasive Ablative Method to Treat Localized Prostate Cancer

The use of high-intensity focused ultrasound (HIFU) as a method for ablation of a localized tumor growth is not new. Several attempts have been made to apply the principles of HIFU to the treatment of pelvic, brain, and gastrointestinal tumors. However, only in the past decade has our understanding of the basic principles of HIFU allowed us to further exploit its application as a radical and truly noninvasive, intent-to-treat, ablative method for treating organ-confined prostate cancer. Prostate cancer remains an elusive disease, with many questions surrounding its natural history and the selection of appropriate patients for treatment yet to be answered. HIFU may play a crucial role in our search for an efficacious and safe primary treatment for localized prostate cancer. Its noninvasive and unlimited repeatability potential is appealing and unique; however, long-term results from controlled studies are needed before we embrace this new technology. Furthermore, a better understanding of HIFU's clinical limitations is vital before this treatment modality can be recommended to patients who are not involved in well-designed clinical studies. This review summarizes current knowledge about the basic principles of HIFU and its reported efficacy and morbidity in clinical series published since 2000.

Prostate cancer remains the second most common cause of cancer-related mortality in the United States.[1] Although many treatments (eg, radical prostatectomy and radiation therapy) have been used to try and eradicate this disease, these options are still associated with significant morbidity. The goal of developing minimally invasive ablative techniques is to achieve tumor control with the least impact on quality of life.

The use of high-intensity focused ultrasound (HIFU) has been investigated as a minimally invasive ablative technology. HIFU uses single-focus ultrasound transducers that are moved mechanically to generate thermal damage and coagulative necrosis in the target tissue. This method is gaining rapid clinical acceptance among urologists and patients, due in part to its minimally invasive character, single-session treatment, minimal anesthesia, and perceived short recovery period and quick return to daily activity. The potential clinical efficacy and progression-free survival benefit of HIFU have not yet been thoroughly investigated, and long-term evidence of disease control is lacking. The main advantage of HIFU over other minimally invasive modalities for treatment of localized prostate cancer (eg, cryotherapy) is its truly noninvasive nature, ie, the fact that there is no need for percutaneous needle insertion.

HIFU has been used with variable success in the targeted ablation of malignant growths in several other organs.[2-4] This review summarizes information about the current status and understanding of the emerging use of HIFU for the local treatment of prostate cancer. It will include a critical analysis of the published HIFU clinical safety and efficacy trials, future trends for its clinical use, and the challenges facing its widespread application.

HIFU Principles and Challenges

HIFU involves the generation of an extracorporal ultrasound wave that is focused on a particular coordinate within the prostate gland. It generates enough energy at the target point to totally destroy the intended tissue. The practical use of focused ultrasound energy for neurologic therapeutic purposes was first suggested in the 1960s.[5] However, it was not until the 1990s that HIFU became a clinically acceptable ablation modality, primarily due to advances in three-dimensional imaging and precision targeting technology, which paved the way for its wider use.

A crucial characteristic of focused ultrasound energy is its ability to generate a highly confined lesion in the target tissue. The area of demarcation is so clearly marked that the temperature is not cytotoxic outside of this region. The "trackless" nature of the HIFU is unique because the energy source is placed some distance from the target area and does not require the use of radiation (Figure 1).[6]

It is hypothesized that HIFU achieves its cytotoxic effect by two distinct mechanisms: thermal and acoustic cavitation. A target temperature of 55°C held for at least 1 second appears to be the threshold beyond which irreversible coagulative necrosis and tissue death is achieved.[7] Acoustic cavitation (AC) refers to the ability of ultrasonic waves to form small cavities within the target tissue, a process known as acoustically induced cavity nucleation, which is medium-dependent. Additional ultrasonic excitation leads to volumetric pulsation of these cavities, also referred to as bubbles. AC plays a crucial role in augmenting thermal deposition efficiency during HIFU treatment, allowing higher focal destruction at the target point, while minimizing damage to the intervening path, and thereby reducing the potential for collateral damage. Since AC directly correlates with the heating process, it is currently being investigated as a potentially noninvasive method for monitoring treatment efficacy by registering the broadband noise emissions during the bubble-collapse process.[8]

In spite of significant advances in imaging in the past decade, several aspects of applying HIFU to the treatment of prostate cancer remain challenging. Adaptive focusing due to breathing and body movement remains the most challenging aspect of wide application of this technology.[9] The "piecemeal" nature of an ablation process in which the volume of lesion destroyed at any given time is small (ie, 1–3 mm in width and 5–20 mm in height)[10] makes it difficult to achieve complete and homogeneous ablation of the entire gland. In addition, suboptimal prostate ablation can result from the uneven heat tolerance reported in some tumor cells and the influence of local perfusion on heat distribution.[10] Attempts to utilize dynamic magnetic resonance imaging for the evaluation of regional prostate blood flow may refine and contribute to ultimately achieving more complete treatment.[11]

There are currently two ultrasound-guided transrectal HIFU devices for the treatment of prostate cancer: the Ablatherm (EDAP-TMS, Lyon, France) and the more recent Sonablate 500 (Focus Surgery, Indianapolis). Although these devices are approved in Europe and the Far East, their use is still investigational in the United States; phase III trials are underway to assess the safety and efficacy of HIFU. Although both devices utilize HIFU "trackless" principles, they have some important differences.[12] The Ablatherm, which utilizes fixed-power profiles and a single multifrequency probe tip, requires a preoperative transurethral resection of the prostate (TURP). The Sonablate 500, on the other hand, has operator-defined power settings and uses multiple transducers with varying focal lengths within the probe tip. The target destruction lesion is smaller with the Sonablate 500 than with the Ablatherm, which makes further manipulation of the probe necessary during planning.

Clinical Indications and Contraindications for HIFU Use

Primary HIFU has been indicated in most of the published series of patients who have localized prostate cancer (ie, clinical stage T1c–T2b), independent of the Gleason score. In the majority of cases, primary HIFU has been recommended as an alternative to radical prostatectomy or radiation therapy in patients who are not suitable for either of these modalities because of their age, life expectancy, or personal preference. Since most of the published series had only a single arm, it is difficult to draw any conclusions about the efficacy and safety of HIFU compared to other treatment modalities.

The first case reports of the successful use of HIFU for the treatment of prostate cancer were reported by Madersbacher et al in 1995.[13] Since then, the published rates of control of local disease using HIFU have improved, partly due to better patient selection and imaging quality. However, the lack of long-term results hinders our ability to recommend this treatment to younger patients; it is premature to recommend this treatment as a first-line option for local control of the disease. It is currently strongly advisable to recommend HIFU only as part of an ongoing US clinical study.

Prostate size is one of the main contraindications limiting the application of HIFU to a large proportion of patients. A larger prostate volume (> 40 g) can result in incomplete treatment due to the inability of HIFU to reach the anterior and anterobasal regions of the prostate-ie, targeted HIFU waves currently cannot reach the anterior zones of the prostate beyond a limit of 19 to 24 mm in diameter (Figure 2). Some proponents of HIFU argue that this limitation is not clinically significant since the incidence of prostate cancer is relatively low in the anterior and anterobasal regions of the prostate.[14] However, it remains to be seen whether improvements in the technology may overcome this issue of suboptimal ablation.

Other relative contraindications for HIFU treatment include any anatomic or pathologic condition that may interfere with the introduction or displacement of the HIFU probe into the rectum. High-volume calcification within the prostate can lead to HIFU scattering and transmission impairment, thereby raising concerns about the safety and efficacy of the treatment. Illing at al[15] recently reported on a nonrandomized study that compared visually directed HIFU treatment (25 patients) to the conventional predetermined estimated energy-exposure and algorithm-based protocol (9 patients).The authors found significant improvement in achieving a lower nadir level of prostate-specific antigen (PSA) at 3 months with the use of visually directed HIFU, which involves near real-time actively adjusted greyscale changes to guide the energy exposure (Table 1).[15-19]

Some authors advocate reducing the size of prostate glands that weigh > 40 g by performing preoperative TURP; results with this approach have been mixed.[16] Other clinicians have proposed using short-term hormonal therapy or 5-alpha-reductase inhibitors. In their series, Uchida et al did not find any short-term change in clinical outcome after the limited use of neoadjuvant hormonal therapy.[17] However, most of the published series are nonrandomized, are of relatively short duration, and are poorly stratified by risk factors, all of which contribute to their not being appropriate bases for concrete conclusions about neoadjuvant therapy prior to HIFU. At this point, the use of 5-alpha-reductase inhibitors appears to be safer and more acceptable for downsizing the prostate gland prior to HIFU treatment.[21]

Reported HIFU Clinical Efficacy

The most recent series published by Uchida et al[17] included 181 consecutive patients who underwent HIFU with the use of Sonablate 500 (Table 1). Overall, the patients were older (median age of 70 years) and the pretreatment median PSA level was high (9.76 ng/dL, range: 3.3–89.6 ng/ dL). The biochemical disease-free survival (BDFS) rate at 5 years was 78%; BDFS was based on the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of three consecutive rises in PSA after reaching the nadir. However, the BDFS rates among patients in low-, intermediate-, or high-risk groups (based on Gleason score, pretreatment PSA level, and clinical stage) were 92%, 75%, and 64%, respectively. Approximately half the patients (95/181) received neoadjuvant hormonal treatment, which indicates overall high-risk patients. Table 1 shows the reported efficacy and negative biopsy rates as categorized by the use of adjuvant hormonal treatment.

The clinical significance of the nadir PSA level has recently been addressed. Ganzer et al[22] suggested that a PSA nadir ≤ 0.2 ng/dL is associated with better disease-free survival. The study was based on an analysis of data from 103 men who had undergone HIFU treatment for localized prostate cancer.

Data from a number of studies with longer follow-up are available for the Ablatherm technology (Table 2).[23-28] Poissonnier et al[28] reported the results of primary HIFU treatment in 227 patients who had clinical stage T1–T2 localized prostate cancer, with a PSA level ≤ 5 ng/mL, Gleason score ≤ 7, and prostate volume ≤ 40 g. The actuarial 5-year disease-free survival rate (DFSR) was 66%. Pretreatment PSA was the factor most predictive of recurrence, with a DFSR of up to 90% when the pretreatment PSA level was ≤ 4 ng/mL and the Gleason score was low. However, based on these disease characteristics, the expectant management protocol would be likely to have a very similar DFSR.[29]

Blana et al[27] reported the longest (ie, at least 5 years) follow-up multicenter analysis of first-generation Ablatherm HIFU use. The patients' characteristics included localized, early-stage disease with a PSA level < 15 ng/dL. The majority of these men had a Gleason score of 2 to 6. The new definition of biochemical failure (ie, PSA nadir + 2)[30] was used in this cohort. The DFSR was defined by the occurrence of one or more of the following: biochemical failure, positive prostate biopsy at follow-up, and/or initiation of salvage treatment. The DFSR at 5 years was 63% in the cohort with no hormonal treatment (117/140 patients), and the actuarial overall survival rates at 5 and 8 years were 90% and 83%, respectively.[27]

The efficacy reported in various studies using Ablatherm technology is summarized in Table 2. It is important to note that there are still unanswered questions about the accuracy of using the old ASTRO definition vs the newly published ASTRO biochemical failure criteria.[30] The correlation between biochemical survival and the overall survival benefit of the treatment remains elusive, which limits our ability to assess the true efficacy of HIFU as primary treatment for organ-confined prostate cancer. Long-term comparative studies are needed.

Reported HIFU-Related Morbidity

The reported morbidity related to the use of HIFU in prostate cancer patients has been mild; however, its impact on patient quality of life has been poorly documented. Urinary retention due to sloughing of necrotic tissue has been commonly reported. However, the use of suprapubic catheterization and the performance of preoperative TURP in patients with moderate to severe lower urinary tract symptoms appear to substantially reduce the frequency of postoperative retention and catheter duration.[20] Bladder-outlet obstruction, which includes stenosis and strictures, has been reported in up to 22% of the patients in some series.[17] The incidence of erectile dysfunction has ranged from 13%[24] to 61%.[27] However, the long-term recovery rate and the effect of using chemical or mechanical sexual health aids have not yet been reported.

Up to 22% of patients undergoing primary HIFU treatment for localized prostate cancer may require a second or even a third HIFU session to complete the treatment.[27] Studies of both the Ablatherm and Sonablate HIFU devices have reported a similar incidence of repeat treatment sessions: retreatment rates of 1.4 and 1.2 sessions per patient for Ablatherm and Sonablate, respectively.[17,24]

Other side effects after HIFU of the prostate include urinary tract infection, pelvic pain, and retrograde ejaculation (Table 3)[15-17,19,20,23-28]. The first published series of primary HIFU treatment in the United States was recently reported by Koch et al, who used the Sonablate 500 device with 20 men undergoing 1 to 3 sessions. Of this group, 42% achieved a PSA level < 0.5 ng/mL and a negative prostate biopsy. Rectal injury occurred in one patient, and the most commonly reported adverse event beyond the first 30 days postoperatively was urinary retention.[19]

Salvage HIFU Treatment

Approximately one out of three men who undergo primary radiation therapy have a positive prostate biopsy at follow-up.[31,32] Gelet et al[33] first reported the use of HIFU as salvage treatment following failed radiation therapy in 71 patients presenting with a positive biopsy. The majority of the patients (57/71, 80%) had negative biopsies, and 43/71 (61%) achieved a nadir PSA level < 0.5 ng/dL within 3 months after salvage HIFU. The authors reported a 44% DFSR. However, the adverse events related to salvage HIFU, which included rectourethral fistula (6%), grade III incontinence (7%), and bladder-neck stenosis (17%), were significantly higher in comparison to results in patients undergoing primary HIFU. Although the preliminary results are encouraging, further studies with longer follow-up are needed.

Conclusions

The use of HIFU to ablate localized prostate cancer is a promising minimally invasive alternative to current treatment options. However, further refinement of the clinical indications for retreatment sessions and larger randomized, comparative trials with longer follow-up are needed before this technology can be adopted as a primary treatment option.

A large clinical trial is underway in the United States to determine the value of Ablatherm for the treatment of low-risk localized prostate cancer. Men interested in HIFU should consider entering this clinical trial. As several trials mature, more data will emerge about the long-term BDFS and ultimately the overall survival of men treated with HIFU.

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