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- Patients and Methods
- Conflict of Interest
High-intensity focused ultrasound (HIFU) is an alternative treatment option for localized prostate cancer (PCa). There are two HIFU systems currently marketed, the Ablatherm™ (EDAP-TMS, Vaulx-en-Velin, France) and the Sonablate™ (Focus Surgery Inc., Indianapolis, IN, USA). Over the last 15 years, >25 000 HIFU PCa treatments have been performed worldwide. Although there is a growing number of publications reporting on good cancer control and moderate side effects with primary HIFU [1-4], recommendations for HIFU are the subject of controversy among European urological societies . This can be explained by the lack of prospective controlled studies as well as limited follow-up, providing little information on overall and cancer-specific survival . In addition, most publications on HIFU are limited by the fact that they report on a preselected patient population, which inevitably leads to a bias in the reported results. In the USA, Federal Food and Drug Administration approval will be judged on the results of a prospective trial which is under way.
The aim of the present study was to provide oncological and functional follow-up on an unselected series of patients, who underwent HIFU treatment for localized PCa over a 14-year period. This is the longest follow-up of any HIFU series in the current literature.
- Top of page
- Patients and Methods
- Conflict of Interest
The recommendations for HIFU as an alternative treatment option for localized PCa differ among European urological societies. Although the recommendations are based on the same data, HIFU is recommended for a selected group of patients by the associations of Italy, France  and the UK, but it is not routinely recommended by the German and European Association of Urology guidelines . Recently, Warmuth et al.  performed a systemic literature review to assess the efficacy and safety of HIFU in the primary and salvage setting. They considered only prospective studies with >50 patients and assessed their quality using the Recommendations Assessment, Development, and Evaluation (GRADE) approach. After identification of 20 uncontrolled studies they concluded that the available evidence on efficacy and safety of HIFU is of very low quality based on uncontrolled case series and limited follow-up. The ideal setting would be prospective randomized controlled trials with long follow-up comparing HIFU with other standard treatment options. But it is unlikely that such data will be available in the near future, therefore, it is important to get the best information possible from large patient series with long follow-up of good quality.
Most published HIFU series are limited by the fact that their follow-up is too short to provide sufficient information on oncological efficacy and cancer-specific survival. In addition, many authors perform patient selection in their retrospective publications and report only on a subgroup of their treated patients. Currently, a report by Blana et al.  on 140 patients treated at two centres had a mean follow-up of 6.4 years; however, those patients with a PSA >15 ng/mL and a Gleason score >7 were excluded from that study.
Our publication has several special aspects: with a mean follow-up of 8.1 and a range of up to 14 years, the current study has the longest follow-up of any HIFU series to date. We would have been able to create a mean follow-up of 10 years by extending the minimum distance to HIFU treatment; however, we did not choose to do so, as this would have reduced our patient numbers and excluded the valid information on morbidity and early cancer control of those patients treated with the latest generation Ablatherm device.
Furthermore, the study includes all consecutive patients treated for primary PCa over a period of 14 years without pre-selection. In addition to providing follow-up data from 90.1% of all patients, we made an effort to obtain all valid information on life status, metastatic status and cause-specific mortality on those patients who failed HIFU treatment. These aspects give us more insight into the oncological efficacy and the morbidity profile of primary HIFU.
The estimation of biochemical failure after HIFU remains controversial. In the first years of HIFU treatment the initiation of salvage treatment was done individually based on positive biopsy results and PSA kinetics. Nowadays, most authors use the Phoenix criteria to define biochemical failure [1, 2, 10]. With the ‘Stuttgart criteria’ (PSA nadir + 1.2 ng/mL) an attempt was made to propose a HIFU-specific definition of biochemical failure , but this definition is not yet broadly accepted owing to a lack of validation , and the authors consider the Phoenix to be a better definition, especially if one is to compare outcomes with other published series. Using the Phoenix definition in the current study, the BDFS rates were satisfactory at 88 and 83% at 5 years and 71 and 63% at 10 years for the low- and intermediate-risk groups, respectively. Our results are consistent with those of Crouzet et al.  who reported 5- and 7-year BDFS rates of 83 and 75% for low-risk, 72 and 63% for intermediate-risk and 68 and 62% for high-risk patients, respectively. Although we see HIFU mainly indicated in well-informed patients of higher age and low-to-intermediate risk, 91 (16.9%) patients in our series at high risk were selected for treatment based on patient preference or comorbidity. The BDFS rates in this group were acceptable at 48% at 5 years but were lower at 32% at 10 years. These numbers suggest that HIFU should not be recommended as a first-line option to high-risk patients with a life expectancy of 10 years. The fact that patients with high PSA values are not safely treated with HIFU is supported by our multivariate analysis. Among eight tested parameters, a PSA >20 ng/mL was an independent variable affecting biochemical recurrence. Neoadjuvant ADT did not affect biochemical recurrence, a finding recently confirmed by Fujisue et al. . The fact that the Integrated Imaging device had an adverse effect on biochemical outcome in the multivariate analysis (Table 3) can be explained by the fact that the follow-up in this group was shorter; therefore, the rate of censored data is much higher in the Integrated Imaging group, leading to worse results.
Although follow-up biopsies were recommended to all patients in the early part of the study, later it was mostly performed for cause in patients with suspicious local or recurrent disease. In the current study, 55.2% of patients underwent follow-up biopsy with a resultant positive rate of 25.6%. This compares with a negative biopsy rate of between 51 and 96% based on a review by Rebillard et al. .
Without prospective comparative trials it cannot be known to what degree HIFU treatment affects metastasis-free and cancer-specific survival compared with watchful waiting or standard treatment methods. This is a limitation of most PCa treatment options as only radical prostatectomy has been prospectively investigated in this setting ; however, the present results underline the oncological efficacy for low- and intermediate-risk patients with a life expectancy of 10 years as cause-specific survival rates were 100 and 96.2% and metastasis-free survival rates were 99.6 and 94.3% for the low- and intermediate-risk groups, respectively. These results are very similar to a series of 1062 patients who underwent external beam radiotherapy reported by Zelefesky et al.  where metastasis-free survival at 8 years was 93% and PCa-specific death rates for low- and intermediate-risk patients were 0 and 4.5%, respectively. The lack of comparative studies does not allow a comparison of the outcomes of HIFU and cryotherapy of the prostate. Bahn et al.  presented a cryotherapy series of 590 patients with a mean follow-up of 5.4 years. According to ASTRO criteria, the actuarial 7-year BDFS rates were 92, 89 and 89% for low-, intermediate- and high-risk patients, respectively.
The salvage treatment rate of 18% in the present study was relatively low when indirectly compared with the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) database, which reported recurrent disease in 587/935 (63%) patients after external beam radiotherapy at a mean time of 38 months ; the patient population is not directly comparable with that of the current study, as 45% of patients were classified as high risk in the CaPSURE database. In terms of the side effects of HIFU, a complete continence rate of 86.2% at last evaluation supports favourable continence results. By contrast, an impotence rate of 35% 12 months after HIFU with only 25.4% being fully potent does not support the assumption that full-gland HIFU will preserve potency to a high degree. It may be that preservation of erectile function in patients of advanced age is not of paramount importance, as illustrated by the fact that only 202 (37.5%) of our treated patients claimed to be potent prior to treatment. Higher potency rates have been reported when a nerve-sparing approach has been used. Shoji et al.  described potency rates of 52, 63 and 78% at 6, 12 and 24 months, but it is our opinion that attempts to spare the neurovascular bundle with HIFU may undertreat the peripheral zone and that such approaches should only be offered within well-conducted trials of focal therapy.
The most common complication after HIFU is the development of BOO [19, 20]. There was a trend towards a lower BOO rate reported if TURP and HIFU were separated by an interval >3 months. Although this is contradicted by Netsch et al.  who reported rates of 34 and 18% when the interval was 0 or 2 days and >1 month, respectively. Notably, the BOO that occurs can be treated safely by transurethral incision.
The present study has several limitations. They include the fact that this is a single-arm study without comparison with another standard treatment option and that validated questionnaires for continence and potency were not included until 2007 (data not reported). A major limitation is the low number of 55.2% of patients that underwent a post-HIFU biopsy as well as the fact that we could not make a distinction between patients who underwent routine biopsy and those who were biopsied for a rising PSA level. In addition, three different generations of the Ablatherm® device were used, which might influence the results. Comorbidity was not assessed systematically with a scoring system such as the Charlson comorbidity index.
In conclusion, we report on a large consecutive patient series after primary HIFU for clinically localized PCa with the longest follow-up in current literature. Our results improve the understanding of the oncological efficacy, morbidity and side effects of primary HIFU. The study underlines that HIFU is a therapeutic option for patients of advanced age, at low-to-intermediate risk and with a life expectancy of ∼10 years. The rate of serious side effects such as recto-urethral fistulae is low. Before treatment, patients need to be informed about the high rate of BOO. Although continence results are favourable, whole-gland HIFU does not seem to be associated with potency results superior to standard treatment options. The current follow-up is too short to provide evidence that primary HIFU is an oncologically safe treatment option for young patients.