The History of Focused Ultrasound Therapy in Urology



Fig. 22.1
(a, b) Principle of HIFU for prostate treatment: Prostate treatment is performed by the repetition and juxtaposition of several elementary lesions





HIFU in Animal Models


In 1989 a multidisciplinary “task force” was created in Lyon, France for use HIFU in the treatment of cancer in urology. This team consisted of scientists, engineers, radiologist and urologists. The main goal was to provide minimally invasive therapies for urological cancers, especially to patients with localized prostate cancer who were not suitable candidates for radical surgery.

In 1991, Chapelon et al. established the ultrasound parameters required to induce irreversible tissue lesions in animals [2]. In 1992, Chapelon et al. demonstrated in rats (R 3327 AT2 Dunning tumor) that HIFU could be used to ablate tumors and cure cancer without causing metastasis [3]. A complete tumor necrosis occurred in 24 out of 25 animals (96%) receiving high-intensity ultrasound therapy (Fig. 22.2a). A local regrowth of tumor from the periphery was identified in seven animals (28%). Sixteen rats were still alive after treatment without any pathological evidence of tumor regrowth or metastasis (64%). There was a significant difference (P < 0.0001) in survival curves between the two groups (Fig. 22.2b). All rats in the control group died of progressive tumor growth. Of these, seven developed lymph node metastasis (28%). In the treatment group, four animals (16%) also presented lymph node metastasis at autopsy. This occurred, however, only in animals with local tumor regrowth. In 1993, Gelet et al. established that it was possible to induce irreversible coagulation necrosis lesions in dog prostates using a transrectal route without damaging the rectal wall [4]. The experimental probe combined a firing transducer (working at 2.25 MHz) and a rotating imaging system B&K (Fig. 22.3a). Thirty-seven dogs were treated. Lesions in the prostate gland occurred with a combination of moderate acoustic intensity (720 W/cm2) and longer shot duration (4 s). The temperature reached at the focal point of the transducer was 85 °C. The study confirmed the possibility of creating irreversible lesions in the prostatic tissue through the rectal wall (Fig. 22.3b).

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Fig. 22.2
Dunning tumor study. (a) Complete tumor necrosis occurred in animals receiving high-intensity ultrasound therapy (b) Survival curves for 50 rats with AT2 subline R 3327


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Fig. 22.3
Experimental trial in canine prostates (a) Prototype probe used for canine prostate ablation (b) Lesions in canine prostate


First Human Trials in Lyon


The next goal was to find appropriate acoustic parameters able to induce irreversible coagulation necrosis lesions in human prostate via the transrectal route without damaging the rectal wall. The first trial was conducted in 1992: HIFU was carried out with the first prototype in human prostatic adenoma [5] (Fig. 22.4). The device used to produce the HIFU combined a firing system (homemade power amplifier and therapy transducer) and an imaging system (Kretz ultrasound scanner). Nine patients were treated under epidural anesthesia with an ultrasound intensity similar to or higher than the acoustic intensity used in the experiments on canine prostates. Open surgical ablation of adenoma was performed 1 week after the HIFU session. Irreversible necrosis lesions were obtained in the prostate adenoma without any damage to the rectal wall. These lesions were also histologically determined to be coagulation necrosis with a complete destruction of the glandular tissue. The second trial was a pilot study conducted with the same prototype in 1993, in 14 patients with prostate cancer who were not candidates for surgery [6]. Control biopsies demonstrated coagulative necrotic lesions of the treated prostate zones with secondary development into fibrosis. A satisfactory local control with negative control biopsies was achieved in 50% of the cases in this pilot study.

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Fig. 22.4
HIFU Prototype used for the first prostate ablation trials in human


First Trials in Europe: 1995–2009


The first commercial HIFU prototype was the Ablatherm® from Edap-TMS company which was completed in 1995 and introduced to five centers in Europe (Lyon, Paris, Munich, Regensburg, Nijmegen) (Fig. 22.5). The device combined a 2.25-MHz therapy transducer and a 7.5-MHz trans-rectal biplane ultrasound scanner probe. Phase one of the study was performed in Nijmegen [7]. The HIFU treatments were performed 1 week before radical prostatectomy, and meticulous histopathologic examination of the prostate specimens were performed: complete necrosis was seen in the treated region in all cases. Following phase one of the study, almost 500 patients were successfully treated between 1995 and 1999 in France and Germany. Middle term results of these patient treatments were published in 1996 and 1999 [8]. After this study, the company Edap obtained the CE mark for the Ablatherm Maxis® that was used commercially in Europe from 2000 to 2005.

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Fig. 22.5
First prototype of the Ablatherm used for the multiple center study (1995–2000)


Development of HIFU Devices Dedicated to Localized PCa (2000–2010)


The first commercially available device from Edap-TMS combined two separate probes: a bi-plane imaging probe (Kretz) and a therapy probe working at 3 MHz with a mono-element piezo-composite transducer (Fig. 22.6). Results achieved in 227 consecutive patients treated with the Ablatherm Maxis were published in 2006 in European Urology [9]. Histological results showed 81.8% of the patients had negative control biopsies. Their median nadir prostate-specific antigen (PSA ) was 0.16 ng/mL, with 72.7% of the patients having a nadir PSA ≤ 0.5 ng/mL. The actuarial 5-year disease free rate which combined the histological and the biochemical outcomes was 63% for the overall population, ranging from 78% in the low-risk subgroup to 47% in the high-risk subgroup. The Ablatherm II® (Integrated Imaging) was completed in 2005 this device used a new endo-rectal probe. The therapy probe (working at 3 MHZ) had a 45-mm focal length with a 61-mm aperture where the imaging transducer (working at 7.5 MHZ) was placed in the center of the probe (Fig. 22.7). At the same time, another HIFU device for prostate treatment was developed in the USA, the Sonablate (SonaCare Medical LLC, Charlotte, NC, USA) [10]. This device used double-sided and dual-mode transducers for imaging (6.3 MHz) and treatment (4 MHz) (Fig. 22.8a). The probes were available with two focal lengths (from 30 to 40 mm). The probes were capable of creating an elementary lesion 10–12 mm in length and 3 mm in diameter. The Sonablate procedure was conducted with the patient in a supine position on a regular operating table (Fig. 22.8b). The Sonablate used a single treatment protocol in which the power had to be adapted manually by the operator. The probe chosen depended on the prostate size, with larger glands requiring longer focal length probes.

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Fig. 22.6
Ablatherm Maxis, Probe and device (2000–2005)


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Fig. 22.7
Ablatherm II, probe and device (2006–2013)


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Fig. 22.8
Sonablate: Probe and device


Results of Whole Gland Ablation as Primary Care Treatment  of Localized PCa


Using HIFU as a primary treatment for prostate cancer is usually recommended for patients with localized prostate cancer (clinical stage T1-T2, NX/0 MX/0) for whom radical prostatectomies are not an option for one the following reasons: age > 70 year old, life expectancy ≤10 years, major co-morbidities which preclude surgery, or the simple refusal on the part of the patient to undergo one. The five most recent studies reported outcomes of at least 500 patients [1115]. Articles published from three European urology departments confirmed the long-term efficacy (mean follow-up of 76–97 months) of HIFU treatment with the Ablatherm device [1113]. Crouzet et al. reported results of 1002 patients treated for localized PCa from 1997 to 2009 [11]. At 10 years, the PCa-specific survival rates (PCSSR) and metastasis-free survival rates (MFSR) were 97% and 94%, respectively. Salvage therapies included external beam radiation therapy (EBRT) (13.8%), EBRT + androgen deprivation (ADT) (9.7%), and ADT alone (12.1%). Thuroff et al. published outcomes of 709 patients with primary localized prostate cancer [12]. Mean follow-up was 5.3 years. Cancer specific survival was 99%, metastasis-free survival was 95%, and 10-year salvage treatment-free rates were 98% in low risk, 72% in intermediate risk and 68% in high risk patients. Ganzer et al. reported results of a prospective study on 538 consecutive patients who underwent primary HIFU for clinically localized PCa [13]. The mean follow-up was 8.1 years. Metastatic disease was reported in 0.4%, 5.7% and 15.4% of low, intermediate and high-risk patients, respectively. The salvage treatment rate was 18%. PCa-specific death was registered in 18 (3.3%) patients. Two recent articles confirmed the efficacy of whole gland HIFU treatment with the Sonablate device . The study performed by Uchida et al. included 918 patients treated with Sonablate™ devices during 1999–2012 [14]. The 10-year overall and cancer-specific survival rates were 89.6% and 97.4%, respectively. The 5-year biochemical disease-free survival rates in the different versions of the Sonablate device’s tissue change monitor groups were 48.3%, 62.3%, and 82.0% respectively (p < 0.0001). Dickinson et al. reported outcomes in 569 men receiving primary whole-gland HIFU [15]. One hundred and sixty three (29%) of the 569 patients required the HIFU procedures to be redone. Median follow-up was 46 months. Failure-free survival, at 5 years after first HIFU, was 70%, it was 87%, 63% and 58% for low, intermediate and high-risk groups, respectively. Complication rates were low: Urethro-rectal fistula occurred in 0.23–0.7% in the large studies treated with Ablatherm device [1113]. Erectile Dysfunction (ED) occurred in 35–45% of previous potent patients and bladder outlet obstruction in 24–28% (66–67). Incontinence rates reported in recent studies were: 4–5.5% grade I and 1.5–3.1% grade II/III. In the largest study published in [11], severe incontinence and bladder outlet obstruction (BOO) decreased from 5.7% and 10.2% to 3.1% and 5.9%, respectively, thanks to refinement in technology.


Results of Whole Gland Ablation as Salvage Treatment of Locally Recurrent PCa After Radiation Therapy


The rate of positive biopsy after External Beam Radio Therapy (ERBT) for prostate cancer in the literature is between 25 and 32%. Patients with a locally proven recurrence after external-beam radiation therapy and no metastasis are usually treated with androgen deprivation. Since 1995 the Ablatherm device has been used as a salvage treatment in patients with local recurrence after EBRT without metastasis. The first study was published in 2004 [16, 17]. Crouzet et al. examined the outcomes of salvage HIFU in 290 consecutive patients with biopsy-confirmed locally radio recurrent PCa, without evidence of metastasis [18]. Progression was defined using Phoenix biochemical failure criteria or the introduction of androgen deprivation (AD). Local cancer control with negative biopsy results were obtained in 169 patients out of 208 who underwent post-HIFU biopsies (81%). The median PSA nadir was 0.14 ng/mL. The cancer-specific and metastasis free survival rates at 7 years were 80% and 79.6%, respectively. The Progression Free Survival Rate (PFSR) was significantly influenced by three factors: the pre-HIFU PSA level, the Gleason score and a previous AD treatment. With the use of dedicated acoustic parameters, the rate of severe side effects decreased significantly from standard parameters: recto urethral fistula (0.4%), grade II/III incontinence (19.5%), and bladder outlet obstruction (14%). Rouvière et al. demonstrated in [19] that the MRI localization of cancer recurrence anterior to the urethra is an independent significant predictor of salvage HIFU failure after EBRT. Therefore, MRI may be useful for patient selection before post-EBRT salvage HIFU ablation. Two articles reported outcomes of salvage HIFU performed with the Sonablate [20, 21], showing the biochemical survival rate was 71% at 9 months and 52% at 5 years. Nevertheless, the risk–benefit ratio of salvage HIFU compares favorably with those of the other available techniques and with less morbidity and similar oncological outcomes. In this context, HIFU appears to be an effective curative treatment option for local recurrence after radiation failure.


Accurate Mapping of Prostate Cancer with MRI Plus Guided Biopsies and Evaluation of the Destruction of the Target Volume: The Keys for Focal Therapy


For a long time, it has been considered that prostate cancer could not be reliably detected by imaging methods. As a result, even today, it is diagnosed by means of systematically-distributed prostate biopsies. However, current 12-core systematic biopsy schemes can miss prostate cancer in up to 20% of patients. They also may underestimate prostate cancer volume and aggressiveness. The localization value of positive samples is also limited [22, 23]. Extensive research has been performed since the 1990s to develop an imaging method that can accurately show the position and volume of the different prostate cancer foci within the gland. This would dramatically improve the assessment of the tumor volume and aggressiveness by improving the sampling of the suspicious areas. As a result, it would also improve patient management, by selecting the appropriate treatment on more precise data. It is also a necessary condition for any focal treatment [23]. Despite recent improvements, ultrasound-based methods cannot currently provide an accurate mapping of intraprostatic cancer foci [24]. T2-weighted MRI has long been used as a staging method for prostate cancer as it provides a favorable contrast between the hyperintense normal peripheral zone and the hypointense cancer tissue. Unfortunately, it only achieves a 25–60% sensitivity in localizing prostate cancer foci [2527]. Hydrogen MR spectroscopy can provide molecular information, but its added value to T2-weighted imaging has been disappointing [28]. The use of dynamic contrast-enhanced (DCE) imaging at the turn of the 2000s dramatically improved the sensitivity of MRI [27] and started to show good results in predicting biopsy results [29]. The advent of diffusion-weighted imaging a few years later further improved the diagnostic performance of MRI [30] which became the so-called multiparametric MRI (mpMRI) , associating T2-weighted imaging with DCE, diffusion-weighted and/or spectroscopic imaging [31]. mpMRI has shown excellent results in detecting aggressive cancers with detection rates of 56–63% and 88–92% for Gleason 7 cancers of less and greater than 0.5 cc, respectively, and of 96% for Gleason ≥8 cancers [32]. Biopsies guided by mpMRI findings can also outperform systematic biopsies in detecting aggressive cancer [33, 34]. Because of these good results, mpMRI has currently become the cornerstone of focal treatment planning. However, mpMRI has two limitations. First, many benign conditions may mimic prostate cancer when using mpMRI. As a result, 40–75% of focal lesions seen at mpMRI are benign [32, 35]. It is therefore mandatory to biopsy all focal lesions before selecting patients for focal treatment. These so-called targeted biopsies have first been performed using cognitive guidance. The operator uses anatomical landmarks to target under transrectal ultrasound guidance the prostate area that was abnormal on mpMRI. However, there is potential for error in the extrapolation from MR to transrectal ultrasound images, because MR and ultrasound images are not acquired along the same plane. Sophisticated techniques of US/MRI fusion have been developed over the last 10 years to help the biopsy operator target the right area [36]. Some researchers have also proposed direct in-bore MR guidance [37]. This later technique is potentially very accurate but is limited by its cost and the need for dedicated scanning time. mpMRI is also limited by the fact that it underestimates the histological tumor volume [38, 39]. There is currently no reliable estimation of the safety margin that should be applied around malignant focal lesions seen on mpMRI to have a reasonable chance of destroying the entire histological tumor. This will probably be the topic of intensive research in the near future. Some US/MR fusion systems can register the position of the biopsy cores within the prostate. By retrospectively indicating which cores are positive, it is possible to define a target volume for focal treatment. These so-called 3D biopsie s can be performed either transrectally or using a transperineal template. The precision of the tumor localization depends on the co-registration accuracy of the biopsy cores and on the number of cores. Although there is no large series of focal treatment using these 3D co-registered biopsies for treatment planning, this method could be interesting in addition to the tumor mapping provided by mpMRI.

In addition to a precise preoperative mapping of prostate cancer foci, there is also a need for an imaging method that can evaluate the destruction of the target volume. The ablated prostate volume appears on gadolinium-enhanced MRI as a devascularized zone that persists for 1–3 months postoperatively [40]. However, MRI is usually performed a few days following the treatment. It has recently been shown that contrast-enhanced ultrasound (CEUS) using Sonovue (Bracco, Milan, Italy) as a contrast medium showed similar findings as the postoperative gadolinium-enhanced MRI and could predict the presence of residual living tissue at postoperative biopsy [41]. On CEUS images, destroyed tissue appears as devascularized within minutes following the treatment [41]. It is therefore possible to immediately retreat the patient in case of unsatisfactory results.

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Jan 29, 2018 | Posted by in UROLOGY | Comments Off on The History of Focused Ultrasound Therapy in Urology

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