Ultrasound-Guided Treatment of Prostate Cancer: High-Intensity Focused Ultrasound

Fig. 32.1

Prof. W. Fry

In the 1980s, Lizzi proposed a machine that used focused ultrasound for the treatment of glaucoma and intraocular neoplasms (which was rapidly substituted by a laser; Fig. 32.2) [9].

Fig. 32.2

Prof. F.L. Lizzi

At the end of the 1980s, the INSERM (French National Institute for Medical Research), the Hospital of Lyon, and EDAP Technomed started a research programme on the interaction of HIFU with tissues. The main aim of this study was the use of focused ultrasound in the treatment of cancers: thus, the Ablatherm prototype, dedicated to the treatment of PC, was created (Fig. 32.3).

Fig. 32.3

Ablatherm prototype

The crucial impulse for using HIFU in the treatment of cancers started at the beginning of the 1980s because of the development of diagnostic imaging, which led to the adequate planning and monitoring of treatments, with the help of ultrasound and magnetic resonance imaging.

A first clinical trial begun in 1992 by Gelet and colleagues (Fig. 32.4). This trial reported observations on 12 patients subjected to adenomectomy following prostate therablation with HIFU. The specimen of prostate tissue revealed that the tissue lesions varied according to the ultrasound dosage with homogeneous coagulative necrosis and net margins if used with high dosages. In this study, no major complications were described, but anomalies of rectal mucosa were found in a quarter of the patients [10].

Fig. 32.4

Prof. A. Gelet

Gelet and colleagues started the first clinical study on patients with PC in 1993; the first results were published in 1996 [3].

Since that moment, the method has been widely distributed, especially in Europe, involved in 30,000 treatments (both as first-line therapy and re-treatment/salvage treatment after radiotherapy failure), using EDAP machines, excluding the Focal One (Fig. 32.5).

Fig. 32.5

Spread of high intensity focused ultrasound (HIFU) over the last 30 years

32.3 Physics Principles of HIFU

Focused ultrasound is based on the same principles as conventional ultrasound, which are inaudible sound waves with a frequency of > 20,000 Hz. They are generated by a piezoelectric crystal, which vibrates, with a peculiar frequency for the crystal itself, if crossed by electricity. When ultrasound propagates across the human body, the energy also propagates and the waves attenuate; their passage across the tissues determines energy release, which is absorbed by the tissues themselves. This implicates the use in diagnostic imaging of low intensity ultrasound (720 mW/cm²) to induce minor perturbation in the tissues [11]. Conversely, in the case of HIFU, the high intensity, which ranges from 100 up to 10,000 W/cm², and the consequent release of energy, allow tissue damage, which may have therapeutic importance if applied to neoplastic lesions [4].

The HIFU source is represented by a piezoelectric transducer with a spherical shape, which is able to generate and focus ultrasound on a fixed point. According to the voltage used, both the ultrasound frequency (range about 3–4 MHz in the case of HIFU used for thermoablation) and the power applied to the target (values ranging from 1300 up to 2200 W/cm³) are established [12–14].

32.4 Thermoablation and Mechanism of Action of HIFU

The thermoablation is defined as the necrosis induced in human tissues by the increasing temperature obtained by the transmission of energy and its conversion to heat. The ablation can be obtained with a temperature of 56 °C for 1 s [15, 16]. This exposure causes immediate cell death, because of the denaturation of the protein, damage to mitochondrial enzymes and cell cytosol, and of the formation of histone complexes [17, 18]. Considering the pathological aspect, the damage is typical of coagulative necrosis, followed by secondary fibrotic tissue involvement (Fig. 32.6) [3, 19].

Fig. 32.6

On the left, a pathological examination of a prostate biopsy 2 days after HIFU: evidence of coagulative necrosis in the tissue. On the right, a pathological examination of a prostate biopsy 3 months after HIFU: the tissue has been completely replaced by fibrosis

The phenomena of evaporation and carbonisation are typical when the temperature is higher than 100 °C; these are not useful because they limit the transmission of thermal energy and the consequent extent of necrosis in the area (Table 32.1). Thus, the main aim of thermoablative treatments is to reach a temperature of about 65 °C for a few seconds.

Table 32.1

Effects of temperature on the tissues

Temperature (°C)	Biological effect of tissue	Exposure time
>300	Fusion	<1 s
>100	Carbonisation	<1 s
100	Formation of bubbles of vapour, mechanical ruptures	Seconds
56	Denaturation of proteins, coagulation of tissues	Seconds/minutes
>50	Reduction of enzymatic activity, inactivation of the mechanisms of cell reparation	Minutes
42–50	Hyperthermia, destruction of links	Hour/minutes

Thermoablative procedures are largely used in oncology in the treatment of neoplasm in the liver, lung, bone, kidney, prostate, thyroid, breast and pancreas; the procedures differ from each other because of the transmitting source, which can be electromagnetic waves, lasers, radiofrequencies, microwaves and HIFU. The thermoablative effect of HIFU is caused by the controlled release of a large amount of energy inside the tissue, owing to the increasing intensity of ultrasound waves and focus on a single site. The temperature increases in this way in a well-defined tissue volume and this volume is destroyed because of coagulative necrosis [20].

Thus, HIFU is able to induce an increasing temperature inside the tissue, in the fastest way (few seconds). The intensity, which is very high in the focal area (generally very small), rapidly decreases in the adjacent tissue zones. Starting from this concept, HIFU is causes tissue damage at the focused site, sparing the proximal areas (Fig. 32.7).

Fig. 32.7

Silicone gum block used as a target to explain the specific form of the elementary lesion. The area around the lesion is uninjured (Reproduced from Chapelon et al. [21])

There are three mechanisms involved in the generation of tissue damage: thermal effect, mechanical effect and a cavitation effect.

The energy of the ultrasound is absorbed by biological tissues and transformed into heat with the change of the intracellular water into steam (thermal effect). A bubble is then formed with a rapidly increasing temperature and pressure [15]. When the resonance dimension is reached, the bubble implodes and generates cavitation, giving back the accumulated energy to the surrounding space (Fig. 32.8).

Fig. 32.8

Specimen showing a coagulative necrosis surrounding a cavitation area. The tissue slide comes from a site proximal to the focal point, in a perpendicular plane to the axis of the ultrasound (Reproduced from Chapelon et al. [21])

Consequently, there are shock waves with high pressure, the release of active free radicals and the manifestation of intense mechanical forces that participate in the determination of tissue damage [18].

32.5 Transrectal Prostate Thermoablation with HIFU

One of the peculiarities of HIFU is that it can be applied through the rectum with minimal risk of rectal injury.

The prostate is an ideal target for HIFU because it is located proximal to the anus, with a depth about 1–4 mm, respecting the internal rectal wall, which is not influenced by respiratory movements (Figs. 32.9 and 32.10)

Fig. 32.9

Male anatomy

Fig. 32.10

Modality of action of HIFU probe

Elementary lesions caused by the HIFU machines currently available for curing PC have an elliptical shape, similar to a cigar (Fig. 32.11), with a maximum volume of about 300 mm³ and a length that differs according to the machine used, from 5 up to 26 mm and a width of 5 mm [22]. The effects of this kind of energy are summarised in the Table 32.2.