High Intensity Focused Ultrasound: Past, present and future

“Any intelligent fool can make things bigger, more complex, and more violent. It takes a touch of genius–and a lot of courage–to move in the opposite direction.” (Albert Einstein)

In a world in which diagnostic ultrasound is widely used and accepted, and is generally thought to be “safe”, it may be surprising to some that the initial medical interest in ultrasound (US) was as a modality that could cause deliberate tissue damage. It was the Fry brothers based in Illinois, USA, who did much of the pioneering work in concentrating high energy ultrasound into a target volume, with the purpose of selective destruction of specific regions of the brain for neuro-behavioural studies [1]. They realised that the physical properties of ultrasound, most importantly the millimetric wavelengths in soft tissues at megaHertz frequencies, allow the tight focusing of a beam, and thus the potential for “trackless” lesioning–that is, the creation of small volumes in which cells have been rendered non-viable, with no damage to overlying and surrounding tissue structures.

The Frys’ early work used four quartz transducers arranged to allow their beams to overlap within the tissue target. Later studies have used single element spherical bowls, plane transducers fronted by suitable lenses and phased arrays [2]. The Illinois group were able to develop their technique to the point at which they could apply it to humans. High-Intensity Focused Ultrasound (HIFU) found itself in competition with the drug L-dopa which was also being developed at that time. Considerable clinical success was apparently also achieved with HIFU for ophthalmological applications. Lizzi et al. [3–5] used HIFU for sealing retinal tears and glaucoma treatment. Again, however, a competing therapy, in this case laser treatment, appeared at the same time, and became the treatment of choice.

Interest in HIFU waned in the 1970s. Although the ability to produce high intensity focused beams improved with the introduction of piezo-ceramic and piezo-composite transducers capable of being driven at high voltages, full advantage of the potential to create spatially highly localised regions of damage could not be realised until imaging techniques such as magnetic resonance (MR) imaging and US became sufficiently sophisticated to allow accurate identification of the target volume.

Today, HIFU is one of a number of thermal ablation techniques that are entering the clinical arena as minimally invasive treatments. Microwave, radiofrequency, laser and cryoablation techniques have all found roles in cancer therapy. HIFU is unique in that it is not necessary to insert a probe into the target tissue, making it the only truly non-invasive ablative technique. While this removes the risk of seeding tumour cells along the probe insertion track, and has many advantages for patient comfort and acceptability, it allows relative movement between the source and the target that must be overcome. Whereas an in situ probe is only able to ablate a volume in its immediate vicinity with fixed geometry, a HIFU focus can be freely moved over any shape of volume until the whole target region has been “painted out”. The main disadvantage of HIFU is the small volume destroyed with each exposure. A typical focal region is ellipsoidal in shape, and may be ∼1.5 cm along the beam axis, and 1.5 mm in diameter. (These dimensions depend on the transducer frequency and focusing geometry.)

In spite of this limitation, HIFU has already shown itself to be a powerful and most promising non-invasive technique for selective tissue destruction. There are a number of challenges that must be successfully met before it will become the treatment of choice. A HIFU treatment essentially has three components. The first is target identification and treatment planning, the second is acoustic energy delivery and its conversion into heat, whilst the third is treatment monitoring.

It is important that the most appropriate imaging methods for each target site are used to identify the treatment volume, and where necessary that image registration techniques are employed to allow more accurate treatment planning and delivery. The development of adaptive focusing techniques for aiding the application of HIFU in sites that are overlain by bone is an important area for the furtherance of its clinical application in the brain [6–10] and in abdominal organs protected by the rib c [8], [11]. Whilst the non-invasive nature of HIFU makes it extremely attractive, it is becoming clear that there will be applications for which an intra-cavitary device may be preferable [12–13]. This has already proven to be the case for prostate treatments where a trans-rectal approach has been shown to be successful [14]. In addition, intra-operative devices for treatment of tumours discovered during surgery, or for those difficult to target by other routes, may prove useful.

The integration of imaging and therapy already available has allowed the potential of image-guided HIFU to be demonstrated. Modern ultrasound and MR scanners have made this possible, and image-guided HIFU treatments have become the norm. There are advantages and disadvantages to each imaging modality for use with HIFU. Ultrasound is capable of providing real-time tissue information, especially when the imaging frames are inter-leaved with the therapeutic pulses to avoid interference effects [15], but changes in the focal region are only clearly visible on B-mode images when bubbles are produced, leading to hyperechogenic regions [16]. The change in stiffness brought about by HIFU induced heating can be visualised using elastographic techniques [17–19]. This is not yet used for real-time monitoring of HIFU treatments. MR imaging provides excellent anatomical images in quasi-real time. It is also possible, using appropriate sequences, to produce temperature maps and to overlay the calculated thermal dose on the image slice [19]. The spatial and temporal resolution is, however, better for US than for MR imaging. Ultrasound scanners are smaller and less expensive than MR devices, and conceptually it seems more attractive to use ultrasound as the imaging modality, given that the imaging and therapy beams will undergo similar distortions and reflections in the tissue path. The introduction of real-time ultrasonic thermometry methods will make the argument for using US far more compelling. US thermometry techniques, based on the temperature dependence of speed of sound and attenuation, are currently under investigation, but are not yet implemented on clinical devices [19].

Techniques for increasing the speed of tissue destruction are being actively sought. Approaches to this include modification of the acoustic field patterns using phased array transducer design and/or scanning geometries, and tissue modification by the introduction or generation of gas bubbles, or alteration of vascular perfusion. It has been demonstrated that the presence of gas bubbles greatly enhances the rate of temperature rise locally [20], [21]. The key to harnessing this phenomenon is its control [22], [23] to ensure that the associated cell killing occurs in the target volume, and not elsewhere in the acoustic field. Effective treatment of hepatocellular carcinoma has been demonstrated when trans-arterial chemo-embolisation is performed prior to HIFU [24]. This appears not only to reduce the vascularity of the tumour, thus reducing heat loss by blood perfusion, but also to increase the acoustic absorption coefficient, thus allowing lower acoustic powers to be used. Another method of altering the blood supply to a tumour is to use the vascular occlusion capability of a HIFU beam. This has considerable future potential not only for reduction of tumour nutritive supply, but also well beyond the field of oncology for the sealing of breached blood vessels [25–27]. An additional benefit of HIFU is the intriguing evidence that it may activate the immune system [28]. This is something that needs further study.

At a time when research and clinical efforts are increasingly focused on the development of minimally invasive cancer therapies that enhance the quality of life of patients and are safe for clinicians to use, HIFU is rapidly emerging as the most promising treatment for truly non-invasive ablation of deep-seated tumours. Pending some much needed advances in treatment targeting, real-time treatment monitoring and speed of ablation, HIFU has genuine potential to become the method of choice for a wide array of oncological and non-oncological applications by virtue of its low cost and intrinsic therapeutic and operational safety. The starting objective of this special issue is to provide both the specialist and non-specialist reader with an overview of the physical principles governing HIFU-induced heating, with reference to currently available extra-corporeal, transrectal, interstitial and intra-luminal devices. Some salient issues in HIFU treatment targeting and delivery are also addressed, ranging from the need to compensate for tissue motion and the presence of bony interfaces during HIFU exposure, to the potentially significant role played by acoustic cavitation in enhancing heat deposition and facilitating treatment monitoring. In this context, the status and limitations of current methods for HIFU treatment monitoring and thermometry are addressed. Potential immunological effects of HIFU are also investigated. Finally, a detailed account of the rapidly expanding range of clinical HIFU uses is given, ranging from abdominal and gynaecological applications to the treatment of tumours in the prostate and the brain, as well as to non-oncological applications such as acoustic haemostasis.