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British Journal of Radiology (2003) 76, 590-599
© 2003 British Institute of Radiology
doi: 10.1259/bjr/17150274
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Review article

High intensity focused ultrasound: surgery of the future?

J E Kennedy, MBBS, MRCS 1 G R ter Haar, MSc, PhD, DSc 2 and D Cranston, DPhil, FRCS 3

1 Research Registrar, Department of Urology, Churchill Hospital, Oxford, 2 Head of Therapeutic Ultrasound, Royal Marsden Hospital, Sutton and 3 Consultant Urologist, Churchill Hospital, Oxford, UK


   Abstract
Top
 Abstract
Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
For 50 years, high intensity focused ultrasound (HIFU) has been a subject of interest for medical research. HIFU causes selective tissue necrosis in a very well defined volume, at a variable distance from the transducer, through heating or cavitation. Over the past decade, the use of HIFU has been investigated in many clinical settings. This literature review aims to summarize recent advances made in the field. A Medline-based literature search (1965–2002) was conducted using the keywords "HIFU" and "high intensity focused ultrasound". Additional literature was obtained from original papers and published meeting abstracts. The most abundant clinical trial data comes from studies investigating its use in the treatment of prostatic disease, although early research looked at applications in neurosurgery. More recently horizons have been broadened, and the potential of HIFU as a non-invasive surgical tool has been demonstrated in many settings including the treatment of tumours of the liver, kidney, breast, bone, uterus and pancreas, as well as conduction defects in the heart, for surgical haemostasis, and the relief of chronic pain of malignant origin. Further clinical evaluation will follow, but recent technological development suggests that HIFU is likely to play a significant role in future surgical practice.


   Introduction
Top
 Abstract
 Introduction
What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
The quest continues for a reliable and minimally-invasive alternative to open surgery. The endoscopic revolution is well underway and there is much research activity in other fields such as laser, radiofrequency, cryo-, thermo- and brachy-therapies. Lithotripsy is now an established treatment for stone disease, but currently, the only non-invasive modalities in mainstream use for cancer treatment are chemotherapy and radiotherapy, both of which carry significant side-effect profiles.

High intensity focused ultrasound (HIFU) has the potential to provide the clinician with another truly non-invasive, targeted treatment option. Its scope is not, however, limited to the direct treatment of cancers. It may also be used in a palliative setting for relief of chronic pain of malignant origin, for haemostasis, or even for the treatment of cardiac conduction or congenital anomalies.


   What is HIFU?
Top
 Abstract
 Introduction
 What is HIFU?
History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
HIFU relies on the same principles as conventional ultrasound. It can propagate harmlessly through living tissue, but if the ultrasound beam carries sufficient energy and is brought into a tight focus, the energy within the focal volume can cause a local rise in temperature of sufficient magnitude to cause tissue necrosis (a "lesion"). This occurs without damage to surrounding or overlying tissues (Figure 1Go). The ability to cause cell death in a volume of tissue distant from the ultrasound source makes HIFU an attractive option for development as a non-invasive surgical tool. This process is variously known as HIFU(S) therapy, ultrasound ablation, focused ultrasound surgery (FUS) and pyrotherapy.



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  		Figure 1. A schematic representation of high intensity focused ultrasound lesion production.

 

   History of HIFU
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
The phenomenon of piezoelectricity [1], the potential of piezoelectric materials as sources of ultrasound [2], and the biological effects of high-intensity ultrasound were all reported around the beginning of the last century [3]. A detailed chronicle of the early work and medical applications of therapeutic ultrasound is given by Kremkau [4].

The first work to consider potential applications of HIFU was published in 1942 [5], and this was built upon in the 1950s, when William Fry et al produced lesions deep in the brains of cats and monkeys [6, 7]. Frank Fry subsequently treated patients with Parkinson's disease and other neurological conditions [8]. Research into the use of HIFU in neurosurgery continued during the 1950s and 1960s [9–12], but practical and technological limitations restricted their progress.

In 1956, Burov had suggested that high intensity ultrasound could be used for the treatment of cancer [13], and in the following years several studies looked at the effects of ultrasound on tissues [14]. The specific properties of focused ultrasound conduction and modes of destruction in normal tissues were investigated further during the 1970s and 1980s [15–17], and studies using HIFU to irradiate experimental tumours followed [18, 19]. In recent years, there have been many independent avenues of research into the potential applications of HIFU across the spectrum of clinical practice. These will be explored below.


   Physical principles
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
Mechanical vibrations above the threshold of human hearing (16 kHz) are called ultrasound. There is a broad spectrum of ultrasonic frequencies, and different applications employ different frequencies. All clinicians will be familiar with diagnostic ultrasound, which usually employs frequencies in the range of 1–20 MHz, and a summary of lower frequency industrial applications such as cleaning, plastic welding and bactericidal water purification can be found elsewhere [20]. A more detailed account of the physics of ultrasound can be found in the text by Williams [21].

Mechanism of therapeutic action
Ultrasound causes tissue damage through two predominant mechanisms. The first is by the conversion of mechanical energy into heat, the second is through cavitation. As an ultrasound beam propagates through tissue, some of its energy is deposited as heat, but in normal circumstances, this heat will dissipate rapidly. If the rate of heating exceeds the rate of cooling, the result will be a local temperature rise. Arrest of cellular reproduction will occur if the temperature is maintained above 43°C for 60 min or longer. This is of particular relevance for existing "hyperthermia" or "thermotherapy" treatments, where the aim is to raise the temperature of the target tissues to a precise temperature (usually just above 42°C) for a defined period of time. In contrast, HIFU relies on the fact that, above a threshold of 56°C (for 1 s), rapid thermal toxicity occurs, causing irreversible cell death through coagulative necrosis. During HIFU treatments, the temperature at the focus can rise rapidly above 80°C [22], which, even for the shortest exposures, should lead to effective cell killing [23] and thus precise monitoring of temperature is unnecessary. There is a steep temperature gradient between the focus and neighbouring tissue, which is demonstrated by the sharp demarcation between the volume of necrotic tissue (lesion) and normal surrounding cells on histology [24].

The cooling effect of perfusion may limit the reliability of other forms of hyperthermia treatment, where there is sufficient time during exposures for local thermal diffusion and heat dissipation from the target region. This factor can be practically eliminated during HIFU treatment by keeping individual exposure times below 3 s [25]. As an illustration, these lesions, under normal exposure parameters at 1.7 MHz, are ellipsoidal, with the long axis parallel to the ultrasound beam, and have dimensions of the order of 1.5 x 15 mm (Figure 2Go) [26]. The dimensions depend on frequency and the geometry of the source.



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  		Figure 2. An example of a high intensity focused ultrasound (HIFU) lesion, created ex vivo in beef liver. Schematic diagram (left) and photograph (right).

 
Acoustic cavitation is complex and unpredictable, but the end result is also cell necrosis induced through a combination of mechanical stresses and thermal injury. Ultrasound causes the tissues to vibrate, and the molecular structure is subjected to alternating compression and rarefaction. During rarefaction, gas can be drawn out of solution to form bubbles, which oscillate in size, or collapse rapidly, causing mechanical stresses and generating temperatures of 2000–5000 K in the microenvironment [20]. Cavitation is dependent, amongst other things, on pulse length, frequency and intensity [27]. It is unlikely to occur with diagnostic ultrasound, but is a factor to be considered when using HIFU. The effect of heating is both more repeatable and more predictable than cavitation [28], which made it the preferred mode of action in early clinical applications of HIFU. This preference is now fading as experience increases.

An important factor in clinical application is the ability to monitor treatment accurately. In current practice, this is achieved in one of two ways–either by using real-time ultrasound [29–31], or MRI [32]. When MR is used to guide HIFU treatments, sublesioning ultrasound exposures are used to identify the target region, local rises in temperature are used to confirm the position of the ultrasound focus and then higher intensity therapeutic exposures are used for the actual treatment. When ultrasound is used to guide treatment, the diagnostic transducer is arranged confocally with the therapeutic transducer, and their relationship is fixed. The position of the therapeutic focus can therefore be reliably identified on the diagnostic image. The extent of treatment can be monitored by recording post-treatment grey-scale changes on the diagnostic image.

MR has the advantage of better image quality and the ability to monitor temperature, but is expensive and has lower spatial resolution. Correlation of the relationship between the focused ultrasound and the MR images is slow and more complex than for ultrasound imaging. Ultrasound has the benefits of lower cost and accessibility, faster treatment times and a gives a good correlation between observed ultrasound changes and the region of necrosis in the tissue. Its disadvantage is that the image quality may be less than optimal [33]. Ultrasound is also obstructed by bone and air-filled viscera, but this may be seen as an advantage, as it is important to identify the position of such structures relative to the therapeutic beam if complications or incomplete treatments are to be avoided.

Other methods of monitoring HIFU treatment such as elastography are being developed [34], but none are currently available clinically.


   HIFU devices in clinical use
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
A large number of devices are used in experimental studies, but there are fewer devices in current clinical use. The two main categories of device are extracorporeal and transrectal in approach. Extracorporeal devices have been used to target many organs. They require a longer focal length than transrectal sources on principle. For this reason, they tend to employ transducers of larger dimensions, which (with the exception of ophthalmic devices) operate at lower frequencies with higher intensities than their transrectal equivalent. Transrectal devices treat the prostate. Technical details of three extracorporeal and two transrectal devices will be given as illustration.

ter Haar et al have built a prototype device for extracorporeal use, which employs a spherical lead zirconate titanate (PZT) ceramic transducer of 10 cm diameter and 15 cm focal length. It is driven at a frequency of 1.7 MHz and operates at free field spatial intensities between 1000 Wcm-2 and 4660 Wcm-2 [22]. Another device has been designed and developed in China (Chongqing HAIFU Technology Company, Chongqing, P.R. China). This uses a 12 cm diameter PZT transducer of focal length 10–16 cm, driven at either 0.8 MHz or 1.6 MHz. It operates at higher intensities (up to 20 000 Wcm-2), and also has a built-in 3.5 MHz diagnostic scanner [29]. A third extracorporeal device uses an MRI compatible 10 cm diameter focused transducer with an 8 cm radius of curvature, operating at 1.5 MHz (GE Medical Systems, Milwaukee, WI) [32]. Details of other extracorporeal devices can be found elsewhere [35, 36].

One transrectal device (Sonablate, Focal Surgery, Milpitas, CA) uses a 4 MHz PZT transducer for both imaging and treatment. The focal length can be 3.0 cm, 3.5 cm or 4.0 cm, and the intensity at the focus is 1680–2000 Wcm-2 depending on the focal length [30]. The other device (Ablatherm, Technomed International, Lyon, France) uses a rectangular transducer of focal length 4 cm, which is driven at 2.25–3.0 MHz and an intensity of 1000 Wcm-2. This probe has a built-in retractable 7.5 MHz imaging element [31].


   HIFU as a surgical tool
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
There has been considerable interest in the development of HIFU, and previous reviews have discussed developments in a variety of fields [23, 37–39]. However, there has been significant progress in recent years, with improvements being made in transducer design, modes of energy delivery and real time imaging, so further analysis is warranted. The various animal studies and clinical trials will now be considered systematically by organ and disease. Animal studies and phase I trials will be mentioned briefly, but the important features of phase II trials will be discussed in context where appropriate.

Liver
The liver has been a target for HIFU since the early days of animal experimentation. Initially, the ability to create lesions was established in small animal models [14, 17], and the thresholds for liver tissue destruction with varying exposure parameters were established in the 1970s and 1980s [16]. Normal tissue studies continued in the 1990s [25, 40, 41]. A number of tumour models have also been used to predict the effects of HIFU on hepatocellular carcinoma or discrete liver metastases in humans [22, 42–47]. A summary of some of these earlier studies can be found in a review by Kopecky et al [37]. Large animal studies have also been carried out in a number of centres [48–53].

Despite this wealth of experience with animal studies, there is a scarcity of published data on human clinical trials. Vallancien et al treated two patients with solitary liver metastases prior to surgical resection, but in one there was no visible effect, and in the other there was extensive tissue laceration and patchy necrosis [54]. Phase I clinical trials using HIFU to treat liver tumours have been completed at the Royal Marsden Hospital in Sutton, UK, and phase II studies are ongoing [55].

Recently, Wu et al reported the treatment of 68 patients with liver malignancies using HIFU. In all 30 cases where the tumour was subsequently excised, the tumour was totally ablated [29]. More recently 474 patients with hepatocellular carcinoma have been treated using the Chongqing HIFU device in China [56]. They have observed clear changes on contrast enhanced MRI at 1–2 weeks post HIFU and subsequent shrinkage over time. Total treatment times vary from 1 h for a superficial 2 cm tumour, to 5 h or more for a 10 cm tumour (Wu F, 2002. Personal communication). Even from experience of this scale, follow-up has been patchy and limited by local referral patterns, so remains little more than anecdotal. However, the situation is being remedied and more robust clinical trial data, describing a statistically significant survival benefit from HIFU with transarterial chemoembolisation (TACE) over TACE alone, is likely to be available soon.

Hepatocellular carcinoma is amongst the most common malignancies worldwide and hepatic metastases are the most common cause of death in cancer patients. Currently surgery remains the only real hope for cure, although even after surgical resection of hepatic metastases survival rates are only 25–30% at 5 years. As a result, a non-invasive alternative to surgery such as HIFU would be of considerable benefit and it is of no surprise that much interest remains in this field. Clinical experience is growing in China, and clinical trials are now also underway at the Churchill Hospital in Oxford to investigate this application further.

Although HIFU is the only non-invasive alternative to surgery, there are a number of minimally invasive treatment options that are being investigated. These include cryotherapy, arterial embolisation, percutaneous alcohol ablation and either percutaneous or laparoscopic radiofrequency ablation [57–59]. These techniques may have advantages such as shorter treatment times, but for all of them there is a disadvantage of invasiveness and an upper size limit for tumours that can be treated of approximately 3 cm or 4 cm diameter.

Prostate
In 1993, Susani et al reported on a phase I clinical trial to study the effect of HIFU on prostatic tissue and confirmed that they could reproducibly achieve tissue damage [60]. Foster et al also treated 15 patients in a pilot study to assess safety in the human clinical situation [61]. Gelet et al described similar success in creating prostatic lesions using another transrectal device [62]. Vallancien et al [63] used an extracorporeal device to target the prostate, but encountered problems from skin burns in 10% of patients. More recently, Koehrmann et al have examined the use of a different prototype extracorporeal device directed at the prostate, once again reporting successful tissue ablation [64], but in this instance with less morbidity (4% skin burns).

Benign prostatic hyperplasia
Since mid-1992, several groups have investigated the potential of HIFU in the treatment of symptomatic benign prostatic hyperplasia (BPH), and this is where the most abundant data recording the clinical use of HIFU can be found [30, 65–78]. Most of the phase II trials in this area were conducted using the same transrectal Sonablate device.

Investigators initially claimed rises of varying degrees in maximum flow rate (Qmax), and falls in symptom scores at early follow-up (up to 1 year) [30, 65–69], but changes were only moderate at best by 1 year [70]. The inclusion of the bladder neck in the treatment area led to improved results [71, 72], as did advances in equipment design [73, 74], but these results were not sustained. Longer-term follow-up data can be found in Table 1Go. It also revealed that 43.8% of patients had to undergo salvage transurethral resection of the prostate (TURP) within 4 years, and results were not considered sufficient to recommend HIFU as a minimally invasive alternative to TURP [78].


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  		Table 1. Longer-term follow-up data from benign prostatic hyperplasia studies

 
TURP, the gold standard, has been shown to reduce symptoms by at least 50% (exceeding 70% in the majority), and increase Qmax by a mean value of 125%. These results should be durable, and an acceptable re-intervention rate should be less than 16% at 8 years [79]. To be taken seriously HIFU must demonstrate comparative long-term results and a reduced complication rate. Excepting the earliest cases, the only frequently reported adverse events with the use of transrectal HIFU seem to be transient retention, haematuria and haematospermia. It remains unclear as to why HIFU has not achieved results comparable with TURP, although it is probably due to the lower treated volumes in a given time, and the fact that the tissue is physically removed during TURP, while the necrotic volume must be phagocytosed following HIFU. In these studies, treatment times were limited to be comparable with TURP, but unless a significantly greater proportion of the gland can be treated in this time, it does not appear as though HIFU will achieve equality with TURP. It thus seems unlikely that HIFU will be accepted as a real alternative in the treatment of BPH.

Carcinoma of the prostate
The treatment of carcinoma of the prostate (CaP) is more complex than that of BPH. Different treatment modalities have a place in the different disease stages and there is no universally agreed gold standard treatment. The therapeutic choice for organ confined CaP lies essentially between radical prostatectomy and external beam radiotherapy, and it is generally agreed that the morbidity of surgery is not justified in patients with a life-expectancy of less than 10 years. Brachytherapy and cryotherapy are alternative non-surgical options, but are not widely available. One major drawback of all of these techniques is that treatment cannot generally be repeated in cases of local recurrence.

The ability to destroy entire tumours successfully was first reported in 1995 by Madersbacher et al [80]. The rates of local control have increased dramatically from 50% at 8 months in early studies to approaching 90% in the latest reports [81, 82]. Early on, HIFU was proposed as an additive tool in the treatment of CaP prior to hormonal ablation [83]. Techniques then progressed from local to global treatment of the gland as treatment times reduced [84, 85], and results improved with experience [86, 87]. A summary of the results of these studies can be found in Table 2Go.


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  		Table 2. Outcome after high intensity focused ultrasound treatment for carcinoma of the prostate

 
Longer term follow-up data come from papers by Chaussy and Thüroff [31] and Gelet et al [88], and the most recent European data (including over 2000 patients) were reported by Chaussy in 2002 [82]. In their overall case series, they have observed negative biopsy rates in 87.2% of patients, and prostate specific antigen (PSA) values remained at their post HIFU nadir in 84.1% at 1 year.

A detailed account of the complications encountered during 3 years' experience (315 treatments) is provided by Thüroff and Chaussy [89], and the most recent data describe stress incontinence in 13% (but only 1% Grade III), erectile dysfunction in 22% and urinary tract infection in only 5% if HIFU is preceded by a limited TURP. Pre-HIFU TURP is indeed now standard for treatment in Europe. It serves to reduce the prostate volume prior to HIFU and has also been shown to reduce post HIFU rates of urinary tract infection and acute retention of urine. A total treatment time of 2–3 h is reported for the combined procedure [82]. There was, however, no perioperative mortality, no requirement for blood transfusion and no instance of urgent surgical revision.

A recent review article compared brachytherapy (BT) with radical prostatectomy (RP) [90]. In patients post-RP, PSA should fall to undetectable levels within months, whereas after BT, either a PSA threshold of 0.5 ng ml-1, or three consecutive increases in specimens taken 6 months apart are used to judge treatment failure. The long-term success rate by PSA measurement is quoted as 84–97.8% for RP, and 79–88% for BT. For those with high-risk disease, 10 year disease-free survival of 58% is reported after RP. This compares with 64% at 8 years in Lyon after HIFU [91], and 74.5% when BT is combined with complementary external beam radiotherapy. Beerlage et al provide further data on other minimally invasive techniques for comparison [92]. Cryosurgery has achieved a negative biopsy rate of 71%, and PSA<1 ng ml-1 in 60% of cases.

To date, HIFU has been assessed for its potential role in the treatment of organ-confined disease in patients who would otherwise not have been offered surgery, and of local recurrence following failed surgery or irradiation. It is clear that further long-term follow-up is required to support early findings and randomized controlled trials will be needed if clinicians are to be convinced. However, it certainly appears as though HIFU already has a valuable niche to fill in an otherwise problematic group, and it is approaching the stage where HIFU could be proposed more widely as a primary therapy.

Bladder
Superficial bladder cancer has also been identified as a potential target for treatment with extracorporeal HIFU. Current surveillance relies on regular cystoscopic monitoring of patients and simultaneous treatment. Diagnostic ultrasound has been proposed as an alternative to cystoscopy [93], and if this could be combined with HIFU ablation of any identified tumours, it would obviate the need for invasive cystoscopic surveillance.

Pre-clinical studies with HIFU [50, 94] culminated in a feasibility study by Watkin et al, in which they created lesions in the bladders of 25 pigs [95]. Vallancien et al published data on another preliminary feasibility study, which included five patients with superficial bladder tumours [96]. In the same episode, they also cystoscoped each patient, noting the disappearance of tumour in two cases and coagulative necrosis in the remainder. The same group later carried out a phase II trial on 25 patients with previous low grade, superficial bladder tumours, and a single papillary recurrence, visible on ultrasound [97]. 67% were tumour free at 1 year and no invasion or metastasis was observed with follow-up of 3–21 months.

Despite these promising results, which are comparable with conventional treatment, HIFU took longer, and still required regional anaesthesia. As a result it has not yet been viewed as a more convenient alternative. There has been no further published data.

Kidney
There have been many small animal studies in which benign and malignant tissue has been destroyed within the kidney [98–101], and also a number of studies in which the normal kidney tissue of large animals has been targeted [96, 98, 103]. Vallancien et al treated four patients with renal cell carcinoma [63], but in all of these preliminary works, there were problems with skin damage, and wide variation in the extent of tissue ablation.

Susani et al included two patients with a single renal tumour in a phase I trial [60]. They claim accurate placement of lesions, but detail is sparse. In a more recent study, Daum et al accurately created seven lesions of 0.5 x 0.5 cm2 in the kidneys of two pigs in vivo [103]. In a human phase I trial, Koehrmann et al targeted 24 kidneys and created lesions reliably enough to proceed to treat a patient with a single renal tumour. They caused coagulative necrosis, which was detectable on MRI at 17 days, and the resulting fibrous tissue volume had almost disappeared at 9 months [64].

Although studies are not numerous, accuracy and reliability of techniques do seem to be improving with technological advances, and 27 patients with advanced renal cell cancer (tumour size 4–13 cm) have already been treated in China (Figure 3Go) [91]. It does seem that HIFU could provide a useful non-invasive alternative to surgery for the treatment of renal tumours, and clinical trials have now commenced in Oxford, UK to evaluate the efficacy of a specific device (HAIFUTM) in this field.



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  		Figure 3. Contrast-enhanced MRI of a left renal tumour (arrowed) in a 37-year-old man, (a) before and (b) 2 weeks after extracorporeal high intensity focused ultrasound in Chongqing, China. Note absence of contrast uptake in ablated volume (images provided courtesy of Professor Feng Wu).

 

   Neurosurgical
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
Some of the earliest clinical research into HIFU was in the field of neurosurgery, and although approximately 200 patients with Parkinson's disease were treated at this time these early studies were all limited in part by the lack of accurate imaging facilities, and in part by the need for craniotomy to provide an acoustic window in the skull. There has been, however, renewed interest in the last 3 years, since Hynynen and Jolesz demonstrated the ability to focus HIFU in the excised brain through an intact skull. They used phase corrections to compensate for field distortions caused by the bone [104]. In subsequent publications, this technique has been refined, and by utilizing the maximum area of skull possible with large-area phased arrays, the feasibility of focused ultrasound surgery through the skull has been indicated [105, 106].


   Obstetrics and gynaecology
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 
In a small animal model, Vaezy et al demonstrated the ability of HIFU to ablate induced uterine fibroid tumours [107]. Koehrmann et al have also treated fibroids in clinical trials [64]. They used an extracorporeal transducer to treat 15 patients in phase I study, and 3 patients in a subsequent phase II trial, but follow-up data are absent. Further investigation continues. Also, Denbow et al have conducted a single pre-clinical study, which looked at the ability to occlude flow in the femoral vessels of rats in vivo, and proposed HIFU as a tool for placental vessel occlusion in the treatment of twin–twin transfusion in utero [108]. Transvaginal HIFU has also been suggested as a potential form of fertility treatment in ladies with polycystic ovary syndrome, although the theory has not yet been tested clinically [109].


   Breast
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
Other applications
 Limitations of HIFU
 Conclusion
 References
 
Hynynen et al recently published results of the successful ablation of 8 out of 11 fibroadenomas, which were treated under MR-guidance [32], and Gianfelice has reported promising early findings in an ongoing study in which 20 patients with localized breast malignancies are being treated. At 6-month follow-up, 53% had negative core biopsies, and of those who had positive biopsies and were retreated, 66% are now tumour free [110]. In China, 106 patients with breast malignancies and 28 patients with benign breast tumours have been included in multicentre studies using the Chongqing HIFU system [56]. They report good results, but little follow-up data are available, and concurrent chemotherapeutic regimens may make interpretation difficult.


   Other applications
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
Limitations of HIFU
 Conclusion
 References
 
HIFU has been used successfully in Chongqing, China for the treatment of osteosarcoma and soft tissue sarcoma, where 150 patients and 77 patients, respectively, have been treated [56]. It has been used as an organ preserving treatment in four patients with a tumour in a solitary testis [111]. The technology has also been postulated as a tool for synovectomy in the treatment of rheumatoid arthritis [112]. In the field of ophthalmology, the use of HIFU has been investigated thoroughly since the late 1960s [113, 114], but the advent of laser has superseded it in most applications. A more recent development has been the design of a device for use through an endoscope [115], and work continues in this area. HIFU has also been used to good effect in Chongqing in over 40 patients for control of opiate refractory pain and palliation in patients with advanced malignancy such as pancreatic cancer [56].

Outside the scope of tumour ablation, HIFU has also been demonstrated to be effective in arresting haemorrhage from either organs or vessels, and devices with this function are now in the advanced stages of development for surgical use [116–118]. Finally, Roberts et al have designed a handheld device with which they have performed vasectomies in dogs during a 1–2 min procedure [119].


   Limitations of HIFU
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
Conclusion
 References
 
The potential advantages and indications of HIFU have been discussed in previous sections. There are however, potential limitations, both to clinical applications and to the actual delivery of treatment. Ultrasound cannot propagate through air filled viscera such as lung or bowel, and other obstructions such as bone can absorb or reflect an ultrasound beam. For this reason tumours of the lung, other than those at the immediate periphery of the organ, are not likely ever to be targets for HIFU. Ablation of tumours lying in close proximity to bowel or indeed of the bowel wall itself, would run the risk of visceral perforation. This may therefore, introduce an anatomical restriction to those to tumours that could be treated by HIFU.

Treatment times may also appear longer than could be desired. A 1 h treatment for a superficial 2 cm tumour would be acceptable when compared with the alternative of surgical resection, but compares less favourably with other minimally invasive techniques such as radiofrequency ablation. For the treatment of large tumours, where there is no minimally invasive option, the longer treatment times may be justified on the grounds of a lower morbidity and mortality than conventional surgery.

In many centres, HIFU is performed under regional or general anaesthesia to ensure patient comfort and immobility. General anaesthesia also has the benefit of providing a means to control respiratory excursion in organs such as liver and kidney. Movement of these organs during HIFU exposure could compromise treatment efficacy, and so an artificial breath hold during any high intensity exposure can overcome what would otherwise be a limitation of HIFU.


   Conclusion
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
References
 
Despite the wealth of research in the field of HIFU, its application as a non-invasive surgical tool is still in its infancy. Already the scope for its use in the treatment of benign and malignant conditions alike has been shown to be large, and in combination with other treatment modalities, this scope is likely to expand. It has been demonstrated that HIFU does not increase the rate of tumour metastasis in animal models [120], and early clinical experience has supported this assertion. For the curative treatment of prostate cancer, HIFU is now becoming an accepted treatment modality in Europe, while in China it is already established as such for the treatment of liver and breast cancers and for the treatment of soft tissue and osteosarcoma. As ongoing clinical research further investigates safety and efficacy, it seems that HIFU may provide an alternative to surgery in variety of applications in the future.


   Footnotes
 
Salary for Mr JE Kennedy is funded through a grant from Ultrasound Therapeutics Ltd. Back

Received for publication September 26, 2002. Revision received May 8, 2003. Accepted for publication June 11, 2003.


   References
Top
 Abstract
 Introduction
 What is HIFU?
 History of HIFU
 Physical principles
 HIFU devices in clinical...
 HIFU as a surgical...
 Neurosurgical
 Obstetrics and gynaecology
 Breast
 Other applications
 Limitations of HIFU
 Conclusion
 References
 

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