Hyperthermia Classic Commentary: ‘A scanned, focused, multiple transducer ultrasonic system for localised hyperthermia treatments’, by K. Hynynen, R. Roemer, D. Anhalt, et al., International Journal of Hyperthermia 1987;3:21–35

Abstract

This commentary reviews the development of image-guided focused ultrasound treatments since the publication of the above paper. The impact of the research presented in the paper on the development of the current image-guided noninvasive surgery and treatments will also be discussed.

• ultrasound
• focused ultrasound
• HIFU
• hyperthermia
• temperature
• tumor treatment

Although the effectiveness of hyperthermia in enhancing both radiation and chemotherapy treatments has been solidly established in clinical trials 1–3, it has been difficult to consistently deliver a well controlled thermal exposure into a deep lying tumour. There are two major issues that make tissue heating difficult. First, for deep tumours the energy absorption in the overlying tissues has to be compensated for such that therapeutic temperatures are achieved in the target volume while keeping the surrounding tissues below the threshold for thermal damage. This requires the focusing of energy into the target tissue. Second, the local tissue properties that influence the rate of energy delivery (speed of sound, ultrasound absorption and attenuation) and heat transfer (blood flow and perfusion) vary spatially in a tumour, between different tumours and in the surrounding tissues resulting in a non-uniform temperature distribution with uniform energy delivery 4–6. Thus, the energy delivery system needs to be able to modify the energy deposition based on the induced temperature distribution. Most of the non-invasive methods, such as microwaves and RF-current heating, lack either the ability to penetrate or to control the distribution of energy and thus cannot provide well controlled thermal exposures. Ultrasound, on the other hand, can be focused to a small focal spot deep into soft tissues 7 and thus offers a method for precise and controllable energy delivery.

The ability to focus ultrasound beams was first employed for hyperthermia induction by Lele 8–10, who developed a complex robotic system that scanned focused ultrasound sources such that relatively uniform temperatures were induced. We 11 adopted the same concepts, but in addition combined the focused ultrasound beams with an ultrasound imaging system such that accurate image-guided treatments could be performed. In addition, the transducers were housed in the patient treatment bed to allow easy patient access and positioning. These added features made the system much more suitable for routine clinical treatments than the earlier systems, which used water bags hanging over the patient to couple the transducer head to the patient 9, 12. Our paper demonstrated in vivo that up to 12-cm deep tissues could be selectively heated with the focused ultrasound beams. The potential of the method for controlling the induced temperature distribution was also shown in our experiments and the feasibility of automated temperature feedback to maintain steady temperatures in vivo. The impact of variations in blood perfusion rate using an in vivo dog kidney model with controllable blood flow was investigated and its effect shown.

The system was used to treat several hundred patients in clinical trials, demonstrating very good temperature distributions 13, 14 that translated to a significant increase in tumour response rates when compared with radiation alone 6. These results were achieved by implanting many multi-sensor thermocouple probes to map the tumour and surrounding tissue temperature, and by using the measured temperatures to guide the treatments. In the later treatments the temperature measurements were also used to perform automatic temperature control that significantly improved the achieved temperature distributions. Similarly, the temporal scanning of the focal spot allowed the patient to identify the locations of the focus that induced pain. This made it possible to seek the highest tolerable power level that varied along the scan trajectory, again improving the overall thermal exposure 15.

This research used AUsonics’ (Sidney, Australia) diagnostic water-bath ultrasound scanner as the platform for the therapy transducers and as the imaging device. Therefore they took the technology and, together with us, developed a prototype clinical system for multi-institutional trials. The system was installed in two hospitals (Hammersmith, London, and Melbourne, Australia) in addition to ours, and they were used in initial clinical trials 16. However, due to a corporate merger the ultrasound hyperthermia section was sold to another company that did not continue the development.

Although the clinical results were very encouraging, the research with this system at the University of Arizona eventually ended with the decrease of interest in clinical hyperthermia and with the main investigators moving to other institutions. However, many of the ideas developed during this research were used in the development of MRI-guided focused ultrasound thermal surgery that utilises focused ultrasound beams guided by MR imaging with MR thermometry monitoring of the exposure to coagulate tumours. 17–21. The use of MR thermometry has made the treatment completely non-invasive by eliminating the need to use invasive temperature sensors. It also provides much improved spatial resolution of the temperature measurements with the potential for complete 3D sampling of the temperature 22. The first such system has been FDA approved for the treatment of uterine fibroids 23–26 with clinical trials in breast 27, 28, bone 29, 30, brain 31, 32 and liver cancer 33.

MRI-guided focused ultrasound surgery uses higher temperatures and shorter treatment times than conventional hyperthermia treatments and it is thus less sensitive to local blood perfusion variations 34. Therefore, focused ultrasound has been clinically used with ultrasound imaging guidance without temperature or exposure monitoring 35, 36, however, the clinical results from focused ultrasound treatments with MRI monitoring have shown the importance of thermometry even for these treatments 37. With the development of MRI-guided focused ultrasound systems and MR-thermometry, the possibility of inducing well controlled hyperthermia exposures has become more feasible in a clinical setting. There are several studies demonstrating that MR thermometry derived temperature information can be used in a closed-loop feedback system with scanned focused ultrasound beam to induce and maintain a desired temperature distribution 38–41. There is now significant interest in using the MRI-guided and controlled hyperthermia for localising and activating gene therapy 42 and enhancing chemotherapy treatments 43–45. Finally, based on the early hyperthermia trials it is expected that the method could significantly improve the local response rate of radiation therapy and thus may eventually make these treatments routine clinical practice.

In summary, our paper reproduced here was a start for the image-guided focused ultrasound treatments of cancer. Although focused ultrasound hyperthermia did not become a method for routine clinical use, the ideas first implemented in the reported system and the research conducted with the system made it possible for us to develop MRI-guided focused ultrasound treatments that are now becoming routine clinical practice. Therefore, the research started by this paper has had a significant indirect impact on clinical patient care and it is expected that there is much more to come in the future.

Acknowledgements

This work was funded by grants from Terry Fox Foundation, Canadian Research Chair program, and Ontario Research Fund. The author is grateful for Meaghan O’Reilly for editing the manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.