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| Fig. 1: Parameters of sound. (Source: Kim et al., courtesy of Korean J. Radiol. [1]) |
We live in a world full of acoustics or sound. In fact, one could say that acoustic waves touch every aspect of our lives, everything from the richness of architecture to the intricacies of music to the chirpings of nature and more. Acoustic waves audible to the human ear are familiar to us in things as diverse as the sonic boom of a fighter jet to the vibration of toothbrushes that use waves to obliterate plaque. We can hear the sound waves and feel the vibrations undulating around us.
Within physics, a disturbance of mechanical energy that passes through a medium in waves is sound. Sound may absolutely move energy from its source to another place as long as a medium is present. Humans perceive these waves in the frequency range of 20-20,000 Hz. [1]
But what of the acoustic waves that we cannot hear? The field that covers these intense and inaudible acoustic waves is coined "ultrasonic." Because ultrasonic waves present phenomena peculiar to its specific ranges of frequencies, far-reaching possibilities manifest themselves in areas like medicine, biology, engineering and more. [2] In order to be categorized as ultrasonic, the wave or vibration possesses a frequency above the human ear's audibility limit of 20,000 hertz. There are, therefore, parameters associated with the physics of sound versus ultrasound. (Fig. 1 shows the parameters of sound).
Since ultrasound is a type of vibration above our auditory threshold, as it travels through mediums, it leads to the vibration that produces alternating cycles of increased and reduced pressure, exposing the medium to compression and rarefaction. [3]
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| Fig. 2: Transducer Interaction with HIFU. (Source: Van den Bijgaart et al., courtesy of Cancer Immunol. Immunother. [9]) |
Yet even within the ultrasonic frequency, there are two broad areas. The first is low-intensity, high frequency applications. The second is high-Intensity, low-frequency applications. Depending upon the medium, the approximate established values between low and high intensity vary between 0.1 and 1 W/cm2. The most commonly known low-intensity, high-frequency application is ultrasound imaging, used in medicine ubiquitously, for exploration and information in determining diagnosis and more. Power levels applied to the transducers in this case are often low and in the milliwatt range, while the frequencies are high in the megahertz range. [2] High-Intensity, low-frequency applications, however, are termed power ultrasonics and are used to permanently change the physical, chemical, or biological properties of the medium to which it is applied. The power levels for ultrasonics range from the 10s-1000s of watts, depending upon the intensity required. Most high-power applications range between 20 and 100 kHz. How we apply power ultrasonics is determined by the effects of non-linear phenomena created by the high-intensity waves. As a result, the energy may produce heat, agitation, diffusion, interface instabilities, friction, mechanical rupture, and chemical effects. Though the clinical use of ultrasonics has been common in imaging, more recently, the medical world is seeing a boom in therapeutic uses, especially in High Intensity Focused Ultrasound. [2]
What does High Intensity Focused Ultrasound (HIFU) as a therapeutic modality mean? First, we must consider that HIFU is classified into two categories - mechanical or thermal based - upon the effects seen. Mechanical derive their effects through cavitation or radiation, whereas thermal mechanisms are dependent upon the absorption of the energy by the tissue, producing heat. The goal is to deposit the energy so that the tissue is heated in a controlled way with minimal heat affecting the tissue intervening or surrounding the focus point and the source transducer. Differing tissues, ultrasound frequencies, acoustic pressures, intensities and the duration of the application all effect how the therapies respond. [2]
Think back to when you were a child and you used a magnifying glass with the suns rays to start a fire. HIFU therapy is similar but instead of using the energy of the suns rays to create the reaction, energy transportation occurs in the form of ultrasonic waves. The wave energy through intervening tissues to specific points in body organs and even bone, increase the temperatures and cause biological interactions in a non-invasive manner. Whereas in other treatments, the intervening tissues may sustain considerable damage, FICU research indicates its use manifests no significant negative biological effects on intervening tissue as long as the ultrasonic energy is appropriately located and focused. [1] Thus, HIFU therapy is an emerging, therapeutic modality in the medical community.
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| Fig. 3: HIFU treatment for Liver Tumors. (Source: Wikimedia Commons) |
The heart of HIFU therapy is a brief, high-intensity, focused ultrasound pulsation, produced by a piezoelectric ultrasound transducer. These brief exposures encourage sharp boundaries between the coagulated and the healthy tissue. When the high-intensity beam is focused, that one area heats rapidly, and thermal coagulation occurs. Frequencies in the range of 600 kHz to 7 MHz are used depending on the type of tissue and penetration depth. In cases that require absolute tissue necrosis, the temperature needs to range from 60°C to 95°C. [3] At any higher of a temperature, the tissue may bubble and boil, leading to undefined and less predictable lesion. growth. In the case of intensity and pressure, values are some thousand Watts per cm2 and some MPa, respectively. [4]
In order to apply treatments, specially-designed for HIFU transducers are used. The most widely used are self-focusing piezoceramic bowls, created from low-loss PZT (Lead Zirconate Titane) or piezocomposite. More expensive and complex, but also used, is a phased-array transducer, with defined phase shifts and amplitudes, thus allowing for an electrical beam formation and the steering of the ultrasound focus (see Fig. 2). [4]
This novel focal treatment, still relatively in its infancy within clinical studies and medical uses compared to more traditional treatments, is enabling cancer amelioration and treatments that reduce the hardships, pain, and other side effects related to radical treatments of the past. HIFU and Magnetic Resonance Guided HIFU (MRgHIFU) are among these focal treatments that seem to have proven to provide some control in the treatment of cancer with a low rate of complications, as compared with historically invasive treatments. [5] MRgHIFU, in particular, is helping the field gain ground as a therapeutic modality, as there were initially difficulties with finding appropriate imaging that would guide treatment and application while giving real-time thermal feedback. MRgHIFU provides the real-time thermal feedback with superior spatial resolution, further aiding oncology treatments that are less invasive. [3]
Tumor removal or ablation remains an important and common aspect of cancer treatment. Each cancer is different and so far only certain cancers are relying more and more on HIFU as an option and, even then, are still in clinical trials. These cancers are Prostate, Liver, Breast, and Bone.
Prostate cancer plagues men as the most frequently diagnosed cancer in its population, with several factors convoluting therapy options, like tumor stage, patient age, other diseases, and the patient's ideas and expectations about their treatment plan. The recommendations have long been actively watching the patient, radical prostatectomy and radiation therapy and have proven effective but also are associated with complications and risks. Then there are the patients who cannot tolerate radiation treatments or are not suitable candidates for radical prostatectomy. Because imaging techniques provide today's doctor with more precise tumor locations, focal targeting tumors with HIFU in tumor destruction, are undergoing continual research and advances have been made in their use to treat prostate cancer effectively. [5] This energy-based ablation seems to be a valid alternative to surveillance protocols in those low risk cancers and in older patients compared to the standard treatments and therapies. [5]
Worldwide, liver cancer is the fifth most common cancer in men and the seventh in women. Treatment usually involves multiple strategies that are often invasive. Moreover, hepatocellular carcinoma and metastatic liver disease are different and, thereby, require separate protocols so different approaches to therapeutic strategies for treating the cancers must be taken. Nevertheless, HIFU or MRgHIFU strategies for treating the liver curatively from tumors is rapidly increasing. [6]
Though HIFU treatment for liver tumors (see Fig. 3) has long been a proposed target, challenges exist. The first challenge relates to acoustic access to focal points of treatment; the targets are often obscured by the rib cage. [2] Ribs present a probability of skin overheating because of the high value of the ultrasonic absorption coefficient of the bone [6], yet research has been promising. In 2008, researchers used a 300 element semi-random array to show that time reversal is well suited in focusing through the rib cage, thereby decreasing the temperature of the rib surface to 0.3 degrees celsius. [7] This could be achieved by automatically and non-invasively by computing the decomposition of the time reversal operator based on the backscattered echoes. Such a technique makes it possible to focus between ribs and not through ribs. [6]
The second challenge to HIFU treatment for liver tumors is respiration. Respiration movement affects the precision and efficiency of the treatment. Researchers in multiple studies found that the abdominal organs can move up to 20 mm during a cycle, reaching speeds of up to 15 mm/s. Solutions include breath holding, MR-based motion tracking, Ultrasound based motion tracking and Motion compensation by electronic beam steering. [6] Regardless of the obstacles related to using HIFU in liver cases, this therapeutic device has the potential to target multiple lesions without the need for radical surgeries, studies are also looking at its use to facilitate focal drug release to support or enhance chemotherapy. [2]
Breast tumors are considered an ideal candidate for HIFU therapies for three reasons: 1) the tumors are acoustically accessible (unlike liver tumors with the ribcage intervening), 2) breast tumors are prevalent, and 3) its use can maintain cosmetic integrity. Early clinical trials showed incredible success but only adenomas and benign tumors were at first studied. More recent studies have targeted breast cancer but these applications have to maintain aggressive protocols and the ablation of a margin around the tumor. Although the treatments have proved well-tolerated by patient, it is difficult to determine how effective it truly is in comparison to traditional lumpectomies and their successes. [2]
With bone cancer, the use of HIFU has less to do with treating the cancer than it has to do with providing pain relief and a better quality of life even if it is at the end. Bone cancer is often the result of the metastasizing of an original cancer and brings with it debilitating pain. Current treatments possibilities for that pain may include analgesics, chemotherapy, and radiation. Radiation is the most common treatment but studies show only about 20-30 percent of those treated receive some kind of relief. [2] And here is where HIFU shows promise. In an early trial in 2009, of 25 patients who received the therapeutic modality, 21 (87.5%) were completely relieved of pain. Moreover, the pain relief came within 72 hours. Sixty-seven percent of those treated were able to decrease their intake of opioid pain relievers. [8] The study did find that the use of chemotherapy after HIFU may have a synergistic effect in healing and recovery. The researchers found many advantages to the bone cancer patients with the therapy that went beyond pain amelioration. Just a few include:
It is non-invasive with no need for surgery or an ultrasound-guided puncture and no risk of bleeding.
There was no harm to ultrasound-penetrated tissues or areas outside the target.
HIFU treatment is not dependent on lesion size with any size able to be completely destroyed. Many large, malignant bone tumors cannot be surgically removed but can be destroyed with HIFU.
HIFU allows selective destruction of blood vessels. Only those with a diameter of < 200 micro meters are targeted for destruction, effectively guaranteeing the safety of the treatment and increasing the scope of treatable lesions. Tumor blood vessels can complicate surgeries. HIFU allows for the treatment of those anatomically problematic tumors. [8]
Bone cancers are debilitating. Although HIFU is still in clinical stages here as well, the results are promising.
In conclusion, the utilization of High Intensity Focused Ultrasound in clinical use is still in its early stages of development. This acoustic energy modality, however, seems to have promise in the treatment of cancers and the ablation of tumors throughout the body. Physicists, biologist, physiologists, physicians and others are looking forward to the advances made in this field. There remains hope that HIFU will make the same strides that ultrasonics in imaging have made over the last half of a century.
© Josh Orrick. The author warrants that the work is the author's own and that Stanford University provided no input other than typesetting and referencing guidelines. The author grants permission to copy, distribute and display this work in unaltered form, with attribution to the author, for noncommercial purposes only. All other rights, including commercial rights, are reserved to the author.
[1] Y. S. Kim et al., "High-intensity Focused Ultrasound Therapy: an Overview for Radiologists," Korean J. Radiol. 9, 291 (2008).
[2] J. A. Gallego-Juárez and K. F.Graff, Power Ultrasonics : Applications of High-Intensity Ultrasound (Woodhead Publishing, 2014).
[3] S. Ellis et al., "Clinical Applications for Magnetic Resonance Guided High Intensity Focused Ultrasound (MRgHIFU): Present and Future," J. Mag. Imaging Radiat. Oncol. 57, 391 (2013).
[4] O. Al-Bataineh, J. Jenne, and P. Huber, "Clinical and Future Applications of High Intensity Focused Ultrasound in Cancer," Cancer Treat. Rev. 38, 346 (2012).
[5] E. R. Cordeiro et al., "High-intensity Focused Ultrasound (HIFU) for Definitive Treatment of Prostate Cancer," Brit. J. Urol. Int. 110, 1228 (2012).
[6] J. F. Aubry et al., "The Road to Clinical Use of High-intensity Focused Ultrasound for Liver Cancer: Technical and Clinical Consensus," J. Ther. Ultrasound 1, 13 (2013).
[7] J. F. Aubry et al., "Transcostal High-Intensity-Focused Ultrasound: Ex Vivo Adaptive Focusing Feasibility Study", Phys. Med. Biol. 53, 2937 (2008).
[8] C. Li et al., "Noninvasive Treatment of Malignant Bone Tumors Using High-intensity Focused Ultrasound", Cancer 116, 3934 (2010).
[9] R. J. E. van den Bijgaart et al., "Thermal and Mechanical High-Intensity Focused Ultrasound: Perspectives on Tumor Ablation, Immune Effects and Combination Strategies," Cancer Immunol. Immunother. 66, 247 (2016).
