High-intensity focused ultrasound

High intensity focused ultrasound (HIFU, or sometimes MRgFUS for magnetic resonance guided focused ultrasound) is an early stage medical technology that is in various stages of development worldwide to treat a range of disorders.

The fundamental principle is analogous to using a magnifying glass to focus sunlight, generating burning heat. Focused ultrasound uses an acoustic lens to concentrate multiple intersecting beams of ultrasound precisely on a target in the body. Each individual beam passes through tissue with no effect. But at the focal point where the beams converge, the energy can have useful thermal or mechanical effects. The approach may be a stand-alone therapy or utilized to enhance the delivery or effects of chemotherapy or immunotherapy.

HIFU is one modality of therapeutic ultrasound, involving minimally-invasive or non-invasive methods to direct acoustic energy into the body. In addition to HIFU, other modalities include ultrasound-assisted drug delivery, hemostasis, lithotripsy, thrombolysis, and immunomodulation.

HIFU is typically performed with real-time imaging via ultrasound or MRI to enable treatment targeting and monitoring (including thermal tracking with MRI).

Currently, there are HIFU systems approved to treat uterine fibroids, pain from bone metastases and the prostate in Asia, Canada, Europe, Israel, Latin America and the United States. There is regulatory approval to treat a range of cancers, including breast, kidney, liver, the pancreas and soft tissue sarcoma in Europe and Asia. There is a brain system approved in Europe, Korea and Russia to treat essential tremor, Parkinsonian tremor and neuropathic pain. Research for other indications is actively underway, including clinical trials evaluating HIFU for treating many neurological conditions, psychological disorders, many cancers, hypertension and other diseases. Non-image guided HIFU devices may be marketed for cosmetic purposes (typically for body fat reduction) in some jurisdictions.

Medical uses

Therapeutic applications use ultrasound to deliver heat or agitation into the body; much higher energies are used than in diagnostic ultrasound. In many cases the frequencies used are different. Specific therapeutic applications of ultrasound include this non-exhaustive list:

Prostate cancer

HIFU is being studied in men with prostate cancer.[4]

In 2015 the FDA authorized two HIFU devices for the ablation of prostate tissue.[5]

The treatment is administered through a transrectal probe and uses heat generated by focusing ultrasound waves to kill cancerous cells in the prostate. These treatments are performed under ultrasound imaging guidance, which allows for treatment planning and some minimal indication of the energy deposition. This is an outpatient procedure that usually lasts 1–3 hours.

There is a system in clinical trials using a transurethral probe to ablate the prostate tissue from the inside-out.[6]

Uterine fibroids

Treatment for symptomatic uterine fibroids became the first approved application of HIFU by the US Food and Drug Administration (FDA) in October 2004.[7] Studies have shown that HIFU is safe and effective, and that patients have sustained symptomatic relief is sustained for at least two years without the risk of complications involved in surgery or other more invasive approaches.[8] Up to 16-20% of patients will require additional treatment.[9]

Neurological disorders

An ultrasound system is approved in Europe, Korea and Russia to treat essential tremor,[10] neuropathic pain,[11] and Parkinsonian tremor.[12] This approach enables treatment of the brain non-invasively without radiation. The US FDA is reviewing the ExAblate system for treatment of essential tremor. The system is also being researched for treating depression[13] and obsessive-compulsive disorder.[14]

Other cancers

Further information: Hyperthermia therapy

HIFU has been successfully applied in treatment of cancer to destroy solid tumors of the bone, brain, breast, liver,[15] pancreas, rectum, kidney, testes, prostate.[16]

HIFU has been found to have palliative effects. CE approval has been given for palliative treatment of bone metastasis.[17] Experimentally, a palliative effect was found in cases of advanced pancreatic cancer.[18]

HIFU may also be used to produce heating for other purposes than cell destruction. For example, HIFU and other devices may be used to activate temperature-sensitive liposomes filled with cancer drug "cargo", to release the drug in high concentrations only at focused tumor sites and when triggered to do so by the hyperthermia device (See Hyperthermia therapy).

Cosmetic medicine

HIFU devices have been cleared to treat subcutaneous adipose tissue for the purposes of body contouring (known colloquially, and incorrectly since there is no suction involved, as "non-invasive liposuction"). These devices are available in the US,[19][20] Canada, the EU, Australia, and certain countries in Asia. HIFU is also cleared, with lower energy levels, for eyebrow lifts.

Other approved applications

Method of use

HIFU beams are precisely focused on a small region of diseased tissue to locally deposit high levels of energy. The temperature of tissue at the focus will rise to between 65° and 85 °C, destroying the diseased tissue by coagulative necrosis. Higher temperatures are usually avoided to prevent boiling of liquids inside the tissue. Each sonication (individual ultrasound energy deposition) treats a precisely defined portion of the targeted tissue. The entire therapeutic target is treated by using multiple sonications to create a volume of treated tissue, according to a protocol developed by the physician. Anesthesia is not required, but sedation is generally recommended.[23]

Mechanism of action

There are many direct mechanical and thermal mechanisms of focused ultrasound that can be utilized to treat many diseases, as well as methods to augment and/or optimize other treatment approaches.

Thermal ablation is the primary mechanism utilized by the currently approved HIFU devices. As an acoustic wave propagates through the tissue, part of it is absorbed and converted to heat. With focused beams, a very small region of heating can be achieved deep in tissues (usually on the order of millimeters. Tissue damage occurs as a function of both the temperature to which the tissue is heated and how long the tissue is exposed to this heat level in a metric referred to as "thermal dose". By focusing at more than one place or by scanning the focus, a volume can be thermally ablated.[24][25]

Focused ultrasound using lower intensities, producing low temperature rise (hyperthermia) and/or mechanical agitation, can also be utilized to deliver drugs to the brain and other areas of the body. For example, focused ultrasound beams are being studied to temporarily open up the blood-brain barrier to enable delivery of drugs to diseased brain tissue. This technique involves infusing a therapeutic agent along with gas-filled microbubbles into the bloodstream. The ultrasound is then applied to target areas in brain, causing the bubbles to vibrate, loosening the tight junctions of the endothelial cells lining the blood vessels and allowing high concentrations of the drug to enter targeted tissues.[26][27]

At high enough acoustic intensities, cavitation (microbubbles forming and interacting with the ultrasound field) can occur. Microbubbles produced in the field oscillate and grow (due to factors including rectified diffusion), and can eventually implode (inertial or transient cavitation). During inertial cavitation, very high temperatures occur inside the bubbles, and the collapse is associated with a shock wave and jets that can mechanically damage tissue.[28]

Because the onset of cavitation and the resulting tissue damage can be unpredictable, it has generally been avoided in clinical applications thus far. However, researchers have been working on a method of controlling this cavitation, called Histotripsy. This technique can be very precise, causing minimal damage to surrounding tissue, and the bubbles used in cavitation are easily visible with ultrasound imaging, enabling accurate targeting and monitoring.[29] Clinically, histotripsy has a wide range of possible uses from cardiovascular disease[30] to various types of cancer.[31] For very sensitive regions such as the brain, more research is needed to confirm the safety profile of treatment with histotripsy. Using injected microbubbles, to lower the threshold for inertial cavitation only at the target, may help reduce damage to adjacent tissues.[32][33]

HIFU can be applied to cancers to disrupt the tumor microenvironment and trigger an immune response, as well as possibly enhance the efficacy of immunotherapy.[34][35] Focused ultrasound, either alone or enhanced by microbubbles and/or thrombolytic agents, can also dissolve blood clots.[36] Ultrasound energy causes vibrations that can either break the clot apart directly — via disruption of the fibrin matrix — or make it more susceptible to the effects of thrombolytic agents.[37][38]

There are a total of 18 biological effects that focused ultrasound can produce.[39]

Theory

There are several ways to focus ultrasound—via a lens (for example, a polystyrene lens), a curved transducer, a phased array, or any combination of the three. This concentrates it into a small focal zone; it is similar in concept to focusing light through a magnifying glass. This can be determined using an exponential model of ultrasound attenuation. The ultrasound intensity profile is bounded by an exponentially decreasing function where the decrease in ultrasound is a function of distance traveled through tissue:

I=I_o {e}^{-2\alpha \mathrm{z}}

I_o is the initial intensity of the beam, \alpha is the attenuation coefficient (in units of inverse length), and z is distance traveled through the attenuating medium (e.g. tissue).

In this model, \frac{-\partial I}{\partial \mathrm{z}} = 2\alpha I= Q[40] is a measure of the power density of the heat absorbed from the ultrasound field. Sometimes, SAR is also used to express the amount of heat absorbed by a specific medium, and is obtained by dividing Q by the tissue density. This demonstrates that tissue heating is proportional to intensity, and that intensity is inversely proportional to the area over which an ultrasound beam is spread—therefore, focusing the beam into a sharp point (i.e. increasing the beam intensity) creates a rapid temperature rise at the focus.

The amount of damage caused in the tissue can be modeled using Cumulative Equivalent Minutes (CEM). Several formulations of the CEM equation have been suggested over the years, but the equation currently in use for most research done in HIFU therapy comes from a 1984 paper by Dewey and Sapareto:[41]

\mathit{CEM} = \int_{t_o}^{t_f} R^{T_{\mathrm{reference}}-T} dt

with the integral being over the treatment time, R=0.5 for temperatures over 43 °C and 0.25 for temperatures between 43 °C and 37 °C, a reference temperature of 43 °C, and time in minutes. This formula is an empirical formula derived from experiments performed by Dewey and Sapareto by measuring the survival of cell cultures after exposure to heat.

Focusing

The ultrasound beam can be focused in these ways:

Image-guided

High Intensity Focused Ultrasound requires a location tracking position to ensure safety and to verify that currents are going to the proper place. This allows lesion formation to be controlled where tissues are destroyed. Examples of this include x-ray, MRI, and Diagnostic Ultrasound. The most basic method of this is Visual monitoring. X-rays were the earliest form of guidance. MRI allows tissue contrast for localization of target volume, characterization of diffusion, perfusion, flow, and temperature, enabling detection of tissue damage. Diagnostic Ultrasound can indicate treatment progress by showing the area as hyper echoic images in real time during the scan.[42]

History

The first investigations of HIFU for non-invasive ablation were reported by Lynn et al. in the early 1940s. Extensive important early work was performed in the 1950s and 1960s by William Fry and Francis Fry at the University of Illinois and Carl Townsend, Howard White and George Gardner at the Interscience Research Institute of Champaign, Ill., culminating in clinical treatments of neurological disorders. In particular High Intensity ultrasound and ultrasound visualization was accomplished stereotaxically with a Cincinnati precision milling machine to perform accurate ablation of brain tumors. Until recently, clinical trials of HIFU for ablation were few (although significant work in hyperthermia was performed with ultrasonic heating), perhaps due to the complexity of the treatments and the difficulty of targeting the beam noninvasively. With recent advances in medical imaging and ultrasound technology, interest in HIFU ablation of tumors has increased.

The first commercial HIFU machine, called the Sonablate 200, was developed by the American company Focus Surgery, Inc. (Milipitas, CA) and launched in Europe in 1994 after receiving CE approval, bringing a first medical validation of the technology for benign prostatic hyperplasia (BPH). Comprehensive studies by practitioners at more than one site using the device demonstrated clinical efficacy for the destruction of prostatic tissue without loss of blood or long term side effects. Later studies on localized prostate cancer by Murat and colleagues at the Edouard Herriot Hospital in Lyon in 2006 showed that after treatment with the Ablatherm (EDAP TMS, Lyon, France), progression-free survival rates are very high for low- and intermediate- risk patients with recurrent prostate cancer (70% and 50% respectively)[43] HIFU treatment of prostate cancer is currently an approved therapy in Europe, Canada, South Korea, Australia, and elsewhere. Clinical trials for the Sonablate 500 in the United States are currently ongoing for prostate cancer patients and those who have experienced radiation failure.[44]

Use of magnetic resonance-guided focused ultrasound was first cited and patented in 1992.[45][46] The technology was later transferred to InsighTec in Haifa Israel in 1998. The InsighTec ExAblate 2000 was the first MRgFUS system to obtain FDA market approval[7] in the United States.

References

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  2. ↑ Baker, KG; Robertson, VJ; Duck, FA (2001). "A review of therapeutic ultrasound: Biophysical effects". Physical therapy 81 (7): 1351–8. PMID 11444998.
  3. ↑ Hynynen, Kullervo; McDannold, Nathan; Sheikov, Nickolai A.; Jolesz, Ferenc A.; Vykhodtseva, Natalia (2005). "Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications". NeuroImage 24 (1): 12–20. doi:10.1016/j.neuroimage.2004.06.046. PMID 15588592.
  4. ↑ Jácome-Pita, F; Sánchez-Salas, R; Barret, E; Amaruch, N; Gonzalez-Enguita, C; Cathelineau, X (2014). "Focal therapy in prostate cancer: the current situation.". Ecancermedicalscience 8: 435. doi:10.3332/ecancer.2014.435. PMID 24944577.
  5. ↑ http://www.accessdata.fda.gov/cdrh_docs/pdf15/DEN150011.pdf[]
  6. ↑ http://www.profoundmedical.com/tulsa/[]
  7. 1 2 Food and Drug Administration Approval, ExAblate® 2000 System - P040003
  8. ↑ Fennessy, Fiona; Fischer, Krisztina; McDannold, Nathan; Jolesz, Ferenc; Tempany, Clare (2015). "Potential of minimally invasive procedures in the treatment of uterine fibroids: a focus on magnetic resonance-guided focused ultrasound therapy". International Journal of Women's Health 7: 901–12. doi:10.2147/IJWH.S55564. PMC 4654554. PMID 26622192.
  9. ↑ Stewart, Elizabeth A.; Gostout, Bobbie; Rabinovici, Jaron; Kim, Hyun S.; Regan, Lesley; Tempany, Clare M. C. (2007). "Sustained Relief of Leiomyoma Symptoms by Using Focused Ultrasound Surgery". Obstetrics & Gynecology 110 (2, Part 1): 279–87. doi:10.1097/01.AOG.0000275283.39475.f6. PMID 17666601.
  10. ↑ Elias, W. Jeffrey; Huss, Diane; Voss, Tiffini; Loomba, Johanna; Khaled, Mohamad; Zadicario, Eyal; Frysinger, Robert C.; Sperling, Scott A.; Wylie, Scott; Monteith, Stephen J.; Druzgal, Jason; Shah, Binit B.; Harrison, Madaline; Wintermark, Max (2013). "A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor". New England Journal of Medicine 369 (7): 640–8. doi:10.1056/NEJMoa1300962. PMID 23944301.
  11. ↑ Jeanmonod, Daniel; Werner, Beat; Morel, Anne; Michels, Lars; Zadicario, Eyal; Schiff, Gilat; Martin, Ernst (2012). "Transcranial magnetic resonance imaging–guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain". Neurosurgical Focus 32 (1): E1. doi:10.3171/2011.10.FOCUS11248. PMID 22208894.
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  13. ↑ Clinical trial number NCT02348411 for "A Feasibility Study to Evaluate Safety and Initial Effectiveness of ExAblate Transcranial MR Guided Focused Ultrasound for Bilateral Anterior Capsulotomy in the Treatment of Medication-Refractory MDD" at ClinicalTrials.gov
  14. ↑ Jung, H H; Kim, S J; Roh, D; Chang, J G; Chang, W S; Kweon, E J; Kim, C-H; Chang, J W (2015). "Bilateral thermal capsulotomy with MR-guided focused ultrasound for patients with treatment-refractory obsessive-compulsive disorder: a proof-of-concept study". Molecular Psychiatry 20 (10): 1205–11. doi:10.1038/mp.2014.154. PMID 25421403.
  15. ↑ Aubry, Jean-Francois; Pauly, Kim; Moonen, Chrit; ter Haar, Gail; Ries, Mario; Salomir, Rares; Sokka, Sham; Sekins, Kevin; Shapira, Yerucham; Ye, Fangwei; Huff-Simonin, Heather; Eames, Matt; Hananel, Arik; Kassel, Neal; Napoli, Alessandro; Hwang, Joo; Wu, Feng; Zhang, Lian; Melzer, Andreas; Kim, Young-sun; Gedroyc, Wladyslaw (2013). "The road to clinical use of high-intensity focused ultrasound for liver cancer: technical and clinical consensus". Journal of Therapeutic Ultrasound 1 (1): 1–13. doi:10.1186/2050-5736-1-13.
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  17. ↑ "Philips Sonalleve receives CE Mark for MR-guided focused ultrasound ablation of metastatic bone cancer" (Press release). Philips Healthcare. April 20, 2011. Archived from the original on October 5, 2013. Retrieved October 4, 2013.
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  19. ↑ Application and FDA permission to market a device, 18 August 2011
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  24. ↑ Huisman, Merel; Lam, Mie K; Bartels, Lambertus W; Nijenhuis, Robbert J; Moonen, Chrit T; Knuttel, Floor M; Verkooijen, Helena M; van Vulpen, Marco; van den Bosch, Maurice A (2014). "Feasibility of volumetric MRI-guided high intensity focused ultrasound (MR-HIFU) for painful bone metastases". Journal of Therapeutic Ultrasound 2: 16. doi:10.1186/2050-5736-2-16. PMC 4193684. PMID 25309743.
  25. ↑ Köhler, Max O.; Mougenot, Charles; Quesson, Bruno; Enholm, Julia; Le Bail, Brigitte; Laurent, Christophe; Moonen, Chrit T. W.; Ehnholm, Gösta J. (2009). "Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry". Medical Physics 36 (8): 3521–35. doi:10.1118/1.3152112. PMID 19746786.
  26. ↑ Park, Juyoung; Zhang, Yongzhi; Vykhodtseva, Natalia; Jolesz, Ferenc A.; McDannold, Nathan J. (2012). "The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound". Journal of Controlled Release 162 (1): 134–42. doi:10.1016/j.jconrel.2012.06.012. PMC 3520430. PMID 22709590.
  27. ↑ Tung, Yao-Sheng; Vlachos, Fotios; Feshitan, Jameel A.; Borden, Mark A.; Konofagou, Elisa E. (2011). "The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice". The Journal of the Acoustical Society of America 130 (5): 3059–67. doi:10.1121/1.3646905. PMC 3248062. PMID 22087933.
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  33. ↑ Wrenn, Steven P.; Dicker, Stephen M.; Small, Eleanor F.; Dan, Nily R.; Mleczko, Michał; Schmitz, Georg; Lewin, Peter A. (2012). "Bursting Bubbles and Bilayers". Theranostics 2 (12): 1140–59. doi:10.7150/thno.4305. PMC 3563150. PMID 23382772.
  34. ↑ Haen, Sebastian P.; Pereira, Philippe L.; Salih, Helmut R.; Rammensee, Hans-Georg; Gouttefangeas, Cécile (2011). "More Than Just Tumor Destruction: Immunomodulation by Thermal Ablation of Cancer". Clinical and Developmental Immunology 2011: 160250. doi:10.1155/2011/160250. PMC 3254009. PMID 22242035.
  35. ↑ Wu, Feng (2013). "High intensity focused ultrasound ablation and antitumor immune response". The Journal of the Acoustical Society of America 134 (2): 1695–701. doi:10.1121/1.4812893. PMID 23927210.
  36. ↑ Wright, Cameron; Hynynen, Kullervo; Goertz, David (2012). "In Vitro and In Vivo High-Intensity Focused Ultrasound Thrombolysis". Investigative Radiology 47 (4): 217–25. doi:10.1097/RLI.0b013e31823cc75c. PMC 3302946. PMID 22373533.
  37. ↑ Monteith, Stephen J.; Kassell, Neal F.; Goren, Oded; Harnof, Sagi (2013). "Transcranial MR-guided focused ultrasound sonothrombolysis in the treatment of intracerebral hemorrhage". Neurosurgical Focus 34 (5): E14. doi:10.3171/2013.2.FOCUS1313. PMID 23634918.
  38. ↑ Abi-Jaoudeh, Nadine; Pritchard, William F.; Amalou, Hayet; Linguraru, Marius; Chiesa, Oscar A.; Adams, Joshua D.; Gacchina, Carmen; Wesley, Robert; Maruvada, Subha; McDowell, Briana; Frenkel, Victor; Karanian, John W.; Wood, Bradford J. (2012). "Pulsed High–Intensity-focused US and Tissue Plasminogen Activator (TPA) Versus TPA Alone for Thrombolysis of Occluded Bypass Graft in Swine". Journal of Vascular and Interventional Radiology 23 (7): 953–961.e2. doi:10.1016/j.jvir.2012.04.001. PMC 3511867. PMID 22609287.
  39. ↑ http://d3nqfeqdtaoni.cloudfront.net/images/pdf/Bioeffects_Paper_July_2015.pdf[]
  40. ↑ P Hariharan et al. (2007)
  41. ↑ Sapareto, Stephen A.; Dewey, William C. (1984). "Thermal dose determination in cancer therapy". International Journal of Radiation Oncology, Biology, Physics 10 (6): 787–800. doi:10.1016/0360-3016(84)90379-1. PMID 6547421.
  42. ↑ Chan, Arthur H.; Vaezy, Shahram; Crum, Lawrence A. (2003). "High-intensity Focused Ultrasound". AccessScience. McGraw-Hill Education. doi:10.1036/1097-8542.YB031005.
  43. ↑ Gelet, A; Murat, François-Joseph; Poissonier, L (2007). "Recurrent Prostate Cancer After Radiotherapy – Salvage Treatment by High-intensity Focused Ultrasound". European Oncological Disease 1 (1): 60–2.
  44. ↑ USHIFU (2012). "Clinical Information about HIFU in the U.S.". Archived from the original on August 7, 2009.
  45. ↑ Hynynen, K.; Damianou, C.; Darkazanli, A.; Unger, E.; Levy, M.; Schenck, J. F. (1992). "On-line MRI monitored noninvasive ultrasound surgery". Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society. doi:10.1109/IEMBS.1992.5760999. ISBN 0-7803-0785-2.
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