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Science to Practice |
Department of Radiology, Thomas Jefferson University Hospital,
Suite 763J, Main Bldg, 132 S 10th St,
Philadelphia, PA 19107,
flemming.forsberg@jefferson.edu
SUMMARY
McDannold et al have demonstrated that the administration of a microbubble-based US contrast agent reduces the acoustic power threshold required to induce lesions in rabbit brains with high-intensity focused ultrasound and that this procedure may potentially be monitored with MR thermometry. If these results can be reproduced in future clinical trials, this combination may enable precisely controlled noninvasive ablation of brain tumors with MR imaging guidance.
THE SETTING
The use of high-intensity focused ultrasound for thermal ablation of brain tissue is a promising alternative to interventions based on surgery or radiation therapy. For this technique to realize its full potential, however, there are substantial problems yet to overcome. The ultrasound beam is defocused by the skull, making accurate lesion control difficult to achieve. Moreover, attenuation losses in the bone necessitate the use of high acoustic power levels, which, in turn, increase the risk of overheating in regions close to the skull, making treatment of tumors in those regions difficult to accomplish (1). In this issue of Radiology, McDannold et al (2) describe how the addition of ultrasonographic (US) contrast microbubbles to high-intensity focused ultrasound procedures reduces the power required to induce ablation by an order of magnitude.
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Encapsulated gas-filled microbubbles (diameter, <8 µm) are commercially available for use as US contrast agents and are known to improve the sensitivity and specificity of diagnostic US imaging (3). It is now well established that at higher acoustic pressures, the expansion and contraction of the microbubbles in the ultrasound field become unequal and markedly exaggerated, leading to destruction. This activity is termed inertial cavitation (4). Contrast agent bubble collapse has been used successfully with therapeutic ultrasound to dissolve thrombi in animal models (5), as well as in human dialysis grafts (as part of phase I and II clinical trials).
McDannold and co-workers (2) investigated in rabbits whether the combination of US contrast microbubbles (Optison; GE Healthcare) and high-intensity focused ultrasound could induce lesions in the brain at lower acoustic power levels than high-intensity focused ultrasound performed without a contrast agent. They also evaluated the effectiveness of magnetic resonance (MR) imaging–based thermometry for predicting the onset and shape of the induced lesions. The lowest values for the production of lesions with the microbubbles were 1.2 W for 10-second pulsed sonications and 0.6 W for 20-second pulsed sonications, almost 12 times lower than a previously determined threshold for lesion creation. The 50% probability for inducing tissue necrosis required a temperature increase of 5.9°C, approximately half the 11.4°C threshold established in prior experiments. Interestingly, the temperature measured with the microbubbles present appeared to be below the threshold for thermal damage, indicating that the lesions induced during high-intensity focused ultrasound with contrast microbubbles are caused by other cavitational bioeffects. Moreover, although MR thermometry appeared to be potentially useful for monitoring the ablations—because the isotherms and the diameter of the lesions observed with MR imaging correlated strongly—the usefulness was not firmly established. A prospective study testing isotherms selected a priori would be required.
Further work is needed to investigate how the threshold for inducing lesions depends on acoustic parameters (eg, frequency, pulse length, duty cycle, duration of exposure). Moreover, because the pressure threshold for destruction of contrast bubbles varies considerably from agent to agent (6), it will also be necessary to study the efficacy of employing different US contrast agents in combination with high-intensity focused ultrasound for inducing ablations.
THE PRACTICE
Clinical use:
High-intensity focused ultrasound for neurosurgical applications offers a truly noninvasive alternative to conventional surgery and radiation therapy. However, the acoustic power requirements associated with the use of high-intensity focused ultrasound in the brain have so far been a stumbling block for the successful development of this technique. The work presented by McDannold et al (2) demonstrates that the addition of a US contrast agent can overcome this limitation and, furthermore, indicates that lesions may be created by mechanisms other than purely thermal ones. Combined with the potential utility of MR thermometry as a monitoring tool, high-intensity focused ultrasound ablation procedures in the brain are now an important step closer to clinical reality.
Future opportunities and challenges:
Hynynen and his group have previously shown (7) that ultrasound insonication of contrast microbubbles can temporarily disrupt the blood-brain barrier, allowing large therapeutic agents to be delivered to the brain. An intriguing possibility, alluded to by McDannold et al (2), is the use of a two-step procedure, where high-intensity focused ultrasound–induced ablation to destroy solid brain tumors is followed by an acoustically induced opening of the blood-brain barrier to supply therapies to destroy any remaining cancer cells within the brain. It may even be possible to design targeted microbubbles carrying drugs or genes as drug delivery vehicles directly to the site of the cancer (3).
Clearly, important questions regarding parameter optimization and the potential for side effects remain to be answered before the full potential of high-intensity focused ultrasound can be achieved in the brain or elsewhere. As with other emerging cancer therapies, extensive and rigorous clinical trials will be required to establish the role of high-intensity focused ultrasound, with or without contrast bubbles, in the future treatment of brain tumors.
FOOTNOTES
See also the article by McDannold et al in this issue.
References
Related Article
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