High-intensity focused ultrasound use widens in research, practice

The use of high-intensity focused ultrasound for various therapeutic applications has continued to grow since Lynn et al first proposed it in 1942.1 Advances in medical imaging technology in the last two decades have led to its widespread use in both research and clinical practice for the treatment of benign and malignant tumors, hemostasis, uterine fibroids, and other conditions.

Beams emitted from a high-powered transducer can target very small tissue volumes inside the body without affecting other tissue. Temperature increases within the focal volume result in tissue coagulative necrosis. Hyperthermia and acoustic cavitation are the principal mechanisms responsible for the tissue destruction.

HIFU systems commonly operate in a frequency range of 1 to 5 MHz, generating focal intensities in the range of 1000 to 10,000 W/cm2 (diagnostic ultrasound, by comparison, generates approximately 0.1 W/cm2). Such rapid ( < 3 sec) high-level intensities can result in cell destruction, protein denaturization, and coagulation necrosis.

This approach has distinct advantages over other thermal ablation techniques such as cryotherapy, laser ablation, microwave coagulation, and radiofrequency ablation. It is noninvasive and nonionizing, so can be repeated as desired as it has no long-term cumulative effects. It increases tissue temperature in the focal area up to 60 degrees C and as high as 100 degrees C in seconds, sufficient to induce thermal coagulation while minimizing blood perfusion effects. The energy can be focused precisely on tissue volumes as small as 10 mm3 without damaging the intervening or surrounding tissue. And ablation of a larger HIFU target can be achieved by multiple sonications in a matrix format that can be repeated many times as required.

IMAGE GUIDANCE

The potential of HIFU for clinical use has been enhanced greatly in recent years by combining it with advanced imaging modalities. Methods in current clinical use and under investigation use MR imaging and ultrasound. The MR-guided focused ultrasound therapy system ExAblate 2000 (InSightec) fully integrates with a Signa 1.5T MRI system (GE Healthcare) to enable direct planning of focused ultrasound therapy with MR images, giving real-time MR thermometry feedback of each sonication.

Ultrasound imaging has also been used to guide and monitor treatment. In clinical practice, the therapeutic system is integrated with the imaging system so that the target region can always be visualized on the diagnostic image. The first commercially available ultrasound-guided HIFU therapeutic system device was designed and developed in China by Chongqing HIFU Technology. This device uses a 12-cm-diameter piezoelectric ceramic transducer PZT-4 with a focal length of 9 to 16 cm and an operating frequency of 0.8 to 3.2 MHz. It has a built-in 3.5 to 5-MHz diagnostic scanner for guidance and monitoring. Most of the published clinical data come from work with this device. Its advantages are lower cost and shorter treatment duration compared with the MR-guided system.

CLINICAL USES OF HIFU

In a clinical setting, HIFU can treat ophthalmologic conditions such as glaucoma, retinal detachment, vitreous hemorrhage, and corneal reshaping. It can be used to treat breast and prostate cancer; uterine fibroids; Parkinson's disease; hemostasis; and brain, liver, renal, and bone tumors.

Use of HIFU for uterine fibroids is approved in the U.S. for MR guidance but not for ultrasound guidance, and several insurance companies reimburse for this procedure. Ultrasound-guided HIFU systems may soon be available as well. In the initial study performed using the ExAblate system, 109 women with symptomatic uterine fibroids were treated with MR-guided HIFU.1 After six months, 70.6% of the women reported a significant improvement in fibroid-related symptoms. Patients returned to normal activity in less than three days, compared with 17 days for a group whose fibroids were treated by hysterectomy. HIFU treatment for uterine fibroids can be performed as an outpatient procedure. Promising results have been reported for experimental work in noninvasive breast cancer treatment. Hynynen et al developed a clinical HIFU technique guided and monitored by MRI,2 and they have recently reported the results of HIFU treatment of 11 breast fibroadenomas in nine patients in which eight lesions were ablated successfully. Huber et al published the first focused ultrasound study on breast cancer treatment.3 They concluded that MR-guided HIFU therapy may become a new strategy for treatment in selected patients with breast cancer.

Gianfelice et al published promising findings on the MR-guided HIFU treatment of 12 patients with small breast cancer tumors ( < 3.5 cm).4 Three patients were treated with the InSightec-TxSonics Mark 1 system and nine with the InSightec-TxSonics Mark 2 system. A mean of 46.7% of the tumor was within the targeted zone, and a mean of 43.3% of the cancerous tissue was ablated in the first group. These values were 95.6% and 88.3%, respectively, in the second group. Results from a phase I study using the ExAblate have been published,5 and more studies are ongoing.

Using the Chongqing HIFU system with ultrasound guidance, Wu et al reported on the treatment of 106 patients with malignant breast cancer and 28 patients with benign breast tumors.6 At one to two-year follow-up, half of the patients showed total resorption of their ablated tumor. The same group in another study reported comparable treatment results on 22 breast cancer patients, in which the survival rates of five-year disease-free and recurrence-free patients were 95% and 89%, respectively.7

The Breast Disease Site Committee Research Strategy group is encouraging research in the use of HIFU for breast cancer applications. The Sonablate HIFU and Ablatherm devices are available for prostate cancer therapy (use of HIFU to treat prostate cancer is approved in Canada, Mexico, Europe, and Japan but not in the U.S.). Other clinical uses of HIFU are being investigated.

HIFU use does not increase the risk of tumor metastasis, but the technique does have drawbacks. Adverse events include local pain, which is often transient or short-lived; fever due to the release of proteins in extracellular space, which can be treated with routine analgesics; and skin toxicity due to small superficial burns. One limitation of HIFU is its inability to pass through air or bone.

HIFU therapy guided with ultrasound or MR imaging is a noninvasive modality that can be used to treat various types of malignancies as an outpatient procedure. Presently, in the U.S., it is approved by the FDA to treat uterine fibroids with MR guidance. It is also approved to treat breast cancer in China and Japan with ultrasound guidance. HIFU is an expanding specialty and its other applications are at various stages of investigation.

Dr. Dogra is a professor of radiology, urology, and biomedical engineering and director of ultrasound at the University of Rochester School of Medicine in Rochester, NY.

References

• Lynn JG, Zwemer RL, Chick AJ, Miller AG. A new method for the generation and use of focused ultrasound in experimental biology. J Gen Physiol 1942;26:179-193.

• Hynynen K, Colucci V, Chung A, Jolesz F. Noninvasive arterial occlusion using MRI-guided focused ultrasound. Ultrasound Med Biol 1996a;22:1071-1077.

• Huber PE, Jenne JW, Rastert R, et al. A new noninvasive approach in breast cancer therapy using magnetic resonance imaging-guided focused ultrasound surgery. Cancer Res 2001;61:8441-8447.

• Gianfelice D, Khiat A, Amara M, et al. MR imaging-guided focused ultrasound surgery of breast cancer: correlation of dynamic contrast-enhanced MRI with histopathologic findings. Breast Cancer Res Treat 2003;82:93-101.

• Zippel DB, Papa MZ. The use of MR imaging guided focused ultrasound in breast cancer patients; a preliminary phase one study and review. Breast Cancer 2005;12:32-38.

• Wu F, Wang ZB, Chen WZ, et al. Extracorporeal high intensity focused ultrasound ablation in the treatment of 1038 patients with solid carcinomas in China: an overview. Ultrason Sonochem 2004;11:149-154.

• Wu F, Wang ZB, Chen WZ, et al. Advanced hepatocellular carcinoma: treatment with high-intensity focused ultrasound ablation combined with transcatheter arterial embolization. Radiology 2005;235:659-667.