Читать книгу Intracranial Gliomas Part III - Innovative Treatment Modalities - Группа авторов - Страница 68

The earliest well-documented experience with clinical application of therapeutic ultrasound in the published literature is from 1959 by Meyers et al. [21]. They reported on 12 patients who underwent lesioning of the substantia nigra or ansa lenticularis for rigidity and tremor. The treatment was performed through a craniotomy and was guided by anatomical landmarks on X-ray imaging of the head following contrast ventriculography. The ultrasound beam was generated by 4 quartz transducers [21] (in comparison, modern arrays composed of over 1,000 elements). The same group reported an unsuccessful attempt to slow the progression of advanced breast cancer with ultrasound ablation of the pituitary gland [22], and in 1985 published the first series of brain tumors treated with thermal ablation, albeit with mixed results [23]. Further small clinical trials were performed through craniotomy sites for the treatment of brain tumors [24, 25].

The first therapeutic application of HIFU through the intact skull was reported in 2009 by Martin et al. [26] who used a 1,024-element hemispherical phased array operating at a frequency of 650 kHz (ExAblate 4000 by Insightec, Ltd.). Nine patients with chronic pain underwent MRI-guided thermal lesioning of the thalamus. The treatment method was based on the experience of an earlier study of 3 patients who underwent transcranial thermal therapy of GBM [3]. Unfortunately in that study, one patient succumbed to a delayed intracerebral hemorrhage. As a result of this event, the ultrasound system was modified to terminate sonications if inertial cavitation was detected, and patients having received previous FRT were excluded from future studies due to the possibility that radiation alters the tolerance of the cerebrovasculature to ultrasound. Studies of thermal ablation of brain tumours have since been slow to be reinitiated, although such trials are recruiting at several sites in North America and Europe.

Overall, the clinical experience with ablative procedures in the brain has been steadily expanding. Most recently, ventral intermediate nucleus lesioning of the thalamus with the ExAblate 4000 for medically refractory essential tremor has been investigated in small phase I trials completed in parallel at the Sunnybrook Health Sciences Centre in Toronto, Canada and the University of Virginia Health System in Charlottesville, USA [1, 2]. The treatment was shown to be safe and provided satisfactory symptom relief up to a year later. This important work has paved the way for larger trials for tremor in the setting of both essential tremor and Parkinson disease [1, 2].

While the only published human trial of transcranial HIFU thermal ablation of GBM was complicated by a serious adverse event, much has been learned in the intervening years and more recent studies have demonstrated safe ablation of tissue in the brain with few and very mild adverse effects [1, 2]. Despite these advances, thermal ablation of brain tumors with HIFU is in its infancy and many questions remain as yet unanswered. What is the maximum volume of the neoplasm that can be ablated while avoiding significant brain edema and mass effect? What is the optimal timing of FRT and/or chemotherapy following HIFU treatment (perhaps concurrent chemotherapy is beneficial in order to heat a margin around the tumor and increase the sensitivity to the chemotherapeutic agent and/or temporary disrupt BBB)? If tissue is required for diagnosis, how long afterwards is it safe to treat with ultrasound? Does HIFU prolong survival or preserve quality of life (QOL) compared to existing treatment modalities? With regards to the final point, the expectations for success with HIFU should be similar to those achieved with other thermal ablative techniques, such as RF and laser-induced interstitial (LITT) thermotherapies, as ultimately the mechanism is similar [27, 28]. The advantages of ultrasound over existing thermal lesioning techniques include its non-invasiveness, which should offer a reduced risk of hemorrhagic complications compared to interstitial devices, as well as a theoretically decreased risk of tumor seeding along the stereotactic tract. The main benefit may eventually come from the combination of chemotherapy with BBB disruption using low power ultrasound and injected microbubbles to augment systemic administration of anticancer drugs.