Jacob I. Fabrikant

Stereotactic Heavy-Charged-Particle Bragg-Peak Radiation for Intracranial Arteriovenous Malformations

BACKGROUND Heavy-charged-particle radiation has several advantages over protons and photons for the treatment of intracranial lesions; it has an improved physical distribution of the dose deep in tissue, a small angle of lateral scattering, and a sharp distal falloff of the dose. METHODS We present detailed clinical and radiologic follow-up in 86 patients with symptomatic but surgically inaccessible cerebral arteriovenous malformations that were treated with stereotactic helium-ion Bragg-peak radiation. The doses ranged from 8.8 to 34.6 Gy delivered to volumes of tissue of 0.3 to 70 cm3. RESULTS Two years after radiation treatment, the rate of complete obliteration of the lesions, as detected angiographically, was 94 percent for lesions smaller than 4 cm3, 75 percent for those of 4 to 25 cm3, and 39 percent for those larger than 25 cm3. After three years, the rates of obliteration were 100, 95, and 70 percent, respectively. Major neurologic complications occurred in 10 patients (12 percent), of whom 8 had permanent deficits. All these complications occurred in the initial stage of the protocol, before the maximal dose of radiation was reduced to 19.2 Gy. In addition, hemorrhage occurred in 10 patients from residual malformations between 4 and 34 months after treatment. Seizures and headaches were less severe in 63 percent of the 35 and 68 percent of the 40 patients, respectively, who had them initially. CONCLUSIONS Given the natural history of these inaccessible lesions and the high risks of surgery, we conclude that heavy-charged-particle radiation is an effective therapy for symptomatic, surgically inaccessible intracranial arteriovenous malformations. The current procedure has two disadvantages: a prolonged latency period before complete obliteration of the vascular lesion and a small risk of serious neurologic complications.

Stereotactic heavy-ion Bragg peak radiosurgery for intra-cranial vascular disorders: method for treatment of deep arteriovenous malformations

The present paper represents the first clinical report of the use of stereotactically-directed narrow beams of helium ions from the 184-inch Synchrocyclotron at the Lawrence Berkeley Laboratory for the radiosurgical treatment of life-threatening vascular disorders of the brain, including inoperable or inaccessible deep arteriovenous malformations (AVMs) and carotid artery-cavernous sinus fistulas ( CCFs ). We describe the methods developed for stereotactic neuroradiological imaging and stereotactic helium-ion Bragg peak radiosurgery in the evaluation and treatment of the first 55 patients with deep AVMs in a clinical research protocol. We discuss the diagnosis and epidemiological characteristics of the diseases, the neurosurgical and radiosurgical methods of treatment available and the initial experience of stereotactic helium-ion Bragg peak radiosurgery , including stereotactic neuroradiological evaluation, treatment planning, heavy-ion beams, patient treatment protocol, early clinical results, patient evaluation and follow-up studies planned, and conclusions thus far obtained.

Heavy-Charged-Particle Radiosurgery of the Pituitary Gland: Clinical Results of 840 Patients

Since 1954, 840 patients have been treated at Lawrence Berkeley Laboratory with stereotactic charged-particle radiosurgery of the pituitary gland. The initial 30 patients were treated with proton beams; the subsequent 810 patients were treated with helium ion beams. In the great majority of the 475 patients treated for pituitary tumors, marked and sustained biochemical and clinical improvement was observed. Variable degrees of hypopituitarism developed in about one-third of patients treated solely with radiosurgery. In the earlier years of the program, 365 patients underwent radiosurgery to treat selected systemic diseases by inducing hypopituitarism. Focal temporal lobe necrosis and cranial nerve injury occurred in about 1% of patients who were treated with doses less than 230 Gy.

Stereotactic heavy-charged-particle bragg peak radiosurgery for the treatment of intracranial arteriovenous malformations in childhood and adolescence

Forty patients aged 6 to 18 years have now been treated for inoperable intracranial arteriovenous malformations (AVMs) using stereotactic heavy-charged-particle Bragg peak radiosurgery at the Lawrence Berkeley Laboratory 184-inch Synchrocyclotron at the University of California, Berkeley. This paper describes the procedures for selection of patients, the treatment protocol, and the neurological and neuroradiological responses to stereotactic radiosurgery in this age group. The volumes of the treated AVMs ranged from 265 mm3 to 60,000 mm3. The results are favorable: thus far, 20 of 25 patients have experienced greater than or equal to 50% obliteration of their AVMs within 1 year after treatment, and 14 of 18 patients have experienced total obliteration of the AVM by 2 years after treatment. Two patients hemorrhaged from radiosurgically treated AVMs within 12 months after treatment, but none thereafter. Complications include vasogenic edema and arterial occlusion; three patients have had neurological worsening as definite or possible sequelae of treatment. The strengths and limitations of the method are discussed.

Comparison of different radiation types and irradiation geometries in stereotactic radiosurgery

Recent interest in stereotactic radiosurgery of intracranial lesions, and the development of stereotactic irradiation techniques has led to the need for a systematic and complete comparison of these methods. A method for conducting these comparisons is proposed and is applied to a set of currently-used stereotactic radiosurgical techniques. Three-dimensional treatment planning calculations are used to compare dose distributions for several different radiation types and irradiation geometries. Calculations were performed using charged particles (H, He, C, and Ne ions) and the irradiation geometry currently used at Lawrence Berkeley Laboratory. Photons in the Gamma Knife configuration and the Heidelberg Linac arc method are used. The 3-dimensional dose distributions were evaluated by means of dose-volume histograms and integral doses to the target volume and to normal brain. The effects of target volume, shape and location are studied. The charged particle dose distributions are more favorable than those of the photon methods. The differences between charged particles and photons increase with increasing target volume. The differences between different charged particle species are small, as are the effects of target shape and location.

Image correlation of MRI and CT in treatment planning for radiosurgery of intracranial vascular malformations

Magnetic resonance imaging (MRI) has been incorporated with stereotactic cerebral angiography and computed tomography (CT) in the treatment planning process of heavy ion radiosurgery of intracranial arteriovenous malformations (AVMs). Correlation of the images of the AVM and normal tissue on each of these neuroradiological imaging modalities is achieved by means of fiducial markers. The computerized transfer of angiographic information to the CT images regarding the size, shape, and location of the abnormal vasculature has been described in an earlier report. A separate computer program calculates a fit between individual fiducial markers on the CT and MR images that enables the transfer of contours between the two imaging modalities. The MR images aid in the determination of the 3-dimensional shape of the AVM, adding to the information derived from the two angiographic projections. Currently, MRI cannot replace cerebral angiography in delineating the entire arterial phase of the AVM. Magnetic resonance imaging is invaluable in the treatment planning of angiographically-occult AVMs, determining the location, size, and shape of the volume to be treated. Correlation of the CT and MRI images allows for the transfer of CT-calculated isodose contours to the MRI images to aid in the determination of optimal treatment plans.

Heavy charged-particle Bragg peak radiosurgery for intracranial vascular disorders.

The program at Donner Pavilion has applied nuclear medicine research to the diagnosis and radiosurgical treatment of life-threatening intracranial vascular disorders that affect approximately one million Americans. Stereotactic heavy-ion Bragg peak radiosurgery, using narrow beams of heavy ions (helium), demonstrates superior biological and physical characteristics in brain over X and gamma rays and protons, viz., improved dose distribution in the Bragg peak, sharp lateral and distal borders, and less multiple scattering and range straggling for the same residual range in CNS tissue. Examination of CNS tissue response and alteration of cerebral blood-flow dynamics related to heavy-ion Bragg peak radiosurgery is being undertaken using three-dimensional treatment planning and quantitative imaging utilizing cerebral angiography, computerized tomography (CT), magnetic resonance imaging (MRI), cine-CT, xenon X-ray CT, and positron emission tomography (PET). Also under examination are the physical properties of narrow heavy-ion beams for improving methods of dose delivery and dose distribution and for establishing clinical RBE/LET and dose-response relationships for human CNS tissues. Based on the evaluation and treatment with stereotactically directed narrow beams of heavy ions of over 130 patients, with cerebral angiography and CT scanning, and with MRI and radioisotope scanning of selected patients, plus extensive clinical and neuroradiological follow-up, it appears that heavy-ion radiosurgery obliterates intracranial arteriovenous malformations or protects against rebleeding with reduced morbidity and mortality.

A helium-ion beam for stereotactic radiosurgery of central nervous system disorders.

A new radiation beamline configuration for stereotactic heavy-ion Bragg peak radiosurgery of patients with intracranial deep arteriovenous malformations, including carotid-cavernous fistulas, has been developed using the 230 MeV/u helium ion beam at the 184-in. Synchrocyclotron at the University of California, Berkeley. The modified beam has five characteristics: uniform field between 10 and 40 mm in diameter; variable depth of penetration between 40 and 140 mm; stopping region for primary ions that can be broadened up to 40 mm; sharply defined lateral and distal borders; and dose rate greater than 2 Gy/min. It is adapted to the ISAH (irradiation stereotactic apparatus for humans) at the 184-in. Synchrocyclotron, with effective stereotactic localization of defined volumes within the brain, and is designed to reach all intracranial targets. It has proven suitable for all patients with intracranial vascular disorders treated with stereotactic radiosurgery at our laboratory.

Stereotactic frame for neuroradiology and -charged particle bragg peak radiosurgery of intracranial disorders

The application of heavy charged particle Bragg peak radiosurgery for the treatment of intracranial vascular and other disorders requires a system of precise patient immobilization and stereotactic localization of defined intracranial targets. The process of using stereotactic neuroradiological procedures (including cerebral angiography, CT scanning and magnetic resonance imaging) for target definition and localization, and complex treatment planning constrain such a system to be adaptable and reusable. This paper describes a removable stereotactic frame-mask system that is used to immobilize and reposition the patient during stereotactic neuroradiological procedures and charged particle radiosurgery. It consists of four parts--(a) a plastic mask for immobilizing the patients head; (b) a lucite-graphite mounting frame; (c) a set of fiducial markers; and (d) interfaces between the frame for immobilization and fixation to various diagnostic and therapeutic patient couches. The relationship between each component and the radiosurgical procedure is discussed. This system has proven to be safe, reliable, and noninvasive and it does not require fixation to the bones of the face or skull. When integrated into the radiosurgical treatment planning and localization procedures developed at Lawrence Berkeley Laboratory, it is capable of reliably repositioning the patient to 1 mm in each of three planes and contouring the intracranial target reliably to this accuracy. The application of this stereotactic system in heavy charged particle radiosurgery of intracranial arteriovenous malformations is described in other reports.

MRI and PET of delayed heavy-ion radiation injury in the rabbit brain

Magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques were used to obtain in vivo scans of delayed (30 GyE helium ion, 230 MeV/u) radiation injury in rabbit brain. T2-weighted (T2W) MRI scans demonstrated alterations that were restricted primarily to the white matter tracts and the deep perithalamic and thalamic regions. Quantitative measurements of T2 and T1 values demonstrated wide variations in absolute values. However, paired comparisons in hemibrain-irradiated rabbits revealed significant increases in T2 (p less than 0.001) and T1 (p less than 0.01) in irradiated versus unirradiated brain. Gadolinium DTPA (GdDTPA) enhanced MRI and 82Rubidium (82Rb) PET detected focal regions of blood-brain barrier (BBB) disruption restricted to the deep white matter and thalamic regions. Sequential GdDTPA enhanced MRI scans showed the spreading of the tracer from the initial site of contrast enhancement. 18Fluorodeoxyglucose (18FDG) PET studies demonstrated the markedly depressed metabolic profiles of irradiated brain. Histological findings of tissue edema and necrosis correlated well with the in vivo imaging abnormalities. These initial studies demonstrate that the irradiated rabbit brain is a suitable animal model for examining the delayed effects of radiation injury in the brain.