Endovascular treatment of cerebral arteriovenous malformations following radiosurgery.

PURPOSE: Previous reports of embolization of cerebral arteriovenous malformations (AVMs) have evaluated the technique as adjunctive therapy prior to surgery or radiosurgery; our aim is to assess the role of embolization following radiosurgery. PATIENTS: Six patients previously treated with radiosurgery and showing no response as judged by cerebral angiography were embolized 24 to 55 months (mean 34.3 months) after initial radiosurgery. RESULTS: In five of six, a significant volume reduction was achieved ranging from 60%-100% (mean 74%). One patient was treated with embolization alone and the AVM has remained fully thrombosed 2 years after treatment. Three patients underwent surgical resection for cure after embolization, and two patients had repeat radiosurgery to a significantly smaller AVM volume. One patient had an asymptomatic carotid dissection at embolization; however, no clinically apparent complications occurred in the treatment group. CONCLUSION: Embolization can be used after radiosurgery to assist in the management of those AVMs that have not responded to initial treatment.

Radiation physics for particle beam radiosurgery.

For the particles and energies considered suitable for radiosurgery, with increasing particle charge, the Bragg peak height reaches a maximum with helium and then decreases, the Bragg peak width narrows, the distal fall-off steepens, and the exit dose increases (Table 1). The helium-ion beam is superior to a proton beam because of the higher peak-plateau ratio, more rapid dose fall-off, and smaller beam deflection, and it suffers only in the modest exit dose. Comparison of the therapeutically useful parameters of these beams is complicated by the change in beam quality (LET) with depth. Considerations of RBE values, which change with the ion species and with depth of penetration, may alter the relative rankings based on one or more of these beam characterization values. For all these beams, the RBE increases with increasing LET. The effect for protons is small and occurs just at the end of range of the particles. Effective isodose distributions based on modeled beams have been reported for helium, carbon, and neon ions. These distributions include the effects of a varying RBE with changes in the beam quality (as measured by a dose-weighted LET) and the change in dose fraction size with depth (the dose per fraction is a function of the depth of penetration). These calculations suggest that the optimal charged-particle beam for radiosurgery might be carbon. Heavy charged-particle beams can produce dose distributions superior to those obtainable with photon or electron beams. In clinical trials, these dose distributions have proved to be useful for the treatment of human diseases, including neoplasia and life-threatening intracranial disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Charged-particle radiosurgery for intracranial vascular malformations.

Heavy charged-particle radiation has unique physical characteristics that offer several advantages over photons and protons for stereotactic radiosurgery of intracranial AVMs. These include improved dose distributions with depth in tissue, small angle of lateral scattering, and sharp distal fall-off of dose in the Bragg ionization peak. Under multi-institutionally approved clinical trials, we have used stereotactic helium-ion Bragg peak radiosurgery to treat approximately 400 patients with symptomatic, surgically inaccessible vascular malformations at the UCB-LBL 184-in synchrocyclotron and bevatron. Treatment planning for stereotactic heavy charged-particle radiosurgery for intracranial vascular disorders integrates anatomic and physical information from the stereotactic cerebral angiogram and stereotactic CT and MR imaging scans for each patient, using computerized treatment-planning calculations for optimal isodose contour distribution. The shape of an intracranial AVM is associated strongly with its treatability and potential clinical outcome. In this respect, heavy charged-particle radiosurgery has distinct advantages over other radiosurgical methods; the unique physical properties allow the shaping of individual beams to encompass the contours of large and complexly shaped AVMs, while sparing important adjacent neural structures. We have had a long-term dose-searching clinical protocol in collaboration with SUMC and UCSF and have followed up over 300 patients for more than 2 years. Initially, treatment doses ranged from 45 GyE to 35 GyE. Currently, total doses up to 25 GyE are delivered to treatment volumes ranging from 0.1 cm3 to 70 cm3. This represents a relatively homogeneous dose distribution, with the 90% isodose surface contoured to the periphery of the lesion; there is considerable protection of normal adjacent brain tissues, and most of the brain receives no radiation exposure. Dose selection depends on the volume, shape, and location of the AVM and several other factors, including the volume of normal brain that must be traversed by the plateau portion of the charged-particle beam. The first 230 patients have been evaluated clinically to the end of 1989. Using the clinical grading of Drake, about 90% of the patients had an excellent or good neurologic grade, about 5% had a poor grade, and about 5% had progression of disease and died, or died as a result of unrelated intercurrent illness. Neuroradiologic follow-up to the end of 1989 indicated the following rates of complete angiographic obliteration 3 years after treatment: 90% to 95% for AVM treatment volumes less than 4 cm3, 90% to 95% for volumes 4 to 14 cm3, and 60% to 70% for volumes greater than 14 cm3.(ABSTRACT TRUNCATED AT 400 WORDS)

High-dose single-fraction brain irradiation: MRI, cerebral blood flow, electrophysiological, and histological studies.

Radiation-induced alterations in cerebrovascular and metabolic function form the basis for the radiosurgical treatment of selected intracranial vascular malformations and tumors in human patients. However, the underlying mechanisms, temporal progression, and modifying factors involved in the radiosurgical obliteration of these intracranial lesions as well as the risks of delayed radiation injury to surrounding normal brain remain poorly understood. In this report, the rabbit brain was used as an animal model to examine the effects of high-dose single-fraction X-irradiation on magnetic resonance imaging (MRI) appearance, neurophysiologic function, and histological integrity. At approximately 10 weeks following left-hemisphere irradiation with 60 Gy (225 kVp) X rays, MRI studies showed radiation-induced changes including blood-brain barrier (BBB) perturbations in the white matter regions and the hippocampus. Significant reductions in regional cerebral blood flow (rCBF) ratios were found in the hippocampus and certain regions of the cortex in irradiated animals. However, no changes in somatosensory evoked potentials (SEP) were observed. Histological studies demonstrated telangiectatic vessels, spreading edema in the white matter, and focal regions of necrosis and hemorrhage in the irradiated cortices and hippocampi. These results demonstrate that the irradiated rabbit brain may be used as an experimental model to correlate the spatiotemporal pattern of functional changes with radiologic and histological changes in delayed radiation injury.

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.

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 (AVM's). 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 AVM's, 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.

An experimental compartmental flow model for assessing the hemodynamic response of intracranial arteriovenous malformations to stereotactic radiosurgery.

Stereotactic radiosurgery has proven to be an effective method of treating selected inaccessible or inoperable arteriovenous malformations (AVMs) of the brain. Radiation-induced obliteration of successfully-treated AVMs, however, occurs only after some latent period after treatment, depending on size, location, and dose. An experimental compartmental flow model is proposed to describe the hemodynamic alterations in the AVM as a result of the pathophysiological changes after radiosurgery, and to analyze temporal alterations in AVM blood flow rates and pressure gradients before complete obliteration. In representative small (low-flow, 150 ml/min) and large (high-flow, 440 ml/min) AVMs, it is found that increases in pressure gradients across certain vascular structures within the AVM occur during the normal course of radiation-induced flow decrease and AVM obliteration. The magnitude of these pressure alterations, however, may be within the normal physiological variations in cerebrovascular blood pressure. The effects of partial-volume irradiation of the AVM is examined by limiting radiosurgical treatment to varying portions of the flow compartments within the model. It is found that alterations in pressure gradients persist in unirradiated vascular shunts, even after complete obliteration of the treated AVM volume. These pressure alterations may increase the probability of hemorrhage from the untreated shunts of the AVM and cause redistribution of regional cerebral blood flow resulting in increased flow through these untreated shunts.

Delayed biologic reactions to stereotactic charged-particle radiosurgery in the human brain.

Over 350 patients have been treated for inoperable intracranial arteriovenous malformations with charged-particle radiosurgery. Focussed accelerated helium ion beams derived from charged-particle cyclotrons are stereotactically directed into the brain to obliterate abnormal shunts. Treated patients demonstrate delayed changes in brain anatomy and function that occur months to years after radiosurgery. The underlying mechanisms of the brain's delayed reaction to charged-particle radiosurgery involve complex perturbations in cerebrovascular and metabolic function. This report describes the wide range of delayed reactions that may occur in the brain after radiosurgery, including hemodynamic changes, blood-brain barrier disruption and vasogenic edema, metabolic suppression, and parenchymal necrosis. These delayed reactions to injury in the brain involve potential target cells that include cerebral endothelial cells, oligodendroglia and astrocytes.

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 helium ion Bragg peak radiosurgery for intracranial arteriovenous malformations. Detailed clinical and neuroradiologic outcome.

89 patients with angiographically documented arteriovenous malformations were treated with helium ion Bragg peak radiation. The rate of complete angiographic obliteration 2 years after radiation was 94% in those lesions smaller than 4 cm3 (2.0 cm in diameter), 75% for those 4-25 cm3 and 39% for those larger than 25 cm3 (3.7 cm in diameter); at 3 years after radiation, the corresponding obliteration rates were 100, 95 and 70%. Major clinical complications occurred in 10 patients (8 permanent, 2 transient) between 3 and 21 months after treatment; all were in the initial stage of the protocol (higher radiation doses). 10 patients bled from residual malformation between 4 and 34 months after treatment. Seizures were improved in 63% and headaches in 68% of patients. Excellent or good clinical outcome was achieved in 94% of patients. Compared to the natural history and risks of surgery for these difficult malformations, we consider these results encouraging. Heavy-charged-particle radiation is a valuable therapy for surgically inaccessible symptomatic cerebral arteriovenous malformations. The current procedure has two disadvantages: the prolonged latent period before complete obliteration and the small risk of serious neurological complications.

Heavy-charged-particle radiosurgery for intracranial arteriovenous malformations.

We have treated over 400 patients with symptomatic inoperable intracranial arteriovenous malformations (AVMs) with stereotactic heavy-charged-particle Bragg peak radiosurgery at the University of California at Berkeley in a collaborative program with Stanford University Medical Center and the University of California Medical Center, San Francisco. A long-term dose-searching clinical trial protocol has been developed and we have followed more than 250 patients for more than 2 years. Initially, radiation doses ranged from 45 to 35 GyE, and now doses of 25, 20, 15 and, under special circumstances, 10 GyE, depending on a number of factors, are being evaluated. The characteristics of charged-particle beams provide a relatively homogeneous dose distribution with the 90% isodose contour to the periphery of the lesion. When the entire arterial phase of the AVM core is included in the treatment field, the rates for complete obliteration 3 years after treatment are: 90-95% for volumes less than or equal to 4 cm3; 90-95% for volumes greater than 4 and less than or equal to 14 cm3; and 60-70% for volumes greater than 14 cm3. The total obliteration rate for all volumes up to 70 cm3 is approximately 80-85%. For complete radiation-induced obliteration there is a relationship of dose and volume primarily, and location secondarily. Results on relationships between dose, AVM obliteration, and complications and sequelae of the radiosurgical procedure are presented and discussed.

Stereotactic helium ion Bragg peak radiosurgery for angiographically occult intracranial vascular malformations.

Between July 1983 and July 1989, we treated 35 patients with surgically inaccessible, symptomatic angiographically occult vascular malformations (AOVMs) using stereotactic heavy-charged-particle radiosurgery. AOVMs were located in the brainstem (19), thalamus or internal capsule (9), basal ganglia (3), deep cerebral hemisphere and motor area (3), or cerebellopontine angle (1). All patients presented with clinical and radiological evidence of previous hemorrhage, usually with multiple episodes of hemorrhage. Treatment volumes ranged from 80 to 15,200 mm3 and treatment doses from 7.7 to 34.6 Gy. Mean follow-up was 40 months, with 31 patients followed for at least 2 years. Clinical outcome was excellent in 46%, good in 34% and poor in 14%; 6% died. Twenty-seven patients in excellent and good condition prior to treatment remained stable or improved neurologically. Two patients initially in poor condition, who had previously received conventional radiotherapy, died at 9 and 14 months after treatment, respectively. Six patients experienced recurrent hemorrhage 2-60 months following treatment. Three of these patients made a complete recovery. Although a larger number of treated patients must be followed over longer periods of time, stereotactic heavy-particle radiotherapy may be a valuable treatment modality for surgically inaccessible intracranial AOVMs.

Charged-particle radiosurgery of the brain.

Charged-particle beams (e.g., protons and helium, carbon and neon ions) manifest unique physical properties which offer advantages for neurosurgery and neuroscience research. The beams have Bragg ionization peaks at depth in tissues, and finite range and are readily collimated to any desired cross-sectional size and shape by metal apertures. Since 1954 nearly 6000 neurosurgical patients worldwide have been treated with stereotactic charged-particle radiosurgery of the brain for various localized and systemic malignant and nonmalignant disorders. Experimental studies with charged-particle beams have been carried out in laboratory animals to characterize anatomic and physiologic correlates of various behavioral and functional properties in the brain. Highly focused charged-particle beams have been used to induce sharply delineated laminar lesions or discrete focal ablation of deep-seated brain structures for the study of the functional anatomy of selected intracranial sites. Charged-particle beam irradiation for stereotactic radiosurgery and radiation oncology of intracranial disorders has achieved increasing importance internationally. More than 30 biomedical accelerator facilities on four continents are currently fully operational, under construction, or in an active planning stage; this last group consists primarily of dedicated biomedical hospital-based facilities. Therapeutic efficacy has been demonstrated clearly for the treatment of selected intracranial sites, e.g., pituitary adenomas and intracranial arteriovenous malformations. Heavier charged particles (e.g., carbon and neon ions) have been found to manifest a number of valuable radiobiologic properties and appear to be of potential advantage in the radiosurgical treatment of those primary or metastatic brain tumors that are radioresistant. The optimal dose and choice of charged-particle species must be determined for the treatment of the different intracranial disorders to improve the cure rate and to minimize potential adverse sequelae of the reaction of the brain to radiation injury.

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.

Factors that modify risks of radiation-induced cancer.

The collective influence of biologic, physical, and other factors that modify risks of radiation-induced cancer introduces uncertainties and assumptions that limit precision of estimates of human cancer risk that can be calculated for populations exposed to low-dose radiation. The important biologic characteristics include the tissue sites and cell types, baseline cancer incidence, latent periods, time-to-tumor recognition, and individual host (e.g., age and sex) and competing etiologic influences. Physical factors include radiation dose, dose rate, and radiation quality. Statistical factors include time-response projection models, risk coefficients, and dose-response relationships. Sources that modify risk also include other carcinogens and biologic factors (e.g., hormonal conditions, immune status, hereditary factors). Discussion includes examples of known influences that modify radiation-associated cancer risks and how they have been dealt with in the risk-estimation process, including extrapolation to low doses, use of relative risk models, and other uncertainties.

Radon and lung cancer: the BEIR IV Report.

The National Academy of Sciences' BEIR IV Report (1988) deals primarily with lung cancer risks in human populations exposed to internally deposited alpha-emitting Rn and its decay products. Quantitative risk estimates for lung cancer are derived from analyses of epidemiologic data. A modified excess relative risk model of lung cancer mortality of worker exposure to Rn progeny in underground miners is developed. This models the excess risk per WLM (working level month) in terms of time intervals prior to an attained age, and is dependent on time since exposure and age at risk. Risk projections for the general public in indoor domestic environments are presented and cover exposure situations of current public health concern. For example, lifetime exposure to 1 WLM y-1 is estimated to increase the number of deaths due to lung cancer by a factor of about 1.5 over the current rate for both males and females in a population having the current prevalence of cigarette smoking. Occupational exposure to 4 WLM y-1 from ages 20 to 40 y is projected to increase lung cancer deaths in the general population by a factor of 1.6 over the current rate of this age cohort. In all of these cases, most of the increased risk occurs to smokers for whom the risk is up to 10 times greater than for nonsmokers. Discussion includes the extrapolation of estimates of lung cancer mortality risks from the underground miner data to the general population exposed to Rn and its decay products in the indoor domestic environment.

Shelter and indoor air in the twenty-first century--radon, smoking, and lung cancer risks.

Recognition that radon and its daughter products may accumulate to high levels in homes and in the workplace has led to concern about the potential lung cancer risk resulting from indoor domestic exposure. While such risks can be estimated with current dosimetric and epidemiological models for excess relative risks, it must be recognized that these models are based on data from occupational exposure and from underground miners' mortality experience. Several assumptions are required to apply risk estimates from an occupational setting to the indoor domestic environment. Analyses of the relevant data do not lead to a conclusive description of the interaction between radon daughters and cigarette smoking for the induction of lung cancer. The evidence compels the conclusion that indoor radon daughter exposure in homes represents a potential life-threatening public health hazard, particularly in males, and in cigarette smokers. Resolution of complex societal interactions will require public policy decisions involving the governmental, scientific, financial, and industrial sectors. These decisions impact the home, the workplace, and the marketplace, and they extend beyond the constraints of science. Risk identification, assessment, and management require scientific and engineering approaches to guide policy decisions to protect the public health. Mitigation and control procedures are only beginning to receive attention. Full acceptance for protection against what could prove to be a significant public health hazard in the twenty-first century will certainly involve policy decisions, not by scientists, but rather by men and women of government and law.