Does Stereotactic Radiosurgery Have a Role in the Management of Patients Presenting With 4 or More Brain Metastases?

Stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) are effective treatments for management of brain metastases. Prospective trials comparing the 2 modalities in patients with fewer than 4 brain metastases demonstrate that overall survival (OS) is similar. Intracranial failure is more common after SRS, while WBRT is associated with neurocognitive decline. As technology has advanced, fewer technical obstacles remain for treating patients with 4 or more brain metastases with SRS, but level I data supporting its use are lacking. Observational prospective studies and retrospective series indicate that in patients with 4 or more brain metastases, performance status, total volume of intracranial disease, histology, and rate of development of new brain metastases predict outcomes more accurately than the number of brain metastases. It may be reasonable to initially offer SRS to some patients with 4 or more brain metastases. Initiating therapy with SRS avoids the acute and late sequelae of WBRT. Multiple phase III trials of SRS vs WBRT, both currently open or under development, are directly comparing quality of life and OS for patients with 4 or more brain metastases to help answer the question of SRS appropriateness for these patients.

A round-robin gamma stereotactic radiosurgery dosimetry interinstitution comparison of calibration protocols.

PURPOSE: Absorbed dose calibration for gamma stereotactic radiosurgery is challenging due to the unique geometric conditions, dosimetry characteristics, and nonstandard field size of these devices. Members of the American Association of Physicists in Medicine (AAPM) Task Group 178 on Gamma Stereotactic Radiosurgery Dosimetry and Quality Assurance have participated in a round-robin exchange of calibrated measurement instrumentation and phantoms exploring two approved and two proposed calibration protocols or formalisms on ten gamma radiosurgery units. The objectives of this study were to benchmark and compare new formalisms to existing calibration methods, while maintaining traceability to U.S. primary dosimetry calibration laboratory standards. METHODS: Nine institutions made measurements using ten gamma stereotactic radiosurgery units in three different 160 mm diameter spherical phantoms [acrylonitrile butadiene styrene (ABS) plastic, Solid Water, and liquid water] and in air using a positioning jig. Two calibrated miniature ionization chambers and one calibrated electrometer were circulated for all measurements. Reference dose-rates at the phantom center were determined using the well-established AAPM TG-21 or TG-51 dose calibration protocols and using two proposed dose calibration protocols/formalisms: an in-air protocol and a formalism proposed by the International Atomic Energy Agency (IAEA) working group for small and nonstandard radiation fields. Each institution's results were normalized to the dose-rate determined at that institution using the TG-21 protocol in the ABS phantom. RESULTS: Percentages of dose-rates within 1.5% of the reference dose-rate (TG-21+ABS phantom) for the eight chamber-protocol-phantom combinations were the following: 88% for TG-21, 70% for TG-51, 93% for the new IAEA nonstandard-field formalism, and 65% for the new in-air protocol. Averages and standard deviations for dose-rates over all measurements relative to the TG-21+ABS dose-rate were 0.999±0.009 (TG-21), 0.991±0.013 (TG-51), 1.000±0.009 (IAEA), and 1.009±0.012 (in-air). There were no statistically significant differences (i.e., p>0.05) between the two ionization chambers for the TG-21 protocol applied to all dosimetry phantoms. The mean results using the TG-51 protocol were notably lower than those for the other dosimetry protocols, with a standard deviation 2-3 times larger. The in-air protocol was not statistically different from TG-21 for the A16 chamber in the liquid water or ABS phantoms (p=0.300 and p=0.135) but was statistically different from TG-21 for the PTW chamber in all phantoms (p=0.006 for Solid Water, 0.014 for liquid water, and 0.020 for ABS). Results of IAEA formalism were statistically different from TG-21 results only for the combination of the A16 chamber with the liquid water phantom (p=0.017). In the latter case, dose-rates measured with the two protocols differed by only 0.4%. For other phantom-ionization-chamber combinations, the new IAEA formalism was not statistically different from TG-21. CONCLUSIONS: Although further investigation is needed to validate the new protocols for other ionization chambers, these results can serve as a reference to quantitatively compare different calibration protocols and ionization chambers if a particular method is chosen by a professional society to serve as a standardized calibration protocol.

Early-delayed, radiation-induced cognitive deficits in adult rats are heterogeneous and age-dependent.

Patients treated with whole-brain irradiation often develop cognitive deficits that are presumed to result from normal tissue injury. Age is a risk factor for these side effects. We compared the cognitive effects of fractionated whole-brain irradiation (300 kV X rays) in rats irradiated either as young adults or in middle age. A deficit in object memory was apparent at 3 months in rats irradiated as young adults, however, no comparable deficit was apparent in rats irradiated in middle age. In addition, the deficit in object memory in young adults was no longer apparent at 6 and 12 months after fractionated whole-brain irradiation and no radiation-induced deficit was detectable in a spatial memory task at any time, regardless of age at time of irradiation. Thus, clinically relevant fractionated whole-brain irradiation in adult rats resulted in early-delayed cognitive changes that were heterogeneous, transient and age-dependent. The results of the current and previous studies of radiation-induced cognitive changes support the continued investigation and validation of rodent models of radiation-induced brain injury, which are critical for developing and testing new therapies for treatment-induced cognitive dysfunction in cancer survivors.

Systemic effects of fractionated, whole-brain irradiation in young adult and aging rats.

Cranial irradiation is a critical and effective treatment for primary brain tumors and metastases. Unfortunately, most patients who are treated and survive for more than a few months develop neural and cognitive problems as the result of radiation-induced normal tissue injury. The neurobiological mechanisms underlying these cognitive deficits remain largely unknown and there are no validated treatments to prevent or ameliorate them; thus, there is a significant and continuing need for preclinical studies in animal models. Investigations from several laboratories have demonstrated neurobiological changes after cranial irradiation in rodents. To date, however, experimental studies in animal models have included little assessment of the systemic effects of cranial irradiation, despite evidence from the clinic that cranial irradiation results in changes throughout the body and recognition that systemic responses may influence the development of neural and cognitive deficits. This study evaluated systemic effects of clinically relevant, fractionated whole-brain irradiation in adult rats and demonstrates effects on the growth hormone/insulin-like growth factor-I axis, which may contribute to the development of neural changes. These and other systemic responses are important to consider in ongoing efforts to understand the mechanisms of radiation-induced normal tissue injury.

Mechanisms and prevention of thermal injury from gamma radiosurgery headframes during 3T MR imaging.

Magnetic resonance imaging (MRI) is regularly used for stereotactic imaging of Gamma Knife (GK) radiosurgery patients for GK treatment planning. MRI-induced thermal injuries have occurred and been reported for GK patients with attached metallic headframes. Depending on the specific MR imaging and headframe conditions, a skin injury from MRI-induced heating can potentially occur where the four headframe screws contact the skin surface of the patient's head. Higher MR field strength has a greater heating potential. Two primary heating mechanisms, electromagnetic induction and the antenna effect, are possible. In this study, MRI-induced heating from a 3T clinical MRI scanner was investigated for stereotactic headframes used in gamma radiosurgery and neurosurgery. Using melons as head phantoms, optical thermometers were used to characterize the temperature profile at various points of the melon headframe composite as a function of two 3T MR pulse sequence protocols. Different combinations of GK radiosurgery headframe post and screw designs were tested to determine best and worst combinations for MRI-induced heating. Temperature increases were measured for all pulse sequences tested, indicating that the potential exists for MRI-induced skin heating and burns at the headframe attachment site. This heating originates with electromagnetic induction caused by the RF fields inducing current in a loop formed by the headframe, mounting screws, and the region of the patient's head located between any of the two screws. This induced current is then resistively dissipated, with the regions of highest resistance, located at the headframe screw-patient head interface, experiencing the most heating. Significant heating can be prevented by replacing the metallic threads holding the screw with electrically insulated nuts, which is the heating prevention and patient safety recommendation of the GK manufacturer. Our results confirm that the manufacturer's recommendation to use insulating nuts reduces the induced currents in the headframe nearly to zero, effectively preventing heating and minimizing the likelihood of thermal injury.

Evaluation of the spatial dependence of the point spread function in 2D PET image reconstruction using LOR-OSEM.

PURPOSE: The use of positron emission tomography (PET) imaging has proved beneficial in the staging and diagnosis of several cancer disease sites. Additional applications of PET imaging in treatment planning and the evaluation of treatment response are limited by the relatively low spatial resolution of PET images. Including point spread function (PSF) information in the system matrix (SM) of iterative reconstruction techniques has been shown to produce improved spatial resolution in PET images. METHODS: In this study, the authors sampled the spatially variant PSF at over 6000 locations in the field of view for a General Electric Discovery ST PET/CT (General Electric Healthcare, Waukesha, WI) scanner in 2D acquisition mode. The authors developed PSF blurred SMs based on different combinations of the radial, depth, and azimuthal spatial dependencies to test the overall spatial dependence of the PSF on image quality. The PSF blurred SMs were included in a LOR-OSEM reconstruction algorithm and used for image reconstruction of geometric phantoms. The authors also examined the effect of sampling density on PSF characterization to design a more efficient sampling scheme. RESULTS: The authors found that depth dependent change in the amplitude of the detector response was the most important factor affecting image quality. A SM created from a PSF that introduced r (perpendicular to the LOR), d (parallel to the LOR), or r and d dependent blurring across the radial lines of response led to visually identifiable improvements in spatial resolution and contrast in reconstructed images compared to images reconstructed with a purely geometric SM with no PSF blurring. Images reconstructed using a SM with r and d dependent blurring across the radial lines of response showed improved spatial resolution and contrast-noise ratios compared to images reconstructed with a SM that had only r dependent blurring. Additionally, the authors determined that the PSF could be adequately characterized with roughly 85% fewer samples through the use of a better optimized sampling scheme. CONCLUSIONS: PET image reconstruction using a SM made from an accurately characterized PSF that accounts for r and d dependencies results in improved spatial resolution and contrast-noise relations, which may aid in lesion boundary detection for treatment planning or quantitative assessment of treatment response.

Gamma knife radiosurgery treatment planning for small animals using high-resolution 7T micro-magnetic resonance imaging.

Gamma Knife stereotactic radiosurgery is capable of providing small, high gradient dose distributions to a target with a high level of precision, which makes it an excellent choice for studies of focal irradiations with small animals. However, the Gamma Knife stereotactic radiosurgery process makes use of a human-sized fiducial marker system that requires a field of view of at least 200 mm(2) to relate computed tomography and magnetic resonance images to the Gamma Knife treatment planning software. Thus the Gamma Knife fiducial marker system is five to six times larger than a typical small animal subject. The required large field of view limits the spatial resolution and structural detail available in the animal treatment planning image set. In response to this challenge we have developed a custom-designed stereotactic jig and miniature fiducial marking system that allow small bore high-resolution micro-imaging techniques, such as 7T MR and micro-CT, to be used for treatment planning of Gamma Knife stereotactic radiosurgery focal irradiation of small animals.

Simulated gamma knife head frame placement for radiosurgical pre-planning.

The Leksell Gamma Knife (GK) is capable of targeting intracranial lesions with a high degree of accuracy. A headframe is rigidly attached to the patient's skull to establish a stereotactic coordinate system and provide a means for precisely positioning the patient in stereotactic space. After stereotactic target localization and radiosurgical treatment planning the skull and headframe are then moved with sub-millimeter precision to bring a target volume to the radiological focus of the GK unit. However, for GK models 4C and earlier, the treatable intracranial volume may be limited by collisions between the skull/headframe and the GK collimator helmet, or by mechanical travel limits of the skull/headframe within the collimator helmet. Both of these treatment-limiting conditions can be found only after the headframe has been placed on the patient. If the volume of interest cannot be treated with the initial headframe placement, additional headframe placements or a different course of treatment are needed. We have developed a software package that allows for simulated headframe placement and collision checks using pre-treatment day image sets, in order to minimize the need for multiple headframe placements. We performed a small validation experiment with an anthropomorphic head phantom to evaluate the software's capabilities for predicting a clinically useable headframe position. We also used the software in an IRB-approved retrospective review for twenty-five GK image sets for a group of patients that could not be treated with the initial headframe placement, to determine if the software tool could locate an optimized headframe position to enable GK radiosurgery of all identified targets with a single headframe placement. We found that four of the cases could have been completed with a single optimized headframe placement and twenty-four of the cases could not be treated with any single headframe placement.

Tradeoffs of integrating real-time tracking into IGRT for prostate cancer treatment.

This study investigated the integration of the Calypso real-time tracking system, based on implanted ferromagnetic transponders and a detector array, into the current process for image-guided radiation treatment (IGRT) of prostate cancer at our institution. The current IGRT process includes magnetic resonance imaging (MRI) for prostate delineation, CT simulation for treatment planning, daily on-board kV and CBCT imaging for target alignment, and MRI/MRS for post-treatment assessment. This study assesses (1) magnetic-field-induced displacement and radio-frequency (RF)-induced heating of transponders during MRI at 1.5 T and 3 T, and (2) image artifacts caused by transponders and the detector array in phantom and patient cases with the different imaging systems. A tissue-equivalent phantom mimicking prostate tissue stiffness was constructed and implanted with three operational transponders prior to phantom solidification. The measurements show that the Calypso system is safe with all the imaging systems. Transponder position displacements due to the MR field are minimal (<1.0 mm) for both 1.5 T and 3 T MRI scanners, and the temperature variation due to MRI RF heating is <0.2 degrees C. The visibility of transponders and bony anatomy was not affected on the OBI kV and CT images. Image quality degradation caused by the detector antenna array is observed in the CBCT image. Image artifacts are most significant with the gradient echo sequence in the MR images, producing null signals surrounding the transponders with radii approximately 1.5 cm and length approximately 4 cm. Thus, Calypso transponders can preclude the use of MRI/MRS in post-treatment assessment. Modifications of the clinical flow are required to accommodate and minimize the substantial MRI artifacts induced by the Calypso transponders.

Three-dimensional conformal radiation treatment planning and delivery for low- and intermediate-grade gliomas.

Three-Dimensional conformal radiation treatment (3D-CRT) planning and delivery is an external beam radiation therapy modality that has the general goal of conforming the shape of a prescribed dose volume to the shape of a 3-dimensional target volume, simultaneously limiting dose to critical normal structures. 3-Dimensional conformal therapy should include at least one volumetric imaging study of the patient. This image should be obtained in the treatment position for visualizing the target and normal anatomic structures that are potentially within the irradiated volume. Most often, computed tomography (CT) and/or magnetic resonance imaging (MRI) are used; however, recently, other imaging modalities such as functional MRI, MR spectroscopy, and positron emission tomography (PET) scans have been used to visualize the clinically relevant volumes. This article will address the clinically relevant issues with regard to low- and intermediate-grade gliomas and the role of 3D-CRT planning. Specific issues that will be addressed will include normal tissue tolerance, target definition, treatment field design in regard to isodose curves and dose-volume histograms, and immobilization.

A film technique for the determination of output factors and end effect times for the Leksell Gamma Knife.

The relative output factors of the four helmets for a model B Leksell Gamma Knife and the end effect times for each helmet have been measured. For the three helmets with the smallest-diameter collimators a technique employing Kodak XV-2 film was used. The measured output factors are in good agreement with the values recommended by the manufacturer. The end effect times vary with the collimator size, with the shorter time occurring with the smaller collimator.

Review of patient safety in time-varying gradient fields.

In magnetic resonance, time-varying gradient magnetic fields (dB/dt) may stimulate nerves or muscles by inducing electric fields in patients. Models predicted mean peripheral nerve and cardiac stimulation thresholds. For gradient ramp durations of less than a few milliseconds, mean peripheral nerve stimulation is a safe indicator of high dB/dt. At sufficient amplitudes, peripheral nerve stimulation is perceptible (i.e., tingling or tapping sensations). Magnetic fields from simultaneous gradient axes combine almost as a vector sum to produce stimulation. Patients may become uncomfortable at amplitudes 50%-100% above perception thresholds. In dogs, respiratory stimulation has been induced at about 300% of mean peripheral nerve thresholds. Cardiac stimulation has been induced in dogs by small gradient coils at thresholds near Reilly's predictions. Cardiac stimulation required nearly 80 times the energy needed to produce nerve stimulation in dogs. Nerve and cardiac stimulation thresholds for dogs were unaffected by 1.5-T magnetic fields.

Electrophysiological control of ventricular rate during atrial fibrillation.

Thirteen anesthetized canine subjects (17-29 kg) were used to demonstrate that mild cervical left vagal stimulation could control ventricular rate effectively during atrial fibrillation (AF). Two studies are presented. The first study used six subjects to demonstrate the inverse relationship between (manually applied) left vagal stimulation and ventricular excitation (R wave) rate during AF. As left vagal stimulation frequency was increased, ventricular excitation rate decreased. In these studies, a left vagal stimulus frequency of 0-10 per second reduced the ventricular excitation rate from > 200/min to < 50/min. The decreasing ventricular excitation rate with increasing left vagal stimulation frequency was universal, occurring in all 26 trials with the six subjects. This fundamental principle was used to construct an automatic controller for use in the second study, in which seven subjects were used to demonstrate that ventricular rate can be brought to and maintained within a targeted range with the use of an automatic (closed-loop) controller. A 45-minute record of automatic ventricular rate control is presented. Similar records were obtained in all seven subjects.

Three-dimensional skeletonization for computer-assisted treatment planning in radiosurgery.

This paper describes a new algorithm for skeletonization of two- (2D) and three-dimensional (3D) objects based on ridge extraction. Ridges are formed when grassfire fronts collapse during grassfire propagation and they correspond to the locus of skeleton. The iso-distance contours/surfaces of a distance map are analogous to the grassfire fronts. They are locally smooth everywhere except at ridge locations. The new skeletonization algorithm extracts these ridge points based on local curvature measurement and is rotational invariant. It requires one scan of the image for curvature detection in any dimension, and is much faster than thinning methods. Connectivity checks are not required and the algorithm is extensible to higher dimensions. Our 3D skeletonization method is used in a novel algorithm to guide computerized planning of radiosurgical treatment of brain tumors.

Morphology-guided radiosurgery treatment planning and optimization for multiple isocenters.

This work merges two distinct fields, 3D morphology and ionizing radiation dosimetry, to solve the problem of 3D-treatment planning and optimization in stereotactic radiosurgery. In Leksell Gamma Knife radiosurgery, dose delivery is based on the unit "shot," a dose distribution approximately spherical in shape. Multiple shots, or isocenters, are used in Gamma Knife treatment to deliver a conformal dose to an irregular radiosurgical target. The medial axis transformation, or skeleton, of the target, which uniquely characterizes the target volume and shape, is used to determine the optimal shot positions (isocenters), sizes (collimator helmet size and dosimetric weight), and the total number of shots that will deliver a conformal dose distribution to the target. The skeletonization approach reduces a complicated 3D-optimization problem to 1D searching with potential savings in computation time and mathematical complexity. In addition, optimization based on target shape replicates and automates manual treatment planning. This approach makes the process easily understandable. The relationship between skeleton discs and the dose distributions they predict is discussed. Results of optimal plans and corresponding dose distributions are presented. This approach is generally applicable to other types of multi-isocentric stereotactic radiosurgery techniques.

Physiologic effects of intense MR imaging gradient fields.

The strength duration relationship for peripheral nerve stimulation by MR imaging pulsed gradient magnetic fields was measured in 84 human subjects. The data were fitted to the hyperbolic strength-duration relationship: dB/dt=b(1 + c/d), where b is rheobase, c is chronaxie, and d is duration, and dB/dt is reported as the maximal value on the axis of the bore. For sensation threshold, average (b,c) (15 T/s, 0.37 ms) for the y-gradient and (26 T/s, 0.38 ms) for the z-gradient coil. The dB/dt intensity to induce a sensation which the subject described as uncomfortable was about 50% above the sensation threshold. Experiments with dogs showed that the cardiac stimulation by pulsed magnetic gradient fields is exceedingly unlikely.

Characterization of atrioventricular nodal response to electrical left vagal stimulation.

The dynamic effect of left vagal stimulation on atrioventricular conduction was studied in six isofluorane-anesthetized dogs ranging in weight from 22 to 29 kg. The cervical vagus nerve trunks were left intact and no beta-adrenergic blockade was produced so that any influences of the sympathetic nervous system and autonomic reflex activity could be observed. Atrial pacing was used to control the heart rate while single, short trains of left vagal stimulation were delivered and timed to occur at different instances during the cardiac cycle. The magnitude of the A-V delay depended on the instant of delivery of the train of vagal stimuli during the cardiac cycle. Vagal effect curves were constructed and fit to a mathematical equation which describes the pharmacokinetic behavior of a bolus injection of a drug whose onset time is of the same order as its half-life. The three parameters of this equation have physiologic significance and are related to nerve propagation time and synaptic delay, acetylcholine concentration rise, and the acetylcholineesterase mechanism. The maximum A-V delay occurred when the short train of left vagal stimuli was applied 200-300 ms after the atrial pacing stimulus and the total effect was virtually over by 800-1,000 ms.

Skin-temperature distribution under a new type of defibrillating electrode.

The temperature rises under a new type of x-ray-transparent, improved current-density-distribution defibrillation electrode applied to pig skin were measured at four sites with fiberoptic thermal probes. Three anesthetized pigs, ranging in weight from 79 to 92 lb, were used. Temperature-time curves were obtained and the maximum temperature was identified. For 17 measurements at each site, the maximum temperature rise for a 360-joule shock was 317.3 +/- 53.0 millidegrees Celsius.

Ventricular defibrillating threshold: strength-duration and percent-success curves.

The term defibrillation threshold is usually understood to mean the shock intensity just enough to defibrillate a specified cardiac chamber (atria or ventricles). With the advent of so many different types of defibrillator, it is important to be able to specify the defibrillation threshold, which has frequently been described by the classical strength-duration curve. Another method of representing defibrillation plots the percent-successful defibrillation against shock-strength area. The mechanism of defibrillation is discussed, and the concepts of the strength-duration curve and percent-success against shock-strength curves are compared. Because defibrillation is associated with a time-varying spectrum of cellular excitability, a given shock strength will not always achieve defibrillation, and this produces the sigmoid shape for the curve that relates percent-successful defibrillation to shock strength. Therefore it is important to recognise two concepts: first, there is a family of strength-duration curves for defibrillation, each curve representing a given percent-successful defibrillation, and, secondly, there is a family of percent-success against shock-strength curves, one for each pulse duration. Canine ventricular defibrillation data are used to bring these two concepts together. Most importantly, the concepts adduced in the paper apply to transventricular, intracardiac and transchest defibrillation; the only difference in these applications is a scale factor that represents electrode location with respect to the heart.