Allan J. Hamilton

Preliminary Clinical Experience with Linear Accelerator-based Spinal Stereotactic Radiosurgery

A prototype device called an extracranial stereotactic radiosurgery frame was used to deliver stereotactic radiosurgery, with a modified linear accelerator, to metastatic neoplasms in the cervical, thoracic, and lumbar regions in five patients. In all patients, the neoplasms had failed to respond to spinal cord tolerance doses delivered by standard external fractionated radiation therapy to a median dose of 45 Gy (range, 33-65 Gy/11-30 fractions). The tumors were treated with single-fraction stereotactic radiosurgery with the spinal stereotactic frame for immobilization, localization, and treatment. The median number of isocenters was one (range, one to five) with a median single fraction dose of 10 Gy (range, 8-10 Gy) with median normalization to 80% isodose contour (range, 80-160%). There has been a single complication of esophagitis to date from radiosurgery of a tumor involving the C6-T1 segments; the esophagitis resolved with medical therapy. Median follow-up in this group of patients has been 6 months (range, 1-12 mo). To date, there has been no radiographic or clinical progression of the treated tumor in any patient. Two patients have died from systemic metastatic disease. In the three surviving patients, there has been computed tomographic- or magnetic resonance-documented regression of the treated tumor with a decrease of thecal sac compression with a median follow-up of 6 months (range, 3-14 mo). These five patients represent the first clinical application of stereotactic radiosurgery in the spine. The results suggest that extracranial radiosurgery may be suitable for the treatment of paraspinal neoplasms after external fractionated radiation therapy, even in the face of spinal cord compression.

A Phase I Trial of Ad.hIFN-β Gene Therapy for Glioma

Interferon-β (IFN-β) is a pleiotropic cytokine with antitumoral activity. In an effort to improve the therapeutic index of IFN-β by providing local, sustained delivery of IFN-β to gliomas, the safety and biological activity of a human IFN-β (hIFN-β)-expressing adenovirus vector (Ad.hIFN-β) was evaluated in patients with malignant glioma by stereotactic injection, followed 4-8 days later by surgical removal of tumor with additional injections of Ad.hIFN-β into the tumor bed. Eleven patients received Ad.hIFN-β in cohorts of 2 × 1010, 6 × 1010, or 2 × 1011 vector particles (vp). The most common adverse events were considered by the investigator as being unrelated to treatment. One patient, who was enrolled in the cohort with the highest dose levels, experienced dose-limiting, treatment-related Grade 4 confusion following the post-operative injection. Ad.hIFN-β DNA was detected within the tumor, blood, and nasal swabs in a dose-dependent fashion and hIFN-β protein was detectable within the tumor. At the highest doses tested, a reproducible increase in tumor cell apoptosis in post-treatment versus pre-treatment biopsies with associated tumor necrosis was observed. Direct Ad.hIFN-β injection into the tumor and the surrounding normal brain areas after surgical removal was feasible and associated with apoptosis induction.Interferon-beta (IFN-beta) is a pleiotropic cytokine with antitumoral activity. In an effort to improve the therapeutic index of IFN-beta by providing local, sustained delivery of IFN-beta to gliomas, the safety and biological activity of a human IFN-beta (hIFN-beta)-expressing adenovirus vector (Ad.hIFN-beta) was evaluated in patients with malignant glioma by stereotactic injection, followed 4-8 days later by surgical removal of tumor with additional injections of Ad.hIFN-beta into the tumor bed. Eleven patients received Ad.hIFN-beta in cohorts of 2 x 10(10), 6 x 10(10), or 2 x 10(11) vector particles (vp). The most common adverse events were considered by the investigator as being unrelated to treatment. One patient, who was enrolled in the cohort with the highest dose levels, experienced dose-limiting, treatment-related Grade 4 confusion following the post-operative injection. Ad.hIFN-beta DNA was detected within the tumor, blood, and nasal swabs in a dose-dependent fashion and hIFN-beta protein was detectable within the tumor. At the highest doses tested, a reproducible increase in tumor cell apoptosis in post-treatment versus pre-treatment biopsies with associated tumor necrosis was observed. Direct Ad.hIFN-beta injection into the tumor and the surrounding normal brain areas after surgical removal was feasible and associated with apoptosis induction.

Stereotactic radiosurgery as an adjunct to surgery and external beam radiotherapy in the treatment of patients with malignant gliomas

PURPOSE To evaluate the efficacy and toxicity of a stereotactic radiosurgery boost as part of the primary management of a minimally selected population of patients with malignant gliomas. METHODS AND MATERIALS Between June, 1991 and January, 1994 a stereotactic radiosurgery boost was given to 30 patients after completion of fractionated external beam radiotherapy. The study population consisted of 22 males and 8 females, with a range in age at treatment from 5 to 74 years (median: 54 years). Tumor volume ranged from 2.1 to 115.5 cubic centimeters (cc) (median: 24 cc). Histology included 17 with glioblastoma multiforme, 10 with anaplastic astrocytoma, 1 with a mixed anaplastic astrocytoma-oligodendroglioma, and 2 with a gliosarcoma. A complete resection was performed in 9 (30%) patients, while 18 (60%) underwent a subtotal resection, and 3 (10%) received a biopsy only. Fractionated radiation dose ranged from 44 to 62 Gy, with a median of 59.4 Gy. Prescribed stereotactic radiosurgery dose ranged from 0.5 to 18 Gy (median: 10 Gy), and the volume receiving the prescription dose ranged from 2.1 to 158.7 cc (median: 46 cc). The volume of tumor receiving the prescription dose ranged from 70-100% (median: 100%). One to four (median: 2) isocenters were used, and collimator size ranged from 12.5 to 50 mm (median size: 32.5 mm). The median minimum stereotactic radiosurgery dose was 70% of the prescription dose and the median maximum dose was 200% of the prescription dose. RESULTS With a minimum follow-up of 1 year from radiosurgery, 7 (23%) of the patients are still living and 22 (73%) have died of progressive disease. One patient died of a myocardial infarction 5 months after stereotactic radiosurgery. Follow-up for living patients ranged from 12 to 45 months, with a median of 30 months. The 1- and 2-year disease-specific survival from the date of diagnosis is 57 [95% confidence interval (CI) 39 to 74%] and 25% (95% CI 9 to 41%), respectively (median survival: 13.9 months). No significant acute or late toxicity has been observed. CONCLUSION Stereotactic radiosurgery provides a safe and feasible technique for dose escalation in the primary management of unselected malignant gliomas. Longer follow-up and a randomized prospective trial is required to more thoroughly evaluate the role of radiosurgery in the primary management of malignant gliomas.

Continuous regional cerebral cortical blood flow monitoring in head- injured patients

Continuous regional cerebral cortical blood flow (rCoBF) was monitored with thermal diffusion flowmetry in 56 severely head-injured patients. Adequate, reliable data were accumulated from 37 patients (21 acute subdural hematomas, 10 cerebral contusions, 4 epidural hematomas, and 2 intracerebral hematomas). The thermal sensor was placed at the time of either craniotomy or burr hole placement. In 15 patients, monitoring was initiated within 8 hours of injury. One-third of the comatose patients monitored within 8 hours had rCoBF measurements of 18 ml per 100 g per minute or less, consistent with previous reports of significant ischemia in the early postinjury period. Initial rCoBF measurements were similar in the patients with Glasgow Coma Scale scores of 3 to 7 and in those with scores of 8 or greater. In patients with poor outcomes, rCoBF measurements did not change significantly from initial measurements; however, in those patients who had better outcomes, final rCoBF measurements were higher than initial rCoBF measurements. The patients who had better outcomes experienced normalization of rCoBF during the period of monitoring, and patients with poor outcomes had markedly reduced final rCoBF. These changes were statistically significant. When management was based strictly upon the intracranial pressure, examples of inappropriate treatment were found. For example, hyperemia and increased intracranial pressure treated with mannitol caused further rCoBF increase, and elevated intracranial pressure with low cerebral blood flow treated with hyperventilation increased the severity of ischemia. In 3 (5%) of 56 patients, wound infections developed. Continuous rCoBF monitoring in head-injured patients offers new therapeutic and prognostic insights into their management.

Treatment of malignant gliomas with interstitial irradiation and hyperthermia

A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population.

Interstitial irradiation versus interstitial thermoradiotherapy for supratentorial malignant gliomas: A comparative survival analysis

PURPOSE To compare the survival of two groups of patients with supratentorial malignant gliomas who were treated on two sequential protocols with either interstitial thermoradiotherapy or with interstitial irradiation without hyperthermia. METHODS AND MATERIALS Between 1988-1992, patients with anaplastic astrocytoma or glioblastoma multiforme were treated at the University of Arizona on a Phase I/II protocol of interstitial thermoradiotherapy with ferro-magnetic seeds. The treatment protocol consisted of debulking surgery, a course of external beam radiotherapy and hyperthermia given immediately before and after brachytherapy. The survival of patients so treated was compared with that of a similar group of patients treated with interstitial brachytherapy alone at the Barrows Neurological Institute between 1982-1990. RESULTS Twenty-five patients with primary tumors treated at the time of initial presentation with thermoradiotherapy were compared with a control group of 37 patients treated with interstitial brachytherapy alone. All primary patients were followed for a minimum of 34 months post implant. Multivariate analysis based on proportional hazards models showed that hyperthermia (p = 0.027), patient age (p < or = 0.00001) and histology (anaplastic astrocytoma vs. glioblastoma multiforme, p = 0.0017) were the only factors significantly associated with survival in this data set. From the fitted model, the hazard of dying when treated with hyperthermia was .53 times (95% confidence intervals 0.29-0.94) than that of the control group. In addition, we treated a small group of patients with recurrent tumors (13 with brachytherapy alone, and eight with thermoradiotherapy) and found no survival difference (p = 0.62). CONCLUSION Within the constraints of the selection factors and the different treatment parameters used in these studies, we conclude that an interstitial thermoradiotherapy boost confers a statistically significant survival benefit to patients with primary high grade gliomas when compared to interstitial brachytherapy alone.

A Prototype Device for Linear Accelerator-Based Extracranial Radiosurgery

A prototype frame for accurate stereotactic localization and linear accelerator (LINAC)-based treatment of extracranial targets was developed. The ECRSF is designed to employ either spinal or skeletal osseous fixation to immobilize the area of interest and then encircle the targeted region with a traditional orthogonal, three-axis system. A series of experiments (n = 5) with semi-radiolucent calibration targets (n = 15) and computed tomography (CT) scanning using the EC showed that a mean localization error of 0.98 +/- 0.22 mm was obtainable in the last two and most accurate series of experiments with these targets (n = 8). Using the LINAC to irradiate these same targets demonstrated an overall radiation treatment accuracy ranging from 1.4 to 2.0 mm. This discrepancy between localization error and overall radiation treatment error can be explained by a lack of isocentricity of the LINAC treatment which is typically less than 1 mm and can be as low as 0.5 mm. These data demonstrate that extracranial stereotactic radiosurgery is now technically feasible and that the accuracy of such treatment would be acceptable for clinical treatment.

High Altitude Cerebral Edema

&NA; Acute mountain sickness (AMS) is usually a benign and self‐limited illness that befalls previously healthy individuals who ascend rapidly to high altitude without sufficient acclimatization. In its more severe forms, AMS can progress to a life‐threatening condition in which pulmonary or cerebral edema can occur singly or in concert. High altitude cerebral edema (HACE) is a little‐known clinical entity that manifests itself by a perplexing array of both generalized and localized neurological symptoms and signs. Furthermore, the development of HACE in climbers offers a unique experimental situation in which to examine the effects of hypoxia on the central nervous system. The epidemiology and clinical picture of HACE are reviewed. In addition, the pathology and predominant pathophysiological mechanisms postulated to explain HACE are examined, and the present recommendations for the prevention and treatment of this dangerous and unusual form of brain swelling are discussed. (Neurosurgery 19:841‐849, 1986)

The use of stereotactic radiosurgical boost in the treatment of medulloblastomas

PURPOSE Starting in 1992, we began using a stereotactic radiosurgical (SRS) boost for the treatment of medulloblastomas. Four patients ranging in age from 7 to 42 years old have since been treated and are the subject of this retrospective study. METHODS AND MATERIALS All patients were initially treated with a maximally debulking surgery and external beam radiotherapy, which were then followed by a stereotactic radiosurgical boost using a modified 6 MeV linear accelerator. Radiosurgical boost doses ranged from 4.50 to 10.0 Gy. Target volumes ranged from 1.1 to 8.1 cc. The procedure was well tolerated with minimal acute toxicities. RESULTS All four patients are alive without evidence of recurrence (at 8 to 35 months). Acute nausea and vomiting was elicited during the radiosurgical procedure in the first patient treated. We have since begun premedicating patients with antiemetics or treating under general anesthesia. Late complications consisted of panhypopituitarism in one patient, which was thought to be attributable to the previous course of whole-brain radiotherapy. We have not observed any incidence of radionecrosis in this small cohort of patients. CONCLUSIONS Our preliminary results with the use of radiosurgery for medulloblastomas are optimistic, and we would like to suggest the inclusion of a radiosurgery boost in future clinical trials for treatment of this disease.

Stereotactic biopsy of intracranial brain lesions: High diagnostic yield without increased complications: 65 consecutive biopsies with early postoperative CT scans

Diagnostic yield and complication rate were analyzed for a series of 65 consecutive stereotactic biopsies of intra-axial brain lesions. The diagnostic yield was 98.5 ± 1.5% and the complication rate was 1.5%. A median number of 14 biopsies (range 1–48) were taken per lesion. The biopsy sites followed a clockwise pattern, going from the superficial margin to the center and the deep margin of the lesion with respect to the inner table of the skull. A side window cannula biopsy needle was used. All patients underwent immediate postoperative CT scans within 4 h of biopsy to rule out intracranial complications. All patients were discharged within 24 h after biopsy, unless medical reasons unrelated to the biopsy required further hospitalization. We attribute the high diagnostic yield in our series to the high number of systematically taken biopsies per lesion. The higher number of biopsies did not lead to an increase in complications. From our experience, it appears safe to discharge patients the same day or within 24 h after a stereotactic biopsy if the postoperative CT shows no complication. Stereotactic biopsy could often safely be performed on an outpatient basis.