William H. Hinson

Stereotactic body radiation therapy: The report of AAPM Task Group 101

Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.

Contribution of visceral fat mass to the insulin resistance of aging

Recent studies have shown that central obesity (increased waist to hip ratio [WHR]) is related to insulin resistance and aging. Furthermore, in central-obesity states, the intraabdominal fat (IAF) depot has been postulated to contribute most to the development of insulin resistance. Therefore, the observed insulin resistance of aging may be related more to changes in body composition than to aging per se. The purpose of this study was to explore the association of IAF with age and insulin sensitivity (SI) after controlling for obesity. We examined 60 healthy nondiabetic subjects (normal 75-g oral glucose tolerance test, aged 23 to 83, 15 men and 45 women). We chose subjects so that those < or = 125% and greater than 125% of ideal body weight were equally represented in each age decade. We quantified total and subcutaneous abdominal fat and IAF at the umbilicus using a validated magnetic resonance imaging (MRI) scanning technique and determined SI using a modified minimal model. IAF correlated significantly with age (r = .49, P = .0001) in the group as a whole, as well as in men (r = .58, P = .022) and women (r = .48, P = .0008) separately. In all subjects, SI was significantly related to IAF (r = -.50, P < .0001) but was not related to age (r = .00, P = .98). In multivariate analysis for various combinations of age, sex, and measures of fat distribution, WHR accounted for 28% and IAF for 51% of the variance in SI, whereas age, sex, and interactions of age and sex accounted for only 1%.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline.

Objective: In a retrospective review to assess neuroanatomical targets of radiation-induced cognitive decline, dose volume histogram (DVH) analyses of specific brain regions of interest (ROI) are correlated to neurocognitive performance in 57 primary brain tumor survivors. Methods: Neurocognitive assessment at baseline included Trail Making Tests A/B, a modified Rey-Osterreith Complex Figure, California or Hopkins Verbal Learning Test, Digit Span, and Controlled Oral Word Association. DVH analysis was performed for multiple neuroanatomical targets considered to be involved in cognition. The %v10 (percent of ROI receiving 10 Gy), %v40, and %v60 were calculated for each ROI. Factor analysis was used to estimate global cognition based on a summary of performance on individual cognitive tests. Stepwise regression was used to determine which dose volume predicted performance on global factors and individual neurocognitive tests for each ROI. Results: Regions that predicted global cognitive outcomes at doses <60 Gy included the corpus callosum, left frontal white matter, right temporal lobe, bilateral hippocampi, subventricular zone, and cerebellum. Regions of adult neurogenesis primarily predicted cognition at %v40 except for the right hippocampus which predicted at %v10. Regions that did not predict global cognitive outcomes at any dose include total brain volume, frontal pole, anterior cingulate, right frontal white matter, and the right precentral gyrus. Conclusions: Modeling of radiation-induced cognitive decline using neuroanatomical target theory appears to be feasible. A prospective trial is necessary to validate these data.

Insulin resistance and fat patterning with aging: Relationship to metabolic risk factors for cardiovascular disease

Both insulin resistance and abdominal fat patterning are related to aging, and have been related to cardiovascular disease (CVD) risk factors such as dyslipidemia and hypertension. However, previous studies have not used direct methods to quantify the independent strength of the association of each of these two putative primary factors with metabolic outcomes. We quantified overall obesity by the body mass index (BMI) and used a previously validated magnetic resonance imaging (MRI) method to quantify abdominal fat in 63 healthy nondiabetic individuals aged 22 to 83 years. We also measured the glucose and insulin response to an oral glucose tolerance test and the insulin sensitivity ([SI] by modified minimal model analysis). Body fat patterning was evaluated by the waist to hip ratio (WHR) and by MRI, which allowed direct measurement of subcutaneous (SCF) and intraabdominal (IAF) fat depots at the umbilicus in these subjects. These independent parameters were related to risk factors for CVD (blood pressure, lipids, and lipoproteins) and to plasma concentrations of free fatty acids (FFAs). Measures of overall obesity (BMI), total fat [TF], and/or SCF measured at the abdomen by MRI), glucose/insulin metabolism and SI, and central fat patterning (WHR or IAF measured by MRI) were correlated with mean arterial pressure (MAP), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels in univariate analysis and after controlling for age and gender. An index of central fat patterning (WHR) added to the informativeness of the insulin area under the curve (IAUC) in explaining 24% of the variability in plasma TG concentration, but measures of overall obesity were not independently related. Both the BMI and TF contributed to the IAUC in explaining 32% to 34% of the variability in MAP, but central fat patterning was not independently related. No index of overall obesity, fat patterning, glucose/insulin metabolism, and/or SI, was independently related to the plasma concentration of HDL-C after controlling for any one of the other two. Direct measurement of glucose/insulin metabolism and SI, as well as fat patterning, provides information on their relative associations with CVD risk factors. The measures of glucose/insulin metabolism and SI were more consistently related to dyslipidemia and hypertension than were the overall obesity and fat patterning in this healthy population.

Thoracic re-irradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment

BACKGROUND AND PURPOSE Management for in-field failures after thoracic radiation is poorly defined. We evaluated SBRT as an initial or second course of treatment re-irradiating in a prior high dose region. MATERIALS AND METHODS Thirty-three patients were treated with re-irradiation defined by the prior 30 Gy isodose line. Kaplan-Meier estimates were performed for local (LC), regional (RC), distant control (DC), and overall survival (OS). The plans when available were summed to evaluate doses to critical structures. Patient and treatment variables were analyzed on UVA for the impact on control and survival measures. RESULTS Median follow-up was 17 months. Treatment for sequential courses was as follows: (course1:course2) EBRT:SBRT (24 patients), SBRT:SBRT (7 patients), and SBRT:EBRT (3 patients). Median re-irradiation dose and fractionation was 50 Gy and 10 fractions (fx), with a median of 18 months (6-61) between treatments. Median OS was 21 months and 2 year LC 67%, yet LC for >1 fraction was 88% (p=0.006 for single vs. multiple). 10 patients suffered chronic grade 2-3 toxicity (6 chest wall pain, 3 dyspnea, 1 esophagitis) and 1 grade 5 toxicity with aorta-esophageal fistula after 54 Gy in 3 fx for a central tumor with an estimated EQD2 to the aorta of 200 Gy. CONCLUSION Tumor control can be established with re-irradiation using SBRT techniques for in-field thoracic failures at the cost of manageable toxicity.

Phase la/lb Chemo-Radiation Trial of Gemcitabine and Dose-Escalated Thoracic Radiation in Patients with Stage III A/B Non-small Cell Lung Cancer

Introduction The safety of dose-escalated thoracic radiation concurrent with gemcitabine in patients with inoperable stage III non-small cell lung cancer has not been studied. Patients and Materials The maximal tolerated dose of 35 mg/m 2 twice-weekly gemcitabine and concurrent standard thoracic radiation was established in a previous phase Ia trial. In this study, a second patient cohort (phase Ib) received twice-weekly gemcitabine concurrent with three-dimensional dose-escalated thoracic radiation (60-74 Gy) after two cycles of induction chemotherapy: gemcitabine (1000 mg/m 2 ) day 1 and 8 and carboplatin (area under the curve 5.0-5.5) day 1 every 21 days. Results Twenty-three patients were entered in the phase Ib portion of this trial. Grade III/IV hematologic toxicity was primarily thrombocytopenia (22%) and neutropenia (26%). Grade III/IV esophageal toxicities occurred in 17% of patients, and grade III radiation pneumonitis/dyspnea was observed in 7 of 23 patients. The median and 2-year survival for phase Ib patients were 17.4 months and 32%, respectively. The overall 1- and 2-year survival for all 39 patients (16 phase Ia, 23 phase Ib) was 69% and 32%, respectively. Conclusions Combining 74-Gy thoracic radiation and concurrent gemcitabine is feasible, but the use of this regimen should be limited to the confines of a clinical trial. A randomized phase II trial through the Cancer and Leukemia Group B is underway to further evaluate the efficacy of this regimen.

A Phase I Study of Gefitinib with Concurrent Dose-Escalated Weekly Docetaxel and Conformal Three-Dimensional Thoracic Radiation Followed by Consolidative Docetaxel and Maintenance Gefitinib for Patients with Stage III Non-small Cell Lung Cancer

Background: Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. Patients and Materials: Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0–1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. Results: Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43–79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. Conclusions: Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.

Limited Margins Using Modern Radiotherapy Techniques Does Not Increase Marginal Failure Rate of Glioblastoma.

Objective:We investigate the patterns of failure in the treatment of glioblastoma (GBM) based on clinical target volume (CTV) margin size, dose delivered to the site of initial failure, and the use of temozolomide and intensity-modulated radiotherapy (IMRT). Methods:Between August 2000 and May 2010, 161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide. Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique. Patterns of failure and time to progression and overall survival were compared based on CTV margin, use of temozolomide, and use of IMRT. Kaplan Meier analysis was used to estimate survival times, and &khgr;2 test was used for comparison of cohorts. Results:For patients treated with 5-, 10-, and 15- to 20-mm CTV, 79%, 77%, and 86% experienced failures in the 60 Gy volume, respectively. Forty-eight percent, 55%, and 66% of patients with 5-, 10-, and 15- to 20-mm CTV experienced failures in the 46 Gy volume, respectively. There was no statistical difference between patients treated with 5-, 10-, 15- to 20-mm margins with regard to 60 Gy failure (P=0.76), 46 Gy failure (P=0.51), or marginal failure (P=0.73). Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume. There was no increased likelihood of marginal failures in patients receiving IMRT (P=0.97). Conclusions:Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.

NMR spin-lattice relaxation in tissues with high concentration of paramagnetic contrast media : evaluation of water exchange rates in intact rat muscle

High concentrations of GdDTPA in extracellular water of tissue cause the intrinsic relaxation rate of water to become greater than the coupling rate between intracellular and extracellular water compartments. The fast exchange limit is no longer valid and distinctly nonexponential spin-lattice recovery is observed. T1 relaxation recovery was characterized by a double exponential curve when striated rat muscle was immersed in a highly concentrated (110 Mm) isotonic solution of GdDTPA. When the water exchange rate through cell membranes in intact muscle tissue was calculated (using a two-compartment exchange model) and compared to similar data determined from T2 Carr-Purcell-Meiboom-Gill experiments, a significant discrepancy was found.

Spectral reconstruction of high energy photon beams for kernel based dose calculations.

A kernel-based dose computation method with finite-size pencil beams (FSPBs) requires knowledge of the photon spectrum. Published methods of indirect spectral measurements using transmission measurements through beam attenuators use mathematical fits with a large number of parameters and constraints. In this study, we examine a simple strategy for fitting transmission data that models important physical characteristics of photon beams produced in clinical linear accelerators. The shape of an unattenuated bremsstrahlung spectrum is known, varying linearly from a maximum at zero energy to a value of zero at a maximum energy. This unattenuated spectrum is altered primarily by absorption of low energy photons by the flattening filter, causing the true spectrum to roll off to zero at low photon energies. A fitting equation models this behavior and has these advantages over previous methods: (1) the equation describes the shape of a bremsstrahlung spectrum based on physical expectations; and (2) only three fit parameters are required with a single constraint. Results for 4 MV and 6 MV accelerators for central axis and off-axis beams show good agreement with the maximum, average and modal energies for known spectra. Previously published models, representations of beam fluence (energy fluence, dN/dE), experimental methods, and the fitting process are discussed.