C. Shun Wong

Reirradiation Human Spinal Cord Tolerance for Stereotactic Body Radiotherapy

PURPOSE We reviewed the treatment for patients with spine metastases who initially received conventional external beam radiation (EBRT) and were reirradiated with 1-5 fractions of stereotactic body radiotherapy (SBRT) who did or did not subsequently develop radiation myelopathy (RM). METHODS AND MATERIALS Spinal cord dose-volume histograms (DVHs) for 5 RM patients (5 spinal segments) and 14 no-RM patients (16 spine segments) were based on thecal sac contours at retreatment. Dose to a point within the thecal sac that receives the maximum dose (P(max)), and doses to 0.1-, 1.0-, and 2.0-cc volumes within the thecal sac were reviewed. The biologically effective doses (BED) using α/β = 2 Gy for late spinal cord toxicity were calculated and normalized to a 2-Gy equivalent dose (nBED = Gy(2/2)). RESULTS The initial conventional radiotherapy nBED ranged from ~30 to 50 Gy(2/2) (median ~40 Gy(2/2)). The SBRT reirradiation thecal sac mean P(max) nBED in the no-RM group was 20.0 Gy(2/2) (95% confidence interval [CI], 10.8-29.2), which was significantly lower than the corresponding 67.4 Gy(2/2) (95% CI, 51.0-83.9) in the RM group. The mean total P(max) nBED in the no-RM group was 62.3 Gy(2/2) (95% CI, 50.3-74.3), which was significantly lower than the corresponding 105.8 Gy(2/2) (95% CI, 84.3-127.4) in the RM group. The fraction of the total P(max) nBED accounted for by the SBRT P(max) nBED for the RM patients ranged from 0.54 to 0.78 and that for the no-RM patients ranged from 0.04 to 0.53. CONCLUSIONS SBRT given at least 5 months after conventional palliative radiotherapy with a reirradiation thecal sac P(max) nBED of 20-25 Gy(2/2) appears to be safe provided the total P(max) nBED does not exceed approximately 70 Gy(2/2), and the SBRT thecal sac P(max) nBED comprises no more than approximately 50% of the total nBED.

Probabilities of Radiation Myelopathy Specific to Stereotactic Body Radiation Therapy to Guide Safe Practice

PURPOSE Dose-volume histogram (DVH) results for 9 cases of post spine stereotactic body radiation therapy (SBRT) radiation myelopathy (RM) are reported and compared with a cohort of 66 spine SBRT patients without RM. METHODS AND MATERIALS DVH data were centrally analyzed according to the thecal sac point maximum (Pmax) volume, 0.1- to 1-cc volumes in increments of 0.1 cc, and to the 2 cc volume. 2-Gy biologically equivalent doses (nBED) were calculated using an α/β = 2 Gy (units = Gy(2/2)). For the 2 cohorts, the nBED means and distributions were compared using the t test and Mann-Whitney test, respectively. Significance (P<.05) was defined as concordance of both tests at each specified volume. A logistic regression model was developed to estimate the probability of RM using the dose distribution for a given volume. RESULTS Significant differences in both the means and distributions at the Pmax and up to the 0.8-cc volume were observed. Concordant significance was greatest for the Pmax volume. At the Pmax volume the fit of the logistic regression model, summarized by the area under the curve, was 0.87. A risk of RM of 5% or less was observed when limiting the thecal sac Pmax volume doses to 12.4 Gy in a single fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. CONCLUSION We report the first logistic regression model yielding estimates for the probability of human RM specific to SBRT.

Hypoxia and Hypoxia-Inducible Factor-1 Target Genes in Central Nervous System Radiation Injury: A Role for Vascular Endothelial Growth Factor

Purpose: Microvascular permeability changes and loss of blood-brain barrier integrity are important features of central nervous system (CNS) radiation injury. Expression of vascular endothelial growth factor (VEGF), an important determinant of microvascular permeability, was examined to assess its role in CNS radiation damage. Because hypoxia mediates VEGF up-regulation through hypoxia-inducible factor-1α (HIF1α) induction, we studied the relationships of hypoxia, HIF1α expression, and expression of VEGF in this damage pathway. Experimental Design: Expression of HIF1α, VEGF, and another hypoxia-responsive gene, glucose transporter-1, was assessed in the irradiated rat spinal cord using immunohistochemistry and in situ hybridization. Hypoxic areas were identified using the nitroimidazole 2-(2-nitro-1H-imidazole-l-yl)-N-(2,2,3,3,3,-pentafluoropropyl) acetamide. To determine the causal importance of VEGF expression in radiation myelopathy, we studied the response of transgenic mice with greater (VEGF-Ahi/+), reduced (VEGF-Alo/+), and wild-type VEGF activity to thoracolumbar irradiation. Results: In rat spinal cord, the number of cells expressing HIF1α and VEGF increased rapidly from 16 to 20 weeks after radiation, before white matter necrosis and forelimb paralysis. A steep dose response was observed in expression of HIF1α and VEGF. HIF1α and VEGF expressing cells were identified as astrocytes. Hypoxia was present in regions where up-regulation of VEGF and glucose transporter-1 and increased permeability was observed. VEGF-Alo/+ mice had a longer latency to development of hindlimb weakness and paralysis compared with wild-type or VEGF-Ahi/+ mice. Conclusions: VEGF expression appears to play an important role in CNS radiation injury. This focuses attention on VEGF and other genes induced in response to hypoxia as targets for therapy to reduce or prevent CNS radiation damage.

Spine Stereotactic Body Radiotherapy Utilizing Cone-Beam CT Image-Guidance With a Robotic Couch: Intrafraction Motion Analysis Accounting for all Six Degrees of Freedom

PURPOSE To evaluate the residual setup error and intrafraction motion following kilovoltage cone-beam CT (CBCT) image guidance, for immobilized spine stereotactic body radiotherapy (SBRT) patients, with positioning corrected for in all six degrees of freedom. METHODS AND MATERIALS Analysis is based on 42 consecutive patients (48 thoracic and/or lumbar metastases) treated with a total of 106 fractions and 307 image registrations. Following initial setup, a CBCT was acquired for patient alignment and a pretreatment CBCT taken to verify shifts and determine the residual setup error, followed by a midtreatment and posttreatment CBCT image. For 13 single-fraction SBRT patients, two midtreatment CBCT images were obtained. Initially, a 1.5-mm and 1° tolerance was used to reposition the patient following couch shifts which was subsequently reduced to 1 mm and 1° degree after the first 10 patients. RESULTS Small positioning errors after the initial CBCT setup were observed, with 90% occurring within 1 mm and 97% within 1°. In analyzing the impact of the time interval for verification imaging (10 ± 3 min) and subsequent image acquisitions (17 ± 4 min), the residual setup error was not significantly different (p > 0.05). A significant difference (p = 0.04) in the average three-dimensional intrafraction positional deviations favoring a more strict tolerance in translation (1 mm vs. 1.5 mm) was observed. The absolute intrafraction motion averaged over all patients and all directions along x, y, and z axis (± SD) were 0.7 ± 0.5 mm and 0.5 ± 0.4 mm for the 1.5 mm and 1 mm tolerance, respectively. Based on a 1-mm and 1° correction threshold, the target was localized to within 1.2 mm and 0.9° with 95% confidence. CONCLUSION Near-rigid body immobilization, intrafraction CBCT imaging approximately every 15-20 min, and strict repositioning thresholds in six degrees of freedom yields minimal intrafraction motion allowing for safe spine SBRT delivery.

PET CT THRESHOLDS FOR RADIOTHERAPY TARGET DEFINITION IN NON- SMALL-CELL LUNG CANCER: HOW CLOSE ARE WE TO THE PATHOLOGIC FINDINGS?

PURPOSE Optimal target delineation threshold values for positron emission tomography (PET) and computed tomography (CT) radiotherapy planning is controversial. In this present study, different PET CT threshold values were used for target delineation and then compared pathologically. METHODS AND MATERIALS A total of 31 non-small-cell lung cancer patients underwent PET CT before surgery. The maximal diameter (MD) of the pathologic primary tumor was obtained. The CT-based gross tumor volumes (GTV(CT)) were delineated for CT window-level thresholds at 1,600 and -300 Hounsfield units (HU) (GTV(CT1)); 1,600 and -400 (GTV(CT2)); 1,600 and -450 HU (GTV(CT3)); 1,600 and -600 HU (GTV(CT4)); 1,200 and -700 HU (GTV(CT5)); 900 and -450 HU (GTV(CT6)); and 700 and -450 HU (GTV(CT7)). The PET-based GTVs (GTV(PET)) were autocontoured at 20% (GTV(20)), 30% (GTV(30)), 40% (GTV(40)), 45% (GTV(45)), 50% (GTV(50)), and 55% (GTV(55)) of the maximal intensity level. The MD of each image-based GTV in three-dimensional orientation was determined. The MD of the GTV(PET) and GTV(CT) were compared with the pathologically determined MD. RESULTS The median MD of the GTV(CT) changed from 2.89 (GTV(CT2)) to 4.46 (GTV(CT7)) as the CT thresholds were varied. The correlation coefficient of the GTV(CT) compared with the pathologically determined MD ranged from 0.76 to 0.87. The correlation coefficient of the GTV(CT1) was the best (r=0.87). The median MD of GTV(PET) changed from 5.72 cm to 2.67 cm as the PET thresholds increased. The correlation coefficient of the GTV(PET) compared with the pathologic finding ranged from 0.51 to 0.77. The correlation coefficient of GTV(50) was the best (r=0.77). CONCLUSION Compared with the MD of GTV(PET), the MD of GTV(CT) had better correlation with the pathologic MD. The GTV(CT1) and GTV(50) had the best correlation with the pathologic results.

A Clonogenic Survival Assay of Neural Stem Cells in Rat Spinal Cord after Exposure to Ionizing Radiation

Abstract Lu, F. and Wong, C. S. A Clonogenic Survival Assay of Neural Stem Cells in Rat Spinal Cord after Exposure to Ionizing Radiation. Radiat. Res. 163, 63–71 (2005). Neural stem cells play an important role in neurogenesis of the adult central nervous system (CNS). Inhibition of neurogenesis has been suggested to be an underlying mechanism of radiation-induced CNS damage. Here we developed an in vivo/ in vitro clonogenic assay to characterize the survival of neural stem cells after exposure to ionizing radiation. Cells were isolated from the rat cervical spinal cord and plated as single cell suspensions in defined medium containing epidermal growth factor and basic fibroblast growth factor. The survival of the proliferating cells was determined by their ability to form neurosphere colonies. The number and size of neurospheres were analyzed quantitatively at day 10, 12, 14 and 16 after plating. Plating cells from 5, 10 and 15 mm of the cervical spinal cord resulted in a linear increase in the number of neurospheres from day 10–16. Compared to the nonirradiated spinal cord, there was a significant decrease in the number and size of neurosphere colonies cultured from a 10-mm length of the rat spinal cord after a single dose of 5 Gy. When dissociated neurospheres derived from a spinal cord that had been irradiated with 5 Gy were allowed to differentiate, the percentages of neurons, oligodendrocytes and astrocytes as determined by immunocytohistochemistry were not altered compared to those from the nonirradiated spinal cord. Secondary neurospheres could be obtained from cells dissociated from primary neurospheres that had been cultured from the irradiated spinal cord. In conclusion, exposure to ionizing radiation reduces the clonogenic survival of neural stem cells cultured from the rat spinal cord. However, neural stem cells retain their pluripotent and self-renewing properties after irradiation. A neurosphere-based assay may provide a quantitative measure of the clonogenic survival of neural stem cells in the adult CNS after irradiation.

Radiation-Induced Alterations in Mouse Brain Development Characterized by Magnetic Resonance Imaging

PURPOSE The purpose of this study was to identify regions of altered development in the mouse brain after cranial irradiation using longitudinal magnetic resonance imaging (MRI). METHODS AND MATERIALS Female C57Bl/6 mice received a whole-brain radiation dose of 7 Gy at an infant-equivalent age of 2.5 weeks. MRI was performed before irradiation and at 3 time points following irradiation. Deformation-based morphometry was used to quantify volume and growth rate changes following irradiation. RESULTS Widespread developmental deficits were observed in both white and gray matter regions following irradiation. Most of the affected brain regions suffered an initial volume deficit followed by growth at a normal rate, remaining smaller in irradiated brains compared with controls at all time points examined. The one exception was the olfactory bulb, which in addition to an early volume deficit, grew at a slower rate thereafter, resulting in a progressive volume deficit relative to controls. Immunohistochemical assessment revealed demyelination in white matter and loss of neural progenitor cells in the subgranular zone of the dentate gyrus and subventricular zone. CONCLUSIONS MRI can detect regional differences in neuroanatomy and brain growth after whole-brain irradiation in the developing mouse. Developmental deficits in neuroanatomy persist, or even progress, and may serve as useful markers of late effects in mouse models. The high-throughput evaluation of brain development enabled by these methods may allow testing of strategies to mitigate late effects after pediatric cranial irradiation.

Cut points for mild, moderate, and severe pain among cancer and non-cancer patients: a literature review

Defining cut points (CPs) for varying levels of pain intensity is important for assessing changes in patients functional status, and guiding the development and evaluation of treatment options. We aimed to summarize CPs identified in the literature for mild, moderate, and severe pain on the numeric rating scale (NRS), and recommend optimal CPs for cancer and non-cancer patients. We searched MEDLINE and EMBASE (inception to May 2015) for studies that used CPs to classify pain intensity on the NRS among patients with cancer or non-cancer conditions leading to acute or chronic pain. A CP was defined as the upper bound of a mild or moderate pain category. Of 1,556 identified articles, 27 were included for review. Among patients with cancer pain, mild-moderate pain CPs ranged from 1 to 4 (mean, 3.5±1.08), with CP4 being the most recommended CP (80%). For moderate-severe pain, CPs ranged from 4 to 7 (mean, 6.2±0.92), and CP6 (50%) was the optimal CPs. Among patients with non-cancer pain, mild-moderate pain CPs ranged from 2 to 5 (mean, 3.62±0.78), and CP4 was the most frequently used CP (52.9%). For moderate-severe non-cancer pain, CPs ranged from 4 to 8 (mean, 6.5±0.99), and CP6 (41.2%) was the most frequently recommended CP. A wide range of CPs for mild, moderate, and severe pain categories were identified in the literature among both cancer and non-cancer patient populations. Further studies are needed to delineate more accurate and precise CPs for pain intensity.

Autocontouring and Manual Contouring: Which Is the Better Method for Target Delineation Using 18F-FDG PET/CT in Non–Small Cell Lung Cancer?

Previously, we showed that a CT window and level setting of 1,600 and –300 Hounsfield units, respectively, and autocontouring using an 18F-FDG PET 50% intensity level correlated best with pathologic results. The aim of this study was to compare this autocontouring with manual contouring, to determine which method is better. Methods: Seventeen patients with non–small cell lung cancer underwent 18F-FDG PET/CT before surgery. The maximum diameter on pathologic examination was determined. Seven sets of gross tumor volumes (GTVs) were defined. The first set (GTVCT) was contoured manually using only CT information. The second set (GTVAuto) was autocontoured using a 50% intensity level for 18F-FDG PET images. The third set (GTVManual) was manually contoured using a visual method on PET images. The other 4 sets combined CT and 18F-FDG PET images fused to one another to become composite volumes: GTVCT+Auto, GTVCT+Manual, GTVCT−Auto, and GTVCT–Manual. To quantitate the degree to which CT and 18F-FDG PET defined the same region of interest, a matching index was calculated for each case. The maximum diameter of GTV was compared with the maximum diameter on pathologic examination. Results: The median GTVCT, GTVAuto, GTVManual, GTVCT+Auto, GTVCT+Manual, GTVCT–Auto, and GTVCT–Manual were 6.96, 2.42, 4.37, 7.46, 10.17, 2.21, and 3.38 cm3, respectively. The median matching indexes of GTVCT versus GTVCT+Auto, GTVAuto versus GTVCT+Auto, GTVCT versus GTVCT+Manual, and GTVManual versus GTVCT+Manual were 0.86, 0.65, 0.88, and 0.81, respectively. Compared with the maximum diameter on pathologic examination, the correlations of GTVCT, GTVAuto, GTVManual, GTVCT+Auto, and GTVCT+Manual were 0.87, 0.83, 0.93, 0.86, and 0.94, respectively. Conclusion: The matching index was higher for manual contouring than for autocontouring using a 50% intensity level on 18F-FDG PET images. When using a 50% intensity level to contour the target of non–small cell lung cancer, one should also consider using manual contouring of 18F-FDG PET to check for any missed disease.

Treatment Age, Dose and Sex Determine Neuroanatomical Outcome in Irradiated Juvenile Mice

Pediatric cranial radiation therapy can induce long-term neurocognitive deficits, the risk and severity of these deficits are amplified in females and in those individuals exposed at a younger age and/or those irradiated at higher doses. To investigate the developmental consequences of these factors in greater detail, male and female C57Bl/6J mice between infancy and late childhood (16 and 36 days) were irradiated at a single time point with a whole-brain dose of 0, 3, 5 or 7 Gy. In vivo and ex vivo magnetic resonance imaging (MRI) and deformation-based morphometry was used to identify radiation-induced volume differences. As expected, exposure to 7 Gy of radiation at 16 days of age induced widespread volume deficits that were largely mitigated by increasing treatment age or decreasing dose. Notable exceptions were regions in the olfactory bulbs and hippocampus that displayed both a detectable difference in volume and a loss in neurogenesis for most doses and ages. Furthermore, white matter regions located at the front of the brain remained sensitive to radiation at later treatment ages, compared to regions at the back. Differences due to sex were subtle, with increased radiosensitivity in females detectable only in the mammillary bodies and fornix. Our results reveal anatomical alterations in brain development consistent with expectations based on pediatric patient neurocognitive outcomes. This data demonstrates that neuroimaging of the mouse is an effective tool for investigating radiation-induced late effects.