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Pediatric Craniospinal Axis Irradiation With Helical Tomotherapy: Patient Outcome and Lack of Acute Pulmonary Toxicity

PURPOSE To present the patient outcomes and risk of symptomatic acute radiation pneumonitis (ARP) in 18 pediatric patients treated with helical tomotherapy to their craniospinal axis for a variety of neoplasms. METHODS AND MATERIALS A total of 18 patients received craniospinal axis irradiation with helical tomotherapy. The median age was 12 years (range, 2.5-21). The follow-up range was 3-48 months (median, 16.5). Of the 18 patients, 15 received chemotherapy in the neoadjuvant, adjuvant, or concomitant setting. Chemotherapy was tailored to the particular histologic diagnosis; 10 of 18 patients underwent surgical removal of the gross primary tumor. The patients were followed and evaluated for ARP starting at 3-6 months after completion of craniospinal axis irradiation. ARP was graded using the Common Toxicity Criteria, version 3. RESULTS At the last follow-up visit, 14, 2, and 2 patients were alive without disease, alive with disease, and dead of disease, respectively. The cause-specific survival rate was 89% (16 of 18), disease-free survival rate was 78% (14 of 18), and overall survival rate was 89% (16 of 18). No patient had treatment failure at the cribriform plate. No patient developed symptoms of ARP. CONCLUSION Craniospinal axis irradiation using helical tomotherapy yielded encouraging patient outcomes and acute toxicity profiles. Although large volumes of the lung received low radiation doses, no patient developed symptoms of ARP during the follow-up period.

Modeling of carbon fiber couch attenuation properties with a commercial treatment planning system

The purpose of this work is to evaluate the modeling of carbon fiber couch attenuation properties with a commercial treatment planning system (TPS, Pinnacle3, v8.0d). A carbon fiber couch (Brain-Lab) was incorporated into the TPS by automatic contouring of all transverse CT slices. The couch shape and dimensions were set according to the vendor specifications. The couch composition was realized by assigning appropriate densities to the delineated contours. The couch modeling by the TPS was validated by absolute dosimetric measurements. A phantom consisting of several solid water slabs was CT scanned, the CT data set was imported into the TPS, and the carbon fiber couch was auto-contoured. Open (unblocked) field plans for different gantry angles and field sizes were generated. The doses to a point at 3 cm depth, placed at the linac isocenter, were computed. The phantom was irradiated according to the dose calculation setup and doses were measured with an ion chamber. In addition, percent depth dose (PDD) curves were computed as well as measured with radiographic film. The calculated and measured doses, transmissions, and PDDs were cross-compared. Doses for several posterior fields (0 degree, 30 degrees, 50 degrees, 75 degrees, 83 degrees) were calculated for 6 and 18 MV photon beams. For model validation a nominal field size of 10 x 10 cm2 was chosen and 100 MU were delivered for each portal. The largest difference between computed and measured doses for those posterior fields was within 1.7%. A comparison between computed and measured transmissions for the aforementioned fields was performed and the results were found to agree within 1.1%. The differences between computed and measured doses for different field sizes, ranging from 5 x 5 cm2 to 25 x 25 cm2 in 5 cm increments, were within 2%. Measured and computed PDD curves with and without the couch agree from the surface up to 30 cm depth. The PDDs indicate a surface dose increase resulting from the carbon fiber couch field modification. The carbon fiber couch attenuation for individual posterior oblique fields (75 degrees) can be in excess of 8% depending on the beam energy and field size. When the couch is contoured in Pinnacle3 its attenuation properties are modeled to within 1.7% with respect to measurements. These results demonstrate that appropriate contouring together with relevant density information for the contours is sufficient for adequate modeling of carbon fiber supporting devices by modern commercial treatment planning systems.

Prevention and mitigation of acute death of mice after abdominal irradiation by the antioxidant N-acetyl-cysteine (NAC).

Abstract Gastrointestinal (GI) injury is a major cause of acute death after total-body exposure to large doses of ionizing radiation, but the cellular and molecular explanations for GI death remain dubious. To address this issue, we developed a murine abdominal irradiation model. Mice were irradiated with a single dose of X rays to the abdomen, treated with daily s.c. injection of N-acetyl-l-cysteine (NAC) or vehicle for 7 days starting either 4 h before or 2 h after irradiation, and monitored for up to 30 days. Separately, mice from each group were assayed 6 days after irradiation for bone marrow reactive oxygen species (ROS), ex vivo colony formation of bone marrow stromal cells, and histological changes in the duodenum. Irradiation of the abdomen caused dose-dependent weight loss and mortality. Radiation-induced acute death was preceded not only by a massive loss of duodenal villi but also, surprisingly, abscopal suppression of stromal cells and elevation of ROS in the nonirradiated bone marrow. NAC diminished these radiation-induced changes and improved 10- and 30-day survival rates to >50% compared with <5% in vehicle-treated controls. Our data establish a central role for abscopal stimulation of bone marrow ROS in acute death in mice after abdominal irradiation.

Evaluation of Spatially Fractionated Radiotherapy (GRID) and Definitive Chemoradiotherapy With Curative Intent for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Initial Response Rates and Toxicity

PURPOSE To present results and acute toxicity in 14 patients with bulky (>or=6 cm) tumors from locally advanced squamous cell carcinoma of the head and neck who received spatially fractionated radiotherapy (GRID) therapy to the bulky mass followed by concomitant chemoradiotherapy using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT). METHODS AND MATERIALS GRID therapy to the GTV was delivered by creating one treatment field with a checkerboard pattern composed of open-closed areas using a multileaf collimator. The GRID prescription was 20 Gy in one fraction. Chemotherapy started the day of GRID therapy and continued throughout the course of SIB-IMRT. The SIB-IMRT prescription was 66, 60, and 54 Gy to the planning target volume (PTV), intermediate-risk PTV, and low-risk PTV, respectively, in 30 fractions. RESULTS With a median follow-up of 19.5 months (range, 2-38 months), the overall control rate of the GRID gross tumor volume was 79% (11 of 14). The most common acute skin and mucosal toxicities were Grade 3 and 2, respectively. CONCLUSION For the treatment of locally advanced neck squamous cell carcinoma of the head and neck, GRID followed by chemotherapy and SIB-IMRT is well tolerated and yields encouraging clinical and pathologic responses, with similar acute toxicity profiles as in patients receiving chemoradiotherapy without GRID.

Spatially Fractionated Radiation Induces Cytotoxicity and Changes in Gene Expression in Bystander and Radiation Adjacent Murine Carcinoma Cells

Radiation-induced bystander effects have been extensively studied at low doses, since evidence of bystander induced cell killing and other effects on unirradiated cells were found to be predominant at doses up to 0.5 Gy. Therefore, few studies have examined bystander effects induced by exposure to higher doses of radiation, such as spatially fractionated radiation (GRID) treatment. In the present study, we evaluate the ability of GRID treatment to induce changes in GRID adjacent (bystander) regions, in two different murine carcinoma cell lines following exposure to a single irradiation dose of 10 Gy. Murine SCK mammary carcinoma cells and SCCVII squamous carcinoma cells were irradiated using a brass collimator to create a GRID pattern of nine circular fields 12 mm in diameter with a center-to-center distance of 18 mm. Similar to the typical clinical implementation of GRID, this is approximately a 50:50 ratio of direct and bystander exposure. We also performed experiments by irradiating separate cultures and transferring the medium to unirradiated bystander cultures. Clonogenic survival was evaluated in both cell lines to determine the occurrence of radiation-induced bystander effects. For the purpose of our study, we have defined bystander cells as GRID adjacent cells that received approximately 1 Gy scatter dose or unirradiated cells receiving conditioned medium from irradiated cells. We observed significant bystander killing of cells adjacent to the GRID irradiated regions compared to sham treated controls. We also observed bystander killing of SCK and SCCVII cells cultured in conditioned medium obtained from cells irradiated with 10 Gy. Therefore, our results confirm the occurrence of bystander effects following exposure to a high-dose of radiation and suggest that cell-to-cell contact is not required for these effects. In addition, the gene expression profile for DNA damage and cellular stress response signaling in SCCVII cells after GRID exposure was studied. The occurrence of GRID-induced bystander gene expression changes in significant numbers of DNA damage and cellular stress response signaling genes, providing molecular evidence for possible mechanisms of bystander cell killing.

Microbeam Radiation Therapy Alters Vascular Architecture and Tumor Oxygenation and is Enhanced by a Galectin-1 Targeted Anti-Angiogenic Peptide

In this study, we sought to determine the therapeutic potential of variably sized (50 μm or 500 μm wide, 14 mm tall) parallel microbeam radiation therapy (MRT) alone and in combination with a novel anti-angiogenic peptide, anginex, in mouse mammary carcinomas (4T1) – a moderately hypoxic and radioresistant tumor with propensity to metastasize. The fraction of total tumor volume that was directly irradiated was approximately 25% in each case, but the distance between segments irradiated by the planar microbeams (width of valley dose region) varied by an order of magnitude from 150-1500 μm corresponding to 200 μm and 2000 μm center-to-center inter-microbeam distances, respectively. We found that MRT administered in 50 μm beams at 150 Gy was most effective in delaying tumor growth. Furthermore, tumor growth delay induced by 50 μm beams at 150 Gy was virtually indistinguishable from the 500 μm beams at 150 Gy. Fifty-micrometer beams at the lower peak dose of 75 Gy induced growth delay intermediate between 150 Gy and untreated tumors, while 500 μm beams at 75 Gy were unable to alter tumor growth compared to untreated tumors. However, the addition of anginex treatment increased the relative tumor growth delay after 500 μm beams at 75 Gy most substantially out of the conditions tested. Anginex treatment of animals whose tumors received the 50 μm beams at 150 Gy also led to an improvement in growth delay from that induced by the comparable MRT alone. Immunohistochemical staining for CD31 (endothelial cells) and αSMA (smooth muscle pericyte-associated blood vessels as a measure of vessel normalization) indicated that vessel density was significantly decreased in all irradiated groups and pericyte staining was significantly increased in the irradiated groups on day 14 after irradiation. The addition of anginex treatment further decreased the mean vascular density in all combination treatment groups and further increased the amount of pericyte staining in these tumors. Finally, evidence of tumor hypoxia was found to decrease in tumors analyzed at 1–14 days after MRT in the groups receiving 150 Gy peak dose, but not 75 Gy peak dose. Our results suggest that tumor vascular damage induced by MRT at these potentially clinically acceptable peak entrance doses may provoke vascular normalization and may be exploited to improve tumor control using agents targeting angiogenesis.

Clinical feasibility of TBI with helical tomotherapy.

Our purpose was to present the clinical feasibility of TBI with helical tomotherapy (HT) in four patients with AML. Treatment planning, delivery, dose verification and summation, toxicity and patient outcomes for each patient are presented. TBI prescription was set in such a manner that 80% of the clinical target volume received 12 Gy in six fractions, at two fractions per day. Dose reconstruction was carried out by recontouring the regions of interest in the daily pretreatment megavoltage computed tomography of each individual fraction and calculating its corresponding dose. A deformable registration model was used for dose summation of all individual fractions. Differences between planned and delivered doses were calculated. Average planned and delivered doses to the regions of interest differed by up to 2.7%. TBI toxicity was limited to radiotherapy oncology group grade 1 dermatitis in all patients and grade 1 headache in one patient. Two patients are alive with no evidence of disease and no GVHD. Two patients died of GVHD, but there was no evidence of disease at the time of death. We conclude that HT simplifies the process of TBI. Dose verification is possible with HT showing small differences between plan and delivered doses.

Retrospective Evaluation of Pediatric Cranio-Spinal Axis Irradiation Plans with the Hi-ART Tomotherapy System

Helical tomotherapy (HT) can be used for the delivery of cranio-spinal axis irradiation (CSAI) without the need for beam matching of conventional linac-based external beam irradiation. The aim of this study is to retrospectively evaluate HT plans used for treatment in nine patients treated with CSAI. Helical tomotherapy cranio-spinal axis irradiation (HT-CSAI) plans were created for each patient. Average length along the cranio-spinal axis of the PTV was 65.6 cm with a range between 53 and 74 cm. Treatment planning optimization and plan evaluation parameters were obtained from the HT planning station for each of the nine patients. PTV coverage by the 95% isodose surface ranged between 98.0 to 100.0% for all nine patients. The clinically acceptable dose variation within the PTV or tolerance range was between 0.7 and 2.5% for all nine patients. Doses to the organs at risk were clinically acceptable. An increasing length along the longitudinal axis of the PTV did not consistently increase the beam-on time indicating that using a larger jaw width had a greater impact on treatment time. With a larger jaw width it is possible to substantially reduce the normalized beam-on treatment time without compromising plan quality and sparing of organs at risk. By using a larger jaw width or lower modulation factor or both, normalized beam-on times were decreased by up to 61% as compared to the other evaluated treatment plans. From the nine cases reported in this study the minimum beam-on time was achieved with a jaw width of 5.0 cm, pitch of 0.287 and a modulation factor of 2.0. Large and long cylindrical volumes can be effectively treated with helical tomotherapy with both clinically acceptable dose distribution and beam-on time.

Cardiac inflammation after local irradiation is influenced by the kallikrein-kinin system

Radiotherapy of intrathoracic and chest wall tumors may lead to exposure of the heart to ionizing radiation, resulting in radiation-induced heart diseases (RIHD). The main manifestations of RIHD become apparent many years after treatment and include cardiomyopathy and accelerated atherosclerosis. This study examines the role of the kallikrein-kinin system (KKS) in RIHD by investigating the cardiac radiation response in a kininogen-deficient Brown Norway Katholiek (BN/Ka) rat model. BN/Ka rats and wild-type Brown Norway (BN) rats were exposed to local heart irradiation with a single dose of 18 Gy or 24 Gy and were observed for 3 to 6 months. Examinations included in vivo and ex vivo cardiac function, histopathology, gene and protein expression measurements, and mitochondrial swelling assays. Upon local heart irradiation, changes in in vivo cardiac function were significantly less in BN/Ka rats. For instance, a single dose of 24 Gy caused a 35% increase in fractional shortening in BN rats compared with a 16% increase in BN/Ka rats. BN rats, but not BN/Ka rats, showed a 56% reduction in cardiac numbers of CD2-positive cells, and a 57% increase in CD68-positive cells, together with a 52% increase in phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2). Local heart irradiation had similar effects on histopathology, mitochondrial changes, and left ventricular mRNA levels of NADPH oxidases in the two genotypes. These results suggest that the KKS plays a role in the effects of radiation on cardiac function and recruitment of inflammatory cells. The KKS may have these effects at least in part by altering Erk1/2 signaling.

Dead or alive? Autofluorescence distinguishes heat-fixed from viable cells

Purpose: A proof-of-concept study to evaluate a new autofluorescence method to differentiate necrotic thermally fixed cells from viable tissue following thermal ablation. Methods: A conductive interstitial thermal therapy (CITT) device was used to ablate swine mammary tissue and rabbit VX-2 carcinomas in vivo. The ablated regions and 10-mm margins were resected 24 h following treatment, embedded in HistOmer® and sectioned at 3 mm. The fresh sections were evaluated for gross viability with triphenyl tetrazolium chloride, 1 h post-resection. Representative non-viable and viable areas were then processed and embedded into paraffin, and sectioned at 5 µm. Standard H&E staining and proliferating cell nuclear antigen (PCNA) immunohistochemistry were compared against autofluorescence intensity, at 488-nm wavelength, for cellular viability. Results: Heat-fixed cells in non-viable regions exhibit increased autofluorescence intensity compared to viable tissue (area under receiver operating characteristics (ROC) curve = 0.96; Mann-Whitney P < 0.0001). An autofluorescence intensity-based classification rule achieved 92% sensitivity with 100% specificity for distinguishing non-viable from viable samples. In contrast, PCNA staining did not reliably distinguish heat-fixed, dead cells from viable cells. Conclusions: Examination of H&E-stained sections using autofluorescence intensity-based classification is a reliable and readily available method to accurately identify heat-fixed cells in ablated surgical margins.