Todd F. Atwood

PHD Inhibition Mitigates and Protects Against Radiation-Induced Gastrointestinal Toxicity via HIF2

Pharmacologic inhibition or knockout of HIF-prolyl hydroxylases in mice reduces morbidity and mortality from radiation-induced gastrointestinal syndrome. Going with the Gut for Radiation Protection Radiation is a valuable adjunct to cancer therapy, but it also causes many side effects that limit the doses patients can tolerate. Accidental exposure is a less common source of radiation but one that is widely feared because of the lack of control over dose and timing and the resulting potential for severe side effects or death. The bone marrow toxicity of radiation can be mitigated with a bone marrow transplant, but there are no approved treatments for another lethal effect of radiation, gastrointestinal toxicity. Here, Taniguchi and colleagues present the radioprotective effects of a small-molecule, dimethyloxallyl glycine (DMOG), an inhibitor of prolyl hydroxylases. The authors demonstrate that mice treated with DMOG are protected from gastrointestinal damage and survive otherwise lethal amounts of irradiation to the abdomen. The protective effects of DMOG are observed even when it is given up to 24 hours after exposure to the lethal doses of radiation, which makes it a promising candidate for treatment of unplanned radiation exposures. The current study is in mice, and the effectiveness and safety of DMOG will have to be confirmed in humans before this drug can be used in the clinical setting. However, even if DMOG itself turns out to be unsuitable for human use, the understanding of its mechanism and the knowledge that targeting prolyl hydroxylases can mitigate radiation toxicity will be invaluable for developing future treatments to protect human patients from radiation. Radiation-induced gastrointestinal (GI) toxicity can be a major source of morbidity and mortality after radiation exposure. There is an unmet need for effective preventative or mitigative treatments against the potentially fatal diarrhea and water loss induced by radiation damage to the GI tract. We report that prolyl hydroxylase inhibition by genetic knockout or pharmacologic inhibition of all PHD (prolyl hydroxylase domain) isoforms by the small-molecule dimethyloxallyl glycine (DMOG) increases hypoxia-inducible factor (HIF) expression, improves epithelial integrity, reduces apoptosis, and increases intestinal angiogenesis, all of which are essential for radioprotection. HIF2, but not HIF1, is both necessary and sufficient to prevent radiation-induced GI toxicity and death. Increased vascular endothelial growth factor (VEGF) expression contributes to the protective effects of HIF2, because inhibition of VEGF function reversed the radioprotection and radiomitigation afforded by DMOG. Additionally, mortality from abdominal or total body irradiation was reduced even when DMOG was given 24 hours after exposure. Thus, prolyl hydroxylase inhibition represents a treatment strategy to protect against and mitigate GI toxicity from both therapeutic radiation and potentially lethal radiation exposures.

Quantitative Magnetic Resonance Spectroscopy Reveals a Potential Relationship between Radiation-Induced Changes in Rat Brain Metabolites and Cognitive Impairment

Abstract Atwood, T., Payne, V. S., Zhao, W., Brown, W. R., Wheeler, K. T., Zhu, J-M. and Robbins, M. E. Quantitative Magnetic Resonance Spectroscopy Reveals a Potential Relationship between Radiation-Induced Changes in Rat Brain Metabolites and Cognitive Impairment. Radiat. Res. 168, 574–581 (2007). To test the efficacy of magnetic resonance spectroscopy (MRS) in identifying radiation-induced brain injury, adult male Fischer 344 rats received fractionated whole-brain irradiation (40 or 45 Gy given in 5-Gy fractions twice a week for 4 or 4.5 weeks, respectively); control rats received sham irradiation. Twelve and 52 weeks after whole-brain irradiation, rats were subjected to high-resolution MRI and proton MRS. No apparent lesions or changes in T1- or T2-weighted images were noted at either time. This is in agreement with no gross changes being found in histological sections from rats 50 weeks postirradiation. Analysis of the MR spectra obtained 12 weeks after fractionated whole-brain irradiation also failed to show any significant differences (P > 0.1) in the concentration of brain metabolites between the whole-brain-irradiated and sham-irradiated rats. In contrast, analysis of the MR spectra obtained 52 weeks postirradiation revealed significant differences between the irradiated and sham-irradiated rats in the concentrations of several brain metabolites, including increases in the NAA/tCr (P < 0.005) and Glx/tCr (P < 0.001) ratios and a decrease in the mI/tCr ratio (P < 0.01). Although the cognitive function of these rats measured by the object recognition test was not significantly different (P > 0.1) between the irradiated and sham-irradiated rats at 14 weeks postirradiation, it was significantly different (P < 0.02) at 54 weeks postirradiation. These findings suggest that MRS may be a sensitive, noninvasive tool to detect changes in radiation-induced brain metabolites that may be associated with the radiation-induced cognitive impairments observed after prolonged fractionated whole-brain irradiation.

Adverse Events Involving Radiation Oncology Medical Devices: Comprehensive Analysis of US Food and Drug Administration Data, 1991 to 2015

PURPOSE Radiation oncology relies on rapidly evolving technology and highly complex processes. The US Food and Drug Administration collects reports of adverse events related to medical devices. We sought to characterize all events involving radiation oncology devices (RODs) from the US Food and Drug Administrations postmarket surveillance Manufacturer and User Facility Device Experience (MAUDE) database, comparing these with non-radiation oncology devices. METHODS AND MATERIALS MAUDE data on RODs from 1991 to 2015 were sorted into 4 product categories (external beam, brachytherapy, planning systems, and simulation systems) and 5 device problem categories (software, mechanical, electrical, user error, and dose delivery impact). Outcomes included whether the device was evaluated by the manufacturer, adverse event type, remedial action, problem code, device age, and time since 510(k) approval. Descriptive statistics were performed with linear regression of time-series data. Results for RODs were compared with those for other devices by the Pearson χ2 test for categorical data and 2-sample Kolmogorov-Smirnov test for distributions. RESULTS There were 4234 ROD and 4,985,698 other device adverse event reports. Adverse event reports increased over time, and events involving RODs peaked in 2011. Most ROD reports involved external beam therapy (50.8%), followed by brachytherapy (24.9%) and treatment planning systems (21.6%). The top problem types were software (30.4%), mechanical (20.9%), and user error (20.4%). RODs differed significantly from other devices in each outcome (P<.001). RODs were more likely to be evaluated by the manufacturer after an event (46.9% vs 33.0%) but less likely to be recalled (10.5% vs 37.9%) (P<.001). Device age and time since 510(k) approval were shorter among RODs (P<.001). CONCLUSIONS Compared with other devices, RODs may experience adverse events sooner after manufacture and market approval. Close postmarket surveillance, improved software design, and manufacturer-user training may help mitigate these events.

Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema

PURPOSE Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema. METHODS AND MATERIALS We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3). RESULTS 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001). CONCLUSIONS We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

Lung stereotactic body radiotherapy (SBRT): a single institution's outcomes and methodology in the context of a literature review

Lung cancer is the leading cause of cancer death in the United States and worldwide, with the incidence of early stage lung cancer anticipated to rise with increasing use of screening CT. Improvements in systemic therapy have increased the need for durable local control both in primary lung cancer as well as oligometastatic disease to the lung. Since 2007, the University of California San Diego (UCSD) has employed SBRT in the treatment of early stage primary non-small cell histology (NSCLC), intrapulmonary oligometastases, and multiple primary lung cancers (MPLCs) with high efficacy and low toxicity using a frameless technique that involves non-invasive image guidance. We review our center’s general approach to management including our experience with clinical outcomes and toxicity in the context of a review of the literature, details of our preferred technique (including simulation and real-time tumor tracking), as well as our results and strategy for patient follow-up using PET to monitor tumor response in the post-SBRT setting.

TG‐51 reference dosimetry for the Halcyon™: A clinical experience

Abstract Halcyon™ is a single‐energy (6 MV‐FFF), bore‐enclosed linear accelerator. Patient setup is performed by first aligning to external lasers mounted to the front of the bore, and then loading to isocenter through pre‐defined couch shifts. There is no light field, optical distance indicator or front pointer mechanism, so positioning is verified through MV imaging with kV imaging scheduled to become available in the future. TG‐51 reference dosimetry was successfully performed for Halcyon™ in this imaging‐based setup paradigm. The beam quality conversion factor, k Q, was determined by measuring %dd(10)x three ways: (a) using a Farmer chamber with lead filtering, (b) using a Farmer chamber without lead filtering, and (c) using a PinPoint chamber without lead filtering. Values of k Q were determined to be 0.995, 0.996, and 0.996 by each measurement technique, respectively. Halcyon™s 6 MV‐FFF beam was found to be broader than other FFF beams produced by Varian accelerators, and profile measurements at d max showed the beam to vary less than 0.5% over the dimensions of our Farmer chambers active volume. Reference dosimetry can be performed for the Halcyon™ accelerator simply, without specialized equipment or lead filtering with minimal dosimetric impact. This simplicity will prove advantageous in clinics with limited resources or physics support.

Automatic patient positioning and gating window settings in respiratory-gated stereotactic body radiation therapy for pancreatic cancer using fluoroscopic imaging

Abstract Before treatment delivery of respiratory‐gated radiation therapy (RT) in patients with implanted fiducials, both the patient position and the gating window thresholds must be set. In linac‐based RT, this is currently done manually and setup accuracy will therefore be dependent on the skill of the user. In this study, we present an automatic method for finding the patient position and the gating window thresholds. Our method uses sequentially acquired anterior–posterior (AP) and lateral fluoroscopic imaging with simultaneous breathing amplitude monitoring and intends to reach 100% gating accuracy while keeping the duty cycle as high as possible. We retrospectively compared clinically used setups to the automatic setups by our method in five pancreatic cancer patients treated with hypofractionated RT. In 15 investigated fractions, the average (±standard deviation) differences between the clinical and automatic setups were −0.4 ± 0.8 mm, −1.0 ± 1.1 mm, and 1.8 ± 1.3 mm in the left–right (LR), the AP, and the superior–inferior (SI) direction, respectively. For the clinical setups, typical interfractional setup variations were 1–2 mm in the LR and AP directions, and 2–3 mm in the SI direction. Using the automatic method, the duty cycle could be improved in six fractions, in four fractions the duty cycle had to be lowered to improve gating accuracy, and in five fractions both duty cycle and gating accuracy could be improved. Our automatic method has the potential to increase accuracy and decrease user dependence of setup for patients with implanted fiducials treated with respiratory‐gated RT. After fluoroscopic image acquisition, the calculated patient shifts and gating window thresholds are calculated in 1–2 s. The method gives the user the possibility to evaluate the effect of different patient positions and gating window thresholds on gating accuracy and duty cycle. If deemed necessary, it can be used at any time during treatment delivery.

Bullet fragment fiducials in stereotactic body radiotherapy as a bridge to transplant for hepatocellular carcinoma

Jamie S. K. Takayesu, Kathryn R. Tringale, Deborah C. Marshall, Jeffrey Burkeen, Mark A. Valasek, Alan Hemming, Todd Atwood, Daniel Simpson and Jona Hattangadi-Gluth John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA; Department of Surgery, University of California San Diego, La Jolla, CA, USA

Poster — Thur Eve — 75: Patient-specific Dose Escalation Using Patient-Matching Machine Learning

Several studies have concluded that dose-escalation may improve tumor control rates for patients with localized prostate cancer; however, toxicity remains a concern. We evaluated the ability of a new machine-learning approach, patient-matching, to stratify patients that would have been eligible for dose-escalation. With this knowledge, clinicians may prescribe patient-specific target dose-escalation. DVH parameters from 319 historical treatment plans were evaluated to delineate previously-approved plans that met the Pollack et al. dose constraints for dose-escalation in the prostate. Patient-matching was performed to predict the amount of dose-escalation that could be met without exceeding the toxicity dose-constraints (rectal V40Gy<35%, V65Gy<17%, and bladder V40Gy<25%, V65Gy<50%, and 95% of the target volume receiving prescription). Dose-escalation predictions were then made on the library of patients to determine the max dose escalation while still meeting dose objectives. Plans were processed using software that enables patient matching (QuickMatch, Siris Medical, Mountain View, CA); this software has been previously shown to successfully aid treatment planning systems to perform faster, more favorable plans. The use of patient-matching identified the ability to dose-escalate the PTV from an average of 78Gy to an average of 83.5Gy (range 78.5Gy to 91.3Gy) while meeting toxicity constraints. Across all patients investigated, mean rectal V40Gy was 4.8%, and V65Gy was 21.1%. Mean bladder V40Gy was 8.3%, and V65Gy was 21.6%. Patient-matching is a promising method to identify eligible patients for dose-escalation. This study warrants investigation in a prospective cohort. Additionally, further study will investigate other disease states.

SU-E-T-622: Identification and Improvement of Patients Eligible for Dose Escalation with Matched Plans

PURPOSE Radiation-therapy dose-escalation beyond 80Gy may improve tumor control rates for patients with localized prostate cancer. Since toxicity remains a concern, treatment planners must achieve dose-escalation while still adhering to dose-constraints for surrounding structures. Patientmatching is a machine-learning technique that identifies prior patients that dosimetrically match DVH parameters of target volumes and critical structures prior to actual treatment planning. We evaluated the feasibility of patient-matching in (1)identifying candidates for safe dose-escalation; and (2)improving DVH parameters for critical structures in actual dose-escalated plans. METHODS We analyzed DVH parameters from 319 historical treatment plans to determine which plans could achieve dose-escalation (8640cGy) without exceeding Zelefsky dose-constraints (rectal and bladder V47Gy<53%, and V75.6Gy<30%, max-point dose to rectum of 8550cGy, max dose to PTV< 9504cGy). We then estimated the percentage of cases that could achieve safe dose-escalation using software that enables patient matching (QuickMatch, Siris Medical, Mountain View, CA). We then replanned a case that had violated DVH constraints with DVH parameters from patient matching, in order to determine whether this previously unacceptable plan could be made eligible with this automated technique. RESULTS Patient-matching improved the percentage of patients eligible for dose-escalation from 40% to 63% (p=4.7e-4, t-test). Using a commercial optimizer augmented with patient-matching, we demonstrated a case where patient-matching improved the toxicity-profile such that dose-escalation would have been possible; this plan was rapidly achieved using patientmatching software. In this patient, all lower-dose constraints were met with both the denovo and patient-matching plan. In the patient-matching plan, maximum dose to the rectum was 8385cGy, while the denovo plan failed to meet the maximum rectal constraint at 8571cGy. CONCLUSION Patientmatching is a promising method to identify eligible patients, and to assist in creating acceptable plans for dose-escalation. Further study will investigate other disease states. Additionally, the time-savings provided by patientmatching warrants further investigation. The following authors have equity ownership in Siris Medical, Inc: K Bush, TF Atwood.