Matthew P. Larocque

Temporal and dose dependence of T2 and ADC at 9.4 T in a mouse model following single fraction radiation therapy

The purpose of this study is to use magnetic resonance imaging to monitor the response of human glioma tumor xenografts to single fraction radiation therapy. Mice were divided into four treatment groups (n = 6 per group) that received 50, 200, 400, or 800 cGy of 200 kVp x rays. A fifth group (n = 6) received no radiation dose and served as the control. Quantitative maps of the treated tumor tissue were produced of water apparent diffusion coefficient (ADC) and transverse relaxation time (T2). Mice were imaged before and at multiple time points after treatment. There was a statistically significant difference in tumor growth relative to that of the control for all treatment groups. Only the highest dose group showed T2 values that were significantly different at all measured time points after treatment. In this group, there was an 8.3% increase in T2 relative to controls 2 days after treatment, but when measured 14 days after treatment, mean tumor T2 had dropped to 10.1% below the initial value. ADC showed statistically significant differences from the control at all dose points. A radiation dose dependence was observed. In the highest dose group, the fractional increases in ADC were higher than those observed for T2. ADC was sensitive to radiation-induced changes in lower dose groups that did not have significant T2 change. At all doses, elevation of mean tumor ADC preceded deviations in tumor growth from the control. These observations support the potential application of ADC as a time and dose sensitive marker of tumor response to radiation therapy.

Monitoring T2 and ADC at 9.4 T following fractionated external beam radiation therapy in a mouse model

The purpose of this study is to investigate the response of transverse relaxation time (T2) and apparent diffusion coefficient (ADC) in human glioma tumor xenografts during and after fractionated radiotherapy. Tumor-bearing mice were divided into four treatment groups (n=6 per group) that received a total dose of 800 cGy of 200 kVp x-rays, given over two or three fractions, with a fraction spacing of either 24 or 72 h. A fifth treatment group received 800 cGy in a single fraction, and a sixth group of mice served as an untreated control. All mice were scanned pretreatment, before each fraction and at multiple points after treatment using a 9.4 T magnetic resonance imaging (MRI) system. Quantitative T2 and ADC maps were produced. All treated groups showed an increase in mean tumor ADC, though the time for this response to reach a maximum and return toward baseline was delayed in the fractionated groups. The highest ADC was measured 7 days after the final fraction of treatment for all groups. There were no significant differences in the maximum measured change in ADC between any of the treated groups, with the average measured maximum value being 20.5% above baseline. After treatment, all groups showed an increase in mean tumor T2, with the average measured maximum T2 being 4.7% above baseline. This increase was followed by a transition to mean T2 values below baseline values, with the average measured tumor T2 being 92.4% of the pretreatment value. The transition between elevated and depressed T2 values was delayed in the cases of fractionated therapies and occurred between 3.6 and 7.3 days after the last fraction of treatment. These results further the understanding of the temporal evolution of T2 and ADC during fractionated radiotherapy and support their potential use as time-sensitive biomarkers for tumor response.

ADC response to radiation therapy correlates with induced changes in radiosensitivity.

PURPOSE Magnetic resonance imaging was used to compare the responses of human glioma tumor xenografts to a single fraction of radiation, where a change in radiosensitivity was induced by use of a suture-based ligature. METHODS Ischemia was induced by use of a suture-based ligature. Six mice were treated with 800 cGy of 200 kVp x rays while the ligature was applied. An additional six mice had the ligature applied for the same length of time but were not irradiated. Quantitative maps of each tumor were produced of water apparent diffusion coefficient (ADC) and transverse relaxation time (T2). Mice were imaged before and at multiple points after treatment. Volumetric, ADC, and T2 responses of the ligated groups were compared to previously measured responses of the same tumor model to the same radiation treatment, as well as those from an untreated control group. RESULTS Application of the ligature without irradiation did not affect tumor ADC values, but did produce a temporary decrease in tumor T2 values. Average tumor T2 was reduced by 6.2% 24 h after the ligature was applied. Average tumor ADC increased by 9.6% 7 days after irradiation with a ligature applied. This response was significantly less than that observed in the same tumor model when no ligature is present (21.8% at 7 days after irradiation). CONCLUSIONS These observations indicate that the response of ADC to radiation therapy is not determined entirely by physical dose deposition, but at least in part by radiosensitivity and resultant biological response.

Management of uveal melanoma: a consensus-based provincial clinical practice guideline.

INTRODUCTION Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. METHODS A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. RESULTS Eighty-four publications, including five existing guidelines, formed the evidence base. SUMMARY Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.

Delivered dose uncertainty analysis at the tumor apex for ocular brachytherapy

PURPOSE To estimate the total dosimetric uncertainty at the tumor apex for ocular brachytherapy treatments delivered using 16 mm Collaborative Ocular Melanoma Study (COMS) and Super9 plaques loaded with (125)I seeds in order to determine the size of the apex margin that would be required to ensure adequate dosimetric coverage of the tumor. METHODS The total dosimetric uncertainty was assessed for three reference tumor heights: 3, 5, and 10 mm, using the Guide to the expression of Uncertainty in Measurement/National Institute of Standards and Technology approach. Uncertainties pertaining to seed construction, source strength, plaque assembly, treatment planning calculations, tumor height measurement, plaque placement, and plaque tilt for a simple dome-shaped tumor were investigated and quantified to estimate the total dosimetric uncertainty at the tumor apex. Uncertainties in seed construction were determined using EBT3 Gafchromic film measurements around single seeds, plaque assembly uncertainties were determined using high resolution microCT scanning of loaded plaques to measure seed positions in the plaques, and all other uncertainties were determined from the previously published studies and recommended values. All dose calculations were performed using plaque simulator v5.7.6 ophthalmic treatment planning system with the inclusion of plaque heterogeneity corrections. RESULTS The total dosimetric uncertainties at 3, 5, and 10 mm tumor heights for the 16 mm COMS plaque were 17.3%, 16.1%, and 14.2%, respectively, and for the Super9 plaque were 18.2%, 14.4%, and 13.1%, respectively (all values with coverage factor k = 2). The apex margins at 3, 5, and 10 mm tumor heights required to adequately account for these uncertainties were 1.3, 1.3, and 1.4 mm, respectively, for the 16 mm COMS plaque, and 1.8, 1.4, and 1.2 mm, respectively, for the Super9 plaque. These uncertainties and associated margins are dependent on the dose gradient at the given prescription depth, thus resulting in the changing uncertainties and margins with depth. CONCLUSIONS The margins determined in this work can be used as a guide for determining an appropriate apex margin for a given treatment, which can be chosen based on the tumor height. The required margin may need to be increased for more complex scenarios (mushroom shaped tumors, tumors close to the optic nerve, oblique muscle related tilt, etc.) than the simple dome-shaped tumor examined and should be chosen on a case-by-case basis. The sources of uncertainty contributing most significantly to the total dosimetric uncertainty are seed placement within the plaques, treatment planning calculations, tumor height measurement, and plaque tilt. This work presents an uncertainty-based, rational approach to estimating an appropriate apex margin.

Gene Expression Profiling as an Adjunctive Measure to Guide the Management of Indeterminate, High-Risk Choroidal Melanocytic Lesions: A Pilot Study

Purpose: To describe our early experience with gene expression profiling (GEP) assessment for juxtafoveal, subfoveal, and peripapillary indeterminate high-risk melanocytic lesions to assist in making early treatment decisions in patients who did not feel comfortable with either close observation or definitive treatment. Methods: A prospective cohort of patients with indeterminate lesions who underwent GEP were enrolled. Nonparametric statistical analysis was utilized given the small sample size. Results: Fifteen patients were included in this series. Six (40%) were class 1A and 9 (60%) class 1B. Class 1A and 1B lesions had a median of three and four clinical risk factors, respectively (p = 0.27). There was no statistically significant difference for the largest basal diameter between the classes (p = 0.31); however, class 1B lesions were thicker than class 1A lesions (p = 0.03). None of the class 1A lesions showed definite growth or metastasis over a mean follow-up period of 17.1 ± 1.8 months from fine needle aspiration biopsy. All class 1B patients opted for plaque brachytherapy, and to date none of these patients have developed metastasis, with a mean follow-up of 18.7 ± 8.4 months. Conclusion: There may be a role for GEP assessment in high-risk, indeterminate, posteriorly located choroidal lesions to assist in treatment planning.

The Use of Intravitreal Anti-VEGF and Triamcinolone in the Treatment of Radiation Papillopathy

Background/Aims: To evaluate a treatment regimen for radiation papillopathy. Methods: This is a prospective noncomparative interventional case series of patients who developed radiation papillopathy after plaque brachytherapy for uveal melanoma. Treatment consisted of intravitreal bevacizumab (IVB) (1.25 mg in 0.05 mL) at the time of diagnosis, and 1 week later, intravitreal triamcinolone (IVK) (2.00 mg in 0.05 mL). One month later, patients again received both IVB and IVK. Patients were then switched to monotherapy with monthly IVB until the papillopathy resolved. Results: Eleven patients developed radiation papillopathy, with 9 receiving treatment. On multivariate analysis, total radiation dose to the optic nerve was the only significant predictor of papillopathy (p = 0.005). Four of nine patients presented with a significant decline in visual acuity (VA) at the time of diagnosis of papillopathy. In all 4, significant improvement was documented following treatment. Five patients did not present with a decrease in VA, and in this group, 80% remained stable with treatment. Conclusions: In this series, patients who had a precipitous drop in VA at the time of diagnosis of radiation papillopathy returned to baseline VA following this treatment algorithm. This protocol was effective at maintaining stability of VA in 80% of those who developed papillopathy but did not present with an acute drop in VA.

Advanced Collapsed cone Engine dose calculations in tissue media for COMS eye plaques loaded with I‐125 seeds

Purpose To investigate the dose calculation accuracy of the Advanced Collapsed cone Engine (ACE) algorithm for ocular brachytherapy using a COMS plaque loaded with I‐125 seeds for two heterogeneous patient tissue scenarios. Methods The Oncura model 6711 I‐125 seed and 16 mm COMS plaque were added to a research version (v4.6) of the Oncentra® Brachy (OcB) treatment planning system (TPS) for dose calculations using ACE. Treatment plans were created for two heterogeneous cases: (a) a voxelized eye phantom comprising realistic eye materials and densities and (b) a patient CT dataset with variable densities throughout the dataset. ACE dose calculations were performed using a high accuracy mode, high‐resolution calculation grid matching the imported CT datasets (0.5 × 0.5 × 0.5 mm3), and a user‐defined CT calibration curve. The accuracy of ACE was evaluated by replicating the plan geometries and comparing to Monte Carlo (MC) calculated doses obtained using MCNP6. The effects of the heterogeneous patient tissues on the dose distributions were also evaluated by performing the ACE and MCNP6 calculations for the same scenarios but setting all tissues and air to water. Results Average local percent dose differences between ACE and MC within contoured structures and at points of interest for both scenarios ranged from 1.2% to 20.9%, and along the plaque central axis (CAX) from 0.7% to 7.8%. The largest differences occurred in the plaque penumbra (up to 17%), and at contoured structure interfaces (up to 20%). Other regions in the eye agreed more closely, within the uncertainties of ACE dose calculations (˜5%). Compared to that, dose differences between water‐based and fully heterogeneous tissue simulations were up to 27%. Conclusions Overall, ACE dosimetry agreed well with MC in the tumor volume and along the plaque CAX for the two heterogeneous tissue scenarios, indicating that ACE could potentially be used for clinical ocular brachytherapy dosimetry. In general, ACE data matched the fully heterogeneous MC data more closely than water‐based data, even in regions where the ACE accuracy was relatively low. However, depending on the plaque position, doses to critical structures near the plaque penumbra or at tissue interfaces were less accurate, indicating that improvements may be necessary. More extensive knowledge of eye tissue compositions is still required.

SU‐E‐T‐443: Geometric Uncertainties in Eye Plaque Dosimetry for a Fully Loaded 16 Mm COMS Plaque

Purpose: To determine the effect of geometric uncertainties in the seed positions in a COMS eye plaque on the central axis (CAX) dose. Methods: A Silastic insert was placed into a photopolymer 3D printed 16 mm COMS plaque, which was then positioned onto a custom-designed PMMA eye phantom. High resolution 3D images were acquired of the setup using a Siemens Inveon microPET/CT scanner. Images were acquired with the plaque unloaded and loaded with IsoAid I-125 seed shells (lack of silver core to minimize metal artifacts). Seed positions and Silastic thickness beneath each slot were measured. The measured seed coordinates were used to alter the seed positions within a standard 16 mm COMS plaque in Plaque Simulator v5.7.3 software. Doses along the plaque CAX were compared for the original and modified plaque coordinates using 3.5 mCi seeds with treatment times set to deliver 70 Gy to tumour apexes of 3.5, 5, and 10 mm height. Results: The majority of seeds showed length-wise displacement, and all seeds showed displacement radially outward from the eye center. The average radial displacement was 0.15 mm larger than the expected 1.4 mm offset, approximately half of which was due to increased Silastic thickness beneath each slot. The CAX doses for the modified seed positions were consistently lower for all tumour heights due to geometric displacement of the seeds; dose differences were found to increase to a maximum of 2.6% at a depth of ∼10 mm, after which they decreased due to the inverse square dose fall-off minimizing this effect. Conclusion: This work presents initial results of a broader dosimetric uncertainty evaluation for fully loaded COMS eye plaques and demonstrates the effects of seed positioning uncertainties. The small shifts in seed depths had noticeable effects on the CAX doses indicating the importance of careful Silastic loading. Funding provided by Alberta Cancer Foundation Grant #26655, Vanier Canada Graduate Scholarship, and Alberta Innovates Health Sciences Graduate Studentship

Sci—Fri PM: Delivery — 09: Response of a tumor xenograft model to radiation therapy using magnetic resonance spectroscopy

9.4T 1 H magnetic resonance spectroscopy (MRS) was utilized to track the response of mouse xenograft glioblastoma multiform (GBM) brain tumors to single fraction radiation therapy. Six metabolites were analyzed with LCModel: alanine (Ala), myo-inositol (Ins), taurine (Tau), creatine and phosphocreatine (Cr + PCr), glutamine and glutamate (Glu + Gln), and total choline (glycerophosphocholine + phosphocholine) (GPC + PCh). 11 mice received 800 cGy of 200 kVp x-rays, 5 were untreated controls. PRESS spectra (27 μL volumes) were acquired at multiple time points for treated and control animals. In treated animals, all metabolite : water ratios decreased 3 days post-treatment, with further decreases at day 7, and then increases at day 14 relative to the 7 day mark. Concentrations on day 7 relative to pre-treatment were as follows: 0.42 (Ala), 0.43 (Ins), 0.68 (Tau), 0.52 (GPC+PCh), 0.49 (Cr + PCr) and 0.78 (Glu + Gln). Metabolite ratios did not correlate with tumor volume in control animals, suggesting a real therapeutic response was observed. Our 1 H MRS data suggests that perturbations in the metabolic signature of GBM cancers occur in response to irradiation. Such changes in the metabolite : water concentration ratios could potentially be exploited for the improvement of radiotherapy.