Phillip Prior

Calculation of Optical Signal Using Three-Dimensional Bidomain/Diffusion Model Reveals Distortion of the Transmembrane Potential

Optical mapping experiments allow investigators to view the effects of electrical currents on the transmembrane potential, V(m), as a shock is applied to the heart. One important consideration is whether the optical signal accurately represents V(m). We have combined the bidomain equations along with the photon diffusion equation to study the excitation and emission of photons during optical mapping of cardiac tissue. Our results show that this bidomain/diffusion model predicts an optical signal that is much smaller than V(m) near a stimulating electrode, a result consistent with experimental observations. Yet, this model, which incorporates the effect of lateral averaging, also reveals an optical signal that overestimates V(m) at distances >1 mm away from the electrode. Although V(m) falls off with distance r from the electrode as exp(-r/lambda)/r, the optical signal decays as a simple exponential, exp(-r/lambda). Moreover, regions of hyperpolarization adjacent to a cathode are emphasized in the optical signal compared to the region of depolarization under the cathode. Imaging methods utilizing optical mapping techniques will need to account for these distortions to accurately reconstruct V(m).

A phase I/II study piloting accelerated partial breast irradiation using CT-guided intensity modulated radiation therapy in the prone position.

BACKGROUND AND PURPOSE External beam accelerated partial breast irradiation (EB-aPBI) is noninvasive with broader potential applicability than aPBI using brachytherapy. However, it has inherent challenges in daily reproducibility. Image-guide radiotherapy (IGRT) can improve daily reproducibility, allowing smaller treatment margins. Our institution proposed IG-IMRT in the prone position to evaluate dose homogeneity, conformality, normal tissue avoidance, and reliable targeting for EB-aPBI. We report preliminary results and toxicity from a phase I/II study evaluating the feasibility of EB-aPBI in the prone position using IG-IMRT. MATERIALS AND METHODS Twenty post-menopausal women with node-negative breast cancer, excised tumors <3.0 cm, negative sentinel lymph node biopsy, and surgical clips demarcating the lumpectomy cavity underwent prone EB-aPBI using IG-IMRT on an IRB-approved phase I/II study. All patients underwent CT planning in the prone position. The lumpectomy cavity PTV represented a 2.0 cm expansion. 38.5 Gy was delivered in 10 fractions over 5 days, such that 95% of the prescribed dose covered >99% of the PTV. Dose constraints for the whole breast, lungs and heart were met. RESULTS The median patient age was 61.5. Mean tumor size was 1.0 cm. 35% of patients had DCIS. Median PTV was 243 cc (108-530) and median breast reference volume was 1698 cc (647-3627). Average daily shifts for IGRT were (0.6, -4.6, 1.7 mm) with standard deviations of (6.3, 6.5, 6.4mm). Acute toxicity was G1 erythema in 80%, and G2 erythema, G2 fatigue, and G2 breast pain each occurred in 1 patient. With a median follow-up of 18.9 months (12-35), 40% of patients have G1 fibrosis and 30% have G1 hyperpigmentation. 95% of patients have good to excellent cosmesis. There have been no recurrences. CONCLUSIONS These data demonstrate that EB-aPBI in the prone position using IG-IMRT is well tolerated, yields good dosimetric conformality, and results in promising early toxicity profiles.

Consolidating Risk Estimates for Radiation-Induced Complications in Individual Patient: Late Rectal Toxicity

PURPOSE To test the feasibility of a new approach to synthesize published normal tissue complication data using late rectal toxicity in prostate cancer as an example. METHODS AND MATERIALS A data survey was performed to identify the published reports on the dose-response relationships for late rectal toxicity. The risk estimates for Grade 1 or greater, Grade 2 or greater, and Grade 3 or greater toxicity were obtained for a test cohort of patients treated at our institution. The influence of the potential factors that might have affected the reported toxicity levels was investigated. The studies that did not conform to the general data trends were excluded, and single, combined risk estimates were derived for each patient and toxicity level. RESULTS A total of 21 studies of nonoverlapping patient populations were identified. Three studies provided dose-response models for more than one level of toxicity. Of these 21 studies, 6, 14, and 5 were used to derive the initial risk estimates for Grade 1, 2, and 3 or greater toxicity, respectively. A comparison of risk estimates between the studies reporting rectal bleeding and rectal toxicity (bleeding plus other symptoms) or between studies with follow-up <36 months and ≥36 months did not reveal significant differences (p ≥ .29 for all comparisons). After excluding three reports that did not conform to the general data trends, the combined risk estimates were derived from 5 reports (647 patients), 11 reports (3,369 patients), and 5 reports (1,330 patients) for Grade 1, 2, and 3 or greater toxicity, respectively. CONCLUSIONS The proposed approach is feasible and allows for more systematic use of published dose-response data to estimate the complication risks for the individual patient.

Development of an imaging modality utilizing 2D optical signals during an EPI-fluorescent optical mapping experiment

Optical mapping is a commonly used technique to visualize the electrical activity in the heart. Recently, several groups have attempted to use the signals acquired in optical mapping to image the transmembrane potential in the heart, which would be particularly advantageous when studying the effects of defibrillation-type shocks throughout the wall of the heart. Our work presents an alternative imaging method that makes use of data obtained using multiple wavelengths and therefore multiple optical decay constants. A modified form of the diffusion equation Greens function for a semi-infinite slab of tissue is derived and used to relate the detected optical signals to the source of emission photons. Images using the optical signals are reconstructed using Gaussian quadrature and matrix inversion. Our results show that images can be obtained for source terms located below the tissue surface. Furthermore, we demonstrate that our reconstruction methods susceptibility to noise can be alleviated using sophisticated matrix inverse techniques, such as singular value decomposition. Sources that rapidly decay with depth or are highly localized in the image plane require more sophisticated techniques (e.g., regularization methods) to image the electrical activity in the heart. The work presented here demonstrates the feasibility of a new imaging technique of cardiac electrical activity using optical mapping.

P3-13-05: Analysis of Heart Dose-Volume Parameters and Cardiac Events among Node Positive Breast Cancer (NPBC) Patients Treated with Three-Dimensional Conformal Radiation Therapy (3D-CRT).

Background For NPBC patients the use of regional nodal irradiation (RNI) to the supraclavicular, axillary, internal mammary lymph nodes (IMN) in addition to the chest wall and/or breast can maximize locoregional control and improve overall survival. However, comprehensive RNI for breast cancers located on the left side has been linked to late cardiac morbidity, potentially lessening the therapeutic benefit of treatment. The optimal radiation dose-volume constraints for the heart in this setting are not fully understood. We examined NPBC patients treated with RNI using 3D-CT based radiation therapy (RT) to evaluate cardiac dose and incidence of cardiac events. Methods: Between 2000 and 2007, 150 NPBC patients were treated with RNI following lumpectomy or mastectomy using 3D-CRT. In all cases, treatment target and normal tissue volumes were delineated on treatment CT scans. The heart contour included the ventricles and the left atrium. The dose-volume histogram of the cardiac doses delivered and the incidence of cardiac events is reported. Results: Median follow-up of surviving patients is 7 (1-10.6) years. Median patient age is 50 (27-91). 52.35% are premenopausal, 75.7% estrogen receptor positive, 66.3% progesterone receptor positive and 15.92% HER-2 positive. Mean positive lymph nodes is 5 (1-29). Extracapsular extension is present in 47.31%. Mean microscopic tumor size is 3.73 (0.1-21) cm. The IMN receive > 40 Gy in 65.5%. 94% had chemotherapy, and in 82.3% it was anthracycline-based. At the time of RT, 12.2% smoked, 9.5% had diabetes, 32.4% with hypertension, and 4.7% with a history of coronary artery disease. There was 1 (0.7%) right sided patient with cardiac events and 4 (2.7%) left sided experiencing cardiac events (p = 0.121, Fisher9s Exact test). A total of 10 cardiac diagnoses were experienced among the 5 patients: coronary artery disease with myocardial infarction (3), congestive heart failure (2), cardiomyopathy (2), and arrhythmia (3). The median time interval to onset of the events is 2.5 years (0-4.3 years). The cardiac doses among 150 patients are as follows: mean V25 is 5.7, (0.0 - 20.0%), V25 is Conclusions: The cardiac event rate among these NPBC patients treated with RNI and anthracycline-based chemotherapy is low. However, those patients with cardiac events have a higher mean V45. No other dose-volume relationships are discernible. Additional analysis using 3DCRT volumes are important to validate these findings and better define the dose-volume parameters for cardiac toxicity. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-05.

SU-G-JeP2-05: Dose Effects of a 1.5T Magnetic Field On Air-Tissue and Lung-Tissue Interfaces in MRI-Guided Radiotherapy

PURPOSE The purpose of the study is to investigate the dose effects of electron-return-effect (ERE) at air-tissue and lung-tissue interfaces under a 1.5T transverse-magnetic-field (TMF). METHODS IMRT and VMAT plans for representative pancreas, lung, breast and head & neck (H&N) cases were generated following clinical dose volume (DV) criteria. The air-cavity walls, as well as the lung wall, were delineated to examine the ERE. In each case, the original plan generated without TMF is compared with the reconstructed plan (generated by recalculating the original plan with the presence of TMF) and the optimized plan (generated by a full optimization with TMF), using a variety of DV parameters, including V100%, D95% and dose heterogeneity index for PTV, Dmax, and D1cc for OARs (organs at risk) and tissue interface. RESULTS The dose recalculation under TMF showed the presence of the 1.5 T TMF can slightly reduce V100% and D95% for PTV, with the differences being less than 4% for all but lung case studied. The TMF results in considerable increases in Dmax and D1cc on the skin in all cases, mostly between 10-35%. The changes in Dmax and D1cc on air cavity walls are dependent upon site, geometry, and size, with changes ranging up to 15%. In general, the VMAT plans lead to much smaller dose effects from ERE compared to fixed-beam IMRT. When the TMF is considered in the plan optimization, the dose effects of the TMF at tissue interfaces are significantly reduced in most cases. CONCLUSION The doses on tissue interfaces can be significantly changed by the presence of a 1.5T TMF during MR-guided RT when the TMF is not included in plan optimization. These changes can be substantially reduced or even removed during VMAT/IMRT optimization that specifically considers the TMF, without deteriorating overall plan quality.

Abstract P1-15-17: Sustained acceptable cosmetic outcomes and local control following accelerated partial breast irradiation using CT-guided IMRT in the prone position: Results from a phase I/II feasibility study

Objective/Purpose External beam accelerated partial breast irradiation (EB-aPBI) can have potential challenges in daily reproducibility, although it has broader potential use than aPBI using brachytherapy. Image-guide radiotherapy (IGRT) can improve daily reproducibility and allow smaller treatment margins. Our institution utilized IG-IMRT to administer EB-aPBI in the prone position in a Phase I/II study to increase dose homogeneity, conformality, normal tissue avoidance, and reliable targeting. Our preliminary results and toxicity were promising. Here we report final physician- and patient-reported cosmetic outcomes from this prospective trial. Materials and Methods Women with node-negative invasive breast cancer or DCIS, tumors less than 3.0 cm, a negative sentinel lymph node biopsy, and surgical clips demarcating the lumpectomy cavity underwent prone EB-aPBI using IG-IMRT on an IRB-approved phase I/II study. The lumpectomy PTV represented a 2.0 cm lumpectomy cavity expansion. 38.5 Gy was delivered in 10 fractions over 5 days, such that 95% of the prescribed dose covered greater than 99% of the PTV. Dose constraints for the whole breast, lungs and heart were met. Results Twenty patients were enrolled, with a median patient age of 61.5 and a mean tumor size of 1.0 cm. 35% of patients had DCIS. At a median follow-up of 18.9 months, 40% and 10% of patients had G1 and G2 fibrosis, respectively, and 95% of patients had good to excellent physician-assessed cosmesis. At a median follow-up of 60.0 months (range 54-79 months), physician-assessed cosmetic outcome was good to excellent in 80%, with 30% and 20% of patients experiencing G1 and G2 fibrosis. Patient-reported outcomes at one year yielded 90% of patients with good to excellent cosmetic outcomes. At 3 years, 75% of patients reported good to excellent cosmesis. Eighty-eight percent of patients were completely satisfied with the treatment and results, and 94% of patients would choose aPBI again. With one local recurrence, the actuarial five year rate of local control was 95%. Conclusions These data demonstrate that EB-aPBI in the prone position using IG-IMRT continues to yield acceptable cosmetic outcomes at longer term follow-up, and a very high percentage of patients would choose this treatment again. (Supported by Komen Grant: BCTR0504070). Citation Format: Carmen Bergom, Phillip Prior, Kristofer Kainz, Natalya V Morrow, Ergun E Ahunbay, Alonzo Walker, X Allen Li, Tracy Kelly, Adam D Currey, Julia White. Sustained acceptable cosmetic outcomes and local control following accelerated partial breast irradiation using CT-guided IMRT in the prone position: Results from a phase I/II feasibility study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-17.

SU‐E‐T‐252: Consolidating Duodenal/Small Bowel Toxicity Data via Iso‐Effective Dose Calculations Based on Compiled Clinical Data

PURPOSE To consolidate duodenal toxicity data from clinical studies with different dose fractionation schemes using the modified linear quadratic (MLQ) model. A methodology of adjusting the dose-volume parameters todifferent levels of normal tissue complication probability (NTCP) was proposed and used to estimate dose-volume constrains for treatment planning. METHODS A set of modified Lyman model parameters for duodenum NTCP were estimated by the chi-squared fitting method using tolerance dose and equivalent uniform dose (EUD) data obtained in a literature search. These model parameters were then used to convert the dose-volume pair, (D, V) to the iso-effective dose (in 2 Gy per fraction)- volume pair, (DMLQED2, V). A relationship was derived to convert a given DMLQED2 at one level of NTCP, to an iso-effective dose at another NTCP. RESULTS The literature search yielded six reports useful in making estimates of small bowel/duodenal toxicity. The modified Lyman model parameters were found to be TD50 = 60.9 ± 7.9 Gy, m = 0.21 ± 0.05, and Î = 0.09 ± 0.03 Gy-1. The toxicity rates associated with hypo-fractionated radiotherapy (HBRT) were found to be consistent with other clinical data of conventional fractionations found in the literature. The conversion of DMLQED2 between different NTCP levels remains consistent with each other over a narrow range of NTCP. CONCLUSION MLQ based iso-effective calculations of dose-response data corresponding to Grade > 2 toxicity were found to be consistent with one another within the uncertainty of DMLQED2 due to model parameter uncertainty. The dose-volume data that can be converted to different NTCP levels may be used to estimate duodenal/small bowel dose-volume constrains for new dose fractionation and/or dose escalation strategies. Medical College of Wisconsin Cancer Center Meinerz Foundation.