Tumor Subvolumes Research Articles

Predicting Location of Recurrence Using FDG, FLT, and Cu-ATSM PET in Canine Sinonasal Tumors Treated With Radiation Therapy

Biologically-conformal radiation therapy relies on the ability of functional imaging to identify resistant tumor subvolumes to be targeted for additional boosting. The goal of this work was to assess the ability of FDG, FLT, and Cu-ATSM PET imaging to predict the locations of recurrent tumor following radiation therapy, as assessed by follow-up FDG PET, in canine sinonasal tumors.

18F-FMISO PET/CT Visualization of Tumor Hypoxia in Patients With Chordoma of the Mobile and Sacrococcygeal Spine

Local recurrence (LR) rates in chordoma patients following surgery ± radiation therapy (RT) or definitive RT are high. Tumor hypoxia is associated with radioresistance and LR. In this prospective study, [18F]-FMISO-PET/CT detected hypoxic tumor sub-volumes in 60% of patients with chordoma of the mobile and sacrococcygeal spine, the majority of which were sufficiently large to allow an RT boost. Further study of hypoxia-directed, dose-escalated RT, particularly in patients at high risk for LR, is warranted. Purpose/Objectives Local recurrence (LR) rates in chordoma patients following surgery ± radiation therapy (RT) or definitive RT are high. Tumor hypoxia is associated with radioresistance and LR. [18F] fluoromisonidazole positron emission tomography/computed tomography (FMISO-PET/CT) can visualize skull base chordoma hypoxic sub-volumes (HSV) and feasibility of hypoxia-directed RT dose-escalation has been demonstrated in head and neck cancer. This study investigates FMISO-PET/CT detection of targetable HSVs in chordoma of the mobile or sacrococcygeal spine.

Interstitial diffusion and the relationship between compartment modelling and multi-scale spatial-temporal modelling of 18F-FLT tumour uptake dynamics

Tumour cell proliferation can be imaged via positron emission tomography of the radiotracer 3ʹ-deoxy-3ʹ-18F-fluorothymidine (18F-FLT). Conceptually, the number of proliferating cells might be expected to correlate more closely with the kinetics of 18F-FLT uptake than with uptake at a fixed time. Radiotracer uptake kinetics are standardly visualized using parametric maps of compartment model fits to time-activity-curves (TACs) of individual voxels. However the relationship between the underlying spatiotemporal accumulation of FLT and the kinetics described by compartment models has not yet been explored.In this work tumour tracer uptake is simulated using a mechanistic spatial-temporal model based on a convection-diffusion-reaction equation solved via the finite difference method. The model describes a chain of processes: the flow of FLT between the spatially heterogeneous tumour vasculature and interstitium; diffusion and convection of FLT within the interstitium; transport of FLT into cells; and intracellular phosphorylation. Using values of model parameters estimated from the biological literature, simulated FLT TACs are generated with shapes and magnitudes similar to those seen clinically. Results show that the kinetics of the spatial-temporal model can be recovered accurately by fitting a 3-tissue compartment model to FLT TACs simulated for those tumours or tumour sub-volumes that can be viewed as approximately closed, for which tracer diffusion throughout the interstitium makes only a small fractional change to the quantity of FLT they contain. For a single PET voxel of width 2.5–5 mm we show that this condition is roughly equivalent to requiring that the relative difference in tracer uptake between the voxel and its neighbours is much less than one.

WE-G-BRE-03: Dose Painting by Numbers Using Targeted Gold Nanoparticles

Purpose: Homogeneous dose enhancement in tumor cells of lung cancer patients treated with conventional dose of 60–66 Gy in five fractions is limited due to increased risk of toxicity to normal structures. Dose painting by numbers (DPBN) is the prescription of a non-uniform radiation dose distribution in the tumor for each voxel based on the intensity level of that voxel obtained from the tumor image. The purpose of this study is to show that DPBN using targeted gold nanoparticles (GNPs) could enhance conventional doses in the more resistant tumor areas. Methods: Cone beam computed tomography (CBCT) images of GNPs after intratumoral injection into human tumor were taken at 0, 48, 144 and 160 hours. The dose enhancement in the tumor voxels by secondary electrons from the GNPs was calculated based on analytical microdosimetry methods. The dose enhancement factor (DEF) is the ratio of the doses to the tumor with and without the presence of GNPs. The DEF was calculated for each voxel of the images based on the GNP concentration in the tumor sub-volumes using 6-MV photon spectra obtained using Monte Carlo simulations at 5 cm depth (10×10 cm2 field). Results: The results revealed DEF values of 1.05–2.38 for GNPsmore » concentrations of 1–30 mg/g which corresponds to 12.60 – 28.56 Gy per fraction for delivering 12 Gy per fraction homogenously to lung tumor region. Conclusion: Our preliminary results verify that DPBN could be achieved using GNPs to enhance conventional doses to high risk tumor sub-volumes. In practice, DPBN using GNPs could be achieved due to diffusion of targeted GNPs sustainably released in-situ from radiotherapy biomaterials (e.g. fiducials) coated with polymer film containing the GNPs.« less

SU‐E‐T‐312: Test of the Generalized Tumor Dose (gTD) Model with An Independent Lung Tumor Dataset

Purpose:We previously developed a novel approach to tumor response modeling which was inspired by the gEUD model of tumor cell kill under inhomogeneous dose profiles. The model assumes that the cell‐kill law is valid, but further adds a parameter analogous to the generalized equivalent uniform dose model to test the independence of response of tumor subvolumes. The purpose of this study was to test the resulting generalized tumor dose (gTD) model on an independent lung cancer subset.Methods:Niemierko's gEUD model of cell kill introduces a generalization term describing interactions among tumor sub‐volumes under non‐uniform dose distributions. This parameter effectively applies weights to sub‐volumes based off of tumor type‐specific sensitivities to variance in dose. We combine the gEUD with the cell‐kill based cEUD to form the “generalized tumor dose” (gTD) model, which is given by gTD=‐α−1*ln(Vt/Vref)‐ (α*a)−1*ln(Σi=1:subvolsM#subvols−1 *e (‐α*a*di)). This model was previously applied to lung and H&N data. Here, we apply the model to an independent lung dataset (N= 36).Results:We found that the model does not perform well for large tumors (volume > 70 cc.) However,. However, for tumors smaller than this volume, the model was well‐correlated with local control, with a normalized log‐likelihood value (log‐likelihood divided by the number of cases) of −0.604.Conclusion:The presented model continues to predict tumor response in this dataset, for tumors less than 70 cc. To date, no other TCP model has been validated on clinical datasets for tumors with varying volumes and dose distributions. More tests are needed to further refine and validate the model.

Arterial Perfusion Imaging–Defined Subvolume of Intrahepatic Cancer

To assess whether an increase in a subvolume of intrahepatic tumor with elevated arterial perfusion during radiation therapy (RT) predicts tumor progression after RT. Twenty patients with unresectable intrahepatic cancers undergoing RT were enrolled in a prospective, institutional review board-approved study. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed before RT (pre-RT), after delivering ∼60% of the planned dose (mid-RT) and 1 month after completion of RT to quantify hepatic arterial perfusion. The arterial perfusions of the tumors at pre-RT were clustered into low-normal and elevated perfusion by a fuzzy clustering-based method, and the tumor subvolumes with elevated arterial perfusion were extracted from the hepatic arterial perfusion images. The percentage changes in the tumor subvolumes and means of arterial perfusion over the tumors from pre-RT to mid-RT were evaluated for predicting tumor progression post-RT. Of the 24 tumors, 6 tumors in 5 patients progressed 5 to 21 months after RT completion. Neither tumor volumes nor means of tumor arterial perfusion at pre-RT were predictive of treatment outcome. The mean arterial perfusion over the tumors increased significantly at mid-RT in progressive tumors compared with the responsive tumors (P=.006). From pre-RT to mid-RT, the responsive tumors had a decrease in the tumor subvolumes with elevated arterial perfusion (median, -14%; range, -75% to 65%), whereas the progressive tumors had an increase of the subvolumes (median, 57%; range, -7% to 165%) (P=.003). Receiver operating characteristic analysis of the percentage change in the subvolume for predicting tumor progression post-RT had an area under the curve of 0.90. The increase in the subvolume of the intrahepatic tumor with elevated arterial perfusion during RT has the potential to be a predictor for tumor progression post-RT. The tumor subvolume could be a radiation boost candidate for response-driven adaptive RT.

An alternative approach to histopathological validation of PET imaging for radiation therapy image-guidance: A proof of concept

PurposeIn radiotherapy, PET images can be used to guide the delivery of selectively escalated doses to biologically relevant tumour subvolumes. Validation of PET for such applications requires demonstration of spatial coincidence between PET tracer uptake pattern and the histopathologically confirmed target. This study introduces a novel approach to histopathological validation of PET image segmentation for radiotherapy guidance. Methods and materialsSequential tissue sections from surgically excised whole-tumour specimens were used to acquire full 3D-sets of both histopathological images (microscopy) and PET tracer distribution images (autoradiography). After these datasets were accurately registered, a full 3D autoradiographic distribution of PET tracer was reconstructed and used to obtain synthetic PET images (sPET) by simulating the image deterioration induced by processes involved in PET image formation. To illustrate the method, sPET images were used in this study to investigate spatial coincidence between high FDG uptake areas and the distribution of viable tissue in two small animal tumour models. ResultsThe reconstructed 3D autoradiographic distribution of the PET tracer was spatially coherent, as indicated by the high average value of the normalised pixel-by-pixel correlation of intensities between successive slices (0.84±0.05 and 0.94±0.02). The loss of detail in the sPET images versus the 3D autoradiography was significant as indicated by Dice coefficient values corresponding to the two tumours (0 and 0.1 at 70% threshold). The maximum overlap between the FDG segmented volumes and the extent of the viable tissue as indicated by Dice coefficient values, was 0.8 for one tumour (for the image thresholded at 22% of max intensity) and 0.88 for the other (threshold of 14% of max intensity). ConclusionIt was demonstrated that the use of synthetic PET images for histopathological validation allows for bypassing a technically challenging and error-prone step of registering non-invasive PET images with histopathology.

Anatomical and functional volume concordance between FDG PET, and T2 and diffusion-weighted MRI for cervical cancer: a hybrid PET/MR study

To evaluate the concordance among (18)F-FDG PET imaging, MR T2-weighted (T2-W) imaging and apparent diffusion coefficient (ADC) maps with diffusion-weighted (DW) imaging in cervical cancer using hybrid whole-body PET/MR. This study prospectively included 35 patients with cervical cancer who underwent pretreatment (18)F-FDG PET/MR imaging. (18)F-FDG PET and MR images were fused using standard software. The percent of the maximum standardized uptake values (SUV max) was used to contour tumours on PET images, and volumes were calculated automatically. Tumour volumes measured on T2-W and DW images were calculated with standard techniques of tumour area multiplied by the slice profile. Parametric statistics were used for data analysis. FDG PET tumour volumes calculated using SUV max (14.30 ± 4.70) and T2-W imaging volume (33.81 ± 27.32 cm(3)) were similar (P > 0.05) at 35 % and 40 % of SUV max (32.91 ± 18.90 cm(3) and 27.56 ± 17.19 cm(3) respectively) and significantly correlated (P < 0.001; r = 0.735 and 0.766). The mean DW volume was 30.48 ± 22.41 cm(3). DW volumes were not significantly different from FDG PET volumes at either 35 % SUV max or 40 % SUV max or from T2-W imaging volumes (P > 0.05). PET subvolumes with increasing SUV max cut-off percentage showed an inverse change in mean ADC values on DW imaging (P < 0.001, ANOVA). Hybrid PET/MR showed strong volume concordance between FDG PET, and T2-W and DW imaging in cervical cancer. Cut-off at 35 % or 40 % of SUV max is recommended for (18)F-FDG PET/MR SUV-based tumour volume estimation. The linear tumour subvolume concordance between FDG PET and DW imaging demonstrates individual regional concordance of metabolic activity and cell density.

Hypoxia in Head and Neck Cancer in Theory and Practice: A PET-Based Imaging Approach

Hypoxia plays an important role in tumour recurrence among head and neck cancer patients. The identification and quantification of hypoxic regions are therefore an essential aspect of disease management. Several predictive assays for tumour oxygenation status have been developed in the past with varying degrees of success. To date, functional imaging techniques employing positron emission tomography (PET) have been shown to be an important tool for both pretreatment assessment and tumour response evaluation during therapy. Hypoxia-specific PET markers have been implemented in several clinics to quantify hypoxic tumour subvolumes for dose painting and personalized treatment planning and delivery. Several new radiotracers are under investigation. PET-derived functional parameters and tracer pharmacokinetics serve as valuable input data for computational models aiming at simulating or interpreting PET acquired data, for the purposes of input into treatment planning or radio/chemotherapy response prediction programs. The present paper aims to cover the current status of hypoxia imaging in head and neck cancer together with the justification for the need and the role of computer models based on PET parameters in understanding patient-specific tumour behaviour.

Head and Neck Tumor Hypoxia Imaging by 18F-Fluoroazomycin-arabinoside (18F-FAZA)-PET

Tumor hypoxia is known to be associated with poor clinical outcome; therefore, patients with hypoxic tumors might benefit from more intensive treatment approaches. This is particularly true for patients with head and neck cancer. Pretreatment assessment of hypoxia in tumors would be desirable, not only to predict prognosis but also to select patients for more aggressive treatment.As an alternative to the invasive polarographic needle electrode method, there is the possibility of using PET with radiopharmaceuticals visualizing hypoxia. Most hypoxia imaging studies on head and cancer have been performed using F-labeled fluoromisonidazole (F-FMISO). A chemically related molecule, F-fluoroazomycin-arabinoside (F-FAZA), seems to have superior kinetic properties and may therefore be the radiopharmaceutical of choice.This minireview summarizes the published literature on animal and human F-FAZA PET studies. Furthermore, future perspectives on how individualized treatment could be applied in patients with hypoxic head and neck tumors are discussed, for instance, the use of hypoxia sensitizers or special intensity-modulated radiation therapy techniques achieving tumor subvolume dose escalation.

DCE-MRI defined subvolumes of a brain metastatic lesion by principle component analysis and fuzzy-c-means clustering for response assessment of radiation therapy

To develop a pharmacokinetic modelfree framework to analyze the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data for assessment of response of brain metastases to radiation therapy. Twenty patients with 45 analyzable brain metastases had MRI scans prior to whole brain radiation therapy (WBRT) and at the end of the 2-week therapy. The volumetric DCE images covering the whole brain were acquired on a 3T scanner with approximately 5 s temporal resolution and a total scan time of about 3 min. DCE curves from all voxels of the 45 brain metastases were normalized and then temporally aligned. A DCE matrix that is constructed from the aligned DCE curves of all voxels of the 45 lesions obtained prior to WBRT is processed by principal component analysis to generate the principal components (PCs). Then, the projection coefficient maps prior to and at the end of WBRT are created for each lesion. Next, a pattern recognition technique, based upon fuzzy-c-means clustering, is used to delineate the tumor subvolumes relating to the value of the significant projection coefficients. The relationship between changes in different tumor subvolumes and treatment response was evaluated to differentiate responsive from stable and progressive tumors. Performance of the PC-defined tumor subvolume was also evaluated by receiver operating characteristic (ROC) analysis in prediction of nonresponsive lesions and compared with physiological-defined tumor subvolumes. The projection coefficient maps of the first three PCs contain almost all response-related information in DCE curves of brain metastases. The first projection coefficient, related to the area under DCE curves, is the major component to determine response while the third one has a complimentary role. In ROC analysis, the area under curve of 0.88 ± 0.05 and 0.86 ± 0.06 were achieved for the PC-defined and physiological-defined tumor subvolume in response assessment. The PC-defined subvolume of a brain metastasis could predict tumor response to therapy similar to the physiological-defined one, while the former is determined more rapidly for clinical decision-making support.

Hypofractionated Image-Guided IMRT in Advanced Pancreatic Cancer With Simultaneous Integrated Boost to Infiltrated Vessels Concomitant With Capecitabine: A Phase I Study

To determine the maximum tolerated radiation dose (MTD) of an integrated boost to the tumor subvolume infiltrating vessels, delivered simultaneously with radical dose to the whole tumor and concomitant capecitabine in patients with pretreated advanced pancreatic adenocarcinoma. Patients with stage III or IV pancreatic adenocarcinoma without progressive disease after induction chemotherapy were eligible. Patients underwent simulated contrast-enhanced four-dimensional computed tomography and fluorodeoxyglucose-labeled positron emission tomography. Gross tumor volume 1 (GTV1), the tumor, and GTV2, the tumor subvolume 1 cm around the infiltrated vessels, were contoured. GTVs were fused to generate Internal Target Volume (ITV)1 and ITV2. Biological tumor volume (BTV) was fused with ITV1 to create the BTV+Internal Target Volume (ITV) 1. A margin of 5/5/7 mm (7 mm in cranium-caudal) was added to BTV+ITV1 and to ITV2 to create Planning Target Volume (PTV) 1 and PTV2, respectively. Radiation therapy was delivered with tomotherapy. PTV1 received a fixed dose of 44.25 Gy in 15 fractions, and PTV2 received a dose escalation from 48 to 58 Gy as simultaneous integrated boost (SIB) in consecutive groups of at least 3 patients. Concomitant chemotherapy was capecitabine, 1250 mg/m(2) daily. Dose-limiting toxicity (DLT) was defined as any treatment-related G3 nonhematological or G4 hematological toxicity occurring during the treatment or within 90 days from its completion. From June 2005 to February 2010, 25 patients were enrolled. The dose escalation on the SIB was stopped at 58 Gy without reaching the MTD. One patient in the 2(nd) dose level (50 Gy) had a DLT: G3 acute gastric ulcer. Three patients had G3 late adverse effects associated with gastric and/or duodenal mucosal damage. All patients received the planned dose of radiation. A dose of 44.25 Gy in 15 fractions to the whole tumor with an SIB of 58 Gy to small tumor subvolumes concomitant with capecitabine is feasible in chemotherapy-pretreated patients with advanced pancreatic cancer.

EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose

Clinical trials to ameliorate hypoxia as a strategy to relieve the radiation resistance it causes have prompted a need to assay the precise extent and location of hypoxia in tumors. Electron paramagnetic resonance oxygen imaging (EPR O2 imaging) provides a noninvasive means to address this need. To obtain a preclinical proof-of-principle that EPR O2 images could predict radiation control, we treated mouse tumors at or near doses required to achieve 50% control (TCD50). Mice with FSa fibrosarcoma or MCa4 carcinoma were subjected to EPR O2 imaging and immediately radiated to a TCD50 or TCD50 ± 10 Gy. Statistical analysis was permitted by collection of approximately 1,300 tumor pO2 image voxels, including the fraction of tumor voxels with pO2 less than 10 mm Hg (HF10). Tumors were followed for 90 days (FSa) or 120 days (MCa4) to determine local control or failure. HF10 obtained from EPR images showed statistically significant differences between tumors that were controlled by the TCD50 and those that were not controlled for both FSa and MCa4. Kaplan-Meier analysis of both types of tumors showed that approximately 90% of mildly hypoxic tumors were controlled (HF10%< 10%), and only 37% (FSA) and 23% (MCa4) tumors controlled if hypoxic. EPR pO2 image voxel distributions in these approximately 0.5 mL tumors provide a prediction of radiation curability independent of radiation dose. These data confirm the significance of EPR pO2 hypoxic fractions. The 90% control of low HF10 tumors argue that 0.5 mL subvolumes of tumors may be more sensitive to radiation and may need less radiation for high tumor control rates. Cancer Res; 73(17); 5328-35. ©2013 AACR.

Failure-probability driven dose painting

To demonstrate a data-driven dose-painting strategy based on the spatial distribution of recurrences in previously treated patients. The result is a quantitative way to define a dose prescription function, optimizing the predicted local control at constant treatment intensity. A dose planning study using the optimized dose prescription in 20 patients is performed. Patients treated at our center have five tumor subvolumes from the center of the tumor (PET positive volume) and out delineated. The spatial distribution of 48 failures in patients with complete clinical response after (chemo)radiation is used to derive a model for tumor control probability (TCP). The total TCP is fixed to the clinically observed 70% actuarial TCP at five years. Additionally, the authors match the distribution of failures between the five subvolumes to the observed distribution. The steepness of the dose-response is extracted from the literature and the authors assume 30% and 20% risk of subclinical involvement in the elective volumes. The result is a five-compartment dose response model matching the observed distribution of failures. The model is used to optimize the distribution of dose in individual patients, while keeping the treatment intensity constant and the maximum prescribed dose below 85 Gy. The vast majority of failures occur centrally despite the small volumes of the central regions. Thus, optimizing the dose prescription yields higher doses to the central target volumes and lower doses to the elective volumes. The dose planning study shows that the modified prescription is clinically feasible. The optimized TCP is 89% (range: 82%-91%) as compared to the observed TCP of 70%. The observed distribution of locoregional failures was used to derive an objective, data-driven dose prescription function. The optimized dose is predicted to result in a substantial increase in local control without increasing the predicted risk of toxicity.

Modelling the interplay between hypoxia and proliferation in radiotherapy tumour response

A tumour control probability computational model for fractionated radiotherapy was developed, with the goal of incorporating the fundamental interplay between hypoxia and proliferation, including reoxygenation over a course of radiotherapy. The fundamental idea is that the local delivery of oxygen and glucose limits the amount of proliferation and metabolically-supported cell survival a tumour sub-volume can support. The model has three compartments: a proliferating compartment of cells receiving oxygen and glucose; an intermediate, metabolically-active compartment receiving glucose; and a highly hypoxic compartment of starving cells. Following the post-mitotic cell death of proliferating cells, intermediate cells move into the proliferative compartment and hypoxic cells move into the intermediate compartment. A key advantage of the proposed model is that the initial compartmental cell distribution is uniquely determined from the assumed local growth fraction (GF) and volume doubling time (TD) values. Varying initial cell state distributions, based on the local (voxel) GF and TD, were simulated. Tumour response was simulated for head and neck squamous cell carcinoma using relevant parameter values based on published sources. The tumour dose required to achieve a 50% local control rate (TCD50) was found for various GFs and TD’s, and the effect of fraction size on TCD50 was also evaluated. Due to the advantage of reoxygenation over a course of radiotherapy, conventional fraction sizes (2–2.4 Gy fx−1) were predicted to result in smaller TCD50's than larger fraction sizes (4–5 Gy fx–1) for a 10 cc tumour with GFs of around 0.15. The time to eliminate hypoxic cells (the reoxygenation time) was estimated for a given GF and decreased as GF increased. The extra dose required to overcome accelerated stem cell accumulation in longer treatment schedules was estimated to be 0.68 Gy/day (in EQD26.6), similar to published values derived from clinical data. The model predicts, for a 2 Gy/weekday fractionation, that increased initial proliferation (high GF) should, surprisingly, lead to moderately higher local control values. Tumour hypoxia is predicted to increase the required dose for local control by approximately 30%. Predicted tumour regression patterns are consistent with clinical observations. This simple yet flexible model shows how the local competition for chemical resources might impact local control rates under varying fractionation conditions.

TU‐A‐WAB‐02: Arterial Perfusion Imaging‐Defined Aggressive Subvolume of Intrahepatic Cancer for Radiation Therapy

Purpose: To assess whether subvolumes of tumors extracted from hepatic arterial perfusion images can predict treatment outcome in radiation therapy (RT) of intrahepatic cancer. Methods: 21 patients who had 25 unresectable intrahepatic cancers and underwent focal RT were enrolled in a prospective IRB‐approved study of dynamic contrast‐enhanced (DCE) MRI. DCE MRI scans of the patients were acquired prior to RT, after delivering ∼60% planned doses and 1 month after the completion of RT. Hepatic arterial perfusion images were quantified by using a dual‐input single‐compartment pharmacokinetic model of DCE MRI. Each treated tumor was classified into the subvolumes with low‐normal, or high hepatic arterial perfusion. The changes in the subvolumes with high hepatic arterial perfusion and in the volumetric means of hepatic arterial perfusion over the whole tumors from pre‐RT to during‐RT were evaluated for differentiation of responsive and progressive tumors using Mann‐Whitney U test. The performance of the early changes in the new metrics for predicting tumor progression following treatment was evaluated by receiver operating characteristic (ROC) analysis. Results: Of the 25 tumors, 6 tumors in 5 patients progressed 5–21 months after the completion of RT, the other tumors responded to treatment. From pre‐RT to during‐RT, the tumor subvolumes with high hepatic arterial perfusion significantly increased (118%, p=0.007) in the progressive tumors compared to responsive ones. For predicting tumor progression, the change percentage in the tumor subvolume with high hepatic arterial perfusion had an area under curve (AUC) of 0.87 ± 0.09, while the change in mean hepatic arterial perfusion over the whole tumors had AUC of 0.85 ± 0.10. Conclusion: The tumor subvolume with high hepatic arterial perfusion could be an early predictor for treatment outcome in RT of intrahepatic cancer, and could be a candidate for radiation boost. (Supported by NIH grant RO1CA132834)

SU-F-500-02: Early Prediction of Brain Metastases Response to Radiation Therapy by Combination of Changes in Tumor Vascular and Cellularity Properties

Purpose: To investigate the impact of combining image-based measurements related to alterations of vascular and cellularity properties of brain metastases for early prediction of tumor response to radiation therapy (RT). Methods: 24 patients undergoing treatment for metastases had perfusion (DCE) and diffusion MRI scans. Tumor subvolumes with high regional cerebral blood volume (rCBV) and high Gd-DTAP transfer constant (Ktrans) were extracted. The apparent diffusion coefficient (ADC) histograms of the tumor volume were categorized into low, normal and high ADC subvolumes. Changes in different tumor subvolumes and their combination from pre-RT to week 2 after start of radiation were evaluated in differentiation of responsive, stable and progressive tumors for patients treated by either whole brain radiation therapy (WBRT, 28 lesions) alone or combined with Bortezomib as a radiation sensitizer (39 lesions). Receiver Operating Characteristic (ROC) analysis compared a combined perfusion/diffusion prediction model with changes in gross tumor volume (GTV) within the same time interval. Results: For lesions treated with WBRT alone, a decrease in both high cellularity and edema subvolumes were associated with response. A decrease in the tumor subvolumes with high cellularity and vascularity was associated with response in lesions treated with RT combined with Bortezomib. In ROC analysis, areas under curve (AUCs) of 0.96 (WBRT alone) and 0.96 (WBRT + Bortezomib) were seen in prediction of non-responsive lesions when changes in different subvolumes were combined. Also, GTV changes could predict the non-responsive lesions treated with WBRT alone (AUC = 0.91) but failed to predict the response in lesions treated with WBRT combined with Bortezomib (AUC = 0.57). Conclusion: Combining the changes in tumor cellularity and vascularity could be used for early prediction of brain metastases response to RT and perform better than the GTV changes, suggesting that physiological changes could occur earlier than the morphological changes. (Support: NIH RO1NS064973) NIH grant ROl NS064973

SU‐E‐T‐586: Brachytherapy Application with in Situ Dose‐Painting Administered Via Gold‐Nanoparticle Eluters (BANDAGE) for Prostate Cancer (PCa)

Purpose: A potential new therapeutic strategy to help prevent prostate cancer (PCa) recurrence involves loading routinely used brachytherapy spacers with non‐toxic/biocompatible radiosensitizing gold nanoparticles (GNPs), which can be sustainably released in situ for radiation boosting of high‐risk tumor subvolume. In this study, we investigated the intra‐tumor biodistribution and corresponding dose enhancement (DEF) over time for the released GNPs, as a function of nanoparticle size. Methods: An experimentally determined diffusion coefficient (D) for 10 nm nanoparticles in mouse PCa tumor model from previous studies was employed to estimate D for other sizes using the Stoke‐Einstein equation. The error function diffusion model in the experimental study was applied to generate the intratumor concentration profile for released GNPs from the spacer over time. The corresponding DEF profiles were then determined based on previously published results of DEF versus concentration when GNPs are employed during Pd‐103 and I‐125 brachytherapy. Results: As expected, the generated profiles showed greater DEF over time for smaller GNPs sizes at sample distances from the spacer. For example, for a centrally located spacer, clinically significant DEF (&gt; 20%) could be achieved near the tumor periphery (for average PCa tumor size of about 2 cm diameter) after 14, and 65 days, respectively for GNPs sizes 2 nm, and 10 nm, when treating with I‐125. Meanwhile for Pd‐103, clinically significant DEF could be achieved at the same position after 13, and 57 days, respectively, for 2 nm and 10 nm nanoparticles. Conclusion: Our preliminary results verify that intra‐tumor dose enhancement or sub‐volume boosting profiles can be customized by varying the sizes of nanoparticle released or eluted from nanoparticle‐loaded brachytherapy spacers. These results provide a useful reference for further studies towards development of Brachytherapy Application with in situ Dose‐painting Administered via Gold‐nanoparticle Eluters (BANDAGE) for prostate cancer.

WE‐C‐WAB‐03: Correspondence Between FDG‐PET and Diffusion‐Weighted MRI After Deformable Registration in Locally‐Advanced Non‐Small Cell Lung Cancer

Purpose: To develop and evaluate a framework for aligning diffusion‐weighted MR images (DWI) to CT and PET/CT in locally‐advanced lung cancer, and to evaluate the correspondence of FDG‐PET and DWI prior to radiation therapy. Methods: Pretreatment FDG‐PET/CT, 4D fan beam planning CT, and MR were acquired in five locally‐advanced lung cancer patients. Deformable registration was used to align the b=0 s/m2 DWI to a high‐resolution morphological MRI to reduce spatial distortion and respiratory effects. The morphological MRI was then registered to planning CT to map DWI to the planning CT reference frame. Apparent diffusion coefficient (ADC) was computed from DWI. PET/CT was also registered to planning CT. 40% of maximum lesion SUV (SUVmax) threshold was used to delineate primary tumor on PET, and a physician delineated the lesion on DWI. Dice coefficient between PET and DWI primary tumor volumes was computed to assess whole lesion location. To establish correspondence of tumor subvolumes, the region of 70% SUVmax on PET (high SUV) was delineated, and the ADC distribution from the spatially‐registered DWI extracted in this region. This process was repeated for the 40%–50% SUVmax (low SUV) region. Results: All registrations were judged visually acceptable. The PET and DWI‐defined primary tumor Dice coefficient was 0.6 +/‐0.1 after registration. The mean ADC corresponding to the high SUV region was lower than the mean ADC in the low SUV region in 4/5 patients (mean difference of −130 m2/s). One patient had higher ADC in the high SUV region, with a difference of 94 m2/s between regions. This patient had a highly heterogeneous lesion with small hyperintense pockets on ADC images indicating necrosis. Conclusion: Deformable registration of thoracic MR appears feasible to reduce the effects of distortion and motion artifacts. High SUV generally corresponded with the most restricted diffusion signal from DWI.

Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma

Background and purposeHypofractionated radiotherapy (RT) of pancreatic adenocarcinoma is limited by the tolerance of adjacent normal tissues. A better understanding of the influence of dosimetric variables on the rate of toxicity after RT must be considered an important goal. Methods and materialsSixty-one patients with histologically proven locally advanced disease (LAPD) were analyzed. The therapeutic strategy consisted of induction chemotherapy (ChT) followed by concurrent chemoradiotherapy (CRT). In 39 out of 61 patients the target volume was based on a four-dimensional CT (4D-CT) procedure. Delivered dose was 44.25Gy in 15 fractions to PTV2, which consisted of pancreatic tumor and regional lymph nodes considered radiologically involved; 23 out of 61 patients received a simultaneous integrated boost (SIB) to a tumor sub-volume infiltrating the great abdominal vessels (PTV1) with dose in the range of 48–58Gy. RT was delivered with Helical Tomotherapy. Dose–volume histograms (DVHs) of target volumes and organs at risk (OARs) were collected for analysis. The predictive value of clinical/dosimetric parameters was tested by univariate/multivariate analyses. ResultsThe crude incidence of acute gastrointestinal (GI) grade 2 toxicity was 33%. The 12-month actuarial rate of “anatomical” (gastro-duodenal mucosa damage) toxicity was 13% (95% CI: 4–22%). On univariate analysis, several stomach and duodenum DVH endpoints are predictive of toxicity after moderately hypofractionated radiotherapy. Multivariate analysis confirmed that baseline performance status and the stomach V20[%] were strong independent predictors of acute GI grade ⩾2 toxicity. The high-dose region of duodenum DVH (V45[%]; V40[%]) was strongly correlated with grade ⩾2 “anatomical” toxicity; the best V40[%] and V45[%] cut-off values were 16% and 2.6% respectively. ConclusionRegarding dosimetric indices, stomach V20[%] correlates with a higher rate of acute toxicity; more severe acute and late anatomical toxicities are related to the high dose region of duodenum DVH.