Benjamin Titz

An imaging-based tumour growth and treatment response model: Investigating the effect of tumour oxygenation on radiation therapy response

A multiscale tumour simulation model employing cell-line-specific biological parameters and functional information derived from pre-therapy PET/CT imaging data was developed to investigate effects of different oxygenation levels on the response to radiation therapy. For each tumour voxel, stochastic simulations were performed to model cellular growth and therapeutic response. Model parameters were fitted to published preclinical experiments of head and neck squamous cell carcinoma (HNSCC). Using the obtained parameters, the model was applied to a human HNSCC case to investigate effects of different uniform and non-uniform oxygenation levels and results were compared for treatment efficacy. Simulations of the preclinical studies showed excellent agreement with published data and underlined the models ability to quantitatively reproduce tumour behaviour within experimental uncertainties. When using a simplified transformation to derive non-uniform oxygenation levels from molecular imaging data, simulations of the clinical case showed heterogeneous tumour response and variability in radioresistance with decreasing oxygen levels. Once clinically validated, this model could be used to transform patient-specific data into voxel-based biological objectives for treatment planning and to investigate biologically optimized dose prescriptions.

Alkylphosphocholine Analogs for Broad-Spectrum Cancer Imaging and Therapy

Tumor-specific alkylphosphocholine analogs were evaluated as imaging and therapy agents in patients and in animal models of human cancer. A Broad View of Cancer Many consider targeted or molecular imaging to be the optimal way to image cancer. Weichert and colleagues feel differently: Uptake of certain small molecules by all cancer cells can give a broad view of cancer, and perhaps also treat it. These small molecules are alkylphosphocholine (APC) analogs, which are taken up preferentially by cancer cells—as compared to, for example, fibroblasts—via plasma membranes and transported into the cells by lipid rafts. The authors tested the uptake of radiolabeled APC analogs in vitro and in vivo in animals in 57 different spontaneous and transgenic tumors, of both human and rodent origin. Because of the well-established efficacy of radiotherapy, the authors demonstrated that the APC analogs could be used to not only visualize tumors but also kill them. Translating this to cancer patients, Weichert et al. showed preliminary preferential uptake of a radiolabeled APC analog in brain tumors. These broadly applicable imaging and therapeutic APC-based agents have been tested in dozens of different human cancers, and preliminarily in people, and are now well poised for further translation to clinical trials. Many solid tumors contain an overabundance of phospholipid ethers relative to normal cells. Capitalizing on this difference, we created cancer-targeted alkylphosphocholine (APC) analogs through structure-activity analyses. Depending on the iodine isotope used, radioiodinated APC analog CLR1404 was used as either a positron emission tomography (PET) imaging (124I) or molecular radiotherapeutic (131I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. 131I-CLR1404 also displayed efficacy (tumor growth suppression and survival extension) in a wide range of human tumor xenograft models. Human PET/CT (computed tomography) and SPECT (single-photon emission computed tomography)/CT imaging in advanced-cancer patients with 124I-CLR1404 or 131I-CLR1404, respectively, demonstrated selective uptake and prolonged retention in both primary and metastatic malignant tumors. Combined application of these chemically identical APC-based radioisosteres will enable personalized dual modality cancer therapy of using molecular 124I-CLR1404 tumor imaging for planning 131I-CLR1404 therapy.

A Phase 1 Study of 131I-CLR1404 in Patients with Relapsed or Refractory Advanced Solid Tumors: Dosimetry, Biodistribution, Pharmacokinetics, and Safety

Introduction 131I-CLR1404 is a small molecule that combines a tumor-targeting moiety with a therapeutic radioisotope. The primary aim of this phase 1 study was to determine the administered radioactivity expected to deliver 400 mSv to the bone marrow. The secondary aims were to determine the pharmacokinetic (PK) and safety profiles of 131I-CLR1404. Methods Eight subjects with refractory or relapsed advanced solid tumors were treated with a single injection of 370 MBq of 131I-CLR1404. Whole body planar nuclear medicine scans were performed at 15–35 minutes, 4–6, 18–24, 48, 72, 144 hours, and 14 days post injection. Optional single photon emission computed tomography imaging was performed on two patients 6 days post injection. Clinical laboratory parameters were evaluated in blood and urine. Plasma PK was evaluated on 127I-CLR1404 mass measurements. To evaluate renal clearance of 131I-CLR1404, urine was collected for 14 days post injection. Absorbed dose estimates for target organs were determined using the RADAR method with OLINDA/EXM software. Results Single administrations of 370 MBq of 131I-CLR1404 were well tolerated by all subjects. No severe adverse events were reported and no adverse event was dose-limiting. Plasma 127I-CLR1404 concentrations declined in a bi-exponential manner with a mean t½ value of 822 hours. Mean Cmax and AUC(0-t) values were 72.2 ng/mL and 15753 ng•hr/mL, respectively. An administered activity of approximately 740 MBq is predicted to deliver 400 mSv to marrow. Conclusions Preliminary data suggest that 131I-CLR1404 is well tolerated and may have unique potential as an anti-cancer agent. Trial Registration ClinicalTrials.gov NCT00925275

Impact of PET and MRI threshold-based tumor volume segmentation on patient-specific targeted radionuclide therapy dosimetry using CLR1404

Variations in tumor volume segmentation methods in targeted radionuclide therapy (TRT) may lead to dosimetric uncertainties. This work investigates the impact of PET and MRI threshold-based tumor segmentation on TRT dosimetry in patients with primary and metastatic brain tumors. In this study, PET/CT images of five brain cancer patients were acquired at 6, 24, and 48 h post-injection of 124I-CLR1404. The tumor volume was segmented using two standardized uptake value (SUV) threshold levels, two tumor-to-background ratio (TBR) threshold levels, and a T1 Gadolinium-enhanced MRI threshold. The dice similarity coefficient (DSC), jaccard similarity coefficient (JSC), and overlap volume (OV) metrics were calculated to compare differences in the MRI and PET contours. The therapeutic 131I-CLR1404 voxel-level dose distribution was calculated from the 124I-CLR1404 activity distribution using RAPID, a Geant4 Monte Carlo internal dosimetry platform. The TBR, SUV, and MRI tumor volumes ranged from 2.3-63.9 cc, 0.1-34.7 cc, and 0.4-11.8 cc, respectively. The average  ±  standard deviation (range) was 0.19  ±  0.13 (0.01-0.51), 0.30  ±  0.17 (0.03-0.67), and 0.75  ±  0.29 (0.05-1.00) for the JSC, DSC, and OV, respectively. The DSC and JSC values were small and the OV values were large for both the MRI-SUV and MRI-TBR combinations because the regions of PET uptake were generally larger than the MRI enhancement. Notable differences in the tumor dose volume histograms were observed for each patient. The mean (standard deviation) 131I-CLR1404 tumor doses ranged from 0.28-1.75 Gy GBq-1 (0.07-0.37 Gy GBq-1). The ratio of maximum-to-minimum mean doses for each patient ranged from 1.4-2.0. The tumor volume and the interpretation of the tumor dose is highly sensitive to the imaging modality, PET enhancement metric, and threshold level used for tumor volume segmentation. The large variations in tumor doses clearly demonstrate the need for standard protocols for multimodality tumor segmentation in TRT dosimetry.

WE‐EF‐BRA‐04: Evaluation of Dosimetric Uncertainties in Individualized Targeted Radionuclide Therapy (TRT) Treatment Planning Using Pre‐Clinical Data

Purpose: Dosimetry for targeted radionuclide therapy (TRT) is moving away from conventional model-based methods towards patient-specific approaches. To address this need, a Monte Carlo (MC) dosimetry platform was developed to estimate patient-specific therapeutic 3D dose distributions based on pre-treatment imaging. However, because a standard practice for patient-specific internal dosimetry has not yet been established, there are many sources of dosimetric uncertainties. The goal of this work was to quantify the sensitivity of various parameters on MC dose estimations. Methods: The ‘diapeutic’ agent, CLR1404, was used as a proof-of-principle compound in this work. CLR1404 can be radiolabeled with either 1 2⁴I for PET imaging or 1 3 1I for radiotherapy or SPECT imaging. PET/CT images of 5 mice were acquired out to 240 hrs post-injection of 1 2⁴I-CLR1404. The therapeutic 1 3 1I-CLR1404 absorbed dose (AD) distribution was calculated using a Geant4-based MC dosimetry platform. A series of sensitivity studies were performed. The variables that were investigated included the PET/CT voxel resolution, partial volume corrections (PVC), material segmentation, inter-observer contouring variability, and the pre-treatment image acquisition frequency. Results: Resampling the PET/CT voxel size between 0.2–0.8 mm resulted in up to a 13% variation in the mean AD. Application of the PVC increased the mean AD by 0.5–11.2%. Less than 1% differences in ROI mean AD were observed between the tissue segmentation schemes using 4 and 27 different material compositions. Inter-observer contouring variability led to up to a 20% CoV (stdev/mean) in the mean AD between the users. Varying the number and frequency of pre-treatment images used resulted in changes in mean AD up to 176% compared to the case using all 12 images. Conclusion: Voxel resolution, contour segmentation, the image acquisition protocol most significantly impacted patient-specific TRT dosimetry. Further work is needed to develop a standard protocol that optimizes accuracy and efficiency for patient-specific internal dosimetry. BT and JG are affiliated with Cellectar Biosciences which owns the licensing rights to CLR1404 and related compounds.

MO-G-BRF-05: Determining Response to Anti-Angiogenic Therapies with Monte Carlo Tumor Modeling

PURPOSE Patient response to anti-angiogenic therapies with vascular endothelial growth factor receptor - tyrosine kinase inhibitors (VEGFR TKIs) is heterogeneous. This study investigates key biological characteristics that drive differences in patient response via Monte Carlo computational modeling capable of simulating tumor response to therapy with VEGFR TKI. METHODS VEGFR TKIs potently block receptors, responsible for promoting angiogenesis in tumors. The model incorporates drug pharmacokinetic and pharmacodynamic properties, as well as patientspecific data of cellular proliferation derived from [18F]FLT-PET data. Sensitivity of tumor response was assessed for multiple parameters, including initial partial oxygen tension (pO2 ), cell cycle time, daily vascular growth fraction, and daily vascular regression fraction. Results were benchmarked to clinical data (patient 2 weeks on VEGFR TKI, followed by 1-week drug holiday). The tumor pO2 was assumed to be uniform. RESULTS Among the investigated parameters, the simulated proliferation was most sensitive to the initial tumor pO2 . Initial change of 5 mmHg can already Result in significantly different levels of proliferation. The model reveals that hypoxic tumors (pO2 ≥ 20 mmHg) show the highest decrease of proliferation, experiencing mean FLT standardized uptake value (SUVmean) decrease for at least 50% at the end of the clinical trial (day 21). Oxygenated tumors (pO2 20 mmHg) show a transient SUV decrease (30-50%) at the end of the treatment with VEGFR TKI (day 14) but experience a rapid SUV rebound close to the pre-treatment SUV levels (70-110%) at the time of a drug holiday (day 14-21) - the phenomenon known as a proliferative flare. CONCLUSION Models high sensitivity to initial pO2 clearly emphasizes the need for experimental assessment of the pretreatment tumor hypoxia status, as it might be predictive of response to antiangiogenic therapies and the occurrence of proliferative flare. Experimental assessment of other model parameters would further improve understanding of patient response.

TU‐E‐141‐08: Dosimetric Impact of Partial Volume Correction On PET‐Based Targeted Radionuclide Therapy Planning

PURPOSE Partial volume effects have been shown to introduce a significant error in positron emission tomography (PET) quantitation. In this study, we investigated the impact of PET partial volume correction (PVC) on the dosimetry of PET-based targeted radionuclide therapy (TRT) planning. METHODS Five tumor-bearing nude mice were injected with ∼230 μCi of a 124 I-CLR1404, a small-molecule, phospholipid ether analog featuring selective retention and accumulation in malignant cells. PET/CT data were acquired at 1, 6, 12, 24, 36, 48, 60, 72, 96, 120, 168, and 240 hours post injection and reconstructed with and without PVC using an OSEM3D algorithm. Assuming identical uptake between 124 I-CLR1404 and its therapeutic analog, 131 I-CLR1404, absorbed doses of 131 I-CLR1404 were modeled by applying a piecewise trapezoidal integration to the 124 I-CLR1404 kinetics. Dose volume histograms (DVHs) and normalized differential DVHs (dDVHs) were used to quantify the impact of PVC on PET-based TRT planning. RESULTS Partial volume corrected PET images showed higher tumor uptake, increased the recovery of tumor heterogeneity structures, and a generally improved recovery of small normal tissue structures such as the heart ventricles. In tumors, the mean and maximum 124 I-CLR1404 standardized uptake value at peak drug concentration increased by 1.95±0.86% and 34.97±9.36%, respectively. DVHs of planned 131 I-CLR1404 doses showed an increase in maximum tumor dose levels by 15.63±3.53% due to PVC. Tumor dDVHs confirmed a shift towards higher therapeutic doses with an average increase of 13.09±1.21 mGy per mCi of injected 131 I-CLR1404 activity. CONCLUSION PVC of PET data more accurately recovered the biodistribution of 124 I-CLR1404 and thus further improved TRT planning and delivery by increasing the quantitative accuracy. PVC will especially benefit the identification of cold spots in the target volume and the dose estimation in dose limiting organs. JJG and JPWare affiliated with Novelos Therapeutics, Inc., which owns the licensing rights to CLR1404 and related compounds.

TH‐C‐220‐08: Simulating the Effects of Molecular Targeted Drugs on Tumor and Vasculature Development Using An Imaging‐Based, Computational Model

Purpose: Molecular targeted therapies affecting tumor and vasculature are currently used as anti‐cancer strategies. However, their effect on the tumor‐ vasculature system is currently poorly understood and quantified. We developed an imaging‐basedcomputational model to simulate tumor and vasculature development, and investigated the effects of Sunitinib, an anti‐ angiogenic receptor tyrosine kinase inhibitor, in silico. Methods: PET scans of tumor hypoxia ([61Cu]Cu‐ATSM) and proliferation ([18F]FLT) were taken as model input. The hypoxia scan reflecting tumor oxygenation (pO2) was used to simulate initial tumor vasculature. Vessel growth rate and tumorcell division probability were hypoxia dependent. The proliferation scan determined the tumorcell division rate. Vascular regression was Sunitinib dependent and tumor cell death hypoxia dependent. Tumor volume and oxygenation were temporally evaluated for drug dosage of 0, 10 and 40 mg/kg/day and therapy discontinuation. Results: Dose dependent changes in tumor pO2 and volume could be observed by day 2 and 5 respectively, indicating a 3 day lag between micro‐environmental and physical characteristic changes. As compared to an untreated tumor, 40 mg/kg/day dosage was twice as effective in decreasing tumor pO2 as compared to 10 mg/kg/day dosage. Discontinuation of therapy on day 5 lead to increase in the tumor pO2, with both regimen pO2 tending to the pO2 of an untreated tumor. The rebound rate of pO2 for the 40 mg/kg/day regimen was four times that of the 10 mg/kg/day dosage. Conclusions: Discontinuation of more aggressive therapy leads to a faster rebound of tumor pO2 due to increased vessel recruitment rate which eventually increases in tumor volume. The model being a part of a more comprehensive tumor‐vascular model will be useful for providing insight into the effects of therapy on the tumor‐vasculature system. Incorporation of patient specific parameters enables the model to be used as a potential tool for tailoring therapy in future.

MO‐E‐BRB‐01: Development of a Computational Model for Quantifying Vascular Response to TKI Therapy

Purpose: Tyrosine kinase inhibitors (TKIs) which target tumor vasculature have emerged as potential anti‐cancer drugs. However their effect on the vasculature and tumor oxygenation status currently lacks proper quantification. We developed a computational model to analyze and quantify changes in vasculature and tumor oxygenation in response to TKI therapy. Method and Materials: A three dimensional capillary structure was simulated and capillaries were classified as either mature or immature. Two effects of the TKI drug were simulated: vessel maturation and vessel regression. The initial proportion of mature vessels and vessel maturation fraction during therapy and were user‐defined model parameters. Dose dependent vessel regression was simulated based on preclinical experimental data regarding the TKI drug sunitinib. The tissue oxygen tension (pO2) from the modified vasculature was calculated and analyzed as a function of drug concentration, maturation fraction and initial state of vascular maturity. Results:Tumor hypoxia was observed to increase with increased drug dosage up to a dose of 50 mg/kg/day. Further increase in dose did not affect the mean tumor oxygen tension significantly. As a model parameter, vessel maturation fraction was most effective in increasing the tissue pO2 when the status of the initial vasculature was highly immature. Varying vessel maturation fraction (0 – 100%) resulted in a sevenfold increase in the mean tissue pO2when the initial vasculature maturity was set to 10% as compared to a twofold increase when the initial maturity was set to 50%. Conclusion: The model suggests that TKIs have a more significant effect on vasculature when the initial vessel structure is highly immature. This model presents a key step in the development of a comprehensive vasculature model which can be used to tumor vasculature interactions during TKI therapy, and provide insight into the effects of therapy on the tumor vasculature system.

MO‐E‐BRB‐05: A Computational Tumor Modeling Framework for the Optimization of Molecular Targeted Therapies

Purpose: Current treatment schedules of molecular targeted therapies are established through costly clinical trials. Although several dosing schemes are used clinically, optimal dosing regimens remain unknown. We developed a computational tumor modeling framework to compare dosing schedules based on simulated therapeutic response. Method and Materials: A pharmacokinetic/pharmacodynamic model was developed to simulate changes in tumorcell proliferation and vascular function. The model was applied to data from a clinical trial in which patients received sunitinib, a molecular targeted agent with anti‐angiogenic and anti‐proliferative effects, on a 4/2 (4 weeks on, 2 week break) or 2/1 schedule. Using [18F]FLT PET/CT imaging, levels of tumor proliferation and vascular function were assessed at baseline, peak drug exposure, and during treatment break. After testing the model on data from the 4/2 schedule, we compared simulated therapeutic responses for these dosing regimens: 4/2 cycle, two consecutive 2/1 cycles, and continuous dosing. Results: Trends in proliferative response were successfully simulated within one standard error of the population means. Two consecutive 2/1 cycles resulted in a 12% greater decrease in tumor proliferation as compared to one 4/2 cycle due to decreased drug washout during the off‐drug period. For iso‐response conditions, the dose for the 2/1 schedule could be reduced to 80% of the 4/2 schedule (from 50mg/kg/day to 40mg/kg/day). Continuous dosing using lower daily doses (32.5mg/kg/day) yielded the best growth inhibition after 6 weeks. Conclusion: The implemented model successfully reproduced trends in proliferative response observed in patients receiving sunitinib. Continuous dosing yielded the best growth inhibition, and outperformed two consecutive 2/1 cycles and the 4/2 regimen, indicating that this regimen might be favorable, especially for patients requiring lower daily doses to manage toxic side effects. Upon successful validation, the implemented model could serve as a cost‐effective tool to help identify improved drug regimens.