A Besemer

Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer model systems

BACKGROUND AND PURPOSE CLR1404 is a phospholipid ether that exhibits selective uptake and retention in malignant tissues. Radiolabeled CLR1404 enables tumor-specific positron-emission tomography (PET) imaging ((124)I) and targeted delivery of ionizing radiation ((131)I). Here we describe the first preclinical studies of this diapeutic molecule in head and neck cancer (HNC) models. MATERIAL AND METHODS Tumor-selective distribution of (124)I-CLR1404 and therapeutic efficacy of (131)I-CLR1404 were tested in HNC cell lines and patient-derived xenograft tumor models. Monte Carlo dose calculations and (124)I-CLR1404 PET/CT imaging were used to examine (131)I-CLR1404 dosimetry in preclinical HNC tumor models. RESULTS HNC tumor xenograft studies including patient-derived xenografts demonstrate tumor-selective uptake and retention of (124)I-CLR1404 resulting in a model of highly conformal dose distribution for (131)I-CLR1404. We observe dose-dependent response to (131)I-CLR1404 with respect to HNC tumor xenograft growth inhibition and this effect is maintained together with external beam radiation. CONCLUSIONS We confirm the utility of CLR1404 for tumor imaging and treatment of HNC. This promising agent warrants further investigation in a developing phase I trial combining (131)I-CLR1404 with reduced-dose external beam radiation in patients with loco-regionally recurrent HNC.

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.

TU‐C‐BRB‐04: A Monte Carlo‐Based Small Animal Dosimetry Platform for Pre‐Clinical Trials: Proof of Concept

Purpose: The development of novel agents for targeted radionuclide therapy has led to an important need for accurate dosimetry characterization during pre‐clinical trials. The purpose of this study is to discuss our progress in developing a fully automated Monte Carlo‐based dosimetry platform for external and/or internal absorbed dose quantification in small animals. Methods: The dosimetry platform was built entirely around the Monte Carlo code Geant4 version 9.3. CT and PETimage datasets of a mouse injected with CLR1404, a novel tumor target pharmaceutical that is tagged with both I‐124 and I‐131 for imaging and therapy, were used for this preliminary study. The activity distribution in the tumor acquired from the PET scan was modeled as a simple spherical source. The same CTimage set was used to generate external dose distributions from a 6 MV photon beam spectrum. Results: The external dose distributions from the 6 MV photon source and the internal dose distributions from CLR1404 were combined to get a relative dose distribution within the mouse. Conclusions: We provided a proof‐of‐concept for a fully automated dose calculation platform in small animals that can be used for developing protocols for pre‐clinical trials. We are currently working on additional modifications to better represent both the external beam source for our small animal irradiator as well as the activity distributions gathered by the PET scan.

Radiation treatment planning and delivery strategies for a pregnant brain tumor patient

Abstract The management of a pregnant patient in radiation oncology is an infrequent event requiring careful consideration by both the physician and physicist. The aim of this manuscript was to highlight treatment planning techniques and detail measurements of fetal dose for a pregnant patient recently requiring treatment for a brain cancer. A 27‐year‐old woman was treated during gestational weeks 19–25 for a resected grade 3 astrocytoma to 50.4 Gy in 28 fractions, followed by an additional 9 Gy boost in five fractions. Four potential plans were developed for the patient: a 6 MV 3D‐conformal treatment plan with enhanced dynamic wedges, a 6 MV step‐and‐shoot (SnS) intensity‐modulated radiation therapy (IMRT) plan, an unflattened 6 MV SnS IMRT plan, and an Accuray TomoTherapy HDA helical IMRT treatment plan. All treatment plans used strategies to reduce peripheral dose. Fetal dose was estimated for each treatment plan using available literature references, and measurements were made using thermoluminescent dosimeters (TLDs) and an ionization chamber with an anthropomorphic phantom. TLD measurements from a full‐course radiation delivery ranged from 1.0 to 1.6 cGy for the 3D‐conformal treatment plan, from 1.0 to 1.5 cGy for the 6 MV SnS IMRT plan, from 0.6 to 1.0 cGy for the unflattened 6 MV SnS IMRT plan, and from 1.9 to 2.6 cGy for the TomoTherapy treatment plan. The unflattened 6 MV SnS IMRT treatment plan was selected for treatment for this particular patient, though the fetal doses from all treatment plans were deemed acceptable. The cumulative dose to the patients unshielded fetus is estimated to be 1.0 cGy at most. The planning technique and distance between the treatment target and fetus both contributed to this relatively low fetal dose. Relevant treatment planning strategies and treatment delivery considerations are discussed to aid radiation oncologists and medical physicists in the management of pregnant patients.

Development and Validation of RAPID: A Patient-Specific Monte Carlo Three-Dimensional Internal Dosimetry Platform

This work describes the development and validation of a patient-specific Monte Carlo internal dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry). RAPID utilizes serial PET/CT or SPECT/CT images to calculate voxelized three-dimensional (3D) internal dose distributions with the Monte Carlo code Geant4. RAPIDs dosimetry calculations were benchmarked against previously published S-values and specific absorbed fractions (SAFs) calculated for monoenergetic photon and electron sources within the Zubal phantom and for S-values calculated for a variety of radionuclides within spherical tumor phantoms with sizes ranging from 1 to 1000 g. The majority of the S-values and SAFs calculated in the Zubal Phantom were within 5% of the previously published values with the exception of a few 10 keV photon SAFs that agreed within 10%, and one value within 16%. The S-values calculated in the spherical tumor phantoms agreed within 2% for 177Lu, 131I, 125I, 18F, and 64Cu, within 3.5% for 211At and 213Bi, within 6.5% for 153Sm, 111In, 89Zr, and 223Ra, and within 9% for 90Y, 68Ga, and 124I. In conclusion, RAPID is capable of calculating accurate internal dosimetry at the voxel-level for a wide variety of radionuclides and could be a useful tool for calculating patient-specific 3D dose distributions.

Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in Triple-Negative Breast Cancer Patient

INTRODUCTION CLR1404 is a theranostic molecular agent that can be radiolabeled with 124I (CLR 124) for positron emission tomography (PET) imaging, or 131I (CLR 131) for single-photon emission computed tomography (SPECT) imaging and targeted radionuclide therapy. This pilot study evaluated a pretreatment dosimetry methodology in a triple-negative breast cancer patient who was uniquely enrolled in both a CLR 124 PET imaging clinical trial and a CLR 131 therapeutic dose escalation clinical trial. MATERIALS AND METHODS Three-dimensional PET/CT images were acquired at 1, 3, 24, 48, and 120 h postinjection of 178 MBq CLR 124. One month later, pretherapy 2D whole-body planar images were acquired at 0.25, 5, 24, 48, and 144 h postinjection of 370 MBq CLR 131. Following the therapeutic administration of 1990 MBq CLR 131, 3D SPECT/CT images were acquired at 74, 147, 334, and 505 h postinjection. The therapeutic CLR 131 voxel-level absorbed dose was estimated from PET (RAPID PET) and SPECT (RAPID SPECT) images using a Geant4-based Monte Carlo dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry), and region of interest (ROI) mean doses were also estimated using the OLINDA/EXM software based on PET (OLINDA PET), SPECT (OLINDA SPECT), and planar (OLINDA planar) images. RESULTS The RAPID PET and OLINDA PET tracer-predicted ROI mean doses correlated well (m ≥ 0.631, R2 ≥ 0.694, p ≤ 0.01) with both the RAPID SPECT and OLINDA SPECT therapeutic mean doses. The 2D planar images did not have any significant correlations. The ROI mean doses differed by -4% to -43% between RAPID and OLINDA/EXM, and by -19% to 29% between PET and SPECT. The 3D dose distributions and dose volume histograms calculated with RAPID were similar for the PET/CT and SPECT/CT. CONCLUSIONS This pilot study demonstrated that CLR 124 pretreatment PET images can be used to predict CLR 131 3D therapeutic dosimetry better than CLR 131 2D planar images. In addition, unlike OLINDA/EXM, Monte Carlo dosimetry methods were capable of accurately predicting dose heterogeneity, which is important for predicting dose-response relationships and clinical outcomes.

WE‐DE‐201‐06: Impact of Temporal Image Coregistration Methods On 3D Internal Dose Calculations in Targeted Radionuclide Therapy

PURPOSE The calculation of 3D internal dose calculations in targeted radionuclide therapy requires the acquisition and temporal coregistration of a serial PET/CT or SPECT/CT images. This work investigates the dosimetric impact of different temporal coregistration methods commonly used for 3D internal dosimetry. METHODS PET/CT images of four mice were acquired at 1, 24, 48, 72, 96, 144 hrs post-injection of 124 I-CLR1404. The therapeutic 131 I-CLR1404 absorbed dose rate (ADR) was calculated at each time point using a Geant4-based MC dosimetry platform using three temporal image coregistration METHODS: (1) no coregistration (NC), whole body sequential CT-CT affine coregistration (WBAC), and individual sequential ROI-ROI affine coregistration (IRAC). For NC, only the ROI mean ADR was integrated to obtain ROI mean doses. For WBAC, the CT at each time point was coregistered to a single reference CT. The CT transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the whole CT volume. For IRAC, each individual ROI was isolated and sequentially coregistered to a single reference ROI. The ROI transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the ROI volumes. RESULTS The percent differences in the ROI mean doses were as large as 109%, 88%, and 32%, comparing the WBAC vs. IRAC, NC vs. IRAC, and NC vs. WBAC methods, respectively. The CoV in the mean dose between the all three methods ranged from 2-36%. The pronounced curvature of the spinal cord was not adequately coregistered using WBAC which resulted in large difference between the WBAC and IRAC. CONCLUSION The method used for temporal image coregistration can result in large differences in 3D internal dosimetry calculations. Care must be taken to choose the most appropriate method depending on the imaging conditions, clinical site, and specific application. This work is partially funded by NIH Grant R21 CA198392-01.

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.

Abstract 4536: Combination external beam and internal radiation via 131I-CLR1404 in the treatment of head and neck squamous cell carcinoma xenografts.

Radiotherapy (RT) is a central treatment modality for head and neck cancer (HNC). However, optimal outcome is commonly limited by the radiation tolerance of adjacent normal tissue structures. Radiation is sometimes valuable in the setting of locoregional tumor recurrence, however the risk of significant normal tissue toxicity is substantial with repeat irradiation and can have a profound adverse impact on patient quality of life. Although technical advances including intensity modulated radiotherapy (IMRT) can reduce normal tissue effects, the problem of repeat exposure of normal tissues to radiation is frequently limiting. The radiolabeled drug 124/131I-CLR1404 is a phospholipid ether analogue (PLE) that accumulates preferentially within malignant tumors and enables internal delivery of radiation. This allows a combination of external and internal radiotherapy delivery with a goal of improving treatment outcome without enhanced normal tissue toxicities. In this study, we characterized the ability of 131I-CLR1404 to augment RT response using xenografted mice harboring human squamous cell carcinomas (SCC). We determined tumor growth delay as well as tumor and normal tissue dose distribution of 131I-CLR-1404 via Monte Carlo simulation using PET data generated with 124I-CLR1404 imaging. Tumor growth delay was extended by 15.5 days using combined 3.7MBq 131I-CLR1404 and RT compared to RT or 131I-CLR1404 alone. In combination therapy, single dose administration of 7.4 MBq 131I-CLR1404 as well as split dosing with 2 x 3.7 MBq separated by one week showed the same additional growth delay of 27 days compared to single dose of 3.7 MBq. Monitoring drug distribution via PET/CT showed high tumor selectivity with a tumor-to-liver ratio of 6.2±0.65 and a tumor-to-muscle ratio of 6.7±0.21. These data illustrate the tumor selectivity of the CLR1404 PLE delivery platform as well as augmentation of tumor response with combined RT and 131I-CLR1404 treatment. De-intensification of external beam radiation dose, with attendant reduction in normal tissue toxicities so common in HNC patients represents a central objective to be tested in controlled clinical trials with the ultimate goal of improving treatment outcome and quality of life for HNC patients. Citation Format: Jarob Saker, Eric Armstrong, Bryan Bednarz, Mohammed Farhoud, Abigail Besemer, Jamey Weichert, Paul Harari. Combination external beam and internal radiation via 131I-CLR1404 in the treatment of head and neck squamous cell carcinoma xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4536. doi:10.1158/1538-7445.AM2013-4536