Implementation of a real-time, ultrasound-guided prostate HDR brachytherapy program.

This work presents a comprehensive commissioning and workflow development process of a real-time, ultrasound (US) image-guided treatment planning system (TPS), a stepper and a US unit. To adequately benchmark the system, commissioning tasks were separated into (1) US imaging, (2) stepper mechanical, and (3) treatment planning aspects. Quality assurance US imaging measurements were performed following the AAPM TG-128 and GEC-ESTRO recommendations and consisted of benchmarking the spatial resolution, accuracy, and low-contrast detectability. Mechanical tests were first used to benchmark the electronic encoders within the stepper and were later expanded to evaluate the needle free length calculation accuracy. Needle reconstruction accuracy was rigorously evaluated at the treatment planning level. The calibration length of each probe was redundantly checked between the calculated and measured needle free length, which was found to be within 1 mm for a variety of scenarios. Needle placement relative to a reference fiducial and coincidence of imaging coordinate origins were verified to within 1 mm in both sagittal and transverse imaging planes. The source strength was also calibrated within the interstitial needle and was found to be 1.14% lower than when measured in a plastic needle. Dose calculations in the TPS and secondary dose calculation software were benchmarked against manual TG-43 calculations. Calculations among the three calculation methods agreed within 1% for all calculated points. Source positioning and dummy coincidence was tested following the recommendations of the TG-40 report. Finally, the development of the clinical workflow, checklists, and planning objectives are discussed and included within this report. The commissioning of real-time, US-guided HDR prostate systems requires careful consideration among several facets including the image quality, dosimetric, and mechanical accuracy. The TPS relies on each of these components to develop and administer a treatment plan, and as such, should be carefully examined.

Diagnosing atmospheric communication of a sealed monitor chamber.

Daily output variations of up to ±2% were observed for a protracted time on a Varian TrueBeam® STx; these output variations were hypothesized to be the result of atmospheric communication of the sealed monitor chamber. Daily changes in output relative to baseline, measured with an ionization chamber array (DQA3) and the amorphous silicon flat panel detector (IDU) on the TrueBeam®, were compared with daily temperature-pressure corrections (PTP ) determined from sensors within the DQA3. Output measurements were performed using a Farmer® ionization chamber over a 5-hour period, during which there was controlled variation in the monitor chamber temperature. The root mean square difference between percentage output change from baseline measured with the DQA3 and IDU was 0.50% over all measurements. Over a 7-month retrospective review of daily changes in output and PTP , weak correlation (R2  = 0.30) was observed between output and PTP for the first 5 months; for the final 2 months, daily output changes were linearly correlated with changes in PTP , with a slope of 0.84 (R2  = 0.89). Ionization measurements corrected for ambient temperature and pressure during controlled heating and cooling of the monitor chamber differed from expected values for a sealed monitor chamber by up to 4.6%, but were consistent with expectation for an air-communicating monitor chamber within uncertainty (1.3%, k = 2). Following replacement of the depressurized monitor chamber, there has been no correlation between daily percentage change in output and PTP (R2  = 0.09). The utility of control charts is demonstrated for earlier identification of changes in the sensitivity of a sealed monitor chamber.

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

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 patient's 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.

Minimum dose rate estimation for pulsed FLASH radiotherapy: A dimensional analysis.

PURPOSE/OBJECTIVES: To provide an order of magnitude estimate of the minimum dose rate ( R min ) required by pulsed ultra-high dose rate radiotherapy (FLASH RT) using dimensional analysis. MATERIALS/METHODS: In this study, we postulate that radiation-induced transient hypoxia inside normal tissue cells during FLASH RT results in better normal tissue sparing over conventional dose rate radiotherapy. We divide the process of cell irradiation by an ultra-short radiation pulse into three sequential phases: (a) The radiation pulse interacts with the normal tissue cells and produces radiation-induced species. (b) The radiation-induced species react with oxygen molecules and reduce the cell environmental oxygen concentration ( O 2 ). (c) Oxygen molecules, from nearest capillaries, diffuse slowly back into the resulted low O 2 regions. By balancing the radiation-induced oxygen depletion in phase II and diffusion-resulted O 2 replenishment in phase III, we can estimate the maximum allowed pulse repetition interval to produce a pulse-to-pulse superimposed O 2 reduction against the baseline O 2 . If we impose a threshold in radiosensitivity reduction to achieve clinically observable radiotherapy oxygen effect and combine the processes mentioned above, we could estimate the R min required for pulsed FLASH RT through dimensional analysis. RESULTS: The estimated R min required for pulsed FLASH RT is proportional to the product of the oxygen diffusion coefficient and O 2 inside the cell, and inversely proportional to the product of the square of the oxygen diffusion distance and the drop of intracellular O 2 per unit radiation dose. Under typical conditions, our estimation matches the order of magnitude with the dose rates observed in the recent FLASH RT experiments. CONCLUSIONS: The R min introduced in this paper can be useful when designing a FLASH RT system. Additionally, our analysis of the chemical and physical processes may provide some insights into the FLASH RT mechanism.

Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in a 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.

Preclinical Pharmacokinetics and Dosimetry Studies of 124I/131I-CLR1404 for Treatment of Pediatric Solid Tumors in Murine Xenograft Models.

Cancer is the second leading cause of death for children between the ages of 5 and 14 y. For children diagnosed with metastatic or recurrent solid tumors, for which the utility of external-beam radiotherapy is limited, the prognosis is particularly poor. The availability of tumor-targeting radiopharmaceuticals for molecular radiotherapy (MRT) has demonstrated improved outcomes in these patient populations, but options are nonexistent or limited for most pediatric solid tumors. 18-(p-iodophenyl)octadecylphosphocholine (CLR1404) is a novel antitumor alkyl phospholipid ether analog that broadly targets cancer cells. In this study, we evaluated the in vivo pharmacokinetics of 124I-CLR1404 (CLR 124) and estimated theranostic dosimetry for 131I-CLR1404 (CLR 131) MRT in murine xenograft models of the pediatric solid tumors neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Methods: Tumor-bearing mice were imaged with small-animal PET/CT to evaluate the whole-body distribution of CLR 124 and, correcting for differences in radioactive decay, predict that of CLR 131. Image volumes representing CLR 131 provided input for Geant4 Monte Carlo simulations to calculate subject-specific tumor dosimetry for CLR 131 MRT. Pharmacokinetics for CLR 131 were extrapolated to adult and pediatric humans to estimate normal-tissue dosimetry. In neuroblastoma, a direct comparison of CLR 124 with 124I-metaiodobenzylguanidine (124I-MIBG) in an MIBG-avid model was performed. Results: In vivo pharmacokinetics of CLR 124 showed selective uptake and prolonged retention across all pediatric solid tumor models investigated. Subject-specific tumor dosimetry for CLR 131 MRT presents a correlative relationship with tumor-growth delay after CLR 131 MRT. Peak uptake of CLR 124 was, on average, 22% higher than that of 124I-MIBG in an MIBG-avid neuroblastoma model. Conclusion: CLR1404 is a suitable theranostic scaffold for dosimetry and therapy with potentially broad applicability in pediatric oncology. Given the ongoing clinical trials for CLR 131 in adults, these data support the development of pediatric clinical trials and provide detailed dosimetry that may lead to improved MRT treatment planning.

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. RAPID's 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.

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.

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.

The clinical impact of uncertainties in the mean excitation energy of human tissues during proton therapy.

Uncertainties in the estimated mean excitation energies (I-values) needed for calculating proton stopping powers can be in the order of 10-15%, which introduces a fundamental limitation in the accuracy of proton range determination. Previous efforts have quantified shifts in proton depth dose distributions due to I-value uncertainties in water and homogenous tissue phantoms. This study is the first to quantify the clinical impact of I-value uncertainties on proton dose distributions within patient geometries. A previously developed Geant4 based Monte Carlo code was used to simulate a proton treatment plan for three patients (prostate, pancreases, and liver) with varying tissue I-values. A uniform variation study was conducted in which the tissue I-values were varied by ±5% and ±10% of the nominal values as well as a probabilistic variation study in which the I-values were randomly sampled according to a normal distribution with the mean equal to the nominal I-value and a standard deviation of 5 and 10% of the nominal values. Modification of tissue I-values impacted both the proton range and SOBP width. R(90) range shifts up to 7.7 mm (4.4.%) and R(80) range shifts up to 4.8 mm (1.9%) from the nominal range were recorded. Modulating the tissue I-values by 10% the nominal value resulted in up to a 3.5% difference mean dose in the target volumes and organs at risk compared to the nominal case. The range and dose differences were the largest for the deeper-seated prostate and pancreas cases. The treatments that were simulated with randomly sampled I-values resulted in range and dose differences that were generally within the upper and lower bounds set by the 10% uniform variations. This study demonstrated the impact of I-value uncertainties on patient dose distributions. Clearly, sub-millimeter precision in proton therapy would necessitate a reduction in I-value uncertainties to ensure an efficacious clinical outcome.