Tumor Control Probability and Small-Scale Monte Carlo Dosimetry: Effects of Heterogenous Intratumoral Activity Distribution in Radiopharmaceutical Therapy.

In radiopharmaceutical therapy, intratumoral uptake of radioactivity usually leads to heterogeneous absorbed dose distribution. The likelihood of treatment success can be estimated with the tumor control probability (TCP), which requires accurate dosimetry, estimating the absorbed dose rate per unit activity to individual tumor cells. Methods: Xenograft cryosections of the prostate cancer cell line LNCaP treated with [177Lu]Lu-PSMA-617 were evaluated with digital autoradiography and stained with hematoxylin and eosin. The digital autoradiography images were used to define the source in a Monte Carlo simulation of the absorbed dose, and the stained sections were used to detect the position of cell nuclei to relate the intratumoral absorbed dose heterogeneity to the cell density. Simulations were performed for 225Ac, 177Lu, and 90Y. TCP was calculated to estimate the mean necessary injected activity for a high TCP. A hypothetical case of activity mainly taken up on the tumor borders was generated and used to simulate the absorbed dose. Results: The absorbed dose per decay to tumor cells was calculated from the staining and simulation results to avoid underestimating the tumor response from low absorbed doses in tumor regions with low cell density. The mean of necessary injected activity to reach a 90% TCP for 225Ac, 177Lu, and 90Y was found to be 18.3 kBq (range, 18-22 kBq), 24.3 MBq (range, 20-29 MBq), and 5.6 MBq (range, 5-6 MBq), respectively. Conclusion: To account for the heterogeneous absorbed dose generated from nonuniform intratumoral activity uptake, dosimetry models can estimate the mean necessary activity to reach a sufficient TCP for treatment response. This approach is necessary to accurately evaluate the efficacy of suggested radiopharmaceuticals for therapy.

Small-scale dosimetry for alpha particle 241Am source cell irradiation and estimation of γ-H2AX foci distribution in prostate cancer cell line PC3.

BACKGROUND: The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets. Since a large variance is expected of alpha particle hits in individual cell nuclei irradiated by an uncollimated alpha-emitting source, the damage induced should have a similar distribution. The induction of DSB can be measured by immunofluorescent γ-H2AX staining. The cell γ-H2AX foci distribution and alpha particle hits distribution should be comparable and thereby verify the necessity to consider the relevant dosimetric volumes. METHODS: A Monte Carlo simulation model of an 241Am source alpha particle irradiation setup was combined with two versions of realistic cell nuclei phantoms. These were generated from DAPI-stained PC3 cells imaged with fluorescent microscopy, one consisting of elliptical cylinders and the other of segmented mesh volumes. PC3 cells were irradiated with the 241Am source for 4, 8 and 12 min, and after 30 min fixated and stained with immunofluorescent γ-H2AX marker. The detected radiation-induced foci (RIF) were compared to simulated RIF. RESULTS: The mesh volume phantom detected a higher mean of alpha particle hits and energy imparted (MeV) per cell nuclei than the elliptical cylinder phantom, but the mean specific energy (Gy) was very similar. The mesh volume phantom detected a slightly larger variance between individual cells, stemming from the more extreme and less continuous distribution of cell nuclei sizes represented in this phantom. The simulated RIF distribution from both phantoms was in good agreement with the detected RIF, although the detected distribution had a zero-inflated shape not seen in the simulated distributions. An estimate of undetected foci was used to correct the detected RIF distribution and improved the agreement with the simulations. CONCLUSION: Two methods to generate cell nuclei phantoms for Monte Carlo dosimetry simulations were tested and generated similar results. The simulated and detected RIF distributions from alpha particle-irradiated PC3 cells were in good agreement, proposing the necessity to consider microscopic targets in alpha particle dosimetry.

Preserving Preclinical PET Quality During Intratherapeutic Imaging in Radionuclide Therapy with Rose Metal Shielding Reducing Photon Flux.

Performing PET imaging during ongoing radionuclide therapy can be a promising method to follow tumor response in vivo. However, the high therapeutic activity can interfere with the PET camera performance and degrade both image quality and quantitative capabilities. As a solution, low-energy photon emissions from the therapeutic radionuclide can be highly attenuated, still allowing sufficient detection of annihilation photons in coincidence. Methods: Hollow Rose metal cylinders with walls 2-4 mm thick were used to shield a 22Na point source and a uniform phantom filled with 18F as they were imaged on a preclinical PET camera with increasing activities of 177Lu. A mouse with a subcutaneous tumor was injected with 18F-FDG and imaged with an additional 120 MBq of 177Lu and repeated with shields surrounding the animal. Results: The addition of 177Lu to the volume imaged continuously degraded the image quality with increasing activity. The image quality was improved when shielding was introduced. The shields showed a high ability to produce stable and reproducible results for both spatial resolution and quantification of up to 120 MBq of 177Lu activity (maximum activity tested). Conclusion: Without shielding, the activity quantification will be inaccurate for time points at which therapeutic activities are high. The suggested method shows that the shields reduce the noise induced by the 177Lu and therefore enable longitudinal quantitative intratherapeutic imaging studies.

Counting Rate Characteristics and Image Distortion in Preclinical PET Imaging During Radiopharmaceutical Therapy.

PET may provide important information on the response during radiopharmaceutical therapy (RPT). Emission of radiation from the RPT radionuclide may disturb coincidence detection and impair image resolution. In this study, we tested the feasibility of performing intratherapeutic PET on 3 preclinical PET systems. METHODS: Using 22Na point sources and phantoms filled with 18F, as well as a phantom filled with either 99mTc or 177Lu, we evaluated the coincidence counting rate and spatial resolution when both a PET and a therapeutic radionuclide were in the PET system. Because 99mTc has a suitable half-life and is easy obtainable, we used it as a substitute for a generic therapeutic radionuclide. RESULTS: High activities of 99mTc deteriorated the coincidence counting rate from the 18F-filled phantom and the 22Na point source on all 3 systems. The counting rate could be corrected to a high degree on one of the systems by its dead-time correction. Spatial resolution was degraded at high 99mTc activities for all systems. On one of the systems, 177Lu increased the coincidence counting rate and slightly affected the spatial resolution. The results for high 177Lu activities were similar to those for 99mTc. CONCLUSION: Intratherapeutic imaging might be a feasible method of studying the response to RPT. However, some sensitive preclinical PET systems, unable to handle high counting rates, will have count losses and may also introduce image artifacts.