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. Xenograft cryosections of the prostate cancer cell line LNCaP treated with [Lu]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 Ac, Lu, and Y. 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. 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 Ac, Lu, and Y 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. 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.