Monte Carlo calculation of the maximum therapeutic gain of tumor antivascular alpha therapy

Purpose: Metastatic melanoma lesions experienced marked regression after systemic targeted alpha therapy in a phase 1 clinical trial. This unexpected response was ascribed to tumor antivascular alpha therapy (TAVAT), in which effective tumor regression is achieved by killing endothelial cells (ECs)...

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Bibliographic Details
Published in:Medical physics (Lancaster) 2012-03, Vol.39 (3), p.1282-1288
Main Authors: Huang, Chen-Yu, Oborn, Bradley M., Guatelli, Susanna, Allen, Barry J.
Format: Article
Language:English
Subjects:
ALPHA PARTICLES
Alpha Particles - therapeutic use
Biomedical modeling
BISMUTH 213
BLOOD
Blood Vessels - pathology
Blood Vessels - radiation effects
cancer
CAPILLARIES
Capillaries - pathology
Cell membranes
Cell nucleus
Cell Survival - radiation effects
cellular biophysics
CLINICAL TRIALS
Clinical Trials as Topic
Diffusion
dosimetry
Dosimetry/exposure assessment
endothelial cell
Endothelial Cells - radiation effects
ENERGY TRANSFER
Geant4
Humans
Melanoma - blood supply
Melanoma - pathology
Melanoma - radiotherapy
MELANOMAS
METASTASES
MICRODOSIMETRY
Monte Carlo
Monte Carlo calculations
MONTE CARLO METHOD
Monte Carlo methods
Monte Carlo simulations
patient treatment
probability
RADIATION DOSES
RADIOLOGY AND NUCLEAR MEDICINE
RADIOTHERAPY
Radiotherapy - methods
Therapeutic applications, including brachytherapy
Therapeutics
Tissues
TOXICITY
tumor antivascular alpha therapy
tumours
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Summary:Purpose: Metastatic melanoma lesions experienced marked regression after systemic targeted alpha therapy in a phase 1 clinical trial. This unexpected response was ascribed to tumor antivascular alpha therapy (TAVAT), in which effective tumor regression is achieved by killing endothelial cells (ECs) in tumor capillaries and, thus, depriving cancer cells of nutrition and oxygen. The purpose of this paper is to quantitatively analyze the therapeutic efficacy and safety of TAVAT by building up the testing Monte Carlo microdosimetric models. Methods: Geant4 was adapted to simulate the spatial nonuniform distribution of the alpha emitter213Bi. The intraluminal model was designed to simulate the background dose to normal tissue capillary ECs from the nontargeted activity in the blood. The perivascular model calculates the EC dose from the activity bound to the perivascular cancer cells. The key parameters are the probability of an alpha particle traversing an EC nucleus, the energy deposition, the lineal energy transfer, and the specific energy. These results were then applied to interpret the clinical trial. Cell survival rate and therapeutic gain were determined. Results: The specific energy for an alpha particle hitting an EC nucleus in the intraluminal and perivascular models is 0.35 and 0.37 Gy, respectively. As the average probability of traversal in these models is 2.7% and 1.1%, the mean specific energy per decay drops to 1.0 cGy and 0.4 cGy, which demonstrates that the source distribution has a significant impact on the dose. Using the melanoma clinical trial activity of 25 mCi, the dose to tumor EC nucleus is found to be 3.2 Gy and to a normal capillary EC nucleus to be 1.8 cGy. These data give a maximum therapeutic gain of about 180 and validate the TAVAT concept. Conclusions: TAVAT can deliver a cytotoxic dose to tumor capillaries without being toxic to normal tissue capillaries.
ISSN:0094-2405
2473-4209
DOI:10.1118/1.3681010