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 emitter
213Bi. 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.