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

Journal Article


Abstract


  • 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.

Publication Date


  • 2012

Citation


  • Huang, C., Oborn, B. M., Guatelli, S. & Allen, B. J. (2012). Monte Carlo calculation of the maximum therapeutic gain of tumor antivascular alpha therapy. Medical Physics, 39 (3), 1282-1288.

Scopus Eid


  • 2-s2.0-84863272302

Ro Metadata Url


  • http://ro.uow.edu.au/eispapers/11

Has Global Citation Frequency


Number Of Pages


  • 6

Start Page


  • 1282

End Page


  • 1288

Volume


  • 39

Issue


  • 3

Place Of Publication


  • United States

Abstract


  • 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.

Publication Date


  • 2012

Citation


  • Huang, C., Oborn, B. M., Guatelli, S. & Allen, B. J. (2012). Monte Carlo calculation of the maximum therapeutic gain of tumor antivascular alpha therapy. Medical Physics, 39 (3), 1282-1288.

Scopus Eid


  • 2-s2.0-84863272302

Ro Metadata Url


  • http://ro.uow.edu.au/eispapers/11

Has Global Citation Frequency


Number Of Pages


  • 6

Start Page


  • 1282

End Page


  • 1288

Volume


  • 39

Issue


  • 3

Place Of Publication


  • United States