title: Monte Carlo calculation of the maximum therapeutic gain of tumor antivascular alpha therapy.
abstract: OBJECTIVE
  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 (213)Bi. 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.
authors.affiliation: University of New South Wales, Kogarah, New South Wales, Australia.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Oborn
authors.forename: Susanna
authors.initials: S
authors.lastname: Guatelli
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Allen
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D001808:Blood Vessels / Q000473:pathology / Q000528:radiation effects*; D002196:Capillaries / Q000473:pathology; D002470:Cell Survival / Q000528:radiation effects; D002986:Clinical Trials as Topic; D042783:Endothelial Cells / Q000528:radiation effects; D006801:Humans; D008545:Melanoma / Q000098:blood supply* / Q000473:pathology / Q000532:radiotherapy*; D009010:Monte Carlo Method; D011878:Radiotherapy / Q000379:methods*