Determining optimal eluter design by modeling physical dose enhancement in brachytherapy

In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio.

The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for ¹²⁵ I permanent prostate implants. Compound concentrations were calculated using steady-state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (ϕ_b ). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (c_sat ). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion-elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other.

The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm³ , ϕ_b from 0.01 to 4 mm^-1 , c_sat from 0.05 to 7.5 times the steady-state compound concentration released from the surface of the eluter. The number of used eluters (n_e ) was simulated from 10 to 60 eluters. For the region of (c_sat , Φ)-space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (c_sat , Φ)-space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations.

Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.