WE-H-BRA-05: Investigation of LET Spectral Dependence of the Biological Effects of Therapeutic Protons




To investigate the dependence of biologic effect (BE) of therapeutic protons on LET spectra by comparing BEs with equal dose-averaged LET (LETd) derived from different LET spectra using high-throughput in vitro clonogenic survival assays.


We used Geant4 to design the relevant experimental setups and perform the dose, LETd, and LET spectra calculations for spot-scanning protons. The clonogenic assay was performed using the H460 lung cancer cell line cultured in 96-well plates. In the first experimental setup (S1), cells were irradiated using 127.4 MeV protons with a 93.22 mm Lucite buildup resulting in a LETd value of 3.4 keV/µm in the cell layer. In the second experimental setup (S2), cells were irradiated by a combination of 127.4 MeV and 136.4 MeV protons with a 96.61 mm Lucite buildup. The LETd values in the cell layer were 11.4 keV/µm and 1.5 keV/µm respectively, but an average LETd of 3.4 keV/µm was obtained by adjusting the relative fluence of each beam. Ten discrete dose levels with 0.5 Gy increments were delivered.


In the two setups, the energies or LET spectra were different but resulted in identical LETd values. We quantified the dose contributions from high-LET (≥10 keV/µm, threshold determined by previous experiments) events in the LET spectra separately for these two setups as 3.2% and 10.5%. The biologic effects at each identical dose level yielded statistically significant different survival curves (extra sum-of-squares F-test, P<0.0001). The second setup with a higher contribution from high-LET events exhibited the higher biologic effect with a dose enhancement factor of 1.17±0.03 at 0.10 surviving fraction.


The dose-averaged LET may not be an accurate indicator of the biological effects of protons. Detailed LET spectra may need to be considered explicitly to accurately quantify the biologic effects of protons.

Funding Support: U19 CA021239-35, R21 CA187484-01 and MDACC-IRG