Linear energy transfer optimized proton therapy for rectal cancer

To evaluate the feasibility and utility of an LET-optimized proton treatment planning algorithm in locally advanced rectal cancer and to assess whether the degree of LET-optimization achieved in clinical plans improves efficacy and toxicity in preclinical models.

A series of five rectal cancer patients treated with standard 25 fraction clinical proton plans were re-planned using an LET-optimization treatment planning algorithm and evaluated for dosimetric endpoints. LET-optimized plans were generated using an algorithm which iteratively increases the weights of higher LET spots in GTV and lower LET in OARs. Murine and in vitro preclinical models of tumor efficacy and normal tissue toxicity were evaluated using comparable LET_d range to that achieved in clinical LET-optimized plans.

LET-optimized proton plans increased dose-averaged LET (LET_d) in the GTV and LET-weighted dose in the GTV, and CTV_5625cGy V_100% coverage. At the same time, LET-optimization also decreased mean LET-weighted dose to bladder and small bowel, as well as small bowel V_30Gy(cc) compared to standard proton plans. Optimizing the LET_d to a volume of GTV-3 mm further increased LET_d compared to total GTV. LET-optimization in preclinical models increased tumor efficacy in colorectal cancer cell lines in vitro and decreased small bowel radiation enteropathy in murine models of normal tissue toxicity.

LET-optimized proton plans increased LET_d in gross tumor while maintaining or improving target coverage and OAR sparing, with acceptable plan robustness. Preclinical models demonstrated that comparable LET-optimization may increase tumor efficacy and decrease normal tissue toxicity in rectal cancer.