A critical review of LET-based intensity- modulated proton therapy plan evaluation and optimization for head and neck cancer management

In this review article, we review the 3 important aspects of linear-energy-transfer (LET) in intensity-modulated proton therapy (IMPT) for head and neck (H&N) cancer management. Accurate LET calculation methods are essential for LET-guided plan evaluation and optimization, which can be calculated either by analytical methods or by Monte Carlo (MC) simulations. Recently, some new 3D analytical approaches to calculate LET accurately and efficiently have been proposed. On the other hand, several fast MC codes have also been developed to speed up the MC simulation by simplifying nonessential physics models and/or using the graphics processor unit (GPU)- acceleration approach. Some concepts related to LET are also briefly summarized including (1) dose-weighted versus fluence-weighted LET; (2) restricted versus unrestricted LET; and (3) microdosimetry versus macrodosimetry. LET-guided plan evaluation has been clinically done in some proton centers. Recently, more and more studies using patient outcomes as the biological endpoint have shown a positive correlation between high LET and adverse events sites, indicating the importance of LET-guided plan evaluation in proton clinics. Various LET-guided plan optimization methods have been proposed to generate proton plans to achieve biologically optimized IMPT plans. Different optimization frameworks were used, including 2-step optimization, 1-step optimization, and worst-case robust optimization. They either indirectly or directly optimize the LET distribution in patients while trying to maintain the same dose distribution and plan robustness. It is important to consider the impact of uncertainties in LET-guided optimization (ie, LET-guided robust optimization) in IMPT, since IMPT is sensitive to uncertainties including both the dose and LET distributions. We believe that the advancement of the LET-guided plan evaluation and optimization will help us exploit the unique biological characteristics of proton beams to improve the therapeutic ratio of IMPT to treat H&N and other cancers.