Abstract
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.
Highlights
Particle radiation therapy is a rapidly evolving technology
Many in vitro and in vivo studies have demonstrated the importance of the LET and variation of relative biological effectiveness (RBE) in proton therapy, especially for head and neck (H&N) cancer
We have focused on the advantages and disadvantages of different LET calculation methods from the points of view of accuracy, efficiency, and the relevance to biological effects in proton therapy
Summary
Compared with conventional photon-based radiation therapy, particle therapy has a significantly lower entrance to peak dose ratio, since most of the particle energy is released near the end of its range (Bragg peak). It is essential to develop an LET-based plan evaluation and optimization method for proton therapy This issue is especially relevant in cancer treatment of disease sites such as head and neck (H&N), where there are many OARs such as brainstem and optic-nerve structures in the proximity [24,25,26]. We will briefly review 3 topics related to LET calculation in the following 3 subsections: (1) analytical methods versus MC simulations; (2) dose-weighted average (LETD) versus fluence-weighted average (LETf); and (3) macroscopic versus microscopic dosimetry
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