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Dose-Dependent LET Constraints and Constraint Resolution for Interpreting Proton Therapy Toxicity.

Hong Qi Tan¹, Calvin Wei Yang Koh², Kah Seng Lew³

¹Division of Radiation Oncology, National Cancer Centre Singapore, Singapore; Division of Physics and Applied Physics, School of Physical and Mathematical Science, Nanyang Technological University, Singapore; Oncology Academic Clinical Programme, Duke-NUS Medical School, Singapore.

International Journal of Radiation Oncology, Biology, Physics

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Summary

Probabilistic dose-averaged linear energy transfer (LET_D) constraints offer a biologically consistent approach to proton therapy, improving upon single-value thresholds by accounting for dose and LET dependencies in normal tissue toxicity.

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Area of Science:

Radiation Oncology
Medical Physics
Radiobiology

Background:

Dose-averaged linear energy transfer (LET_D) is crucial for predicting normal tissue toxicity in proton therapy.
Current LET_D constraints often use single-value thresholds, neglecting the coupled dose-LET relationship vital for biological effects.

Purpose of the Study:

Develop and evaluate a probabilistic framework for dose-dependent LET_D constraints.
Assess the consistency of these probabilistic constraints with existing clinical toxicity data.

Main Methods:

Derived dose-LET_D constraint curves using linear quadratic-based variable relative biological effectiveness (RBE) models.
Incorporated uncertainty from RBE models, tissue radiosensitivity, and fractionation into probabilistic envelopes.
Compared derived constraints with clinical toxicity data for brainstem necrosis, brain necrosis, RIBI, rib fracture, and osteoradionecrosis.

Main Results:

Probabilistic constraints aligned well with clinical data for brainstem necrosis, RIBI, and osteoradionecrosis.
Toxicity-associated dose-LET_D values in patients exceeded constraint envelope upper bounds.
Limited empirical support for higher LET constraints was found, especially with the newest RBE model.

Conclusions:

Dose-dependent probabilistic LET_D constraints offer a biologically sound alternative to single-value thresholds in proton therapy.
This framework better reflects the interplay of dose and LET in predicting normal tissue complications.