The LET trilemma: Conflicts between robust target coverage, uniform dose, and dose-averaged LET in carbon therapy

Linear energy transfer (LET) is closely related to the biological effect of ionizing radiation. Increasing the dose-averaged LET (LET_d ) within the target volume has been proposed as a means to improve clinical outcome for hypoxic tumors. However, doing so can lead to reduced robustness to range uncertainty.

To quantify the relationship between robust target coverage, target dose uniformity, and LET_d , we employ robust optimization using dose-based and LET_d -based functions and allow varying amounts of target non-uniformity.

Robust carbon therapy optimization is used to create plans for phantom cases with increasing target sizes (radii 1, 3, and 5 cm). First, the influence of respectively range and setup uncertainty on the LET_d in the target is studied. Second, we employ strategies allowing overdosage in the clinical target volume (CTV) or gross tumor volume (GTV), which enable increased LET_d in the target. The relationship between robust target coverage and LET_d in the target is illustrated by tradeoff curves generated by optimization using varying weights for the LET_d -based functions.

As the range uncertainty used in the robust optimization increased from 0% to 5%, the near-minimum nominal LET_d decreased by 17%-29% (9-21 keV/µm) for the different target sizes. The effect of increasing setup uncertainty was marginal. Allowing 10% overdosage in the CTV enabled 9%-29% (6-12 keV/µm) increased near-minimum worst case LET_d for the different target sizes, compared to uniform dose plans. When 10% overdosage was allowed in the GTV only, the increase was 1%-20% (1-8 keV/µm).

There is an inherent conflict between range uncertainty robustness and high LET_d in the target, which is aggravated with increasing target size. For large tumors, it is possible to simultaneously achieve two of the three qualities range robustness, uniform dose, and high LET_d in the target.