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

Abstract

BackgroundLinear energy transfer (LET) is closely related to the biological effect of ionizing radiation. Increasing the dose‐averaged LET (LETd) 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.PurposeTo quantify the relationship between robust target coverage, target dose uniformity, and LETd, we employ robust optimization using dose‐based and LETd‐based functions and allow varying amounts of target non‐uniformity.Methods and MaterialsRobust 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 LETd 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 LETd in the target. The relationship between robust target coverage and LETd in the target is illustrated by tradeoff curves generated by optimization using varying weights for the LETd‐based functions.ResultsAs the range uncertainty used in the robust optimization increased from 0% to 5%, the near‐minimum nominal LETd 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 LETd 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).ConclusionsThere is an inherent conflict between range uncertainty robustness and high LETd 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 LETd in the target.

Potential Therapeutic Improvements in Prostate Cancer Treatment Using Pencil Beam Scanning Proton Therapy with LETd Optimization and Disease-Specific RBE Models

“…This effect is mitigated by creating less steep distal edges, but this also decreases the LET d . Hence, the antagonism between high LET d , uniform dose, and robustness has recently been dubbed the LET d trilemma [52]. In spite of this, we found that even the LET-optimized plans with "watered down" LET d (~3-3.5 keV/µm) to achieve better robustness still outperform SFO plans in terms of TODRs and minimum average RBE-dose coverage.…”

“…To investigate the effects of density uncertainty on LET d optimization, we performed robust evaluations for an example patient; a more detailed analysis on robustness and LET d optimization for carbon ion beams is presented by Fredriksson et al [52]. Fredriksson et al describe an LET d trilemma in which improving two of the factors of range robustness, uniform dose, and high LET d comes at the expense of the third factor.…”

Dose averaged linear energy transfer optimization for large sacral chordomas in carbon ion therapy

“…24 The implementation specifications of LET d optimization is described in another work. 22 In order to increase the LET d in the CTV-HD, the "minimum LET d " optimization function (L min ) of the TPS was utilized for the seven PTV-HD fractions. The nine PTV-LD fractions were not re-optimized and their reference plans were used.…”

“…Target: Increasing the LET d in the tumor and maintaining the robustness is not possible without accepting certain deterioration in the RBE-weighted dose uniformity. 22 The clinical goals related to target coverage were therefore slightly adapted,allowing 10% over-and underdosage in the CTV-HD and 5% under-dosage in the GTV as summarized in Table 2. To have a more thorough investigation on the different optimization parameters, additional low-prio-target-LEM-goals were determined as summarized in Table S2.…”

“…Moreover, the existing conflicts between robustness, uniform RBE-weighted dose,and high LET d are aggravated in the case of large tumors. 22 The distal patching optimization approach was introduced for improving the LET d in large pelvic chordomas and sarcomas by modifying the beam arrangements. 13 Considering low LET d in the target as one potential factor among several other medical or biological factors for the poorer outcome of large tumors, 1,3 research focusing on LET d -optimization in large tumors are still scarce.…”