Investigation on the physical dose filtered by linear energy transfer for treatment plan evaluation in carbon ion therapy.

BACKGROUND: Large tumor size has been reported as a predicting factor for inferior clinical outcome in carbon ion radiotherapy (CIRT). Besides the clinical factors accompanied with such tumors, larger tumors receive typically more low linear energy transfer (LET) contributions than small ones which may be the underlying physical cause. Although dose averaged LET is often used as a single parameter descriptor to quantify the beam quality, there is no evidence that this parameter is the optimal clinical predictor for the complex mixed radiation fields in CIRT. PURPOSE: Purpose of this study was to investigate on a novel dosimetric quantity, namely high-LET-dose ( D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ , the physical dose filtered based on an LET threshold) as a single parameter estimator to differentiate between carbon ion treatment plans (cTP) with a small and large tumor volume. METHODS: Ten cTPs with a planning target volume, PTV ≥ 500 cm 3 $\mathrm{PTV}\ge {500}\,{{\rm cm}^{3}}$ (large) and nine with a PTV < 500 cm 3 $\mathrm{PTV}<{500}\,{{\rm cm}^{3}}$ (small) were selected for this study. To find a reasonable LET threshold ( L thr $\textrm {L}_{\textrm {thr}}$ ) that results in a significant difference in terms of D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ , the voxel based normalized high-LET-dose ( D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) distribution in the clinical target volume (CTV) was studied on a subset (12 out of 19 cTPs) for 18 LET thresholds, using standard distribution descriptors (mean, variance and skewness). The classical dose volume histogram concept was used to evaluate the D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ distributions within the target of all 19 cTPs at the before determined L thr $\textrm {L}_{\textrm {thr}}$ . Statistical significance of the difference between the two groups in terms of mean D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ volume histogram parameters was evaluated by means of (two-sided) t-test or Mann-Whitney-U-test. In addition, the minimum target coverage at the above determined L thr $\textrm {L}_{\textrm {thr}}$ was compared and validated against three other thresholds to verify its potential in differentiation between small and large volume tumors. RESULTS: An L thr $\textrm {L}_{\textrm {thr}}$ of approximately 30 keV / µ m ${30}\,{\rm keV/}\umu {\rm m}$ was found to be a reasonable threshold to classify the two groups. At this threshold, the D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ were significantly larger ( p < 0.05 $p<0.05$ ) in small CTVs. For the small tumor group, the near-minimum and median D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ (and D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) in the CTV were in average 9.3 ± 1.5 Gy $9.3\pm {1.5}\,{\rm Gy}$ (0.31 ± 0.08) and 13.6 ± 1.6 Gy $13.6\pm {1.6}\,{\rm Gy}$ (0.46 ± 0.06), respectively. For the large tumors, these parameters were 6.6 ± 0.2 Gy $6.6\pm {0.2}\,{\rm Gy}$ (0.20 ± 0.01) and 8.6 ± 0.4 Gy $8.6\pm {0.4}\,{\rm Gy}$ (0.28 ± 0.02). The difference between the two groups in terms of mean near-minimum and median D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ ( D ̂ > L thr $\hat{\textrm {D}}_{>\textrm {L}_{\textrm {thr}}}$ ) was 2.7 Gy (11%) and 5.0 Gy (18%), respectively. CONCLUSIONS: The feasibility of high-LET-dose based evaluation was shown in this study where a lower D > L thr $\textrm {D}_{>\textrm {L}_{\textrm {thr}}}$ was found in cTPs with a large tumor size. Further investigation is needed to draw clinical conclusions. The proposed methodology in this work can be utilized for future high-LET-dose based studies.

The dirty and clean dose concept: Towards creating proton therapy treatment plans with a photon-like dose response.

BACKGROUND: Applying tolerance doses for organs at risk (OAR) from photon therapy introduces uncertainties in proton therapy when assuming a constant relative biological effectiveness (RBE) of 1.1. PURPOSE: This work introduces the novel dirty and clean dose concept, which allows for creating treatment plans with a more photon-like dose response for OAR and, thus, less uncertainties when applying photon-based tolerance doses. METHODS: The concept divides the 1.1-weighted dose distribution into two parts: the clean and the dirty dose. The clean and dirty dose are deposited by protons with a linear energy transfer (LET) below and above a set LET threshold, respectively. For the former, a photon-like dose response is assumed, while for the latter, the RBE might exceed 1.1. To reduce the dirty dose in OAR, a MaxDirtyDose objective was added in treatment plan optimization. It requires setting two parameters: LET threshold and max dirty dose level. A simple geometry consisting of one target volume and one OAR in water was used to study the reduction in dirty dose in the OAR depending on the choice of the two MaxDirtyDose objective parameters during plan optimization. The best performing parameter combinations were used to create multiple dirty dose optimized (DDopt) treatment plans for two cranial patient cases. For each DDopt plan, 1.1-weighted dose, variable RBE-weighted dose using the Wedenberg RBE model and dose-average LETd distributions as well as resulting normal tissue complication probability (NTCP) values were calculated and compared to the reference plan (RefPlan) without MaxDirtyDose objectives. RESULTS: In the water phantom studies, LET thresholds between 1.5 and 2.5 keV/µm yielded the best plans and were subsequently used. For the patient cases, nearly all DDopt plans led to a reduced Wedenberg dose in critical OAR. This reduction resulted from an LET reduction and translated into an NTCP reduction of up to 19 percentage points compared to the RefPlan. The 1.1-weighted dose in the OARs was slightly increased (patient 1: 0.45 Gy(RBE), patient 2: 0.08 Gy(RBE)), but never exceeded clinical tolerance doses. Additionally, slightly increased 1.1-weighted dose in healthy brain tissue was observed (patient 1: 0.81 Gy(RBE), patient 2: 0.53 Gy(RBE)). The variation of NTCP values due to variation of α/ß from 2 to 3 Gy was much smaller for DDopt (2 percentage points (pp)) than for RefPlans (5 pp). CONCLUSIONS: The novel dirty and clean dose concept allows for creating biologically more robust proton treatment plans with a more photon-like dose response. The reduced uncertainties in RBE can, therefore, mitigate uncertainties introduced by using photon-based tolerance doses for OAR.

Comparing biological effectiveness guided plan optimization strategies for cranial proton therapy: potential and challenges.

BACKGROUND: To introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE) induced dose burden in organs at risk (OAR) while maintaining plan quality with a constant RBE. METHODS: Dose-optimized (DOSEopt) proton pencil beam scanning reference treatment plans were generated for ten cranial patients with prescription doses ≥ 54 Gy(RBE) and ≥ 1 OAR close to the clinical target volume (CTV). For each patient, four additional BG plans were created. BG objectives minimized either proton track-ends, dose-averaged linear energy transfer (LETd), energy depositions from high-LET protons or variable RBE-weighted dose (DRBE) in adjacent serially structured OARs. Plan quality (RBE = 1.1) was assessed by CTV dose coverage and robustness (2 mm setup, 3.5% density), dose homogeneity and conformity in the planning target volumes and adherence to OAR tolerance doses. LETd, DRBE (Wedenberg model, α/ßCTV = 10 Gy, α/ßOAR = 2 Gy) and resulting normal tissue complication probabilities (NTCPs) for blindness and brainstem necrosis were derived. Differences between DOSEopt and BG optimized plans were assessed and statistically tested (Wilcoxon signed rank, α = 0.05). RESULTS: All plans were clinically acceptable. DOSEopt and BG optimized plans were comparable in target volume coverage, homogeneity and conformity. For recalculated DRBE in all patients, all BG plans significantly reduced near-maximum DRBE to critical OARs with differences up to 8.2 Gy(RBE) (p < 0.05). Direct DRBE optimization primarily reduced absorbed dose in OARs (average ΔDmean = 2.0 Gy; average ΔLETd,mean = 0.1 keV/µm), while the other strategies reduced LETd (average ΔDmean < 0.3 Gy; average ΔLETd,mean = 0.5 keV/µm). LET-optimizing strategies were more robust against range and setup uncertaintes for high-dose CTVs than DRBE optimization. All BG strategies reduced NTCP for brainstem necrosis and blindness on average by 47% with average and maximum reductions of 5.4 and 18.4 percentage points, respectively. CONCLUSIONS: All BG strategies reduced variable RBE-induced NTCPs to OARs. Reducing LETd in high-dose voxels may be favourable due to its adherence to current dose reporting and maintenance of clinical plan quality and the availability of reported LETd and dose levels from clinical toxicity reports after cranial proton therapy. These optimization strategies beyond dose may be a first step towards safely translating variable RBE optimization in the clinics.