Study of relationship between dose, LET and the risk of brain necrosis after proton therapy for skull base tumors

Garbacz, M.; Cordoni, Francesco; Durante, Marco; Gajewski, J.; Kisielewicz, K.; Krah, Nils; Kopeć, Renata; Olko, P.; Patera, V.; Rinaldi, I.; Rydygier, Marzena; Schiavi, A.; Scifoni, E.; Skóra, Tomasz; Tommasino, Francesco; Ruciński, Antoni

doi:10.1016/j.radonc.2021.08.015

Cited by 16 publications

(21 citation statements)

References 40 publications

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“…The volume of the AE regions was increased greatly from 2.81 to 22 cm 3 in 11 months, which indicated that more than 90% of the voxels in the AE regions were due to the biological expansion if the AE regions were contoured in the last follow-up CT images, that is, the "noise" (voxels damaged by the biological expansion) was significantly higher than the "signal" (voxels damaged by dosimetric effect, i.e., dose and LET) itself. Similar phenomenon was also reported in other voxel-based analyses 58,59,83 to investigate dosimetric effects upon AEs. If we want to understand the impact of dosimetric effects upon AE initialization, it is critical to mitigate the impact from such biological processes.…”

Section: Ae Regions May Expand Over Time Due To Biological Effectssupporting

confidence: 86%

“…This could be one of the reasons that inconsistent conclusions have been derived in different AE studies in proton therapy. 50,54,78,83 Seed spot analysis is in-line with the concept of "lesion origin" proposed by Bahn et al 54 In their study, they grounded their analysis by stating the hypothesis that the AE region "originates from a single spot of tissue breakdown from which it expands, possibly in a nonisotropic fashion, because of cascading deteriorative reactions." Seed spot analysis resembles the patchbased methods in medical imaging analysis in finding spatial clusters of voxels that possess similar characteristics or patterns in a limited number of patients, 85 but it is from a dosimetry perspective.…”

Section: Discussionmentioning

confidence: 68%

“…Thus, treating each voxel in the AE region of the same patient individually as independent data points and studying the AE initialization may lead to noninformative results. This could be one of the reasons that inconsistent conclusions have been derived in different AE studies in proton therapy 50,54,78,83 …”

Section: Discussionmentioning

confidence: 99%

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Exploratory study of seed spots analysis to characterize dose and linear‐energy‐transfer effect in adverse event initialization of pencil‐beam‐scanning proton therapy

et al. 2022

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Background: Both dose and linear energy transfer (LET) could play a substantial role in adverse event (AE) initialization of cancer patients treated with pencil-beam-scanning (PBS) proton therapy. However, not all the voxels within the AE regions are directly induced from the dose and LET effect. It is important to study the synergistic effect of dose and LET in AE initialization by only including a subset of voxels that are dosimetrically important. Purpose: To perform exploratory investigation of the dose and LET effects upon AE initialization in PBS using seed spots analysis. Methods: A total of 113 head-and-neck (H&N) cancer patients receiving curative PBS were included. Among them, 20 patients experienced unanticipated CTCAEv4.0 grade ≥3 AEs (AE group) and 93 patients did not (control group). Within the AE group, 13 AE patients were included in the seed spot analysis to derive the descriptive features of AE initialization and the remaining 7 mandible osteoradionecrosis patients and 93 control patients were used to derive the feature-based volume constraint of mandible osteoradionecrosis. The AE regions were contoured and the corresponding dose-LET volume histograms of AE regions were generated for all patients in the AE group. We selected high LET voxels (the highest 5% of each dose bin) with a range of moderate-to-high dose (≥∼40-Gy relative biological effectiveness) as critical voxels. Critical voxels that were contiguous with each other were grouped into clusters. Each cluster was considered a potential independent seed spot for AE initialization. Seed spots were displayed in a 2D dose-LET plane based on their mean dose and LET to derive the descriptive features of AE initialization. A volume constraint of mandible osteoradionecrosis was then established based on the extracted features using a receiver operating characteristic curve. Results: The product of dose and LET (xBD) was found to be a descriptive feature of seed spots leading to AE initialization in this preliminary study. The derived xBD volume constraint for mandible osteoradionecrosis showed good performance with an area under curve of 0.87 (sensitivity of 0.714 and specificity of 0.807 in the leave-one-out cross-validation) for the very limited patient data included in this study. Conclusion: Our exploratory study showed that both dose and LET were observed to be important in AE initializations. The derived xBD volume

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Section: Ae Regions May Expand Over Time Due To Biological Effectssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 68%

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Exploratory study of seed spots analysis to characterize dose and linear‐energy‐transfer effect in adverse event initialization of pencil‐beam‐scanning proton therapy

et al. 2022

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“…A further strength of the current study is that the analysis was performed on a voxelwise level instead of relying on crude contours of organs or subregions allowing for a deeper understanding and evaluation of the lesions. Table 3 summarizes results from other investigations of RICE after PRT [18,19,[21][22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Radiation induced contrast enhancement after proton beam therapy in patients with low grade glioma – How safe are protons?

Harrabi

Nettelbladt

Gudden

et al. 2022

Radiotherapy and Oncology

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“…Therefore in LETopt, LET d values above a set LET d level were only penalized in voxels with a dose above a user-specified threshold. Clinical follow-up studies consistently reported LET d values around 2.5 keV/µm and D 1.1 above 40 Gy(RBE) in radiation-induced image change areas after cranial proton therapy [ 8 , 12 , 13 , 29 – 31 ]. Accordingly, here, LET d values above 2.5 keV/µm were penalized in critical OAR but only in voxels with D 1.1 above 40 Gy(RBE).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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/βCTV = 10 Gy, α/βOAR = 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.

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Study of relationship between dose, LET and the risk of brain necrosis after proton therapy for skull base tumors

Cited by 16 publications

References 40 publications

Exploratory study of seed spots analysis to characterize dose and linear‐energy‐transfer effect in adverse event initialization of pencil‐beam‐scanning proton therapy

Exploratory study of seed spots analysis to characterize dose and linear‐energy‐transfer effect in adverse event initialization of pencil‐beam‐scanning proton therapy

Radiation induced contrast enhancement after proton beam therapy in patients with low grade glioma – How safe are protons?

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

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