Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy

Paganetti, Harald

doi:10.1016/j.ijrobp.2021.08.015

Cited by 46 publications

(32 citation statements)

References 160 publications

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“…It was found that none of the BG optimization strategies systematically outperformed the others in terms of NTCP(D RBE ) reduction. Still, the absolute values for D RBE and NTCP(D RBE ) must be considered with caution [ 4 ], since the transferability of in-vitro data based RBE models to the clinical situation is limited, the applied NTCP models are based on photon data and the observed NTCP values for DOSEopt plans do not correlate to our clinical findings. The Wedenberg model with α/β = 2 Gy, as used in our study, incorporates the RBE dependencies known for protons from in-vitro data [ 3 ] and was found to be consistent with a clinically derived RBE model for brain tissue [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…In proton therapy treatment planning and delivery, a generic constant relative biological effectiveness (RBE) of 1.1 is used to account for the higher cell killing efficiency of protons over photons [1,2]. However, in-vitro and invivo studies show that RBE varies within a treatment field as a function of physical and biological parameters [3,4]. While emerging clinical studies showed that RBE varies with the linear energy transfer (LET) and tissue-specific radiosensitivity [5][6][7][8][9][10][11], some studies did not find correlations between LET and toxicity with the interpatient variability being a potential obscuring effect [12,13].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…Models in which the RBE is a function of parameters like dose and LET are being investigated 47–49 . However, RBE will depend on the specific endpoint that is considered, and variable RBE models are generally based on data for clonogenic cell survival and therefore more relevant for target structures than organs‐at‐risk, in addition to being associated with considerable uncertainties 50,51 …”

Section: Discussionmentioning

confidence: 99%

“…[47][48][49] However, RBE will depend on the specific endpoint that is considered, and variable RBE models are generally based on data for clonogenic cell survival and therefore more relevant for target structures than organs-at-risk, in addition to being associated with considerable uncertainties. 50,51 For brainstem necrosis specifically, clinical studies of pediatric patients with central nervous system (CNS) malignancies, low-grade glioma, and posterior fossa tumors indicate that proton therapy is associated with lower or comparable toxicity rates than conventional photon treatments. [52][53][54] In addition, a study which included 111 medulloblastoma patients who received proton therapy and which focused on patients with clinical symptoms of CNS or brainstem injury observed higher LET values compared to the target but statistically not significant RBE differences in 8 out of 10 treatment change areas identified using magnetic resonance imaging (MRI).…”

Section: Radiobiological Effects At the End Of Rangementioning

confidence: 99%

Range uncertainty reductions in proton therapy may lead to the feasibility of novel beam arrangements which improve organ‐at‐risk sparing

et al. 2022

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In proton therapy, dose distributions are currently often conformed to organs at risk (OARs) using the less sharp dose fall-off at the lateral beam edge to reduce the effects of uncertainties in the in vivo proton range. However, range uncertainty reductions may make greater use of the sharper dose fall-off at the distal beam edge feasible, potentially improving OAR sparing. We quantified the benefits of such novel beam arrangements. Methods: For each of 10 brain or skull base cases, five treatment plans robust to 2 mm setup and 0%-4% range uncertainty were created for the traditional clinical beam arrangement and a novel beam arrangement making greater use of the distal beam edge to conform the dose distribution to the brainstem. Metrics including the brainstem normal tissue complication probability (NTCP) with the endpoint of necrosis were determined for all plans and all setup and range uncertainty scenarios. Results: For the traditional beam arrangement, reducing the range uncertainty from the current level of approximately 4% to a potentially achievable level of 1% reduced the brainstem NTCP by up to 0.9 percentage points in the nominal and up to 1.5 percentage points in the worst-case scenario. Switching to the novel beam arrangement at 1% range uncertainty improved these values by a factor of 2, that is, to 1.8 percentage points and 3.2 percentage points, respectively. The novel beam arrangement achieved a lower brainstem NTCP in all cases starting at a range uncertainty of 2%. Conclusion:The benefits of novel beam arrangements may be of the same magnitude or even exceed the direct benefits of range uncertainty reductions. Indirect effects may therefore contribute markedly to the benefits of reducing proton range uncertainties.

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“…In recent years, several reports have emerged indicating a potential correlation between toxicity and increased RBE [11][12][13][14][15][16][17][18][19]. Nevertheless, the evidence for correlation is not decisive [20], in particular for symptomatic toxicity, emphasizing the need for further study.…”

Section: Introductionmentioning

confidence: 99%

A case-control study of linear energy transfer and relative biological effectiveness related to symptomatic brainstem toxicity following pediatric proton therapy

Fjæra¹,

Indelicato²,

Handeland³

et al. 2022

Radiotherapy and Oncology

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Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy

Cited by 46 publications

References 160 publications

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

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

Range uncertainty reductions in proton therapy may lead to the feasibility of novel beam arrangements which improve organ‐at‐risk sparing

A case-control study of linear energy transfer and relative biological effectiveness related to symptomatic brainstem toxicity following pediatric proton therapy

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