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Spatial correlation of linear energy transfer and relative biological effectiveness with treatment related toxicities following proton therapy for intracranial tumors
Stockholm University, Faculty of Science, Department of Physics. RaySearch Laboratories AB, Sweden.
Stockholm University, Faculty of Science, Department of Physics. Karolinska Institutet, Sweden.ORCID iD: 0000-0002-7101-240X
The Skandion Clinic, Sweden.ORCID iD: 0000-0002-7400-3234
RaySearch Laboratories AB, Sweden.
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2019 (English)In: Medical physics (Lancaster), ISSN 0094-2405Article in journal (Refereed) Epub ahead of print
Abstract [en]

Purpose: The enhanced relative biological effectiveness (RBE) at the end of the proton range might increase the risk of radiation-induced toxicities. This is of special concern for intracranial treatments where several critical organs at risk (OARs) surround the tumor.  In the light of this, a retrospective analysis of dose-averaged linear energy transfer (LETd) and RBE-weighted dose (DRBE) distributions was conducted for three clinical cases with suspected treatment related toxicities following intracranial proton therapy. Alternative treatment strategies aiming to reduce toxicity risks are also presented.

Methods: The clinical single-field optimized (SFO) plans were recalculated for 81 error scenarios with a Monte Carlo dose engine. The fractionation DRBE was 1.8 Gy (RBE) in 28 or 30 fractions assuming a constant RBE of 1.1. Two LETd- and α/β-dependent variable RBE models were used for evaluation, including a sensitivity analysis of the α/β parameter. Resulting distributions of DRBE and LETd were analyzed together with normal tissue complication probabilities (NTCPs). Subsequently, four multi-field optimized (MFO) plans, with an additional beam and/or objectives penalizing protons stopping in OARs, were created to investigate the potential reduction of LETd, DRBE and NTCP.

Results: The two variable RBE models agreed well and predicted average RBE values around 1.3 in the toxicity volumes, resulting in increased near-maximum DRBE of 7-11 Gy (RBE) compared to RBE=1.1 in the nominal scenario. The corresponding NTCP estimates increased from 0.8%, 0.0% and 3.7% (RBE=1.1) to 15.5%, 1.8% and 45.7% (Wedenberg RBE model) for the three patients, respectively. The MFO plans generally allowed for LETd, DRBE and NTCP reductions in OARs, without compromising the target dose. Compared to the clinical SFO plans, the maximum reduction of the near-maximum LETd was 56%, 63% and 72% in the OAR exhibiting the toxicity for the three patients, respectively.

Conclusions: Although a direct causality between RBE and toxicity cannot be established here, high LETd and DRBE correlated spatially with the observed toxicities, whereas setup and range uncertainties had a minor impact. Individual factors, which might affect the patient-specific radiosensitivity, were however not included in these calculations. The MFO plans using both an additional beam and proton track-end objectives allowed the largest reductions in LETd, DRBE and NTCP, and might be future tools for similar cases.

Place, publisher, year, edition, pages
2019.
Keywords [en]
proton therapy, relative biological effectiveness, radiation-induced toxicity
National Category
Other Physics Topics
Research subject
Medical Radiation Physics
Identifiers
URN: urn:nbn:se:su:diva-174015DOI: 10.1002/mp.13911OAI: oai:DiVA.org:su-174015DiVA, id: diva2:1358132
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2019-11-11
In thesis
1. Relative biological effectiveness in proton therapy: accounting for variability and uncertainties
Open this publication in new window or tab >>Relative biological effectiveness in proton therapy: accounting for variability and uncertainties
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Radiation therapy is widely used for treatments of malignant diseases. The search for the optimal radiation treatment approach for a specific case is a complex task, ultimately seeking to maximise the tumour control probability (TCP) while minimising the normal tissue complication probability (NTCP). Conventionally, standard curative treatments have been delivered with photons in daily fractions of 2 Gy over a period of approximately three to eight weeks. However, the interest in hypofractionated treatments and proton therapy have rapidly increased during the last decades. Given the same TCP for a photon and a proton plan, the proton plan selection could be made purely based on the reduction in NTCP. Such a plan selection system is clean and elegant but is not flawless. The nominal plans are typically optimised on a single three-dimensional scan of the patient trying to account for the treatment related uncertainties such as particle ranges, patient setup, breathing and organ motion. The comparison also relies on the relative biological effectiveness (RBE), which relates the doses required by photons and protons to achieve the same biological effect. The clinical standard of using a constant proton RBE of 1.1 does not reflect the complex nature of the RBE, which varies with parameters such as linear energy transfer (LET), fractionation dose, tissue type and biological endpoint.

These aspects of proton therapy planning have been investigated in this thesis through five individual studies. Paper I investigated the impact of including models accounting for the variability of the RBE into the plan comparison between proton and photon prostate plans for various fractionation schedules. In paper II, a method of incorporating RBE uncertainties into the robustness evaluation was proposed. Paper III evaluated the impact of variable RBE models and breathing motion for breast cancer treatments using photons and protons. In Paper IV, a novel optimisation method was proposed, where the number of protons stopping in critical structures is reduced in order to control the enhanced LET and the related RBE. Paper V presented a retrospective analysis with alternative treatment plans for intracranial cases with suspected radiation-induced toxicities.

The results indicate that the inclusion of variable RBE models and their uncertainties into the proton plan evaluation could lead to differences from the nominal plans made under the assumption of a constant RBE of 1.1 for both target and normal tissue doses. The RBE-weighted dose (DRBE) for high α/β targets (e.g. head and neck (H&N) tumours) was predicted to be slightly lower, whereas the opposite was predicted for low α/β targets (e.g. breast and prostate) in comparison to the nominal DRBE. For most normal tissues, the predicted DRBE were often substantially higher, resulting in higher NTCP estimates for several organs and clinical endpoints. By combining uncertainties in patient setup, range and breathing motion with RBE uncertainties, comprehensive robustness evaluations could be performed. Such evaluations could be included in the plan selection process in order to mitigate potential adverse effects caused by an enhanced RBE. Furthermore, objectives penalising protons stopping in risk organ were proven able to reduce LET, RBE and NTCP for H&N and intracranial tumours. Such approach might be a future optimisation tool in order to further reduce toxicity risks and maximise the benefit of proton therapy.

Place, publisher, year, edition, pages
Stockholm: Department of Physics, Stockholm University, 2019. p. 76
Keywords
proton therapy, relative biological effectiveness, linear energy transfer, proton track-end optimisation, radiation-induced toxicity
National Category
Physical Sciences Other Physics Topics Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-174012 (URN)978-91-7797-859-6 (ISBN)978-91-7797-860-2 (ISBN)
Public defence
2019-11-22, CCK Lecture Hall, Building R8, Karolinska University Hospital, Solna, 09:00 (English)
Opponent
Supervisors
Available from: 2019-10-30 Created: 2019-10-08 Last updated: 2019-10-18Bibliographically approved

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