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Introducing Proton Track-End Objectives in Intensity Modulated Proton Therapy Optimization to Reduce Linear Energy Transfer and Relative Biological Effectiveness in Critical Structures
Stockholm University, Faculty of Science, Department of Physics. RaySearch Laboratories AB, Sweden.
Number of Authors: 22019 (English)In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 103, no 3, p. 747-757Article in journal (Refereed) Published
Abstract [en]

Purpose: We propose the use of proton track-end objectives in intensity modulated proton therapy (IMPT) optimization to reduce the linear energy transfer (LET) and the relative biological effectiveness (RBE) in critical structures. Methods and Materials: IMPT plans were generated for 3 intracranial patient cases (1.8 Gy (RBE) in 30 fractions) and 3 head-and-neck patient cases (2 Gy (RBE) in 35 fractions), assuming a constant RBE of 1.1. Two plans were generated for each patient: (1) physical dose objectives only (DOSEopt) and (2) same dose objectives as the DOSEopt plan, with additional proton track-end objectives (TEopt). The track-end objectives penalized protons stopping in the risk volume of choice. Dose evaluations were made using a RBE of 1.1 and the LET-dependent Wedenberg RBE model, together with estimates of normal tissue complication probabilities (NTCPs). In addition, the distributions of proton track-ends and dose-average LET (LETd) were analyzed. Results: The TEopt plans reduced the mean LETd in the critical structures studied by an average of 37% and increased the mean LETd in the primary clinical target volume (CTV) by an average of 23%. This was achieved through a redistribution of the proton track-ends, concurrently keeping the physical dose distribution virtually unchanged compared to the DOSEopt plans. This resulted in substantial RBE-weighted dose (DRBE) reductions, allowing the TEopt plans to meet all clinical goals for both RBE models and reduce the NTCPs by 0 to 19 percentage points compared to the DOSEopt plans, assuming the Wedenberg RBE model. The DOSEopt plans met all clinical goals assuming a RBE of 1.1 but failed 10 of 19 normal tissue goals assuming the Wedenberg RBE model. Conclusions: Proton track-end objectives allow for LETd reductions in critical structures without compromising the physical target dose. This approach permits the lowering of DRBE and NTCP in critical structures, independent of the variable RBE model used, and it could be introduced in clinical practice without changing current protocols based on the constant RBE of 1.1.

Place, publisher, year, edition, pages
2019. Vol. 103, no 3, p. 747-757
National Category
Physical Sciences Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
URN: urn:nbn:se:su:diva-166671DOI: 10.1016/j.ijrobp.2018.10.031ISI: 000458558100030PubMedID: 30395906OAI: oai:DiVA.org:su-166671DiVA, id: diva2:1294019
Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-10-09Bibliographically approved
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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