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Relative biological effectiveness in proton therapy: accounting for variability and uncertainties
Stockholm University, Faculty of Science, Department of Physics. RaySearch Laboratories AB, Stockholm, Sweden.
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 [en]
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: urn:nbn:se:su:diva-174012ISBN: 978-91-7797-859-6 (print)ISBN: 978-91-7797-860-2 (electronic)OAI: oai:DiVA.org:su-174012DiVA, id: diva2:1359050
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
List of papers
1. Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy
Open this publication in new window or tab >>Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy
2017 (English)In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 44, no 3, p. 810-822Article in journal (Refereed) Published
Abstract [en]

Purpose: A constant relative biological effectiveness (RBE) of 1.1 is currently used in proton radiation therapy to account for the increased biological effectiveness compared to photon therapy. However, there is increasing evidence that proton RBE vary with the linear energy transfer (LET), the dose per fraction and the type of the tissue. Therefore, this study aims to evaluate the impact of disregarding variations in RBE when comparing proton and photon dose plans for prostate treatments for various fractionation schedules using published RBE models and several α/β assumptions.

Methods: Photon and proton dose plans were created for three generic prostate cancer cases. Three BED3Gy equivalent schedules were studied, 78, 57.2 and 42.8 Gy in 39, 15 and 7 fractions, respectively. The proton plans were optimized assuming a constant RBE of 1.1. By using the Monte Carlo calculated dose-averaged LET (LETd) distribution and assuming α/β values on voxel level, three variable RBE models were applied to the proton dose plans. The impact of the variable RBE was studied in the plan comparison, which was based on the dose distribution, DVHs and normal tissue complication probabilities (NTCP) for the rectum. Subsequently, the physical proton dose was re-optimized for each proton plan based on the LETd distribution, to achieve a homogeneous RBE weighted target dose when applying a specific RBE model and still fulfil the clinical goals for the rectum and bladder.

Results: All the photon and proton plans assuming RBE=1.1 met the clinical goals with similar target coverage. The proton plans fulfilled the robustness criteria in terms of range and setup uncertainty. Applying the variable RBE models generally resulted in higher target doses and rectum NTCP compared to the photon plans. The increase was most pronounced for the fractionation dose of 2 Gy(RBE) whereas it was of less magnitude and more dependent on model and α/β assumption for the hypofractionated schedules. The re-optimized proton plans proved to be robust and showed similar target coverage and doses to the organs at risk as the proton plans optimized with a constant RBE.

Conclusions: Model predicted RBE values may differ substantially from 1.1. This is most pronounced for fractionation doses of around 2 Gy(RBE) with higher doses to the target and the OARs, whereas the effect seems to be of less importance for the hypofractionated schedules. This could result in misleading conclusions when comparing proton plans to photon plans. By accounting for a variable RBE in the optimization process, robust and clinically acceptable dose plans, with the potential of lowering rectal NTCP, may be generated by re-optimizing the physical dose. However, the direction and magnitude of the changes in the physical proton dose to the prostate are dependent on RBE model and α/β assumptions and should therefore be used conservatively.

Keywords
biological modeling, fractionation, prostate radiotherapy, proton therapy, RBE
National Category
Physical Sciences Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-138746 (URN)10.1002/mp.12117 (DOI)000397870800004 ()28107554 (PubMedID)2-s2.0-85016325763 (Scopus ID)
Available from: 2017-01-25 Created: 2017-01-25 Last updated: 2019-10-09Bibliographically approved
2. Incorporation of relative biological effectiveness uncertainties into proton plan robustness evaluation
Open this publication in new window or tab >>Incorporation of relative biological effectiveness uncertainties into proton plan robustness evaluation
2017 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 6, p. 769-778Article in journal (Refereed) Published
Abstract [en]

Background: The constant relative biological effectiveness (RBE) of 1.1 is typically assumed in proton therapy. This study presents a method of incorporating the variable RBE and its uncertainties into the proton plan robustness evaluation.

Material and methods: The robustness evaluation was split into two parts. In part one, the worst-case physical dose was estimated using setup and range errors, including the fractionation dependence. The results were fed into part two, in which the worst-case RBE-weighted doses were estimated using a Monte Carlo method for sampling the input parameters of the chosen RBE model. The method was applied to three prostate, breast and head and neck (H&N) plans for several fractionation schedules using two RBE models. The uncertainties in the model parameters, linear energy transfer and α/β were included. The resulting DVH error bands were compared with the use of a constant RBE without uncertainties.

Results: All plans were evaluated as robust using the constant RBE. Applying the proposed methodology using the variable RBE models broadens the DVH error bands for all structures studied. The uncertainty in α/β was the dominant factor. The variable RBE also shifted the nominal DVHs towards higher doses for most OARs, whereas the direction of this shift for the clinical target volumes (CTVs) depended on the treatment site, RBE model and fractionation schedule. The average RBE within the CTV, using one of the RBE models and 2 Gy(RBE) per fraction, varied between 1.11–1.26, 1.06–1.16 and 1.14–1.25 for the breast, H&N and prostate patients, respectively.

Conclusions: A method of incorporating RBE uncertainties into the robustness evaluation has been proposed. By disregarding the variable RBE and its uncertainties, the variation in the RBE-weighted CTV and OAR doses may be underestimated. This could be an essential factor to take into account, especially in normal tissue complication probabilities based comparisons between proton and photon plans.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:su:diva-139928 (URN)10.1080/0284186X.2017.1290825 (DOI)000400796200004 ()28464736 (PubMedID)2-s2.0-85014502184 (Scopus ID)
Available from: 2017-02-20 Created: 2017-02-20 Last updated: 2019-10-08Bibliographically approved
3. The influence of breathing motion and a variable relative biological effectiveness in proton therapy of left-sided breast cancer
Open this publication in new window or tab >>The influence of breathing motion and a variable relative biological effectiveness in proton therapy of left-sided breast cancer
Show others...
2017 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 11, p. 1428-1436Article in journal (Refereed) Published
Abstract [en]

Background: Proton breast radiotherapy has been suggested to improve target coverage as well as reduce cardiopulmonary and integral dose compared with photon therapy. This study aims to assess this potential when accounting for breathing motion and a variable relative biological effectiveness (RBE).

Methods: Photon and robustly optimized proton plans were generated to deliver 50 Gy (RBE) in 25 fractions (RBE=1.1) to the CTV (whole left breast) for 12 patients. The plan evaluation was performed using the constant RBE and a variable RBE model. Robustness against breathing motion, setup, range and RBE uncertainties was analyzed using CT data obtained at free-breathing, breath-hold-at-inhalation and breath-hold-at-exhalation.

Results: All photon and proton plans (RBE=1.1) met the clinical goals. The variable RBE model predicted an average RBE of 1.18 for the CTVs (range 1.14–1.21) and even higher RBEs in organs at risk (OARs). However, the dosimetric impact of this latter aspect was minor due to low OAR doses. The normal tissue complication probability (NTCP) for the lungs was low for all patients (<1%), and similar for photons and protons. The proton plans were generally considered robust for all patients. However, in the most extreme scenarios, the lowest dose received by 98% of the CTV dropped from 96 to 99% of the prescribed dose to around 92–94% for both protons and photons. Including RBE uncertainties in the robustness analysis resulted in substantially higher worst-case OAR doses.

Conclusions: Breathing motion seems to have a minor effect on the plan quality for breast cancer. The variable RBE might impact the potential benefit of protons, but could probably be neglected in most cases where the physical OAR doses are low. However, to be able to identify outlier cases at risk for high OAR doses, the biological evaluation of proton plans taking into account the variable RBE is recommended.

National Category
Physical Sciences Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-146097 (URN)10.1080/0284186X.2017.1348625 (DOI)000423464400013 ()
Available from: 2017-08-22 Created: 2017-08-22 Last updated: 2019-10-09Bibliographically approved
4. Introducing Proton Track-End Objectives in Intensity Modulated Proton Therapy Optimization to Reduce Linear Energy Transfer and Relative Biological Effectiveness in Critical Structures
Open this publication in new window or tab >>Introducing Proton Track-End Objectives in Intensity Modulated Proton Therapy Optimization to Reduce Linear Energy Transfer and Relative Biological Effectiveness in Critical Structures
2019 (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.

National Category
Physical Sciences Cancer and Oncology
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-166671 (URN)10.1016/j.ijrobp.2018.10.031 (DOI)000458558100030 ()30395906 (PubMedID)
Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-10-09Bibliographically approved
5. Spatial correlation of linear energy transfer and relative biological effectiveness with treatment related toxicities following proton therapy for intracranial tumors
Open this publication in new window or tab >>Spatial correlation of linear energy transfer and relative biological effectiveness with treatment related toxicities following proton therapy for intracranial tumors
Show others...
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.

Keywords
proton therapy, relative biological effectiveness, radiation-induced toxicity
National Category
Other Physics Topics
Research subject
Medical Radiation Physics
Identifiers
urn:nbn:se:su:diva-174015 (URN)10.1002/mp.13911 (DOI)
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2019-11-11

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