Introducing Proton Track-End Objectives in Intensity Modulated Proton Therapy Optimization to Reduce Linear Energy Transfer and Relative Biological Effectiveness in Critical Structures.

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. 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. 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. 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.

Traneus E ，Ödén J 《-》

Spatial correlation of linear energy transfer and relative biological effectiveness with suspected treatment-related toxicities following proton therapy for intracranial tumors.

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. 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. The two variable RBE models agreed well and predicted average RBE values around 1.3 in the toxicity volumes, resulting in an 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 in the near-maximum LETd was 56%, 63%, and 72% in the OAR exhibiting the toxicity for the three patients, respectively. 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.

Ödén J ，Toma-Dasu I ，Witt Nyström P ，Traneus E ，Dasu A ... -  《-》

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

Hahn C ，Heuchel L ，Ödén J ，Traneus E ，Wulff J ，Plaude S ，Timmermann B ，Bäumer C ，Lühr A ... -  《Radiation Oncology》

Interlaced proton grid therapy - Linear energy transfer and relative biological effectiveness distributions.

Interlaced beams have previously been proposed for delivering proton grid therapy. This study aims to assess dose-averaged LET (LETd) and RBE-weighted dose (DRBE) distributions of such beam geometries, and compare them with conventional intensity modulated proton therapy (IMPT). IMPT plans and four different interlaced proton grid therapy plans were generated for five patient cases (esophagus, lung, liver, prostate, anus). The constant RBE = 1.1 was assumed for optimization. The LETd was subsequently Monte Carlo calculated for each plan and used as input for two LET-dependent variable RBE models. The fulfilment of clinical goals, along with DVH and spatial distribution evaluations, were then assessed and compared. All plans fulfilled the clinical target goals assuming RBE = 1.1. The target coverage was slightly compromised for some grid plans when assuming the variable RBE models. All IMPT plans, and 18 of 20 grid plans, fulfilled all clinical goals for the organs at risk when assuming RBE = 1.1, whereas most plans failed at least one goal when assuming the variable RBE models. Compared with the IMPT plans, the grid plans demonstrated substantially different LETd distributions due to the fundamentally different beam geometries. However, DRBE distributions in the target were similar. Despite the unconventional beam geometries of interlaced proton grid plans, with resulting alternating dose and LETd patterns, the fulfillment of realistic clinical goals seems to be comparable to regular IMPT plans, both assuming RBE = 1.1 and variable RBE models. In addition, the alternating grid patterns do not seem to give rise to unexpected DRBE hot-spots.

Henry T ，Ödén J 《-》

Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy.

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. 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 reoptimized 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 fulfill the clinical goals for the rectum and bladder. 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 reoptimized 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. 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 reoptimizing 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.

Ödén J ，Eriksson K ，Toma-Dasu I 《-》