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Background and Purpose: To investigate the trade-off between bone marrow sparing (BMS) and dose to organs at risk (OARs) for intensity modulated proton therapy (IMPT) for women with locally advanced cervical cancer (LACC)., Materials and Methods: Twenty LACC patients were retrospectively included. IMPT plans were created for each patient using automated treatment planning. These plans progressively reduced bone marrow mean doses by steps of 1 GyRBE, while constraining target coverage and conformality. The relation between bone marrow dose and bladder, small bowel, rectum, and sigmoid doses was evaluated., Results: A total of 140 IMPT plans were created. Plans without BMS had an average [range] bone marrow mean dose of 17.3 [14.7-21.6] Gy RBE  , which reduced to 12.0 [10.0-14.0] Gy RBE  with maximum BMS. The mean OAR dose [range] increased modestly for 1 Gy RBE  BMS: 0.2 [0.0 - 0.6] Gy RBE  for bladder, 0.3 [-0.2 - 0.7] Gy RBE  for rectum, 0.4 [0.1 - 0.8] Gy RBE  for small bowel, and 0.2 [-0.2 - 0.4] Gy RBE  for sigmoid. Moreover, for maximum BMS, mean OAR doses [range] escalated by 3.3 [0.1 - 6.7] Gy RBE  for bladder, 5.8 [1.8 - 12.4] Gy RBE  for rectum, 3.9 [1.6 - 5.9] Gy RBE  for small bowel, and 2.7 [0.6 - 5.9] Gy RBE  for sigmoid., Conclusion: Achieving 1 Gy RBE  BMS for IMPT is feasible for LACC patients with limited dosimetric impact on other OARs. While further bone marrow dose reduction is possible for some patients, it may increase OAR doses substantially for others. Hence, we recommend a personalized approach when introducing BMS into clinical IMPT treatment planning to carefully assess individual patient benefits and risks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective . In head-and-neck cancer intensity modulated proton therapy, adaptive radiotherapy is currently restricted to offline re-planning, mitigating the effect of slow changes in patient anatomies. Daily online adaptations can potentially improve dosimetry. Here, a new, fully automated online re-optimization strategy is presented. In a retrospective study, this online re-optimization approach was compared to our trigger-based offline re-planning (offline TB re-planning) schedule, including extensive robustness analyses. Approach . The online re-optimization method employs automated multi-criterial re-optimization, using robust optimization with 1 mm setup-robustness settings (in contrast to 3 mm for offline TB re-planning). Hard planning constraints and spot addition are used to enforce adequate target coverage, avoid prohibitively large maximum doses and minimize organ-at-risk doses. For 67 repeat-CTs from 15 patients, fraction doses of the two strategies were compared for the CTVs and organs-at-risk. Per repeat-CT, 10.000 fractions with different setup and range robustness settings were simulated using polynomial chaos expansion for fast and accurate dose calculations. Main results . For 14/67 repeat-CTs, offline TB re-planning resulted in <50% probability of D 98% ≥ 95% of the prescribed dose ( D pres ) in one or both CTVs, which never happened with online re-optimization. With offline TB re-planning, eight repeat-CTs had zero probability of obtaining D 98% ≥ 95% D pres for CTV 7000 , while the minimum probability with online re-optimization was 81%. Risks of xerostomia and dysphagia grade ≥ II were reduced by 3.5 ± 1.7 and 3.9 ± 2.8 percentage point [mean ± SD] ( p < 10 -5 for both). In online re-optimization, adjustment of spot configuration followed by spot-intensity re-optimization took 3.4 min on average. Significance . The fast online re-optimization strategy always prevented substantial losses of target coverage caused by day-to-day anatomical variations, as opposed to the clinical trigger-based offline re-planning schedule. On top of this, online re-optimization could be performed with smaller setup robustness settings, contributing to improved organs-at-risk sparing., (Creative Commons Attribution license.)

Background and Purpose: Since 2011, our center has been using a library-based Plan-of-the-Day (PotD) strategy for external beam radiotherapy of cervical cancer patients to reduce normal tissue dose while maintaining adequate target coverage. With the advent of fully online-adaptive techniques such as daily online-adaptive replanning, further dose reduction may be possible. However, it is unknown how this reduction relates to plan library approaches, and how the most recent PotD strategies relate to no adaptation. In this study we compare the performance of our current PotD strategy with non-adaptive and fully online-adaptive techniques in terms of target volume size and normal tissue sparing., Materials and Methods: Treatment data of 376 patients treated with the PotD protocol between June 2011 and April 2020 were included. The size of the Planning Target Volumes (PTVs) was reconstructed for different strategies: full online adaptation, no adaptation, and the latest clinical version of the PotD protocol. Normal tissue sparing was estimated by the difference in margin volume to construct the PTV and the volume overlap of the PTV with bladder and rectum., Results: The current version of our PotD approach reduced the PTV margin volume by a median of 250 cm 3 compared to no adaptation. Bladder-PTV overlap decreased from a median of 142 to 71 cm 3 , and from 39 to 16 cm 3 for rectum-PTV. Fully online-adaptive approaches could further decrease the PTV volume by 144 cm 3 using a 5 mm margin for residual errors. In this scenario, bladder-PTV overlap was reduced to 35 cm 3 and rectum-PTV overlap to 11 cm 3 ., Conclusion: The current version of the PotD protocol is an effective technique to improve normal tissue sparing compared to no adaptation. Further sparing can be achieved using fully online-adaptive techniques, but at the cost of a more complex workflow and with a potentially limited impact. PotD-type protocols can therefore be considered as a suitable alternative to fully online-adaptive approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa)., Methods: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT., Results: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints., Conclusion: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: In intensity modulated proton therapy (IMPT), the impact of setup errors and anatomical changes is commonly mitigated by robust optimization with population-based setup robustness (SR) settings and offline replanning. In this study we propose and evaluate an alternative approach based on daily plan selection from patient-specific pre-treatment established plan libraries (PLs). Clinical implementation of the PL strategy would be rather straightforward compared to daily online re-planning., Materials and Methods: For 15 head-and-neck cancer patients, the planning CT was used to generate a PL with 5 plans, robustly optimized for increasing SR: 0, 1, 2, 3, 5 mm, and 3% range robustness. Repeat CTs (rCTs) and realistic setup and range uncertainty distributions were used for simulation of treatment courses for the PL approach, treatments with fixed SR (fSR 3 ) and a trigger-based offline adaptive schedule for 3 mm SR (fSR 3 OfA). Daily plan selection in the PL approach was based only on recomputed dose to the CTV on the rCT., Results: Compared to using fSR 3 and fSR 3 OfA, the risk of xerostomia grade ≥ II & III and dysphagia ≥ grade III were significantly reduced with the PL. For 6/15 patients the risk of xerostomia and/or dysphagia ≥ grade II could be reduced by > 2% by using PL. For the other patients, adherence to target coverage constraints was often improved. fSR 3 OfA resulted in significantly improved coverage compared to PL for selected patients., Conclusion: The proposed PL approach resulted in overall reduced NTCPs compared to fSR 3 and fSR 3 OfA at limited cost in target coverage., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose and Objective: Besides a dose-rate threshold of 40-100 Gy/s, the FLASH effect may require a dose > 3.5-7 Gy. Even in hypofractioned treatments, with all beams delivered in each fraction (ABEF), most healthy tissue is irradiated to a lower fraction dose. This can be circumvented by single-beam-per-fraction (SBPF) delivery, with a loss of healthy tissue sparing by fractionation. We investigated the trade-off between FLASH and loss of fractionation in SBPF stereotactic proton therapy of lung cancer and determined break-even FLASH-enhancement ratios (FERs)., Materials and Methods: Treatment plans for 12 patients were generated. GTV delineations were available and a 5 mm GTV-PTV margin was applied. Equiangular arrangements of 3, 5, 7, and 9 244 MeV proton transmission beams were used. To facilitate SBPF, the number of fractions was equal to the number of beams. Iso-effective fractionation schedules with a single field uniform dose prescription were used: D 95%,PTV  = 100%D pres per beam. All plans were evaluated in terms of dose to lung and conformity of dose to target of FLASH-enhanced biologically equivalent dose (EQD2)., Results: Compared to ABEF, SBPF resulted in a median increase of EQD2 mean to healthy lung of 56%, 58%, 55% and 54% in plans with 3, 5, 7 and 9 fractions respectively and of 236%, 78%, 50% and 41% in V 100% EQD2 , quantifying conformity. This can be compensated for by FERs of at least 1.28, 1.32, 1.30 and 1.23 respectively for EQD2 mean and 1.29, 1.18, 1.28 and 1.15 for V 100%,EQD2 ., Conclusion: A FLASH effect outweighing the loss of fractionation in SBPF may be achieved in stereotactic lung treatments. The trade-off with fractionation depends on the conditions under which the FLASH effect occurs. Better understanding of the underlying biology and the impact of delivery conditions is needed., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: The 15-year results of the EORTC 229922-10925 phase III trial showed a significant reduction in breast cancer mortality and breast cancer recurrences after internal mammary chain (IMC) and medio-supraclavicular irradiation. Unexpectedly, cardiac death was not increased, and the incidence of cardiac events did not differ between left- and right-sided cases, although target volume coverages and organ at risk doses were unknown. Therefore, a planning study was carried out comparing the past and the present, to eventually enable, thereafter, an increased therapeutic ratio of IMC irradiation., Materials and Methods: A planning study was carried out on target volume coverage and organ at risk doses for whole-breast irradiation (WBI) ± IMC comparing the results between two-dimensional radiotherapy (free-breathing), hybrid intensity-modulated radiotherapy (IMRT; breath-hold) and robust intensity-modulated proton therapy (IMPT; free-breathing) for 10 left-sided breast cancer cases. Two-dimensional radiotherapy consisted of two tangential wedged photon breast fields and mixed electron/photon beams for the IMC. Hybrid IMRT included two tangential photon breast fields (70%) complemented with IMRT (30%). IMPT plans were created using multi-field robust optimisation (5 mm set-up and 3% range uncertainties) with two (WBI) or three (WBI + IMC) beams., Results: Target volume dose objectives were met for hybrid IMRT and IMPT. For two-dimensional radiotherapy, target coverage was 97% and 83% for breast and IMC, respectively. The mean heart dose for WBI only was <2 Gy for all techniques. For WBI + IMC, heart doses (mean heart dose, mean left anterior descending region, volume of the heart receiving 5 Gy (V5) were significantly higher for two-dimensional radiotherapy when compared with contemporary techniques. The V5 left anterior descending region reduced from 100% (two-dimensional radiotherapy) to 70% and 20% for hybrid IMRT and IMPT, respectively., Conclusion: Contemporary radiotherapy techniques result in improved target volume coverage and significantly decreased heart doses for WBI + IMC radiotherapy. Hence, nowadays an increased therapeutic ratio of elective IMC irradiation may be anticipated., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Breathing interplay effects in Intensity Modulated Proton Therapy (IMPT) arise from the interaction between target motion and the scanning beam. Assessing the detrimental effect of interplay and the clinical robustness of several mitigation techniques requires statistical evaluation procedures that take into account the variability of breathing during dose delivery. In this study, we present such a statistical method to model intra-fraction respiratory motion based on breathing signals and assess clinical relevant aspects related to the practical evaluation of interplay in IMPT such as how to model irregular breathing, how small breathing changes affect the final dose distribution, and what is the statistical power (number of different scenarios) required for trustworthy quantification of interplay effects. First, two data-driven methodologies to generate artificial patient-specific breathing signals are compared: a simple sinusoidal model, and a precise probabilistic deep learning model generating very realistic samples of patient breathing. Second, we investigate the highly fluctuating relationship between interplay doses and breathing parameters, showing that small changes in breathing period result in large local variations in the dose. Our results indicate that using a limited number of samples to calculate interplay statistics introduces a bigger error than using simple sinusoidal models based on patient parameters or disregarding breathing hysteresis during the evaluation. We illustrate the power of the presented statistical method by analyzing interplay robustness of 4DCT and Internal Target Volume (ITV) treatment plans for a 8 lung cancer patients, showing that, unlike 4DCT plans, even 33 fraction ITV plans systematically fail to fulfill robustness requirements., (Creative Commons Attribution license.)

Background and Purpose: Patient selection for intensity modulated proton therapy (IMPT), using comparative photon therapy planning, is workload-intensive and time-consuming. Pre-selection aims at avoidance of manual IMPT planning for patients that are in the end ineligible. We investigated the use of machine learning together with automated IMPT treatment planning for pre-selection of head and neck cancer patients, and validated the methodology for the Dutch model based selection (MBS) approach., Materials & Methods: For forty-five head and neck patients with a previous MBS, an IMPT plan was generated with non-clinical, fully-automated planning. Dosimetric differences of these plans with the corresponding previously generated photon plans, and the outcomes of the former MBS, were used to train a Gaussian naïve Bayes classifier for MBS outcome prediction. During training, strong emphasis was placed on avoiding misclassification of IMPT eligible patients (i.e. false negatives)., Results: Pre-selection with the classifier resulted in 0 false negatives, 12 (27%) true negatives, 27 (60%) true positives, and only 6 (13%) false positive predictions. Using this pre-selection, the number of formal selection procedures with involved manual IMPT planning that resulted in a negative outcome could be reduced by 67%., Conclusion: With pre-selection, using machine learning and automated treatment planning, the percentage of patients with unnecessary manual IMPT planning for MBS could be drastically reduced, thereby saving costs, labor and time. With the developed approach, larger patient populations can be screened, and likely bias in pre-selection of patients can be mitigated by assisting the physician during patient pre-selection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT., Methods and Materials: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm., Results: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 Gy RBE1.1 (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 Gy RBE1.1 . When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 Gy RBE1.1 . In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders., Conclusions: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Library-of-plans ART is used to manage daily anatomy changes in locally advanced cervical cancer. In our institute, the library contains 2 VMAT plans for patients with large cervix-uterus motion. Increasing this number could be beneficial for tissue sparing, but is burdensome while the dosimetric gain is yet unclear. This study's aim is to determine the optimal number of plans at an individual patient level., Material and Methods: Data of 14 treated patients were analyzed. Plan libraries were created containing 1-4 VMAT plans. Pre-treatment extent of uterus motion was defined by the 99th percentile of the Hausdorff distance (HD99). For dosimetric evaluations, OARs were contoured in daily CBCT scans, plan selection was simulated, and the V 45Gy and V 40Gy parameters were recorded., Results: Moderate to strong correlations were found between HD99 and the volume of spared OARs. All patients benefitted from adding a 2nd plan, as is the clinical practice. For patients with a HD99 between 30 and 50mm, a 3-plan library reduced the composite V 40Gy with 11-21ml compared to a 2-plan library., Conclusion: Patients with large uterus motion (HD99>30mm) would benefit from an extension of the plan library to 3. HD99 is an easy-to-implement criteria to select those patients pre-treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Proton therapy is very sensitive to daily density changes along the pencil beam paths. The purpose of this study is to develop and evaluate an automated method for adaptation of IMPT plans to compensate for these daily tissue density variations. A two-step restoration method for 'densities-of-the-day' was created: (1) restoration of spot positions (Bragg peaks) by adapting the energy of each pencil beam to the new water equivalent path length; and (2) re-optimization of pencil beam weights by minimizing the dosimetric difference with the planned dose distribution, using a fast and exact quadratic solver. The method was developed and evaluated using 8-10 repeat CT scans of 10 prostate cancer patients. Experiments demonstrated that giving a high weight to the PTV in the re-optimization resulted in clinically acceptable restorations. For all scans we obtained V 95%   ⩾  98% and V 107%   ⩽  2%. For the bladder, the differences between the restored and the intended treatment plan were below  +2 Gy and  +2%-point. The rectum differences were below  +2 Gy and  +2%-point for 90% of the scans. In the remaining scans the rectum was filled with air, which partly overlapped with the PTV. The air cavity distorted the Bragg peak resulting in less favorable rectum doses.

The highly conformal planned dose distribution achievable in intensity modulated proton therapy (IMPT) can severely be compromised by uncertainties in patient setup and proton range. While several robust optimization approaches have been presented to address this issue, appropriate methods to accurately estimate the robustness of treatment plans are still lacking. To fill this gap we present Polynomial Chaos Expansion (PCE) techniques which are easily applicable and create a meta-model of the dose engine by approximating the dose in every voxel with multidimensional polynomials. This Polynomial Chaos (PC) model can be built in an automated fashion relatively cheaply and subsequently it can be used to perform comprehensive robustness analysis. We adapted PC to provide among others the expected dose, the dose variance, accurate probability distribution of dose-volume histogram (DVH) metrics (e.g. minimum tumor or maximum organ dose), exact bandwidths of DVHs, and to separate the effects of random and systematic errors. We present the outcome of our verification experiments based on 6 head-and-neck (HN) patients, and exemplify the usefulness of PCE by comparing a robust and a non-robust treatment plan for a selected HN case. The results suggest that PCE is highly valuable for both research and clinical applications.

Purpose: We aimed to derive a "robustness recipe" giving the range robustness (RR) and setup robustness (SR) settings (ie, the error values) that ensure adequate clinical target volume (CTV) coverage in oropharyngeal cancer patients for given gaussian distributions of systematic setup, random setup, and range errors (characterized by standard deviations of Σ, σ, and ρ, respectively) when used in minimax worst-case robust intensity modulated proton therapy (IMPT) optimization., Methods and Materials: For the analysis, contoured computed tomography (CT) scans of 9 unilateral and 9 bilateral patients were used. An IMPT plan was considered robust if, for at least 98% of the simulated fractionated treatments, 98% of the CTV received 95% or more of the prescribed dose. For fast assessment of the CTV coverage for given error distributions (ie, different values of Σ, σ, and ρ), polynomial chaos methods were used. Separate recipes were derived for the unilateral and bilateral cases using one patient from each group, and all 18 patients were included in the validation of the recipes., Results: Treatment plans for bilateral cases are intrinsically more robust than those for unilateral cases. The required RR only depends on the ρ, and SR can be fitted by second-order polynomials in Σ and σ. The formulas for the derived robustness recipes are as follows: Unilateral patients need SR = -0.15Σ(2) + 0.27σ(2) + 1.85Σ - 0.06σ + 1.22 and RR=3% for ρ = 1% and ρ = 2%; bilateral patients need SR = -0.07Σ(2) + 0.19σ(2) + 1.34Σ - 0.07σ + 1.17 and RR=3% and 4% for ρ = 1% and 2%, respectively. For the recipe validation, 2 plans were generated for each of the 18 patients corresponding to Σ = σ = 1.5 mm and ρ = 0% and 2%. Thirty-four plans had adequate CTV coverage in 98% or more of the simulated fractionated treatments; the remaining 2 had adequate coverage in 97.8% and 97.9%., Conclusions: Robustness recipes were derived that can be used in minimax robust optimization of IMPT treatment plans to ensure adequate CTV coverage for oropharyngeal cancer patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This study investigates whether 'pencil beam resampling', i.e. iterative selection and weight optimization of randomly placed pencil beams (PBs), reduces optimization time and improves plan quality for multi-criteria optimization in intensity-modulated proton therapy, compared with traditional modes in which PBs are distributed over a regular grid. Resampling consisted of repeatedly performing: (1) random selection of candidate PBs from a very fine grid, (2) inverse multi-criteria optimization, and (3) exclusion of low-weight PBs. The newly selected candidate PBs were added to the PBs in the existing solution, causing the solution to improve with each iteration. Resampling and traditional regular grid planning were implemented into our in-house developed multi-criteria treatment planning system 'Erasmus iCycle'. The system optimizes objectives successively according to their priorities as defined in the so-called 'wish-list'. For five head-and-neck cancer patients and two PB widths (3 and 6 mm sigma at 230 MeV), treatment plans were generated using: (1) resampling, (2) anisotropic regular grids and (3) isotropic regular grids, while using varying sample sizes (resampling) or grid spacings (regular grid). We assessed differences in optimization time (for comparable plan quality) and in plan quality parameters (for comparable optimization time). Resampling reduced optimization time by a factor of 2.8 and 5.6 on average (7.8 and 17.0 at maximum) compared with the use of anisotropic and isotropic grids, respectively. Doses to organs-at-risk were generally reduced when using resampling, with median dose reductions ranging from 0.0 to 3.0 Gy (maximum: 14.3 Gy, relative: 0%-42%) compared with anisotropic grids and from -0.3 to 2.6 Gy (maximum: 11.4 Gy, relative: -4%-19%) compared with isotropic grids. Resampling was especially effective when using thin PBs (3 mm sigma). Resampling plans contained on average fewer PBs, energy layers and protons than anisotropic grid plans and more energy layers and protons than isotropic grid plans. In conclusion, resampling resulted in improved plan quality and in considerable optimization time reduction compared with traditional regular grid planning.

Purpose: To design and evaluate individualized nonadaptive and online-adaptive strategies based on a pretreatment established motion model for the highly deformable target volume in cervical cancer patients., Methods and Materials: For 14 patients, nine to ten variable bladder filling computed tomography (CT) scans were acquired at pretreatment and after 40 Gy. Individualized model-based internal target volumes (mbITVs) accounting for the cervix and uterus motion due to bladder volume changes were generated by using a motion-model constructed from two pretreatment CT scans (full and empty bladder). Two individualized strategies were designed: a nonadaptive strategy, using an mbITV accounting for the full-range of bladder volume changes throughout the treatment; and an online-adaptive strategy, using mbITVs of bladder volume subranges to construct a library of plans. The latter adapts the treatment online by selecting the plan-of-the-day from the library based on the measured bladder volume. The individualized strategies were evaluated by the seven to eight CT scans not used for mbITVs construction, and compared with a population-based approach. Geometric uniform margins around planning cervix-uterus and mbITVs were determined to ensure adequate coverage. For each strategy, the percentage of the cervix-uterus, bladder, and rectum volumes inside the planning target volume (PTV), and the clinical target volume (CTV)-to-PTV volume (volume difference between PTV and CTV) were calculated., Results: The margin for the population-based approach was 38 mm and for the individualized strategies was 7 to 10 mm. Compared with the population-based approach, the individualized nonadaptive strategy decreased the CTV-to-PTV volume by 48% ± 6% and the percentage of bladder and rectum inside the PTV by 5% to 45% and 26% to 74% (p < 0.001), respectively. Replacing the individualized nonadaptive strategy by an online-adaptive, two-plan library further decreased the percentage of bladder and rectum inside the PTV (0% to 10% and -1% to 9%; p < 0.004) and the CTV-to-PTV volume (4-96 ml)., Conclusions: Compared with population-based margins, an individualized PTV results in better organ-at-risk sparing. Online-adaptive radiotherapy further improves organ-at-risk sparing., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Purpose: To design and evaluate a 3D patient-specific model to predict the cervix-uterus shape and position., Methods and Materials: For 13 patients lying in prone position, 10 variable bladder filling CT-scans were acquired, 5 at planning and 5 after 40Gy. The delineated cervix-uterus volumes in 2-5 pre-treatment CT-scans were used to generate patient-specific models that predict the cervix-uterus geometry by bladder volume. Model predictions were compared to delineations, excluding those used for model construction. The prediction error was quantified by the margin required around the predicted volumes to accommodate 95% of the delineated volume and by the predicted-to-delineated surface distance., Results: The prediction margin was significantly smaller (average 50%) than the margin encompassing the cervix-uterus motion. The prediction margin could be decreased (from 7 to 5mm at planning and from 10 to 8mm after 40Gy) by increasing (from 2 to 5) the number of CT-scans used for the model construction., Conclusion: For most patients, even with a model based on only two CT-scans, the prediction error was well below the margin encompassing the cervix-uterus motion. The described approach could be used to create prior to treatment, an individualized treatment strategy., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)