Search

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 cm3 compared to no adaptation. Bladder-PTV overlap decreased from a median of 142 to 71 cm3, and from 39 to 16 cm3 for rectum-PTV. Fully online-adaptive approaches could further decrease the PTV volume by 144 cm3 using a 5 mm margin for residual errors. In this scenario, bladder-PTV overlap was reduced to 35 cm3 and rectum-PTV overlap to 11 cm3. 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

BackgroundThe first clinical trials to assess the feasibility of FLASH radiotherapy in humans have started (FAST-01, FAST-02) and more trials are foreseen. To increase comparability between trials it is important to assure treatment quality and therefore establish a standard for machine quality assurance (QA). Currently, the AAPM TG-224 report is considered as the standard on machine QA for proton therapy, however, it was not intended to be used for ultra-high dose rate (UHDR) proton beams, which have gained interest due to the observation of the FLASH effect.PurposeThe aim of this study is to find consensus on practical guidelines on machine QA for UHDR proton beams in transmission mode in terms of which QA is required, how they should be done, which detectors are suitable for UHDR machine QA, and what tolerance limits should be applied.MethodsA risk assessment to determine the gaps in the current standard for machine QA was performed by an international group of medical physicists. Based on that, practical guidelines on how to perform machine QA for UHDR proton beams were proposed.ResultsThe risk assessment clearly identified the need for additional guidance on temporal dosimetry, addressing dose rate (constancy), dose spillage, and scanning speed. In addition, several minor changes from AAPM TG-224 were identified; define required dose rate levels, the use of clinically relevant dose levels, and the use of adapted beam settings to minimize activation of detector and phantom materials or to avoid saturation effects of specific detectors. The final report was created based on discussions and consensus.ConclusionsConsensus was reached on what QA is required for UHDR scanning proton beams in transmission mode for isochronous cyclotron-based systems and how they should be performed. However, the group discussions also showed that there is a lack of high temporal resolution detectors and sufficient QA data to set appropriate limits for some of the proposed QA procedure

Purpose: One-table treatments with treatment imaging, preparation and delivery occurring at one treatment couch, could increase patients’ comfort and throughput for palliative treatments. On regular C-arm linacs, however, cone-beam CT (CBCT) imaging quality is currently insufficient. Therefore, our goal was to assess the suitability of AI-generated CBCT based synthetic CT (sCT) images for target delineation and treatment planning for palliative radiotherapy. Materials and methods: CBCTs and planning CT-scans of 22 female patients with pelvic bone metastasis were included. For each CBCT, a corresponding sCT image was generated by a deep learning model in ADMIRE 3.38.0. Radiation oncologists delineated 23 target volumes (TV) on the sCTs (TVsCT) and scored their delineation confidence. The delineations were transferred to planning CTs and manually adjusted if needed to yield gold standard target volumes (TVclin). TVsCT were geometrically compared to TVclin using Dice coefficient (DC) and Hausdorff Distance (HD). The dosimetric impact of TVsCT inaccuracies was evaluated for VMAT plans with different PTV margins. Results: Radiation oncologists scored the sCT quality as sufficient for 13/23 TVsCT (median: DC = 0.9, HD = 11 mm) and insufficient for 10/23 TVsCT (median: DC = 0.7, HD = 34 mm). For the sufficient category, remaining inaccuracies could be compensated by +1 to +4 mm additional margin to achieve coverage of V95% > 95% and V95% > 98%, respectively in 12/13 TVsCT. Conclusion: The evaluated sCT quality allowed for accurate delineation for most targets. sCTs with insufficient quality could be identified accurately upfront. A moderate PTV margin expansion could address remaining delineation inaccuracies. Therefore, these findings support further exploration of CBCT based one-table treatments on C-arm linacs.

Background and purpose:To evaluate the performance of automated surface-guided gating for left-sided breast cancer with DIBH and VMAT. Materials and methods: Patients treated in the first year after introduction of DIBH with VMAT were retrospectively considered for analysis. With automated surface-guided gating the beam automatically switches on/off, if the surface region of interest moved in/out the gating tolerance (±3 mm, ±3°). Patients were coached to hold their breath as long as comfortably possible. Depending on the patient's preference, patients received audio instructions during treatment delivery. Real-time positional variations of the breast/chest wall surface with respect to the reference surface were collected, for all three orthogonal directions. The durations and number of DIBHs needed to complete dose delivery, and DIBH position variations were determined. To evaluate an optimal gating window threshold, smaller tolerances of ±2.5 mm, ±2.0 mm, and ±1.5 mm were simulated. Results: 525 fractions from 33 patients showed that median DIBH duration was 51 s (range: 30–121 s), and median 4 DIBHs per fraction were needed to complete VMAT dose delivery. Median intra-DIBH stability and intrafractional DIBH reproducibility approximated 1.0 mm in each direction. No large differences were found between patients who preferred to perform the DIBH procedure with (n = 21) and without audio-coaching (n = 12). Simulations demonstrated that gating window tolerances could be reduced from ±3.0 mm to ±2.0 mm, without affecting beam-on status. Conclusion: Independent of the use of audio-coaching, this study demonstrates that automated surface-guided gating with DIBH and VMAT proved highly efficient. Patients’ DIBH performance far exceeded our expectations compared to earlier experiences and literature. Furthermore, gating window tolerances could be reduced.

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 (offlineTB 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 offlineTB 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, offlineTB 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 offlineTB re-planning, eight repeat-CTs had zero probability of obtaining D 98% ≥ 95%D pres for CTV7000, 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. Sig

Objective. Determining and verifying the number of monitor units is crucial to achieving the desired dose distribution in radiotherapy and maintaining treatment efficacy. However, current commercial treatment planning system(s) dedicated to ocular passive eyelines in proton therapy do not provide the number of monitor units for patient-specific plan delivery. Performing specific pre-treatment field measurements, which is time and resource consuming, is usually gold-standard practice. This proof-of-concept study reports on the development of a multi-institutional-based generalized model for monitor units determination in proton therapy for eye melanoma treatments. Approach. To cope with the small number of patients being treated in proton centers, three European institutes participated in this study. Measurements data were collected to address output factor differences across the institutes, especially as function of field size, spread-out Bragg peak modulation width, residual range, and air gap. A generic model for monitor units prediction using a large number of 3748 patients and broad diversity in tumor patterns, was evaluated using six popular machine learning algorithms: (i) decision tree; (ii) random forest, (iii) extra trees, (iv) K-nearest neighbors, (v) gradient boosting, and (vi) the support vector regression. Features used as inputs into each machine learning pipeline were: Spread-out Bragg peak width, range, air gap, fraction and calibration doses. Performance measure was scored using the mean absolute error, which was the difference between predicted and real monitor units, as collected from institutional gold-standard methods. Main results. Predictions across algorithms were accurate within 3% uncertainty for up to 85.2% of the plans and within 10% uncertainty for up to 98.6% of the plans with the extra trees algorithm. Significance. A proof-of-concept of using machine learning-based generic monitor units determination in ocular proton therapy has be

Background and purpose: To quantify the increase in bladder and rectum dose of a bone marrow sparing (BMS) VMAT strategy for primary treatment of locally advanced cervical cancer (LACC). Materials and methods: Twenty patients with stage IB-IVA cervical cancer were selected for this study. The whole Pelvic Bones (PB) was taken as substitute for bone marrow. For every patient, Pareto-optimal plans were generated to explore the trade-off between rectum, bladder, and PB mean dose. The PB mean dose was decreased in steps of 1 Gy. For each step, the increase in rectum and bladder mean dose was quantified. The increase in mean dose of other OAR compared to no BMS was constrained to 1 Gy. Results: In total, 931 plans of 19 evaluable patients were analyzed. The average [range] mean dose of PB without BMS was 22.8 [20.7-26.2] Gy. When maximum BMS was applied, the average reduction in mean PB dose was 5.4 [3.0-6.8] Gy resulting in an average mean PB dose of 17.5 [15.8-19.8] Gy. For <1 Gy increase in both the bladder and the rectum mean dose, the PB mean dose could be decreased by >2 Gy, >3 Gy, >4 Gy, and >5 Gy for 19/19, 13/19, 5/19, and 1/19 patients, respectively. Conclusion: Based on the comprehensive three-dimensional Pareto front analysis, we conclude that 2-5 Gy BMS can be implemented without a clinically relevant increase in mean dose to other OAR. If BMS is too dominant, it results in a large increase in mean dose to other OAR. Therefore, we recommend implementing moderate BMS for the treatment of LACC patients with VMAT.

Objective:The Dutch proton robustness evaluation protocol prescribes the dose of the clinical target volume (CTV) to the voxel-wise minimum (VWmin) dose of 28 scenarios. This results in a consistent but conservative near-minimum CTV dose (D98%,CTV). In this study, we analyzed (i) the correlation between VWmin/voxel-wise maximum (VWmax) metrics and actually delivered dose to the CTV and organs at risk (OARs) under the impact of treatment errors, and (ii) the performance of the protocol before and after its calibration with adequate prescription-dose levels.Approach. Twenty-one neuro-oncological patients were included. Polynomial chaos expansion was applied to perform a probabilistic robustness evaluation using 100,000 complete fractionated treatments per patient. Patient-specific scenario distributions of clinically relevant dosimetric parameters for the CTV and OARs were determined and compared to clinical VWmin and VWmax dose metrics for different scenario subsets used in the robustness evaluation protocol.Main results. The inclusion of more geometrical scenarios leads to a significant increase of the conservativism of the protocol in terms of clinical VWmin and VWmax values for the CTV and OARs. The protocol could be calibrated using VWmin dose evaluation levels of 93.0%-92.3%, depending on the scenario subset selected. Despite this calibration of the protocol, robustness recipes for proton therapy showed remaining differences and an increased sensitivity to geometrical random errors compared to photon-based margin recipes.Significance. The Dutch proton robustness evaluation protocol, combined with the photon-based margin recipe, could be calibrated with a VWmin evaluation dose level of 92.5%. However, it shows limitations in predicting robustness in dose, especially for the near-maximum dose metrics to OARs. Consistent robustness recipes could improve proton treatment planning to calibrate residual differences from photon-based assumptions.

Background: Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient’s immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA). Methods: The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included. Discussion: In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination

Purpose: Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy of the head and neck, but not all regions of the mandible may be equally at risk. Therefore our goal was to explore a local dose response relationship for subregions of the mandible. Materials and methods: All oropharyngeal cancer patients treated at our hospital between 2009 and 2016 were reviewed. Follow-up was cut-off at 3 years. For patients that developed ORN, the ORN volume was delineated on the planning CT. Each mandible was divided into 16 volumes of interest (VOIs) based on the location of the dental elements and the presence of ORN in each was scored. Generalized estimating equations were used to build a model for the probability of developing ORN in an element VOI. Results: Of the 219 included patients, 22 developed ORN in 89 element VOIs. Mean dose to the element VOI (odds ratio (OR) = 1.05 per Gy, 95% confidence interval (CI): (1.04,1.07)), pre-radiotherapy extractions of an element ipsilateral to element of interest (OR = 2.81, 95% CI: (1.12,7.05)), and smoking at start of radiotherapy (OR = 3.37, 95% CI: (1.29,8.78)) were significantly associated with an increased probability of ORN in the VOI. Conclusion: The developed dose-response model indicates that the probability of ORN varies within the mandible and strongly depends on the local dose, the location of extractions, and smoking.

Background and purpose: In the Netherlands, head-and-neck cancer (HNC) patients are referred for proton therapy (PT) through model-based selection (MBS). However, treatment errors may compromise adequate CTV dose. Our aims are: (i) to derive probabilistic plan evaluation metrics on the CTV consistent with clinical metrics; (ii) to evaluate plan consistency between photon (VMAT) and proton (IMPT) planning in terms of CTV dose iso-effectiveness and (iii) to assess the robustness of the OAR doses and of the risk toxicities involved in the MBS. Materials and methods: Sixty HNC plans (30 IMPT/30 VMAT) were included. A robustness evaluation with 100,000 treatment scenarios per plan was performed using Polynomial Chaos Expansion (PCE). PCE was applied to determine scenario distributions of clinically relevant dosimetric parameters, which were compared between the 2 modalities. Finally, PCE-based probabilistic dose parameters were derived and compared to clinical PTV-based photon and voxel-wise proton evaluation metrics. Results: Probabilistic dose to near-minimum volume v = 99.8% for the CTV correlated best with clinical PTV-D98% and VWmin-D98%,CTV doses for VMAT and IMPT respectively. IMPT showed slightly higher nominal CTV doses, with an average increase of 0.8 GyRBE in the median of the D99.8%,CTV distribution. Most patients qualified for IMPT through the dysphagia grade II model, for which an average NTCP gain of 10.5 percentages points (%-point) was found. For all complications, uncertainties resulted in moderate NTCP spreads lower than 3 p.p. on average for both modalities. Conclusion: Despite the differences between photon and proton planning, the comparison between PTV-based VMAT and robust IMPT is consistent. Treatment errors had a moderate impact on NTCPs, showing that the nominal plans are a good estimator to qualify patients for PT.

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.

Objective. In radiotherapy, the internal movement of organs between treatment sessions causes errors in the final radiation dose delivery. To assess the need for adaptation, motion models can be used to simulate dominant motion patterns and assess anatomical robustness before delivery. Traditionally, such models are based on principal component analysis (PCA) and are either patient-specific (requiring several scans per patient) or population-based, applying the same set of deformations to all patients. We present a hybrid approach which, based on population data, allows to predict patient-specific inter-fraction variations for an individual patient. Approach. We propose a deep learning probabilistic framework that generates deformation vector fields warping a patient's planning computed tomography (CT) into possible patient-specific anatomies. This daily anatomy model (DAM) uses few random variables capturing groups of correlated movements. Given a new planning CT, DAM estimates the joint distribution over the variables, with each sample from the distribution corresponding to a different deformation. We train our model using dataset of 312 CT pairs with prostate, bladder, and rectum delineations from 38 prostate cancer patients. For 2 additional patients (22 CTs), we compute the contour overlap between real and generated images, and compare the sampled and ‘ground truth’ distributions of volume and center of mass changes. Results. With a DICE score of 0.86 ± 0.05 and a distance between prostate contours of 1.09 ± 0.93 mm, DAM matches and improves upon previously published PCA-based models, using as few as 8 latent variables. The overlap between distributions further indicates that DAM’s sampled movements match the range and frequency of clinically observed daily changes on repeat CTs. Significance. Conditioned only on planning CT values and organ contours of a new patient without any pre-processing, DAM can accurately deformations seen during following treatment

Background and purpose: Image-guided adaptive brachytherapy (IGABT) is an important modality in the cervical cancer treatment, and plan quality is sensitive to time pressure in the workflow. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) has been demonstrated to detect suboptimal plans (outliers). This analysis quantifies the possible improvement of plans detected as outliers, and investigates its suitability as a clinical QA tool in a multi-center setting. Materials and methods: In previous work OVH-based models were investigated for the use of QA. In this work a total of 160 plans of 68 patients treated in accordance with the current state-of-the-art IGABT protocol from Erasmus MC (EMC) were analyzed, with a model based on 120 plans (60 patients) from UMC Utrecht (UMCU). Machine-learning models were trained to define QA thresholds, and to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs of the EMC cohort. Plans out of set thresholds (outliers) were investigated and retrospectively replanned based on predicted D2cm3 values. Results: Analysis of replanned plans demonstrated a median improvement of 0.62 Gy for all Organs At Risk (OARs) combined and an improvement for 96 % of all replanned plans. Outlier status was resolved for 36 % of the replanned plans. The majority of the plans that could not be replanned were reported having implantation complications or insufficient coverage due to tumor geometry. Conclusion: OVH-based QA models can detect suboptimal plans, including both unproblematic BT applications and suboptimal planning circumstances in general. OVH-based QA models demonstrate potential for clinical use in terms of performance and user-friendliness, and could be used for knowledge transfer between institutes. Further research is necessary to differentiate between (sub)optimal planning circumstances.

Perfusion MRI is promising for the assessment, prediction, and monitoring of radiation toxicity in organs at risk in head and neck cancer. Arterial spin labeling (ASL) may be an attractive alternative for conventional perfusion MRI, that does not require the administration of contrast agents. However, currently, little is known about the characteristics and performance of ASL in healthy tissues in the head and neck region. Therefore, the purpose of this study was to optimize and evaluate multidelay pseudocontinuous ASL (pCASL) for the head and neck region and to explore nominal values and measurement repeatability for the blood flow (BF), and the transit time and T1 values needed for BF quantification in healthy tissues. Twenty healthy volunteers underwent a scan session consisting of four repeats of multidelay pCASL (postlabel delays: 1000, 1632, 2479 ms). Regions of interest were defined in the parotid glands, submandibular glands, tonsils, and the cerebellum (as a reference). Nominal values of BF were calculated as the average over four repeats per volunteer. The repeatability coefficient and within-subject coefficient of repeatability (wCV) of BF were calculated. The effect of T1 (map vs. cohort average) and transit time correction on BF was investigated. The mean BF (+/- SE) was 55.7 +/- 3.1 ml/100 g/min for the parotid glands, 41.2 +/- 2.8 ml/100 g/min for the submandibular glands, and 32.3 +/- 2.2 ml/100 g/min for the tonsils. The best repeatability was found in the parotid glands (wCV = 13.3%-16.1%), followed by the submandibular glands and tonsils (wCV = 20.0%-24.6%). On average, the effect of T1 and transit time correction on BF was limited, although substantial bias occurred in individual acquisitions. In conclusion, we demonstrated the feasibility of BF measurements in the head and neck region using multidelay pCASL and reported on nominal BF values, BF repeatability, the effect of T1, and transit time in various tissues in the head and neck region.

Background/purpose: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients’ quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. Material and methods: We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. Results: All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. Conclusion: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

Background: Due to its specific physical characteristics, proton irradiation is especially suited for irradiation of chordomas and chondrosarcoma in the axial skeleton. Robust plan optimization renders the proton beam therapy more predictable upon individual setup errors. Reported experience with the planning and delivery of robustly optimized plans in chordoma and chondrosarcoma of the mobile spine and sacrum, is limited. In this study, we report on the clinical use of robustly optimized, intensity modulated proton beam therapy in these patients. Methods: We retrospectively reviewed patient, treatment and acute toxicity data of all patients with chordoma and chondrosarcoma of the mobile spine and sacrum, treated between 1 April 2019 and 1 April 2020 at our institute. Anatomy changes during treatment were evaluated by weekly cone-beam CTs (CBCT), supplemented by scheduled control-CTs or ad-hoc control-CTs. Acute toxicity was scored weekly during treatment and at 3 months after therapy according to CTCAE 4.0. Results: 17 chordoma and 3 chondrosarcoma patients were included. Coverage of the high dose clinical target volume was 99.8% (range 56.1–100%) in the nominal and 80.9% (range 14.3–99.6%) in the voxel-wise minimum dose distribution. Treatment plan adaptation was needed in 5 out of 22 (22.7%) plans. Reasons for plan adaptation were either reduced tumor coverage or increased dose to the OAR. Conclusions: Robustly optimized intensity modulated proton beam therapy for chordoma and chondrosarcoma of the mobile spine is feasible. Plan adaptations due to anatomical changes were required in approximately 23 percent of treatment courses.

A review of studies on seminal vesicle motion was performed to improve the understanding of these treatment uncertainties. This will aid planning target volume margin reduction, which is necessary for hypofractionation of high-risk prostate cancer. Embase, Medline, Web of science Core collection, Cochrane CENTRAL register of trials and Google scholar were searched for publications including 3D information on seminal vesicle motion. In total 646 publications were found of which 22 publications were eligible for inclusion. The mean, systematic and random error of inter- and intra-fraction translations are reported, as well as rotations. The translations of the seminal vesicles is smallest in the left–right direction, whereas the rotation was largest around this axis. Although rectal and bladder filling status were the main cause for seminal vesicle motion, no apparent effect on magnitude of motion was seen when different bladder and rectal preparation protocols were used. Inter- and intra-fraction motion of the seminal vesicles is significant. In the studies, systematic and random errors range between 1–7 mm and 1–5 mm respectively, and are largely uncorrelated to prostate motion. The maximum correlation between seminal vesicle and prostate motion was reported with an R2 of 0.7, while 3 other studies report lower and/or non-significant correlations. Five studies report a planning target volume margin of approximately 8 mm. This margin is in line with the results of four relevant dosimetric studies. Mitigating the inter- and intra-fraction motion of the seminal vesicles, including prostate tracking, has the potential to reduce planning target volume margins.

Purpose: To investigate the potential clinical benefit of a two-beam arrangement technique using three-dimensional (3D) imaging of uveal melanoma (UM) patients treated with proton therapy and a dedicated eyeline. Material/Methods: Retrospective CT-based treatment plans of 39 UM patients performed using a single beam (SB) were compared to plans with two beams (TB) optimized for better trade-offs in organs-at-risk sparing. The RBE-weighted prescribed dose was 60 Gy (DRBE, GTV = 60 Gy) in four fractions, assuming an RBE of 1.1. Dosimetric findings were analyzed for three patient groups based on tumor-optic nerve distance and UM staging (group GrA: ≤3 mm, T1 T2 UM; GrB: ≤3 mm, T3 UM; GrC: >3 mm, T1 T2 T3 UM). Finally, two schedules were compared on biologically effective dose (BED): both beams being delivered either the same day (TB), or on alternate days (TBalter). Results: All strategies resulted in dosimetrically acceptable plans. A dose reduction to the anterior structures was achieved in 23/39 cases with the two-beam plans. D25% was significantly lowered compared to SB plans by 12.4 and 15.4 Gy RBE-weighted median dose in GrA and GrB, respectively. D2% was reduced by 18.6 and 6.0 Gy RBE-weighted median dose in GrA and GrB, respectively. A cost to the optic nerve was observed with a median difference up to 3.8 Gy RBE-weighted dose in GrB. BED differences were statistically significant for all considered parameters in favor of two beams delivered the same day. Conclusion: A two-beam strategy appears beneficial for posterior tumors abutting the optic nerve. This strategy might have a positive impact on the risk of ocular complications.

Purpose: To determine the dosimetric impact of using unedited autocontours in daily plan adaptation of patients with locally advanced pancreatic cancer (LAPC) treated with stereotactic body radiotherapy using tumor tracking. Materials and Methods: The study included 98 daily CT scans of 35 LAPC patients. All scans were manually contoured (MAN), and included the PTV and main organs-at-risk (OAR): stomach, duodenum and bowel. Precision and MIM deformable image registration (DIR) methods followed by contour propagation were used to generate autocontour sets on the daily CT scans. Autocontours remained unedited, and were compared to MAN on the whole organs and at 3, 1 and 0.5 cm from the PTV. Manual and autocontoured OAR were used to generate daily plans using the VOLO™ optimizer, and were compared to non-adapted plans. Resulting planned doses were compared based on PTV coverage and OAR dose-constraints. Results: Overall, both algorithms reported a high agreement between unclipped MAN and autocontours, but showed worse results when being evaluated on the clipped structures at 1 cm and 0.5 cm from the PTV. Replanning with unedited autocontours resulted in better OAR sparing than non-adapted plans for 95% and 84% plans optimized using Precision and MIM autocontours, respectively, and obeyed OAR constraints in 64% and 56% of replans. Conclusion: For the majority of fractions, manual correction of autocontours could be avoided or be limited to the region closest to the PTV. This practice could further reduce the overall timings of adaptive radiotherapy workflows for patients with LAPC.

Introduction The locoregional failure (LRF) rate in human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) remains disappointingly high and toxicity is substantial. Response prediction prior to or early during treatment would provide opportunities for personalised treatment. Currently, there are no accurate predictive models available for correct OPSCC patient selection. Apparently, the pivotal driving forces that determine how a OPSCC responds to treatment, have yet to be elucidated. Therefore, the holistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts study focuses on a holistic approach to gain insight in novel potential prognostic biomarkers, acquired before and early during treatment, to predict response to treatment in HPV-negative patients with OPSCC. Methods and analysis This single-centre prospective observational study investigates 60 HPV-negative patients with OPSCC scheduled for primary radiotherapy (RT) with cisplatin or cetuximab, according to current clinical practice. A holistic approach will be used that aims to map the macroscopic (with Intra Voxel Incoherent Motion Diffusion Kurtosis Imaging (IVIM-DKI); before, during, and 3 months after RT), microscopic (with biopsies of the primary tumour acquired before treatment and irradiated ex vivo to assess radiosensitivity), and molecular landscape (with circulating tumour DNA (ctDNA) analysed before, during and 3 months after treatment). The main end point is locoregional control (LRC) 2 years after treatment. The primary objective is to determine whether a relative change in the mean of the diffusion coefficient D (an IVIM-DKI parameter) in the primary tumour early during treatment, improves the performance of a predictive model consisting of tumour volume only, for 2 years LRC after treatment. The secondary objectives investigate the potential of other IVIM-DKI parameters, ex vivo sensitivity characteristics, ctDNA, and combinations thereof as potential nove

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 (fSR3) and a trigger-based offline adaptive schedule for 3 mm SR (fSR3OfA). Daily plan selection in the PL approach was based only on recomputed dose to the CTV on the rCT. Results: Compared to using fSR3 and fSR3OfA, 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. fSR3OfA resulted in significantly improved coverage compared to PL for selected patients. Conclusion: The proposed PL approach resulted in overall reduced NTCPs compared to fSR3 and fSR3OfA at limited cost in target coverage.

Background and purpose: Image-guided adaptive brachytherapy (IGABT) is a key component in the treatment of cervical cancer, but the nature of the clinical workflow makes it vulnerable to suboptimal plans, as the theoretical optimal plan depends heavily on organ configuration. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) is a promising tool to detect such suboptimal plans, and in this analysis its suitability as a multi-institutional clinical QA tool is investigated. Materials and methods: A total of 223 plans of 145 patients treated in accordance with the current state-of-the-art IGABT protocols from UMC Utrecht (UMCU) and Erasmus MC (EMC) were included. Machine-learning models were trained to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs. For this strategy, points are sampled on the organs-at-risk (OARs), and the distances of the sampled points to the target are computed and combined in a histogram. Machine-learning models can then be trained to predict dose-volume histograms (DVHs) for unseen data. Single-center model robustness to needle use and applicator type and multi-center model translatability were investigated. Performance of models was assessed by the difference between planned (clinical) and predicted D2cm3 values. Results: Intra-validation of UMCU data demonstrated OVH model robustness to needle use and applicator type. The model trained on UMCU data was found to be robust within the same protocol on EMC data, for all investigated OARs. Mean squared error between planned and predicted D2cm3 values of OARs ranged between 0.13 and 0.40 Gy within the same protocol, indicating model translatability. For the former protocol cohort of Erasmus MC large deviations were found between the planned and predicted D2cm3 values, indicating plan deviation from protocol. Mean squared error for this cohort ranged from 0.84 to 4.71 Gy. Conclusion: OV

Background and purpose: A potential challenge in single-isocenter multi-lesion lung stereotactic body radiotherapy (SBRT) is that patient positioning is not based on each lesion individually, but on the average position of all lesions. This may lead to larger margins compared to treating with one isocenter per lesion, but increases workflow efficiency. The aim of this study was to investigate whether a single-isocenter technique leads to increased normal lung dose compared to a conventional multiple-isocenters technique. Materials and methods: A cohort of 15 NSCLC patients with two or three lesions previously treated with SBRT was subjected to treatment planning with a multiple-isocenter technique and a single-isocenter technique. For the latter, two margin approaches were evaluated: (1) identical margins for each internal target volume (ITV), assuming an average registration for all lesions in cone-beam CT (CBCT) positioning verification and (2) a smaller margin for the largest lesion, assuming an optimal registration for that lesion. For all 45 treatment plans, mean lung dose (MLD) and lungs-V20Gy were evaluated. The study was performed following RATING guidelines. Results: The MLD was 4.9 ± 1.9 Gy (mean ± SD) for multiple-isocenters and 5.4 ± 2.1 Gy and 5.3 ± 2.2 Gy for single-isocenter approach 1 and 2, respectively. V20Gy was 5.5 ± 3.7%, 5.5 ± 3.2% and 5.4 ± 3.3%. A median [range] increase in MLD of 11.6% [−14.9 – 26.8] was observed when comparing single-isocenter treatment plans to those with multiple isocenters. V20Gy increased by 0.2 [−3.4 – 1.3] percentage points. Conclusion: A single-isocenter SBRT technique for lung patients with multiple targets results in clinically acceptable increases in normal lung dose.

BACKGROUND AND PURPOSE A potential challenge in single-isocenter multi-lesion lung stereotactic body radiotherapy (SBRT) is that patient positioning is not based on each lesion individually, but on the average position of all lesions. This may lead to larger margins compared to treating with one isocenter per lesion, but increases workflow efficiency. The aim of this study was to investigate whether a single-isocenter technique leads to increased normal lung dose compared to a conventional multiple-isocenters technique. MATERIALS AND METHODS A cohort of 15 NSCLC patients with two or three lesions previously treated with SBRT was subjected to treatment planning with a multiple-isocenter technique and a single-isocenter technique. For the latter, two margin approaches were evaluated: 1) identical margins for each internal target volume (ITV), assuming an average registration for all lesions in cone-beam CT (CBCT) positioning verification and 2) a smaller margin for the largest lesion, assuming an optimal registration for that lesion. For all 45 treatment plans, mean lung dose (MLD) and lungs-V$_{20Gy}$ were evaluated. The study was performed following RATING guidelines. RESULTS The MLD was 4.9±1.9 Gy (mean±SD) for multiple-isocenters and 5.4±2.1 Gy and 5.3±2.2 Gy for single-isocenter approach 1 and 2, respectively. V$_{20Gy}$ was 5.5±3.7%, 5.5±3.2% and 5.4±3.3%. A median [range] increase in MLD of 11.6% [-14.9 - 26.8] was observed when comparing single-isocenter treatment plans to those with multiple isocenters. V$_{20Gy}$ increased by 0.2 [-3.4 - 1.3] percentage points. CONCLUSION A single-isocenter SBRT technique for lung patients with multiple targets results in clinically acceptable increases in normal lung dose.

Background/purpose: Intensity-modulated proton therapy is highly sensitive to anatomical variations. A dose restoration method and a full plan adaptation method have been developed earlier, both requiring several parameter settings. This study evaluates the validity of the previously selected settings by systematically comparing them to alternatives. Materials/methods: The dose restoration method takes a prior plan and uses an energy-adaptation followed by a spot-intensity re-optimization to restore the plan to its initial state. The full adaptation method uses an energy-adaptation followed by the addition of new spots and a spot-intensity optimization to fit the new anatomy. We varied: 1) The margins and robustness settings of the prior plan, 2) the spot-addition sample size, i.e. the number of added spots, 3) the spot-addition stopping criterion, and 4) the spot-intensity optimization approach. The last three were evaluated only for the full plan adaptation. Evaluations were done on 88 CT scans of 11 prostate cancer patients. Dose was prescribed as 55 Gy(RBE) to the lymph nodes and seminal vesicles with a boost to 74 Gy(RBE) to the prostate. Results: For the dose restoration method, changing the applied CTV-to-PTV margins and plan robustness in the prior plans yielded insufficient target coverage or increased OAR doses. For the full plan adaptation, more spot-addition iterations and using a different optimization approach resulted in lower OAR doses compared to the default settings while maintaining target coverage. However, the calculation times increased by up to 20 times, making these variations infeasible for online-adaptation. Conclusion: We recommend maintaining the default setting for the dose restoration approach. For the full plan adaptation we recommend to focus on fine-tuning the optimization-parameters, and apart from this using the default settings.