Multidelay pseudocontinuous arterial spin labeling to measure blood flow in the head and neck.

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.

HYpofractionated, dose-redistributed RAdiotherapy with protons and photons to combat radiation-induced immunosuppression in head and neck squamous cell carcinoma: study protocol of the phase I HYDRA trial.

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 of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA's expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022).

Post radiation mucosal ulcer risk after a hypofractionated stereotactic boost and conventional fractionated radiotherapy for oropharyngeal carcinoma.

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.

An optimal acquisition and post-processing pipeline for hybrid IVIM-DKI in head and neck.

PURPOSE: To optimize the diffusion-weighting b values and postprocessing pipeline for hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region. METHODS: Optimized diffusion-weighting b value sets ranging between 5 and 30 b values were constructed by optimizing the Cramér-Rao lower bound of the hybrid intravoxel incoherent motion diffusion kurtosis imaging model. With this model, the perfusion fraction, pseudodiffusion coefficient, diffusion coefficient, and kurtosis were estimated. Sixteen volunteers were scanned with a reference b value set and 3 repeats of the optimized sets, of which 1 with volunteers swallowing on purpose. The effects of (1) b value optimization and number of b values, (2) registration type (none vs. intervolume vs. intra- and intervolume registration), and (3) manual swallowing artifact rejection on the parameter precision were assessed. RESULTS: The SD was higher in the reference set for perfusion fraction, diffusion coefficient, and kurtosis by a factor of 1.7, 1.5, and 2.3 compared to the optimized set, respectively. A smaller SD (factor 0.7) was seen in pseudodiffusion coefficient. The sets containing 15, 20, and 30 b values had comparable repeatability in all parameters, except pseudodiffusion coefficient, for which set size 30 was worse. Equal repeatability for the registration approaches was seen in all parameters of interest. Swallowing artifact rejection removed the bias when present. CONCLUSION: To achieve optimal hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region, b value optimization and swallowing artifact image rejection are beneficial. The optimized set of 15 b values yielded the optimal protocol efficiency, with a precision comparable to larger b value sets and a 50% reduction in scan time.

Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy.

Background: Stereotactic body radiation therapy (SBRT) results in high local control (LC) rates in patients with non-small cell lung cancer (NSCLC). For central lung tumors, risk-adapted fractionation schedules are used and underdosage to the Planned Target Volume (PTV) is often accepted to respect the dose constraints of the organs at risk in order to avoid high rates of toxicity. The purpose of this study was to analyze the effect of PTV underdosage and other possible prognostic factors on local- and disease control after SBRT in patients with central lung tumors.Material and Methods: Patients with centrally located NSCLC treated with SBRT were included. The doses were converted into biologically equivalent dose using α/ß-value of 10 Gy (BED10). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED10; (%)PTV < 100 BED10. Potential prognostic factors for LC and Disease Free Survival (DFS) were evaluated using Cox regression analysis.Results: Two hundred and twenty patients received ≤12 fractions of SBRT. LC-rates were 88% at 2 years and 81% at 3 years. Twenty-seven patients developed a local recurrence. Both the PTV < 100 BED10 and %PTV < 100 BED10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV1) were independently prognostic for LC. Disease progression was reported in 75 patients with DFS-rates of 66% at 2 years and 56% at 3 years. Disease recurrence was independent significantly associated with larger tumor diameter, lower lobe tumor location and decreased FEV1. Grade 4-5 toxicity was reported in 10 patients (8 with ultra-central tumors) and was fatal in at least 3 patients.Conclusion: Decrease in tumor coverage was not correlated with the local recurrence probability. The LC and DFS were promising after SBRT of centrally located NSCLC with tumor size, FEV1 and tumor location (for DFS only) as prognostic factors.

Commissioning and clinical implementation of the first commercial independent Monte Carlo 3D dose calculation to replace CyberKnife M6™ patient-specific QA measurements.

PURPOSE: To report on the commissioning and clinical validation of the first commercially available independent Monte Carlo (MC) three-dimensional (3D) dose calculation for CyberKnife robotic radiosurgery system® (Accuray, Sunnyvale, CA). METHODS: The independent dose calculation (IDC) by SciMoCa® (Scientific RT, Munich, Germany) was validated based on water measurements of output factors and dose profiles (unshielded diode, field-size dependent corrections). A set of 84 patient-specific quality assurance (QA) measurements for multi-leaf collimator (MLC) plans, using an Octavius two-dimensional SRS1000 array (PTW, Freiburg, Germany), was compared to results of respective calculations. Statistical process control (SPC) was used to detect plans outside action levels. RESULTS: Of all output factors for the three collimator systems of the CyberKnife, 99% agreed within 2% and 81% within 1%, with a maximum deviation of 3.2% for a 5-mm fixed cone. The profiles were compared using a one-dimensional gamma evaluation with 2% dose difference and 0.5 mm distance-to-agreement (Γ(2,0.5)). The off-centre ratios showed an average pass rate >99% (92-100%). The agreement of the depth dose profiles depended on field size, with lowest pass rates for the smallest MLC field sizes. The average depth dose pass rate was 88% (35-99%). The IDCs showed a Γ(2,1) pass rate of 98%. Statistical process control detected six plans outside tolerance levels in the measurements, all of which could be attributed the measurement setup. Independent dose calculations showed problems in five plans, all due to differences in the algorithm between TPS and IDC. Based on these results changes were made in the class solution for treatment plans. CONCLUSION: The first commercially available MC 3D dose IDC was successfully commissioned and validated for the CyberKnife and replaced all routine patient-specific QA measurements in our clinic.

Plan-library supported automated replanning for online-adaptive intensity-modulated proton therapy of cervical cancer.

Background: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day-to-day variations are seen for cervical cancer patients. The purpose of this study was to develop and evaluate a novel method for online selection of a plan from a patient-specific library of prior plans for different anatomies, and adapt it for the daily anatomy. Material and methods: The patient-specific library of prior plans accounting for altered target geometries was generated using a pretreatment established target motion model. Each fraction, the best fitting prior plan was selected. This prior plan was adapted using (1) a restoration of spot-positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast optimization of the spot-weights with the reference point method (RPM) to obtain a Pareto-optimal plan for the daily anatomy. Spot addition and spot-weight optimization could be repeated iteratively. The patient cohort consisted of six patients with in total 23 repeat-CT scans, with a prescribed dose of 45 Gy(RBE) to the primary tumor and the nodal CTV. Using a 1-plan-library (one prior plan based on all motion in the motion model) was compared to choosing from a 2-plan-library (two prior plans based on part of the motion). Results: Applying the prior-plan adaptation method with one iteration of adding spots resulted in clinically acceptable target coverage ( V95%≥95% and V107%≤2% ) for 37/46 plans using the 1-plan-library and 41/46 plans for the 2-plan-library. When adding spots twice, the 2-plan-library approach could obtain acceptable coverage for all scans, while the 1-plan-library approach showed V107%>2% for 3/46 plans. Similar OAR results were obtained. Conclusion: The automated prior-plan adaptation method can successfully adapt for the large day-to-day variations observed in cervical cancer patients.

Impact of model and dose uncertainty on model-based selection of oropharyngeal cancer patients for proton therapy.

BACKGROUND: Proton therapy is becoming increasingly available, so it is important to apply objective and individualized patient selection to identify those who are expected to benefit most from proton therapy compared to conventional intensity modulated radiation therapy (IMRT). Comparative treatment planning using normal tissue complication probability (NTCP) evaluation has recently been proposed. This work investigates the impact of NTCP model and dose uncertainties on model-based patient selection. MATERIAL AND METHODS: We used IMRT and intensity modulated proton therapy (IMPT) treatment plans of 78 oropharyngeal cancer patients, which were generated based on automated treatment planning and evaluated based on three published NTCP models. A reduction in NTCP of more than a certain threshold (e.g. 10% lower NTCP) leads to patient selection for IMPT, referred to as 'nominal' selection. To simulate the effect of uncertainties in NTCP-model coefficients (based on reported confidence intervals) and planned doses on the accuracy of model-based patient selection, the Monte Carlo method was used to sample NTCP-model coefficients and doses from a probability distribution centered at their nominal values. Patient selection accuracy within a certain sample was defined as the fraction of patients which had similar selection in both the 'nominal' and 'sampled' scenario. RESULTS: For all three NTCP models, the median patient selection accuracy was found to be above 70% when only NTCP-model uncertainty was considered. Selection accuracy decreased with increasing uncertainty resulting from differences between planned and delivered dose. In case of excessive dose uncertainty, selection accuracy decreased to 60%. CONCLUSION: Model and dose uncertainty highly influence the accuracy of model-based patient selection for proton therapy. A reduction of NTCP-model uncertainty is necessary to reach more accurate model-based patient selection.

CyberKnife robotic spinal radiosurgery in prone position: dosimetric advantage due to posterior radiation access?

CyberKnife spinal radiosurgery suffers from a lack of posterior beams due to workspace limitations. This is remedied by a newly available tracking modality for fiducial-free, respiration-compensated spine tracking in prone patient position. We analyzed the potential dosimetric benefit in a planning study. Fourteen exemplary cases were compared in three scenarios: supine (PTV=CTV), prone (PTV=CTV), and prone position with an additional margin (PTV=CTV+2 mm), to incorporate reduced accuracy of respiration-compensated tracking. Target and spinal cord constraints were chosen according to RTOG 0631 protocol for spinal metastases. Plan quality was scored based on four predefined parameters: dose to cord (D0.1cc and D1cc), high dose (V10Gy), and low dose (V4Gy) volume of healthy tissue. Prescription dose was 16 Gy to the highest isodose line encompassing 90% of the target. Results were related to target size and position. All plans fulfilled RTOG 0631 constraints for coverage and dose to cord. When no additional margin was applied, a majority of eight cases benefitted from prone position, mainly due to a reduction of V4Gy by 23% ± 26%. In the 2 mm prone scenario, the benefit was nullified by an average increase of V10Gy by 43% ± 24%, and an increase of D1cc to cord (four cases). Spinal cord D0.1cc was unchanged (< ± 1 Gy) in all but two cases for both prone scenarios. Conformity (nCI) and number of beams were equivalent in all scenarios, but supine plans used a significantly higher number of monitor units (+16%) than prone. Posterior beam access can reduce dose to healthy tissue in CyberKnife spinal radiosurgery when no additional margin is applied. When a target margin of 2 mm is added, this potential gain is lost. Relative anterior-posterior position and size of the target are selection criteria for prone treatment.

Clinical practicality and patient performance for surface-guided automated VMAT gating for DIBH breast cancer radiotherapy.

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.

Relating pre-treatment non-Gaussian intravoxel incoherent motion diffusion-weighted imaging to human papillomavirus status and response in oropharyngeal carcinoma.

Background and purpose: Diffusion-weighted imaging (DWI) is a promising technique for response assessment in head-and-neck cancer. Recently, we optimized Non-Gaussian Intravoxel Incoherent Motion Imaging (NG-IVIM), an extension of the conventional apparent diffusion coefficient (ADC) model, for the head and neck. In the current study, we describe the first application in a group of patients with human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma. The aim of this study was to relate ADC and NG-IVIM DWI parameters to HPV status and clinical treatment response. Materials and methods: Thirty-six patients (18 HPV-positive, 18 HPV-negative) were prospectively included. Presence of progressive disease was scored within one year. The mean pre-treatment ADC and NG-IVIM parameters in the gross tumor volume were compared between HPV-positive and HPV-negative patients. In HPV-negative patients, ADC and NG-IVIM parameters were compared between patients with and without progressive disease. Results: ADC, the NG-IVIM diffusion coefficient D, and perfusion fraction f were significantly higher, while pseudo-diffusion coefficient D* and kurtosis K were significantly lower in the HPV-negative compared to HPV-positive patients. In the HPV-negative group, a significantly lower D was found for patients with progressive disease compared to complete responders. No relation with ADC was observed. Conclusion: The results of our single-center study suggest that ADC is related to HPV status, but not an independent response predictor. The NG-IVIM parameter D, however, was independently associated to response in the HPV-negative group. Noteworthy in the opposite direction as previously thought based on ADC.

Adaptive radiotherapy in locally advanced prostate cancer using a statistical deformable motion model.

UNLABELLED: Daily treatment plan selection from a plan library is a major adaptive radiotherapy strategy to account for individual internal anatomy variations. This strategy depends on the initial input images being representative for the variations observed later in the treatment course. Focusing on locally advanced prostate cancer, our aim was to evaluate if residual motion of the prostate (CTV-p) and the elective targets (CTV-sv, CTV-ln) can be prospectively accounted for with a statistical deformable model based on images acquired in the initial part of treatment. METHODS: Thirteen patients with locally advanced prostate cancer, each with 9-10 repeat CT scans, were included. Displacement vectors fields (DVF) obtained from contour-based deformable registration of delineations in the repeat- and planning CT scans were used to create patient-specific statistical motion models using principal component analysis (PCA). For each patient and CTV, four PCA-models were created: one with all 9-10 DVF as input in addition to models with only four, five or six DVFs as input. Simulations of target shapes from each PCA-model were used to calculate iso-coverage levels, which were converted to contours. The levels were analyzed for sensitivity and precision. RESULTS: A union of the simulated shapes was able to cover at least 97%, 97% and 95% of the volumes of the evaluated CTV shapes for PCA-models using six, five and four DVFs as input, respectively. There was a decrease in sensitivity with higher iso-coverage levels, with a sharper decline for greater target movements. Apart from having the steepest decline in sensitivity, CTV-sv also displayed the greatest influence on the number of geometries used in the PCA-model. CONCLUSIONS: PCA-based simulations of residual motion derived from four to six DVFs as input could account for the majority of the target shapes present during the latter part of the treatment. CTV-sv displayed the greatest range in both sensitivity and precision.

Pencil-beam Delivery Pattern Optimization Increases Dose Rate for Stereotactic FLASH Proton Therapy.

PURPOSE: FLASH dose rates >40 Gy/s are readily available in proton therapy (PT) with cyclotron-accelerated beams and pencil-beam scanning (PBS). The PBS delivery pattern will affect the local dose rate, as quantified by the PBS dose rate (PBS-DR), and therefore needs to be accounted for in FLASH-PT with PBS, but it is not yet clear how. Our aim was to optimize patient-specific scan patterns for stereotactic FLASH-PT of early-stage lung cancer and lung metastases, maximizing the volume irradiated with PBS-DR >40 Gy/s of the organs at risk voxels irradiated to >8 Gy (FLASH coverage). METHODS AND MATERIALS: Plans to 54 Gy/3 fractions with 3 equiangular coplanar 244 MeV proton shoot-through transmission beams for 20 patients were optimized with in-house developed software. Planning target volume-based planning with a 5 mm margin was used. Planning target volume ranged from 4.4 to 84 cc. Scan-pattern optimization was performed with a Genetic Algorithm, run in parallel for 20 independent populations (islands). Mapped crossover, inversion, swap, and shift operators were applied to achieve (local) optimality on each island, with migration between them for global optimality. The cost function was chosen to maximize the FLASH coverage per beam at >8 Gy, >40 Gy/s, and 40 nA beam current. The optimized patterns were evaluated on FLASH coverage, PBS-DR distribution, and population PBS-DR-volume histograms, compared with standard line-by-line scanning. Robustness against beam current variation was investigated. RESULTS: The optimized patterns have a snowflake-like structure, combined with outward swirling for larger targets. A population median FLASH coverage of 29.0% was obtained for optimized patterns compared with 6.9% for standard patterns, illustrating a significant increase in FLASH coverage for optimized patterns. For beam current variations of 5 nA, FLASH coverage varied between -6.1%-point and 2.2%-point for optimized patterns. CONCLUSIONS: Significant improvements on the PBS-DR and, hence, on FLASH coverage and potential healthy-tissue sparing are obtained by sequential scan-pattern optimization. The optimizer is flexible and may be further fine-tuned, based on the exact conditions for FLASH.

PTV-based VMAT vs. robust IMPT for head-and-neck cancer: A probabilistic uncertainty analysis of clinical plan evaluation with the Dutch model-based selection.

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.

Multi-center dosimetric predictions to improve plan quality for brachytherapy for cervical cancer 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.

Robustness analysis of CTV and OAR dose in clinical PBS-PT of neuro-oncological tumors: prescription-dose calibration and inter-patient variation with the Dutch proton robustness evaluation protocol.

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.

Development of a local dose-response relationship for osteoradionecrosis within the mandible.

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.

Accounting for fractionation and heterogeneous dose distributions in the modelling of osteoradionecrosis in oropharyngeal carcinoma treatment.

BACKGROUND AND PURPOSE: Osteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy (RT). With a renewed interest in hypofractionation for head and neck radiotherapy, more information concerning ORN development after high fraction doses is important. The aim of this explorative study was to develop a model for ORN risk prediction applicable across different fractionation schemes using Equivalent Uniform Doses (EUD). MATERIAL AND METHODS: We performed a retrospective cohort study in 334 oropharyngeal squamous cell carcinoma (OPSCC) patients treated with either a hypofractionated Stereotactic Body Radiation Therapy (HF-SBRT) boost or conventional Intensity Modulated Radiation Therapy (IMRT). ORN was scored with the CTCAE v5.0. HF-SBRT and IMRT dose distributions were converted into equivalent dose in 2 Gy fractions (α/ß = 0.85 Gy) and analyzed using EUD. The parameter a that led to an EUD that best discriminated patients with and without grade ≥ 2 ORN was selected. Patient and treatment-related risk factors of ORN were analyzed with uni- and multivariable regression analysis. RESULTS: A total of 32 patients (9.6%) developed ORN grade ≥ 2. An EUD(a = 8) best discriminated between ORN and non-ORN (AUC = 0.71). In multivariable regression, pre-RT extractions (SHR = 2.34; p = 0.012), mandibular volume (SHR = 1.04; p = 0.003), and the EUD(a = 8) (SHR = 1.14; p < 0.001) were significantly associated with ORN. CONCLUSION: Risk models for ORN based on conventional DVH parameters cannot be directly applied to HF-SBRT fractionation schemes and dose distributions. However, after correcting for fractionation and non-uniform dose distributions using EUD, a single model can distinguish between ORN and non-ORN after conventionally fractionated radiotherapy and hypofractionated boost treatments.

Early and late contrast enhancing lesions after photon radiotherapy for IDH mutated grade 2 diffuse glioma.

OBJECTIVE: The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy. METHODS: We reviewed all follow-up MRI's of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1-1-2007 and 31-12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD. RESULTS: A total of 860 MRI's of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI's. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients. CONCLUSION: The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD.

Cochlear-optimized treatment planning in photon and proton radiosurgery for vestibular schwannoma patients.

Objective: To investigate the potential to reduce the cochlear dose with robotic photon radiosurgery or intensity-modulated proton therapy planning for vestibular schwannomas. Materials and Methods: Clinically delivered photon radiosurgery treatment plans were compared to five cochlear-optimized plans: one photon and four proton plans (total of 120). A 1x12 Gy dose was prescribed. Photon plans were generated with Precision (Cyberknife, Accuray) with no PTV margin for set-up errors. Proton plans were generated using an in-house automated multi-criterial planning system with three or nine-beam arrangements, and applying 0 or 3 mm robustness for set-up errors during plan optimization and evaluation (and 3 % range robustness). The sample size was calculated based on a reduction of cochlear Dmean > 1.5 Gy(RBE) from the clinical plans, and resulted in 24 patients. Results: Compared to the clinical photon plans, a reduction of cochlear Dmean > 1.5 Gy(RBE) could be achieved in 11/24 cochlear-optimized photon plans, 4/24 and 6/24 cochlear-optimized proton plans without set-up robustness for three and nine-beam arrangement, respectively, and in 0/24 proton plans with set-up robustness. The cochlea could best be spared in cases with a distance between tumor and cochlea. Using nine proton beams resulted in a reduced dose to most organs at risk. Conclusion: Cochlear dose reduction is possible in vestibular schwannoma radiosurgery while maintaining tumor coverage, especially when the tumor is not adjacent to the cochlea. With current set-up robustness, proton therapy is capable of providing lower dose to organs at risk located distant to the tumor, but not for organs adjacent to it. Consequently, photon plans provided better cochlear sparing than proton plans.