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This study provided normal tissue complication probability (NTCP) calculations from photon radiotherapy techniques in eleven patients with thymoma. Five plans were created for each participant using three-dimensional conformal radiotherapy (3D-CRT), five-field intensity modulated radiotherapy (5F-IMRT), seven-field IMRT (7F-IMRT), and volumetric modulated arc therapy with full arcs (FA-VMAT) and partial arcs (PA-VMAT). The target coverage, homogeneity index and conformation number for the planning target volume (PTV) and dosimetric parameters for the organs-at-risk (OARs) were taken from the fifty-five generated plans. The patient-specific NTCP of the lungs, heart and esophagus was calculated with an in-house software tool using differential dose-volume histograms and the equivalent uniform dose model. The PTV dose metrics from 3D-CRT were inferior to those from IMRT and VMAT plans. The dose constraints for the OARs were met in all treatment plans. The NTCP range of the lungs, heart and esophagus was 0.34-0.49%, 0.03-0.06% and 0.08-0.10%, respectively. The NTCPs of the heart for the incidence of peridarditis from IMRT and VMAT were significantly smaller than those from conformal treatment ( p < 0.05). The 7F-IMRT was significantly superior to FA-VMAT in reducing the NTCP of the lungs and the risk of pneumonitis ( p = 0.001). Similar superiority of 5F-IMRT over PA-VMAT for lung protection was found ( p = 0.009). The presented results may be employed in the selection of the appropriate irradiation technique for restricting the complications in the adjacent OARs.

This study proposes phenomenological models for total normal tissue complication probability (TNTCP) and NTCP0. NTCP0 is a new acronym for reformulating the current complication-free cure (P+) and uncomplicated tumor control probability (UTCP) concepts, and TNTCP will reformulate the current NTCP involving multiple organs at risks. The current probabilistic concepts are incoherently formulated with mathematical operations of tumor control probability (TCP) and normal tissue complication probability (NTCP) that are associated with different stochastic processes and random variables. NTCP0 is equal to NTCP 0 (normal tissue non-complication probability) that is calculated as the ratio of a number of patients of a population without late complications and a total of them. As a cumulative distribution function (CDF) of late complications, TNTCP = sum(NTCP i ), where NTCP i is the NTCP of the i th late complication. TNTCP is also a new acronym, and the probabilistic complement of NTCP0, then NTCP0 = 100% - TNTCP. The NTCP0/TNTCP (D(d)) proposing models are based on the relationship between the NTCP0/TNTCP and total dose ( D  =  n × d ; where d = dose per fraction, and n = number of fractions). TNTCP(D) model will be correlated with LKB model (the normal CDF) that is an increasing function; and NTCP0(D) model with a decreasing function, which additionally will define clear limits of three possible regions for NTCP0: 0 and 100% deterministic, and a stochastic. These models are function D , which is widely used for characterizing radiation therapies.

Mathematical models of normal tissue complication probability (NTCP) able to robustly predict radiation-induced morbidities (RIM) play an essential role in the identification of a personalized optimal plan, and represent the key to maximizing the benefits of technological advances in radiation therapy (RT). Most modern RT techniques pose, however, new challenges in estimating the risk of RIM. The aim of this report is to schematically review NTCP models in the framework of advanced radiation therapy techniques. Issues relevant to hypofractionated stereotactic body RT and ion beam therapy are critically reviewed. Reirradiation scenarios for new or recurrent malignances and NTCP are also illustrated. A new phenomenological approach to predict RIM is suggested., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC)., Materials and Methods: Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression., Results: CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V 35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity . The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm 3 ). Using a threshold of 30 cm 3 , risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V 35-45Gy . Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort., Conclusions: In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The normal tissue complication probability (NTCP) is a measure for the estimated side effects of a given radiation treatment schedule. Here we use a stochastic logistic birth-death process to define an organ-specific and patient-specific NTCP. We emphasize an asymptotic simplification which relates the NTCP to the solution of a logistic differential equation. This framework is based on simple modelling assumptions and it prepares a framework for the use of the NTCP model in clinical practice. As example, we consider side effects of prostate cancer brachytherapy such as increase in urinal frequency, urinal retention and acute rectal dysfunction., (© The authors 2016. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)

OBJECTIVE In this study, different fraction sizes in prostate cancer will be examined using a radiobiological model. METHODS Fifty patients diagnosed with low-risk prostate cancer who were treated between 2009 and 2021 were identified retrospectively. Conventional (CF) and ultra-hypofractionated (HF) volume-adjusted arc plans were calculated for selected prostate patients. Mathematical formulations were created for radiobiological modeling of tumor control probability (TCP) and normal tissue complication probability (NTCP) in the Matlab program. Dose-volume histogram (DVH) data of the plans were examined in the Matlab program. RESULTS Bladder and rectum NTCP values were significantly lower in the HF technique compared to the CF technique (p<0.05). For femoral heads, NTCP was similar (p=0.317). For the planned target volume, TCP values obtained with the HF technique are significantly higher compared to the CF technique (p=0.000). CONCLUSION Higher TCP values were obtained with the HF technique. It has been observed that normal tissues receive lower doses. This may be associated with high local control rates while providing similar toxicity. HF treatment may be preferred in prostate cancer because the total treatment duration is shorter and the dose applied to critical organs is lower. Radiobiological models are very instructive for comparing treatment schemes in radiotherapy plans. The Matlab program we created is a very helpful tool for the radiation oncologist and medical physicist to evaluate their plans. [ABSTRACT FROM AUTHOR]

Simple Summary: Juvenile nasopharyngeal angiofibroma (JNA) presents a therapeutic challenge in its advanced stages due to the close proximity to critical structures at the skull base. While radiotherapy is an effective treatment alternative, radiation-induced complications due to dose deposition in healthy tissue remain a major concern. Particle radiotherapy offers a high degree of conformality, and notably, helium ions present a promising treatment option due to their favorable biophysical characteristics between protons and carbon ions, supporting their reconsideration for clinical application. We retrospectively designed helium ion therapy (HRT) plans for all patients previously treated with proton therapy (PRT) at the Heidelberg Ion-Beam Therapy Center. Our findings indicate potential dosimetric advantages of HRT over PRT for advanced JNA, suggesting enhanced target coverage along with reduced dose deposition in healthy tissue, thereby potentially mitigating acute and late-term complications, including secondary neoplasms. This is particularly important given the benign nature of JNA and the patients' young age. Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications. [ABSTRACT FROM AUTHOR]

Purpose: The number of older adults with head and neck squamous cell carcinoma (HNSCC) is continuously increasing. Older HNSCC patients may be more vulnerable to radiotherapy-related toxicities, so that extrapolation of available normal tissue complication probability (NTCP) models to this population may not be appropriate. Hence, we aimed to investigate the correlation between organ at risk (OAR) doses and chronic toxicities in older patients with HNSCC undergoing definitive radiotherapy. Methods: Patients treated with definitive radiotherapy, either alone or with concomitant systemic treatment, between 2009 and 2019 in a large tertiary cancer center were eligible for this analysis. OARs were contoured based on international consensus guidelines, and EQD2 doses using α/ß values of 3 Gy for late effects were calculated based on the radiation treatment plans. Treatment-related toxicities were graded according to Common Terminology Criteria for Adverse Events version 5.0. Logistic regression analyses were carried out, and NTCP models were developed and internally validated using the bootstrapping method. Results: A total of 180 patients with a median age of 73 years fulfilled the inclusion criteria and were analyzed. Seventy-three patients developed chronic moderate xerostomia (grade 2), 34 moderate dysgeusia (grade 2), and 59 moderate-to-severe (grade 2–3) dysphagia after definitive radiotherapy. The soft palate dose was significantly associated with all analyzed toxicities (xerostomia: OR = 1.028, dysgeusia: OR = 1.022, dysphagia: OR = 1.027) in the multivariable regression. The superior pharyngeal constrictor muscle was also significantly related to chronic dysphagia (OR = 1.030). Consecutively developed and internally validated NTCP models were predictive for the analyzed toxicities (optimism-corrected AUCs after bootstrapping: AUCxerostomia=0.64, AUCdysgeusia=0.60, AUCdysphagia=0.64). Conclusions: Our data suggest that the dose to the soft palate is associated with chronic moderate xerostomia, moderate dysgeusia and moderate-to-severe dysphagia in older HNSCC patients undergoing definitive radiotherapy. If validated in external studies, efforts should be undertaken to reduce the soft palate dose in these patients. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to set four NTCP models on clinical data and develop a model that calculates the possibility of hearing damage due to irradiation of healthy and at-risk brainstem tissue. Materials and Methods: ABR tests were performed on 50 head-and-neck cancer patients three years after radiotherapy for evaluation of lesions in a part of the auditory nerve or the auditory pathway in the brainstem. Results: It indicated a significant difference in the latency of the waves assessed by the ABR test between the two groups. The paired sample t-test indicated the latency time of waves I, III, V, I-III, and I-V (P < 0.001) in the right ear, and in the left ear latency time of waves III, V, I-III, I-V, and III-V (P < 0.001) were significantly higher in the case group's ear than those in the control group. The confidence interval of the fitted parameters was 95% for NTCP models. ABR test's binary outcome with differential dose-volume histograms (dDVHs) was calculated and imported as input to the NTCP modeling. The values of the parameters n = 2.3-2.9 and the value s = 1 were obtained, which indicated that the brainstem organ is seriality. Conclusion: The best model ranked for the prediction of brainstem hearing damage was the logit model, which had the lowest Akaike value. The nervousness of the auditory organ of the brainstem (VIII nerve) can be declared as one of the reasons for being independent of the received dose. [ABSTRACT FROM AUTHOR]

Normal Tissue Complication Probability (NTCP) models have the potential to enable head and neck (H&N) oncologists to adopt a personalised treatment strategy for their patients by quantifying individual risks to developing specific toxicities. [1] While NCTP models for dysphagia in patients receiving definitive radiotherapy for head and neck cancer are available [1-5], suitable models, that contain the most relevant OAR with reliable dose-response estimates, are lacking in the adjuvant (postoperative) setting. This study aimed to develop a NTCP model for dysphagia, following transoral surgery and adjuvant radiotherapy for patients in the PATHOS trial [NCT: A25317]. This trial examines whether reducing the intensity of adjuvant treatment following minimally invasive transoral surgery in HPV related Oropharyngeal Squamous Cell Cancer (OPSCC) patients, either by lowering radiotherapy (RT) dose or omitting chemotherapy, will result in improved swallowing function, whilst maintaining excellent clinical outcomes.[6] The dataset consisted of 116 patients allocated into arms B1 & C2 of PATHOS from Jul 2007 to Feb 2020, who received 60Gy in 30 fractions IMRT following transoral surgery. The model endpoint of dysphagia was defined as MDADI composite score <80 at 12months post treatment (MDADI_12m). Candidate predictors included mean dose in Gy to nine swallowing OARs (SWOARs). SWOARs were outlined as per PATHOS swallowing atlas by a single investigator and checked by 2 senior investigators. To develop the prediction model, first a univariable analysis was conducted to show the raw uncorrected effects of each candidate variable on MDADI_12m. Next non-linear transformations were evaluated for continuous variables and multicollinearity was assessed. Finally a multivariate logistic regression analysis with stepwise backward elimination was used. Model performance was evaluated using discrimination specified by the area under the receiver operating curve (AUC) and calibration using calibration-in-the-large (CITL) and calibration slope (C-slope). [7] Internal validation was completed using bootstrapping and model performance was subsequently adjusted for optimism. Statistical analysis was conducted using Stata© software (version 17.0 SE, statacorp). The prevalence of MDADI_12m of <80 was 54%. Following pre-selection based on clinical expertise and prior knowledge, the candidate predictor variables included in the model were as follows; superior, middle and inferior pharyngeal constrictors, crico-oesophgeal inlet, supraglottic and glottic larynx and oral cavity. The multivariable model with the best performance consisted of the superior pharyngeal constrictor muscle (PCM_Superior) and the supraglottic larynx (Larynx_SG). In individual cases the risk of MDADI_12m <80 can be estimated using the following equation: NTCP MDADI_12m = 1/(1+ e-S), where S= -5.99 + (mean dose PCM Superior x 0.086) + (mean dose Larynx_SG x 0.035). (Figure 1) Apparent model performance is presented in the calibration plot (Figure2). The AUC was 0.70 (p=0.001) showing good discrimination indicating good potential performance in populations with similar case-mix. The measures of CITL, ratio of expected to observed endpoints and C-slope were 0, 1 and 1 respectively indicating apparent perfect calibration performance as we would expect when we fit the developed model in the development cohort. Optimism adjusted AUC, CITL and C-slope were 0.66, -0.003 and 0.73 respectively indicating good internal performance in terms of discrimination and minimal mis-calibration in CITL. However the C-slope of 0.66 suggests a moderate amount of shrinkage is required to adjust the predictor effects in the model for overfitting. [Display omitted] A novel NTCP model for MDADI_12m was developed to identify patients at risk for dysphagia after transoral surgery and adjuvant radiotherapy in PATHOS. Mean doses to the PCM_Superior and Larynx_SG were most predictive. An NTCP model including these parameters could be used to direct limited resources such as speech and language therapy to patients who are at highest risk of dysphagia, as well as in treatment planning to prioritise SWOAR optimisation. In future this model will need to be further updated in a larger dataset and externally validated before use in clinical practice. The PATHOS trial is funded by Cancer Research UK (Grant no: A25317) and co-sponsored by Cardiff University and Velindre University NHS Trust. [ABSTRACT FROM AUTHOR]

This systematic review study aims to provide comprehensive data on different radiobiological models, parameters, and endpoints used for calculating the normal tissue complication probability (NTCP) based on clinical data from head and neck cancer patients treated with conformal radiotherapy. A systematic literature search was carried out according to the PRISMA guideline for the identification of relevant publications in six electronic databases of Embase, PubMed, Scopus, and Google Scholar to July 2022 using specific keywords in the paper's title and abstract. The initial search resulted in 1368 articles for all organs for the review article about the NTCP parameters. One hundred and seventy‐eight articles were accepted for all organs with complete parameters for the mentioned models and finally, 20 head and neck cancer articles were accepted for review. Analysis of the studies shows that the Lyman‐Kutcher‐Burman (LKB) model properly links the NTCP curve parameters to the postradiotherapy endpoints. In the LKB model for esophagus, the minimum, and maximum corresponding parameters were reported as TD50 = 2.61 Gy with grade ≥3 radiation‐induced esophagitis endpoints as the minimum TD50 and TD50 = 68 Gy as the maximum ones. nmin = 0.06, nmax = 1.04, mmin = 0.1, and mmax = 0.65, respectively. Unfortunately, there was not a wide range of published articles on other organs at risk like ear or cauda equina except Burman et al. (Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys Ther. 1991;21:123–135). Findings suggest that the validation of different radiobiological models and their corresponding parameters need to be investigated in vivo and in vitro for developing a more accurate NTCP model to be used for radiotherapy treatment planning optimization. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced juvenile nasopharyngeal angiofibroma (JNA) can present a considerable therapeutic challenge. Photon radiotherapy has been recognized as an effective treatment approach for recurrent or inoperable advanced JNA in an additive or definitive setting. However, due to the benign nature of JNA and the young age of the affected patients, concerns about long-term radiation-induced morbidity have led to a certain hesitance towards this treatment modality. Proton therapy (PRT) presents a promising alternative for treating benign conditions in young patients, yet there remains a gap in the literature regarding its application to JNA. We retrospectively examined the outcomes of patients with JNA who underwent PRT in our center and evaluated the dosimetric advantages of PRT over conformal radiotherapy. This study is the first report investigating PRT for advanced JNA, highlighting PRT's safety and effectiveness as a viable therapeutic option. Dosimetric and complication risk evaluations suggest that PRT holds the potential to reduce long-term radiation-induced complications, including the development of secondary neoplasms or decline in neurocognitive function. Purpose: To provide the first report on proton radiotherapy (PRT) in the management of advanced nasopharyngeal angiofibroma (JNA) and evaluate potential benefits compared to conformal photon therapy (XRT). Methods: We retrospectively reviewed 10 consecutive patients undergoing PRT for advanced JNA in a definitive or postoperative setting with a relative biological effectiveness weighted dose of 45 Gy in 25 fractions between 2012 and 2022 at the Heidelberg Ion Beam Therapy Center. Furthermore, dosimetric comparisons and risk estimations for short- and long-term radiation-induced complications between PRT plans and helical XRT plans were conducted. Results: PRT was well tolerated, with only low-grade acute toxicities (CTCAE I–II) being reported. The local control rate was 100% after a median follow-up of 27.0 (interquartile range 13.3–58.0) months. PRT resulted in considerable tumor shrinkage, leading to complete remission in five patients and bearing the potential to provide partial or complete symptom relief. Favorable dosimetric outcomes in critical brain substructures by the use of PRT translated into reduced estimated risks for neurocognitive impairment and radiation-induced CNS malignancies compared to XRT. Conclusions: PRT is an effective treatment option for advanced JNA with minimal acute morbidity and the potential for reduced radiation-induced long-term complications. [ABSTRACT FROM AUTHOR]

Simple Summary: The availability of high-quality image guidance and fully integrated online adaptation now allows for an efficient online adaptation for photon treatments. Since proton treatments can deliver a lower dose to healthy tissue, a combination of protons with online adaptation might further reduce side effects. This study compares the calculated side effects for the liver and duodenal toxicity of hypofractionated liver cancer treatments for protons and photons in an adaptive and non-adaptive setting. The results show that the differences between photons and protons are often significant, while the differences between adaptive and non-adaptive treatment schemes are not. With the availability of MRI linacs, online adaptive intensity modulated radiotherapy (IMRT) has become a treatment option for liver cancer patients, often combined with hypofractionation. Intensity modulated proton therapy (IMPT) has the potential to reduce the dose to healthy tissue, but it is particularly sensitive to changes in the beam path and might therefore benefit from online adaptation. This study compares the normal tissue complication probabilities (NTCPs) for liver and duodenal toxicity for adaptive and non-adaptive IMRT and IMPT treatments of liver cancer patients. Adaptive and non-adaptive IMRT and IMPT plans were optimized to 50 Gy (RBE = 1.1 for IMPT) in five fractions for 10 liver cancer patients, using the original MRI linac images and physician-drawn structures. Three liver NTCP models were used to predict radiation-induced liver disease, an increase in albumin-bilirubin level, and a Child–Pugh score increase of more than 2. Additionally, three duodenal NTCP models were used to predict gastric bleeding, gastrointestinal (GI) toxicity with grades >3, and duodenal toxicity grades 2–4. NTCPs were calculated for adaptive and non-adaptive IMRT and IMPT treatments. In general, IMRT showed higher NTCP values than IMPT and the differences were often significant. However, the differences between adaptive and non-adaptive treatment schemes were not significant, indicating that the NTCP benefit of adaptive treatment regimens is expected to be smaller than the expected difference between IMRT and IMPT. [ABSTRACT FROM AUTHOR]

Background: Most nasopharyngeal carcinoma (NPC) protocols define primary gross tumor volume (GTVnx) plus a range from 2 to 5 mm as the high‐dose clinical target volume (hd‐CTV). However, in China, hd‐CTV is defined as GTVnx plus 0 mm. Methods: A total of 40 patients with newly diagnosed nonmetastatic NPC (T1–T4 ten cases each) treated with IMRT were consecutively enrolled. Real and virtual treatment plans were designed according to the definitions of hd‐CTV recommended by China and Radiation Therapy Oncology Group (RTOG), respectively. Results: The hd‐CTV in China was significantly smaller than that of RTOG. Exposure doses to 5 mm subclinical involvement and OARs as well as NTCP in the China treatment plan were significantly lower than those of RTOG. Conclusion: It could be recommended to divide the hd‐CTV into GTV and subclinical target volume and to prescribe different doses for the GTV and subclinical involvement in the IMRT plan of NPC. [ABSTRACT FROM AUTHOR]

Purpose: To provide the first report on proton radiotherapy (PRT) in the management of advanced nasopharyngeal angiofibroma (JNA) and evaluate potential benefits compared to conformal photon therapy (XRT). Methods: We retrospectively reviewed 10 consecutive patients undergoing PRT for advanced JNA in a definitive or postoperative setting with a relative biological effectiveness weighted dose of 45 Gy in 25 fractions between 2012 and 2022 at the Heidelberg Ion Beam Therapy Center. Furthermore, dosimetric comparisons and risk estimations for short- and long-term radiation-induced complications between PRT plans and helical XRT plans were conducted. Results: PRT was well tolerated, with only low-grade acute toxicities (CTCAE I–II) being reported. The local control rate was 100% after a median follow-up of 27.0 (interquartile range 13.3–58.0) months. PRT resulted in considerable tumor shrinkage, leading to complete remission in five patients and bearing the potential to provide partial or complete symptom relief. Favorable dosimetric outcomes in critical brain substructures by the use of PRT translated into reduced estimated risks for neurocognitive impairment and radiation-induced CNS malignancies compared to XRT. Conclusions: PRT is an effective treatment option for advanced JNA with minimal acute morbidity and the potential for reduced radiation-induced long-term complications.

Simple Summary: The radiotherapy plans are usually judged using physical quantities, including dose and dose-volume values. Biological indices may also be applied for plan evaluation. A new software was developed for the quick and automatic calculation of tumor control probability (TCP) and normal tissue control probability (NTCP) from any radiation therapy plan and any fractionation scheme. Limited information has been published about the radiobiological metrics associated with gastric cancer irradiation. The new software was applied to radiobiologically compare photon plans for gastric malignancies generated with three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). The IMRT and VMAT plans provided higher TCPs than 3D-CRT. They also reduced the NTCPs and the risk of late adverse effects in most of the surrounding healthy organs compared to 3D-CRT. The presented results are useful for the plan optimization and choice of the appropriate radiotherapy technique for gastric cancer. (1) Aim: This study was conducted to radiobiologically compare radiotherapy plans for gastric cancer with a newly developed software tool. (2) Methods: Treatment planning was performed on two computational phantoms simulating adult male and female patients. Three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans for gastric cancer were generated with three-photon beam energies. The equivalent uniform dose (EUD), tumor control probability (TCP) of the target and normal tissue control probability (NTCP) of eight different critical organs were calculated. A new software was employed for these calculations using the EUD-based model and dose-volume-histogram data. (3) Results: The IMRT and VMAT plan led to TCPs of 51.3–51.5%, whereas 3D-CRT gave values up to 50.2%. The intensity-modulated techniques resulted in NTCPs of (5.3 × 10−6–3.3 × 10−1)%. The corresponding NTCPs from 3D-CRT were (3.4 × 10−7–7.4 × 10−1)%. The above biological indices were automatically calculated in less than 40 s with the software. (4) Conclusions: The direct and quick radiobiological evaluation of radiotherapy plans is feasible using the new software tool. The IMRT and VMAT reduced the probability of the appearance of late effects in most of the surrounding critical organs and slightly increased the TCP compared to 3D-CRT. [ABSTRACT FROM AUTHOR]

Background and purposeIncidental irradiation of normal brain tissue during radiotherapy is linked to cognitive decline, and may be mediated by damage to healthy cortex. Non-coplanar techniques may be used for cortical sparing. We compared normal brain sparing and probability of cortical atrophy using 4π radiation therapy planning vs. standard fixed gantry intensity-modulated radiotherapy (IMRT).Material and methodsPlans from previously irradiated brain tumor patients ("original IMRT", n = 13) were re-planned to spare cortex using both 4π optimization ("4π") and IMRT optimization ("optimized IMRT"). Homogeneity index (HI), gradient measure, doses to cortex and white matter (excluding tumor), brainstem, optics, and hippocampus were compared with matching PTV coverage. Probability of three grades of post-treatment cortical atrophy was modeled based on previously established dose response curves.ResultsWith matching PTV coverage, 4π significantly improved HI by 27% (p = 0.005) and gradient measure by 8% (p = 0.001) compared with optimized IMRT. 4π optimization reduced mean and equivalent uniform doses (EUD) to all standard OARs, with 14-15% reduction in hippocampal EUD (p ≤ 0.003) compared with the other two plans. 4π significantly reduced dose to fractional cortical volumes (V50, V40 and V30) compared with the original IMRT plans, and reduced cortical V30 by 7% (p = 0.008) compared with optimized IMRT. White matter EUD, mean dose, and fractional volumes V50, V40 and V30 were also significantly lower with 4π (p ≤ 0.001). With 4π, probability of grade 1, 2 and 3 cortical atrophy decreased by 12%, 21% and 26% compared with original IMRT and by 8%, 14% and 3% compared with optimized IMRT, respectively (p ≤ 0.001).Conclusions4π radiotherapy significantly improved cortical sparing and reduced doses to standard brain OARs, white matter, and the hippocampus. This was achieved with superior PTV dose homogeneity. Such sparing could reduce the probability of cortical atrophy that may lead to cognitive decline.

BACKGROUND AND PURPOSE:Incidental irradiation of normal brain tissue during radiotherapy is linked to cognitive decline, and may be mediated by damage to healthy cortex. Non-coplanar techniques may be used for cortical sparing. We compared normal brain sparing and probability of cortical atrophy using 4π radiation therapy planning vs. standard fixed gantry intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS:Plans from previously irradiated brain tumor patients ("original IMRT", n = 13) were re-planned to spare cortex using both 4π optimization ("4π") and IMRT optimization ("optimized IMRT"). Homogeneity index (HI), gradient measure, doses to cortex and white matter (excluding tumor), brainstem, optics, and hippocampus were compared with matching PTV coverage. Probability of three grades of post-treatment cortical atrophy was modeled based on previously established dose response curves. RESULTS:With matching PTV coverage, 4π significantly improved HI by 27% (p = 0.005) and gradient measure by 8% (p = 0.001) compared with optimized IMRT. 4π optimization reduced mean and equivalent uniform doses (EUD) to all standard OARs, with 14-15% reduction in hippocampal EUD (p ≤ 0.003) compared with the other two plans. 4π significantly reduced dose to fractional cortical volumes (V50, V40 and V30) compared with the original IMRT plans, and reduced cortical V30 by 7% (p = 0.008) compared with optimized IMRT. White matter EUD, mean dose, and fractional volumes V50, V40 and V30 were also significantly lower with 4π (p ≤ 0.001). With 4π, probability of grade 1, 2 and 3 cortical atrophy decreased by 12%, 21% and 26% compared with original IMRT and by 8%, 14% and 3% compared with optimized IMRT, respectively (p ≤ 0.001). CONCLUSIONS:4π radiotherapy significantly improved cortical sparing and reduced doses to standard brain OARs, white matter, and the hippocampus. This was achieved with superior PTV dose homogeneity. Such sparing could reduce the probability of cortical atrophy that may lead to cognitive decline.

Radiation therapy is a double‐edged sword which damages both tumor and normal cells. Achieving treatments with high tumor control probability (TCP) yet low normal tissue complication probability (NTCP) is often a struggle because we rarely have a unified understanding of the dosimetric and clinical correlates of the desired outcomes. I am fortunate to have participated in some of these struggles, including analyzing and using in‐house data and being involved in the AAPM and ASTRO "TEC" projects—QUANTEC (Quantitatie Analysis of Normal Tissue Effects in the Clinic), HyTEC (Hypofractionated Treatment Effects in the Clinic) and PENTEC (Pediatric Normal Tissue Effects in the Clinic). [ABSTRACT FROM AUTHOR]

Simple Summary: Definitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To avoid or minimize these critical side effects, radiation exposure to each inner ear must be balanced between target volume coverage and toxicity. However, normal tissue complication probability (NTCP) models of the inner ear validated by clinical data are rare. In this retrospective study of 46 patients, an NTCP model and a cutoff dose logistic regression model (CDLR) were created. There is a sigmoidal relation between radiation dose and incidence of inner ear toxicities. Dose constraints for the inner ear of <44 Gy (Dmean) or <58 Gy (Dmax) are suggested to limit the probability of inner ear toxicity < 25%. Background: Definitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To avoid or minimize these critical side effects, radiation exposure to each inner ear must be balanced between target volume coverage and toxicity. However, normal tissue complication probability (NTCP) models of the inner ear validated by clinical data are rare. Patients and Methods: This retrospective study investigates the inner ear toxicity of 46 patients who received radio(chemo-)therapy for nasopharyngeal carcinoma at our institution from 2004 to 2021 according to CTCAE 5.0 criteria. For each inner ear, the mean (D m e a n) and maximum (D m a x) dose in Gray (G y) was evaluated and correlated with clinical toxicity data. Based on the data, an NTCP model and a cutoff dose logistic regression model (CDLR) were created. Results: In 11 patients ( 23.9 % ) hearing impairment and/or tinnitus was observed as a possible therapy-associated toxicity. D m e a n was between 15– 60 Gy, whereas D m a x was between 30– 75 Gy. There was a dose-dependent, sigmoidal relation between inner ear dose and toxicity. A D m e a n of 44 Gy and 65 Gy was associated with inner ear damage in 25 % and 50 % of patients, respectively. The maximum curve slope (m) was found at 50 % and is m = 0.013 . The Dmax values showed a 25 % and 50 % complication probability at 58 Gy and 69 Gy, respectively, and a maximum slope of the sigmoid curve at 50 % with m = 0.025 . Conclusion: There is a sigmoidal relation between radiation dose and incidence of inner ear toxicities. Dose constraints for the inner ear of < 44 Gy (D m e a n) or < 58 Gy (D m a x) are suggested to limit the probability of inner ear toxicity < 25 % . [ABSTRACT FROM AUTHOR]

We compared dynamic trajectory radiotherapy (DTRT) to state-of-the-art volumetric modulated arc therapy (VMAT) for 46 head and neck cancer cases. DTRT had lower dose to salivary glands and swallowing structure, resulting in lower predicted xerostomia and dysphagia compared to VMAT. DTRT is deliverable on C-arm linacs with high dosimetric accuracy. [ABSTRACT FROM AUTHOR]

• IHU is a prospective multi-institute study dealing with toxicity after PNI. • Dosimetry and clinical predictors of 2-year G2+ lymphopenia were investigated. • DVHs of Body and of pelvic bone marrow were associated with the end-point. • Multi-variable modelling showed baseline ALC as the most relevant predictor. • Smoke, lumbosacral DVH and acute G3 lymphopenia independently modulate the risk. Given the substantial lack of knowledge, we aimed to assess clinical/dosimetry predictors of late hematological toxicity on patients undergoing pelvic-nodes irradiation (PNI) for prostate cancer (PCa) within a prospective multi-institute study. Clinical/dosimetry/blood test data were prospectively collected including lymphocytes count (ALC) at baseline, mid/end-PNI, 3/6 months and every 6 months up to 5-year after PNI. DVHs of the Body, ileum (BMILEUM), lumbosacral spine (BMLS), lower pelvis (BMPELVIS), and whole pelvis (BMTOT) were extracted. Current analysis focused on 2-year CTCAEv4.03 Grade ≥ 2 (G2+) lymphopenia (ALC < 800/μL). DVH parameters that better discriminate patients with/without toxicity were first identified. After data pre-processing to limit overfitting, a multi-variable logistic regression model combining DVH and clinical information was identified and internally validated by bootstrap. Complete data of 499 patients were available: 46 patients (9.2 %) experienced late G2+ lymphopenia. DVH parameters of BMLS/BMPELVIS/BMTOT and Body were associated to increased G2+ lymphopenia. The variables retained in the resulting model were ALC at baseline [HR = 0.997, 95 %CI 0.996–0.998, p < 0.0001], smoke (yes/no) [HR = 2.9, 95 %CI 1.25–6.76, p = 0.013] and BMLS-V ≥ 24 Gy (cc) [HR = 1.006, 95 %CI 1.002–1.011, p = 0.003]. When acute G3+ lymphopenia (yes/no) was considered, it was retained in the model [HR = 4.517, 95 %CI 1.954–10.441, p = 0.0004]. Performances of the models were relatively high (AUC = 0.87/0.88) and confirmed by validation. Two-year lymphopenia after PNI for PCa is largely modulated by baseline ALC, with an independent role of acute G3+ lymphopenia. BMLS-V24 was the best dosimetry predictor: constraints for BMTOT (V10Gy < 1520 cc, V20Gy < 1250 cc, V30Gy < 850 cc), and BMLS (V24y < 307 cc) were suggested to potentially reduce the risk. [ABSTRACT FROM AUTHOR]

Introduction. The main aim of this study was to evaluate the doses delivered to heart substructures and calculate normal tissue complication probability (NTCP) for the intensity modulation radiotherpy (IMRT) irradiated group of left-sided post-mastectomy patients. Material and methods. In this retrospective study for 30 randomly chosen breast cancer patients, the mean dose, V2, V4, V10, V20 and D2% in the heart substructures were evaluated. Results. The mean heart dose was 12.3 Gy, the mean left anterior descending artery (LAD) dose was 28.5 Gy. The average value of long-term cardiac mortality was 0.17%, pericarditis 0.0%, left ventricle perfusion defects 24.5% and LAD toxicity 0.2%. In the literature, for the IMRT technique for left-sided mastectomy patients, the mean heart dose ranged from 8.7–14.0 Gy and the V20 10.5–14%. Additional studies are needed to describe the cardiac toxicity. Conclusions. It is necessary to contour cardiac substructures for reliable assessment of the dose distribution, although the mean heart dose is simplification for modern radiotherapy techniques. [ABSTRACT FROM AUTHOR]

Background: Definitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To avoid or minimize these critical side effects, radiation exposure to each inner ear must be balanced between target volume coverage and toxicity. However, normal tissue complication probability (NTCP) models of the inner ear validated by clinical data are rare. Patients and Methods: This retrospective study investigates the inner ear toxicity of 46 patients who received radio(chemo-)therapy for nasopharyngeal carcinoma at our institution from 2004 to 2021 according to CTCAE 5.0 criteria. For each inner ear, the mean (Dmean) and maximum (Dmax) dose in Gray (Gy) was evaluated and correlated with clinical toxicity data. Based on the data, an NTCP model and a cutoff dose logistic regression model (CDLR) were created. Results: In 11 patients (23.9%) hearing impairment and/or tinnitus was observed as a possible therapy-associated toxicity. Dmean was between 15–60 Gy, whereas Dmax was between 30–75 Gy. There was a dose-dependent, sigmoidal relation between inner ear dose and toxicity. A Dmean of 44 Gy and 65 Gy was associated with inner ear damage in 25% and 50% of patients, respectively. The maximum curve slope (m) was found at 50% and is m=0.013. The Dmax values showed a 25% and 50% complication probability at 58 Gy and 69 Gy, respectively, and a maximum slope of the sigmoid curve at 50% with m=0.025. Conclusion: There is a sigmoidal relation between radiation dose and incidence of inner ear toxicities. Dose constraints for the inner ear of <44 Gy (Dmean) or <58 Gy (Dmax) are suggested to limit the probability of inner ear toxicity <25%.

Introduction: The pituitary gland is frequently irradiated during radiation therapy of head and neck tumors which can influence the quality of life of the patients after radiation therapy. This study aimed to estimate the normal tissue complication probability (NTCP) for the pituitary gland in head and neck cancers using two radiobiological models. Material and Methods: 53 patients including 20 cases with nasopharyngeal cancer and 33 cases with brain tumor were studied. The dosimetric properties of each plan including minimum, mean and maximum doses were extracted from the dose-volume histogram curve. For estimation of pituitary gland response for each patient, the BIOPLAN software was used to calculate NTCP by LKB model and Matlab software was applied to calculate NTCP by equivalent uniform dose (EUD) model. Models' parameters including TD50, 𝛾50, and 'a' were extracted from a previous study of radiobiological modeling of pituitary gland response to radiation therapy. For statistical analysis, the T-test was used to compare two models. Results: The average mean doses of 30.42 and 51.29 (Gy) of the pituitary gland were obtained for nasopharyngeal and brain tumor patients, respectively. The average NTCPs of the pituitary gland for nasopharyngeal patients estimated by LKB and Log-logistic models were 3.84 and 3.91%, respectively. In brain tumors, the average NTCP was 16.33% for LKB and 16.41% for Log-logistic models. The results showed that the log-logistic and LKB models provided comparable results and no statistically significant difference (P-value< 0.05) was found between two models. Conclusion: The NTCP results indicated that the average NTCP of the pituitary gland for nasopharyngeal patients was approximately four times lower than that of brain tumors. Finally, implementation of follow up studies and modeling investigations are recommended for accurate estimation of pituitary gland complications following radiation therapy. [ABSTRACT FROM AUTHOR]

Background: Whole brain radiation (WBRT) may lead to acute xerostomia and dry eye from incidental parotid and lacrimal exposure, respectively. We performed a prospective observational study to assess the incidence/severity of this toxicity. We herein perform a secondary analysis relating parotid and lacrimal dosimetric parameters to normal tissue complication probability (NTCP) rates and associated models.Methods: Patients received WBRT to 25-40 Gy in 10-20 fractions using 3D-conformal radiation therapy without prospective delineation of the parotids or lacrimals. Patients completed questionnaires at baseline and 1 month post-WBRT. Xerostomia was assessed using the University of Michigan xerostomia score (scored 0-100, toxicity defined as ≥ 20 pt increase) and xerostomia bother score (scored from 0 to 3, toxicity defined as ≥ 2 pt increase). Dry eye was assessed using the Subjective Evaluation of Symptom of Dryness (SESoD, scored from 0 to 4, toxicity defined as ≥ 2 pt increase). The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models.Results: Of 55 evaluable patients, 19 (35%) had ≥ 20 point increase in xerostomia score, 11 (20%) had ≥ 2 point increase in xerostomia bother score, and 13 (24%) had ≥ 2 point increase in SESoD score. For xerostomia, parotid V10Gy-V20Gy correlated best with toxicity, with AUC 0.68 for xerostomia score and 0.69-0.71 for bother score. The values for the D50, m and n parameters of the LKB model were 22.3 Gy, 0.84 and 1.0 for xerostomia score and 28.4 Gy, 0.55 and 1.0 for bother score, respectively. The corresponding values for the D50, γ and s parameters of the RS model were 23.5 Gy, 0.28 and 0.0001 for xerostomia score and 32.0 Gy, 0.45 and 0.0001 for bother score, respectively. For dry eye, lacrimal V10Gy-V15Gy were found to correlate best with toxicity, with AUC values from 0.67 to 0.68. The parameter values of the LKB model were 53.5 Gy, 0.74 and 1.0, whereas of the RS model were 54.0 Gy, 0.37 and 0.0001, respectively.Conclusions: Xerostomia was most associated with parotid V10Gy-V20Gy, and dry eye with lacrimal V10Gy-V15Gy. NTCP models were successfully created for both toxicities and may help clinicians refine dosimetric goals and assess levels of risk in patients receiving palliative WBRT. [ABSTRACT FROM AUTHOR]

NeoSCOPE is a trial of two different neoadjuvant chemoradiotherapy regimens for resectable oesophageal cancer and was the first multicentre trial in the UK to incorporate four-dimensional computed tomography (4D-CT) into radiotherapy planning. Despite 4D-CT being increasingly accepted as a standard of care for lower third and junctional oesophageal tumours, there is limited evidence of its benefit over standard three-dimensional computed tomography (3D-CT). Using NeoSCOPE 4D-CT cases, we undertook a dosimetric comparison study of 3D-CT versus 4D-CT plans comparing target volume coverage and dose to organs at risk. We used established normal tissue complication probability models to evaluate the potential toxicity reduction of using 4D-CT plans in oesophageal cancer. 4D-CT resulted in a smaller median absolute PTV volume and lower dose levels for all reported constraints with comparable target volume coverage. NTCP modelling suggests a significant relative risk reduction of cardiac and pulmonary toxicity endpoints with 4D-CT. Our work shows that incorporating 4D-CT into treatment planning may significantly reduce the toxicity burden from this treatment. • Dosimetric comparison study of 4D-CT vs 3D-CT using lower oesophageal cancer cases from the NeoSCOPE trial. • Integral dose and volume of PTV is significantly reduced with 4D-CT. • 4D-CT plans result in significantly lower doses to critical organs at risk. • NTCP modelling suggests significant relative risk reduction in cardiac and pulmonary toxicities with 4D-CT. [ABSTRACT FROM AUTHOR]

Purpose: Late gastrointestinal (GI) toxicity after radiotherapy for prostate cancer may have significant impact on the cancer survivor's quality of life. To date, little is known about local dose-effects after modern radiotherapy including hypofractionation. In the current study we related the local spatial distribution of radiation dose in the rectum to late patient-reported gastrointestinal (GI) toxicities for conventionally fractionated (CF) and hypofractionated (HF) modern radiotherapy in the randomized HYPRO trial.Material and Methods: Patients treated to 78 Gy in 2 Gy fractions (n = 298) or 64.6 Gy in 3.4 Gy fractions (n = 295) with available late toxicity questionnaires (n ≥ 2 within 1–5 years post-treatment) and available 3D planning data were eligible for this study. The majority received intensity modulated radiotherapy (IMRT). We calculated two types of dose surface maps: (1) the total delineated rectum with its central axis scaled to unity, and (2) the delineated rectum with a length of 7 cm along its central axis aligned on the prostate's half-height point (prostate-half). For each patient-reported GI symptom, dose difference maps were constructed by subtracting average co-registered EQD2 (equivalent dose in 2 Gy) dose maps of patients with and without the symptom of interest, separately for HF and CF. P-values were derived from permutation tests. We evaluated patient-reported moderate to severe GI symptoms.Results: Observed incidences of rectal bleeding and increased stool frequency were significantly higher in the HF group. For rectal bleeding (p = 0.016), mucus discharge (p = 0.015), and fecal incontinence (p = 0.001), significant local dose-effects were observed in HF patients but not in CF patients. For rectal pain, similar local dose-effects (p < 0.05) were observed in both groups. No significant local dose-effects were observed for increased stool frequency. Total rectum mapping vs. prostate-half mapping showed similar results.Conclusion: We demonstrated significant local dose-effect relationships for patient-reported late GI toxicity in patients treated with modern RT. HF patients were at higher risk for increased stool frequency and rectal bleeding, and showed the most pronounced local dose-effects in intermediate-high dose regions. These findings suggest that improvement of current treatment optimization protocols could lead to clinical benefit, in particular for HF treatment.

La prescription de la dose en radiothérapie est actuellement basée sur des abaques qui ne prennent pas en compte la complexité de la relation patient/dose/effet. Leurs performances prédictives tant sur l'efficacité anti-tumorale que sur la toxicité peuvent être améliorées par l'utilisation de modèles radiobiologiques. C'est dans cette optique qu'ont été développés les modèles de calculs TCP (Tumor Control Probability) et NTCP (Normal Tissue Complication Probability). Leur construction comporte plusieurs étapes importantes utiles à comprendre. La première étape est basée sur les modèles radiobiologiques permettant de définir de manière plus ou moins complexe des taux de cellules survivantes après irradiation. Deux étapes supplémentaires sont nécessaires pour convertir la dose physique en dose biologique équivalente, notamment en dose biologique équivalente à 2 Gy (EQD 2) ; d'une part, pour prendre en compte l'effet du fractionnement de la dose, tant pour le volume cible que les organes à risque, et d'autre part, pour réaliser sa conversion en une dose uniforme qui permet de modéliser l'effet produit par une dose hétérogène sur un organe (dose uniforme équivalente généralisée (gEUD) de Niemierko). Enfin, les modèles radiobiologiques de prédiction des effets cliniques transforment les doses en probabilités de contrôle tumoral (TCP) ou de toxicité (NTCP) en recourant aux paramètres qui rendent compte des caractéristiques radiobiologiques des tissus en question. L'utilisation de ces modèles est encore limitée en pratique courante mais comme les logiciels de radiothérapie en propose l'utilisation, il est important d'en connaître les conditions d'application. In radiotherapy, the dose prescription is currently based on discretized dose-effects records that do not take into fully account for the complexity of the patient-dose-response relationship. Their predictive performance on both anti-tumour efficacy and toxicity can be optimized by integrating radiobiological models. It is with this in mind that the calculation models TCP (Tumor Control Probability) and NTCP (Normal Tissue Complication Probability) have been developed. Their construction involves several important steps that are necessary and important to understand. The first step is based on radiobiological models allowing to calculate according to more or less complexity the rate of surviving cells after irradiation. Two additional steps are required to convert the physical dose into an equivalent biological dose, in particular a 2 Gy equivalent biological dose (EQD2): first to take into account the effect of the fractionation of the dose for both the target volume and the organs at risk; second to convert an heterogeneous dose to an organ into an homogeneous dose having the same effect (Niemierko generalized equivalent uniform dose (gEUD)). Finally, the process of predicting clinical effects based on radiobiological models transform doses into tumour control (TCP) or toxicity (NTCP) probabilities using parameters that reflect the radiobiological characteristics of the tissues in question. The use of these models in current practice is still limited, but since the radiotherapy softwares increasingly integrate them, it is important to know the principle and limits of application of these models. [ABSTRACT FROM AUTHOR]

Purpose: Late gastrointestinal (GI) toxicity after radiotherapy for prostate cancer may have significant impact on the cancer survivor's quality of life. To date, little is known about local dose-effects after modern radiotherapy including hypofractionation. In the current study we related the local spatial distribution of radiation dose in the rectum to late patient-reported gastrointestinal (GI) toxicities for conventionally fractionated (CF) and hypofractionated (HF) modern radiotherapy in the randomized HYPRO trial. Material and Methods: Patients treated to 78 Gy in 2 Gy fractions (n = 298) or 64.6 Gy in 3.4 Gy fractions (n = 295) with available late toxicity questionnaires (n ≥ 2 within 1–5 years post-treatment) and available 3D planning data were eligible for this study. The majority received intensity modulated radiotherapy (IMRT). We calculated two types of dose surface maps: (1) the total delineated rectum with its central axis scaled to unity, and (2) the delineated rectum with a length of 7 cm along its central axis aligned on the prostate's half-height point (prostate-half). For each patient-reported GI symptom, dose difference maps were constructed by subtracting average co-registered EQD2 (equivalent dose in 2 Gy) dose maps of patients with and without the symptom of interest, separately for HF and CF. P -values were derived from permutation tests. We evaluated patient-reported moderate to severe GI symptoms. Results: Observed incidences of rectal bleeding and increased stool frequency were significantly higher in the HF group. For rectal bleeding (p = 0.016), mucus discharge (p = 0.015), and fecal incontinence (p = 0.001), significant local dose-effects were observed in HF patients but not in CF patients. For rectal pain, similar local dose-effects (p < 0.05) were observed in both groups. No significant local dose-effects were observed for increased stool frequency. Total rectum mapping vs. prostate-half mapping showed similar results. Conclusion: We demonstrated significant local dose-effect relationships for patient-reported late GI toxicity in patients treated with modern RT. HF patients were at higher risk for increased stool frequency and rectal bleeding, and showed the most pronounced local dose-effects in intermediate-high dose regions. These findings suggest that improvement of current treatment optimization protocols could lead to clinical benefit, in particular for HF treatment. [ABSTRACT FROM AUTHOR]

• This study derives an actuarial normal tissue complication probability (NTCP) model for radiation necrosis based on three-dimensional (3D) dose distribution and tumor location in patients who underwent proton therapy. • Equivalent uniform dose (EUD) was the most significant dosimetric index associated with radiation necrosis. High-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. All patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. Of 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D 50 = 57.7 Gy for intracranial tumors, D 50 = 39.5 Gy for extracranial tumors, and γ 50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. In the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy. [ABSTRACT FROM AUTHOR]

• Delivered-planned dose differences were quantified with daily CT-on-Rails. • Considerable dose differences were observed in 17% of HNSCC patients. • These dose differences changed normal tissue complication probability (ΔNTCP) >5%. • ΔNTCP can identify patients for adaptive radiotherapy better than clinical judgement. Anatomical changes induce differences between planned and delivered dose. Adaptive radiotherapy (ART) may reduce these differences but the optimal implementation is insufficiently clear. The aims of this study were to quantify the difference between planned and delivered dose in HNC patients, assess the consequential difference in normal tissue complication probability (ΔNTCP) and to explore the value of ΔNTCP as an objective selection strategy for ART. For 52 patients, daily doses were accumulated to estimate the delivered dose. The difference from planned dose was analyzed for CTVs and 9 organs-at-risk (OAR). ΔNTCP was calculated for xerostomia, dysphagia, parotid gland dysfunction and tube feeding dependency at 6 months. ART was deemed necessary if ΔNTCP was >5%. The positive predicted value (PPV) was calculated for identification of ART-patients by clinical judgement, and ΔNTCP at fraction 10 and 15. ΔNTCP >5% was seen five times for dysphagia and twice for the other toxicities. Only 5/9 patients with any ΔNTCP >5% clinically received ART, although ART had been done for 13/52 patients (PPV: 0.38). PPV was 0.86 and 0.75 for accumulated dose at fraction 10 and 15, respectively, using a ΔNTCP cut-off for the allocation of ART of 5%. Using other ΔNTCP cut-offs did not substantially improve PPV. With this cut-off the negative predictive value was 0.93 for ΔNTCP method of fraction 10 and fraction 15, and 0.90 for clinical judgement. To identify patients accurately for ART, NTCP calculations based on the dose differences between planned and delivered dose at fraction 10 are superior to clinical judgement. [ABSTRACT FROM AUTHOR]

Standard treatment for locally advanced cervical cancer (LACC) is chemoradiotherapy followed by brachytherapy. Despite radiation therapy advances, the toxicity rate remains significant. In this study, we compared the prediction of toxicity events after radiotherapy for locally advanced cervical cancer (LACC), based on either dose-volume histogram (DVH) parameters or the use of a radiomics approach applied to dose maps at the voxel level. Toxicity scores using the Common Terminology Criteria for Adverse Events (CTCAE v4), spatial dose distributions, and usual clinical predictors for the toxicity of 102 patients treated with chemoradiotherapy followed by brachytherapy for LACC were used in this study. In addition to usual DVH parameters, 91 radiomic features were extracted from rectum, bladder and vaginal 3D dose distributions, after discretization into a fixed bin width of 1 Gy. They were evaluated for predictive modelling of rectal, genitourinary (GU) and vaginal toxicities (grade ≥ 2). Logistic Normal Tissue Complication Probability (NTCP) models were derived using clinical parameters only or combinations of clinical, DVH and radiomics. For rectal acute/late toxicities, the area under the curve (AUC) using clinical parameters was 0.53/0.65, which increased to 0.66/0.63, and 0.76/0.87, with the addition of DVH or radiomics parameters, respectively. For GU acute/late toxicities, the AUC increased from 0.55/0.56 (clinical only) to 0.84/0.90 (+DVH) and 0.83/0.96 (clinical + DVH + radiomics). For vaginal acute/late toxicities, the AUC increased from 0.51/0.57 (clinical only) to 0.58/0.72 (+DVH) and 0.82/0.89 (clinical + DVH + radiomics). The predictive performance of NTCP models based on radiomics features was higher than the commonly used clinical and DVH parameters. Dosimetric radiomics analysis is a promising tool for NTCP modelling in radiotherapy.

Objectives: To compare treatment plans of intensity modulated radiotherapy (IMRT), volumetric modulated arc radiotherapy (VMAT), and helical tomotherapy (HT) with simultaneous integrated boost (SIB) technique for esophageal cancer (EC) of different locations using dosimetry and radiobiology. Methods: Forty EC patients were planned for IMRT, VMAT, and HT plans, including 10 cases located in the cervix, upper, middle, and lower thorax, respectively. Dose-volume metrics, conformity index (CI), homogeneity index (HI), tumor control probability (TCP), and normal tissue complication probability (NTCP) were analyzed to evaluate treatment plans. Results: HT showed significant improvement over IMRT and VMAT in terms of CI (p = 0.007), HI (p < 0.001), and TCP (p < 0.001) in cervical EC. IMRT yielded more superior CI, HI and TCP compared with VMAT and HT in upper and middle thoracic EC (all p < 0.05). Additionally, V30 (27.72 ± 8.67%), mean dose (1801.47 ± 989.58cGy), and NTCP (Niemierko model: 0.44 ± 0.55%; Lyman-Kutcher-Burman model: 0.61 ± 0.59%) of heart in IMRT were sharply reduced than VMAT and HT in middle thoracic EC. For lower thoracic EC, the three techniques offered similar CI and HI (all p > 0.05). But VMAT dramatically lowered liver V30 (9.97 ± 2.84%), and reduced NTCP of lungs (Niemierko model: 0.47 ± 0.48%; Lyman-Kutcher-Burman model: 1.41 ± 1.07%) and liver (Niemierko model: 0.10 ± 0.08%; Lyman-Kutcher-Burman model: 0.17 ± 0.17%). Conclusions: HT was a good option for cervical EC with complex target coverage but little lungs and heart involvement as it achieved superior dose conformity and uniformity. Due to potentially improving tumor control and reducing heart dose with acceptable lungs sparing, IMRT was a preferred choice for upper and middle thoracic EC with large lungs involvement. VMAT could ameliorate therapeutic ratio and lower lungs and liver toxicity, which was beneficial for lower thoracic EC with little thoracic involvement but being closer to heart and liver. Individually choosing optimal technique for EC in different location will be warranted. [ABSTRACT FROM AUTHOR]

Purpose: Internal organ motion reduces the accuracy and efficacy of radiation therapy. However, there is a lack of tools to objectively (based on a medical or scientific task) assess the dosimetric consequences of motion, especially on an individual basis. We propose to use therapy operating characteristic (TOC) analysis to quantify the effects of motion on treatment efficacy for individual patients. We demonstrate the application of this tool with pancreatic stereotactic body radiation therapy (SBRT) clinical data and explore the origin of motion sensitivity. Methods: The technique is described as follows. (a) Use tumor‐motion data measured from patients to calculate the motion‐convolved dose of the gross tumor volume (GTV) and the organs at risk (OARs). (b) Calculate tumor control probability (TCP) and normal tissue complication probability (NTCP) from the motion‐convolved dose–volume histograms. (c) Construct TOC curves from TCP and NTCP models. (d) Calculate the area under the TOC curve (AUTOC) and use it as a figure of merit for treatment efficacy. We used tumor motion data measured from patients to calculate the relation between AUTOC and motion magnitude for 25 pancreatic SBRT treatment plans. Furthermore, to explore the driving factor of motion sensitivity of a given plan, we compared the dose distribution of motion‐sensitive plans and motion‐robust plans and studied the dependence of motion sensitivity to motion directions. Results: Our technique is able to recognize treatment plans that are sensitive to motion. Under the presence of motion, the treatment efficacy of some plans changes from providing high tumor control and low risks of complications to providing no tumor control and high risks of side effects. Several treatment plans experience falloffs in AUTOC at a smaller magnitude of motion than other plans. In our dataset, a potential indicator of a motion‐sensitive treatment plan is that the duodenum is in proximity to the tumor in the SI direction. Conclusions: The TOC framework can serve as a tool to quantify the effects of internal organ motion in radiation therapy. With pancreatic SBRT clinical data, we applied this tool to study the change in treatment efficacy induced by motion for individual treatment plans. This framework could potentially be used clinically to understand the effects of motion in an individual patient and to design a patient‐specific motion management plan. This framework could also be used in research to evaluate different components of the treatment process, such as motion‐management techniques, treatment‐planning algorithms, and treatment margins. [ABSTRACT FROM AUTHOR]

Purposes: 1) To establish a new methodology for evaluating efficacy and toxicity in chemotherapy (CTX) following the same probabilistic principles that have been used in the radiation oncology therapies (ROTs) in the tumor control/normal tissue complication probability (TCP/NTCP). In CTX, the sickness control probability (SCP) and a NTCP1 (NTCP for CTX) function of a dose of reference are proposed; 2) To establish a new methodology of dosage in CTX using optimal values of these proposed indices; 3) To provide SMp models for the stochastic processes (SPs) involved into the CTX; and 4) To develop simple computer tools using TCP, NTCP, SCP and NTCP1. The following results were obtained: 1) Two Excel calculation sheets that determine the TCP and NTCP for the ROT using the SMp models; and evaluating until three organs at risk, as well as indices for a real CTX treatment, the SCP and NTCP1; and 2) SMp models for SPs involved in CTX. [ABSTRACT FROM AUTHOR]

Background: We studied the relationship between trismus (maximum interincisor opening [MIO] ≤35 mm) and the dose to the ipsilateral masseter muscle (iMM) and ipsilateral medial pterygoid muscle (iMPM). Methods: Pretreatment and post‐treatment measurement of MIO at 13 weeks revealed 17% of trismus cases in 83 patients treated with chemoradiation and intensity‐modulated radiation therapy. Logistic regression models were fitted with dose parameters of the iMM and iMPM and baseline MIO (bMIO). A risk classification tree was generated to obtain optimal cut‐off values and risk groups. Results: Dose levels of iMM and iMPM were highly correlated due to proximity. Both iMPM and iMM dose parameters were predictive for trismus, especially mean dose and intermediate dose volume parameters. Adding bMIO, significantly improved Normal Tissue Complication Probability (NTCP) models. Optimal cutoffs were 58 Gy (mean dose iMPM), 22 Gy (mean dose iMM) and 46 mm (bMIO). Conclusions: Both iMPM and iMM doses, as well as bMIO, are clinically relevant parameters for trismus prediction. [ABSTRACT FROM AUTHOR]

Objectives: We evaluated the dosimetric and radiobiological impact of abdominal compression (AC) on nearby gastrointestinal critical structures (GI-CS) and reported toxicities of patients treated with non-hepatic abdominal stereotactic body radiotherapy (SBRT). Methods: Two sets of CT scans, planning scans with AC and pre-treatment diagnostic scans without AC (non-AC) were compared for patients treated with a prescription dose to planning target volume (PTV) =25 Gy/5-fractions at a single institution. Target volumes were delineated on both sets of scans and PTV was expanded isotropically by 2 cm (PTV+2) and 4 cm (PTV+4). All GI-CS were summated to create a composite CS (GI-lumen). Rigid registration of AC and non-AC scans was done using Velocity AI (Varian Medical Systems) to obtain dose distribution information. Lymann-Probit and logit models were used for radiobiological calculations. Toxicity scores were obtained from prospectively collected clinical data. Results: A total of 12 patients were included. Mean PTV volumes were 190.3cc and 196.4cc with AC and non-AC (p=0.95). Significant improvement in V30 of GI-lumen was seen with AC (0.11cc vs. 4.97cc, p=0.04). There were no differences in the normal tissue complication probabilities of the individual GI-CS or the summary indices except a notable trend towards better NTCP for small bowel late effects with AC (0.21% vs. 2.45%; p=0.055). Three patients had acute grade-1 anorexia, one patient had acute grade-2 gastritis. There was no grade =3 GI toxicity. At a median follow-up of 2.6 years, total of 8/12 (66.7%) patients developed local recurrence of whom 4 (33.3%) had isolated local recurrence. Conclusion: Use of AC did not result in any dosimetric or radiobiological inferiority for GI-CS. The current cohort completed their treatment with minimal toxicity. [ABSTRACT FROM AUTHOR]

There are no quantitative selection criteria for identifying high-grade glioma (HGG) patients who are suited for volumetric-modulated arc therapy (VMAT). This study aimed to develop selection criteria that can be used for the selection of the optimal treatment modality in HGG. We analyzed 20 patients with HGG treated by 3D conformal radiotherapy (3DCRT). First, VMAT plans were created for each patient retrospectively. For each plan, the normal tissue complication probability (NTCP) for normal brain was calculated. We then divided the patients based on the NTCP s of the 3DCRT plans for normal brain, using the threshold of 5%. We compared the NTCP s of the two plans and the gross tumor volumes (GTV s) of the two groups. For the GTV s, we used receiver operating characteristic curves to identify the cut-off value for predicting NTCP < 5%. We determined the respective correlations between the GTV and the GTV's largest cross-sectional diameter and largest cross-sectional area. In the NTCP ≥ 5% group, the NTCP s for the VMAT plans were significantly lower than those for the 3DCRT plans (P = 0.0011). The NTCP ≥ 5% group's GTV was significantly larger than that of the NTCP < 5% group (P = 0.0016), and the cut-off value of the GTV was 130.5 cm3. The GTV was strongly correlated with the GTV 's largest cross-sectional diameter (R 2 = 0.82) and largest cross-sectional area (R 2 = 0.94), which produced the cut-off values of 7.5 cm and 41 cm2, respectively. It was concluded that VMAT is more appropriate than 3DCRT in cases in which the GTV is ≥130.5 cm3. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the radiobiological parameters of three popular NTCP models, which describe the dose–response relations of carotid blowout syndrome (CBOS) after stereotactic body radiotherapy (SBRT). To evaluate the goodness‐of‐fit and the correlation of those models with CBOS. Methods: The study included 61 patients with inoperable locally recurrent head and neck cancer treated with SBRT using CyberKnife (Accuray, Sunnyvale, CA) at the Department of Radiation Oncology, Hacettepe University, Ankara, Turkey between June 2007 and March 2011. The dose‐volume histograms of the internal carotid were exported from the plans of all the patients. The follow‐up results regarding the end point of carotid blowout syndrome were collected retrospectively. Initially, univariable analyses (Wilcoxon rank‐sum or Chi‐square tests) and a multivariate logistic regression analysis were performed between the outcome data and a list of clinical and treatment factors to identify significant correlations. Additionally, the Lyman–Kutcher–Burman (LKB), Relative Seriality (RS), and Logit NTCP models were used to fit the clinical data. The fitting of the different models was assessed through the area under the receiver operating characteristic curve (AUC), Akaike information criterion (AIC), and Odds Ratio methods. Results: The clinical/treatment factors that were found to have a significant or close to significant correlations with acute CBOS were Age at the time of CK (P‐value = 0.03), Maximum carotid dose (P‐value = 0.06), and CK prescription dose (P‐value = 0.08). Using Dmax, physical DVH, and EQD2 Gy‐DVH as the dosimetric metrics in the NTCP models, the derived LKB model parameters were: (a) D50 = 45.8 Gy, m = 0.24, n = n/a; (b) D50 = 44.8 Gy, m = 0.28, n = 0.01; and (c) D50 = 115.8 Gy, m = 0.45, n = 0.01, respectively. The AUC values for the dosimetric metrics were 0.70, 0.68, and 0.61, respectively. The differences in AIC between the different models were less than 2 and ranged within ±0.9. Conclusion: The maximum dose to the internal carotid less than 34 Gy appears to significantly reduce the risk for CBOS. Age at the time of CK, Maximum carotid dose, and CK prescription dose were also found to correlate with CBOS. The values of the parameters of three NTCP models were determined for this endpoint. A threshold of gEUD <34.5 Gy appears to be significantly associated with lower risks of CBOS. [ABSTRACT FROM AUTHOR]

• Eyelid skin erythema after brain and head and neck cancer affect the patient's quality of life. • LKB model is provided for acute eyelid skin erythema. • Eyelid skin erythema is predicted with high accuracy: ROC-AUC = 0.80(CI: 0.66–0.94), Brier score = 0.20. Radiation therapy is broadly used as one of the main treatment methods for patients with head and neck cancers and skull base tumors. However, it can lead to normal tissue complications. Therefore, this study aimed to model normal tissue complication probability (NTCP) of eyelid skin erythema after radiation therapy. The dataset of 45 patients with head and neck and skull base tumors was prospectively collected from their dose-volume histograms (DVHs). Grade 1 + eyelid skin erythema based on the Common Terminology Criteria for Adverse Events (CTCAE 4.0) was evaluated as the endpoint after a three-month follow-up. The Lyman-Kutcher-Burman (LKB) radiobiological model was developed based on generalized equivalent uniform dose (gEUD). Model parameters were calculated by maximum likelihood estimation. Model performance was evaluated by ROC-AUC, Brier score and Hosmer-Lemeshow test. After three months of follow-up, 13.33% of patients experienced eyelids skin erythema grade 1 or more. The parameters of the LKB model were: TD 50 = 30 Gy, m = 0.14, and n = 0.10. The model showed good predictive performance with ROC-AUC = 0.80 (CI:0.66–0.94) and a Brier score of 0.20. In this study, NTCP of eyelid skin erythema was modeled based on the LKB radiobiological model with good predictive performance. [ABSTRACT FROM AUTHOR]

PurposeThe purpose of this study is to investigate whether machine learning with dosiomic, radiomic, and demographic features allows for xerostomia risk assessment more precise than normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands.Material and methodsA cohort of 153 head-and-neck cancer patients was used to model xerostomia at 0–6 months (early), 6–15 months (late), 15–24 months (long-term), and at any time (a longitudinal model) after radiotherapy. Predictive power of the features was evaluated by the area under the receiver operating characteristic curve (AUC) of univariate logistic regression models. The multivariate NTCP models were tuned and tested with single and nested cross-validation, respectively. We compared predictive performance of seven classification algorithms, six feature selection methods, and ten data cleaning/class balancing techniques using the Friedman test and the Nemenyi post hoc analysis.ResultsNTCP models based on the parotid mean dose failed to predict xerostomia (AUCs 0.85), dose gradients in the right–left (AUCs > 0.78), and the anterior–posterior (AUCs > 0.72) direction. Multivariate models of long-term xerostomia were typically based on the parotid volume, the parotid eccentricity, and the dose–volume histogram (DVH) spread with the generalization AUCs ranging from 0.74 to 0.88. On average, support vector machines and extra-trees were the top performing classifiers, whereas the algorithms based on logistic regression were the best choice for feature selection. We found no advantage in using data cleaning or class balancing methods.ConclusionWe demonstrated that incorporation of organ- and dose-shape descriptors is beneficial for xerostomia prediction in highly conformal radiotherapy treatments. Due to strong reliance on patient-specific, dose-independent factors, our results underscore the need for development of personalized data-driven risk profiles for NTCP models of xerostomia. The facilitated machine learning pipeline is described in detail and can serve as a valuable reference for future work in radiomic and dosiomic NTCP modeling.

Proton beam therapy (PBT) is still relatively new in cancer treatment and the clinical evidence base is relatively sparse. Mathematical modelling offers assistance when selecting patients for PBT and predicting the demand for service. Discrete event simulation, normal tissue complication probability, quality-adjusted life-years and Markov Chain models are all mathematical and statistical modelling techniques currently used but none is dominant. As new evidence and outcome data become available from PBT, comprehensive models will emerge that are less dependent on the specific technologies of radiotherapy planning and delivery. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to investigate whether machine learning with dosiomic, radiomic, and demographic features allows for xerostomia risk assessment more precise than normal tissue complication probability (NTCP) models based on the mean radiation dose to parotid glands. Material and methods: A cohort of 153 head-and-neck cancer patients was used to model xerostomia at 0-6 months (early), 6-15 months (late), 15-24 months (long-term), and at any time (a longitudinal model) after radiotherapy. Predictive power of the features was evaluated by the area under the receiver operating characteristic curve (AUC) of univariate logistic regression models. The multivariate NTCP models were tuned and tested with single and nested cross-validation, respectively. We compared predictive performance of seven classification algorithms, six feature selection methods, and ten data cleaning/class balancing techniques using the Friedman test and the Nemenyi post hoc analysis. Results: NTCP models based on the parotid mean dose failed to predict xerostomia (AUCs<0.60). The most informative predictors were found for late and long-term xerostomia. Late xerostomia correlated with the contralateral dose gradient in the anterior- posterior (AUC=0.72) and the right-left (AUC=0.68) direction, whereas long-term xerostomia was associated with parotid volumes (AUCs>0.85), dose gradients in the right-left (AUCs>0.78), and the anterior-posterior (AUCs>0.72) direction. Multivariate models of long-term xerostomia were typically based on the parotid volume, the parotid eccentricity, and the dose-volume histogram (DVH) spread with the generalization AUCs ranging from 0.74 to 0.88. On average, support vector machines and extra-trees were the top performing classifiers, whereas the algorithms based on logistic regression were the best choice for feature selection. We found no advantage in using data cleaning or class balancing methods. Conclusion: We demonstrated that incorporation of organ- and dose-shape descriptors is beneficial for xerostomia prediction in highly conformal radiotherapy treatments. Due to strong reliance on patient-specific, dose-independent factors, our results underscore the need for development of personalized data-driven risk profiles for NTCP models of xerostomia. The facilitated machine learning pipeline is described in detail and can serve as a valuable reference for future work in radiomic and dosiomic NTCP modeling. [ABSTRACT FROM AUTHOR]