Radiotherapy for patients with ledderhose disease:long-term effects, side effects and patient-rated outcome

BACKGROUND: The purpose of this study was to investigate the long-term effects of radiotherapy for patients with Ledderhose disease. METHODS: Questionnaires were sent to all patients with Ledderhose disease who had been treated with radiotherapy at our centre between 2008 and 2017 and who consented to participate. Radiotherapy was performed with orthovolt or electrons in two separate courses of five daily fractions of 3 Gy. The questionnaires addressed items such as pain from Ledderhose disease (Brief Pain Inventory), quality of life (EURO-QOL-5D-5L), long-term side effects, and patients' levels of satisfaction with the effect of treatment. Descriptive statistics and non-parametric tests were used to analyse the results. RESULTS: A total of 102 feet were irradiated in 67 patients (28 men, 39 women). Radiotherapy resulted in significant pain reduction: the mean pain score prior to radiotherapy, collected retrospectively, was 5.7 and 1.7 at time of assessment (p-value<0.001). The following pain response scores were reported: progressive pain (0%), no change (22%; 22 feet), partial pain response (37%; 38 feet) and complete pain response (absence of pain) (41%; 42 feet). Seventy-eight percent of patients were satisfied with the treatment effect and 57% did not consider radiotherapy burdensome. The scores for societal perspective (0.856) and patients' perspective on quality of life (82.3) were each comparable to the reference values from the Dutch population in the same age category (0.857 and 80.6, respectively). The most commonly reported residual long-term side effect was dryness of the skin (n=10; 15%). CONCLUSION: Radiotherapy for Ledderhose disease results in long-term pain reduction in the majority of patients and has limited side effects. The treatment is well tolerated, patients feel satisfied, and quality of life is comparable to the reference population

A Decision Support Tool to Optimize Selection of Head and Neck Cancer Patients for Proton Therapy

SIMPLE SUMMARY: A decision support tool was developed to select head and neck cancer patients for proton therapy. The tool uses delineation data to predict expected toxicity risk reduction with proton therapy and can be used before a treatment plan is created. The positive predictive value of the tool is >90%. This tool significantly reduces delays in commencing treatment and avoid redundant photon vs. proton treatment plan comparison. ABSTRACT: Selection of head and neck cancer (HNC) patients for proton therapy (PT) using plan comparison (VMAT vs. IMPT) for each patient is labor-intensive. Our aim was to develop a decision support tool to identify patients with high probability to qualify for PT, at a very early stage (immediately after delineation) to avoid delay in treatment initiation. A total of 151 HNC patients were included, of which 106 (70%) patients qualified for PT. Linear regression models for individual OARs were created to predict the D(mean) to the OARs for VMAT and IMPT plans. The predictors were OAR volume percentages overlapping with target volumes. Then, actual and predicted plan comparison decisions were compared. Actual and predicted OAR D(mean) (VMAT R(2) = 0.953, IMPT R(2) = 0.975) and NTCP values (VMAT R(2) = 0.986, IMPT R(2) = 0.992) were highly correlated. The sensitivity, specificity, PPV and NPV of the decision support tool were 64%, 87%, 92% and 51%, respectively. The expected toxicity reduction with IMPT can be predicted using only the delineation data. The probability of qualifying for PT is >90% when the tool indicates a positive outcome for PT. This tool will contribute significantly to a more effective selection of HNC patients for PT at a much earlier stage, reducing treatment delay

CT-measured skeletal muscle mass used to assess frailty in patients with head and neck cancer

BACKGROUND: Skeletal muscle depletion or sarcopenia is related to multiple adverse clinical outcome. However, frailty questionnaires are currently applied in the daily practice to identify patients who are potentially (un)suitable for treatment but are time consuming and straining for patients and the clinician. Screening for sarcopenia in patients with head and neck cancer (HNC) could be a promising fast biomarker for frailty. Our objective was to quantify sarcopenia with pre-treatment low skeletal muscle mass from routinely obtained neck computed tomography scans at level of third cervical vertebra in patients diagnosed with HNC and evaluate its association with frailty. METHODS: A total of 112 HNC patients with Stages III and IV disease were included from a prospective databiobank. The amount of skeletal muscle mass was retrospectively defined using the skeletal muscle index (SMI). Correlation analysis between SMI and continuous frailty data and the observer agreement were analysed with Pearson's r correlation coefficients. Sarcopenia was present when SMI felt below previously published non-gender specific thresholds (<43.2 cm2 /m2 ). Frailty was evaluated by Geriatrics 8 (G8), Groningen Frailty Indicator, Timed Up and Go test, and Malnutrition Universal Screening Tool. A univariate and multivariate logistic regression analysis was performed for all patients and men separately to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: The cohort included 82 men (73%) and 30 women (27%), with a total mean age of 63 (±9) years. The observer agreement for cross-sectional measurements was excellent for both intra-observer variability (r = 0.99, P < 0.001) and inter-observer variability (r = 0.98, P < 0.001). SMI correlated best with G8 frailty score (r = 0.38, P < 0.001) and did not differ per gender. Sarcopenia was present in 54 (48%) patients, whereof 25 (46%) men and 29 (54%) women. Prevalence of frailty was between 5% and 54% depending on the used screening tool. The multivariate regression analysis for all patients and men separately isolated the G8 questionnaire as the only independent variable associated with sarcopenia (OR 0.76, 95% CI 0.66-0.89, P < 0.001 and OR 0.76, 95% CI 0.66-0.88, P < 0.001, respectively). CONCLUSIONS: This is the first study that demonstrates that sarcopenia is independently associated with frailty based on the G8 questionnaire in HNC patients. These results suggest that in the future, screening for sarcopenia on routinely obtained neck computed tomography scans may replace time consuming frailty questionnaires and help to select the (un)suitable patients for therapy, which is highly clinically relevant

Head and neck IMPT probabilistic dose accumulation:Feasibility of a 2 mm setup uncertainty setting

OBJECTIVE: To establish optimal robust optimization uncertainty settings for clinical head and neck cancer (HNC) patients undergoing 3D image-guided pencil beam scanning (PBS) proton therapy. METHODS: We analyzed ten consecutive HNC patients treated with 70 and 54.25 GyRBE to the primary and prophylactic clinical target volumes (CTV) respectively using intensity-modulated proton therapy (IMPT). Clinical plans were generated using robust optimization with 5 mm/3% setup/range uncertainties (RayStation v6.1). Additional plans were created for 4, 3, 2 and 1 mm setup and 3% range uncertainty and for 3 mm setup and 3%, 2% and 1% range uncertainty. Systematic and random error distributions were determined for setup and range uncertainties based on our quality assurance program. From these, 25 treatment scenarios were sampled for each plan, each consisting of a systematic setup and range error and daily random setup errors. Fraction doses were calculated on the weekly verification CT closest to the date of treatment as this was considered representative of the daily patient anatomy. RESULTS: Plans with a 2 mm/3% setup/range uncertainty setting adequately covered the primary and prophylactic CTV (V95≥ 99% in 98.8% and 90.8% of the treatment scenarios respectively). The average organ-at-risk dose decreased with 1.1 GyRBE/mm setup uncertainty reduction and 0.5 GyRBE/1% range uncertainty reduction. Normal tissue complication probabilities decreased by 2.0%/mm setup uncertainty reduction and by 0.9%/1% range uncertainty reduction. CONCLUSION: The results of this study indicate that margin reduction below 3 mm/3% is possible but requires a larger cohort to substantiate clinical introduction

Practical robustness evaluation in radiotherapy - A photon and proton-proof alternative to PTV-based plan evaluation

Background and purpose: A planning target volume (PTV) in photon treatments aims to ensure that the clinical target volume (CTV) receives adequate dose despite treatment uncertainties. The underlying static dose cloud approximation (the assumption that the dose distribution is invariant to errors) is problematic in intensity modulated proton treatments where range errors should be taken into account as well. The purpose of this work is to introduce a robustness evaluation method that is applicable to photon and proton treatments and is consistent with (historic) PTV-based treatment plan evaluations. Materials and methods: The limitation of the static dose cloud approximation was solved in a multi-scenario simulation by explicitly calculating doses for various treatment scenarios that describe possible errors in the treatment course. Setup errors were the same as the CTV-PTV margin and the underlying theory of 3D probability density distributions was extended to 4D to include range errors, maintaining a 90% confidence level. Scenario dose distributions were reduced to voxel-wise minimum and maximum dose distributions; the first to evaluate CTV coverage and the second for hot spots. Acceptance criteria for CTV D98 and D2 were calibrated against PTV-based criteria from historic photon treatment plans. Results: CTV D98 in worst case scenario dose and voxel-wise minimum dose showed a very strong correlation with scenario average D98 (R-2 > 0.99). The voxel-wise minimum dose visualised CTV dose conformity and coverage in 3D in agreement with PTV-based evaluation in photon therapy. Criteria for CTV D98 and D2 of the voxel-wise minimum and maximum dose showed very strong correlations to PTV D98 and D2 (R-2 > 0.99) and on average needed corrections of -0.9% and +2.3%, respectively. Conclusions: A practical approach to robustness evaluation was provided and clinically implemented for PTV-less photon and proton treatment planning, consistent with PTV evaluations but without its static dose cloud approximation. (C) 2019 The Authors. Published by Elsevier B.V

(18)F-FDG PET image biomarkers improve prediction of late radiation-induced xerostomia

BACKGROUND AND PURPOSE: Current prediction of radiation-induced xerostomia 12months after radiotherapy (Xer12m) is based on mean parotid gland dose and baseline xerostomia (Xerbaseline) scores. The hypothesis of this study was that prediction of Xer12m is improved with patient-specific characteristics extracted from (18)F-FDG PET images, quantified in PET image biomarkers (PET-IBMs). PATIENTS AND METHODS: Intensity and textural PET-IBMs of the parotid gland were collected from pre-treatment (18)F-FDG PET images of 161 head and neck cancer patients. Patient-rated toxicity was prospectively collected. Multivariable logistic regression models resulting from step-wise forward selection and Lasso regularisation were internally validated by bootstrapping. The reference model with parotid gland dose and Xerbaseline was compared with the resulting PET-IBM models. RESULTS: High values of the intensity PET-IBM (90th percentile (P90)) and textural PET-IBM (Long Run High Grey-level Emphasis 3 (LRHG3E)) were significantly associated with lower risk of Xer12m. Both PET-IBMs significantly added in the prediction of Xer12m to the reference model. The AUC increased from 0.73 (0.65-0.81) (reference model) to 0.77 (0.70-0.84) (P90) and 0.77 (0.69-0.84) (LRHG3E). CONCLUSION: Prediction of Xer12m was significantly improved with pre-treatment PET-IBMs, indicating that high metabolic parotid gland activity is associated with lower risk of developing late xerostomia. This study highlights the potential of incorporating patient-specific PET-derived functional characteristics into NTCP model development

Selection of head and neck cancer patients for adaptive radiotherapy to decrease xerostomia

AbstractBackground and purposeThe aim of this study was to develop and validate a method to select head and neck cancer patients for adaptive radiotherapy (ART) pre-treatment. Potential pre-treatment selection criteria presented in recent literature were included in the analysis.Materials and methodsDeviations from the planned parotid gland mean dose (PG ΔDmean) were estimated for 113 head and neck cancer patients by re-calculating plans on repeat CT scans. Uni- and multivariable linear regression analyses were performed to select pre-treatment parameters, and ROC curve analysis was used to determine cut off values, for selecting patients with a PG dose deviation larger than 3Gy. The patient selection method was validated in a second patient cohort of 43 patients.ResultsAfter multivariable analysis, the planned PG Dmean remained the only significant parameter for PG ΔDmean. A sensitivity of 91% and 80% could be obtained using a threshold of PG Dmean of 22.2Gy, for the development and validation cohorts, respectively. This would spare 38% (development cohort) and 24% (validation cohort) of patients from the labour-intensive ART procedure.ConclusionsThe presented method to select patients for ART pre-treatment reduces the labour of ART, contributing to a more effective allocation of the department resources

Impact of radiation-induced toxicities on quality of life of patients treated for head and neck cancer

PURPOSE: The aim of this study is to establish the relative impact of physician-rated toxicities and patient-rated symptoms in head and neck cancer (HNC) on quality of life (QOL) and to weigh the various toxicities and symptoms during treatment plan optimization and selection. MATERIALS AND METHODS: This prospective cohort study comprised 1,083 HNC patients (development: 750, validation: 333) treated with definitive radiotherapy with or without chemotherapy. Clinical factors were scored at baseline. Physician-rated and patient-rated outcome measures and QOL (EORTC QLQ-HN35 and QLQ-C30) were prospectively scored at baseline and 6, 12, 18 and 24 months after radiotherapy. The impact of 20 common toxicities and symptoms (related to swallowing, salivary function, speech, pain and general complaints) on QOL (0-100 scale) was established for each time point by combining principal component analysis and multivariable linear regression. RESULTS: Radiation-induced toxicities and symptoms resulted in a significant decline in QOL of patients with 12.4±12.8 points at 6 months to 16.6±17.1 points at 24 months. The multivariable linear models described the QOL points subtracted for each toxicity and symptom after radiotherapy. For example, xerostomia and weight loss had a significant but minor effect (on average -0.5 and -0.6 points) while speech problems and fatigue had a much greater impact (on average -11.9 and -17.4 points) on QOL. R2 goodness-of-fit values for the QOL models ranged from 0.64 (6 months) to 0.72 (24 months). CONCLUSION: The relative impact of physician-rated toxicities and patient-rated symptoms on QOL was quantified and can be used to optimize, compare and select HNC radiotherapy treatment plans, to balance the relevance of toxicities and to achieve the best QOL for individual patients

CT image biomarkers to improve patient-specific prediction of radiation-induced xerostomia and sticky saliva

AbstractBackground and purposeCurrent models for the prediction of late patient-rated moderate-to-severe xerostomia (XER12m) and sticky saliva (STIC12m) after radiotherapy are based on dose-volume parameters and baseline xerostomia (XERbase) or sticky saliva (STICbase) scores. The purpose is to improve prediction of XER12m and STIC12m with patient-specific characteristics, based on CT image biomarkers (IBMs).MethodsPlanning CT-scans and patient-rated outcome measures were prospectively collected for 249 head and neck cancer patients treated with definitive radiotherapy with or without systemic treatment. The potential IBMs represent geometric, CT intensity and textural characteristics of the parotid and submandibular glands. Lasso regularisation was used to create multivariable logistic regression models, which were internally validated by bootstrapping.ResultsThe prediction of XER12m could be improved significantly by adding the IBM “Short Run Emphasis” (SRE), which quantifies heterogeneity of parotid tissue, to a model with mean contra-lateral parotid gland dose and XERbase. For STIC12m, the IBM maximum CT intensity of the submandibular gland was selected in addition to STICbase and mean dose to submandibular glands.ConclusionPrediction of XER12m and STIC12m was improved by including IBMs representing heterogeneity and density of the salivary glands, respectively. These IBMs could guide additional research to the patient-specific response of healthy tissue to radiation dose

Frailty and restrictions in geriatric domains are associated with surgical complications but not with radiation-induced acute toxicity in head and neck cancer patients:A prospective study

OBJECTIVES: We aimed to evaluate the association between frailty screening and geriatric assessment (GA) on short term adverse events in patients treated for head and neck cancer (HNC) for the first time in a prospective study. MATERIALS AND METHODS: Newly diagnosed HNC patients undergoing curative treatment were prospectively included in OncoLifeS, a data biobank. Prior to the start of treatment, frailty was assessed with a GA, Groningen Frailty Indicator (GFI) and Geriatric-8 (G8). The GA included comorbidity (Adult Comorbidity Evaluation - 27), nutritional status (Malnutrition Universal Screening Tool), functional status ((instrumental) Activities of Daily Living), mobility (Timed Up & Go), psychological (Geriatric Depression Scale 15) and cognitive (Mini Mental State Examination) measures. Clinically relevant postoperative complications (Clavien-Dindo ≥ grade 2) and acute radiation-induced toxicity (Common Terminology Criteria for Adverse Events version 4.0 ≥ grade 2) were defined as outcome measures. Univariable and multivariable logistic regression analyses were performed, yielding odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS: Of the 369 included patients, 259 patients were eligible for analysis. Postoperative complications occurred in 41/148 (27.7%) patients and acute radiation-induced toxicity was present in 86/160 (53.7%) patients. Number of deficit domains of GA (OR = 1.71, 95%CI = 1.14-2.56), GFI (OR = 2.54, 95%CI = 1.02-6.31) and G8 (OR5.59, 95%CI = 2.14-14.60) were associated with postoperative complications, but not with radiation-induced toxicity. CONCLUSION: Frailty and restrictions in geriatric domains were associated with postoperative complications, but not with radiation-induced acute toxicity in curatively treated HNC patients. The results of this prospective study further emphasizes the importance of geriatric evaluation, particularly before surgery