A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE).

BACKGROUND AND PURPOSE: This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. MATERIALS AND METHODS: Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. RESULTS: Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74-89 %) vs. 74 % (66-83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43-1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05-0.93) and oropharyngeal cancer (0.31, 0.10-0.95), regardless of HPV. CONCLUSION: Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.

Radiation-induced xerostomia is related to stem cell dose-dependent reduction of saliva production.

BACKGROUND AND PURPOSE: Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (Dmean,SCR) is the strongest dosimetric predictor for the risk of patient-reported daytime xerostomia. This study aimed to test whether the relationship between patient-reported xerostomia and Dmean,SCR is explained by a dose-dependent reduction of saliva production. MATERIAL/METHODS: In 570 head and neck cancer patients treated with definitive radiation therapy (RT), flow from the parotid (FLOWPAR) and submandibular/sublingual glands (FLOWSMSL) and patient-reported daytime (XERDAY) and nighttime xerostomia (XERNIGHT) were prospectively measured before, and at 6 and 12 months after RT. Using linear mixed effect models, the relations of mean dose to the parotid glands (Dmean,par), Dmean,SCR, non-SCR parotid gland tissue (Dmean,non-SCR), submandibular glands (Dmean,sub) and oral cavity (Dmean,oral) with salivary flow and xerostomia were analyzed while correcting for known confounders. RESULTS: Dmean,SCR proved to be responsible for the effect of Dmean,par on FLOWPAR (p≤0.03), while Dmean,non-SCR did not affect FLOWPAR (p≥0.11). To illustrate, increasing Dmean,SCR by 10 Gy at fixed Dmean,non-SCR, reduced FLOWPAR by 0.02 (25%) after RT. However, if the opposite happened, no change in FLOWPAR was observed (0.00 ml/min [4%]). As expected, Dmean,sub was significantly associated with FLOWSMSL (p<0.001). For example, increasing Dmean,sub by 10 Gy, reduced FLOWSMSL with 0.07 ml/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. Dmean,SCR and Dmean,oral were associated with higher XERDAY scores (p≤0.05), while Dmean,sub increased XERNIGHT scores (p=0.01). For example, an increase of 10 Gy in Dmean,SCR raised XERDAY scores with 2.13 (5%) points after RT, while an additional 10 Gy in Dmean,subs increased XERNIGHT scores with 2.20 points (6%) after RT. Salivary flow was not only associated with radiation dose, but also with xerostomia scores in line with the salivary glands' functions, i.e., FLOWPAR only influenced XERDAY (p<0.001, 10.92 points lower XERDAY per 1 ml/min saliva), while FLOWSMSL affected XERDAY and XERNIGHT (p≤0.004, 6.69 and 5.74 points lower XERDAY and XERNIGHT, respectively, per 1 ml/min saliva). Therefore, the observed relations between dose and xerostomia were corrected for salivary flow. As hypothesized, Dmean,SCR only increased XERDAY scores via reducing FLOWPAR; whereas the effects of Dmean,oral on XERDAY and of Dmean,sub on XERNIGHT were independent of salivary flow. CONCLUSION: Higher SCR region dose reduced parotid gland saliva production, subsequently resulting in higher daytime xerostomia scores. Consequently, this study supports the clinical implementation of stem cell sparing RT to preserve salivary flow with the aim of reducing the risk of xerostomia.

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.

An economic evaluation of radiotherapy for patients with symptomatic Ledderhose disease.

BACKGROUND: Evidence for effectiveness of radiotherapy for Ledderhose disease was demonstrated in the LedRad-study. However, the health economic impact of Ledderhose disease is unclear. Therefore, an economic evaluation alongside the LedRad-study was planned. METHODS: The economic evaluation was performed as a cost-effectiveness and cost-utility analysis from the societal perspective. Primary outcome parameters were pain burden and Quality Adjusted Life Years (QALY), until 12 months after the end of treatment. Secondary analyses were performed with outcomes until 18 months. Incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were calculated to express costs per unit improvement in pain burden and costs per QALY gained, for radiotherapy compared to sham-radiotherapy. Bootstrap replication was used to assess uncertainty surrounding the ratios and to construct cost-effectiveness acceptability curves for QALY gain. RESULTS: Previous analysis showed a statistically significant improvement in pain- and QoL scores in favour of radiotherapy at 12 and 18 months. At these timepoints and excluding treatment costs, cumulative total costs were considerably lower in the radiotherapy group. The ICER until 12 months after treatment was 4987 euro per unit of pain burden reduction. The ICUR was 14249 euro per QALY gained. Most of the bootstrap replications were in the upper right quadrant, indicating that health gain can be achieved at higher costs. At increasing levels of willingness to pay for a gain in QALY, the probability of cost-utility gradually increased to approximately 85%. CONCLUSIONS: In patients with symptomatic Ledderhose disease, radiotherapy, at a moderate threshold for willingness to pay, is cost-effective in terms of QoL gain.

Effects of proton therapy on regional [18F]FDG uptake in non-tumor brain regions of patients treated for head and neck cancer.

Background and purpose: Previous pre-clinical research using [18F]FDG-PET has shown that whole-brain photon-based radiotherapy can affect brain glucose metabolism. This study, aimed to investigate how these findings translate into regional changes in brain [18F]FDG uptake in patients with head and neck cancer treated with intensity-modulated proton therapy (IMPT). Materials and methods: Twenty-three head and neck cancer patients treated with IMPT and available [18F]FDG scans before and at 3 months follow-up were retrospectively evaluated. Regional assessment of the [18F]FDG standardized uptake value (SUV) parameters and radiation dose in the left (L) and right (R) hippocampi, L and R occipital lobes, cerebellum, temporal lobe, L and R parietal lobes and frontal lobe were evaluated to understand the relationship between regional changes in SUV metrics and radiation dose. Results: Three months after IMPT, [18F]FDG brain uptake calculated using SUVmean and SUVmax, was significantly higher than that before IMPT. The absolute SUVmean after IMPT was significantly higher than before IMPT in seven regions of the brain (p ≤ 0.01), except for the R (p = 0.11) and L (p = 0.15) hippocampi. Absolute and relative changes were variably correlated with the regional maximum and mean doses received in most of the brain regions. Conclusion: Our findings suggest that 3 months after completion of IMPT for head and neck cancer, significant increases in the uptake of [18F]FDG (reflected by SUVmean and SUVmax) can be detected in several individual key brain regions, and when evaluated jointly, it shows a negative correlation with the mean dose. Future studies are needed to assess whether and how these results could be used for the early identification of patients at risk for adverse cognitive effects of radiation doses in non-tumor tissues.

Prediction of Radiation-Induced Parotid Gland-Related Xerostomia in Patients With Head and Neck Cancer: Regeneration-Weighted Dose.

PURPOSE: Despite improvements to treatment, patients with head and neck cancer (HNC) still experience radiation-induced xerostomia due to salivary gland damage. The stem cells of the parotid gland (PG), concentrated in the gland's main ducts (stem cell rich [SCR] region), play a critical role in the PG's response to radiation. Treatment optimization requires a dose metric that properly accounts for the relative contributions of dose to this SCR region and the PG's remainder (non-SCR region) to the risk of xerostomia in normal tissue complication probability (NTCP) models for xerostomia. MATERIALS AND METHODS: Treatment and toxicity data of 1013 prospectively followed patients with HNC treated with definitive radiation therapy (RT) were used. The regeneration-weighted dose, enabling accounting for the hypothesized different effects of dose to the SCR and non-SCR region on the risk of xerostomia, was defined as Dreg PG = Dmean SCR region + r × Dmean non-SCR region, where Dreg is the regeneration-weighted dose, Dmean is the mean dose, and r is the weighting factor. Considering the different volumes of these regions, r > 3.6 in Dreg PG demonstrates an enhanced effect of the SCR region. The most predictive value of r was estimated in 102 patients of a previously published trial testing stem cell sparing RT. For each endpoint, Dreg PG, dose to other organs, and clinical factors were used to develop NTCP models using multivariable logistic regression analysis in 663 patients. The models were validated in 350 patients. RESULTS: Dose to the contralateral PG was associated with daytime, eating-related, and physician-rated grade ≥2 xerostomia. Consequently, r was estimated and found to be smaller than 3.6 for most PG function-related endpoints. Therefore, the contribution of Dmean SCR region to the risk of xerostomia was larger than predicted by Dmean PG. Other frequently selected predictors were pretreatment xerostomia and Dmean oral cavity. The validation showed good discrimination and calibration. CONCLUSIONS: Tools for clinical implementation of stem cell sparing RT were developed: regeneration-weighted dose to the parotid gland that accounted for regional differences in radiosensitivity within the gland and NTCP models that included this new dose metric and other prognostic factors.

CT-based deep multi-label learning prediction model for outcome in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: Personalized treatment is increasingly required for oropharyngeal squamous cell carcinoma (OPSCC) patients due to emerging new cancer subtypes and treatment options. Outcome prediction model can help identify low or high-risk patients who may be suitable to receive de-escalation or intensified treatment approaches. PURPOSE: To develop a deep learning (DL)-based model for predicting multiple and associated efficacy endpoints in OPSCC patients based on computed tomography (CT). METHODS: Two patient cohorts were used in this study: a development cohort consisting of 524 OPSCC patients (70% for training and 30% for independent testing) and an external test cohort of 396 patients. Pre-treatment CT-scans with the gross primary tumor volume contours (GTVt) and clinical parameters were available to predict endpoints, including 2-year local control (LC), regional control (RC), locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS), overall survival (OS), and disease-free survival (DFS). We proposed DL outcome prediction models with the multi-label learning (MLL) strategy that integrates the associations of different endpoints based on clinical factors and CT-scans. RESULTS: The multi-label learning models outperformed the models that were developed based on a single endpoint for all endpoints especially with high AUCs ≥ 0.80 for 2-year RC, DMFS, DSS, OS, and DFS in the internal independent test set and for all endpoints except 2-year LRC in the external test set. Furthermore, with the models developed, patients could be stratified into high and low-risk groups that were significantly different for all endpoints in the internal test set and for all endpoints except DMFS in the external test set. CONCLUSION: MLL models demonstrated better discriminative ability for all 2-year efficacy endpoints than single outcome models in the internal test and for all endpoints except LRC in the external set.

Radiotherapy for Ledderhose disease: Results of the LedRad-study, a prospective multicentre randomised double-blind phase 3 trial.

BACKGROUND AND PURPOSE: Radiotherapy is considered a treatment option for Ledderhose disease. However, its benefits have never been confirmed in a randomised controlled trial. Therefore, the LedRad-study was conducted. MATERIALS AND METHODS: The LedRad-study is a prospective multicentre randomised double-blind phase three trial. Patients were randomised to sham-radiotherapy (placebo) or radiotherapy. The primary endpoint was pain reduction at 12 months after treatment, measured with the Numeric Rating Scale (NRS). Secondary endpoints were pain reduction at 6 and 18 months after treatment, quality of life (QoL), walking abilities and toxicity. RESULTS: A total of 84 patients were enrolled. At 12 and 18 months, patients in the radiotherapy group had a lower mean pain score compared to patients in the sham-radiotherapy group (2.5 versus 3.6 (p = 0.03) and 2.1 versus 3.4 (p = 0.008), respectively). Pain relief at 12 months was 74% in the radiotherapy group and 56% in the sham-radiotherapy group (p = 0.002). Multilevel testing for QoL scores showed higher QoL scores in the radiotherapy group compared to the sham-radiotherapy group (p < 0.001). Moreover, patients in the radiotherapy group had a higher mean walking speed and step rate with barefoot speed walking (p = 0.02). Erythema, skin dryness, burning sensations and increased pain were the most frequently reported side effects. These side effects were generally graded as mild (95%) and the majority (87%) were resolved at 18 months follow-up. CONCLUSION: Radiotherapy for symptomatic Ledderhose disease is an effective treatment resulting in a significant pain reduction, improvement of QoL scores and bare feet walking abilities, in comparison to sham-radiotherapy.

Dutch Multidisciplinary Guideline on Dupuytren Disease.

Purpose: To provide a comprehensive, evidence-based overview of the treatment for Dupuytren disease, specifically needle techniques, radiotherapy, primary conservative therapy, surgery, lipofilling, operative arthrolysis, salvage techniques, and the postoperative protocol and to make clinical recommendations for health care practitioners and patients. Methods: Comprehensive multidisciplinary guideline process funded by the Quality Foundation of the Dutch Federation of Medical Specialists. This process included a development, commentary, and authorization phase. Patients participated in every phase. Multiple databases and existing guidelines up to August 2020 were searched. Studies on Dupuytren disease were considered eligible. Specific eligibility criteria were described per module. To appraise the certainty of the evidence, reviewers extracted data, assessed the risk of bias, and used the Grading of Recommendations Assessment, Development and Evaluation method, where applicable. Important considerations were as follows: patient values and preferences, costs, acceptability of other stakeholders, and feasibility of implementation. Recommendations were made based on the evidence from the literature and the considerations. The primary and secondary outcome measures were defined per module based on the input of patients obtained in collaboration with the Netherlands Patient Federation and health care providers from different professions. Results: The following 8 specific modules were completed for Dupuytren disease: (1) needle techniques, (2) radiotherapy, (3) primary conservative therapy, (4) surgery, (5) lipofilling, (6) operative arthrolysis, (7) salvage techniques, and (8) the postoperative protocol. Conclusions: Our Dutch multidisciplinary guideline on Dupuytren disease provides 8 modules developed according to the standards of the Dutch Federation of Medical Specialists. Evidence-based recommendations for clinical practice are provided for needle techniques, radiotherapy, primary conservative therapy, surgery, lipofilling, operative arthrolysis, salvage techniques, and the postoperative protocol. This guideline can assist health care providers and patients in clinical practice. Type of study/level of evidence: Systematic review/I-II.

Effect of painful Ledderhose disease on dynamic plantar foot pressure distribution during walking: a case-control study.

BACKGROUND: Plantar pressure distribution during walking in patients with painful Ledderhose disease is unknown. RESEARCH QUESTION: Do patients with painful Ledderhose disease have an altered plantar pressure distribution during walking compared to individuals without foot pathologies? It was hypothesized that plantar pressure is shifted away from the painful nodules. METHODS: Pedobarography data of 41 patients with painful Ledderhose disease (cases, mean age: 54.2 ± 10.4 years) was collected and compared to pedobarography data from 41 individuals without foot pathologies (controls, mean age: 21.7 ± 2.0 years). Peak Pressure (PP), Maximum Mean Pressure (MMP) and Force-Time Integral (FTI) were calculated for eight regions (heel, medial midfoot, lateral midfoot, medial forefoot, central forefoot, lateral forefoot, hallux and other toes) under the soles of the feet. Differences between cases and controls were calculated and analysed by means of linear (mixed models) regression. RESULTS: Proportional differences in PP, MMP and FTI showed increased values for the cases compared to the controls, especially in the heel, hallux and other toes regions, and decreased values in the medial- and lateral midfoot regions. In naïve regression analysis, being a patient was a predictor for increased- and decreased values for PP, MMP and FTI for several regions. When dependencies in the data were taken into account with linear mixed-model regression analysis, the increased- and decreased values for the patients were most prevalent for FTI at the heel, medial midfoot, hallux and other toes regions. SIGNIFICANCE: In patients with painful Ledderhose disease, during walking, a shift of pressure was found towards the proximal and distal foot regions, while offloading the midfoot regions.

Accurate segmentation of head and neck radiotherapy CT scans with 3D CNNs: consistency is key.

Objective.Automatic segmentation of organs-at-risk in radiotherapy planning computed tomography (CT) scans using convolutional neural networks (CNNs) is an active research area. Very large datasets are usually required to train such CNN models. In radiotherapy, large, high-quality datasets are scarce and combining data from several sources can reduce the consistency of training segmentations. It is therefore important to understand the impact of training data quality on the performance of auto-segmentation models for radiotherapy.Approach.In this study, we took an existing 3D CNN architecture for head and neck CT auto-segmentation and compare the performance of models trained with a small, well-curated dataset (n= 34) and then a far larger dataset (n= 185) containing less consistent training segmentations. We performed 5-fold cross-validations in each dataset and tested segmentation performance using the 95th percentile Hausdorff distance and mean distance-to-agreement metrics. Finally, we validated the generalisability of our models with an external cohort of patient data (n= 12) with five expert annotators.Main results.The models trained with a large dataset were greatly outperformed by models (of identical architecture) trained with a smaller, but higher consistency set of training samples. Our models trained with a small dataset produce segmentations of similar accuracy as expert human observers and generalised well to new data, performing within inter-observer variation.Significance.We empirically demonstrate the importance of highly consistent training samples when training a 3D auto-segmentation model for use in radiotherapy. Crucially, it is the consistency of the training segmentations which had a greater impact on model performance rather than the size of the dataset used.

Dose response modelling of secretory cell loss in salivary glands using PSMA PET.

BACKGROUND AND PURPOSE: Xerostomia remains a common side effect of radiotherapy (RT) for patients with head and neck (H&N) cancer despite advancements in treatment planning and delivery. Secretory salivary gland cells express the prostate-specific membrane antigen (PSMA), and show significant uptake on PET scans using 68Ga/18F-PSMA-ligands. We aimed to objectively quantify the dose-response of salivary glands to RT using PSMA PET. METHODS AND MATERIALS: 28H&N cancer patients received RT with 70 Gy in 35 fractions over 7 weeks. PSMA PET/CT was acquired at baseline (BL), during treatment (DT) and at 1-&6-months post-treatment (PT1M/PT6M). Dose, BL- PT1M- and PT6M-SUV were extracted for every voxel inside each parotid (PG) and submandibular (SMG) gland. The PT1M/6M data was analysed using a generalised linear mixed effects model.Patient-reported xerostomia and DT-PSMA loss was also analysed. RESULTS: Dose had a relative effect on BL SUV. For a population average gland (BL-SUV of 10), every 1 Gy increment, decreased the PT1M/PT6M-SUV by 1.6 %/1.6 % for PGs and by 0.9 %/1.8 % for SMGs. TD50 of the population curves was 26.5/31.3 Gy for PGs, and 22.9/27.8 Gy for SMGs at PT1M /PT6M. PSMA loss correlated well with patient-reported xerostomia at DT/PT1M (Spearman's ρ = -0.64, -0.50). CONCLUSION: A strong relationship was demonstrated between radiation dose and loss of secretory cells in salivary glands derived using PSMA PET/CT. The population curve could potentially be used as a dose planning objective, by maximising the predicted post-treatment SUV. BL scans could be used to further tailor this to individual patients.

Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer.

BACKGROUND AND PURPOSE: We aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC). MATERIALS AND METHODS: We performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia. We analyzed the effect of variants on the average burden (measured as area under curve, AUC) per each RIT, and standardized total average acute toxicity (STATacute) score using a multivariate linear regression. We tested suggestive variants (p < 1.0x10-5) in discovery set (three cohorts; n = 2,640) in a replication set (four cohorts; n = 1,402). We meta-analysed all cohorts to calculate RITs specific SNP-based heritability, and effect of polygenic risk scores (PRSs), and genetic correlations among RITS. RESULTS: From 393 suggestive SNPs identified in discovery set; 37 were nominally significant (preplication < 0.05) in replication set, but none reached genome-wide significance (pcombined < 5 × 10-8). In-silico functional analyses identified "3'-5'-exoribonuclease activity" (FDR = 1.6e-10) for dysphagia, "inositol phosphate-mediated signalling" for mucositis (FDR = 2.20e-09), and "drug catabolic process" for STATacute (FDR = 3.57e-12) as the most enriched pathways by the RIT specific suggestive genes. The SNP-based heritability (±standard error) was 29 ± 0.08 % for dysphagia, 9 ± 0.12 % (mucositis) and 27 ± 0.09 % (STATacute). Positive genetic correlation was rg = 0.65 (p = 0.048) between dysphagia and STATacute. PRSs explained limited variation of dysphagia (3 %), mucositis (2.5 %), and STATacute (0.4 %). CONCLUSION: In HNC patients, acute RITs are modestly heritable, sharing 10 % genetic susceptibility, when PRS explains < 3 % of their variance. We identified numerus suggestive SNPs, which remain to be replicated in larger studies.

Sex-Specific Cut-Off Values for Low Skeletal Muscle Mass to Identify Patients at Risk for Treatment-Related Adverse Events in Head and Neck Cancer.

A low skeletal muscle index (SMI), defined with cut-off values, is a promising predictor for adverse events (AEs) in head and neck squamous cell cancer (HNSCC) patients. The aim was to generate sex-specific SMI cut-off values based on AE to diagnose low SMI and to analyse the relationship between low SMI and AEs in HNSCC patients. In this present study, HNSCC patients were prospectively included in a large oncological data-biobank and SMI was retrospectively measured using baseline neck scans. In total, 193 patients were included and were stratified according to treatment modality: (chemo-)radiotherapy ((C)RT) (n = 135) and surgery (n = 61). AE endpoints were based on the occurrence of clinically relevant toxicities (Common Terminology Criteria for Adverse Events grade ≥ III) and postoperative complications (Clavien-Dindo Classification grade ≥ II). Sex-specific SMI cut-off values were generated with receiver operating characteristic curves, based on the AE endpoints. The relationship of the baseline characteristics and AEs was analysed with logistic regression analysis, with AEs as the endpoint. Multivariable logistic analysis showed that low SMI (OR 3.33, 95%CI 1.41-7.85) and tumour stage (OR 3.45, 95%CI 1.28-9.29) were significantly and independently associated to (C)RT toxicity. Low SMI was not related to postoperative complications. To conclude, sex-specific SMI cut-off values, were generated based on the occurrence of AEs. Low SMI and tumour stage were independently related to (C)RT toxicity in HNSCC patients.

The association of frailty and outcomes of geriatric assessment with acute radiation-induced toxicity in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Geriatric impairments and frailty are highly prevalent in patients with head and neck cancer (HNC). This study investigated the association of frailty and outcomes of geriatric assessment (GA) with radiation-induced toxicity (RIT) in patients undergoing (chemo)radiotherapy ((C)RT) for HNC. MATERIALS AND METHODS: Between October 2014 and April 2016, patients with HNC were prospectively included in OncoLifeS, an institutional data-biobank. Before treatment initiation, patients underwent GA and frailty screening (Groningen Frailty Indicator and Geriatric 8). The main outcome of this study was RIT (weight loss, mucositis, salivary gland inflammation, oral pain, sore throat, hoarseness, dry mouth, dysgeusia, dysphagia and general pain) according to the common terminology criteria of adverse events (CTCAE) version 4.0. Linear mixed models were performed, to analyse factors associated with increasing mean RIT over time during the treatment period. RESULTS: 160 patients were included. 114 (71.3%) were male and the mean age was 66.1 years. Age ≥ 65 (ß = 0.03(95 %CI = 0.01;0.05), p = 0.01), regional RT (ß = 0.05(95 %CI = 0.02;0.09), p = 0.004), and concurrent chemotherapy (ß = 0.04(95 %CI = 0.02;0.07), p = 0.001), were independent factors associated with increasing toxicity during the 7-week treatment period, adjusted for relevant covariates. None of the single items of GA, as well as the frailty screening instruments, were associated with increasing RIT. CONCLUSION: In this study, frailty and GA were not associated with additional RIT during treatment. These results suggest that (C)RT is equally tolerated in frail and non-frail patients, with respect to acute RIT. RT could be a suitable alternative to surgery in selected frail patients.

Impact of sarcopenia on acute radiation-induced toxicity in head and neck cancer patients.

BACKGROUND AND PURPOSE: Sarcopenia is related to late radiation-induced toxicities and worse survival in head and neck cancer (HNC) patients. This study tested the hypothesis that sarcopenia improves the performance of current normal tissue complication probability (NTCP) models of radiation-induced acute toxicity in HNC patients. MATERIAL/METHODS: This was a retrospective analysis in a prospective cohort of HNC patients treated from January 2007 to December 2018 with (chemo)radiotherapy. Planning CT scans were used for evaluating skeletal muscle mass. Characteristics of sarcopenic and non-sarcopenic patients were compared. The impact of sarcopenia was analysed by adding sarcopenia to the linear predictors of current NTCP models predicting physician- and patient-rated acute toxicities. RESULTS: The cut-off values of sarcopenia in the study population (n = 977) were established at skeletal muscle index < 42.0 cm2/m2 (men) and < 31.2 cm2/m2 (women), corresponding to the lowest sex-specific quartile. Compared to non-sarcopenic patients, sarcopenic patients were more frequently smokers (61% vs. 48%, p < 0.001), had more often advanced stage of disease (stage III-IV, p = 0.004), higher age (67 vs. 63 years, p < 0.001) and experienced more pretreatment complaints, such as dysphagia (grade ≥ 2, p < 0.001). Sarcopenia remained statistically significant, next to the linear predictor, only for physician-rated grade ≥ 3 dysphagia (week 3-6 during RT, p < 0.01). However, sarcopenia did not improve the performance of these NTCP models (p > 0.99). CONCLUSION: Sarcopenia in HNC patients was an independent prognostic factor for radiation-induced physician-rated acute grade ≥ 3 dysphagia, which might be explained by its impact on swallowing muscles. However, addition of sarcopenia did not improve the NTCP model performance.

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

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 Dmean 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 Dmean (VMAT R2 = 0.953, IMPT R2 = 0.975) and NTCP values (VMAT R2 = 0.986, IMPT R2 = 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.