Prognostic models for radiation-induced complications after radiotherapy in head and neck cancer patients

Objectives: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows:. Primary objective The review question is “Which prognostic models are available to predict the risk of radiation-induced side effects after radiation exposure to patients with head and neck cancer, what is their quality, and what is their predictive performance?”. Investigation of sources of heterogeneity between studies We will assess sources of heterogeneity among the prognostic models developed in the eligible studies. The potential sources are study population (e.g. site/stage of cancer, the use of other treatment [surgery and chemotherapy]), predictors, definition and incidence of the predicted outcomes, and prediction horizons. If there are multiple validation studies for the same model, the same sources of between-study heterogeneity will be investigated

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 (β = 0.03(95 %CI = 0.01;0.05), p = 0.01), regional RT (β = 0.05(95 %CI = 0.02;0.09), p = 0.004), and concurrent chemotherapy (β = 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

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.</p

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.TRIAL REGISTRATION NUMBERS: NCT03507010, NL62429.042.17.</p

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

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.</p

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 &lt; 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.</p

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

COMPASS dose reconstruction in patient CT:the next step in pre-treatment verification

The main objective of this study was to make the transition from a film (2D) based pre-treatment IMRT / IMAT QA into a more efficient and clinical relevant method of verification by reconstructing the dose directly in the patient CT using the COMPASS system. The evaluation of the reconstructed dose includes DVHs and a gamma index evaluation