The influence of radiation dose on taste impairment in a prospective observational study cohort of oropharyngeal cancer patients.

BACKGROUND: To analyze the influence of radiation dose on late radiation-associated taste impairment in oropharyngeal cancer (OPC) patients treated with intensity-modulated radiotherapy (IMRT) using the taste bud bearing tongue mucosa as organ at risk. MATERIAL AND METHODS: This study is part of an ongoing, prospective observational study. Cancer-free OPC survivors with at least 24 months from IMRT were included in this analysis. Scores for taste impairment and dry mouth were extracted from the MD Anderson Symptom Inventory Head and Neck module (MDASI-HN) with scores of ≥5 considered as moderate-to-severe symptoms. The mean dose, minimum and maximum dose to the taste bud bearing tongue mucosa, the ipsi- and contralateral parotid and submandibular glands were extracted and analyzed for correlation with moderate-to-severe taste impairment. RESULTS: One hundred sixteen T1-4 OPC patients were included (81% males, median age: 55). The primary tumor was in the tonsil in 92 cases (79%) and in the base of tongue in 21 cases (18%). Patients were treated with 64.2-72.0 Gy; 37 patients (32%) received concurrent chemotherapy and 22 (19%) concurrent targeted therapy. After a median of 58 months from RT (IQR: 43-68) 38 patients (33%) suffered from moderate-to-severe long-term radiation-associated taste impairment. No dose volume parameter of the taste bud bearing tongue mucosa and the salivary glands was significantly associated with moderate-to-severe taste impairment for the whole patient cohort. For patients without concurrent chemotherapy, the minimum and mean dose to the ipsilateral parotid gland, and the maximum dose to the submandibular gland was significantly associated with late taste impairment (all p < 0.05). A significant correlation was found between taste impairment and dry mouth (p < 0.001). CONCLUSION: The dose to the ipsilateral parotid gland seems to play an important role in the development of late taste impairment. The influence of dose to the taste bud bearing tongue mucosa remains unclear and needs further investigation.

Novel Autosegmentation Spatial Similarity Metrics Capture the Time Required to Correct Segmentations Better Than Traditional Metrics in a Thoracic Cavity Segmentation Workflow.

Automated segmentation templates can save clinicians time compared to de novo segmentation but may still take substantial time to review and correct. It has not been thoroughly investigated which automated segmentation-corrected segmentation similarity metrics best predict clinician correction time. Bilateral thoracic cavity volumes in 329 CT scans were segmented by a UNet-inspired deep learning segmentation tool and subsequently corrected by a fourth-year medical student. Eight spatial similarity metrics were calculated between the automated and corrected segmentations and associated with correction times using Spearman's rank correlation coefficients. Nine clinical variables were also associated with metrics and correction times using Spearman's rank correlation coefficients or Mann-Whitney U tests. The added path length, false negative path length, and surface Dice similarity coefficient correlated better with correction time than traditional metrics, including the popular volumetric Dice similarity coefficient (respectively ρ = 0.69, ρ = 0.65, ρ = - 0.48 versus ρ = - 0.25; correlation p values < 0.001). Clinical variables poorly represented in the autosegmentation tool's training data were often associated with decreased accuracy but not necessarily with prolonged correction time. Metrics used to develop and evaluate autosegmentation tools should correlate with clinical time saved. To our knowledge, this is only the second investigation of which metrics correlate with time saved. Validation of our findings is indicated in other anatomic sites and clinical workflows. Novel spatial similarity metrics may be preferable to traditional metrics for developing and evaluating autosegmentation tools that are intended to save clinicians time.

Dependency of the blood oxygen level dependent-response to hyperoxic challenges on the order of gas administration in intracranial malignancies.

PURPOSE: Literature reports contradicting results on the response of brain tumors to vascular stimuli measured in T2*-weighted MRI. Here, we analyzed the potential dependency of the MRI-response to (hypercapnic) hyperoxia on the order of the gas administration. METHODS: T2* values were quantified at 3 Tesla in eight consenting patients at rest and during inhalation of hyperoxic/hypercapnic gas mixtures. Patients were randomly divided into two groups undergoing different gas administration protocols (group A: medical air-pure oxygen-carbogen; group B: medical air-carbogen-pure oxygen). Mann-Whitney U test and Wilcoxon signed rank test have been used to proof differences in T2* regarding respiratory challenge or different groups, respectively. RESULTS: T2* values at rest for gray and white matter were 50.3 ± 2.6 ms and 46.1 ± 2.0 ms, respectively, and slightly increased during challenge. In tumor areas, T2* at rest were: necrosis = 74.1 ± 10.1 ms; edema = 60.3 ± 17.6 ms; contrast-enhancing lesions = 48.6 ± 20.7 ms; and solid T2-hyperintense lesions = 45.0 ± 3.0 ms. Contrast-enhancing lesions strongly responded to oxygen (+ 20.7%) regardless on the gas protocol (p = 0.482). However, the response to carbogen significantly depended on the order of gas administration (group A, + 18.6%; group B, - 6.4%, p = 0.042). In edemas, a different trend between group was found when breathing oxygen (group A, - 9.9%; group B, + 19.5%, p = 0.057). CONCLUSION: Preliminary results show a dependency of the T2* response of contrast-enhancing brain tumor lesions on the order of the gas administration. The gas administration protocol is an important factor in the interpretation of the T2*-response in areas of abnormal vascular growth.

Longitudinal PET imaging of tumor hypoxia during the course of radiotherapy.

Hypoxia results from an imbalance between oxygen supply and consumption. It is a common phenomenon in solid malignant tumors such as head and neck cancer. As hypoxic cells are more resistant to therapy, tumor hypoxia is an indicator for poor prognosis. Several techniques have been developed to measure tissue oxygenation. These are the Eppendorf O2 polarographic needle electrode, immunohistochemical analysis of endogenous (e.g., hypoxia-inducible factor-1α (HIF-1a)) and exogenous markers (e.g., pimonidazole) as well as imaging methods such as functional magnetic resonance imaging (e.g., blood oxygen level dependent (BOLD) imaging, T1-weighted imaging) and hypoxia positron emission tomography (PET). Among the imaging modalities, only PET is sufficiently validated to detect hypoxia for clinical use. Hypoxia PET tracers include 18F-fluoromisonidazole (FMISO), the most commonly used hypoxic marker, 18F-flouroazomycin arabinoside (FAZA), 18Ffluoroerythronitroimidazole (FETNIM), 18F-2-nitroimidazolpentafluoropropylacetamide (EF5) and 18F-flortanidazole (HX4). As technical development provides the opportunity to increase the radiation dose to subregions of the tumor, such as hypoxic areas, it has to be ensured that these regions are stable not only from imaging to treatment but also through the course of radiotherapy. The aim of this review is therefore to characterize the behavior of tumor hypoxia during radiotherapy for the whole tumor and for subregions by using hypoxia PET tracers, with focus on head and neck cancer patients.

Radiation recall dermatitis induced by sorafenib : A case study and review of the literature.

BACKGROUND: Radiation recall dermatitis (RRD) is an acute inflammatory reaction confined to previously irradiated skin, mainly subsequent to the administration of certain chemotherapeutics. Here we present a rare case of RRD induced by the oral multikinase inhibitor sorafenib. CASE REPORT: A 77-year-old male with hepatocellular carcinoma was irradiated at ten different sites for bone metastases with 20-36 Gray in 5-12 fractions from January to March 2015. Sorafenib 400 mg was administered twice daily from mid-March. One week later the patient presented with fever and erythematous lesions on the right upper arm, mandible, and trunk. All skin symptoms were confined to previously irradiated areas. After RRD was diagnosed by exclusion of other causes and skin biopsy, sorafenib was paused. With the administration of topical corticosteroids and oral antihistamines, the skin reaction subsided within several days. Sorafenib was readministered after 3 weeks, which did not lead to recurrence of RRD but did cause fluctuating fever. DISCUSSION: Only four other such cases have been reported in the literature and WHO pharmacovigilance database on individual case safety reports. The current report is the first to show a potential relationship between the severity of sorafenib-induced RRD and radiation dose, histopathological features, and simultaneous acute radiation dermatitis and mucositis. CONCLUSION: RRD induced by sorafenib is a rare phenomenon, but should be considered in patients showing erythematous skin lesions 1-2 weeks after initiation of the drug, predominantly in areas where skin has been irradiated with an equivalent dose ≥ 30 Gy. Discontinuation of sorafenib with possible readministration should be evaluated with respect to the clinical situation and severity of reaction.

Radiation-associated changes in saliva composition of head and neck cancer patients: A systematic review.

Xerostomia is a common radiation-associated toxicity in patients with head and neck cancer. Although several studies examined the decrease in saliva production due to radiotherapy (RT) and investigated the factors associated with this side effect, little is known about the change in radiation-associated saliva composition. This systematic review is the first to summarize existing data and give an overview of the change in pH/buffer capacity, electrolytes, proteins, enzymes, and mucins due to radiation to the salivary glands. Literature search was performed in PubMed and Embase with 47 articles finally eligible for the review, analyzing the saliva composition at several time points before, during and/or after RT, or comparing findings in irradiated patients to a healthy control group. Overall, RT leads to a substantial decrease in salivary pH and buffer capacity. For sodium, chloride and calcium ion, as well as amylase, an increased concentration or activity during RT was reported in most of the studies, followed by a subsequent decrease either already during RT or after the end of treatment. Different trends have been described for the total protein concentration during and after RT. Lactoferrin, however, increased considerably, especially in the first phase of RT. Mucin 5B (MUC5B) concentrations showed a slight increase during RT and concentrations around baseline values again six months post-radiotherapy.

Mixed Effect Modeling of Dose and Linear Energy Transfer Correlations With Brain Image Changes After Intensity Modulated Proton Therapy for Skull Base Head and Neck Cancer.

PURPOSE: Intensity modulated proton therapy (IMPT) could yield high linear energy transfer (LET) in critical structures and increased biological effect. For head and neck cancers at the skull base this could potentially result in radiation-associated brain image change (RAIC). The purpose of the current study was to investigate voxel-wise dose and LET correlations with RAIC after IMPT. METHODS AND MATERIALS: For 15 patients with RAIC after IMPT, contrast enhancement observed on T1-weighted magnetic resonance imaging was contoured and coregistered to the planning computed tomography. Monte Carlo calculated dose and dose-averaged LET (LETd) distributions were extracted at voxel level and associations with RAIC were modelled using uni- and multivariate mixed effect logistic regression. Model performance was evaluated using the area under the receiver operating characteristic curve and precision-recall curve. RESULTS: An overall statistically significant RAIC association with dose and LETd was found in both the uni- and multivariate analysis. Patient heterogeneity was considerable, with standard deviation of the random effects of 1.81 (1.30-2.72) for dose and 2.68 (1.93-4.93) for LETd, respectively. Area under the receiver operating characteristic curve was 0.93 and 0.95 for the univariate dose-response model and multivariate model, respectively. Analysis of the LETd effect demonstrated increased risk of RAIC with increasing LETd for the majority of patients. Estimated probability of RAIC with LETd = 1 keV/µm was 4% (95% confidence interval, 0%, 0.44%) and 29% (95% confidence interval, 0.01%, 0.92%) for 60 and 70 Gy, respectively. The TD15 were estimated to be 63.6 and 50.1 Gy with LETd equal to 2 and 5 keV/µm, respectively. CONCLUSIONS: Our results suggest that the LETd effect could be of clinical significance for some patients; LETd assessment in clinical treatment plans should therefore be taken into consideration.

18FDG positron emission tomography mining for metabolic imaging biomarkers of radiation-induced xerostomia in patients with oropharyngeal cancer.

PURPOSE: Head and neck cancers radiotherapy (RT) is associated with inevitable injury to parotid glands and subsequent xerostomia. We investigated the utility of SUV derived from 18FDG-PET to develop metabolic imaging biomarkers (MIBs) of RT-related parotid injury. METHODS: Data for oropharyngeal cancer (OPC) patients treated with RT at our institution between 2005 and 2015 with available planning computed tomography (CT), dose grid, pre- & first post-RT 18FDG-PET-CT scans, and physician-reported xerostomia assessment at 3-6 months post-RT (Xero 3-6 ms) per CTCAE, was retrieved, following an IRB approval. A CT-CT deformable image co-registration followed by voxel-by-voxel resampling of pre & post-RT 18FDG activity and dose grid were performed. Ipsilateral (Ipsi) and contralateral (contra) parotid glands were sub-segmented based on the received dose in 5 Gy increments, i.e. 0-5 Gy, 5-10 Gy sub-volumes, etc. Median and dose-weighted SUV were extracted from whole parotid volumes and sub-volumes on pre- & post-RT PET scans, using in-house code that runs on MATLAB. Wilcoxon signed-rank and Kruskal-Wallis tests were used to test differences pre- and post-RT. RESULTS: 432 parotid glands, belonging to 108 OPC patients treated with RT, were sub-segmented & analyzed. Xero 3-6 ms was reported as: non-severe (78.7%) and severe (21.3%). SUV- median values were significantly reduced post-RT, irrespective of laterality (p = 0.02). A similar pattern was observed in parotid sub-volumes, especially ipsi parotid gland sub-volumes receiving doses 10-50 Gy (p < 0.05). Kruskal-Wallis test showed a significantly higher mean RT dose in the contra parotid in the patients with more severe Xero 3-6mo (p = 0.03). Multiple logistic regression showed a combined clinical-dosimetric-metabolic imaging model could predict the severity of Xero 3-6mo; AUC = 0.78 (95%CI: 0.66-0.85; p < 0.0001). CONCLUSION: We sought to quantify pre- and post-RT 18FDG-PET metrics of parotid glands in patients with OPC. Temporal dynamics of PET-derived metrics can potentially serve as MIBs of RT-related xerostomia in concert with clinical and dosimetric variables.

Development and validation of a contouring guideline for the taste bud bearing tongue mucosa.

PURPOSE: To introduce a contouring guideline for the taste bud bearing tongue mucosa for head and neck cancer patients receiving radiotherapy. METHODS AND MATERIALS: CT simulation images of oropharyngeal cancer patients were used to delineate both the whole tongue (extrinsic/intrinsic tongue muscles, floor of mouth) and the taste bud bearing tongue mucosa (method A: adaptation of the whole tongue structure; method B: axial adaptation of a mid-sagittal contour). Volumetric and dosimetric parameters of the whole tongue and the two methods of mucosal delineation, spatial overlap between methods A and B, and inter-observer variability for method B were calculated. RESULTS: The study cohort was comprised of 70 patients with T1-4 N0-1 tonsillar (83%) and base of tongue (17%) cancers. Most of the comparative parameters between the whole tongue and mucosa (method A) significantly differed (mean, minimum, and maximum dose, V5-V70, D40-D90). The mean dose calculated for the whole tongue deviated on average 3.77 Gy compared to method A. No significant differences were found between methods A and B of the taste bud bearing tongue mucosa structure, and none of the dosimetric parameters differed more than 1.03 Gy on average. The mean Dice similarity coefficient for both mucosal structures was 0.79 ± 0.05, and 0.63 ± 0.12 for the inter-observer analysis of method B. CONCLUSIONS: We defined two methods for delineating the taste bud bearing mucosa and both are equally satisfactory procedures. Either method is preferable over delineation of the whole tongue as organ at risk for taste impairment.

Fully automatic classification of breast MRI background parenchymal enhancement using a transfer learning approach.

Marked enhancement of the fibroglandular tissue on contrast-enhanced breast magnetic resonance imaging (MRI) may affect lesion detection and classification and is suggested to be associated with higher risk of developing breast cancer. The background parenchymal enhancement (BPE) is qualitatively classified according to the BI-RADS atlas into the categories "minimal," "mild," "moderate," and "marked." The purpose of this study was to train a deep convolutional neural network (dCNN) for standardized and automatic classification of BPE categories.This IRB-approved retrospective study included 11,769 single MR images from 149 patients. The MR images were derived from the subtraction between the first post-contrast volume and the native T1-weighted images. A hierarchic approach was implemented relying on 2 dCNN models for detection of MR-slices imaging breast tissue and for BPE classification, respectively. Data annotation was performed by 2 board-certified radiologists. The consensus of the 2 radiologists was chosen as reference for BPE classification. The clinical performances of the single readers and of the dCNN were statistically compared using the quadratic Cohen's kappa.Slices depicting the breast were classified with training, validation, and real-world (test) accuracies of 98%, 96%, and 97%, respectively. Over the 4 classes, the BPE classification was reached with mean accuracies of 74% for training, 75% for the validation, and 75% for the real word dataset. As compared to the reference, the inter-reader reliabilities for the radiologists were 0.780 (reader 1) and 0.679 (reader 2). On the other hand, the reliability for the dCNN model was 0.815.Automatic classification of BPE can be performed with high accuracy and support the standardization of tissue classification in MRI.

Correction for fast pseudo-diffusive fluid motion contaminations in diffusion tensor imaging.

In this prospective study, we quantified the fast pseudo-diffusion contamination by blood perfusion or cerebrospinal fluid (CSF) intravoxel incoherent movements on the measurement of the diffusion tensor metrics in healthy brain tissue. Diffusion-weighted imaging (TR/TE = 4100 ms/90 ms; b-values: 0, 5, 10, 20, 35, 55, 80, 110, 150, 200, 300, 500, 750, 1000, 1300 s/mm2, 20 diffusion-encoding directions) was performed on a cohort of five healthy volunteers at 3 Tesla. The projections of the diffusion tensor along each diffusion-encoding direction were computed using a two b-value approach (2b), by fitting the signal to a monoexponential curve (mono), and by correcting for fast pseudo-diffusion compartments using the biexponential intravoxel incoherent motion model (IVIM) (bi). Fractional anisotropy (FA) and mean diffusivity (MD) of the diffusion tensor were quantified in regions of interest drawn over white matter areas, gray matter areas, and the ventricles. A significant dependence of the MD from the evaluation method was found in all selected regions. A lower MD was computed when accounting for the fast-diffusion compartments. A larger dependence was found in the nucleus caudatus (bi: median 0.86 10-3 mm2/s, Δ2b: -11.2%, Δmono: -14.4%; p = 0.007), in the anterior horn (bi: median 2.04 10-3 mm2/s, Δ2b: -9.4%, Δmono: -11.5%, p = 0.007) and in the posterior horn of the lateral ventricles (bi: median 2.47 10-3 mm2/s, Δ2b: -5.5%, Δmono: -11.7%; p = 0.007). Also for the FA, the signal modeling affected the computation of the anisotropy metrics. The deviation depended on the evaluated region with significant differences mainly in the nucleus caudatus (bi: median 0.15, Δ2b: +39.3%, Δmono: +14.7%; p = 0.022) and putamen (bi: median 0.19, Δ2b: +3.1%, Δmono: +17.3%; p = 0.015). Fast pseudo-diffusive regimes locally affect diffusion tensor imaging (DTI) metrics in the brain. Here, we propose the use of an IVIM-based method for correction of signal contaminations through CSF or perfusion.

Imaging for Response Assessment in Radiation Oncology: Current and Emerging Techniques.

Imaging in radiation oncology is essential for the evaluation of treatment response in tumors and organs at risk. This influences further treatment decisions and could possibly be used to adapt therapy. This review article focuses on the currently used imaging modalities for response assessment in radiation oncology and gives an overview of new and promising techniques within this field.

Evaluation of 18F-FDG PET/CT as an early imaging biomarker for response monitoring after radiochemotherapy using cetuximab in head and heck squamous cell carcinoma.

BACKGROUND: To determine whether 18 F-PET/CT is able to identify treatment response as early as 1 week after the end of chemoradiotherapy, whether 18 F-PET/CT can identify prognostic markers concerning progression free survival and can identify patients who need additional consolidation therapy. METHODS: A total of 54 patients with head and neck cancer were prospectively enrolled in this single-center, randomized study from 03/2012-04/2015. Patients underwent FDG-PET/CT imaging at three predefined time points: pretreatment (PET/CT1), 1 week postprimary radiochemotherapy (PET/CT2) and 3 months postprimary radiochemotherapy (PET/CT3). Tumors were assessed quantitatively based on size and glucose uptake (SUVmax) concerning response at each time point. Response assessment was correlated with progression free survival. All patients had a minimum follow-up period of 18 months. Multivariate regression analysis was performed to find independent predictors for progression free survival (PFS). RESULTS: Thirty-two (32) patients (64%) overall remained disease free, 11 patients (22%) had recurrence and 7 patients (14%) had persistent disease. There was no significantly different metabolic parameter ratio found concerning responders and nonresponders at posttreatment (PET/CT2 and 3) time points (P > .05) during clinical follow-up. Multivariate regression analysis demonstrated both SUVmax and diameter assessed at time point PET/CT3 represent independent predictors of progression free survival (PFS). There was also no statistically significant difference in PFS between responders and nonresponders by means of PET/CT2 in both study arms (P > .05). Imaging responders at time point PET/CT3 showed a significantly longer PFS compared to nonresponders after the end of consolidation therapy (P < .01). CONCLUSIONS: Early response of head/neck cancer after radiochemotherapy can be accurately assessed with PET/CT 1 week after RCT. SUVmax and lesion diameter are independent predictors of PFS at time point PET/CT3. PET/CT2 has no prognostic value concerning PFS and cannot identify high risk patients for consolidation therapy. Imaging responders showed a significantly longer PFS compared to nonresponders and therefore PET/CT might serve as a prognostic biomarker. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT01435252.

PleThora: Pleural effusion and thoracic cavity segmentations in diseased lungs for benchmarking chest CT processing pipelines.

This manuscript describes a dataset of thoracic cavity segmentations and discrete pleural effusion segmentations we have annotated on 402 computed tomography (CT) scans acquired from patients with non-small cell lung cancer. The segmentation of these anatomic regions precedes fundamental tasks in image analysis pipelines such as lung structure segmentation, lesion detection, and radiomics feature extraction. Bilateral thoracic cavity volumes and pleural effusion volumes were manually segmented on CT scans acquired from The Cancer Imaging Archive "NSCLC Radiomics" data collection. Four hundred and two thoracic segmentations were first generated automatically by a U-Net based algorithm trained on chest CTs without cancer, manually corrected by a medical student to include the complete thoracic cavity (normal, pathologic, and atelectatic lung parenchyma, lung hilum, pleural effusion, fibrosis, nodules, tumor, and other anatomic anomalies), and revised by a radiation oncologist or a radiologist. Seventy-eight pleural effusions were manually segmented by a medical student and revised by a radiologist or radiation oncologist. Interobserver agreement between the radiation oncologist and radiologist corrections was acceptable. All expert-vetted segmentations are publicly available in NIfTI format through The Cancer Imaging Archive at https://doi.org/10.7937/tcia.2020.6c7y-gq39. Tabular data detailing clinical and technical metadata linked to segmentation cases are also available. Thoracic cavity segmentations will be valuable for developing image analysis pipelines on pathologic lungs - where current automated algorithms struggle most. In conjunction with gross tumor volume segmentations already available from "NSCLC Radiomics," pleural effusion segmentations may be valuable for investigating radiomics profile differences between effusion and primary tumor or training algorithms to discriminate between them.

Outcomes and patterns of radiation associated brain image changes after proton therapy for head and neck skull base cancers.

BACKGROUND AND PURPOSE: To characterize patterns and outcomes of brain MR image changes after proton therapy (PT) for skull base head and neck cancer (HNC). MATERIAL AND METHODS: Post-treatment MRIs ≥6 months were reviewed for radiation-associated image changes (RAIC) in 127 patients. All patients had received at least a point dose of 40 Gy(RBE) to the brain. The MRIs were rigidly registered to planning CTs and RAIC lesions were contoured both on T1 weighted (post-contrast) and T2 weighted sequences, and dose-volume parameters extracted. Probability of RAIC was calculated using multistate survival analysis. Univariate/multivariate analyses were performed using Cox Regression. Recursive partitioning analysis was used to investigate dose-volume correlates of RAIC development. RESULTS: 17.3% developed RAIC. All RAIC events were asymptomatic and occurred in the temporal lobe (14), frontal lobe (6) and cerebellum (2). The median volume of the contrast enhanced RAIC lesion was 0.5 cc at their maximum size. The RAIC resolved or improved in 45.5% of the patients and were stable or progressed in 36.4%. The 3-year actuarial rate of developing RAIC was 14.3%. RAIC was observed in 63% of patients when V67 Gy(RBE) of the brain ≥0.17 cc. CONCLUSION: Small RAIC lesions after PT occurred in 17.3% of the patients; the majority in nasopharyngeal or sinonasal cancer. The estimated dose-volume correlations confirm the importance of minimizing focal high doses to brain when achievable.

Prospective observational evaluation of radiation-induced late taste impairment kinetics in oropharyngeal cancer patients: Potential for improvement over time?

BACKGROUND AND PURPOSE: Taste impairment is a common radiation-induced toxicity in head and neck cancer (HNC) patients acutely. However, data on the potential for recovery and the time dependent course of late taste impairment are limited. MATERIALS AND METHODS: As part of an IRB-approved observational prospective study, HNC patients underwent serial surveys including the MD Anderson Symptom Inventory - Head and Neck module (MDASI-HN). For our analysis, we extracted MDASI-HN taste item results from oropharyngeal cancer patients treated with intensity-modulated radiotherapy or volumetric modulated arc therapy and at least two taste assessments after ≥1 year from end of radiotherapy (RT). RESULTS: 1214 MDASI taste items from 326 patients between 1 and 13 years post-RT were included. Median prescribed dose to the high-dose clinical target volume (CTV1) was 66.0 Gy, with 180 patients (55%) receiving chemotherapy. Taste markedly improved in the first years from end of RT, but plateaued after year 5. In patients with taste assessment in subsequent years, a significant reduction in taste impairment was found from the second to the third year (p = 0.001) and tended towards significance from the third to the fourth year (p = 0.058). Multivariate analysis revealed treatment site as significant factor in the sixth year from RT and CTV1 dose and age in the seventh year. CONCLUSION: Radiation-induced taste impairment may improve over an extended time interval, but becomes relatively stable from year 5 post-RT. Direct characterization of RT-induced taste impairment and the calculation of normal tissue complication probability should include consideration of the time-dependent course in taste recovery.

Consolidation cetuximab after concurrent triplet radiochemotherapy+cetuximab in patients with advanced head and neck cancer: A randomized phase II study.

BACKGROUND AND PURPOSE: Preclinical data suggest that cetuximab should be continued after end of concurrent radiotherapy+cetuximab due to its efficacy against residual tumor cells in the irradiated tumor bed. Based on this concept the phase II add-on cetuximab (AOC) study was designed. MATERIALS AND METHODS: Altogether 63 patients with advanced head and neck cancer were treated with radiochemotherapy (70 Gy, cisplatin 40 mg/m2 weekly) in combination with concurrent cetuximab (loading dose 400 mg/m2, then 250 mg/m2 weekly). Thereafter patients were randomized to cetuximab consolidation (500 mg/m2 biweekly × 6) or no further treatment. The primary endpoint was the 2-year locoregional control (LRC) rate. As translational research endpoints serum markers were analyzed before and during treatment and CT-based quantitative image analysis (radiomics) was performed. RESULTS: Median follow-up was 24 months. The 2-year LRC rates were 67.9% and 67.7% in the treatment arms with and without consolidation cetuximab, respectively. Higher than median levels of three serum markers were negatively associated with the 2-year LRC rate in the overall patient cohort: Osteopontin, IL8 and FasL2 (p ≤ 0.05). A radiomics model consisting of two radiomics features could be built showing that higher entropy and higher complexity of tumor Hounsfield unit distribution indicates worse LRC (concordance index 0.66). No correlation was found between biological and imaging markers. CONCLUSIONS: There was no evidence that consolidation cetuximab would improve the 2-year LRC rate. Prognostic biological and imaging markers could be identified for the overall patient cohort. Studies with larger patient numbers are needed to correlate biological and imaging markers.

The impact of tongue-deviating and tongue-depressing oral stents on long-term radiation-associated symptoms in oropharyngeal cancer survivors.

OBJECTIVES: To evaluate whether the use of oral stents during intensity modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC) is associated with long-term patient reported symptoms. MATERIALS AND METHODS: Data was obtained from a prospective observational study of disease-free head and neck cancer survivors. Radiation-associated patient reported symptoms were assessed using the MD Anderson Symptom Inventory Head and Neck module (MDASI-HN). Scores of ≥5 (11-point Likert scale, 0-10) were considered moderate/severe. Stratification was performed regarding IMRT volume (uni- versus bilateral neck) and stent utilization, with non-parametric analyses between groups. RESULTS: 462 OPC survivors formed the cohort (54% tonsil, 46% base of tongue primaries). A tongue-deviating stent was used in 17%, tongue-depressing stent in 46%, and no stent in 37%. Median prescribed dose to the high dose clinical target volume was 66.0 Gy. Median follow-up from RT to MDASI-HN assessment was 68 months. Twenty percent had received unilateral neck RT (all had tonsil primaries), in whom a significant improvement in the proportion of patients with moderate/severe taste impairment (2% vs. 15%, p = 0.047) and lack of appetite (0% vs. 9%, p = 0.019) was associated with the use of tongue-deviating stents compared to no oral stent. In those who had received bilateral neck RT, a significant improvement in the proportion of patients with moderate/severe difficulty swallowing/chewing was associated with use of a tongue-depressing stent (21% vs. 31% without oral stent, p = 0.013). CONCLUSION: Disease-site specific select use of oral stents during IMRT was associated with reduced long-term patient reported symptoms in OPC survivors.

A Dosimetric Comparison of Oral Cavity Sparing in the Unilateral Treatment of Early Stage Tonsil Cancer: IMRT, IMPT, and Tongue-Deviating Oral Stents.

INTRODUCTION: Tongue-deviating oral stents (TDOS) are commonly used during unilateral neck radiation therapy to reduce unnecessary dose to nontarget oral structures. Their benefit in the setting of highly conformal treatment techniques, however, is not defined. The goal of this study was to investigate the potential benefit of TDOS use on dosimetric parameters in unilateral intensity modulated radiation therapy (IMRT) and intensity modulated proton therapy (IMPT). METHODS: A total of 16 patients with T1-2 tonsil cancer treated at a single institution were selected, of which 8 were simulated/treated with a TDOS and 8 without a TDOS. All received definitive unilateral IMRT to a dose of 66 Gy in 30 fx. IMPT plans were generated for each patient for study purposes and optimized according to standard institutional practice. RESULTS: For IMRT plans, the presence of a TDOS (vs without) was associated with a significantly lower oral mucosa mean dose (31.4 vs 35.3 Gy; P = .020) and V30 (42.7% vs 57.1%; P = .025). For IMPT plans, the presence of TDOS (vs without) was not associated with any improvement in oral mucosa mean dose (18.3 vs 19.9 Gy; P = .274) or V30 (25.0% vs 26.2%; P = .655). IMPT plans without TDOS compared with IMRT plans with TDOS demonstrated reduced oral mucosa mean dose (P < .001) and V30 (P < .001). CONCLUSION: The use of a TDOS for the unilateral treatment of well-lateralized tonsil cancers was associated with oral mucosa sparing for IMRT, but not for IMPT. Moreover, mucosa sparing was improved for IMPT plans without a TDOS compared to IMRT plans with a TDOS.

Repetitive MRI of organs at risk in head and neck cancer patients undergoing radiotherapy.

With emerging technical advances like real-time MR imaging during radiotherapy (RT) with an integrated MR linear accelerator, it will soon be possible to analyze changes in the organs at risk (OARs) during radiotherapy without additional effort for the patients. Until then, patients have to undergo additional MR imaging and often without the same immobilization devices as used for radiotherapy. Consequently, studies with repetitive MRI during the course of radiotherapy are rare, with low patient numbers and with the challenge of registration between the different MR sequences and the varying imaging time points. This review focuses on studies with at least two MRIs, one before and another either during or post-RT, in order to report on RT-induced changes in normal tissues and their correlation with toxicity. We therefore included clinical studies published in English until March 2019, with repetitive MRI of OARs in head and neck cancer patients receiving external beam radiotherapy. OARs analyzed were salivary glands, musculoskeletal structures and bones. MR sequences used included T1, T2, dynamic contrast enhanced (DCE) imaging, diffusion-weighted imaging (DWI), DIXON and MR sialography.