Self-efficacy and coping style in relation to psychological distress and quality of life in informal caregivers of patients with head and neck cancer: a longitudinal study.

OBJECTIVE: In order to understand how informal caregivers of head and neck cancer (HNC) patients deal with the consequences of the disease, we investigated their self-efficacy and coping style in relation to symptoms of anxiety and depression (distress) and quality of life (QoL) over time. In addition, factors associated with self-efficacy and coping style were investigated. METHODS: A total of 222 informal caregivers and their related HNC patients were prospectively followed as part from the multicenter cohort NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). Self-efficacy and coping style were measured at baseline, and distress and QoL at baseline and 3, 6, 12, and 24 months after treatment. RESULTS: Informal caregivers had a high level of self-efficacy comparable with patients. Caregivers used "seeking social support," "passive reacting," and "expression of emotions" more often than patients. Factors associated with self-efficacy and coping were higher age and lower education. Higher self-efficacy was related with better QoL and "active tackling" was associated with less depression symptoms. "Passive reacting" and "expression of emotions" were associated with higher psychological distress and reduced QoL. CONCLUSION: Among informal caregivers of HNC patients, higher self-efficacy and "active tackling" were associated with better functioning over time, while "passive reacting" and "expression of negative emotions" were associated with worse functioning. Awareness of the differences in self-efficacy skills and coping and their relationship with QoL and psychological distress will help clinicians to identify caregivers that may benefit from additional support that improve self-efficacy and "active tackling" and reduce negative coping styles.

The course of health-related quality of life in the first 2 years after a diagnosis of head and neck cancer: the role of personal, clinical, psychological, physical, social, lifestyle, disease-related, and biological factors.

PURPOSE: The aim of this prospective cohort study was to estimate the relationship between the course of HRQOL in the first 2 years after diagnosis and treatment of head and neck cancer (HNC) and personal, clinical, psychological, physical, social, lifestyle, HNC-related, and biological factors. METHODS: Data were used from 638 HNC patients of the NETherlands QUality of life and BIomedical Cohort study (NET-QUBIC). Linear mixed models were used to investigate factors associated with the course of HRQOL (EORTC QLQ-C30 global quality of life (QL) and summary score (SumSc)) from baseline to 3, 6, 12, and 24 months after treatment. RESULTS: Baseline depressive symptoms, social contacts, and oral pain were significantly associated with the course of QL from baseline to 24 months. Tumor subsite and baseline social eating, stress (hyperarousal), coughing, feeling ill, and IL-10 were associated with the course of SumSc. Post-treatment social contacts and stress (avoidance) were significantly associated with the course of QL from 6 to 24 months, and social contacts and weight loss with the course of SumSc. The course of SumSc from 6 to 24 months was also significantly associated with a change in financial problems, speech problems, weight loss, and shoulder problems between baseline and 6 months. CONCLUSION: Baseline clinical, psychological, social, lifestyle, HNC-related, and biological factors are associated with the course of HRQOL from baseline to 24 months after treatment. Post-treatment social, lifestyle, and HNC-related factors are associated with the course of HRQOL from 6 to 24 months after treatment.

Unmet supportive care needs among informal caregivers of patients with head and neck cancer in the first 2 years after diagnosis and treatment: a prospective cohort study.

OBJECTIVE: Informal caregivers of head and neck cancer (HNC) patients have a high caregiver burden and often face complex practical caregiving tasks. This may result in unmet supportive care needs, which can impact their quality of life (QoL) and cause psychological distress. In this study, we identify caregivers' unmet needs during long-term follow-up and identify caregivers prone to unmet supportive care needs. METHODS: Data were used from the multicenter prospective cohort study NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). The unmet supportive care needs, psychological distress, caregiver burden, and QoL were measured for 234 informal caregivers and their related patients at baseline, 3, 6, 12, and 24 months after. Mixed effect models for repeated measurements were used. RESULTS: At baseline, most caregivers (70.3%) reported at least one unmet supportive care need, with most of the identified needs in the "healthcare & illness" domain. During the follow-up period, caregivers' unmet needs decreased significantly in all domains. Nevertheless, 2 years after treatment, 28.3% were still reporting at least one unmet need. Financial problems were increasingly associated with unmet needs over time. Furthermore, caring for a patient who themselves had many unmet needs, an advanced tumor stage, or severe comorbidity was associated with significantly more unmet needs in caregivers. CONCLUSIONS: The current study shows the strong likelihood of caregivers of HNC patients facing unmet supportive care needs and the interaction between the needs of patients and caregivers. It is important to optimally support informal caregivers by involving them from the start when counseling patients, by providing them with relevant and understandable information, and by referring vulnerable caregivers for (psychosocial) support.

Factors associated with swallowing dysfunction in patients with head and neck cancer.

BACKGROUND: The aim of this prospective cohort study was to investigate swallowing function in relation to personal and clinical factors among patients with head and neck cancer (HNC) from diagnosis up to 2 years after treatment. METHODS: The 100 ml water swallow test was measured before treatment, and 3, 6, 12, and 24 months after treatment. Linear mixed-effects model analysis was conducted to investigate changes over time and the association with personal (sex and age) and clinical (tumor site, tumor stage, and treatment modality) factors. RESULTS: Among 128 included patients, number of swallows increased from baseline to 3 months after treatment and decreased to baseline again at 6 months after treatment. The number of swallows was associated with age and treatment modality. CONCLUSIONS: In patients with HNC, swallowing (dys)function changes over time with the worst score 3 months after treatment. A higher age and being treated with surgery are factors associated with swallowing dysfunction over time.

Study retention and attrition in a longitudinal cohort study including patient-reported outcomes, fieldwork and biobank samples: results of the Netherlands quality of life and Biomedical cohort study (NET-QUBIC) among 739 head and neck cancer patients and 262 informal caregivers.

BACKGROUND: Longitudinal observational cohort studies in cancer patients are important to move research and clinical practice forward. Continued study participation (study retention) is of importance to maintain the statistical power of research and facilitate representativeness of study findings. This study aimed to investigate study retention and attrition (drop-out) and its associated sociodemographic and clinical factors among head and neck cancer (HNC) patients and informal caregivers included in the Netherlands Quality of Life and Biomedical Cohort Study (NET-QUBIC). METHODS: NET-QUBIC is a longitudinal cohort study among 739 HNC patients and 262 informal caregivers with collection of patient-reported outcome measures (PROMs), fieldwork data (interview, objective tests and medical examination) and biobank materials. Study retention and attrition was described from baseline (before treatment) up to 2-years follow-up (after treatment). Sociodemographic and clinical characteristics associated with retention in NET-QUBIC components at baseline (PROMs, fieldwork and biobank samples) and retention in general (participation in at least one component) were investigated using Chi-square, Fisher exact or independent t-tests (p< 0.05). RESULTS: Study retention at 2-years follow-up was 80% among patients alive (66% among all patients) and 70% among caregivers of patients who were alive and participating (52% among all caregivers). Attrition was most often caused by mortality, and logistic, physical, or psychological-related reasons. Tumor stage I/II, better physical performance and better (lower) comorbidity score were associated with participation in the PROMs component among patients. No factors associated with participation in the fieldwork component (patients), overall sample collection (patients and caregivers) or PROMs component (caregivers) were identified. A better performance and comorbidity score (among patients) and higher age (among caregivers) were associated with study retention at 2-years follow-up. CONCLUSIONS: Retention rates were high at two years follow-up (i.e. 80% among HNC patients alive and 70% among informal caregivers with an active patient). Nevertheless, some selection was shown in terms of tumor stage, physical performance, comorbidity and age, which might limit representativeness of NET-QUBIC data and samples. To facilitate representativeness of study findings future cohort studies might benefit from oversampling specific subgroups, such as patients with poor clinical outcomes or higher comorbidity and younger caregivers.

Factors associated with masticatory function as measured with the Mixing Ability Test in patients with head and neck cancer before and after treatment: a prospective cohort study.

PURPOSE: After treatment for head and neck cancer (HNC), patients often experience major problems in masticatory function. The aim of this prospective cohort study among patients with HNC was to investigate which personal and clinical factors are associated with masticatory function from diagnosis up to 2 years after treatment with curative intent. METHODS: Masticatory function was measured using the Mixing Ability Test (MAT) before treatment (baseline), and 3, 6, 12, and 24 months after treatment. A linear mixed-effects model with a random intercept and slope was conducted to investigate changes over time and the association with personal (sex, age) and clinical (tumor site, tumor stage, treatment modality) factors as measured at baseline. RESULT: One-hundred-twenty-five patients were included. The prevalence of masticatory dysfunction was estimated at 29% at M0, 38% at M3, 28% at M6, 26% at M12, and 36% at M24. A higher (worse) MAT score was associated with age, tumor stage, tumor site, timing of assessment, and the interaction between assessment moment and tumor site. CONCLUSION: In patients with HNC, masticatory function changed over time and dysfunction was associated with a higher age, a tumor in the oral cavity, a higher tumor stage, and a shorter time since treatment. The prevalence of masticatory dysfunction ranged from 26 to 38%.

The course of swallowing problems in the first 2 years after diagnosis of head and neck cancer.

INTRODUCTION: Head and neck cancer (HNC) and its treatment often negatively impact swallowing function. The aim was to investigate the course of patient-reported swallowing problems from diagnosis to 3, 6, 12, and 24 months after treatment, in relation to demographic, clinical, and lifestyle factors. METHODS: Data were used of the Netherlands Quality of Life and Biomedical Cohort Study in head and neck cancer research (NET-QUBIC). The primary outcome measures were the subscales of the Swallowing Quality of Life Questionnaire (SWAL-QOL). Linear mixed-effects models (LMM) were conducted to investigate changes over time and associations with patient, clinical, and lifestyle parameters as assessed at baseline. RESULTS: Data were available of 603 patients. There was a significant change over time on all subscales. Before treatment, 53% of patients reported swallowing problems. This number increased to 70% at M3 and decreased to 59% at M6, 50% at M12, and 48% at M24. Swallowing problems (i.e., longer eating duration) were more pronounced in the case of female, current smoking, weight loss prior to treatment, and stage III or IV tumor, and were more prevalent at 3 to 6 months after treatment. Especially patients with an oropharynx and oral cavity tumor, and patients receiving (C)RT following surgery or CRT only showed a longer eating duration after treatment, which did not return to baseline levels. CONCLUSION: Half of the patients with HNC report swallowing problems before treatment. Eating duration was associated with sex, smoking, weight loss, tumor site and stage, and treatment modality, and was more pronounced 3 to 6 months after treatment.

Mastication, swallowing, and salivary flow in patients with head and neck cancer: objective tests versus patient-reported outcomes.

PURPOSE: Before and after treatment for head and neck cancer (HNC), many patients have problems with mastication, swallowing, and salivary flow. The aim of this study was to investigate the association between objective test outcomes of mastication, swallowing, and salivary flow versus patient-reported outcomes (PROs) measuring mastication-, swallowing-, and salivary flow-related quality of life. METHODS: Data of the prospective cohort "Netherlands Quality of Life and Biomedical Cohort Study" was used as collected before treatment, and 3 and 6 months after treatment. Spearman's rho was used to test the association between objective test outcomes of the mixing ability test (MAT) for masticatory performance, the water-swallowing test (WST) for swallowing performance, and the salivary flow test versus PROs (subscales of the EORTC QLQ-H&N35, Swallow Quality of Life questionnaire (SWAL-QoL-NL) and Groningen Radiation-Induced Xerostomia (GRIX)). RESULTS: Data of 142 patients were used, and in total, 285 measurements were performed. No significant correlations were found between the MAT or WST and subscales of the EORTC QLQ-H&N35. Significant but weak correlations were found between the MAT or WST and 4 subscales of the SWAL-QoL-NL. Weak to moderate correlations were found between the salivary flow test and GRIX at 3 and 6 months after treatment, with the highest correlation between salivary flow and xerostomia during the day (Spearman's rho = - 0.441, p = 0.001). CONCLUSION: The association between objective test outcomes and PROs is weak, indicating that these outcome measures provide different information about masticatory performance, swallowing, and salivary flow in patients with HNC.

Poor sleep quality among newly diagnosed head and neck cancer patients: prevalence and associated factors.

BACKGROUND: Head and neck cancer (HNC) patients often suffer from distress attributed to their cancer diagnosis which may disturb their sleep. However, there is lack of research about poor sleep quality among newly diagnosed HNC patients. Therefore, our aim was to investigate the prevalence and the associated factors of poor sleep quality among HNC patients before starting treatment. MATERIALS AND METHODS: A cross-sectional study was conducted using the baseline data from NET-QUBIC study, an ongoing multi-center cohort of HNC patients in the Netherlands. Poor sleep quality was defined as a Pittsburgh Sleep Quality Index (PSQI) total score of > 5. Risk factors examined were sociodemographic factors (age, sex, education level, living situation), clinical characteristics (HNC subsite, tumor stage, comorbidity, performance status), lifestyle factors, coping styles, and HNC symptoms. RESULTS: Among 560 HNC patients, 246 (44%) had poor sleep quality before start of treatment. Several factors were found to be significantly associated with poor sleep: younger age (odds ratio [OR] for each additional year 0.98, 95% CI 0.96-1.00), being female (OR 2.6, 95% CI 1.7-4.1), higher passive coping style (OR 1.18, 95% CI 1.09-1.28), more oral pain (OR 1.10, 95% CI 1.01-1.19), and less sexual interest and enjoyment (OR 1.13, 95% CI 1.06-1.20). CONCLUSION: Poor sleep quality is highly prevalent among HNC patients before start of treatment. Early evaluation and tailored intervention to improve sleep quality are necessary to prepare these patients for HNC treatment and its consequences.

Digital pathology-aided assessment of tumor-infiltrating T lymphocytes in advanced stage, HPV-negative head and neck tumors.

AIM: This study aimed to evaluate the presence and prognostic value of tumor-infiltrating T cells in the tumor epithelium in advanced stage, HPV-negative head and neck squamous cell carcinoma (HNSCC) patients treated with primary chemoradiotherapy using digital pathology. METHODS: Pre-treatment biopsies from 80 oropharyngeal, 52 hypopharyngeal, and 29 laryngeal cancer patients were collected in a tissue microarray (TMA) and immunohistochemically stained for T-cell markers CD3, CD4, CD8, FoxP3, and PD1, and for immune checkpoint PD-L1. For each marker, the number of positive tumor-infiltrating lymphocytes (TILs) per mm2 tumor epithelium was digitally quantified and correlated to overall survival (OS), disease-free survival (DFS), and locoregional control (LRC), as well as to clinicopathological characteristics. Differences in clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. RESULTS: The patient cohort had a 3-year OS of 58%, with a median follow-up of 53 months. None of the T-cell markers showed a correlation with OS, DFS or LRC. A low N stage was correlated to a better prognosis (OS: HR 0.39, p = 0.0028, DFS: HR 0.34, p = < 0.001, LRC: HR 0.24, p = 0.008). High TIL counts were more often observed in PD-L1-positive tumors (p < 0.05). CONCLUSION: This study showed an objective, digital pathology-aided method to assess TILs in the tumor epithelium. However, it did not provide evidence for a prognostic role of the presence of CD3 + , CD4 + , CD8 + , FoxP3 + , and PD1 + TILs in the tumor epithelium of advanced stage, HPV-negative HNSCC patients treated with primary chemoradiotherapy.

Pretreatment ADC is not a prognostic factor for local recurrences in head and neck squamous cell carcinoma when clinical T-stage is known.

OBJECTIVES: Pretreatment identification of radio-insensitive head and neck squamous cell carcinomas (HNSCC) would affect treatment modality selection. The apparent diffusion coefficient (ADC) of a tumor could be a predictor of local recurrence. However, little is known about its prognostic value next to known factors such as clinical T-stage. The aim of the present study is to determine the added value of pretreatment ADC to clinical T-stage as a prognostic factor for local recurrence. METHODS: This retrospective cohort study included 217 patients with HNSCC treated with (chemo)radiotherapy between April 2009 and December 2015. All patients underwent diffusion-weighted MRI prior to treatment. Median ADC values of all tumors were obtained using a semi-automatic delineation method. Univariate models containing ADC and T-stage were compared with a multivariable model containing both variables. RESULTS: Fifty-eight patients experienced a local recurrence within 3 years. On average, the ADC value in the group of patients with a recurrence was 1.01 versus 1.00 (10-3 mm2/s) in the group without a recurrence. Univariate analysis showed no significant association between tumor ADC and local recurrence within 3 years after (chemo)radiotherapy (p = 0.09). Cox regression showed that clinical T-stage was an independent predictor of local recurrence and adding ADC to the model did not increase its performance. CONCLUSION: Pretreatment ADC has no added value as a prognostic factor for local recurrence to clinical T-stage. KEY POINTS: • Pretreatment identification of head and neck squamous cell carcinoma patients who do not benefit from (chemo)radiotherapy could improve personalized cancer care. • The apparent diffusion coefficient (ADC) obtained from diffusion-weighted MRI has been reported to be a prognostic factor for local recurrence. • In this study, ADC has no added value as a prognostic factor compared with clinical T-stage.

Reliability of the mixing ability test testing masticatory performance in patients with head and neck cancer and healthy controls.

BACKGROUND: Treatment of patients with head and neck cancer can result in disrupted mastication. To measure masticatory performance in people with compromised mastication, the mixing ability test (MAT) was developed. OBJECTIVE: In this study, the reliability of the MAT was evaluated in patients with head and neck cancer and healthy controls. METHODS: Thirty-four patients with head and neck cancer and 42 healthy controls performed the MAT twice on the same day. To assess reliability, the intra-class correlation coefficient (ICC2,1 ), standard error of measurement (SEM), smallest detectable change (SDC) and limits of agreement (LoA) were calculated. RESULTS: A good (ICC = 0.886) and moderate correlation (ICC = 0.525) were found for patients and healthy controls, respectively. Patients had a worse mixing ability (mean = 19.12, SD = 4.56) in comparison with healthy controls (mean = 16.42, SD = 2.04). The SEM was 0.76 in patients and 1.45 in healthy controls, with a SDC of 2.12 and 4.02, respectively. The LoA was -4.46 to 4.42 in patients and -3.65 to 4.59 in healthy controls. CONCLUSION: The MAT has a good reliability in patients with head and neck cancer and a moderate reliability in healthy controls.

Prediction of ultrasound guided fine needle aspiration cytology results by FDG PET-CT for lymph node metastases in head and neck squamous cell carcinoma patients.

INTRODUCTION: Accurate assessment of cervical lymph node status is essential in patients with head and neck squamous cell carcinoma (HNSCC) as it influences prognosis and treatment decisions. During patient workup, lymph node status is often examined by ultrasound guided fine needle aspiration cytology (USgFNAC). 18F-Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET-CT) is frequently used to assess primary tumor and distant metastases but provides information on lymph node status as well. It is possible that FDG PET-CT (if already made for abovementioned indications) can predict the results of USgFNAC in subgroups of lymph nodes based on FDG-uptake and size. The objective of this study is to identify maximum standardized uptake (SUVmax) and short axis diameter cutoff values of lymph nodes at which FDG PET-CT can reliably predict USgFNAC results. METHODS: One hundred and seventeen patients with HNSCC were retrospectively analyzed. Patients were included when FDG PET-CT and USgFNAC were available. SUVmax measurements were performed and compared to the USgFNAC results. RESULTS: Using USgFNAC as a reference standard, the area under the curve of the receiver operating curve was 0.91. At an SUVmax cutoff value of 4.9, the accuracy of FDG PET-CT was the highest (85%). Lymph nodes with short axis diameter ≥1.0 cm and SUVmax ≥4.9 were in 91% positive on USgFNAC. If SUVmax was below 2.2, no nodes were positive on USgFNAC. Of all lymph nodes 52% either had a short axis diameter ≥1.0 cm and SUVmax ≥4.9 or an SUVmax <2.2. FDG PET-CT and USgFNAC results were very similar in these nodes. CONCLUSIONS: By measuring SUVmax values and minimal axial diameters of lymph nodes and using appropriate cutoff values, FDG PET-CT can predict the results of USgFNAC examinations in half of the examined lymph nodes. This information may lead to a reduction of USgFNAC examinations in HNSCC patients if FDG PET-CT is already performed for other indications.

Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma.

BACKGROUND: In definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called 'elective dose' in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary. Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment. METHODS: UPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial. Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4 N0-2 M0 squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors. In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level. Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5 weeks. The primary endpoint is 'normalcy of diet' at 1 year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment (safety). DISCUSSION: The objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02442375 .

The accuracy of target delineation in laryngeal and hypopharyngeal cancer.

BACKGROUND AND PURPOSE: To determine the spatial correspondence between the gross tumor volume (GTV) delineated on computer tomography (CT) and the actual tumor on histopathology. MATERIAL AND METHODS: Sixteen patients with T3 or T4 laryngeal or hypopharyngeal cancer underwent a CT scan before total laryngectomy. The GTV was delineated on CT by three independent observers and by consensus between the three observers. After surgery, whole-mount hematoxylin-eosin stained (H&E) sections were obtained. One pathologist delineated the tumor in the H&E sections (tumorH&E). The reconstructed specimen was registered to the CT scan in order to compare the GTV to the tumorH&E in three dimensions. The overlap between the GTV and the tumorH&E was calculated and the distance between the volumes was determined. RESULTS: Tumor tissue was delineated in 203 of 516 H&E sections. For 14 patients a detailed analysis could be performed. The GTV volume was on average 1.7 times larger than the volume of the tumorH&E. The mean coverage of the tumorH&E by the consensus GTV was 88%. tumorH&E tissue was found at 1.6 mm to 12.9 mm distance outside the GTV depending on observer and patient. CONCLUSIONS: GTVs delineated on CT for laryngeal and hypopharyngeal cancer were 1.7 times larger than the tumor. Complete coverage of the tumor by the GTV was, however, not obtained.

Diffusion-weighted MR imaging in laryngeal and hypopharyngeal carcinoma: association between apparent diffusion coefficient and histologic findings.

PURPOSE: To investigate the relationship between the histologic characteristics of head and neck squamous cell carcinoma and apparent diffusion coefficient (ADC) at diffusion-weighted magnetic resonance (MR) imaging. MATERIALS AND METHODS: The institutional ethics committee approved this study and waived informed consent. In head and neck squamous cell carcinoma, local failure after chemotherapy and/or radiation therapy correlates with pretreatment ADC. However, the histopathologic basis of this correlation remains unclear. In this study, 16 patients with head and neck squamous cell carcinoma were enrolled (median age, 60 years; range, 49-78 years). Before undergoing total laryngectomy, patients underwent 1.5-T diffusion-weighted MR imaging. After resection, whole-mount hematoxylin-eosin-stained sections were registered to the MR images. Cellular density; nuclear, cytoplasmic, and stromal area; and nuclear-cytoplasmic ratio within the tumor were calculated by using image-based segmentation on four consecutive slices. Mean ADC of the corresponding tumor region was calculated. Spearman correlations between ADC and histologic characteristics were calculated. RESULTS: ADC was significantly and inversely correlated with cell density (n = 16, r = -0.57, P = .02), nuclear area (n = 12, r = -0.64, P = .03), and nuclear-cytoplasmic ratio (n = 12, r = -0.77, P ≤ .01). ADC was significantly and positively correlated with percentage area of stroma (n = 12, r = 0.69, P = .01). Additionally, the percentage area of stroma was strongly interdependent with the percentage area of nuclei (n = 12, r = -0.97, P ≤ .01). CONCLUSION: ADC was significantly correlated with cellularity, stromal component, and nuclear-cytoplasmic ratio. The positive correlation of ADC and stromal component suggests that the poor prognostic value of high pretreatment ADC might partly be attributed to the tumor-stroma component, a known predictor of local failure.

Improved delineation with diffusion weighted imaging for laryngeal and hypopharyngeal tumors validated with pathology.

OBJECTIVE: This study aims to determine the added value of a geometrically accurate diffusion-weighted (DW-) MRI sequence on the accuracy of gross tumor volume (GTV) delineations, using pathological tumor delineations as a ground truth. METHODS: Sixteen patients with laryngeal or hypopharyngeal carcinoma were included. After total laryngectomy, the specimen was cut into slices. Photographs of these slices were stacked to create a 3D digital specimen reconstruction, which was registered to the in vivo imaging. The pathological tumor (tumorHE) was delineated on the specimen reconstruction. Six observers delineated all tumors twice: once with only anatomical MR imaging, and once (a few weeks later) when DW sequences were also provided. The majority voting delineation of session one (GTVMRI) and session two (GTVDW-MRI), as well as the clinical target volumes (CTVs), were compared to the tumorHE. RESULTS: The mean tumorHE volume was 11.1 cm3, compared to a mean GTVMRI volume of 18.5 cm3 and a mean GTVDW-MRI volume of 15.7 cm3. The median sensitivity (tumor coverage) was comparable between sessions: 0.93 (range: 0.61-0.99) for the GTVMRI and 0.91 (range: 0.53-1.00) for the GTVDW-MRI. The CTV volume also decreased when DWI was available, with a mean CTVMR of 47.1 cm3 and a mean CTVDW-MRI of 41.4 cm3. Complete tumor coverage was achieved in 15 and 14 tumors, respectively. CONCLUSION: GTV delineations based on anatomical MR imaging tend to overestimate the tumor volume. The availability of the geometrically accurate DW sequence reduces the GTV overestimation and thereby CTV volumes, while maintaining acceptable tumor coverage.

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.

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.