Tooth extractions prior to chemoradiation or bioradiation are associated with weight loss during treatment for locally advanced oropharyngeal cancer.

PURPOSE: Prior to radiotherapy combined with chemotherapy (CRT) or biotherapy (BRT) for oropharyngeal squamous cell carcinoma (OPSCC), teeth with poor prognosis that pose a risk for post-RT osteoradionecrosis (ORN) are removed. The effect of tooth loss on body weight loss and tube feeding (TF) dependency during CRT/BRT is unknown. This study aimed to evaluate the effect of incomplete dentition, tooth extractions prior to CRT/BRT, and the subsequent loss of functional units on (1) weight loss during CRT/BRT and (2) the need for TF during CRT/BRT for OPSCC. METHODS: OPSCC patients treated with CRT/BRT between 2013 and 2016 were included in this retrospective cohort study. Dental status was determined during the dental assessment at first visit and after tooth extractions prior to the start of CRT/BRT. Weight loss during CRT/BRT was scored dichotomously, comparing weight loss > 5% to stable or increased weight. Potential factors associated with weight loss were identified, including patient, tumor, and treatment characteristics. RESULTS: Seventy-seven OPSCC patients were included. Forty patients (52%) experienced weight loss > 5% during CRT/BRT. Extractions were performed in 66% of the OPSCC patients. The mean number of extracted teeth was 4.1 ± 5.6 per patient. Tooth extractions prior to CRT/BRT were associated with weight loss > 5% during CRT/BRT (HR 1.130 (95% CI 1.011-1.262), p = 0.031). None of the dental status-related parameters showed any significant associative value for TF during CRT/BRT. CONCLUSIONS: Pre-CRT/BRT tooth extractions intended to reduce the risk of ORN, are a risk factor for weight loss during CRT/BRT for OPSCC. TRIAL REGISTRATION NUMBER: This study was approved by the medical ethics committee of the MUMC + (METC 2020-1589) on July 28, 2020.

A national study to assess outcomes of definitive chemoradiation regimens in proximal esophageal cancer.

Background: Proximal esophageal cancer (EC) is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone are still under debate. The objective of this study was to compare the treatment outcomes of contemporary CRT regimens.Material and Methods: In this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal esophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004 and 2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin-paclitaxel (CP) combined with low (≤50.4 Gy) or high (>50.4 Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) weighted model. Safety profiles were compared using a multilevel logistic regression model.Results: Two hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI: 47.9-77.2 months). Median OS (21.9 months; 95% CI: 16.9-27.0 months) was comparable between treatment groups (logrank p = .88), confirmed in the fully adjusted and PS weighted model (p > .05). Grades 3-5 acute adverse events were less frequent in patients treated with CP-low-dose RT versus Cis-high-dose RT (OR 3.78; 95% CI: 1.31-10.87; p = .01). The occurrence of grades 3-5 late toxicities was not different between treatment groups.Conclusion: Our study was unable to demonstrate a difference in OS between the CRT regimens, probably related to the relatively small sample size. Based on the superior safety profile, carboplatin and paclitaxel-based CRT regimens are preferred in patients with locally advanced proximal EC.

Variation in Integrated Head and Neck Cancer Care: Impact of Patient and Hospital Characteristics.

Background: Monitoring and effectively improving oncologic integrated care requires dashboard information based on quality registrations. The dashboard includes evidence-based quality indicators (QIs) that measure quality of care. This study aimed to assess the quality of current integrated head and neck cancer care with QIs, the variation between Dutch hospitals, and the influence of patient and hospital characteristics. Methods: Previously, 39 QIs were developed with input from medical specialists, allied health professionals, and patients' perspectives. QI scores were calculated with data from 1,667 curatively treated patients in 8 hospitals. QIs with a sample size of >400 patients were included to calculate reliable QI scores. We used multilevel analysis to explain the variation. Results: Current care varied from 29% for the QI about a case manager being present to discuss the treatment plan to 100% for the QI about the availability of a treatment plan. Variation between hospitals was small for the QI about patients discussed in multidisciplinary team meetings (adherence: 95%, range 88%-98%), but large for the QI about malnutrition screening (adherence: 50%, range 2%-100%). Higher QI scores were associated with lower performance status, advanced tumor stage, and tumor in the oral cavity or oropharynx at the patient level, and with more curatively treated patients (volume) at hospital level. Conclusions: Although the quality registration was only recently launched, it already visualizes hospital variation in current care. Four determinants were found to be influential: tumor stage, performance status, tumor site, and volume. More data are needed to assure stable results for use in quality improvement.

Methadone versus Fentanyl in Patients with Radiation-Induced Nociceptive Pain with Head and Neck Cancer: A Randomized Controlled Noninferiority Trial.

BACKGROUND: Pain is still a burden for many patients with cancer. A recent trial showed the superiority of methadone over fentanyl in neuropathic pain, and we expect that this finding could influence the number of patients treated with methadone. METHODS: We performed a randomized controlled noninferiority trial in patients with nociceptive pain. Eighty-two strong-opioid-naïve patients with head and neck cancer with substantial pain (pain numeric rating scale [NRS] score ≥ 4) due to radiation therapy were included. Forty-two patients were treated with methadone, and 40 with fentanyl. Patients were evaluated at 1, 3, and 5 weeks. The primary outcomes were reduction in average pain and clinical success (50% pain decrease). We set the predefined noninferiority margin at 1 on the NRS and 10% clinical success. Secondary outcomes were pain interference, global perceived effect (GPE), side effects, and opioid escalation index. RESULTS: Noninferiority was shown for decrease in NRS for maximum and mean pain scores at 1 and 3 weeks. Noninferiority was shown for clinical success at 1 week only. The opioid escalation index was lower in the methadone group at 3 and 5 weeks as compared to fentanyl (1.44 vs. 1.99, P = 0.004; and 1.50 vs. 2.32, P = 0.013). The pain interference in the methadone group was significantly decreased at 3 weeks only. GPE and side effects were not different. CONCLUSION: This is the first study to show noninferiority of methadone compared to fentanyl at 1 and 3 weeks in the treatment of radiation-induced nociceptive pain in patients with head and neck cancer.

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 .

Detection of Bone Marrow Edema Pattern With Dual-Energy Computed Tomography of the Pig Mandible Treated With Radiotherapy and Surgery Compared With Magnetic Resonance Imaging.

OBJECTIVE: The aim of the study was to investigate the accuracy of dual-energy computed tomography (DECT) compared with magnetic resonance (MR) imaging for the detection of edema of the mandible. MATERIALS AND METHODS: Fifteen adult Göttingen mini pigs received irradiation to the mandible with an equivalent dose of 0, 25, 50, or 70 Gy. Six months after irradiation, all animals underwent DECT and MR imaging of the mandible. Magnetic resonance short tau inversion recovery (STIR) was used for the grading of the bone marrow edema (0-3). Dual-energy CT (80 and 140 kVp) was performed, and virtual noncalcium (VNCa) images were calculated. RESULTS: Increased signal intensity at STIR was found in the higher radiation groups. An increase of signal intensity in MR imaging was accompanied by a significant increase in the Hounsfield unit value of the VNCa images of the bone marrow (STIR: 0, 1, 2, 3; mean Hounsfield unit: -103, -90, -76, -34, respectively; P < 0.05; R = 0.388). CONCLUSIONS: The VNCa images derived from DECT are able to demonstrate bone marrow edema in radiation-induced bone changes in the mandible.

Feedback preferences of patients, professionals and health insurers in integrated head and neck cancer care.

BACKGROUND: Audit and feedback on professional practice and health care outcomes are the most often used interventions to change behaviour of professionals and improve quality of health care. However, limited information is available regarding preferred feedback for patients, professionals and health insurers. OBJECTIVE: Investigate the (differences in) preferences of receiving feedback between stakeholders, using the Dutch Head and Neck Audit as an example. METHODS: A total of 37 patients, medical specialists, allied health professionals and health insurers were interviewed using semi-structured interviews. Questions focussed on: "Why," "On what aspects" and "How" do you prefer to receive feedback on professional practice and health care outcomes? RESULTS: All stakeholders mentioned that feedback can improve health care by creating awareness, enabling self-reflection and reflection on peers or colleagues, and by benchmarking to others. Patients prefer feedback on the actual professional practice that matches the health care received, whereas medical specialists and health insurers are interested mainly in health care outcomes. All stakeholders largely prefer a bar graph. Patients prefer a pie chart for patient-reported outcomes and experiences, while Kaplan-Meier survival curves are preferred by medical specialists. Feedback should be simple with firstly an overview, and 1-4 times a year sent by e-mail. Finally, patients and health professionals are cautious with regard to transparency of audit data. CONCLUSIONS: This exploratory study shows how feedback preferences differ between stakeholders. Therefore, tailored reports are recommended. Using this information, effects of audit and feedback can be improved by adapting the feedback format and contents to the preferences of stakeholders.

Evaluation of tumour hypoxia during radiotherapy using [18F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [18F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence. MATERIAL AND METHODS: [18F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [18F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed. RESULTS: At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm3 during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased. CONCLUSIONS: [18F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.

(99m)Tc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials.

PURPOSE: (99m)Tc-Annexin A5 has been used as a molecular imaging probe for the visualization, characterization and measurement of apoptosis. In an effort to define the quantitative (99m)Tc-annexin A5 uptake criteria that best predict tumor response to treatment, we performed a systematic review and meta-analysis of the results of all clinical imaging trials found in the literature or publicly available databases. METHODS: Included in this review were 17 clinical trials investigating quantitative (99m)Tc-annexin A5 (qAnx5) imaging using different parameters in cancer patients before and after the first course of chemotherapy and/or radiation therapy. Qualitative assessment of the clinical studies for diagnostic accuracy was performed using the QUADAS-2 criteria. Of these studies, five prospective single-center clinical trials (92 patients in total) were included in the meta-analysis after exclusion of one multicenter clinical trial due to heterogeneity. Pooled positive predictive values (PPV) and pooled negative predictive values (NPV) (with 95% CI) were calculated using Meta-Disc software version 1.4. RESULTS: Absolute quantification and/or relative quantification of (99m)Tc-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of (99m)Tc-annexin A5 tumor uptake and delta (Δ) tumor changes post-treatment compared to baseline including: tumor-to-background ratio (TBR), ΔTBR, tumor-to-noise ratio, relative tumor ratio (TR), ΔTR, standardized tumor uptake ratio (STU), ΔSTU, maximum count per pixel within the tumor volume (Cmax), Cmax%, absolute ΔU and percentage (ΔU%), maximum ΔU counts, semiquantitative visual scoring, percent injected dose (%ID) and %ID/cm(3). Clinical trials investigating qAnx5 imaging have included patients with lung cancer, lymphoma, breast cancer, head and neck cancer and other less common tumor types. In two phase I/II single-center clinical trials, an increase of ≥25% in uptake following treatment was considered a significant threshold for an apoptotic tumor response (partial response, complete response). In three other phase I/II clinical trials, increases of ≥28%, ≥42% and ≥47% in uptake following treatment were found to be the mean cut-off levels in responders. In a phase II/III multicenter clinical trial, an increase of ≥23% in uptake following treatment was found to be the minimum cut-off level for a tumor response. In one clinical trial, no significant difference in (99m)Tc-annexin A5 uptake in terms of %ID was found in healthy tissues after chemotherapy compared to baseline. In two other clinical trials, intraobserver and interobserver measurements of (99m)Tc-annexin A5 tumor uptake were found to be reproducible (mean difference <5%, kappa = 0.90 and 0.82, respectively) and to be highly correlated with treatment outcome (Spearman r = 0.99, p < 0.0001). The meta-analysis demonstrated a pooled positive PPV of 100% (95% CI 92 - 100%) and a pooled NPV of 70% (95% CI 55 - 82%) for prediction of a tumor response after the first course of chemotherapy and/or radiotherapy in terms of ΔU%. In a symmetric sROC analysis, the AUC was 0.919 and the Q* index was 85.21 %. CONCLUSION: Quantitative (99m)Tc-annexin A5 imaging has been investigated in clinical trials for the assessment of apoptotic tumor responses. This meta-analysis showed a high pooled PPV and a moderate pooled NPV with ΔU cut-off values ranging between 20% and 30%. Standardization of quantification and harmonization of results are required for high-quality clinical research. A standardized uptake value score (SUV, ΔSUV) using quantitative SPECT/CT imaging may be a promising approach to the simple, reproducible and semiquantitative assessment of apoptotic tumor changes.

Imaging of tumour hypoxia and metabolism in patients with head and neck squamous cell carcinoma.

BACKGROUND: Tumour hypoxia and a high tumour metabolism increase radioresistance in patients with head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the correlation between hypoxia ([(18)F]HX4 PET) and glucose metabolism ([(18)F]FDG PET) molecular imaging. MATERIAL AND METHODS: [(18)F]HX4 and [(18)F]FDG PET/CT images of 20 HNSCC patients were acquired prior to (chemo)radiotherapy, in an immobilisation mask, with a median time interval of seven days (NCT01347281). Gross tumour volumes of the primary lesions (GTVprim) and pathological lymph nodes (GTVln) were included in the analysis. [(18)F]FDG PET/CT images were rigidly registered to the [(18)F]HX4 PET/CT images. The maximum and mean standardised uptake values (SUVmax, SUVmean) within both GTVs were determined. In addition, the overlap was compared between the [(18)F]HX4 high volume ([(18)F]HX4 HV) with a tumour-to-muscle ratio > 1.4 and the [(18)F]FDG high volume ([(18)F]FDG HV) with an SUV > 50% of the SUVmax. We report the mean ± standard deviation. RESULTS: PET/CT scans including 20 GTVprim and 12 GTVln were analysed. There was a significant correlation between several [(18)F]FDG and [(18)F]HX4 parameters, the most pronounced being the correlation between [(18)F]FDG HV and [(18)F]HX4 HV (R = 0.93, p < 0.001). The fraction of the GTVprim with a high HX4 uptake (9 ± 10%) was on average smaller than the FDG high fraction (51 ± 26%; p < 0.001). In 65% (13/20) of the patients, the GTVprim was hypoxic. In four of these patients the [(18)F]HX4 HV was located within the [(18)F]FDG HV, whereas for the remaining nine GTVprim a partial mismatch was observed. In these nine tumours 25 ± 21% (range 5-64%) of the HX4 HV was located outside the FDG HV. CONCLUSIONS: There is a correlation between [(18)F]HX4 and [(18)F]FDG uptake parameters on a global tumour level. In the majority of lesions a partial mismatch between the [(18)F]HX4 and [(18)F]FDG high uptake volumes was observed, therefore [(18)F]FDG PET imaging cannot be used as a surrogate for hypoxia. [(18)F]HX4 PET provides complementary information to [(18)F]FDG PET imaging.

Weekly kilovoltage cone-beam computed tomography for detection of dose discrepancies during (chemo)radiotherapy for head and neck cancer.

BACKGROUND: Use of highly conformal radiotherapy in patients with head and neck carcinoma may lead to under-/overdosage of gross target volume (GTV) and organs at risk (OAR) due to changes in patients' anatomy. A method to achieve more effective radiation treatment combined with less toxicity is dose-guided radiotherapy (DGRT). The aim of this study was to evaluate discrepancies between planned and actually delivered radiation dose in head and neck patients and to identify predictive factors. METHODS: In this retrospective analysis, 20 patients with cT2-4 N0-3 M0 carcinoma originating from oropharynx, oral cavity, larynx and hypopharynx (Cohort 1), and seven patients with cT1-4 N0-3 M0 nasopharyngeal carcinoma (Cohort 2) treated with primary (chemo)radiotherapy and undergoing weekly kV-CBCT scans were included. Radiation dose was recalculated on 184 kV-CBCT images, which was quantified by D95% (GTV), Dmean (parotid and submandibular glands) and D2% (spinal cord). Predictive factors investigated for changes in these dose metrics were: gender, age, cT/N-stage, tumor grade, HPV-status, systemic therapy, body mass index at start of treatment, weight loss and volume change over the duration of the radiotherapy. RESULTS: There was no significant difference between the planned and delivered dose for GTV and OARs of Week 1 to subsequent weeks for Cohort 1. In Cohort 2, actually delivered Dmean to parotid glands was significant higher than planned dose (1.1 Gy, p = 0.002). No clinically relevant correlations between dose changes and predictive factors were found. CONCLUSION: Weekly dose calculations do not seem to improve dose delivery for patients with tumors of the oral cavity, oropharynx, larynx and hypopharynx. In patients with nasopharyngeal carcinoma, however, mid-treatment imaging may facilitate DGRT.

External validation of a prognostic CT-based radiomic signature in oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is one of the fastest growing disease sites of head and neck cancers. A recently described radiomic signature, based exclusively on pre-treatment computed tomography (CT) imaging of the primary tumor volume, was found to be prognostic in independent cohorts of lung and head and neck cancer patients treated in the Netherlands. Here, we further validate this signature in a large and independent North American cohort of OPSCC patients, also considering CT artifacts. METHODS: A total of 542 OPSCC patients were included for which we determined the prognostic index (PI) of the radiomic signature. We tested the signature model fit in a Cox regression and assessed model discrimination with Harrell's c-index. Kaplan-Meier survival curves between high and low signature predictions were compared with a log-rank test. Validation was performed in the complete cohort (PMH1) and in the subset of patients without (PMH2) and with (PMH3) visible CT artifacts within the delineated tumor region. RESULTS: We identified 267 (49%) patients without and 275 (51%) with visible CT artifacts. The calibration slope (ß) on the PI in a Cox proportional hazards model was 1.27 (H0: ß = 1, p = 0.152) in the PMH1 (n = 542), 0.855 (H0: ß = 1, p = 0.524) in the PMH2 (n = 267) and 1.99 (H0: ß = 1, p = 0.002) in the PMH3 (n = 275) cohort. Harrell's c-index was 0.628 (p = 2.72e-9), 0.634 (p = 2.7e-6) and 0.647 (p = 5.35e-6) for the PMH1, PMH2 and PMH3 cohort, respectively. Kaplan-Meier survival curves were significantly different (p < 0.05) between high and low radiomic signature model predictions for all cohorts. CONCLUSION: Overall, the signature validated well using all CT images as-is, demonstrating a good model fit and preservation of discrimination. Even though CT artifacts were shown to be of influence, the signature had significant prognostic power regardless if patients with CT artifacts were included.

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.

The extent of unnecessary tooth loss due to extractions prior to radiotherapy based on radiation field and dose in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Prior to radiotherapy (RT), teeth with poor prognosis that pose a risk for post-RT osteoradionecrosis (ORN) are removed. To allow enough time for adequate wound healing prior to RT, decisions are made based on the estimated radiation dose. This study aimed to gain insight into (1) the overall number of teeth extracted and (2) the patient and tumor characteristics associated with the number of redundantly extracted teeth. MATERIALS AND METHODS: Patients with head and neck cancer (HNC), treated with RT between 2015 and 2019, were included in this cross-sectional study. For each extracted tooth the radiation dose was calculated retrospectively. The cut-off point for valid extraction was set at ≥ 40 Gy in accordance with the national protocol. Potential factors for doses ≥ 40 Gy were identified, including age, sex, tumor location, tumor (T) and nodal stage (N), overall tumor stage and number of teeth extracted. RESULTS: A total of 1759 teeth were removed from 358 patients. Of these 1759 teeth, 1274 (74%) appeared to have been removed redundantly, based on the mean dose (Dmean) of < 40 Gy. Using the maximum dose (Dmax) of < 40 Gy, 1080 teeth (61%) appeared to have been removed redundantly. Tumor location and N-classification emerged as the most important associative variables in the multivariable regression analysis. CONCLUSION: To our knowledge this is the first study to provide insight into the amount of teeth redundantly extracted prior to RT and represents a step forward in de-escalating the damage to the masticatory system prior to RT.

Oropharyngeal dysphagia and cachexia: Intertwined in head and neck cancer.

BACKGROUND: This study aims to investigate the relationship between cancer cachexia and oropharyngeal dysphagia (OD) in patients with head and neck cancer (HNC) prior to chemoradiotherapy or bioradiotherapy (CRT/BRT). METHODS: A prospective cohort study with patients with HNC undergoing CRT/BRT (2018-2021) was conducted. Body composition and skeletal muscle function were evaluated using bioelectrical impedance analysis, handgrip strength, and the short physical performance battery (SPPB). The M. D. Anderson Dysphagia Inventory (MDADI), Eating Assessment Tool (EAT)-10 questionnaire, and patient characteristics were collected. A standardized videofluoroscopic swallowing study was offered to patients. RESULTS: Sixty-six patients were included. Twenty-six patients scored EAT-10 ≥ 3 and seventeen were cachectic. ACE-27 score >1, cachexia, abnormal SPPB-derived repeated chair-stand test, lower MDADI scores, and higher overall stage grouping showed potential predictive value (p ≤ 0.10) for EAT-10 ≥ 3. Using multivariable regression analysis, only cachexia remained a significant predictor of EAT-10 ≥ 3 (HR 9.000 [95%CI 2.483-32.619], p = 0.001). CONCLUSION: Cachexia independently predicted the presence of patient-reported OD.

The relation between prediction model performance measures and patient selection outcomes for proton therapy in head and neck cancer.

BACKGROUND: Normal-tissue complication probability (NTCP) models predict complication risk in patients receiving radiotherapy, considering radiation dose to healthy tissues, and are used to select patients for proton therapy, based on their expected reduction in risk after proton therapy versus photon radiotherapy (ΔNTCP). Recommended model evaluation measures include area under the receiver operating characteristic curve (AUC), overall calibration (CITL), and calibration slope (CS), whose precise relation to patient selection is still unclear. We investigated how each measure relates to patient selection outcomes. METHODS: The model validation and consequent patient selection process was simulated within empirical head and neck cancer patient data. By manipulating performance measures independently via model perturbations, the relation between model performance and patient selection was studied. RESULTS: Small reductions in AUC (-0.02) yielded mean changes in ΔNTCP between 0.9-3.2 %, and single-model patient selection differences between 2-19 %. Deviations (-0.2 or +0.2) in CITL or CS yielded mean changes in ΔNTCP between 0.3-1.4 %, and single-model patient selection differences between 1-10 %. CONCLUSIONS: Each measure independently impacts ΔNTCP and patient selection and should thus be assessed in a representative sufficiently large external sample. Our suggested practical model selection approach is considering the model with the highest AUC, and recalibrating it if needed.

Changes in survival in de novo metastatic cancer in an era of new medicines.

BACKGROUND: Over the past decades, the therapeutic landscape has markedly changed for patients with metastatic solid cancer, yet few studies have evaluated its effect on population-based survival. The objective of this study was to evaluate the change in survival of patients with de novo metastatic solid cancers during the last 30 years. METHODS: For this retrospective study, data from almost 2 million patients diagnosed with a solid cancer between January 1, 1989, and December 31, 2018, were obtained from the Netherlands Cancer Registry, with follow-up until January 31, 2021. We classified patients as with or without de novo metastatic disease (M1 or M0, respectively) at diagnosis and determined the proportion with M1 disease over time. Changes in age-standardized net survival were calculated as the difference in the 1- and 5-year survival rates of patients diagnosed in 1989-1993 and 2014-2018. RESULTS: Different cancers showed divergent trends in the proportion of M1 disease and increases in net survival for M1 disease (approximately 0-50 percentage points at both 1 and 5 years). Patients with gastrointestinal stromal tumors saw the largest increases in 5-year survival, but we also observed substantial 5-year survival increases for patients with neuroendocrine tumors, melanoma, prostate cancer, and breast cancer. CONCLUSION: Over 30 years, the survival of patients with de novo M1 disease modestly and unevenly increased among cancers. Metastatic cancer still remains a very lethal disease. Next to better treatment options, we call for better preventive measures and early detection to reduce the incidence of metastatic disease.

Defining High-Quality Integrated Head and Neck Cancer Care Through a Composite Outcome Measure: Textbook Outcome.

OBJECTIVES/HYPOTHESIS: To further improve the quality of head and neck cancer (HNC) care, we developed a composite measure defined as "textbook outcome" (TO). METHODS: We analyzed a retrospective cohort of patients after curvative-intent primary surgery, radiotherapy (RT), or chemoradiation (CRT) for HNC between 2015 and 2018 at the Netherlands Cancer Institute. TO was defined as 1) the start of treatment within 30 days, 2a) satisfactory pathologic outcomes, without 30-day postoperative complications, for the surgically treated group, and 2b), for RT and CRT patients, no unexpected or prolonged hospitalization and toxicity after the completion of treatment as planned. RESULTS: In total, 392 patients with HNC were included. An overall TO was achieved in 9.6% of patients after surgery, 20.6% after RT, and 2.2% after CRT. Two indicators (margins >5 mm and start treatment <30 days) reduced TO radically for both groups. CONCLUSION: TO can aid the evaluation of the quality of care for HNC patients and guide improvement processes. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:78-87, 2022.

Fewer head and neck cancer diagnoses and faster treatment initiation during COVID-19 in 2020: A nationwide population-based analysis.

BACKGROUND: Inevitably, the emergence of COVID-19 has impacted non-COVID care. Because timely diagnosis and treatment are essential, especially for patients with head and neck cancer (HNC) with fast-growing tumours in a functionally and aesthetically important area, we wished to quantify the impact of the COVID-19 pandemic on HNC care in the Netherlands. MATERIAL AND METHODS: This population-based study covered all, in total 8468, newly diagnosed primary HNC cases in the Netherlands in 2018, 2019 and 2020. We compared incidence, patient and tumour characteristics, primary treatment characteristics, and time-to-treatment in the first COVID-19 year 2020 with corresponding periods in 2018 and 2019 (i.e. pre-COVID). RESULTS: The incidence of HNC was nearly 25% less during the first wave (n = 433) than in 2019 (n = 595) and 2018 (n = 598). In April and May 2020, the incidence of oral cavity and laryngeal carcinomas was significantly lower than in pre-COVID years. There were no shifts in tumour stage or alterations in initial treatment modalities. Regardless of the first treatment modality and specific period, the median number of days between first visit to a HNC centre and start of treatment was significantly shorter during the COVID-19 year (26-28 days) than pre-COVID (31-32 days, p < 0.001). CONCLUSION: The incidence of HNC during the Netherlands' first COVID-19 wave was significantly lower than expected. The expected increase in incidence during the remainder of 2020 was not observed. Despite the overloaded healthcare system, the standard treatment for HNC patients could be delivered within a shorter time interval.

Assessing the prognostic value of tumor-infiltrating CD57+ cells in advanced stage head and neck cancer using QuPath digital image analysis.

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805-0.863, and 0.741, CI 0.692-0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis.