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Background/objectives: Studies have shown that dose to the parotid gland stem cell rich (SCR) regions should be reduced to lower the risk of xerostomia after radiotherapy (RT). This study aimed to assess whether stem cell sparing (SCS)-RT can be adopted in routine clinical practice., Methods: Multiple planning studies were performed to compare SCS-RT with standard (ST)-RT using 30 head and neck cancer patients. Shifts in mean dose to the SCR regions (D mean,SCR ) and other organs at risk and their estimated impact on normal tissue complication probability (NTCP) for side-effects were compared using Wilcoxon signed-rank test. A multicenter study was performed (eight institutions, three patients) to test the generalizability of SCS-RT using the Friedman test., Results: Using photons, D mean,SCR was reduced with median 4.1/3.5 Gy for ipsilateral/contralateral ( p < 0.001). The largest reductions were when the SCR regions overlapped less with target volumes. Subsequently, NTCPs for xerostomia decreased ( p < 0.001). Using protons, D mean,SCR was also reduced (2.2/1.9 Gy for ipsilateral/contralateral, p < 0.002). Nevertheless, SCS-RT did not further decrease NTCPs for xerostomia ( p > 0.17). Target coverage and prevention of other side-effects were not compromised. However, increased mean oral cavity dose was observed in some patients. Lastly, in the multicenter study D mean,SCR could be reduced by slightly adjusting the standard optimization. Contralateral D mean,SCR reductions differed between centers ( p = 0.01), which was attributed to differences in ST-RT plans., Conclusions: Stem cell sparing radiotherapy can be clinically introduced by making small adjustments to the optimization strategy and can reduce the risk of xerostomia.

Background and Purpose: Radiotherapy for brain, head & neck (HN), and skull base (SB) tumors may deliver significant radiation dose to the hypothalamic-pituitary axis (HPA), leading to impaired functioning of this region and hence, to endocrine disorders. The purpose of this systematic review and meta -analysis is to investigate literature on HP dysfunction after radiation for non-pituitary brain, HN, or SB tumors at adult age, aiming to give insight in the prevalence of HP dysfunction related to radiation dose., Materials and Methods: Literature search of the PubMed database was performed for HP dysfunction after radiotherapy in adult patients. A risk of bias assessment was performed to rate the quality of the included papers. Besides clinical and treatment variables, reported insufficiencies for adrenocorticotrophic hormone, thyroid stimulating hormone, growth hormone, prolactin and follicle stimulating hormone and luteinizing hormone and for insufficiency of any axis were extracted. The prevalence for hormonal insufficiency per axis and for multiple axes was calculated using a random effects meta -regression with a random effect at the study level., Results: The literature selection process resulted in a total of 22 original papers, suitable for full assessment (n = 1,462 patients). Literature showed a wide variation in HP dysfunction, along with wide dose ranges given to the hypothalamus and pituitary, with varying follow-up times. The calculated prevalence for any pituitary insufficiency was on average 0.61 (95 % CI 0.44-0.75). For growth hormone the mean prevalence was 0.40 (95 % CI 0.22-0.61), for prolactin 0.22 (95 % CI 0.17-0.28), for gonadotropin 0.20 (95 % CI 0.14-0.28), for adrenocorticotropic hormone 0.16 (95 % CI 0.08-0.30) and for thyroid stimulating hormone 0.16 (95 % CI 0.11-0.23). The prevalence for any insufficiency of 1 axis was 0.19 (95 % CI 0.11-0.30), of 2 axes 0.22 (95 % CI 0.12-0.38), of 3 axes 0.05 (95 % CI 0.03-0.09) and of panhypopituitarism 0.17 (95 % CI 0.08-0.32). Patients irradiated for nasopharyngeal carcinoma (NPC) seemed to be at highest risk for developing any endocrine insufficiency with a mean prevalence of 0.68 (95 % CI 0.45-0.85). A significant correlation between any endocrine insufficiency and follow-up time was observed (p = 0.015). A correlation between dose to the pituitary and occurrence of insufficiency on the hormonal axes could not be observed., Conclusion: Endocrine insufficiency is reported in over half of the patients irradiated for brain, HN and SB malignancies. The hypothalamus is likely to be more vulnerable to radiation dose compared to the pituitary gland. More research is needed to establish dose thresholds for the hypothalamus and the pituitary to minimize the risk for pituitary insufficiency. Based on this knowledge, radiotherapy and follow-up of these patient groups should be standardized to establish a normal tissue complication probability (NTCP) model for the HPA., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The use of artificial intelligence (AI) holds great promise for radiation oncology, with many applications being reported in the literature, including some of which are already in clinical use. These are mainly in areas where AI provides benefits in efficiency (such as automatic segmentation and treatment planning). Prediction models that directly impact patient decision-making are far less mature in terms of their application in clinical practice. Part of the limited clinical uptake of these models may be explained by the need for broader knowledge, among practising clinicians within the medical community, about the processes of AI development. This lack of understanding could lead to low commitment to AI research, widespread scepticism, and low levels of trust. This attitude towards AI may be further negatively impacted by the perception that deep learning is a "black box" with inherently low transparency. Thus, there is an unmet need to train current and future clinicians in the development and application of AI in medicine. Improving clinicians' AI-related knowledge and skills is necessary to enhance multidisciplinary collaboration between data scientists and physicians, that is, involving a clinician in the loop during AI development. Increased knowledge may also positively affect the acceptance and trust of AI. This paper describes the necessary steps involved in AI research and development, and thus identifies the possibilities, limitations, challenges, and opportunities, as seen from the perspective of a practising radiation oncologist. It offers the clinician with limited knowledge and experience in AI valuable tools to evaluate research papers related to an AI model application., Competing Interests: Dr R.H.M. reported receiving personal fees from ViewRay, AstraZeneca, Novartis, Varian Medical Systems, and Sio Capital and grants from ViewRay outside the submitted work. Dr D.S.B. reported serving as an associate editor for HemOnc.org and her institution received support for research from the American Association for Cancer Research outside the submitted work. No disclosures relevant for this submitted work were reported by the other authors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life., Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment., Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background and Purpose: Head and neck cancer (HNC) patients treated with radiotherapy often suffer from radiation-induced toxicities. Normal Tissue Complication Probability (NTCP) modeling can be used to determine the probability to develop these toxicities based on patient, tumor, treatment and dose characteristics. Since the currently used NTCP models are developed using supervised methods that discard unlabeled patient data, we assessed whether the addition of unlabeled patient data by using semi-supervised modeling would gain predictive performance., Materials and Methods: The semi-supervised method of self-training was compared to supervised regression methods with and without prior multiple imputation by chained equation (MICE). The models were developed for the most common toxicity outcomes in HNC patients, xerostomia (dry mouth) and dysphagia (difficulty swallowing), measured at six months after treatment, in a development cohort of 750 HNC patients. The models were externally validated in a validation cohort of 395 HNC patients. Model performance was assessed by discrimination and calibration., Results: MICE and self-training did not improve performance in terms of discrimination or calibration at external validation compared to current regression models. In addition, the relative performance of the different models did not change upon a decrease in the amount of (labeled) data available for model development. Models using ridge regression outperformed the logistic models for the dysphagia outcome., Conclusion: Since there was no apparent gain in the addition of unlabeled patient data by using the semi-supervised method of self-training or MICE, the supervised regression models would still be preferred in current NTCP modeling for HNC patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.A. Langendijk reports a relationship with Dutch Cancer Society: funding grants. J.A. Langendijk reports his department has research contracts with IBA, RaySearch, Siemens, Elekta, Leoni, and Mirada. J.A. Langendijk reports a relationship with Global Scientific Advisory Board of IBA, RayCare International Advisory Board of RaySearch that includes: board membership, consulting or advisory, and speaking and lecture fees. J.A. Langendijk reports a relationship with Netherlands Society for Radiation Oncology that includes: board membership. Funding AL is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement N° 825162. This dissemination reflects only the author's view and the Commission is not responsible for any use that may be made of the information it contains., (© 2023 The Authors.)

Background: Radiotherapy induced impairment of cognitive function can lead to a reduced quality of life. The aim of this study was to describe the implementation and compliance of standardized neurocognitive assessment. In addition, the first results of cognitive changes for patients receiving a radiation dose to the brain are described., Materials and Methods: Patients that received radiation dose to the brain (neuro, head and neck and prophylactic cranial irradiation between April-2019 and Dec-2021 were included. Three neuro cognitive tests were performed a verbal learning and memory test, the Hopkins Verbal Learning Test; a verbal fluency test, the Controlled Oral Word Association Test and a speed and cognitive flexibility test, the Trail Making Test A&B. Tests were performed before the start of radiation, 6 months (6 m) and 1 year (1y) after irradiation. The Reliable Change Index (RCI) between baseline and follow-up was calculated using reference data from literature., Results: 644 patients performed the neurocognitive tests at baseline, 346 at 6 months and 205 at 1y after RT, with compliance rates of 90.4%, 85.6%, and 75.3%, respectively. Reasons for non-compliance were: 1. Patient did not attend appointment (49%), 2. Patient was unable to perform the test due to illness (12%), 3. Patient refused the test (8 %), 4. Various causes, (31%). A semi-automated analysis was developed to evaluate the test results. In total, 26% of patients showed a significant decline in at least one of variables at 1y and 11% on at least 2 variables at 1y. However, an increase in cognitive performance was observed in 49% (≥1 variable) and 22% (≥2 variables)., Conclusion: Standardized neurocognitive testing within the radiotherapy clinic was successfully implemented, with a high patient compliance. A semi-automatic method to evaluate cognitive changes after treatment was defined. Data collection is ongoing, long term follow-up (up to 5 years after treatment) and dose-effect analysis will be performed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

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., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Locoregionally advanced head and neck squamous cell carcinoma (HNSCC) patients have high relapse and mortality rates. Imaging-based decision support may improve outcomes by optimising personalised treatment, and support patient risk stratification. We propose a multifactorial prognostic model including radiomics features to improve risk stratification for advanced HNSCC, compared to TNM eighth edition, the gold standard., Patient and Methods: Data of 666 retrospective- and 143 prospective-stage III-IVA/B HNSCC patients were collected. A multivariable Cox proportional-hazards model was trained to predict overall survival (OS) using diagnostic CT-based radiomics features extracted from the primary tumour. Separate analyses were performed using TNM8, tumour volume, clinical and biological variables, and combinations thereof with radiomics features. Patient risk stratification in three groups was assessed through Kaplan-Meier (KM) curves. A log-rank test was performed for significance ( p -value < 0.05). The prognostic accuracy was reported through the concordance index (CI)., Results: A model combining an 11-feature radiomics signature, clinical and biological variables, TNM8, and volume could significantly stratify the validation cohort into three risk groups ( p < 0∙01, CI of 0.79 as validation)., Conclusion: A combination of radiomics features with other predictors can predict OS very accurately for advanced HNSCC patients and improves on the current gold standard of TNM8.

Purpose: Radiation therapy is a standard modality in the treatment for cancers of the head and neck, but is associated with significant short- and long-term side effects. Proton therapy, with its unique physical characteristics, can deliver less dose to normal tissues, resulting in fewer side effects. Proton therapy is currently being used for the treatment of head and neck cancer, with increasing clinical evidence supporting its use. However, barriers to wider adoption include access, cost, and the need for higher-level evidence., Methods: The clinical evidence for the use of proton therapy in the treatment of head and neck cancer are reviewed here, including indications, advantages, and challenges., Results: The Particle Therapy Cooperative Group Head and Neck Subcommittee task group provides consensus guidelines for the use of proton therapy for head and neck cancer., Conclusion: This report can be used as a guide for clinical use, to understand clinical trials, and to inform future research efforts., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. The authors have no other relevant conflicts of interest to disclose., (©Copyright 2021 The Author(s) 2020.)

In the Netherlands, the model-based approach is used to identify patients with head and neck cancer who may benefit most from proton therapy in terms of prevention of late radiation-induced side effects in comparison with photon therapy. To this purpose, a National Indication Protocol Proton therapy for Head and Neck Cancer patients (NIPP-HNC) was developed, which has been approved by the health care authorities. When patients qualify according to the guidelines of the NIPP-HNC, proton therapy is fully reimbursed. This article describes the procedures that were followed to develop this NIPP-HNC and provides all necessary information to introduce model-based selection for patients with head and neck cancer into routine clinical practice., Competing Interests: Conflicts of Interest: J. A. Langendijk is Member of the International Scientific Advisory Committees of IBA and RaySearch; consultant for IBA, honorarium paid to UMCG Research BV. The department of Radiation Oncology has Research Agreement/Grant Support from Siemens, IBA, Elekta, Leonie, RaySearch, and Mirada., (©Copyright 2021 The Author(s).)

Background: Cancer cachexia is highly prevalent in advanced non-small cell lung cancer (NSCLC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC), and compromises treatment tolerance and overall survival (OS). NSCLC and LAHNSCC patients share similar risk factors, and receive comparable anti-cancer treatment regimens. The aim of this study was to determine the predictive value of body composition assessed by bioelectrical impedance analysis (BIA) and handgrip strength (HGS) (baseline and early changes during therapy) on OS in NSCLC and LAHNSCC patients treated with platinum-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (BRT). To elucidate potential underlying determinants of early changes in body composition and HGS, specific (fat and fat free) mass loss patterns of squamous NSCLC (sNSCLC) were compared to human papilloma virus negative (HPV-) LAHNSCC patients treated with CRT. Methods: Between 2013 and 2016, BIA and HGS were performed at baseline and after 3 weeks of CRT/BRT in LAHNSCC and NSCLC patients treated with curative intent. Results: Two hundred thirty-three patients were included for baseline measurements. Fat free mass index (FFMI) and HGS<10th percentile of reference values at baseline were both prognostic for poor OS in NSCLC and LAHNSCC [HR 1.64 [95%CI 1.13-2.39], p = 0.01 and HR 2.30 [95%CI 1.33-3.97], p = 0.003, respectively], independent of Charlson Comorbidity Index, cancer site, and gross tumor volume. Early fat mass (FM) loss during CRT was predictive for poor OS in sNSCLC ( n = 64) [HR 3.80 [95%CI 1.79-8.06] p ≤ 0.001] but not in HPV- LAHNSCC ( n = 61). In patients with significant weight loss (>2%) in the first 3 weeks of CRT (sNSCLC n = 24, HPV- LAHNSCC n = 23), the FM change was -1.4 ± 14.5% and -8.7 ± 9.0% in sNSCLC and HPV- LAHNSCC patients, respectively ( p < 0.05). Fat fee mass change was -5.6 ± 6.3% and -4.0 ± 4.3% for sNSCLC and HPV- LAHNSCC, respectively ( p = 0.31). Conclusion: FFMI and HGS<10th percentile at baseline are independent prognostic factors for poor OS in NSCLC and LAHNSCC patients treated with CRT/BRT. The specific composition of mass loss during first 3 weeks of CRT significantly differs between sNSCLC and HPV- LAHNSCC patients. Early FM loss was prognostic in sNSCLC only., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Willemsen, Degens, Baijens, Dingemans, Hoeben, Hoebers, De Ruysscher and Schols.)

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., (© 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.)