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Background: Radiotherapy is essential for treating head and neck cancer but often leads to severe toxicity. Traditional predictors include anatomical location, tumor extent, and dosimetric data. Recently, biomarkers have been explored to better predict and understand toxicity. This review aims to summarize the current literature, assess data quality, and guide future research., Methods: Two reviewers independently screened EMBASE and PubMed for studies published between 2010 and 2023. Endpoints were dermatitis, mucositis, sticky saliva/xerostomia, and dysphagia. Statistical analysis was performed using R, and bias assessed via a modified QUIPS questionnaire. Pathway analysis was conducted using gProfiler. The study adhered to PRISMA and COSMOS-E guidelines and was registered in the PROSPERO database (#CRD42023361245)., Results: Of 2,550 abstracts, 69 publications met the inclusion criteria. These studies involved a median of 81 patients, primarily male (75 %), with common primary tumors in the nasopharynx (32 %) and oropharynx (27 %). Most patients (84 %) had advanced disease (stage III/IV). The most frequently studied biomarkers were DNA-based single-nucleotide polymorphisms (SNPs, 59 %), salivary proteins (13 %), and bacteria (10 %). Ten statistically-significant biomarkers (all SNPs) in low-bias publications were identified, particularly in DNA repair and cell detoxification pathways. Data quality was often poor and few validation studies were present in the dataset., Conclusion: This review provides an overview of the research landscape, highlights research gaps and provides recommendations for future research directions. We identified several potential biomarkers, particularly in DNA repair pathways, that align with current understanding of radiation-induced cell damage. However, the overall data quality was poor, with key clinical variables often missing. Overall, rigorous standardization of reporting, validation studies and multi-center collaborations to increase study power and sample sizes are necessary to build high-level evidence for clinical application., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: The potential impact of the daytime and season of radiotherapy application on acute and late toxicity burden was analyzed on a cohort of curatively treated head and neck squamous cell carcinoma patients., Methods: Through a retrospective chart review, patient and tumor characteristics, treatment parameters and outcome were obtained. Patients treated with definitive or adjuvant radiotherapy with and without chemotherapy receiving ≥60 Gy between 2002 and 2015 were included (n = 617). Daily fraction times and dates were extracted. Median radiotherapy delivery time of each patient was categorized as morning (AM) and afternoon (PM). Treatment season was defined by the median day of the treatment course. Each year was divided into DARK and LIGHT by the March and September equinoxes. Acute (T) and late (A) toxicity were defined by TAME methodology., Results: Median follow-up was 51 months. Mean T and A scores during and after radiotherapy in DARK vs. LIGHT were 1.98 vs. 1.61 (p = 0.0127) and 0.41 vs. 0.30 (p = 0.1699), respectively. Mean T and A scores during and after AM vs. PM radiotherapy were 1.71 vs. 1.88 (p = 0.0387) and 0.31 vs. 0.41 (p = 0.2638), respectively. Multivariate analyses indicated DARK vs. LIGHT as the only independent treatment time-related factor among other factors such as tumor subsite, UICC stage, radiotherapy technique, and chemotherapy for T., Conclusion: This is the first study investigating the impact of seasonality on toxicity burden, showing higher acute toxicity with radiotherapy in DARK. The daytime did not predict the toxicity. The hypothesis-generating findings of this retrospective study should be further investigated., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The potential impact of daytime and season of radiotherapy application on prognosis is unclear. This was analyzed in a retrospective cohort of patients who were diagnosed with non-metastatic head and neck squamous cell carcinoma (HNSCC) and treated with definitive radiotherapy with or without chemotherapy., Materials and Methods: Patient and tumor characteristics, treatment parameters and outcome until last follow-up or death were obtained. Median radiotherapy delivery daytime of each patient was categorized as morning (AM) and afternoon (PM). Treatment season was defined by median date of treatment course. Each year was divided into DARK and LIGHT according to equinoxes. Time-to-event endpoints were defined by first biopsy confirming the HNSCC., Results: Six hundred fifty-five cases were identified who were treated with (chemo)radiotherapy between 2002 and 2015. Median follow-up was 47 months. No significant heterogeneity in patient, tumor and treatment characteristics were observed between DARK and LIGHT or regarding median daily fraction time (X2 p > 0.05). Five-year loco-regional control (73% vs. 61%; p = 0.0108) and progression-free survival (51% vs. 43%; p = 0.0374) were superior when radiotherapy was administered in DARK. Neither the daytime nor any other treatment time-related parameter affected prognosis., Conclusion: This is the first study investigating and presenting the prognostic impact of seasonality regarding the treatment course on loco-regional control and progression-free survival (DARK > LIGHT). The biological mechanism of action is unclear. These results should be interpreted with caution and our findings have to be validated externally., Competing Interests: Conflict of interest The authors declare the absence of any conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Evaluation of the effect of co-registered 4D-(18)FDG-PET/CT for SBRT target delineation in patients with central versus peripheral lung tumors., Methods: Analysis of internal target volume (ITV) delineation of central and peripheral lung lesions in 21 SBRT-patients. Manual delineation was performed by 4 observers in 2 contouring phases: on respiratory gated 4DCT with diagnostic 3DPET available aside (CT-ITV) and on co-registered 4DPET/CT (PET/CT-ITV). Comparative analysis of volumes and inter-reader agreement., Results: 11 cases of peripheral and 10 central lesions were evaluated. In peripheral lesions, average CT-ITV was 6.2 cm(3) and PET/CT-ITV 8.6 cm(3), resembling a mean change in hypothetical radius of 2 mm. For both CT-ITVs and PET/CT-ITVs inter reader agreement was good and unchanged (0.733 and 0.716; p=0.58). All PET/CT-ITVs stayed within the PTVs derived from CT-ITVs. In central lesions, average CT-ITVs were 42.1 cm(3), PET/CT-ITVs 44.2 cm(3), without significant overall volume changes. Inter-reader agreement improved significantly (0.665 and 0.750; p<0.05). 2/10 PET/CT-ITVs exceeded the PTVs derived from CT-ITVs by >1 ml in average for all observers., Conclusion: The addition of co-registered 4DPET data to 4DCT based target volume delineation for SBRT of centrally located lung tumors increases the inter-observer agreement and may help to avoid geographic misses., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)