Robust quality assurance (QA) of clinical trials in radiotherapy (RT) is paramount for minimising uncertainties in treatment delivery, thereby strengthening the statistical power of the study and increasing the likelihood of accurately answering the research question. As RT techniques evolve and become more complex, establishing an appropriate QA program for a specific clinical trial becomes increasingly challenging, highlighting the importance of clear and standardised recommendations. This study provide such recommendations for Principal Investigators (PIs) to consider when planning and conducting RT Quality Assurance (RTQA) for clinical trials. They arise from experiences with RTQA in the clinical trials conducted in the Danish Multidisciplinary Cancer Groups (DMCGs). The recommendations include a checklist to guide PIs in developing an effective RTQA program.

Background and purpose: One of the factors influencing disease control and toxicity risk after radiotherapy is selection of treatment volume margin. This study evaluates whether different gross tumour volume (GTV) to high-dose clinical target volume (CTV1) margins impact dysphagia in a cohort of head and neck squamous cell carcinoma (SCC) patients. Patient/material and methods: Data of patients receiving primary IMRT-based radiotherapy for SCC for the oropharynx, hypopharynx, and larynx at three treatment centres between 2010 and 2015 were retrospectively collected. Treatment planning followed two DAHANCA guideline periods: pre-2013 (varying GTV-CTV1 margins), and post-2013 (isotropic 5 mm margin). Treatment plans were collected for 1,913 patients. GTV–CTV1 margins were calculated as median surface distance from GTV to CTV1. Dysphagia was graded using modified DAHANCA ordinal scale. For each patient, the highest score of dysphagia during 5-year follow-up period was chosen for analysis. Results: Dysphagia data were available for 1,706 patients (89%). The median GTV–CTV1 margin was 9.0 mm in 2010–2012 and 4.7 mm in 2013–2015. The severity of dysphagia was more pronounced in patients treated during 2010–2012 (p = 0.003). Predictors of grade ≥ 2 dysphagia included larger GTV (odds ratio [OR]: 1.7; p < 0.001), larger GTV–CTV1 margin (odds ratio [OR] of 1.3 per cm; p = 0.04), and tumour localisation other than oropharyngeal p16+carcinomas (p = 0.002). Male sex, non/previous smoking status, and application of chemotherapy were associated with less severe dysphagia. Interpretation: Tumour volume and GTV–CTV1 margin are dominant geometric parameters influencing dysphagia risk following curative radiotherapy

Background and purpose: Reliable and accessible biomarkers for patients with Head and Neck Squamous Cell Carcinoma (HNSCC) are warranted for biologically driven radiotherapy (RT). This study aimed to investigate the prognostic value of putative cancer stem cell (CSC) markers, hypoxia, and tumor volume using loco-regional high-dose failure (HDF) as endpoint. Materials and methods: Tumor tissue was retrieved from patients treated with primary chemo-(C-)RT and nimorazole for HNSCC in the Danish Head and Neck Cancer Study Group (DAHANCA) 19 study. Tumor volume, hypoxic classification, and expression of CSC markers CD44, SLC3A2, and MET were analyzed. For patients with eligible data on all parameters (n = 340), the risk of HDF following primary chemo-(C-)RT were analyzed by these biomarkers as a whole and stratified for p16-positive oropharynx (p16 + OPSCC) vs p16-negative (p16-) tumors (oral cavity, p16- oropharynx, hypopharynx and larynx). Results: Higher risk of HDF was seen for patients with larger primary and nodal volume (>25 cm(3), Hazard Ratio (HR): 3.00 [95 % CI: 1.73-5.18]), high SLC3A2 (HR: 2.99 [1.28-6.99]), CD44 (>30 % positive, HR: 2.29 [1.05-5.00]), and p16- tumors (HR: 2.53 [1.05-6.11]). p16- tumors had a higher CSC marker expression than p16 + OPSCC. The factors associated with the highest risk of HDF were larger volume (HR: 3.29 [1.79-6.04]) for p16- tumors (n = 178) and high SLC3A2 (HR: 6.19 [1.58-24.23]) for p16 + OPSCC (n = 162). Conclusion: Tumor volume, p16, and CSC markers are potential biomarkers for HDF for patients with HNSCC treated with (C-)RT. Lower expression of CSC in p16 + OPSCC may contribute to better tumor control.

Background and purpose:As preparation for a national randomized study comparing proton radiotherapy to photon radiotherapy, DAHANCA 35, we performed a non-randomized pilot study to investigate patient selection, logistics, planning, and treatment delivery. With the present study, as a comprehensive safety analysis, we want to compare toxicity during and up to two months after therapy to a historically matched group of patients treated with photon radiotherapy. Materials and methods:62 patients treated with protons were matched to 124 patients who received photon treatment outside a protocol. Available data were retrieved from the DAHANCA database. Patients were matched on treatment centre, concurrent chemotherapy, tumour site, stage, p16 status for oropharynx cancers. Selection of patients for proton therapy was based on comparative treatment plans with a NTCP reduction for dysphagia and xerostomia at six months. Results:Baseline characteristics between groups were well balanced, except for the type of drug used concurrently; more photon patients received Carboplatin (21.2 % vs 5.8 %, p = 0.01). Proton therapy was associated with significantly less weight loss at the end of treatment, mean weight loss of 3 % for protons and 5 % for photons (p < 0.001). There were more grade 3 skin reactions and grade 3 mucositis after proton treatment compared with photons at the end of treatment, Risk Ratio (RR) 1.9 (95 % CI: 1.01-3.5, p = 0.04) and RR 1.5 (95 % CI: 1.3-1.7, p < 0.001), respectively. All differences resolved at follow up two months after treatment. There were no significant differences between groups on opioid use, use of feeding tubes, or hospitalization during the observation period. Conclusion:Proton treatment resulted in excess objective mucositis and dermatitis, which was transient and did not seem to negatively influence weight or treatment compliance and intensity. Selection bias was likely especially since NTCP models were used for selection of proton treatment and photon treated patients were matched manually. We are currently including patients in a randomized controlled trial.

Introduction: Treatment planning using a five-millimetre geometrical margin from GTV to high-dose CTV (CTV1) has been used in DAHANCA treatment centres since 2013. We aimed to evaluate changes in CTV1 volumes, local control (LC), and recurrence pattern after the implementation of five-millimetre geometrical margins nationally.Materials and Methods: 1,948 patients with pharyngeal, and laryngeal squamous cell carcinomas completed definitive IMRT-based treatment in 2010-2012 and 2013-2015 in three centres. The patient-specific margin was calculated as median surface distance from primary tumour GTV (GTV-T) to CTV1. Radiologically verified local recurrences were analysed using a centre of mass (COM) of the delineated recurrence volume, measuring the shortest distance between COM to GTV-T and CTV1 boundaries.Results: Median GTV-CTV1 was 0.9 (0.0-0.97) and 0.47 cm (0.4-0.5) for 2010-2012 and 2013-2015, respectively. Median CTV1 changed in three centres from 76, 28, 42 cm3 to 61, 53, 62 cm3 for 2010-2012 and 2013-2015, respectively. Local failures occurred at 247 patients during first three years after radiotherapy. The 3-year LC rate for 2010-2012 and 2013-2015 was 0.84 and 0.87 (p=0.06).Out of 146 radiology-verified analysable local recurrences, 102 (69.9%) were inside the CTV1. In 74.6% and 91% of cases, the LRs were covered by 95% isodose in 2010-2012 and 2013-2015, respectively.Conclusion: DAHANCA radiotherapy guidelines based on a geometrically generated isotropic CTV1 margin led to less variation in treatment volumes and between centres than previous guidelines. The transition towards consensus GTV-CTV1 margins did not influence local tumour control. The majority of local recurrences were inside CTV1 and covered by the prescription dose.

Introduction: Patients with failure after primary radiotherapy (RT) for head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. This study investigates pattern of failure after primary curatively intended IMRT in a randomized controlled trial in relation to HPV/p16 status. Material and methods: Patients with HNSCC of the oral cavity, oropharynx (OPSCC), hypopharynx or larynx were treated with primary curative IMRT (+/-cisplatin) and concomitant nimorazole between 2007 and 12. Of 608 patients, 151 had loco-regional failure within five years, from whom 130 pairs of scans (planning-CT and diagnostic failure scan) were collected and deformably co-registered. Point of origin-based pattern of failure analysis was conducted, including distance to CTV1 and GTV, and estimated dose coverage of the point of origin. Results: Of 130 patients with pairs of scans, 104 (80 %) had at least one local or regional failure site covered by 95 % of prescribed dose and 87 (67 %) of the failures had point of origin within the high-dose CTV (CTV1). Of failures from primary p16 + OPSCC, the majority of both mucosal (84 %) and nodal (61 %) failures were covered by curative doses. For p16- tumors (oral cavity, OPSCC p16neg, hypopharynx and larynx), 75 % of mucosal and 66 % of nodal failures were high-dose failures. Conclusion: Radioresistance is the primary cause of failure after RT for HNSCC irrespective of HPV/p16 status. Thus, focus on predictors for the response to RT is warranted to identify patients with higher risk of high-dose failure that might benefit from intensified treatment regimens.

Proton radiotherapy offers a dosimetric advantage compared to photon therapy in sparing normal tissue, but the clinical evidence for toxicity reductions in the treatment of head and neck cancer is limited. The Danish Head and Neck Cancer Group (DAHANCA) has initiated the DAHANCA 35 randomised trial to clarify the value of proton therapy (NCT04607694). The DAHANCA 35 trial is performed in an enriched population of patients selected by an anticipated benefit of proton therapy to reduce the risk of late dysphagia or xerostomia based on normal tissue complication probability (NTCP) modelling. We present our considerations on the trial design and a test of the selection procedure conducted before initiating the randomised study.

Highly conformal treatment plan using volumetric arc therapy (VMAT) and daily image guidance (IGRT) is standard of care in radiotherapy for prostate cancer. However, there are still risks of severe side effects from radiation dose to the rectum. The largest concerns are risk of diarrhoea, rectal strictures and rectal bleeding [1,2]

BackgroundIn the Danish Head and Neck Cancer Group (DAHANCA) 35 trial, patients are selected for proton treatment based on simulated reductions of Normal Tissue Complication Probability (NTCP) for proton compared to photon treatment at the referring departments. After inclusion in the trial, immobilization, scanning, contouring and planning are repeated at the national proton centre. The new contours could result in reduced expected NTCP gain of the proton plan, resulting in a loss of validity in the selection process. The present study evaluates if contour consistency can be improved by having access to AI (Artificial Intelligence) based contours.Materials and MethodsThe 63 patients in the DAHANCA 35 pilot trial had a CT from the local DAHANCA centre and one from the proton centre. A nationally validated convolutional neural network, based on nnU-Net, was used to contour OARs on both scans for each patient. Using deformable image registration, local AI and oncologist contours were transferred to the proton centre scans for comparison. Consistency was calculated with the Dice Similarity Coefficient (DSC) and Mean Surface Distance (MSD), comparing contours from AI to AI and oncologist to oncologist, respectively. Two NTCP models were applied to calculate NTCP for xerostomia and dysphagia.ResultsThe AI contours showed significantly better consistency than the contours by oncologists. The median and interquartile range of DSC was 0.85 [0.78 - 0.90] and 0.68 [0.51 - 0.80] for AI and oncologist contours, respectively. The median and interquartile range of MSD was 0.9 mm [0.7 - 1.1] mm and 1.9 mm [1.5 - 2.6] mm for AI and oncologist contours, respectively. There was no significant difference in & UDelta;NTCP.ConclusionsThe study showed that OAR contours made by the AI algorithm were more consistent than those made by oncologists. No significant impact on the & UDelta;NTCP calculations could be discerned.