Comparison of 3-year local control using DAHANCA radiotherapy guidelines before and after implementation of five millimetres geometrical GTV to high-dose CTV margin.

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.

High-dose loco-regional pattern of failure after primary radiotherapy in p16 positive and negative head and neck squamous cell carcinoma - A DAHANCA 19 study.

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.

Tumor volume and cancer stem cell expression as prognostic markers for high-dose loco-regional failure in head and neck squamous cell carcinoma - A DAHANCA 19 study.

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 cm3, 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.

Evaluation of decentralised model-based selection of head and neck cancer patients for a proton treatment study. DAHANCA 35.

INTRODUCTION: Proton treatment can potentially spare patients with H&N cancer for substantial treatment-related toxicities. The current study investigated the reproducibility of a decentralised model-based selection of patients for a proton treatment study when the selection plans were compared to the clinical treatment plans performed at the proton centre. METHODS: Sixty-three patients were selected for proton treatment in the six Danish Head and Neck Cancer (DAHANCA) centres. The patients were selected based on normal tissue complication probability (NTCP) estimated from local photon and proton treatment plans, which showed a ΔNTCP greater than 5%-point for either grade 2 + dysphagia or grade 2 + xerostomia at six months. The selection plans were compared to the clinical treatment plans performed at the proton centre. RESULTS: Of the 63 patients, 49 and 25 were selected based on an estimated benefit in risk of dysphagia and xerostomia, respectively. Eleven patients had a potential gain in both toxicities. The mean ΔNTCP changed from the local selection plan comparison to the clinical comparison from 6.9 to 5.3 %-points (p = 0.01) and 7.3 to 4.9 %-points (p = 0.03) for dysphagia and xerostomia, respectively. Volume differences in both CTV and OAR could add to the loss in ΔNTCP. 61 of the 63 clinical plans had a positive ΔNTCP, and 38 had a ΔNTCP of 5%-points for at least one of the two endpoints. CONCLUSION: A local treatment plan comparison can be used to select candidates for proton treatment. The local comparative proton plan overestimates the potential benefit of the clinical proton plan. Continuous quality assurance of the delineation procedures and planning is crucial in the subsequent randomised clinical trial setting.

A national repository of complete radiotherapy plans: design, Results, and experiences.

BACKGROUND: Previously, many radiotherapy (RT) trials were based on a few selected dose measures. Many research questions, however, rely on access to the complete dose information. To support such access, a national RT plan database was created. The system focuses on data security, ease of use, and re-use of data. This article reports on the development and structure, and the functionality and experience of this national database. METHODS AND MATERIALS: A system based on the DICOM-RT standard, DcmCollab, was implemented with direct connections to all Danish RT centres. Data is segregated into any number of collaboration projects. User access to the system is provided through a web interface. The database has a finely defined access permission model to support legal requirements. RESULTS: Currently, data for more than 14,000 patients have been submitted to the system, and more than 50 research projects are registered. The system is used for data collection, trial quality assurance, and audit data set generation.Users reported that the process of submitting data, waiting for it to be processed, and then manually attaching it to a project was resource intensive. This was accommodated with the introduction of triggering features, eliminating much of the need for users to manage data manually. Many other features, including structure name mapping, RT plan viewer, and the Audit Tool were developed based on user input. CONCLUSION: The DcmCollab system has provided an efficient means to collect and access complete datasets for multi-centre RT research. This stands in contrast with previous methods of collecting RT data in multi-centre settings, where only singular data points were manually reported. To accommodate the evolving legal environment, DcmCollab has been defined as a 'data processor', meaning that it is a tool for other research projects to use rather than a research project in and of itself.

Consistency in contouring of organs at risk by artificial intelligence vs oncologists in head and neck cancer patients.

BACKGROUND: In 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 METHODS: The 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. RESULTS: The 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 ΔNTCP. CONCLUSIONS: The study showed that OAR contours made by the AI algorithm were more consistent than those made by oncologists. No significant impact on the ΔNTCP calculations could be discerned.

The influence of tumor volume on the risk of distant metastases in head and neck squamous cell carcinomas.

BACKGROUND AND PURPOSE: Distant metastases (DM) in head and neck squamous cell carcinomas (HNSCC) are in most circumstances non-curable. The TNM staging system is insufficient to predict the risk of DM. This study investigates if the DM risk can be predicted using a multivariate model including pre-treatment total tumor volume for both p16-positive oropharyngeal squamous cell carcinoma (OPSCC) and all other sites (other HNSCC). MATERIALS AND METHODS: The study includes patients with localized pharyngeal and laryngeal squamous cell carcinomas treated with primary radiotherapy from 2008-2017 from three head and neck cancer centers. Patients were identified in the Danish Head and Neck Cancer (DAHANCA) database. Total (nodal and primary) tumor volume (Gross Tumor Volume, GTV) was extracted from local treatment planning systems. The GTV was grouped by volume (cm3) in four intervals and included in a multivariate Cox proportional hazard regression controlled for pre-selected clinical values incl. stage. RESULTS: The study includes 2,865 patients, of which 321 (11 %) had DM post-treatment. The risk of DM was assessed in a multivariate model based on 2,751 patients (p16-positive OPSCC: 1,032; and other HNSCC: 1,719). There was a significant association between GTV and the risk of DM, and in tumor volumes ≥ 50 cm3 hazard ratios of 7.6 (2.5-23.4) for p16-positive OPSCC and 4.1 (2.3-7.2) in other HNSCC were observed. CONCLUSION: Tumor volume is an independent risk factor for DM. The addition of total tumor volume to a predictive model is important to identify subgroups of HNSCC patients at high risk of DM.

Larynx cancer survival model developed through open-source federated learning.

INTRODUCTION: Federated learning has the potential to perfrom analysis on decentralised data; however, there are some obstacles to survival analyses as there is a risk of data leakage. This study demonstrates how to perform a stratified Cox regression survival analysis specifically designed to avoid data leakage using federated learning on larynx cancer patients from centres in three different countries. METHODS: Data were obtained from 1821 larynx cancer patients treated with radiotherapy in three centres. Tumour volume was available for all 786 of the included patients. Parameter selection among eleven clinical and radiotherapy parameters were performed using best subset selection and cross-validation through the federated learning system, AusCAT. After parameter selection, ß regression coefficients were estimated using bootstrap. Calibration plots were generated at 2 and 5-years survival, and inner and outer risk groups' Kaplan-Meier curves were compared to the Cox model prediction. RESULTS: The best performing Cox model included log(GTV), performance status, age, smoking, haemoglobin and N-classification; however, the simplest model with similar statistical prediction power included log(GTV) and performance status only. The Harrell C-indices for the simplest model were for Odense, Christie and Liverpool 0.75[0.71-0.78], 0.65[0.59-0.71], and 0.69[0.59-0.77], respectively. The values are slightly higher for the full model with C-index 0.77[0.74-0.80], 0.67[0.62-0.73] and 0.71[0.61-0.80], respectively. Smoking during treatment has the same hazard as a ten-years older nonsmoking patient. CONCLUSION: Without any patient-specific data leaving the hospitals, a stratified Cox regression model based on data from centres in three countries was developed without data leakage risks. The overall survival model is primarily driven by tumour volume and performance status.

Delineation uncertainties of tumour volumes on MRI of head and neck cancer patients.

Background: During the last decade, radiotherapy using MR Linac has gone from research to clinical implementation for different cancer locations. For head and neck cancer (HNC), target delineation based only on MR images is not yet standard, and the utilisation of MRI instead of PET/CT in radiotherapy planning is not well established. We aimed to analyse the inter-observer variation (IOV) in delineating GTV (gross tumour volume) on MR images only for patients with HNC. Material/methods: 32 HNC patients from two independent departments were included. Four clinical oncologists from Denmark and four radiation oncologists from Australia had independently contoured primary tumour GTVs (GTV-T) and nodal GTVs (GTV-N) on T2-weighted MR images obtained at the time of treatment planning. Observers were provided with sets of images, delineation guidelines and patient synopsis. Simultaneous truth and performance level estimation (STAPLE) reference volumes were generated for each structure using all observer contours. The IOV was assessed using the DICE Similarity Coefficient (DSC) and mean absolute surface distance (MASD). Results: 32 GTV-Ts and 68 GTV-Ns were contoured per observer. The median MASD for GTV-Ts and GTV-Ns across all patients was 0.17 cm (range 0.08-0.39 cm) and 0.07 cm (range 0.04-0.33 cm), respectively. Median DSC relative to a STAPLE volume for GTV-Ts and GTV-Ns across all patients were 0.73 and 0.76, respectively. A significant correlation was seen between median DSCs and median volumes of GTV-Ts (Spearman correlation coefficient 0.76, p < 0.001) and of GTV-Ns (Spearman correlation coefficient 0.55, p < 0.001). Conclusion: Contouring GTVs in patients with HNC on MRI showed that the median IOV for GTV-T and GTV-N was below 2 mm, based on observes from two separate radiation departments. However, there are still specific regions in tumours that are difficult to resolve as either malignant tissue or oedema that potentially could be improved by further training in MR-only delineation.

Co-registration of radiotherapy planning and recurrence scans with different imaging modalities in head and neck cancer.

MRI (magnetic resonance imaging) scans are frequently used in follow-up after radiotherapy for head and neck cancer. With the overall aim of enabling MRI-based pattern of failure analysis, this study evaluated the accuracy of recurrence MRI (rMRI) deformable co-registration with planning CT (computed tomography)-scans (pCT). Uncertainty of anatomical changes between pCT and rMRI was assessed by similarity metric analyses of co-registered image structures from 19 patients. Average mean distance to agreement and Dice similarity coefficient performed adequately. Our findings provide proof of concept for reliable co-registration of pCT and rMRI months to years apart for MRI-based pattern of failure analysis.

Open-source distributed learning validation for a larynx cancer survival model following radiotherapy.

INTRODUCTION: Prediction models are useful to design personalised treatment. However, safe and effective implementation relies on external validation. Retrospective data are available in many institutions, but sharing between institutions can be challenging due to patient data sensitivity and governance or legal barriers. This study validates a larynx cancer survival model performed using distributed learning without any sensitive data leaving the institution. METHODS: Open-source distributed learning software based on a stratified Cox proportional hazard model was developed and used to validate the Egelmeer et al. MAASTRO survival model across two hospitals in two countries. The validation optimised a single scaling parameter multiplied by the original predicted prognostic index. All analyses and figures were based on the distributed system, ensuring no information leakage from the individual centres. All applied software is provided as freeware to facilitate distributed learning in other institutions. RESULTS: 1745 patients received radiotherapy for larynx cancer in the two centres from Jan 2005 to Dec 2018. Limiting to a maximum of one missing value in the parameters of the survival model reduced the cohort to 1095 patients. The Harrell C-index was 0.74 (CI95%, 0.71-0.76) and 0.70 (0.66-0.75) for the two centres. However, the model needed a scaling update. In addition, it was found that survival predictions of patients undergoing hypofractionation were less precise. CONCLUSION: Open-source distributed learning software was able to validate, and suggest a minor update to the original survival model without central access to patient sensitive information. Even without the update, the original MAASTRO survival model of Egelmeer et al. performed reasonably well, providing similar results in this validation as in its original validation.

Plan quality in radiotherapy treatment planning - Review of the factors and challenges.

A high-quality treatment plan aims to best achieve the clinical prescription, balancing high target dose to maximise tumour control against sufficiently low organ-at-risk dose for acceptably low toxicity. Treatment planning (TP) includes multiple steps from simulation/imaging and segmentation to technical plan production and reporting. Consistent quality across this process requires close collaboration and communication between clinical and technical experts, to clearly understand clinical requirements and priorities and also practical uncertainties, limitations and compromises. TP quality depends on many aspects, starting from commissioning and quality management of the treatment planning system (TPS), including its measured input data and detailed understanding of TPS models and limitations. It requires rigorous quality assurance of the whole planning process and it links to plan deliverability, assessable by measurement-based verification. This review highlights some factors influencing plan quality, for consideration for optimal plan construction and hence optimal outcomes for each patient. It also indicates some challenges, sources of difference and current developments. The topics considered include: the evolution of TP techniques; dose prescription issues; tools and methods to evaluate plan quality; and some aspects of practical TP. The understanding of what constitutes a high-quality treatment plan continues to evolve with new techniques, delivery methods and related evidence-based science. This review summarises the current position, noting developments in the concept and the need for further robust tools to help achieve it.

Distant metastases in squamous cell carcinoma of the pharynx and larynx: a population-based DAHANCA study.

BACKGROUND: In head and neck cancer, distant metastases may be present at diagnosis (M1) or occur after treatment (DM). It is unknown whether M1 and DM follow the same clinical development and share prognosis, as population-based studies regarding outcomes are scarce. Therefore, we investigated the incidence, location of metastases and overall survival of patients with M1 and DM. MATERIALS AND METHODS: Patients diagnosed with squamous cell carcinoma of the pharynx and larynx in Denmark 2008-2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. We identified 7300 patients, of whom 197 (3%) had M1 and 498 (8%) developed DM during follow-up. RESULTS: The 5-year cumulative incidence of DM was 8%. 1- and 2-year overall survival for DM (27% and 13%) vs. M1 (28% and 9%) were equally poor. There was no significant difference in location of metastases for M1 and DM and the most frequently involved organs were lungs, bone, lymph nodes and liver, in descending order. In oropharyngeal squamous cell carcinomas, the location of metastases did not differ by p16-status. For p16-positive patients, 21% of DM occurred later than three years of follow-up compared to 7% of p16-negative patients. CONCLUSION: Incidence, location of metastases and prognosis of primary metastatic (M1) or post-treatment metastatic (DM) disease in pharyngeal and laryngeal squamous cell carcinoma are similar in this register-based study.

Accuracy of automatic structure propagation for daily magnetic resonance image-guided head and neck radiotherapy.

BACKGROUND AND PURPOSE: Deformable image registration (DIR) and contour propagation are used in daily online adaptation for hybrid MRI linac (MRL) treatments. The accuracy of the propagated contours may vary depending on the chosen workflow (WF), affecting the amount of required manual corrections. This study investigated the impact of three different WFs of contour propagations produced by a clinical treatment planning system for a high-field MRL on head and neck cancer patients. METHODS: Seventeen patients referred for curative radiotherapy for oropharyngeal cancer underwent standard CT-based dose planning and MR scans in the treatment position for planning (pMR), and at the 10th (MR10), 20th (MR20) and 30th (MR30) fraction (±2). The primary tumour, a metastatic lymph node and 8 organs at risk were manually delineated on each set of T2 weighted images. Delineations were repeated one month later on the pMR by the same observer to determine the intra-observer variation (IOV). Three WFs were used to deform images in the treatment planning system for the high-field MRL: In WF1, only the planning image and contours were used as a reference for DIR and propagation to MR10,20,30. The most recently acquired image set prior to the daily images was deformed and uncorrected (WF2) versus manually corrected (WF3) structures propagated to the session image. Dice similarity coefficient (DSC), mean surface distance (MSD) and Hausdorff distance (HD) were calculated for each structure in each model. RESULTS: Population median DSC, MSD and HD for WF1 and WF3 were similar and slightly better than for WF2. WF3 provided higher accuracy than WF1 for structures that are likely to shrink. All DIR workflows were less accurate than the IOV. CONCLUSIONS: WF1 and WF3 provide higher accuracy in structure propagation than WF2. Manual revision and correction of propagated structures are required for all evaluated workflows.

Imaging for Target Delineation in Head and Neck Cancer Radiotherapy.

The definition of tumor involved volumes in patients with head and neck cancer poses great challenges with the increasing use of highly conformal radiotherapy techniques eg, volumetric modulated arc therapy and intensity modulated proton therapy. The risk of underdosing the tumor might increase unless great care is taken in the process. The information gained from imaging is increasing with both PET and MRI becoming readily available for the definition of targets. The information gained from these techniques is indeed multidimensional as one often acquire data on eg, metabolism, diffusion, and hypoxia together with anatomical and structural information. Nevertheless, much work remains to fully exploit the available information on a patient-specific level. Multimodality target definition in radiotherapy is a chain of processes that must be individually scrutinized, optimized and quality assured. Any uncertainties or errors in image acquisition, reconstruction, interpretation, and delineation are systematic errors and hence will potentially have a detrimental effect on the entire radiotherapy treatment and hence; the chance of cure or the risk of unnecessary side effects. Common guidelines and procedures create a common minimum standard and ground for evaluation and development. In Denmark, the treatment of head and neck cancer is organized within the multidisciplinary Danish Head and Neck Cancer Group (DAHANCA). The radiotherapy quality assurance group of DAHANCA organized a workshop in January 2020 with participants from oncology, radiology, and nuclear medicine from all centers in Denmark, treating patients with head and neck cancer. The participants agreed on a national guideline on imaging for target delineation in head and neck cancer radiotherapy, which has been approved by the DAHANCA group. The guidelines are available in the Supplementary. The use of multimodality imaging is being recommended for the planning of all radical treatments with a macroscopic tumor. 2-[18F]FDG-PET/CT should be available, preferable in the treatment position. The recommended MRI sequences are T1, T2 with and without fat suppression, and T1 with contrast enhancement, preferable in the treatment position. The interpretation of clinical information, including thorough physical examination as well as imaging, should be done in a multidisciplinary setting with an oncologist, radiologist, and nuclear medicine specialist.

Awareness and surveillance of radiation treatment schedules reduces head and neck overall treatment time.

BACKGROUND AND PURPOSE: Overall treatment time (OTT) is essential for local tumour control and survival in radiotherapy of head and neck cancer (HNC). National radiotherapy guidelines of the Danish Head and Neck Cancer Group (DAHANCA) recommend a maximum OTT of 41 days for moderately accelerated radiation treatment (6 fractions/week) and 48 days for conventional treatment (5 fractions/week). The purpose of this study was to evaluate the effect of surveillance of the radiotherapy course length and treatment gaps in HNC patients to reduce OTT. METHODS: The study included 2011 patients with HNC undergoing radical radiation treatment with 66-68 Gy in 33-34 fractions in 2003-2017 at Odense University Hospital. In February 2016, a systematic weekly review by two radiation therapists of all planned treatment courses was introduced to check OTT of individual patients to portend likely breaks or treatment prolongations. Schedules that violated the OTT guidelines were conferred with the responsible radiation oncologist, and treatment rescheduled by treating twice daily to catch up with a delay. RESULTS: The mean length of accelerated treatment courses was reduced from a maximum of 40.9 days in 2007 to 38.3 days in 2017 and from 50.3 days to 45.9 days for conventional courses. The percentage of individual treatment courses that violated the recommended OTT was reduced to 3% of the accelerated treatments and 13% for the conventional treatments. CONCLUSION: Continuous surveillance of treatment schedules of HNC patients by a brief weekly survey reduced treatment course duration to an extent that was radiobiologically and clinically meaningful.

Local recurrences after curative IMRT for HNSCC: Effect of different GTV to high-dose CTV margins.

INTRODUCTION: The aim was to analyze position of CT-verified local recurrences (LR) and local control (LC) among three centers that used different GTV to CTV1 margins. MATERIALS AND METHODS: In total, 1576 patients completing radical primary IMRT for larynx, pharynx, oral cavity HNSCC in three centers in Denmark between 2006 and 2012 were included. CT-verified LRs were analyzed as possible points of recurrence origin and compared between groups of small (0-2.5 mm), larger (>2.5 mm), and anatomical GTV-CTV1 margins. The recurrence point's position relative to the GTV and 95% prescription dose was evaluated. Overall local control rate was evaluated using Cox uni- and multi-variate analysis. RESULTS: After a median follow-up of 41 months, 272 patients had local failure. Median GTV-CTV1 margin in Center1, 2 and 3 was 0.0, 3.7 and 9.7 mm, respectively. 51% of local recurrences were inside the GTV. No difference in distribution of LRs in relation to GTV surface (p = 0.4) or the dose to LRs (p = 0.2) was detected between the groups. A difference in LC was found univariate between the centers (p = 0.03), but not in multivariate analysis (p = 0.4). CONCLUSIONS: No relation was found between the recurrences' distributions as function of the margins used at three centers. In multivariate analysis, local control was not influenced by the centers.

Analysis of CT-verified loco-regional recurrences after definitive IMRT for HNSCC using site of origin estimation methods.

INTRODUCTION: A significant part of patients with head and neck squamous cell carcinoma (HNSCC) develop recurrent disease after curative radiotherapy. We aimed to analyze loco-regional recurrence pattern by identifying possible points of recurrence origin by three different methods in relation to treatment volumes. MATERIAL AND METHODS: A total of 455 patients completed IMRT-based treatment for HNSCC from 2006 to 2012. A total of 159 patients had remaining cancer after IMRT, developed loco-regional recurrence or distant disease during follow-up. Among those, 69 patients with loco-regional recurrences had affirmative CT or PET/CT scan. Possible points of origin (POs) of the recurrences were identified on scans by two independent observers, estimated as center of mass and as maximum surface distance. The recurrence position was analyzed in relation to high-dose treatment volume (CTV1) and 95% of prescription dose. RESULTS: In total, 104 loco-regional recurrences (54 in T-site and 50 in N-site) were identified in 69 patients. Median time to recurrence for the 69 patients was 10 months. No clinically relevant difference was found between the four POs, with standard deviation between POs in x, y and z axes of 3, 3 and 6 mm. For recurrences inside CTV1, 0-5 mm and 5-10 mm outside CTV1 the standard deviation of dose differences between the POs were 1, 1.4 and 1 Gy, respectively. 56% and 25% of T-site and N-site recurrences were inside CTV1, respectively. Coverage by 95% prescription dose to high-dose treatment volume was achieved in 78% of T-site and 39% of N-site recurrences. CONCLUSIONS: For recurrences identified by possible points of recurrence origin, no significant difference between observer-based or mathematically estimated methods was found. More than half of T-site recurrences were inside high-dose treatment volume, whereas N-site recurrences were mainly outside.

Automatic treatment planning facilitates fast generation of high-quality treatment plans for esophageal cancer.

BACKGROUND: The quality of radiotherapy planning has improved substantially in the last decade with the introduction of intensity modulated radiotherapy. The purpose of this study was to analyze the plan quality and efficacy of automatically (AU) generated VMAT plans for inoperable esophageal cancer patients. MATERIAL AND METHODS: Thirty-two consecutive inoperable patients with esophageal cancer originally treated with manually (MA) generated volumetric modulated arc therapy (VMAT) plans were retrospectively replanned using an auto-planning engine. All plans were optimized with one full 6MV VMAT arc giving 60 Gy to the primary target and 50 Gy to the elective target. The planning techniques were blinded before clinical evaluation by three specialized oncologists. To supplement the clinical evaluation, the optimization time for the AU plan was recorded along with DVH parameters for all plans. RESULTS: Upon clinical evaluation, the AU plan was preferred for 31/32 patients, and for one patient, there was no difference in the plans. In terms of DVH parameters, similar target coverage was obtained between the two planning methods. The mean dose for the spinal cord increased by 1.8 Gy using AU (p = .002), whereas the mean lung dose decreased by 1.9 Gy (p < .001). The AU plans were more modulated as seen by the increase of 12% in mean MUs (p = .001). The median optimization time for AU plans was 117 min. CONCLUSIONS: The AU plans were in general preferred and showed a lower mean dose to the lungs. The automation of the planning process generated esophageal cancer treatment plans quickly and with high quality.

Open source deformable image registration system for treatment planning and recurrence CT scans : Validation in the head and neck region.

BACKGROUND: Clinical application of deformable registration (DIR) of medical images remains limited due to sparse validation of DIR methods in specific situations, e. g. in case of cancer recurrences. In this study the accuracy of DIR for registration of planning CT (pCT) and recurrence CT (rCT) images of head and neck squamous cell carcinoma (HNSCC) patients was evaluated. PATIENTS AND MATERIALS: Twenty patients treated with definitive IMRT for HNSCC in 2010-2012 were included. For each patient, a pCT and an rCT scan were used. Median interval between the scans was 8.5 months. One observer manually contoured eight anatomical regions-of-interest (ROI) twice on pCT and once on rCT. METHODS: pCT and rCT images were deformably registered using the open source software elastix. Mean surface distance (MSD) and Dice similarity coefficient (DSC) between contours were used for validation of DIR. A measure for delineation uncertainty was estimated by assessing MSD from the re-delineations of the same ROI on pCT. DIR and manual contouring uncertainties were correlated with tissue volume and rigidity. RESULTS: MSD varied 1-3 mm for different ROIs for DIR and 1-1.5 mm for re-delineated ROIs performed on pCT. DSC for DIR varied between 0.58 and 0.79 for soft tissues and was 0.79 or higher for bony structures, and correlated with the volumes of ROIs (r = 0.5, p < 0.001) and tissue rigidity (r = 0.54, p < 0.001). CONCLUSION: DIR using elastix in HNSCC on planning and recurrence CT scans is feasible; an uncertainty of the method is close to the voxel size length of the planning CT images.