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.

Dose planning study of proton versus photon radiotherapy for head and neck squamous cell carcinoma of unknown primary in the primary and recurrent setting.

BACKGROUND: Patients with head and neck squamous cell carcinoma of unknown primary (HNCUP) are often treated with extensive radiotherapy (RT). Frequently, the bilateral nodal clinical target volume (nCTV) and the volumes of suspected mucosal primary sites (mCTV) of the pharynx and larynx is irradiated. This treatment is effective but toxic. New data suggest that omission of the contralateral nCTV and mCTV, results in few recurrences. The present study explores photon versus proton therapy, in the primary and recurrent setting. MATERIAL AND METHODS: An analysis of twelve patients previously treated for HNCUP was performed. A fictitious recurrence was defined in patients treated for unilateral disease. Independently a volumetric arc photon plan and an intensity-modulated proton plan was made for all cases and scenarios. RESULTS: Compared to the standard bilateral treatment this study shows that limiting the target to unilateral nCTV leads to a significant decrease in dysphagia of 18% and 17% and xerostomia of 4.0% and 5% for photon and protons, respectively. Comparing photon RT directly to proton RT shows a small and often insignificant gain, using protons for both bilateral and unilateral targets. Focusing on re-irradiation, benefits from using protons in both the primary setting and at re-irradiation were limited. However, using protons for re-irradiation only leads to a decrease in the tissue volume receiving a specific dose outside the target overlapping region, e.g., V90Gymean was 31, 25, and 22 cm3 for photons-photons, photons-protons, and protons-protons, respectively. For V100Gy of the ipsilateral carotid artery, no differences were observed. CONCLUSION: Omitting contralateral nCTV irradiation and mCTV irradiation will significantly reduce toxicity. The accumulated high dose volumes can be minimised using protons for re-irradiation. However, the use of protons for primary treatment provides limited benefit in most patients.

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.

Patient anatomy-specific trade-offs between sub-clinical disease coverage and normal tissue dose reduction in head-and-neck cancer.

PURPOSE: Risk of subclinical disease decreases with increasing distance from the GTV in head- and-neck squamous cell carcinoma (HNSCC). Depending on individual patient anatomy, OAR sparing could be improved by reducing target coverage in regions with low risk of subclinical spread. Using automated multi-criteria optimization, we investigate patient-specific optimal trade-offs between target periphery coverage and OAR sparing. METHODS: VMAT plans for 39 HNSCC patients were retrospectively created following our clinical three-target-level protocol: high-risk (PTV1), intermediate-risk (PTV2, 5 mm expansion from PTV1), and elective (PTV3). A baseline plan fulfilling clinical constraints (D 99 % ≥95 % for all PTVs) was compared to three plans with reduced PTV2 coverage (goals: PTV2 D 99 % ≥90 % or 85 %, or no PTV2) at the outer edge of PTV2. Plans were compared on PTV D 99 %, OAR D mean, and NTCP (xerostomia/dysphagia). RESULTS: Trade-offs between PTV2 coverage and OAR doses varied considerably between patients. For plans with PTV2 D 99 % -goal 90 %, median PTV2 D 99 % was 91.5 % resulting in xerostomia (≥grade 4) and dysphagia (≥grade 2) NTCP decrease of median [maximum] 1.9 % [5.3 %] and 1.1 % [4.1 %], respectively, compared to nominal PTV2 D 99 % -goal 95 %. For PTV2 D 99 % -goal 85 % median PTV D 99 % was 87 % with NTCP improvements of 4.6 % [9.9 %] and 1.5 % [5.4 %]. For no-margin plans, PTV2 D 99 % decreased to 83.3 % with NTCP reductions of 5.1 % [10.2 %] and 1.4 % [6.1 %]. CONCLUSION: Clinically relevant, patient-specific reductions in OARs and NTCP were observed at limited cost in target under-coverage at the outermost PTV edge. Given the observed inter-patient variations, individual evaluation is warranted to determine whether trade- offs would benefit a specific patient.

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.

Functional image-guided dose escalation in gliomas using of state-of-the-art photon vs. proton therapy.

BACKGROUND: Recurrences of glioma are usually local, suggesting the need for higher tumor dose. We investigated the boundaries for dose escalation of an 18F-fluoro-ethyl-tyrosine positron emission tomography defined target by intensity-modulated photon therapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT). MATERIALS AND METHODS: Standard dose (60 Gy) and dose-escalated plans were calculated for seven patients using IMRT, VMAT and IMPT. The achieved boost dose, the dose to the organs at risk (OAR), the dose homogeneity (defined as overdose volume, ODV) and the ratio of the 30 Gy isodose curve and the boost volume (R30) were compared. The risk of radionecrosis was estimated using the ratio of the dose volume histograms of the brain (range 30-60 Gy). RESULTS: The mean boost dose was 77.1 Gy for IMRT, 79.2 Gy for VMAT and 85.1 GyE for IMPT. Compared with the standard plan, the ODV was unchanged and the R30 increased (17%) for IMRT. For VMAT, the ODV decreased (7%) and the R30 was unchanged whereas IMPT substantially decreased ODV (61%), R30 (22%), OAR doses as well as the risk of radionecrosis. CONCLUSIONS: Dose escalation can be achieved with IMRT, VMAT and IMPT while respecting normal tissue constraints, yet with IMPT being most favorable.

Simultaneous integrated prophylactic cranial irradiation in sino-nasal cancer.

Therapy for small cell cancer and high grade neuroendocrine tumours of the paranasal sinuses is extrapolated from the treatment of small cell lung cancer and paranasal cancer of different histologies. Prophylactic cranial irradiation has proven survival benefit in small cell lung cancer. Two patients with aggressive cancer of the paranasal sinuses received radiotherapy with simultaneous integrated prophylactic brain irradiation, using two sequential plans. Chemotherapy was given before, during and after radiotherapy. None of the patients had intracranial recurrence. One patient experienced severe, but transient encephalitis-like symptoms that could only be attributed to radiotherapy. No long term side effects in the CNS were observed. The treatment was feasible, but with possible severe, but transient side effects. It should be considered in cases with head and neck cancer, with a high risk of intracerebral metastasis, as well as a significant overlap between the primary irradiated volume and the brain.

Vacuum-ultraviolet circular dichroism spectroscopy of DNA: a valuable tool to elucidate topology and electronic coupling in DNA.

Circular dichroism (CD) is a powerful technique to obtain information on electronic transitions and has been used extensively for studies on DNA. Most experiments are done in the UV region but new information is often revealed from extending the wavelength region down into the vacuum ultraviolet (VUV) region. Such experiments are most easily carried out with synchrotron radiation (SR) light sources that provide large photon fluxes. Here we provide a summary of the SRCD data taken on different DNA strands with emphasis on results from our own laboratory within the last five years.(1-3) Signal intensities in the VUV are often significantly larger than those in the UV, and the electronic coupling between bases may increase with excitation energy. CD spectroscopy is particularly useful for investigating the extent of electronic coupling within a strand, i.e., the degree of delocalisation of the excited-state electronic wavefunction. The spatial extent of the wavefunction may be limited to just one base or it extends over two or more bases in a stack or between bases on different strands.(4,5) The actual character of the electronically excited state is linked to base composition and sequence as well as DNA folding motif (A-, B-, Z-DNA, triplexes, quadruplexes, etc.). The latter depends on experimental conditions such as solution acidity, temperature, ionic strength, and solvent.