The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

Clinical outcomes in relapsed oropharyngeal cancer after definitive (chemo) radiotherapy.

OBJECTIVES: To report clinical outcomes of relapsed oropharyngeal squamous cell carcinoma (OPSCC) after definitive intensity-modulated (chemo)radiotherapy [(C)RT]. MATERIALS AND METHODS: Data for all relapsed patients treated for OPSCC with definitive (C)RT between 2010 and 2016 were collected. Primary end-point was post-failure survival (PFS). RESULTS: Overall, 273 OPSCC patients completed definitive (C)RT. Of these, 42 cases (n = 26 human papilloma virus (HPV)-negative; n = 16 HPV-positive) had relapsed (n = 23 persistent disease; n = 19 recurrent disease) and were included in the final analysis. Two-year PFS for the entire population was 30.6%; 20.5% for HPV-negative and 43.8% for HPV-positive patients. Salvage curative surgery was associated with a significantly higher 2 years PFS rate (56.2%) compared with palliative treatment (22.9%) and best supportive care (0%) (p < 0.001). A positive trend in 2 years PFS was recorded in the early complete response cases (49.5%) versus patients who did not achieve a complete response within 3 months of the end of (C)RT (23.0%) (p = 0.11). CONCLUSION: A higher PFS rate is achieved when relapsed OPSCC cases are treated with salvage curative intent. HPV-positive disease and early complete response within 3 months from the end of (C)RT may be related to better PFS.

Robustness and Generalizability of Deep Learning Synthetic Computed Tomography for Positron Emission Tomography/Magnetic Resonance Imaging-Based Radiation Therapy Planning of Patients With Head and Neck Cancer.

PURPOSE: Radiotherapy planning based only on positron emission tomography/magnetic resonance imaging (PET/MRI) lacks computed tomography (CT) information required for dose calculations. In this study, a previously developed deep learning model for creating synthetic CT (sCT) from MRI in patients with head and neck cancer was evaluated in 2 scenarios: (1) using an independent external dataset, and (2) using a local dataset after an update of the model related to scanner software-induced changes to the input MRI. METHODS AND MATERIALS: Six patients from an external site and 17 patients from a local cohort were analyzed separately. Each patient underwent a CT and a PET/MRI with a Dixon MRI sequence over either one (external) or 2 (local) bed positions. For the external cohort, a previously developed deep learning model for deriving sCT from Dixon MRI was directly applied. For the local cohort, we adapted the model for an upgraded MRI acquisition using transfer learning and evaluated it in a leave-one-out process. The sCT mean absolute error for each patient was assessed. Radiotherapy dose plans based on sCT and CT were compared by assessing relevant absorbed dose differences in target volumes and organs at risk. RESULTS: The MAEs were 78 ± 13 HU and 76 ± 12 HU for the external and local cohort, respectively. For the external cohort, absorbed dose differences in target volumes were within ± 2.3% and within ± 1% in 95% of the cases. Differences in organs at risk were <2%. Similar results were obtained for the local cohort. CONCLUSIONS: We have demonstrated a robust performance of a deep learning model for deriving sCT from MRI when applied to an independent external dataset. We updated the model to accommodate a larger axial field of view and software-induced changes to the input MRI. In both scenarios dose calculations based on sCT were similar to those of CT suggesting a robust and reliable method.

A multi-centre survey reveals variations in the standard treatments and treatment modifications for head and neck cancer patients during Covid-19 pandemic.

BACKGROUND: The onset of the COVID-19 pandemic necessitated rapid changes to the practice of head and neck oncology in UK. There was a delay between the onset of the pandemic and the release of guidelines from cancer societies and networks, leading to a variable response of individual centres. This survey was conducted to assess the pre-Covid-19 pandemic standard of practice for head and neck oncology patients and the treatment modifications introduced during the first wave of the pandemic in UK. METHODOLOGY: The UK National Cancer Research Institute (NCRI) Head and Neck Clinical Studies Group initiated a multi-centre survey using questionnaire to investigate the effect on feeding tube practice, radiotherapy (RT) fractionation and volumes, use of chemotherapy in the neo-adjuvant, concurrent and palliative setting, the use of immunotherapy in the palliative setting, access to radiology and histopathology services, and availability of surgical procedures. RESULTS: 30 centres were approached across UK; 23 (76.7%) centres responded and were included in the survey. There were differences in the standard practices in feeding tube policy, RT dose and fractionation as well as concurrent chemotherapy use. 21 (91%) participating centres had at least one treatment modification. 15 (65%) centres initiated a change in radical RT; changing to either a hypofractionation or acceleration schedule. For post-operative RT 10 centres (43.5%) changed to a hypofractionation schedule. 12 (52.2%) centres stopped neo-adjuvant chemotherapy for all patients; 13 (56.5%) centres followed selective omission of chemotherapy in concurrent chemo-radiotherapy patients, 17 (73.9%) centres changed first-line chemotherapy treatment to pembrolizumab (following NHS England's interim guidance) and 8 (34.8%) centres stopped the treatment early or offered delays for patients that have been already on systemic treatment. The majority of centres did not have significant changes associated with surgery, radiology, histopathology and dental screening. CONCLUSION: There are variations in the standard of practice and treatment modifications for head and neck cancer patients during Covid-19 pandemic. A timely initiative is required to form a consensus on head and neck cancer management in the UK and other countries.

TNM 8 staging is a better prognosticator than TNM 7 for patients with locally advanced oral cavity squamous cell carcinoma treated with surgery and post-operative radiotherapy.

PURPOSE: To assess TNM 8 staging in discriminating overall survival (OS) amongst patients with locally advanced oral cavity squamous cell carcinoma (OCSCC) treated with surgery and post-operative radiotherapy (PORT), compared to TNM 7. MATERIAL AND METHODS: Data from OCSCC patients treated with surgery and PORT between January 2010 and December 2018 were reviewed. Demographics, tumour characteristics and treatment response data were collected, and patients staged according to both TNM 7 and TNM 8. OS and disease free survival (DFS) were estimated using the Kaplan Meier method. Univariate and multivariable analyses were conducted for factors affecting OS, DFS and early disease recurrence within 12 months. RESULTS: Overall 172 patients were analyzed. Median follow up was 32 months for all patients and 48 months for surviving patients. TNM 8 staging demonstrated significant stratification of OS and DFS amongst the entire cohort, whereas TNM 7 staging did not. On multivariable analysis, TNM 8 stage, performance status (PS) and a positive surgical margin were prognostic for OS. Looking at disease recurrence within 12 months, TNM 8 stage IVB, presence of lymphovascular invasion (LVSI), younger age and lesser smoking history were predictive factors on multivariable analysis. CONCLUSION: TNM 8 is a good development of its predecessor in terms of predicting survival for patients with locally advanced OCSCC. We have also identified younger age (<60 years) and a smoking history of <10 pack years as risk factors for early disease recurrence, potentially representing a separate biological cohort within OCSCC patients.

Safety and Treatment Outcomes of Nivolumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Retrospective Multicenter Cohort Study.

Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.

Guidance on the use of MRI for treatment planning in radiotherapy clinical trials.

The aim of this article is to propose meaningful guidance covering the technical and safety issues involved when designing or conducting radiotherapy clinical trials that use MRI for treatment planning. The complexity of imaging requirements will depend on the trial aims, design and MRI methods used.The use of MRI within the RT pathway is becoming more prevalent and clinically appropriate as access to MRI increases, treatment planning systems become more versatile and potential indications for MRI-planning in RT are documented. Novel MRI-planning opportunities are often initiated and validated within clinical trials.The guidance in this document is intended to assist researchers designing RT clinical trials involving MRI, so that they may provide sufficient information about the appropriate methods to be used for image acquisition, post-processing and quality assurance such that participating sites complete MRI to consistent standards. It has been produced in collaboration with the National Radiotherapy Trials Quality Assurance Group (RTTQA).As the use of MRI in RT is developed, it is highly recommended for researchers writing clinical trial protocols to include imaging guidance as part of their clinical trial documentation covering the trial-specific requirements for MRI procedures. Many of the considerations and recommendations in this guidance may well apply to MR-guided treatment machines, where clinical trials will be crucial. Similarly, many of these recommendations will apply to the general use of MRI in RT, outside of clinical trials.This document contains a large number of recommendations, not all of which will be relevant to any particular trial. Designers of RT clinical trials must therefore take this into account. They must also use their own judgement as to the appropriate compromise between accessibility of the trial and its technical rigour.

Guidance on the use of PET for treatment planning in radiotherapy clinical trials.

The aim of this article is to propose meaningful guidance covering the practical and technical issues involved when planning or conducting clinical trials involving positron emission tomography (PET)-guided radiotherapy. The complexity of imaging requirements will depend on the study aims, design and PET methods used. Where PET is used to adapt radiotherapy, a high level of accuracy and reproducibility is required to ensure effective and safe treatment delivery. The guidance in this document is intended to assist researchers designing clinical trials involving PET-guided radiotherapy to provide sufficient information about the appropriate methods to complete PET-CT imaging to a consistent standard at participating centres. The guidance is divided into six categories: application of PET in radiotherapy, resource requirements, quality assurance, imaging protocol design, data management and image processing. Each section provides an overview of the recent literature to support the specific recommendations. This guidance builds on previous recommendations from the National Cancer Research Institute PET Research Network and has been produced in collaboration with the National Radiotherapy Trials Quality Assurance Group.

Machine-learned target volume delineation of 18F-FDG PET images after one cycle of induction chemotherapy.

Biological tumour volume (GTVPET) delineation on 18F-FDG PET acquired during induction chemotherapy (ICT) is challenging due to the reduced metabolic uptake and volume of the GTVPET. Automatic segmentation algorithms applied to 18F-FDG PET (PET-AS) imaging have been used for GTVPET delineation on 18F-FDG PET imaging acquired before ICT. However, their role has not been investigated in 18F-FDG PET imaging acquired after ICT. In this study we investigate PET-AS techniques, including ATLAAS a machine learned method, for accurate delineation of the GTVPET after ICT. Twenty patients were enrolled onto a prospective phase I study (FiGaRO). PET/CT imaging was acquired at baseline and 3 weeks following 1 cycle of induction chemotherapy. The GTVPET was manually delineated by a nuclear medicine physician and clinical oncologist. The resulting GTVPET was used as the reference contour. The ATLAAS original statistical model was expanded to include images of reduced metabolic activity and the ATLAAS algorithm was re-trained on the new reference dataset. Estimated GTVPET contours were derived using sixteen PET-AS methods and compared to the GTVPET using the Dice Similarity Coefficient (DSC). The mean DSC for ATLAAS, 60% Peak Thresholding (PT60), Adaptive Thresholding (AT) and Watershed Thresholding (WT) was 0.72, 0.61, 0.63 and 0.60 respectively. The GTVPET generated by ATLAAS compared favourably with manually delineated volumes and in comparison, to other PET-AS methods, was more accurate for GTVPET delineation after ICT. ATLAAS would be a feasible method to reduce inter-observer variability in multi-centre trials.

Osteoradionecrosis following treatment for head and neck cancer and the effect of radiotherapy dosimetry: the Guy's and St Thomas' Head and Neck Cancer Unit experience.

OBJECTIVES: To analyze clinical features, dosimetric parameters, and outcomes of osteoradionecrosis (ORN). STUDY DESIGN: Thirty-six patients with ORN who had been previously treated with radiotherapy (RT) were retrospectively identified between January 2009 and April 2014. ORN volumes were contoured on planning computed tomography (CT) scans. Near maximum dose (D2%), minimum dose (Dmin), mean dose (Dmean), and percentage of bone volume receiving 50 Gy (V50) were examined. Clinical and dosimetric variables were considered to compare ORN resolution versus ORN persistence. RESULTS: Median interval time from end of RT to development of ORN was 6 months. Of the ORN cases, 61% were located in the mandible. Dmean to affected bone was 57.6 Gy, and 44% had a D2% 65 Gy or greater. Smoking was associated with ORN persistence on univariate analysis, but no factors were found to impact ORN resolution or progression on logistic regression. CONCLUSIONS: Prevention strategies for ORN development should be prioritized. Dose-volume parameters could have a role in preventing ORN.

Primary esophageal cancer: heterogeneity as potential prognostic biomarker in patients treated with definitive chemotherapy and radiation therapy.

PURPOSE: To determine the association between tumor heterogeneity, morphologic tumor response, and overall survival in primary esophageal cancer treated with chemotherapy and radiation therapy (CRT). MATERIALS AND METHODS: After an institutional review board waiver was obtained, contrast material-enhanced computed tomographic (CT) studies in 36 patients with stage T2 or greater esophageal tumors who underwent contrast-enhanced CT before and after CRT between 2005 and 2008 were analyzed in terms of whole-tumor texture, with quantification of entropy, uniformity, mean gray-level intensity, kurtosis, standard deviation of the histogram, and skewness for fine to coarse textures (filters 1.0-2.5, respectively). The association between texture parameters and survival time was assessed by using Kaplan-Meier analysis and a Cox proportional hazards model. Survival models involving texture parameters and combinations of texture and morphologic response assessment were compared with morphologic assessment alone by means of receiver operating characteristic (ROC) analysis. RESULTS: Posttreatment medium entropy of less than 7.356 (median overall survival, 33.2 vs 11.7 months; P = .0002), coarse entropy of less than 7.116 (median overall survival, 33.2 vs 11.7 months; P = .0002), and medium uniformity of 0.007 or greater (median overall survival, 33.2 vs 11.7 months; P = .0002) were associated with improved survival time. These remained significant prognostic factors after adjustment for stage and age: entropy (filter 2.0: hazard ratio [HR] = 5.038, P = .0004; filter 2.5: HR = 5.038, P = .0004) and uniformity (HR = 0.199, P = .0004). Survival models that included a combination of pretreatment entropy and uniformity with maximal wall thickness assessment, respectively, performed better than morphologic assessment alone (area under the ROC curve, 0.767 vs 0.487 [P = .00005] and 0.802 vs 0.487 [P = .0003]). CONCLUSION: Posttreatment texture parameters are associated with survival time, and the combination of pretreatment texture parameters and maximal wall thickness performed better in survival models than morphologic tumor response alone.