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.

Radiotherapy to the neck after neck dissection for head and neck squamous cell carcinoma from an unknown primary: A narrative review.

PURPOSE: To conduct a comprehensive narrative review of the evidence for radiotherapy target volumes to the neck, after neck dissection, for head and neck squamous cell carcinoma from an unknown primary (HNSCCUP). Inclusion or exclusion of mucosal irradiation is not the focus of interest for this review article. MATERIALS AND METHODS: Literature (PubMed-Medline, EMBASE database and Cochrane library) was searched using the relevant keywords. The search results were limited to the studies published in year 2000 or after. RESULTS: Eight studies met the inclusion criteria. All studies were retrospective in nature. The incidence of contralateral recurrence rates in the untreated neck when the involved neck only is treated remains very low (0%-10%). Survival has improved over the past two decades, most likely due to improved diagnostic techniques and the increase in incidence of HPV-related disease. CONCLUSION: Given the rarity of disease, level one evidence from randomised controlled trials is lacking. Available data are retrospective but support unilateral post-operative radiotherapy as a treatment option in selected cases.

Impact of the COVID-19 pandemic on stage and incidence of head and neck cancer: A rapid review and meta-analysis.

OBJECTIVES: This rapid review aims to evaluate the impact of the COVID-19 pandemic on incidence of head and neck cancer (HNC) and stage distribution at diagnosis. DESIGN: Rapid review and meta-analysis. PARTICIPANTS: Comparative data for new HNC patients between a pre-pandemic cohort (before March 2020) and a pandemic cohort (after March 2020 during the lockdown period). MAIN OUTCOMES MEASURED: Data on tumour stage, incidence, referral pathway (number of new patient referrals), or workload levels (number of HNC treatments). Data on stage were summarised as odds ratios (OR) with 95% confidence intervals (CI), and data related to changes in numbers of diagnoses, referrals, and workload levels were summarised as a narrative synthesis. RESULTS: A total of 31 reports were included in this review. Individually 16 out of 23 studies did not show a significant impact on stage relative to the pre-pandemic period. However, the meta-analysis revealed that patients diagnosed with HNC during the pandemic were 16% more likely to have nodal involvement (OR = 1.16; 95% CI 1.00-1.35), 17% more likely to have a late overall stage (OR = 1.17; 95% CI 1.01-1.36), and 32% more likely to present with advanced tumour extent (T3 and T4 stage) (OR = 1.32; 95% CI 1.08-1.62). Data on incidence was extremely limited and not currently sufficient to assess trends in burden of disease. CONCLUSIONS: This review indicates that during the COVID-19 pandemic, there was upstaging of HNC at diagnosis, suggesting the provision of care to HNC patients was significantly affected.

The COVID-19 pandemic has not changed stage at presentation nor treatment patterns of head and neck cancer: A retrospective cohort study.

OBJECTIVES: To evaluate the impact of the COVID-19 lockdown measures on HNC, by comparing the stage at presentation and treatment of HNC before and after the most severe COVID-19 restrictions. DESIGN: A retrospective cohort study. SETTING: A regional cancer network serving a patient population of 2.4 million. PARTICIPANTS: Newly diagnosed patients with HNC between June and October 2019 (pre-pandemic) and June and October 2021 (post-pandemic). MAIN OUTCOME MEASURES: Symptom duration before diagnosis, stage at diagnosis, patient performance status (PS) and intent of treatment delivered (palliative vs. curative). RESULTS: Five hundred forty-five patients were evaluated-250 in the 2019 and 295 in the 2021 cohort. There were no significant differences in symptom duration between the cohorts (p = .359) or patient PS (p = .821). There were no increased odds of presenting with a late (Stage III or IV) AJCC cancer stage in 2021 compared with 2019 (odds ratio [OR] = 0.90; 95% confidence interval [CI]: 0.76-1.08); nor increased odds of receiving palliative rather than curative treatment in 2021 compared with 2019 (OR = 0.68; 95% CI: 0.45-1.03). CONCLUSION: The predicted stage shift to more advanced disease at the time of diagnosis of HNC due to the COVID-19 pandemic has not been realised in the longer term. In keeping with this, there was no difference in symptom duration, patient PS, or treatment patterns between the 2019 and 2021 cohorts.

Sub-regional analysis of the parotid glands: model development for predicting late xerostomia with radiomics features in head and neck cancer patients.

BACKGROUND: The irradiation of sub-regions of the parotid has been linked to xerostomia development in patients with head and neck cancer (HNC). In this study, we compared the xerostomia classification performance of radiomics features calculated on clinically relevant and de novo sub-regions of the parotid glands of HNC patients. MATERIAL AND METHODS: All patients (N = 117) were treated with TomoTherapy in 30-35 fractions of 2-2.167 Gy per fraction with daily mega-voltage-CT (MVCT) acquisition for image-guidance purposes. Radiomics features (N = 123) were extracted from daily MVCTs for the whole parotid gland and nine sub-regions. The changes in feature values after each complete week of treatment were considered as predictors of xerostomia (CTCAEv4.03, grade ≥ 2) at 6 and 12 months. Combinations of predictors were generated following the removal of statistically redundant information and stepwise selection. The classification performance of the logistic regression models was evaluated on train and test sets of patients using the Area Under the Curve (AUC) associated with the different sub-regions at each week of treatment and benchmarked with the performance of models solely using dose and toxicity at baseline. RESULTS: In this study, radiomics-based models predicted xerostomia better than standard clinical predictors. Models combining dose to the parotid and xerostomia scores at baseline yielded an AUCtest of 0.63 and 0.61 for xerostomia prediction at 6 and 12 months after radiotherapy while models based on radiomics features extracted from the whole parotid yielded a maximum AUCtest of 0.67 and 0.75, respectively. Overall, across sub-regions, maximum AUCtest was 0.76 and 0.80 for xerostomia prediction at 6 and 12 months. Within the first two weeks of treatment, the cranial part of the parotid systematically yielded the highest AUCtest. CONCLUSION: Our results indicate that variations of radiomics features calculated on sub-regions of the parotid glands can lead to earlier and improved prediction of xerostomia in HNC patients.

Assessing the generalisability of radiomics features previously identified as predictive of radiation-induced sticky saliva and xerostomia.

Background and purpose: While core to the scientific approach, reproducibility of experimental results is challenging in radiomics studies. A recent publication identified radiomics features that are predictive of late irradiation-induced toxicity in head and neck cancer (HNC) patients. In this study, we assessed the generalisability of these findings. Materials and Methods: The procedure described in the publication in question was applied to a cohort of 109 HNC patients treated with 50-70 Gy in 20-35 fractions using helical radiotherapy although there were inherent differences between the two patient populations and methodologies. On each slice of the planning CT with delineated parotid and submandibular glands, the imaging features that were previously identified as predictive of moderate-to-severe xerostomia and sticky saliva 12 months post radiotherapy (Xer12m and SS12m) were calculated. Specifically, Short Run Emphasis (SRE) and maximum CT intensity (maxHU) were evaluated for improvement in prediction of Xer12m and SS12m respectively, compared to models solely using baseline toxicity and mean dose to the salivary glands. Results: None of the associations previously identified as statistically significant and involving radiomics features in univariate or multivariate models could be reproduced on our cohort. Conclusion: The discrepancies observed between the results of the two studies delineate limits to the generalisability of the previously reported findings. This may be explained by the differences in the approaches, in particular the imaging characteristics and subsequent methodological implementation. This highlights the importance of external validation, high quality reporting guidelines and standardisation protocols to ensure generalisability, replication and ultimately clinical implementation.

Predicting radiotherapy-induced xerostomia in head and neck cancer patients using day-to-day kinetics of radiomics features.

Background and purpose: The images acquired during radiotherapy for image-guidance purposes could be used to monitor patient-specific response to irradiation and improve treatment personalisation. We investigated whether the kinetics of radiomics features from daily mega-voltage CT image-guidance scans (MVCT) improve prediction of moderate-to-severe xerostomia compared to dose/volume parameters in radiotherapy of head-and-neck cancer (HNC). Materials and Methods: All included HNC patients (N = 117) received 30 or more fractions of radiotherapy with daily MVCTs. Radiomics features were calculated on the contra-lateral parotid glands of daily MVCTs. Their variations over time after each complete week of treatment were used to predict moderate-to-severe xerostomia (CTCAEv4.03 grade ≥ 2) at 6, 12 and 24 months post-radiotherapy. After dimensionality reduction, backward/forward selection was used to generate combinations of predictors.Three types of logistic regression model were generated for each follow-up time: 1) a pre-treatment reference model using dose/volume parameters, 2) a combination of dose/volume and radiomics-based predictors, and 3) radiomics-based predictors. The models were internally validated by cross-validation and bootstrapping and their performance evaluated using Area Under the Curve (AUC) on separate training and testing sets. Results: Moderate-to-severe xerostomia was reported by 46 %, 33 % and 26 % of the patients at 6, 12 and 24 months respectively. The selected models using radiomics-based features extracted at or before mid-treatment outperformed the dose-based models with an AUCtrain/AUCtest of 0.70/0.69, 0.76/0.74, 0.86/0.86 at 6, 12 and 24 months, respectively. Conclusion: Our results suggest that radiomics features calculated on MVCTs from the first half of the radiotherapy course improve prediction of moderate-to-severe xerostomia in HNC patients compared to a dose-based pre-treatment model.

Head and neck cancer in the UK: what was the stage before COVID-19? UK cancer registries analysis (2011-2018).

Introduction People who present with more advanced stage head and neck cancer (HNC) are associated with poorer outcomes and survival. The burden and trends of advanced stage HNC are not fully known at the population level. The UK national cancer registries routinely collect data on HNC diagnoses.Aims To describe trends in stage of diagnosis of HNCs across the UK before the COVID-19 pandemic.Methods Aggregated HNC incidence data were requested from the national cancer registries of the four UK countries for the ten most recent years of available data by subsite and American Joint Commission on Cancer stage at diagnosis classification. Additionally, data for Scotland were available by age group, sex and area-based socioeconomic deprivation category.Results Across the UK, rates of advanced stage HNC had increased, with 59% of patients having advanced disease at diagnosis from 2016-2018. England had a lower proportion of advanced disease (58%) than Scotland, Wales or Northern Ireland (65-69%) where stage data were available. The completeness of stage data had improved over recent years (87% by 2018).Conclusion Prior to the COVID-19 pandemic, diagnoses of HNC at an advanced stage comprised the majority of HNCs in the UK, representing the major challenge for the cancer healthcare system.

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs.

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

Long term survival in patients with human papillomavirus-positive oropharyngeal cancer and equivocal response on 12-week PET-CT is not compromised by the omission of neck dissection.

BACKGROUND AND AIM: The aim of this study was to evaluate the long-term safety of the omission of immediate neck dissections (IND) in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) achieving a less than complete nodal response on 12-week FDG PET-CT. MATERIAL AND METHODS: Patients with HPV-positive, node-positive HNSCC that were treated with radical (chemo) radiotherapy (RT) between January 2013 and September 2019 were identified. PET-CT responses were classified as complete (CR), incomplete (ICR) or equivocal (EQR) nodal responses. Clinical outcomes were obtained. RESULTS: 347 patients were identified. Median follow-up was 43.9 (IQR, 30.8-61.2) months. 62.8% (218/347) achieved a CR, 23.4% (81/347) EQR and 13.8% (48/347) ICR nodal response. 70 of 81 (86.4%) patients with an EQR and 25 of 48 (52.1%) with an ICR had no residual disease during follow up (a pathologically negative ND if surgery undertaken or no subsequent neck or distant relapse clinically/radiologically). Median survival of the EQR and CR groups were not reached, and despite the omission of IND in 95% of the EQR group there was no statistically significant differences in overall survival (OS) between the groups, p = 1.0. Median survival of ICR was not reached. However, OS for ICR group was significantly worse than that of CR, and EQR, both p < 0.001. CONCLUSION: The omission of IND in those achieving an EQR nodal response does not compromise long-term survival. This supports the safety of extended surveillance in patients with HPV-positive disease and an EQR on 12-week FDG PET-CT.

The dogma of Cetuximab and Radiotherapy in head and neck cancer - A dawn to dusk journey.

Since the introduction of Cetuximab as a biological molecule against Epidermal Growth Factor Receptor (EGFR), its use in the cancers of head and neck region is widely explored. With the recognition that EGFR expression is associated with radioresistance and poor prognosis, incorporation of an anti-EGFR agent along with Radiotherapy (RT) is a logical and attractive option. Cetuximab in combination with RT as Bio-Radiotherapy (BRT) is considered one of the standard treatment modalities in Locally Advanced Head and Neck Squamous Cell Cancers (LA-HNSCC). Many important phase-III clinical trials were undertaken simultaneously, where the use of Cetuximab BRT was tested in various clinical scenarios with different hypothesis. With the studies still ongoing and the results awaited, its use was continued in clinical practice. Today the results are out and definitely not encouraging. After the initial success, Cetuximab has miserably failed to win over cisplatin based chemoradiation which is the current standard of care in LA-HNSCC. Hence, it is the need of the hour to re-evaluate and define the present role of Cetuximab in the definitive management of LA-HNSCC in the light of the latest clinical evidence..

Adaptive dose escalated radiotherapy in oropharyngeal cancers: a treatment planning feasibility study.

BACKGROUND: A significant proportion of patients with poor prognosis squamous cell cancer of the oropharynx relapse loco-regionally despite radical (chemo)radiotherapy. If a predictive biomarker for disease control can be identified during treatment then individualised and adaptive treatment strategies may be employed. The aim of this study is to assess the feasibility of adaptive and dose-escalated RT to the gross tumour volume without increasing surrounding planning target volume doses and maintaining clinically acceptable organs at risk doses. MATERIALS AND METHODS: Twenty representative patients with poor prognosis locally advanced OPSCC who were known to have relapsed post RT, were re-planned retrospectively using Eclipse TPS v15.5, RapidPlan™ and multi-criteria optimisation. In our centre, PTV65 is treated with 65 Gy in 30 fractions while areas at risk of containing microscopic disease (PTV54) are treated synchronously to 54 Gy in 30 fractions. The original clinical plans were re-optimised to act as controls (Group I). These plans were split into two plans of 15 fractions each, with the latter 15 fractions used to escalate the dose to the GTV to 73 Gy (Group II) and 82 Gy (Group III). Plan sums were created for the total 30 fractions to record plan evaluation parameters along with assessments of plan deliverability. RESULTS: For all groups, the dose coverage at D98% and D50% for the PTVs were comparable. The D2% dose levels for PTV65-GTV increased. All dose levels associated with PTV54 remained largely unaffected by the dose escalation regimens. Conformity indices for PTV65 and PTVAll (PTV65 plus PTV54) reveal comparable target volume coverage across all three groups. Despite the GTV being escalated by 12.3% and 26.2% in groups II and III, the volume of GTV receiving > 84 Gy was considerably less than 1.75 cc. While OAR doses increased for the escalated groups, these increases were not clinically significant. CONCLUSION: This planning feasibility study exploring RapidPlan™ combined with multi-criteria optimisation has demonstrated that doses to the GTV may be escalated without increasing PTV65-GTV, PTV54 or OAR doses considerably, suggesting an interventional clinical trial using this approach would be feasible.

Feasibility of DW-MRI analysis of salivary glands during head and neck radiotherapy.

INTRODUCTION: With no effective treatment for xerostomia, there remains an unmet need to reduce radiation induced toxicity. Measuring physiological changes during RT in salivary glands using DW-MRI may predict which patients are most at risk of severe toxicity. This study evaluated the feasibility of measuring apparent diffusion coefficient (ADC) in the major salivary glands and describes the observed changes in volume and ADC during RT. METHODS: Scans were acquired at baseline (MR_base) and after 10 fractions (MR_rpt). Sequences included T1 post contrast fat saturated (T1PCFS) and DW-MRI (5b values, 0-1000 s/mm2). Ipsilateral and contralateral parotid (iPG/cPG), submandibular (iSMG/cSMG) and sublingual glands (iSLG/cSLG) were delineated on T1PCFS, modified on b0 and copied to the ADC map. RESULTS: 31 patients with intermediate/high risk squamous cell carcinoma (SCC) of the oropharynx were evaluated. On 124 scans, SMG and SLG delineations were successful on all; parotids were fully contoured in 90.7%. Baseline mean ADC were significantly different between each gland type (p < 0.0001). IPG and cPG volume decreased during treatment by 6.7% and 11.2%. ISMG, cSMG, iSLG and cSLG volume increased by 6.9, 0.9, 60.8 and 60.3% respectively. All structures showed an increase in mean_ADC values. For each gland the increase in ADC was statistically significant p < 0.0001. A smaller mean percentage increase in ADC was observed in the group experiencing a higher grade (2 or > ) of toxicity. CONCLUSION: It is feasible to measure volume and ADC of the salivary glands prior to and during RT for HNC. Early data suggests a lower rise in ADC during treatment is associated with more severe late xerostomia.

Preservation of swallowing in resected oral cavity squamous cell carcinoma: examining radiation volume effects (PRESERVE): study protocol for a randomized phase II trial.

BACKGROUND: Patients with resected oral cavity squamous cell carcinoma (OCSCC) are often treated with adjuvant radiation (RT) ± concomitant chemotherapy based on pathological findings. Standard RT volumes include all surgically dissected areas, including the tumour bed and dissected neck. RT has significant acute and long-term toxicities including odynophagia, dysphagia, dermatitis and fibrosis. The goal of this study is to assess the rate of regional failure with omission of radiation to the surgically dissected pathologically node negative (pN0) hemi-neck(s) compared to historical control, and to compare oncologic outcomes, toxicity, and quality of life (QoL) profiles between standard RT volumes and omission of RT to the pN0 neck. METHODS: This is a multicentre phase II study randomizing 90 patients with T1-4 N0-2 OCSCC with at least one pN0 hemi-neck in a 1:2 ratio between standard RT volumes and omission of RT to the pN0 hemi-neck(s). Patients will be stratified based on overall nodal status (nodal involvement vs. no nodal involvement) and use of concurrent chemotherapy. The primary endpoint is regional failure in the pN0 hemi-neck(s); we hypothesize that a 2-year regional recurrence of 20% or less will be achieved. Secondary endpoints include overall and progression-free survival, local recurrence, rate of salvage therapy, toxicity and QoL. DISCUSSION: This study will provide an assessment of omission of RT to the dissected pN0 hemi-neck(s) on oncologic outcomes, QoL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03997643 . Date of registration: June 25, 2019, Current version: 2.0 on July 11 2020.