An evaluation of MR based deep learning auto-contouring for planning head and neck radiotherapy.

INTRODUCTION: Auto contouring models help consistently define volumes and reduce clinical workload. This study aimed to evaluate the cross acquisition of a Magnetic Resonance (MR) deep learning auto contouring model for organ at risk (OAR) delineation in head and neck radiotherapy. METHODS: Two auto contouring models were evaluated using deep learning contouring expert (DLCExpert) for OAR delineation: a CT model (modelCT) and an MR model (modelMRI). Models were trained to generate auto contours for the bilateral parotid glands and submandibular glands. Auto-contours for modelMRI were trained on diagnostic images and tested on 10 diagnostic, 10 MR radiotherapy planning (RTP), eight MR-Linac (MRL) scans and, by modelCT, on 10 CT planning scans. Goodness of fit scores, dice similarity coefficient (DSC) and distance to agreement (DTA) were calculated for comparison. RESULTS: ModelMRI contours improved the mean DSC and DTA compared with manual contours for the bilateral parotid glands and submandibular glands on the diagnostic and RTP MRs compared with the MRL sequence. There were statistically significant differences seen for modelMRI compared to modelCT for the left parotid (mean DTA 2.3 v 2.8 mm), right parotid (mean DTA 1.9 v 2.7 mm), left submandibular gland (mean DTA 2.2 v 2.4 mm) and right submandibular gland (mean DTA 1.6 v 3.2 mm). CONCLUSION: A deep learning MR auto-contouring model shows promise for OAR auto-contouring with statistically improved performance vs a CT based model. Performance is affected by the method of MR acquisition and further work is needed to improve its use with MRL images.

A Multicentre UK Study of Outcomes of Nasopharyngeal Carcinoma Treated With Intensity-Modulated Radiotherapy ± Chemotherapy.

AIMS: To report the outcomes of nasopharyngeal carcinoma in adults across three large centres in a non-endemic region in the era of intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Adult patients with nasopharyngeal carcinoma treated in three large cancer centres with IMRT ± chemotherapy with curative intent between 2009 and 2016 were identified from institutional databases. Radiotherapy was delivered with 70 Gy in 33-35 daily fractions. A univariable analysis was carried out to evaluate the relationship of patient, tumour and treatment factors with progression-free survival (PFS) and overall survival. RESULTS: In total, 151 patients were identified with a median follow-up of 5.2 years. The median age was 52 years (range 18-85). Seventy-five per cent were of Caucasian origin; 75% had non-keratinising tumours; Epstein Barr virus status was only available in 23% of patients; 74% of patients had stage III or IV disease; 54% of patients received induction chemotherapy; 86% of patients received concurrent chemotherapy. Five-year overall survival, PFS, local disease-free survival, regional disease-free survival and distant disease-free survival were 70%, 65%, 91%, 94% and 82%, respectively. Keratinising squamous cell carcinoma, older age, worse performance status, smoking and alcohol intake were associated with inferior overall survival and PFS. CONCLUSIONS: Local, regional and distant disease control are relatively high following IMRT ± chemotherapy in a non-endemic population. There was considerable heterogeneity in terms of radiotherapy treatment and the use of chemotherapy, encouraging the development of treatment protocols and expert peer review in non-endemic regions.

Analysis of a National Programme for Selective Internal Radiation Therapy for Colorectal Cancer Liver Metastases.

AIMS: Patients with chemotherapy-refractory colorectal cancer liver metastases have limited therapeutic options. Selective internal radiation therapy (SIRT) delivers yttrium 90 microspheres as a minimally invasive procedure. This prospective, single-arm, observational, service-evaluation study was part of National Health Service England Commissioning through Evaluation. METHODS: Patients eligible for treatment had histologically confirmed carcinoma with liver-only/liver-dominant metastases with clinical progression during or following oxaliplatin-based and irinotecan-based chemotherapy. All patients received SIRT plus standard of care. The primary outcome was overall survival; secondary outcomes included safety, progression-free survival (PFS) and liver-specific PFS (LPFS). RESULTS: Between December 2013 and March 2017, 399 patients were treated in 10 centres with a median follow-up of 14.3 months (95% confidence interval 9.2-19.4). The median overall survival was 7.6 months (95% confidence interval 6.9-8.3). The median PFS and LPFS were 3.0 months (95% confidence interval 2.8-3.1) and 3.7 months (95% confidence interval 3.2-4.3), respectively. During the follow-up period, 143 patients experienced an adverse event and 8% of the events were grade 3. CONCLUSION: Survival estimates from this pragmatic study show clinical outcomes attainable in the National Health Service comparable with previously published data. This study shows the value of a registry-based commissioning model to aid national commissioning decisions for highly specialist cancer treatments.

Randomised feasibility study to compare the use of Therabite® with wooden spatulas to relieve and prevent trismus in patients with cancer of the head and neck.

Our aim was to compare the efficacy of the Therabite® jaw motion rehabilitation system (Atos Medical) with that of wooden spatulas to relieve and prevent trismus in patients who have had radiotherapy for stage three and four oral and oropharyngeal cancer. Secondary aims were to assess the feasibility and the impact of exercise on health-related quality of life (QoL), and the use of health services after treatment. We designed a randomised, open-label, controlled, three-centre feasibility study to compare the effectiveness and cost of the Therabite® and wooden spatulas. We studied compliance with exercises and health-related QoL, assessed cost using three health economics measures, and conducted semistructured interviews with patients. Patients were randomised into two groups: the Therabite® group (n=37) and the wooden spatula group (n=34). All patients had some sense of jaw tightening before the study started. Mean mouth opening after six months increased in both groups, but the difference between the groups was not significant (p=0.39). Completion rates for the three economic measures were good. There was no significant difference between the two groups in frequency of contact with care services or in QoL. Exercises during and after radiotherapy can ameliorate trismus in patients with stage three and four oral and oropharygeal cancers, but differences between groups in efficacy, compliance, QoL, or use of hospital or community health services, were not significant.

Ninety Day Mortality After Radical Radiotherapy for Head and Neck Cancer.

AIMS: Treatment for head and neck cancers using definitive radiotherapy, with or without chemotherapy, is associated with significant acute toxicity. Our aim was to assess 90 day mortality after radical radiotherapy. A further aim was to identify patient, tumour or treatment factors associated with early death after treatment and whether these could be used to predict outcomes. MATERIALS AND METHODS: In total, 1116 patients with squamous cell pharyngeal and larynx cancer between January 2011 and December 2015 were included. Patients with T1 larynx cancer were excluded. Patients were treated using radical radiotherapy, with or without chemotherapy. Ninety day mortality was calculated using survival of less than 135 days from the planned start date for radical radiotherapy, to include early deaths during and up to 90 days after treatment. RESULTS: Overall, 90 day mortality was 4.7%. Among the subgroup of patients treated with concurrent platinum chemotherapy, the 90 day mortality rate was 0.4%. Overall survival at 1, 3 and 5 years was 84%, 62% and 53%, respectively. Factors associated with a higher risk of early death included performance status > 1, haemoglobin <100 g/l, weight < 60 kg, age > 80 years and presence of multiple comorbidities. CONCLUSION: We report excellent crude overall survival rates among our radically treated cohort of head and neck cancer patients. Several factors were associated with an increased risk of death within 90 days of completion of radical head and neck radiotherapy. Given the potential severe acute effects and the impact on patient quality of life associated with radical head and neck radiotherapy, this information is helpful to inform treatment-related discussions with patients.

Management of lateral skull base cancer: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition. Recommendations • All patients with more than one of: chronic otalgia, bloody otorrhoea, bleeding, mass, facial swelling or palsy should be biopsied. (R) • Magnetic resonance and computed tomography imaging should be performed. (R) • Patients should undergo audiological assessment. (R) • Carotid angiography is recommended in select patients. (G) • The modified Pittsburg T-staging system is recommended. (G) • The minimum operation for cancer involving the temporal bone is a lateral temporal bone resection. (R) • Facial nerve rehabilitation should be initiated at primary surgery. (G) • Anterolateral thigh free flap is the workhorse flap for lateral skull base defect reconstruction. (G) • For patients undergoing surgery for squamous cell carcinoma, at least a superficial parotidectomy and selective neck dissection should be carried out. (R).

Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma.

BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those with HPV-negative tumours. There is interest in de-escalating their treatment but strategies are needed for risk stratification to identify subsets with a poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) in relation to HPV tumour status and patient survival. METHODS: Biopsies from 218 patients diagnosed with OPSCC between 2002 and 2011, who underwent chemo/radiotherapy were analysed for HPV by PCR, in-situ hybridisation and p16 immunohistochemistry (IHC). One hundred and thirty-nine samples with concordant HPV detection were analysed for CD3, CD4, CD8 and FoxP3 expression in tumour and stromal regions using multiplexIHC and multispectral image analysis. Labelling of smooth muscle actin (SMA) identified activated stroma. RESULTS: Human papillomavirus-positive compared with HPV-negative OPSCC had higher infiltration in both tumour and stromal areas of CD4 and CD8 T cells but not FoxP3 T regulatory cells. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). There was significantly higher SMA expression in HPV-positive compared with -negative tumours, which did not correlate with survival. CONCLUSIONS: Studies of TILs for risk stratification in OPSCC should assess stromal infiltration.

Radiotherapy treatment of non-melanoma skin cancer: a survey of current UK practice and commentary.

OBJECTIVE: In the ongoing absence of available trial data, a national survey was carried out to provide details on radiotherapy treatment strategy for non-melanoma skin cancer (NMSC). METHODS: A survey of clinical oncologists treating NMSC was performed. The respondents were asked for basic information on workload as well as a proposed treatment strategy for various clinical scenarios for patients of varying fitness. RESULTS: A total of 43 completed and 20 partially completed surveys were received. There was a wide variation in the workload and additional disease sites that respondents had responsibility for. Kilovoltage radiotherapy was available to 81% of responders. The respondents' approach was affected by the fitness of patients, with longer fractionation regimes proposed for younger, fitter patients and shorter or non-standard fractionations more likely for the infirm elderly. Four daily fractionation regimes (18-20 Gy in 1 fraction, 35 Gy in 5 fractions, 45 Gy in 10 fractions and 55 Gy in 20 fractions) were most commonly suggested. There was a large degree of variation in non-standard fractions proposed with significant potential differences in radiobiological effect. Concern over the use of kilovoltage photons on skin over cartilage was apparent, as was a reluctance to use radiotherapy in areas of increased risk of poor wound healing. CONCLUSION: The survey results largely showed practice to be in line with available published evidence. The variation seen in some areas, such as non-standard fractionation, would benefit from the publication of local outcomes to achieve a more consistent approach. ADVANCES IN KNOWLEDGE: This study provides information on national practices and identifies variations, particularly within widespread use of non-standard fractionation.

Carotid dosimetry for T1 glottic cancer radiotherapy.

OBJECTIVE: Radiotherapy for T1 glottic cancer is commonly delivered using a lateral parallel opposed pair of megavoltage photon fields. There is increasing reported evidence of cerebrovascular events due to radiation-induced carotid stenosis. An alternative field arrangement is to use an anterior oblique technique. This study compares the carotid dosimetry between the two techniques and reviews the evidence for the risk of radiation-induced vascular events. METHODS: The radiotherapy plans of 10 patients with T1 glottic cancer treated with an anterior oblique technique were examined for carotid dose. Alternative plans were then created using a parallel opposed pair of fields and the dose to the carotids compared. All patients received 50 Gy in 16 fractions treating once daily, for 5 days in a week. RESULTS: The average of the mean dose to the carotids with the anterior oblique technique was 21 Gy compared with 37 Gy using the lateral parallel opposed pair arrangement (p < 0.0001). CONCLUSION: An anterior oblique field arrangement for the treatment of T1 glottic cancer results in a significantly lower radiation dose to the carotid arteries, which may be clinically important in terms of reducing the risk of cerebrovascular events in long-term survivors. ADVANCES IN KNOWLEDGE: Although the anterior oblique technique for treating early glottic cancers is well described, and it is predictable that the dose received by the carotid arteries should be lower with this technique, to our knowledge this is the first study to quantify that reduction in dose with a series of patients.

The prognostic significance of the biomarker p16 in oropharyngeal squamous cell carcinoma.

AIMS: There is an increasing incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell cancers (OPSCC) mostly associated with favourable outcomes. p16 immunohistochemistry is a surrogate marker for HPV positivity in OPSCC. The prognostic strength of p16 over traditional prognostic factors is not fully characterised. In this study, we evaluated the clinical and demographic differences between p16-positive and -negative OPSCC and characterised its prognostic strength versus traditional prognostic factors. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded blocks and clinical information from 217 OPSCC patients, treated with radiotherapy (alone or in combination with other therapies) between 2000 and 2010 were collected retrospectively. Immunohistochemistry for p16 protein was carried out; cancer-specific survival (CSS), recurrence-free survival (RFS) and locoregional control (LRC) were calculated for both univariate and multivariate analyses. RESULTS: Ninety-two per cent of the OPSCC originated from tonsil and tongue base sites, 61% were p16 positive. Patients with p16-positive OPSCC were younger (P < 0.0001), with lower alcohol (P = 0.0002) and tobacco (P = 0.0001) exposure. The tumours were less differentiated (P = 0.0069), had a lower T stage (P = 0.0027), higher nodal status (P = 0.014) and higher American Joint Committee on Cancer (AJCC) prognostic group (P = 0.0036). AJCC prognostic group was significant for RFS (P = 0.0096) and CSS (P = 0.018) in patients with p16-negative OPSCC, but not those with p16-positive tumours (P = 0.30 and 0.54). Other significant factors for CSS and RFS in univariate analysis were: pretreatment haemoglobin (P < 0.0001 and <0.0001), chemoradiotherapy (P = 0.005 and 0.03) and P16 status (P < 0.0001 and 0.0001). In multivariate analysis, p16 positivity was the strongest independent prognostic variable for both CSS, RFS and LRC (P < 0.0001, hazard ratio 4.15; 95% confidence interval 2.43-7.08), (P < 0.0001, hazard ratio 6.15; 95% confidence interval 3.57-10.61) and (P = 0.001, hazard ratio 3.74; confidence interval 1.76-7.95). CONCLUSION: This study shows that p16 is the single most important prognostic variable in OPSCC, surpassing traditional prognostic factors for both CSS and RFS. Furthermore, disease stage has no prognostic significance in p16-positive patients, highlighting the need for routine p16 assessment in OPSCC.

Cisplatin plus capecitabine as first-line chemotherapy for recurrent or metastatic head and neck squamous cell cancer: experience outside of a trial setting.

PURPOSE: Cisplatin/5-fluorouracil (5-FU) is an accepted palliative chemotherapy treatment for head and neck squamous cell carcinoma, improving quality of life but not overall survival. Capecitabine in place of 5-FU removes the morbidity of an infusional regime with potential benefit in patient well-being. This study looks at outcomes for cisplatin plus capecitabine (PX) outside of a trial setting. METHODS: Consecutive patients receiving this treatment in a single centre were retrospectively analysed. Cisplatin (mean dose 75 mg/m²) was given on day 1 of a 3-week cycle and capecitabine (mean dose 808 mg/m² twice daily) on days 1-14, for up to 6 cycles. RESULTS: Sixty-five patients (median age 58.6 years) received a median of 4 cycles of chemotherapy. The overall response rate was 30.7%, with a median overall survival of 7.3 months. Treatment was well tolerated with a 10.7% grade 3 and a 1.5% grade 4 neutropenia rate, with no other grade 4 toxicities. One patient died of neutropenic sepsis whilst on treatment. Twenty-seven percent of patients stopped treatment early due to chemotherapy-related side effects. CONCLUSION: PX is well tolerated outside the trial setting with outcomes similar to historical published literature. Ease of administration and benefit to patient convenience make it an attractive alternative to standard palliative treatment.

Value of the Hospital Anxiety and Depression Scale in the follow up of head and neck cancer patients.

BACKGROUND: Few studies have prospectively investigated psychological morbidity in UK head and neck cancer patients. This study aimed to explore changes in psychological symptoms over time, and associations with patients' tumour and treatment characteristics, including toxicity. METHODS: Two hundred and twenty patients were recruited to complete the Hospital Anxiety and Depression Scale and the Late Effects on Normal Tissue (Subjective, Objective, Management and Analytic) ('LENT-SOMA') questionnaires, both pre- and post-treatment. RESULTS: Anxiety was highest pre-treatment (38 per cent) and depressive symptoms peaked at the end of treatment (44 per cent). Anxiety significantly decreased and depression significantly increased, comparing pre- versus post-treatment responses (p < 0.001). Hospital Anxiety and Depression Scale scores were significantly correlated with toxicity, age and chemotherapy (p < 0.01 for all). CONCLUSION: This is the first study to analyse the relationship between Hospital Anxiety and Depression Scale scores and toxicity scores in head and neck cancer patients. It lends support for the use of the Hospital Anxiety and Depression Scale and the Late Effects on Normal Tissue (Subjective, Objective, Management and Analytic) questionnaire in routine clinical practice; furthermore, continued surveillance is required at multiple measurement points.

Nasopharyngeal carcinoma: a retrospective review of demographics, treatment and patient outcome in a single centre.

AIMS: Nasopharyngeal cancer (NPC) is relatively uncommon, especially in the Western world. We report our single institution experience of 20 years of data in 128 patients with NPC, including responses to different treatment modalities and outcomes by histological subtype. MATERIALS AND METHODS: NPC patients presenting from 1992 to 2005 were located on the cancer registry database. Demographic data included age, gender, length of presenting symptoms and stage. World Health Organization classification (2005) was used for histological subtyping. The date of recurrence and survival outcomes were analysed using Kaplan-Meier curves. RESULTS: Presentation data were analysed from 128 patients; the survival analysis included 123 patients. The median age at presentation was 57.7 years. Stage III and IV presentation rates were 34 and 38%, respectively. The most common presenting symptom was a palpable neck lump (55%) and the median duration of symptoms was 16 weeks. Forty-eight patients received radiotherapy alone and 75 received chemoradiotherapy. The median overall survival in chemoradiotherapy patients was 80.3 months versus 28.5 months with radiotherapy alone (P = 0.003). A significant difference was also seen with recurrence-free survival (RFS) (P = 0.017). Type 1 keratinising carcinoma had a significantly worse overall survival (P = 0.04) and a similar but non-statistically significant trend was seen for RFS (P = 0.051). The multivariate analysis for overall survival showed that histological subtype (hazard ratio 2.7, 95% confidence interval 1.3-5.5, P = 0.034), age (hazard ratio 2.3, 95% confidence interval 1.1-4.9, P = 0.018) and N stage (hazard ratio 3.7, 95% confidence interval 1.4-9.4, P = 0.024) were prognostic factors. CONCLUSIONS: We present the first large-scale, single-centre retrospective review of NPC in a UK-based population. Demographic data were similar to that in other Western populations, with a significantly worse survival outcome in the keratinising group. Further prospective study of outcome in Western populations accounting for newer radiotherapy techniques such as intensity-modulated radiotherapy and dose escalation, particularly in the keratinising population who were more likely to present with an isolated local recurrence, is recommended.

Lack of prognostic effect of carbonic anhydrase-9, hypoxia inducible factor-1α and bcl-2 in 286 patients with early squamous cell carcinoma of the glottic larynx treated with radiotherapy.

AIMS: To evaluate the prognostic significance of potential tumour markers of hypoxia and apoptosis in early squamous cell carcinoma of the glottic larynx managed with radiotherapy. MATERIALS AND METHODS: In total, 382 patients with T1 and T2 squamous cell carcinoma of the glottic larynx (vocal cords) received radical radiotherapy (50-55 Gy, in 16 fractions in 98% of cases). Pre-treatment haemoglobin was available for 328 patients; biopsy samples were available for 286. Immunohistochemistry was carried out for carbonic anhydrase-9 (CA-9), hypoxia inducible factor-1α (HIF-1α) and Bcl-2. RESULTS: At 5 years, locoregional control was achieved in 88.2%, cancer-specific survival in 95.0% and overall survival in 78.7%. Adverse prognostic factors for locoregional tumour recurrence were pre-treatment haemoglobin <13.0 g/dl (P = 0.035, Log rank test; sensitivity 0.28, specificity 0.84) and stage T2 rather than T1 (P = 0.002). The effect of haemoglobin level on locoregional control was not significant when stratified by the median of 14.2 g/dl (P = 0.43) or as a continuous variable (P = 0.59). High CA-9 (P = 0.11), HIF-1α (P = 0.67) and Bcl-2 (P = 0.77) expression had no prognostic significance. CONCLUSIONS: High CA-9, HIF-1α and Bcl-2 do not add to the prognostic significance of tumour stage and lower haemoglobin in predicting failure of local control in early glottic larynx squamous cell carcinoma managed with radiotherapy. The effect of haemoglobin was not strong enough to be useful as a prognostic biomarker.

Prediction of post-treatment trismus in head and neck cancer patients.

Our aim was to establish the incidence of trismus over time, together with risk factors (including quality of life (QoL)) for the prediction of trismus after treatment in patients with cancer of the head and neck. It was a longitudinal study of 152 patients accepted for primary operation who attended the head and neck cancer clinic of a tertiary referral cancer centre in the United Kingdom. A total of 87 patients was studied prospectively. Our results showed that 41/87 (47%) of patients presented with trismus, 57/80 (71%) had postoperative trismus, and 41/52 (79%) had trismus 6 months after operation or radiotherapy (trismus defined as a maximum mouth opening of ≤ 35 mm). Men and those who drank a lot of alcohol were less likely to have trismus after treatment. QoL variables showed that pain, eating, chewing, taste, saliva, social functioning, social contact, and dry mouth were significantly more impaired in the trismus group than among those without trismus. Postoperative differences in QoL between the two groups highlighted problems with social function and role-playing, fatigue, activity, recreation, and overall reduction in QoL. Women, and those who do not drink alcohol, are at particularly high risk of developing trismus, and, to prevent it and treat it, patients may benefit from multidisciplinary management at an early stage during treatment.