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Background: Patients with advanced oesophageal cancer have a median survival of 3–6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion. Methods: This was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I–III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed. Findings: 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40–1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4–27·7) with usual care and 18·9 weeks (14·7–25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78–1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3–not reached) with usual care versus 65·9 weeks (52·7–not reached) with EBRT (adjusted subhazard ratio 0·52 [95% CI 0·28–0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3–4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care. Interpretation: Patients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions. Funding: National Institute for Health Research Health Technology Assessment Programme.

Aim This is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pCR) rate favouring CarPacRT. Herein, we report survival, progression patterns, and long-term toxicity after a median follow-up of 40.7 months. Methods NeoSCOPE was an open-label, UK multicentre, randomised, phase II trial. Eighty-five patients with resectable OAC or GOJ adenocarcinoma, ≥cT3 and/or ≥cN1 (TNM v7), suitable for neoadjuvant CRT, were recruited between October 2013 and February 2015. Patients were randomised to OxCapRT (oxaliplatin 85 mg/m2 on Days 1, 15, and 29; capecitabine 625 mg/m2 orally twice daily on days of radiotherapy [RT]) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 on Days 1, 8, 15, 22, and 29). RT dose was 45 Gy/25 fractions/5 weeks. Both arms received induction chemotherapy (two cycles oxaliplatin 130 mg/m2 on Day 1, capecitabine 625 mg/m2 orally twice daily on Days 1–21) before CRT. Surgery was performed 6–8 weeks after CRT. The primary end-point was pCR. Secondary end-points were toxicity, progression-free survival (PFS), overall survival (OS), and patterns of progression. Results Eighty-five patients were recruited from 17 UK centres. The median OS was 41.7 months (95% confidence interval [CI] 19.6 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable hazard ratio [HR] = 0.48, 95% CIs: 0.24–0.95, P = 0.035). The median PFS was 32.6 months (95% CIs: 17.1 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable HR = 0.54, 95% CIs: 0.29–1.01, P = 0.053). In both arms, the distant progression was twice as common as locoregional progression. Conclusions OS and PFS favoured neoadjuvant CarPacRT over OxCapRT. Distant was more common than locoregional progression; therefore, priority should be given to optimising the systemic treatment component. Clinical trial information EudraCT Number: 2012-000640-10; ClinicalTrials.gov: NCT01843829., Highlights • Randomised study of neoadjuvant chemoradiotherapy for oesophageal adenocarcinoma. • The median overall survival was significantly better with CarPacRT. • Across both arms, the distant was more common than locoregional progression.

Background The Phase 2 SCALOP trial compared gemcitabine with capecitabine-based consolidation chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). Methods Thirty-five systematically identified circulating biomarkers were analysed in plasma samples from 60 patients enroled in SCALOP. Each was measured in triplicate at baseline (prior to three cycles of gemcitabine-capecitabine induction chemotherapy) and, for a subset, prior to CRT. Association with overall survival (OS) was determined using univariable Cox regression and optimal thresholds delineating low to high values identified using time-dependent ROC curves. Independence from known prognostic factors was assessed using Spearman correlation and the Wilcoxon rank sum test prior to multivariable Cox regression modelling including independent biomarkers and known prognostic factors. Results Baseline circulating levels of C-C motif chemokine ligand 5 (CCL5) were significantly associated with OS, independent of other clinicopathological characteristics. Patients with low circulating CCL5 (CCL5low) had a median OS of 18.5 (95% CI 11.76–21.32) months compared to 11.3 (95% CI 9.86–15.51) months in CCL5high; hazard ratio 1.95 (95% CI 1.04–8.65; p = 0.037). Conclusions CCL5 is an independent prognostic biomarker in LAPC. Given the known role of CCL5 in tumour invasion, metastasis and the induction of an immunosuppressive micro-environment, targeting of CCL5-mediated pathways may offer therapeutic potential in pancreatic cancer. Clinical trial registration The SCALOP trial was registered with ISRCTN, number 96169987 (registered 29 May 2008).

BACKGROUND: Medullary thyroid cancer (MTC) is a neuroendocrine tumour and a rare variant of thyroid cancer with different aetiology, presentation and treatment to differentiated thyroid cancer. Currently available thyroid cancer-specific quality of life (QoL) tools focus on issues and treatments more relevant to patients with differentiated thyroid cancer and therefore may not address issues specific to a MTC diagnosis and cancer journey. METHOD: This prospective multicentre randomised study involved 204 MTC patients completing four quality of life questionnaires (QOLQ) and stating their most and least preferred. The questionnaires were a general instrument, the EORTC QLQ-C30, two disease-specific tools, the MD Anderson Symptom Inventory (MDASI) thyroid module and the City of Hope Quality of Life Scale/THYROID (amended) and the neuroendocrine questionnaire, EORTC QLQ-GINET21. Patients were randomised to complete the four questionnaires in one of 24 possible orders and then answered questions about which tool they preferred. The primary outcome measure was patients' preferred QoL instrument for describing their concerns and for facilitating communication with their healthcare professional. Secondary analyses looked at differences between preferred QOLQs amongst patient subgroups (WHO performance status [0 and 1+], disease stage: early [T1–3, N0 or N1A], metastatic [T4, any T N1b] and advanced [any T any N M1], and type of MTC [sporadic and inherited]), identification of MTC patients' least preferred questionnaire and clinicians' views on the QoL tools in terms of their ability to highlight problems not otherwise ascertained by a standard clinical review. RESULTS: No evidence of a difference was observed for most preferred QOLQ (p = 0.650). There was however evidence of a difference in least preferred questionnaire in the cohort of 128 patients who stated their least preferred questionnaire (p = 0.042), with 36% (46/128) of patients choosing the EORTC QLQ-GI.NET21 questionnaire. Subgroup analyses showed that there was no evidence of a difference in patients' most preferred questionnaire in sporadic MTC patients (p = 0.637), patients with WHO PS 0 or 1+ (p = 0.844 and p = 0.423) nor when comparing patients with early, advanced local or metastatic disease (p = 0.132, p = 0.463 and p = 0.506, respectively). Similarly, subgroup analyses on patients' least preferred questionnaires showed no evidence of differences in sporadic MTC patients (p = 0.092), patients with WHO PS 0 or 1+ (p = 0.423 and p = 0.276), nor in early or metastatic disease patients (p = 0.682 and p = 0.345, respectively). There was however some evidence to suggest a difference in least preferred questionnaire in patients with advanced local stage disease (p = 0.059), with 43% (16/37) of these patients choosing the EORTC QLQ-GI.NET21 questionnaire. CONCLUSIONS: MTC patients regardless of their performance status, disease aetiology and disease burden did not express a preference for any one particular questionnaire suggesting any of the tools studied could be utilized in this patient cohort. The least preferred questionnaire being a gastrointestinal NET specific tool suggests that diarrhoea was not a significant symptom and concern for the population studied.

Aims Although cisplatin–fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin–paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin–paclitaxel-based dCRT. Materials and methods In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0–2; stage I–III disease) and had been selected to receive weekly carboplatin–paclitaxel-based dCRT as they were considered not suitable for cisplatin–fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. Results In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin–paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin–fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07–30.09) and the median PFS was 16.33 months (95% confidence interval 14.29–20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6–86.8%) and 50.6% (95% confidence interval 40.5–60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin–paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). Conclusion Weekly carboplatin–paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin–fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin–fluoropyrimidine-based dCRT.

Background Most patients with oesophageal cancer present with incurable disease. For those with advanced disease, the mean survival is 3–5 months. Treatment emphasis is therefore on effective palliation, with the majority of patients requiring intervention for dysphagia. Insertion of a self-expanding metal stent provides rapid relief but dysphagia may recur within 3 months owing to tumour progression. Evidence reviews have called for trials of interventions combined with stenting to better maintain the ability to swallow. Objectives The Radiotherapy after Oesophageal Cancer Stenting (ROCS) study examined the effectiveness of palliative radiotherapy, combined with insertion of a stent, in maintaining the ability to swallow. The trial also examined the impact that the ability to swallow had on quality of life, bleeding events, survival and cost-effectiveness. Design A pragmatic, multicentre, randomised controlled trial with follow-up every 4 weeks for 12 months. An embedded qualitative study examined trial experiences in a participant subgroup. Setting Participants were recruited in secondary care, with all planned follow-up at home. Participants Patients who were referred for stent insertion as the primary management of dysphagia related to incurable oesophageal cancer. Interventions Following stent insertion, the external beam radiotherapy arm received palliative oesophageal radiotherapy at a dose of 20 Gy in five fractions or 30 Gy in 10 fractions. Main outcome measures The primary outcome was the difference in the proportion of participants with recurrent dysphagia, or death, at 12 weeks. Recurrent dysphagia was defined as deterioration of ≥ 11 points on the dysphagia scale of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire oesophago-gastric module questionnaire. Secondary outcomes included quality of life, bleeding risk and survival. Results The study recruited 220 patients: 112 were randomised to the usual-care arm and 108 were randomised to the external beam radiotherapy arm. There was no evidence that radiotherapy reduced recurrence of dysphagia at 12 weeks (48.6% in the usual-care arm compared with 45.3% in the external beam radiotherapy arm; adjusted odds ratio 0.82, 95% confidence interval 0.40 to 1.68; p = 0.587) and it was less cost-effective than stent insertion alone. There was no difference in median survival or key quality-of-life outcomes. There were fewer bleeding events in the external beam radiotherapy arm. Exploration of patient experience prompted changes to trial processes. Participants in both trial arms experienced difficulty in managing the physical and psychosocial aspects of eating restriction and uncertainties of living with advanced oesophageal cancer. Limitations Change in timing of the primary outcome to 12 weeks may affect the ability to detect a true intervention effect. However, consistency of results across sensitivity analyses is robust, including secondary analysis of dysphagia deterioration-free survival. Conclusions Widely accessible palliative external beam radiotherapy in combination with stent insertion does not reduce the risk of dysphagia recurrence at 12 weeks, does not have an impact on survival and is less cost-effective than inserting a stent alone. Reductions in bleeding events should be considered in the context of patient-described trade-offs of fatigue and burdens of attending hospital. Trial design elements including at-home data capture, regular multicentre nurse meetings and qualitative enquiry improved recruitment/data capture, and should be considered for future studies. Future work Further studies are required to identify interventions that improve stent efficacy and to address the multidimensional challenges of eating and nutrition in this patient population. Trial registration Current Controlled Trials ISRCTN12376468 and Clinicaltrials.gov NCT01915693. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 31. See the NIHR Journals Library website for further project information.

Purpose: Response rates to treatment of vulval intraepithelial neoplasia (VIN) with imiquimod and cidofovir are approximately 57% and 61%, respectively. Treatment is associated with significant side effects and, if ineffective, risk of malignant progression. Treatment response is not predicted by clinical factors. Identification of a biomarker that could predict response is an attractive prospect. This work investigated HPV DNA methylation as a potential predictive biomarker in this setting.Experimental Design: DNA from 167 cases of VIN 3 from the RT3 VIN clinical trial was assessed. HPV-positive cases were identified using Greiner PapilloCheck and HPV 16 type-specific PCR. HPV DNA methylation status was assessed in three viral regions: E2, L1/L2, and the promoter, using pyrosequencing.Results: Methylation of the HPV E2 region was associated with response to treatment. For cidofovir (n = 30), median E2 methylation was significantly higher in patients who responded (P ≤ 0.0001); E2 methylation >4% predicted response with 88.2% sensitivity and 84.6% specificity. For imiquimod (n = 33), median E2 methylation was lower in patients who responded to treatment (P = 0.03; not significant after Bonferroni correction); E2 methylation Conclusions: These data indicate that cidofovir and imiquimod may be effective in two biologically defined groups. HPV E2 DNA methylation demonstrated potential as a predictive biomarker for the treatment of VIN with cidofovir and may warrant investigation in a biomarker-guided clinical trial. Clin Cancer Res; 23(18); 5460–8. ©2017 AACR.

PATHOS is a phase II/III randomized controlled trial (RCT) of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery (TOS) for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). The study opened in the UK in October 2015 and, after successful recruitment into the phase II, transitioned into phase III in the autumn of 2018. PATHOS aims to establish whether the de-intensification of adjuvant treatment in patients with favorable prognosis HPV-positive OPSCC will confer improved swallowing outcomes, whilst maintaining high rates of cure. In this article, we will outline the rationale for the study and how it aims to answer fundamentally important questions about the safety, effectiveness and functional outcomes of minimally invasive TOS techniques followed by adjuvant radiotherapy (RT) or chemo-radiotherapy (CRT) in this patient population.

The aim of this work was to investigate radiomic analysis of contrast and non-contrast enhanced planning CT images of oesophageal cancer (OC) patients in terms of stability, dimensionality and contrast agent dependency. The prognostic significance of CT-based radiomic features was also evaluated. Different 2D and 3D radiomic features were extracted from contrast and non-contrast enhanced CT images of 213 patients from the multi-centre SCOPE1 randomised controlled trial (RCT) in OC. Feature stability was evaluated by randomly dividing patients into three groups and identifying textures with similar distributions among groups with a Kruskal-Wallis analysis. A paired two-sided Wilcoxon signed rank test was used to assess for significant differences in the remaining corresponding 2D and 3D stable features. A prognostic model was constructed using clinical characteristics and remaining filtered features. The discriminative ability of significant variables was tested using Kaplan-Meier analysis. A total of 238 2D and 3D radiomic features were computed from oesophageal CT images. More than 75 features were stable if extracted from homogeneous cohort (contrast or non-contrast enhanced CT images) and inhomogeneous cohort (contrast and non-contrast enhanced CT images). Among the remaining corresponding stable features computed from both cohorts, only 4 features did not show a statistically significant difference if obtained in 2D or in 3D (p-value < 0.05). A Cox regression model constructed using 5 clinical variables (age, sex, tumour, node and metastasis (TNM) stage, WHO performance status and contrast administration) and 4 radiomic variables (inverse varianceGLCM, large distance emphasisGLDZM, zone distance non uniformity normGLDZM, zone distance varianceGLDZM), identified one radiomic feature (zone distance varianceGLDZM) that was significantly associated with overall survival (p-value = 0.032, HR = 1.25, 95% CI = 1.02–1.52). A significant difference in overall survival between groups was found when considering a threshold of zone distance varianceGLDZM equals to 1.70 (X2 = 7.692, df = 1, p-value = 0.006). Zone distance varianceGLDZM was identified as the only stable CT radiomic feature statistically correlated with overall survival, independent of dimensionality and contrast administration. This feature was able to identify high-risk patients and if validated, could be the subject of a future clinical trial aiming to improve clinical decision making and personalise OC treatment.

4569 Background: Most patients with oesophageal cancer (OC) present with incurable disease; 80% of new cases, and deaths, occur in low and middle income nations. Median survival for advanced disease is 3-5 months, a majority requiring intervention for dysphagia. Insertion of self expanding metal stents is the commonest way of palliating, but dysphagia may recur within three months owing to tumour progression. Evidence reviews have called for trials of combination treatment for OC dysphagia. The ROCS study (funding - UK NIHR programme) examined effectiveness of palliative radiotherapy, following stent, in maintaining swallow. It also examined impact on quality of life, bleeding events, and survival. Methods: A multicentre RCT with follow up monthly for a year. Patients referred for stent insertion as primary management of dysphagia related to incurable OC were recruited in secondary care, with all planned follow up at home. Patients were randomised 1:1 to stent insertion alone or stent insertion plus palliative radiotherapy at a dose of 20Gy in five fractions or 30Gy in ten fractions. Primary outcome was difference in proportions of participants with recurrent dysphagia at 12 weeks, defined as deterioration of 11 points or more in the dysphagia scale of the EORTC QLQ-OG25 questionnaire. Secondary outcomes included quality of life, bleeding risk, survival. Results: 220 patients were randomised Dec 2013-Aug 2018 at 23 UK sites. Addition of radiotherapy did not reduce the proportion of primary events at 12 weeks: 49% in control arm vs 45% in the intervention, adjusted OR 0.82 (95%CI 0.40-1.68; p = 0.587) and it was less cost effective. Sensitivity analyses did not alter the results. Dysphagia deterioration-free survival was similar in both arms: adjusted HR 0.92 (95%CI 0.68-1.26; p = 0.618). Median survival was 19.7 weeks in control arm and 18.9 weeks in the intervention. Those in the radiotherapy arm had significantly fewer bleeding events (18.6% compared to 10.3%), giving a number needed to treat of 12. Conclusions: Palliative external beam radiotherapy is widely accessible to patients with advanced cancer. ROCS is the largest trial assessing its role in combination with stenting for OC dysphagia, and is the first to prospectively assess impact on bleeding risk. It demonstrates no reduction in risk of dysphagia recurrence at 12 weeks, nor impact on survival. Reductions in bleeding events should be considered in the context of patient described trade offs of fatigue and burdens of attending hospital. Clinical trial information: NCT01915693 .

373 Background: Initial results of the NEOSCOPE trial comparing pre-operative CarPac vs OxCap based chemoradiotherapy (CRT) in patients with adenocarcinoma of the oesophagus or oesophagogastric junction showed comparable toxicity and improvement in pathological complete response (pCR) in favour of the CarPacRT. Here we report survival after a median follow-up of 40.7 months (95% CI: 45.1-53.6). Methods: NEOSCOPE was an open, randomised, ‘pick a winner’ phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m2 day 1, 15, 29; capecitabine 625 mg/m2 bd on days of RT) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 day 1, 8, 15, 22, 29). RT dose was 45 Gy/25 fractions/5 weeks. Induction OxCap (2 cycles) was given prior to CRT. Surgery was performed 6–8 weeks after CRT.The primary endpoint was pCR, secondary endpoints were toxicity, PFS and OS. Results: Between Oct 2013 and Feb 2015, 85 patients were recruited from 17 UK centres. Median OS was not reached in the CarPacRT group and was 41.72 months (95% CI 19.58-.)in the OxCap group (HR 0.56[95% CI 0.29-1.07]; p=0.079). 3-year and 5-year OS rates were 74% (95% CI 58%-85%) and 54% (95% CI 34%-71%) (CarPacRT), and 52% (95% CI 35%-67%) and 39% (95% CI 21%-56%) (OxCapRT). Median PFS (not reached vs 35.3 months, HR=0.61 [95% CI 0.33-1.12]; p=0.111) and metastatic PFS (not reached vs 39.0 months, HR=0.61 [95% CI 0.32-1.14], p=0.118) both favoured the CarPacRT arm. Local recurrence rate was low (OxCapRT= 10%; CarPacRT= 7%). The OS benefit for CarPacRT was consistent across subgroups but not statistically significant. Conclusions: In this longer term analysis there was some evidence that induction OxCap followed by switch to CarPacRT was superior to continuing OxCapRT, with efficacy similar to that seen in other published studies such as ‘CROSS’ and ‘FLOT’. Taken together with the previously published pCR results CarPacRT rather than OxCapRT warrants inclusion in future trials. Funding: Cancer Research UK (C44694/A14614). Clinical trial information: NCT01843829.

Background: The ELCID (Early Lung Cancer Investigation and Diagnosis) trial was a feasibility randomised controlled trial examining the effect on lung cancer diagnosis of lowering the threshold for referral for urgent chest x-ray for smokers and recent ex-smokers, aged over 60 years with new chest symptoms. The qualitative component aimed to explore the feasibility of individually randomising patients to an urgent chest x-ray or not and to investigate any barriers to patient recruitment and participation. We integrated this within the feasibility trial to inform the design of any future definitive trial, particularly in view of the lack of research exploring symptomatic patients’ experiences of participating in diagnostic trials for possible/suspected lung cancer. Although previous studies contributed valuable information concerning screening for lung cancer and patient participation in trials, this paper is the first to explore issues relating to this specific patient group.\ud \ud \ud \ud Methods: Qualitative interviews were conducted with 21 patients, comprising 9 who had been randomised to receive an immediate chest x-ray, 10 who were randomised to receive the standard treatment according to the National Institute for Health and Care Excellence guidelines, and 2 who chose not to participate in the trial. Interviews were analysed using a framework approach.\ud \ud \ud \ud Results: The findings of this analysis showed that altruism, personal benefit and the reassurance of not having lung cancer were important factors in patient participation. However, patients largely believed that being in the intervention arm was more beneficial, highlighting a lack of understanding of clinical equipoise. Disincentives to participation in the trial included the stigmatisation of patients who smoked (given the inclusion criteria). Although the majority of patients reported that they were happy with the trial design, there was evidence of poor understanding. Last, for several patients, placing trust in health professionals was preferred to understanding the trial processes.\ud \ud \ud \ud Conclusions: The integration of a qualitative study focusing on participant experience as a secondary outcome of a feasibility trial enabled exploration of patient response to participation and recruitment. The study demonstrated that although it is feasible to recruit patients to the ELCID trial, more work needs to be done to ensure an understanding of study principles and also of smoking stigmatisation.\ud \ud \ud \ud Trial registration: ClinicalTrials.gov, NCT01344005. Registered on 27 April 2011.

BACKGROUND: Achieving earlier stage diagnosis is one option for improving lung cancer outcomes in the United Kingdom. Patients with lung cancer typically present with symptoms to general practitioners several times before referral or investigation. METHODS: We undertook a mixed methods feasibility individually randomised controlled trial (the ELCID trial) to assess the feasibility and inform the design of a definitive, fully powered, UK-wide, Phase III trial of lowering the threshold for urgent investigation of suspected lung cancer. Patients over 60, with a smoking history, presenting with new chest symptoms to primary care, were eligible to be randomised to intervention (urgent chest X-ray) or usual care. RESULTS: The trial design and materials were acceptable to GPs and patients. We randomised 255 patients from 22 practices, although the proportion of eligible patients who participated was lower than expected. Survey responses (89%), and the fidelity of the intervention (82% patients X-rayed within 3 weeks) were good. There was slightly higher anxiety and depression in the control arm in participants aged >75. Three patients (1.2%) were diagnosed with lung cancer. CONCLUSIONS: We have demonstrated the feasibility of individually randomising patients at higher risk of lung cancer, to a trial offering urgent investigation or usual care.British Journal of Cancer advance online publication 10 January 2017; doi:10.1038/bjc.2016.414 www.bjcancer.com.

Aims\ud \ud \ud Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC).\ud \ud \ud \ud Materials and methods\ud \ud \ud Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose–volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression.\ud \ud \ud \ud Results\ud \ud \ud CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35–45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007–1.063) and grade (1.023, 1.003–1.044) of toxicity. The area under the curve was 0.632 (0.516–0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35–45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274–12.342) and weight loss during induction chemotherapy (1.216, 1.043–1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015–1.780). Duodenum dose–volume did not predict toxicity risk or severity in any cohort.\ud \ud \ud \ud Conclusions\ud \ud \ud In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35–45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.

BACKGROUND AND PURPOSE: To evaluate the variation in investigator-delineated volumes and assess plans from the radiotherapy trial quality assurance (RTTQA) program of SCALOP, a phase II trial in locally advanced pancreatic cancer. MATERIALS AND METHODS: Participating investigators (n=25) outlined a pre-trial benchmark case as per RT protocol, and the accuracy of investigators' GTV (iGTV) and PTV (iPTV) was evaluated, against the trials team-defined gold standard GTV (gsGTV) and PTV (gsPTV), using both qualitative and geometric analyses. The median Jaccard Conformity Index (JCI) and Geographical Miss Index (GMI) were calculated. Participating RT centers also submitted a radiotherapy plan for this benchmark case, which was centrally reviewed against protocol-defined constraints. RESULTS: Twenty-five investigator-defined contours were evaluated. The median JCI and GMI of iGTVs were 0.57 (IQR: 0.51-0.65) and 0.26 (IQR: 0.15-0.40). For iPTVs, these were 0.75 (IQR: 0.71-0.79) and 0.14 (IQR: 0.11-0.22) respectively. Qualitative analysis showed largest variation at the tumor edges and failure to recognize a peri-pancreatic lymph node. There were no major protocol deviations in RT planning, but three minor PTV coverage deviations were identified. . CONCLUSIONS: SCALOP demonstrated considerable variation in iGTV delineation. RTTQA workshops and real-time central review of delineations are needed in future trials.

PURPOSE: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. METHODS AND MATERIALS: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm(3). A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared. RESULTS: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P

To investigate delays in first and third dose diphtheria-tetanus-pertussis (DTP1 and DTP3) vaccination in low-birth-weight infants in Ghana, and the associated determinants.We used data from a large, population-based vitamin A trial in 2010-2013, with 22 955 enrolled infants. We measured vaccination rate and maternal and infant characteristics and compared three categories of low-birth-weight infants (2.0-2.4 kg; 1.5-1.9 kg; and 1.5 kg) with infants weighing ≥ 2.5 kg. Poisson regression was used to calculate vaccination rate ratios for DTP1 at 10, 14 and 18 weeks after birth, and for DTP3 at 18, 22 and 24 weeks (equivalent to 1, 2 and 3 months after the respective vaccination due dates of 6 and 14 weeks).Compared with non-low-birth-weight infants (n = 18 979), those with low birth weight (n = 3382) had an almost 40% lower DTP1 vaccination rate at age 10 weeks (adjusted rate ratio, aRR: 0.58; 95% confidence interval, CI: 0.43-0.77) and at age 18 weeks (aRR: 0.63; 95% CI: 0.50-0.80). Infants weighing 1.5-1.9 kg (n = 386) had vaccination rates approximately 25% lower than infants weighing ≥ 2.5 kg at these time points. Similar results were observed for DTP3. Lower maternal age, educational attainment and longer distance to the nearest health facility were associated with lower DTP1 and DTP3 vaccination rates.Low-birth-weight infants are a high-risk group for delayed vaccination in Ghana. Efforts to improve the vaccination of these infants are warranted, alongside further research to understand the reasons for the delays.Investigar los retrasos de la primera y tercera dosis de la vacuna contra la difteria, el tétanos y la tos ferina (DTP1 y DTP3) en recién nacidos con insuficiencia ponderal en Ghana, así como los determinantes relacionados con las mismas.En 2010–2013, se utilizaron datos de un ensayo poblacional de vitamina A a gran escala basado en la población con 22 955 recién nacidos inscritos. Se midió la tasa de vacunación y las características tanto de las madres como de los recién nacidos, y se compararon tres categorías de recién nacidos con insuficiencia ponderal (2,0–2,4 kg; 1,5–1,9 kg; y 1,5 kg) con recién nacidos con un peso de ≥ 2,5 kg. Se utilizaron modelos de regresión de Poisson para calcular los coeficientes de la tasa de vacunación para DTP1 las semanas 10, 14 y 18 después del nacimiento, y para DTP3 las semanas 18, 22 y 24 (lo que equivale a 1, 2 y 3 meses tras las fechas de vencimiento de las vacunaciones correspondiente de las semanas 6 y 14).En comparación con los recién nacidos sin insuficiencia ponderal (Los recién nacidos con insuficiencia ponderal se encuentran en un grupo de alto riesgo para sufrir un retraso de la vacunación en Ghana. Se han garantizado esfuerzos para mejorar la vacunación de estos recién nacidos, junto con una investigación más profunda para comprender las razones de dichos retrasos.استقصاء التأخر في تلقي الجرعة الأولى والثالثة من اللقاح ضد الدفتريا والتيتانوس والسعال الديكي (جرعة اللقاح الثلاثي DTP1 وDTP3) عند الأطفال الرضع منخفضي الوزن عند الولادة في غانا، والمحددات المرتبطة بذلك.استخدمنا البيانات المستمدة من تجربة فيتامين ألف التي تستند إلى قطاعات سكانية معينة والتي تم إجراؤها في الفترة من 2010 إلى 2013 على 22,955 رضيع تم تسجيله. أجرينا قياسًا لمعدل تلقي اللقاح والخصائص المتعلقة بالأمهات والأطفال الرضع، كما أجرينا مقارنة بين ثلاث شرائح من الأطفال الرضع منخفضي الوزن عند الولادة (2.0 – 2.4 كلغ؛ و1.5 – 1.9 كلغ؛ والأقل من 1.5 كلغ) من جانب والأطفال الرضع ممن يبلغ وزنهم 2.5 كلغ أو يزيد عن ذلك من جانب آخر. وتم استخدام نموذج التحوف لبواسون لاحتساب نسب معدل تلقي اللقاح بشأن جرعة اللقاح الثلاثي DTP1 عند بلوغ 10 و14 و18 أسبوعًا بعد الولادة، وبشأن جرعة اللقاح الثلاثي DTP3 عند بلوغ 18 و22 و24 أسبوعًا (بما يساوي 1 و2 و3 أشهر بعد مرور 6 و14 أسبوعًا بعد حلول تواريخ وجوب تلقي اللقاحات المذكورة على التوالي).كان معدل تلقي جرعة اللقاح الثلاثي DTP1 عند الأطفال الرضع منخفضي الوزن عند الولادة (العدد = 3382) أقل بنسبة تقرب من ‏40% مقارنةً بالأطفال الرضع ممن لا يعانون من انخفاض الوزن عند الولادة (العدد = 18,979)، وذلك في عمر 10 أسابيع (بنسبة المعدل المصححة، aRR: 0.58؛ ونسبة أرجحية مقدارها ‏95‏%: 0.43 – 0.77) وعند بلوغ 18 أسبوعًا (aRR: 0.63؛ ونسبة أرجحية مقدارها ‏95‏%: 0.50–0.80). وكانت معدلات تلقي اللقاح عند الأطفال الرضع ممن يبلغ وزنهم 1.5 - 1.9 (العدد = 386) أقل بنسبة تقرب من ‏25% مقارنةً بالأطفال الرضع ممن يبلغ وزنهم 2.5 كلغ أو أكثر في الأوقات المذكورة. وقد لوحظت نتائج مشابهة لذلك فيما يتعلق بجرعة اللقاح الثلاثي DTP3. وكان ثمة ارتباط بين صغر سن الأمهات، وقصر مدة تعليمهن، وبعد المسافة اللازمة للوصول إلى أقرب منشأة صحية من جانب وانخفاض معدلات تلقي جرعة اللقاح الثلاثي DTP1 وDTP3 من جانب آخر.يمثل الأطفال الرضع منخفضو الوزن عند الولادة مجموعة معرضة لدرجة عالية من الخطر فيما يتعلق بتأخر تلقي اللقاحات اللازمة في غانا. وتقتضي الحاجة بذل الجهود لتعزيز تلقي هؤلاء الأطفال الرضع للقاحات، إلى جانب إجراء المزيد من البحوث لإدراك أسباب التأخر في ذلك.旨在调查加纳低出生体重婴儿在进行第一次和第三次白喉、破伤风、百日咳（DTP1 和 DTP3）疫苗接种时的延误情况和相关因素。.我们所采用的数据来源于 2010-2013 年间在 22 955 名接受调查的婴儿中开展的基于群体的大规模维生素 A 试验。 我们衡量了疫苗接种率和母亲及婴儿特征，并将三类低出生体重婴儿（2.0–2.4 公斤；1.5–1.9 公斤；和不足 1.5 公斤）与出生体重大于或等于 2.5 公斤的婴儿相比较，并在出生 10、14 和 18 周后使用泊松回归分析计算 DTP1 疫苗接种率，在 18、22 和 24 周后计算 DTP3 接种率【相当于两个接种截止日期（即 6 周和 14 周）后的第 1、2 和第 3 个月】。.低出生体重婴儿 (低出生体重儿童是加纳接种延迟的高危人群。 努力提高这些婴儿的免疫接种率是必要的，同时开展进一步调查，以了解延误原因。.Изучить несоблюдение сроков первой и третьей вакцинации против дифтерии, коклюша и столбняка (АКДС1 и АКДС3) грудных детей со сниженной массой тела при рождении в Гане и связанные с этим определяющие факторы.Были использованы данные, полученные в результате обширного популяционного исследования приема витамина A, которое проводилось в 2010–2013 гг. при участии 22 955 грудных детей. Был определен охват вакцинацией матерей и грудных детей, были выявлены их характеристики, и были сопоставлены три категории грудных детей со сниженной (≥2,5 кг) массой тела при рождении: 2,0–2,4; 1,5–1,9 и1,5 кг. С помощью регрессии Пуассона были подсчитаны отношения рисков вакцинации для вакцинации АКДС1, проведенной на 10, 14 и 18-й неделе после рождения, и для вакцинации АКДС3, проведенной на 18, 22 и 24-й неделе (что соответствует задержке на 1, 2 и 3 месяца по сравнению с установленными сроками такой вакцинации, проводимой на 6-й и 14-й неделях).Для младенцев, имевших сниженную массу тела при рождении (n = 3382), охват вакцинацией АКДС1 был приблизительно на 40% ниже по сравнению с остальными младенцами (n = 18 979) в возрасте 10 недель (стандартизированное отношение рисков, СОР: 0,58; 95%-й ДИ: 0,43–0,77) и в возрасте 18 недель (СОР: 0,63; 95%-й ДИ: 0,50–0,80). Охват вакцинацией для младенцев с массой тела 1,5–1,9 кг (n = 386) был приблизительно на 25% ниже, чем для младенцев с массой тела ≥2,5 кг на тот же момент времени. Такие же результаты были получены для АКДС3. Более молодой возраст и меньший уровень образования матери, а также большее расстояние до ближайшего медицинского учреждения коррелировали с меньшим охватом вакцинациями АКДС1 и АКДС3.Грудные дети со сниженной массой тела при рождении входят в группу высокого риска несоблюдения сроков вакцинации в Гане. Требуется предпринять меры для повышения охвата вакцинацией этих грудных детей, а также провести дополнительные исследования для понимания причин задержек.

TPS6097Background: Incidence of Oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing as a result of Human Papillomavirus (HPV), genotype 16 infection. Existing treatments for HPV+ OP...

118 Background: One of the largest trials in dCRT for localised oesophageal cancer, SCOPE 1 tested the role of adding cetuximab to conventional dCRT, and showed that this was associated with greater toxicity and worse survival. Here we present the long-term outcomes. Methods: Phase II/III trial. Randomisation: cisplatin 60mg/m2 D1 and capecitabine 625mg/m2 daily D1-21 for 4 cycles with/without Cetuximab 400mg/m2 D1 followed by 250mg/m2weekly. RT: 50Gy in 25 fractions given concurrent with cycles 3 and 4. Recruitment: Feb 2008 - Feb 2012, when the IDMC recommended trial closure on the basis of futility. Results: 258 patients (dCRT = 129; dCRT+C = 129) were recruited from 36 centres. Median follow-up (IQR): 46.7 (36.0-49.0) months for all surviving pts. 65.1% (dCRT arm) and 69.8% (dCRT+C arm) of patients had died. Esophageal cancer was the cause in 82.1% and 86.7% of deaths respectively (p = 0.41). Median OS months (95% CI) was 34.5 (24.7-42.3) in dCRT and 24.7 (18.6-31.3) in dCRT+C (HR 1.25, p = 0.137); corresponding 3-year OS (95% CI) was 47.2% (38.2%-55.7%) and 37.6% (29.1%-46.0%). Median PFS (95% CI): 24.1 (15.3-29.9) and 15.9 (10.7-20.8) months respectively (HR1.28, p = 0.114). There was some evidence that local PFS (within RT field) was lower in the dCRT+C arm (HR1.38, p = 0.051). On multivariable analysis including treatment arm, Stage I-II ds (vs Stage III), full-dose RT and higher cisplatin dose intensity ( ≥ 75% vs < 75%) were associated with improved OS and PFS. Patterns of recurrence (n [%]) were similar in both arms (see table). In dCRT arm, 31/38 pts (81.6%) with local relapse within the RT field compared to 40/48 (83.3%) in the dCRT+C arm (p = 0.8). Conclusions: The mature analysis shows unprecedented survival in dCRT arm, comparable to surgical trials (e.g. 3-year OS % [95% CIs] in OE05: CF 39 [35, 44] and ECX 42 [37, 46], in OE02: 31 [27, 36]). OS inferiority of dCRT+C is no longer statistically significant. The lower PFS (within RT field) in the dCRT+C arm was consistent with the lower number of patients receiving full dose of RT in the dCRT+C arm. Clinical trial information: 47718479. [Table: see text]

3 Background: NEOSCOPE compared toxicity and efficacy of 2 pre-op CRT regimens. Methods: Eligibility: Resectable ACA of the oesophagus/GOJ ≥ T3 and/or ≥ N1. Randomisation: 1:1 to OXCAP-CRT (oxaliplatin 85 mg/m2 Day 1,15,29; capecitabine 625 mg/m2 bd on days of RT) or CarPac-CRT (Carboplatin AUC2; paclitaxel 50 mg/m2 Day 1,8,15,22,29); concurrent RT: 45Gy/25 fractions/5 weeks. Both arms received induction chemo: 2 cycles of OXCAP (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m2D1-21, q 3wk). Surgery: 6-8 weeks after naCRT. Detailed RT and pathology quality assurance was built into the protocol. Primary end-point: pathological complete response (pCR). Secondary: toxicity, surgical morbidity/mortality, R1 rate, OS. Statistics: A pCR of 15% would not warrant further investigation but a pCR of 35% would. 76 patients (38/arm) gave 90% power and one-sided type I error of 10% meaning that either arm having ≥10 pCR out of first 38 patients would be considered for Phase III. 85 patients to be recruited (allows 10% loss to follow up). Results: 85 patients were randomised between Oct 2013 and Feb 2015 from 17 UK centres. Patient characteristics: median age 65 yrs, Male (81%), WHO PS 0 (85%). Tumour characteristics: T3 (86%), N1 (48%), lower third/GOJ (90%), median tumour length 5.8cm. CTCAE grade 3/4 toxicity rate during CRT was OXCAP-CRT 42.1%, CarPac-CRT 52.4% (p=0.358). Protocol dose RT OXCAP-CRT 90.5%, CarPac-CRT 93%. Conclusion:Both regimens were well tolerated. CarPac-CRT passed the criteria for taking forward to a phase III study but OXCAP-RT did not. Funding: Cancer Research UK (C44694/A14614), ClinicalTrials.gov: NCT01843829, coordinated by Wales Cancer Trials Unit. Clinical trial information: NCT01843829. [Table: see text]

272 Background: The ABC-02 trial has defined the standard therapy for patients with advanced biliary tract cancer (ABC), however outcome in an unselected patient population in the UK has not been described. We report the outcome of a series of patients with ABC from two large UK cancer networks. Methods: We retrospectively reviewed all cases of ABC presenting to two UK cancer networks over a 9-year period. Patients with a diagnosis recorded under anatomical site (liver, gallbladder or biliary tree) or histological diagnosis (cholangiocarcinoma or adenocarcinoma, liver), were included. Any patients who had surgery with curative intent were excluded. Overall survival (OS) and factors influencing OS were assessed. For the analysis, chemotherapy regimens were considered as: (i) gemcitabine (G)-based vs. non-G-based, (ii) platinum (P)-based vs. non-P-based and (iii) fluoropyrimidine (F)-based vs. non-F-based. Results: 402 patients were available for analysis. The median OS was 6.2 months. On univariate analysis, age ≥ 70 years (p=0.047), advanced disease stage (p