BACKGROUND:PLATFORM is an adaptive phase II trial assessing maintenance therapies in advanced oesophagogastric adenocarcinoma (OGA). We evaluated maintenance capecitabine in patients with disease control after first-line chemotherapy. METHODS:HER2-negative patients with advanced OGA who had response or stable disease after 18 weeks of first-line chemotherapy were randomised (1:1) to surveillance or capecitabine. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. RESULTS:Between May 2015 and May 2024, 266 patients were randomised (129 surveillance, 137 capecitabine). Median follow up was 70.7 months. Capecitabine significantly improved PFS (HR 0.69; 95% CI 0.54-0.89; p = 0.002), with median PFS of 5.0 vs 2.8 months. One-year PFS rates were 19.9% vs 6.8%; and two-year rates 8.1% vs 4.3%. No OS difference was observed (median OS: 10.5 vs 10.0 months; HR 0.87; 95% CI 0.67-1.12; p = 0.143). One and two-year OS rates were similar (1-year: 44.1% vs 45.7%; 2-year: 18.8% vs 16.8%). Grade ≥3 adverse events were more frequent with capecitabine (46% vs 29%), with 21% experiencing grade 3 treatment related events. DISCUSSION:Maintenance capecitabine significantly prolonged PFS compared to surveillance, meeting the primary endpoint and supporting its use to extend disease control in advanced OGA.

BACKGROUND:Patients with differentiated thyroid cancer can often be treated with postoperative radioiodine (also called radioiodine ablation) after total thyroidectomy. The IoN trial was designed to assess whether recurrence-free survival was non-inferior after no ablation compared with ablation in patients with low-risk differentiated thyroid cancer. METHODS:IoN was a multicentre, non-inferiority, phase 3 randomised trial conducted at 33 UK cancer centres. Eligible patients had complete (R0) resection following total thyroidectomy; stage pT1, pT2, pT3 (according to Tumour, Node, Metastasis staging version 7 [TNM7]), or pT3a (according to TNM8) disease; and N0, Nx, or N1a disease. Participants were randomly assigned (1:1) by minimisation, using a central electronic system, to have either 1·1 GBq ablation or no ablation, following thyroidectomy. Stratification factors were centre, age, T stage, and nodal status. Patients had annual neck ultrasound scans and 6-monthly serum thyroglobulin measurements. The primary endpoint was 5-year recurrence-free survival, defined by the absence of locoregional recurrent or persistent structural disease, distant metastases, or death from thyroid cancer. Non-inferiority was assessed with a margin of 5 percentage points. Per-protocol and intention-to-treat (ITT) analyses were done for the primary endpoint, and safety was analysed in the per-protocol population. The trial is registered with ClinicalTrials.gov (NCT01398085), ISRCTN (ISRCTN80416929), and EUDRACT (2011-000144-21), and is still in active follow-up. FINDINGS:We recruited 504 patients (including 390 [77%] female patients and 114 [23%] male patients) between June 26, 2012 and March 18, 2020 and randomly assigned 251 to receive no ablation and 253 to receive ablation (ITT population). 249 patients in the no ablation group did not have ablation and 231 in the ablation group had ablation (per-protocol population). Median follow-up was 6·8 years (IQR 5·6-8·6) in the no ablation group and 6·6 years (4·8-8·5) in the ablation group; 17 recurrences (eight in the no ablation group and nine in the ablation group; ITT population) occurred during follow-up. 5-year recurrence-free rates were 97·9% (95% CI 96·1-99·7) in the no ablation group versus 96·3% (93·9-98·7) in the ablation group in the ITT analysis, and 97·9% (96·1-99·7) versus 96·9% (94·7-99·1) in the per-protocol analysis. The 5-year absolute risk difference was 0·5 percentage points (95% CI -2·2 to 3·2, pnon-inferiority=0·033; ITT analysis), showing that non-inferiority was reached. The observed recurrence rate was higher among patients with pT3 or pT3a tumours (four [9%] of 46 patients overall with pT3 or pT3a tumours vs 13 [3%] of 458 with pT1 or pT2 tumours), or N1a tumours (six [13%] of 47 with N1a vs 11 [2%] of 457 with N0 or Nx), but they were similar among those who did not receive ablation. Adverse events were similar between the groups, the most common being fatigue (63 [25%] of 249 in the no ablation group vs 65 [28%] of 231 in the ablation group), lethargy (34 [14%] vs 32 [14%]), and dry mouth (24 [10%] vs 21 [9%]), and there were no treatment-related deaths. INTERPRETATION:The IoN trial shows that ablation (or postoperative radioiodine) can be avoided for patients with pT1, pT2, and N0 or Nx tumours with no adverse features. Many patients with low-risk differentiated thyroid cancer worldwide can safely avoid postoperative radioiodine and its related hospitalisation and side-effects, which in turn results in lower health-care costs. FUNDING:Cancer Research UK.

Background Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. Methods CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1–T4, N1–N3 or T3–4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1–T4, N2b–N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2—induction chemotherapy followed by arm 1; arm 3—dose-escalated radiotherapy plus concomitant cisplatin; and arm 4—resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5—induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m 2 or weekly 40 mg/m 2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. Discussion CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. Trial registration ISRCTN ISRCTN41478539 . Registered on 29 April 2015

In this Policy Review we discuss ten key pressure points in the NHS in the delivery of cancer care services that need to be urgently addressed by a comprehensive national cancer control plan. These pressure points cover areas such as increasing workforce capacity and its productivity, delivering effective cancer survivorship services, addressing variation in quality, fixing the reimbursement system for cancer care, and balancing of the cancer research agenda. These areas have been selected based on their relative importance to ensuring sustainable cancer services, persistence as key issues in the NHS, and their impact on delivering better and more equitable and affordable patient outcomes. Many of these pressure points are not acknowledged explicitly in any current discourse. The evidence we provide points to their impact on the ability to deliver world class cancer care, but also to their amenability to affordable solutions if given the relevant prioritisation and investment. The current narrative needs to move away from a technocentric approach to improving care, to one focused on understanding the complexity of cancer services and the wider health system to drive improvements in survival, quality of life, and experience for patients.

AimsThe success and safety of modern radiotherapy relies on accurate contouring. Understanding the time taken to complete radiotherapy contours is critical to informing workforce planning and, in the context of a workforce shortfall, advocating for investment in technology and multi-professional skills mix. We aimed to quantify the time taken to delineate target volumes for radical radiotherapy.MethodsThe Royal College of Radiologists circulated two electronic surveys via email to all clinical oncology consultants in the UK. The individual case survey requested anonymous data regarding the next five patients contoured for radical radiotherapy. The second survey collected data on respondents’ usual practice in radiotherapy contouring.ResultsThe median time to contour one radiotherapy case was 85 minutes (IQR=50-131 minutes). Marked variability between and within tumour sites was evident: paediatric cancers took the most time (median=210 minutes, IQR=87.5 minutes), followed by head and neck and gynaecological cancers (median=120 minutes, IQR=71 and 72.5 minutes respectively). Breast cancer contouring required the least time (median=43 minutes, IQR=60 minutes). Radiotherapy technique, inclusion of nodes and 4D CT planning were associated with longer contouring times. A non-medical professional was involved in contouring in 65% of cases, but clinical oncology consultants were involved in target volume delineation in 90% of cases, and OARs in 74%. Peer review took place in 46% of cases with 56% of consultants reporting no time for peer review in their job plan.DiscussionContouring for radical radiotherapy is complex and time-consuming, and despite increasing involvement of non-medical professionals, clinical oncology consultants remain the primary practitioners. Peer review practice is variable and time is often a limiting factor. Many factors influence the time required for contouring, and departments should take these factors and the need for peer-review into account when developing job plans.

Cancer affects one in two people in the UK and the incidence is set to increase. The UK National Health Service is facing major workforce deficits and cancer services have struggled to recover after the COVID-19 pandemic, with waiting times for cancer care becoming the worst on record. There are severe and widening disparities across the country and survival rates remain unacceptably poor for many cancers. This is at a time when cancer care has become increasingly complex, specialised, and expensive. The current crisis has deep historic roots, and to be reversed, the scale of the challenge must be acknowledged and a fundamental reset is required. The loss of a dedicated National Cancer Control Plan in England and Wales, poor operationalisation of plans elsewhere in the UK, and the closure of the National Cancer Research Institute have all added to a sense of strategic misdirection. The UK finds itself at a crossroads, where the political decisions of governments, the cancer community, and research funders will determine whether we can, together, achieve equitable, affordable, and high-quality cancer care for patients that is commensurate with our wealth, and position our outcomes among the best in the world. In this Policy Review, we describe the challenges and opportunities that are needed to develop radical, yet sustainable plans, which are comprehensive, evidence-based, integrated, patient-outcome focused, and deliver value for money.

We take great pleasure in introducing this supplement dedicated to management of head neck squamous cell cancer from an unknown primary (HSCCUP). The management of HNSCCUP is inherently difficult for several reasons. Firstly, there is a paucity of robust contemporary evidence on the topic. Historic studies predate our understanding of the role of human papillomavirus (HPV) in the head and neck and, with the incidence of HPV related disease rising, management recommendations should necessarily keep abreast of this evolving landscape to be able to offer the greatest certainty of any patient benefit. Secondly, the understanding and definition of what is considered an 'unknown primary' alters during the diagnostic pathway as examination, investigations and biopsies identify disease. As a result, direct interstudy comparisons or meta-analysis are complicated by incongruent cohort definitions and eligibility criteria. Thirdly, true unknown primary disease is not common (3%–5% of all head and neck cancers), and so establishing both a substantial evidence base and reasonable clinical experience regarding its management can be challenging, particularly in the single centre setting. Despite these limitations, many organisations have produced guidelines covering the management of HNSCCUP, using a variety of methodologies. In considering which methodology to adopt to produce the present guidelines, the editors chose to develop a bespoke multi-stage process for several reasons. Firstly, owing to the paucity of contemporary evidence, consensus opinion will undoubtedly be controversial. Without a robust evidence base, consensus opinion would benefit from being as representative of all stakeholders as possible. This lends itself to as much multicentre national engagement as possible to encourage widespread buy-in to the output. Secondly, by involving as many stakeholders and centres as possible, the resultant guidelines are more likely to be considerate of local resource constraints, and so more likely to be adhered to. We put in place an ambitious programme of work in consultation with several stakeholder organisations to realise this aim. The methodology for consensus generation was set out ahead of this exercise, and peer reviewed by an expert team to ensure critical feedback and generate stakeholder support [1]. Consultation with a wide array of professional groups The Head and Neck Society | ENT UK, The British Society of Head & Neck Imaging, The Royal College of Radiology ǀ Clinical Oncology section, and The Royal College of Speech and Language Therapists led to focused questions, the answers for which would inform unknown primary management. These led to the format for consensus day, which closely followed the patient journey. The data to inform consensus was generated from systematic reviews, national audits, prospective study [2] and a Delphi exercise. Both national audits were led by INTEGRATE—The UK ENT Trainee Research Network, with input from experts as needed. The practice guidelines arising from this meta-consensus exercise were published as consensus statements in the sixth edition of the United Kingdom National Multidisciplinary Guidelines [3]. Arain, Madani and Awad [4] offer an evidence-based summary and make recommendations for imaging HNSCCUP, indicating MRI to be an integral part of the cross-sectional imaging, in addition to PET-CT scans. Thomas et al. [5] identify the evidence base for oropharyngeal biopsy in HNSCCUP, while Bowe and Garg [6] inform us that biopsies of non-oropharyngeal sites are not indicated when the imaging and clinical examination is clear. The first national audit on investigations for HNSCCUP [7] captures the national practice for diagnosis of this disease process. Takhar et al. [8] set out the cohort of patients for whom surgery alone will suffice as sole treatment modality, while Iqbal, Jackson and Paterson [9] define the indications for adjuvant radiation therapy to the neck after neck dissection. The second national audit on survival outcomes for HNSCCUP [10] demonstrates the excellent outcomes for HPV positive disease, while cautioning that neck dissection alone might be associated with worse local control, but not overall survival, for patients with HNSCCUP. The works included in the supplement have helped harmonise practice by offering consensus guidelines, define the outcomes of the current treatment paradigms and will help generate further hypothesis driven studies. Additionally, this process offers a model for generating robust guidelines in rare disease processes. We are very grateful to all stakeholders and individual participants for generously offering their time and effort, without which this output would not have been possible. We recommend the contents of this supplement to all colleagues involved in the management of HNSCCUP and, to raise awareness, this editorial is jointly published across Clinical Oncology (R Coll Radiol). List of contributors to the consensus generation process. Vinidh Paleri, John Hardman, Tom Roques and Ben O'Leary made substantial contributions to the conception and design of the work, the analysis and interpretation of data for the work, drafted the work, revised it for intellectual content, gave final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The authors have nothing to report. Vinidh Paleri is proctor for Intuitive surgical. John Hardman, Tom Roques and Ben O'Leary declare no relevant COIs. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/coa.14204. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

BACKGROUND:PLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients. PATIENTS AND METHODS:Patients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with disease control or response to 18 weeks of platinum-based first-line chemotherapy were randomised to active surveillance or maintenance durvalumab. The primary endpoint was progression-free survival (PFS). Safety was assessed in all patients who had commenced surveillance visits or received at least one dose of durvalumab. Exploratory survival analyses according to PD-L1 Combined Positive Score (CPS) and immune (biomarker-positive) or angiogenesis dominant (biomarker-negative) tumour microenvironment (TME) phenotypes were conducted. RESULTS:Between March 2015 and April 2020, 205 patients were randomised to surveillance (n = 100) and durvalumab (n = 105). No significant differences were seen in PFS [hazard ratio (HR) 0.84, P = 0.13] and overall survival (OS; HR 0.98, P = 0.45) between surveillance and durvalumab. Five patients randomised to durvalumab demonstrated incremental radiological responses compared with none with surveillance. Treatment-related adverse events occurred in 77 (76.2%) durvalumab-assigned patients. A favourable effect in OS with durvalumab over surveillance in CPS ≥5 and immune biomarker-positive patients was observed compared with CPS <5 and biomarker-negative subgroups, respectively: CPS ≥5 versus <5: HR 0.63, 95% confidence interval (CI) 0.32-1.22 versus HR 0.93, 95% CI 0.44-1.96; biomarker-positive versus negative: HR 0.60, 95% CI 0.29-1.23 versus HR 0.84, 95% CI 0.42-1.65. CONCLUSION:Maintenance durvalumab does not improve PFS in patients with OG adenocarcinoma who respond to first-line chemotherapy but induced incremental radiological responses in a subset of patients. TME characterisation could refine patient selection for anti-PD-L1 therapy above PD-L1 CPS alone.

Background Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with chemoradiotherapy with curative intent but at the consequence of adverse effects on quality of life. We aimed to investigate if dysphagia-optimised intensity-modulated radiotherapy (DO-IMRT) reduced radiation dose to the dysphagia and aspiration related structures and improved swallowing function compared with standard IMRT.Methods DARS was a parallel-group, phase 3, multicentre, randomised, controlled trial done in 22 radiotherapy centres in Ireland and the UK. Participants were aged 18 years and older, had T1-4, N0-3, M0 oropharyngeal or hypopharyngeal cancer, a WHO performance status of 0 or 1, and no pre-existing swallowing dysfunction. Participants were centrally randomly assigned (1:1) using a minimisation algorithm (balancing factors: centre, chemotherapy use, tumour type, American Joint Committee on Cancer tumour stage) to receive DO-IMRT or standard IMRT. Participants and speech language therapists were masked to treatment allocation. Radiotherapy was given in 30 fractions over 6 weeks. Dose was 65 Gy to primary and nodal tumour and 54 Gy to remaining pharyngeal subsite and nodal areas at risk of microscopic disease. For DO-IMRT, the volume of the superior and middle pharyngeal constrictor muscle or inferior pharyngeal constrictor muscle lying outside the high-dose target volume had a mandatory 50 Gy mean dose constraint. The primary endpoint was MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after radiotherapy, analysed in the modified intention-to-treat population that included only patients who completed a 12-month assessment; safety was assessed in all randomly assigned patients who received at least one fraction of radiotherapy. The study is registered with the ISRCTN registry, ISRCTN25458988, and is complete.Findings From June 24, 2016, to April 27, 2018, 118 patients were registered, 112 of whom were randomly assigned (56 to each treatment group). 22 (20%) participants were female and 90 (80%) were male; median age was 57 years (IQR 52-62). Median follow-up was 39 & BULL;5 months (IQR 37 & BULL;8-50 & BULL;0). Patients in the DO-IMRT group had significantly higher MDADI composite scores at 12 months than patients in the standard IMRT group (mean score 77 & BULL;7 [SD 16 & BULL;1] vs 70 & BULL;6 [17 & BULL;3]; mean difference 7 & BULL;2 [95% CI 0 & BULL;4-13 & BULL;9]; p=0 & BULL;037). 25 serious adverse events (16 serious adverse events assessed as unrelated to study treatment [nine in the DO-IMRT group and seven in the standard IMRT group] and nine serious adverse reactions [two vs seven]) were reported in 23 patients. The most common grade 3-4 late adverse events were hearing impairment (nine [16%] of 55 in the DO-IMRT group vs seven [13%] of 55 in the standard IMRT group), dry mouth (three [5%] vs eight [15%]), and dysphagia (three [5%] vs eight [15%]). There were no treatment-related deaths.Interpretation Our findings suggest that DO-IMRT improves patient-reported swallowing function compared with standard IMRT. DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers.Funding Cancer Research UK.Copyright & COPY; 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Aims: The protracted COVID-19 pandemic has overwhelmed health systems globally, including many aspects of cancer control. This has underscored the multidimensional nature of cancer control, which requires a more comprehensive approach involving taking a wider perspective of health systems. Here, we investigated aspects of health system resilience in maintaining cancer services globally during the COVID-19 pandemic. This will allow for health systems to be resilient to different types of system stressors/shocks in the future, to allow cancer care to be maintained optimally.Materials and methods: Using the World Health Organization health system framework (capturing aspects of service delivery, health workforce, information, medical products, vaccines and technologies, financing and governance and leadership), we carried out a comparative analysis of the impact of COVID-19 and the synthesis of the findings in responses in cancer care in 10 countries/jurisdictions across four continents comprising a wide diversity of health systems, geographical regions and socioeconomic status (China, Colombia, Egypt, Hong Kong SAR, Indonesia, India, Singapore, Sri Lanka, UK and Zambia). A combination of literature and document reviews and interviews with experts was used.Results: Our study revealed that: (i) underlying weaknesses of health systems before the pandemic were exacerbated by the pandemic (e.g. economic issues in low-and middle-income countries led to greater shortage of medication and resource constraints compounded by inadequacies of public financing and issues of engagement with stakeholders and leadership/governance); (ii) no universal adaptive strategies were applicable to all the systems, highlighting the need for health systems to design emergency plans based on local context; (iii) despite the many differences between health systems, common issues were identified, such as the lack of contingency plan for pandemics, inadequate financial policies for cancer patients and lack of evidence-based approaches for competing priorities of cancer care/pandemic control.Conclusion: We identified four key points/recommendations to enhance the resilient capacity of cancer care during the COVID-19 pandemic and other system stressors: (i) effective pandemic control approaches in general are essential to maintain the continuity of cancer care during the emergency health crises; (ii) strong health systems (with sufficient cancer care resources, e.g. health workforce, and universal health coverage) are fundamental to maintain quality care; (iii) the ability to develop response strategies and adapt to evolving evidence/circumstances is critical for health system resilience (including introducing systematic, consistent and evidence-based changes, national support and guidance in policy development and implementation); (iv) preparedness and contingency plans for future public health emergencies, engaging the whole of society, to achieve health system resilience for future crises and to transform healthcare delivery beyond the pandemic.(c) 2023 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

With the widespread use of 18F-fluorodeoxyglucose positron emission tomography (FDG PET/CT) in the investigation and staging of cancers, incidental discovery of FDG-avid thyroid nodules is becoming increasingly common, with a reported incidence in the range 1%-4% of FDG PET/CT scans. The risk of malignancy in an incidentally discovered FDG avid thyroid nodule is not clear due to selection bias in reported retrospective series but is likely to be less than 15%. Even in cases where the nodule is found to be malignant, the majority will be differentiated thyroid cancers with an excellent prognosis even without treatment. If, due to index cancer diagnosis, age and co-morbidities, it is unlikely that the patient will survive 5 years, further investigation of an incidental FDG avid thyroid nodule is unlikely to be warranted. We provide a consensus statement on the circumstances in which further investigation of FDG avid thyroid nodules with ultrasound and fine needle aspiration might be appropriate.