Sarah Rose Brown

Introduction Randomised clinical trials (RCTs) are gold standard in evidence-based medicine, but follow-up typically relies on clinic visits and trial-specific data collection. Much of this information overlaps with routinely collected healthcare systems data (HSD), such as electronic health records and national registries. Leveraging HSD for trial follow-up has the potential to reduce cost, time and resource burden. However, concerns remain about data quality and evidence is needed to show that HSD-based outcomes are reported to an equivalent standard to trial-specific data. The Blood Cancer Clinical Trials Long-term Follow-up Using Integrated Healthcare Systems platform will link data collected from multiple myeloma clinical trials with HSD to create a research database supporting extended follow-up and further methodological and clinical research. Methods and analysis This data-linkage study includes participants from multiple myeloma RCTs conducted by the University of Leeds between 2008 and 2021. NHS (National Health Service) England will link these participants to HSD, including deaths and cancer registrations, systemic anticancer therapy, radiotherapy and Hospital Episode Statistics. We will compare trial-collected outcomes with those derived from HSD, including mortality, treatment, second cancer incidence and major adverse events. Long-term overall survival will be estimated using national mortality data. HSD-derived demographic and clinical variables will be used to assess population representativeness relative to the wider myeloma population. Time to next treatment will be derived and evaluated as a surrogate for progression-free survival. HSD-derived frailty measures will be examined for prognostic utility, and radiotherapy and hospital records will be analysed to characterise bone-related treatments and skeletal complications. Ethics and dissemination Ethical approval has been obtained from the East of England–Cambridge Central Research Ethics Committee, with Section 251 support from the Health Research Authority on advice from the Confidentiality Advisory Group. Findings will be disseminated through publications, conference presentations and engagement with stakeholders and patient groups. Trial registration ISRCTN60123120, ISRCTN49407852, ISRCTN90889843, ISRCTN24989786, ISRCTN08577602, ISRCTN17354232,ISRCTN59395590, ISRCTN24593488, ISRCTN58227268, ISRCTN15028850.

Introduction The incidence of anal carcinoma is increasing, with the current gold standard treatment being chemoradiotherapy. There is currently a wide range in the radiotherapy dose used internationally which may lead to overtreatment of early-stage disease and potential undertreatment of locally advanced disease. PLATO is an integrated umbrella trial protocol which consists of three trials focused on assessing risk-adapted use of adjuvant low-dose chemoradiotherapy in anal margin tumours (ACT3), reduced-dose chemoradiotherapy in early anal carcinoma (ACT4) and dose-escalated chemoradiotherapy in locally advanced anal carcinoma (ACT5), given with standard concurrent chemotherapy. Methods and analysis The primary endpoints of PLATO are locoregional failure (LRF)-free rate for ACT3 and ACT4 and LRF-free survival for ACT5. Secondary objectives include acute and late toxicities, colostomy-free survival and patient-reported outcome measures. ACT3 will recruit 90 participants: participants with removed anal tumours with margins ≤1 mm will receive lower dose chemoradiotherapy, while participants with anal tumours with margins >1 mm will be observed. ACT4 will recruit 162 participants, randomised on a 1:2 basis to receive either standard-dose intensity modulated radiotherapy (IMRT) in combination with chemotherapy or reduced-dose IMRT in combination with chemotherapy. ACT5 will recruit 459 participants, randomised on a 1:1:1 basis to receive either standard-dose IMRT in combination with chemotherapy, or one of two increased-dose experimental arms of IMRT with synchronous integrated boost in combination with chemotherapy. Ethics and dissemination This study has been approved by Yorkshire & The Humber – Bradford Leeds Research Ethics Committee (ref: 16/YH/0157, IRAS: 204585), July 2016. Results will be disseminated via national and international conferences, peer-reviewed journal articles and social media. A plain English report will be shared with the study participants, patients’ organisations and media. Trial registration number ISRCTN88455282.

PURPOSE: Survival for patients with multiple myeloma (MM) has improved but outcomes remain heterogeneous. Consistent diagnostic identification of high-risk disease is desirable to address unmet patient need. The aim was to investigate the consistency of association of co-occurrence of high-risk cytogenetic abnormalities (HRCAs) with prognosis in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), and across a range of treatment modalities. METHODS: A systematic review of randomized controlled trials of MM that reported testing for HRCA between January 1, 2000, and December 9, 2021, was performed. Groups were contacted and asked to locally perform a novel, federated analysis of their data for single hit (one HRCA) and double hit (≥two HRCAs), using a centrally provided algorithm. Analysis results were centrally collated and meta-analyzed to assess the hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) for one/≥two HRCAs across patient subgroups using random-effects models. RESULTS: Twenty-four trials including 13,926 patients were included. The median age of participants was 66.5 years (IQR, 59-72) and 56.5% were male (IQR, 52-60). The HR for PFS was 2.28 (95% CI, 2.05 to 2.54) for patients with ≥two HRCAs and 1.51 (95% CI, 1.38 to 1.65) for patients with one HRCA. The HR for OS was 2.94 (95% CI, 2.49 to 3.47) and 1.69 (95% CI, 1.52 to 1.88) for the two subgroups, respectively. In studies initiated since 2015, the effect abides (≥two HRCA PFS, HR, 2.39 [95% CI, 1.96 to 2.91]; OS, 3.10 [95% CI, 2.10 to 4.60]) both for NDMM and RRMM. Heterogeneity related to transplant eligibility and relapsed/refractory status was as expected. CONCLUSION: The association of ≥two HRCAs with the poorest outcome in NDMM and RRMM, and across treatment modalities, as demonstrated here for the first time to our knowledge, allows for more focused development of novel approaches to these patients with high unmet need.

Introduction Oligodendroglioma (ODG) is a rare type of brain tumour, typically diagnosed in younger adults and associated with prolonged survival following treatment. The current standard of care is maximal safe debulking surgery, radiotherapy (RT) and adjuvant procarbazine, lomustine and vincristine (PCV) chemotherapy. Patients may experience long-term treatment-related toxicities, with RT linked to impairments of neurocognitive function (NCF) and health-related quality of life (HRQoL). With proton beam therapy (PBT), radiation dose falls off sharply beyond the target with reduced normal brain tissue radiation doses compared with photon RT. Therefore, PBT might result in reduced radiation-induced toxicity compared with photon RT. Methods and analysis APPROACH is a multicentre open-label phase III randomised controlled trial of PBT versus photon RT in patients with ODG, investigating the impact of PBT on long-term NCF measured using the European Organisation for Research and Treatment of Cancer (EORTC) Core Clinical Trial Battery Composite (CTB COMP). The trial will randomise 246 participants from 18 to 25 UK RT sites, allocated 1:1 to receive PBT or photon RT, with PBT delivered at one of the two UK PBT centres. Participants with grade 2 and grade 3 ODG will receive 54 Gy in 30 fractions and 59.4 Gy in 33 fractions, respectively, followed by 6×6-weekly cycles of PCV chemotherapy. The trial contains staged analyses, with an internal pilot for feasibility of recruitment at 12 months, early assessment of efficacy at 2 years, futility assessment and final primary endpoint comparison of NCF between arms at 5 years. Secondary endpoints include additional NCF, treatment compliance, acute and late toxicities, endocrinopathies, HRQoL, tumour response, progression-free survival and overall survival. Ethics and dissemination Ethical approval was obtained from Newcastle North Tyneside REC (reference 22/NE/0232). Final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors (ICMJE) guidelines. Trial registration number ISRCTN:13390479.

Introduction Prostate cancer (PCa) is the most common cancer in men. Recurrence may occur in up to half of patients initially treated with curative intent for high-risk localised/locally advanced PCa. Pelvic nodal recurrence is common in this setting, but no clear standard of care exists for these patients, with potential therapeutic approaches including stereotactic body radiotherapy (SBRT) to the involved node(s) alone, extended nodal irradiation (ENI) to treat sites of potential micrometastatic spread in addition to involved node(s) and androgen deprivation therapy with or without additional systemic anticancer therapies. Based on observational studies, ENI is associated with promising metastasis-free survival (MFS) compared with SBRT and appears to result in low rates of severe late toxicity. Methods and analysis Pelvis Or Involved Node Treatment: Eradicating Recurrence in Prostate Cancer is a UK multicentre, open-label, phase III randomised controlled trial, which will deliver much needed, high-quality evidence of the impact on metastatic progression from ENI compared with SBRT in patients with PCa pelvic nodal recurrence. The trial will also evaluate the long-term toxicity of 5-fraction ENI compared with a standard 20-fraction schedule. The trail will randomise 480 participants in a ratio of 2:1:1 to SBRT, 5-fraction ENI or 20-fraction ENI from 35 to 40 UK radiotherapy sites over 4 years. Coprimary endpoints are MFS at 3 years and participant-reported late bowel toxicity at 3 years. Secondary endpoints include overall survival, biochemical progression-free survival, failure-free survival, patterns of failure, participant-reported/clinician-reported toxicity and health-related quality of life. Collection of blood and tissue samples will enable future evaluation of biomarkers of disease and toxicity and support stratification of salvage therapeutic approaches. Ethics and dissemination Ethical approval was obtained from NHS Health Research Authority, East of England – Cambridgeshire and Hertfordshire Research Ethics Committee (24/EE/0099). Trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors guidelines. Trial registration number ISRCTN11089334, registered on 23 September 2024.