David Sebag-Montefiore’s research while affiliated with University of Leeds and other places

Background In patients with squamous cell carcinoma of the anus (SCCA), magnetic resonance (MR) imaging is recommended for pre-treatment staging prior to chemo-radiotherapy (CRT), but large-scale evaluation of its staging performance is lacking. Methods We re-characterised pre-treatment MRs from 228 patients with non-metastatic SCCA treated consecutively by CRT (2006–2015) at one UK cancer centre. We derived TN staging from tumour size (mrTr) and nodal involvement (mrN), and additionally characterised novel beyond TN features such as extramural vascular invasion (mrEMVI) and tumour signal heterogeneity (mrTSH). Primary outcomes were 5-year overall survival (OS) and 3-year loco-regional failure (LRF). Time-to-event analyses used Kaplan-Meier estimates; Hazard Ratios (HRs) with confidence intervals (CIs) were derived from Cox models. Results With a median follow up of 60.9 months, 5-year OS was 74%. Poor OS was associated with increasing mrT (HR: 1.12 per cm [95% CI: 1.07–1.33]), nodal positivity (HR 2.08 [95% CI 1.23–3.52]) and mrEMVI (HR 3.66 [95% CI: 1.88–7.41]). 3-year LRF rate was 16.5%. Increased LRF was associated with increasing mrT (HR: 1.43 per cm [95% CI: 1.26–1.63]), nodal positivity (HR 2.70 [95% CI 1.39–5.24]) and mrTSH (HR 2.66 [95% CI 1.29–5.48]). Conclusions In SCCA, the study demonstrates that mrT and mrN stages are prognostic, while mrEMVI and mrTSH may be novel prognostic factors.

Response to neoadjuvant radiotherapy (RT) in rectal cancer has been associated with immune and stromal features that are captured by transcriptional signatures. However, how such associations perform across different chemoradiotherapy regimens and within individual consensus molecular subtypes (CMS) and how they affect survival remain unclear. In this study, gene expression and clinical data of pretreatment biopsies from nine cohorts of primary rectal tumors were combined (N = 826). Exploratory analyses were done with transcriptomic signatures for the endpoint of pathologic complete response (pCR), considering treatment regimen or CMS subtype. Relevant findings were tested for overall survival and recurrence-free survival. Immune and stromal signatures were strongly associated with pCR and lack of pCR, respectively, in RT and capecitabine (Cap)/5-fluorouracil (5FU)–treated patients (N = 387), in which the radiosensitivity signature (RSS) showed the strongest association. Upon addition of oxaliplatin (Ox; N = 123), stromal signatures switched direction and showed higher chances to achieve pCR than without Ox (p for interaction 0.02). Among Cap/5FU patients, most signatures performed similarly across CMS subtypes, except cytotoxic lymphocytes that were associated with pCR in CMS1 and CMS4 cases compared with other CMS subtypes (p for interaction 0.04). The only variables associated with survival were pCR and RSS. Although the frequency of pCR across different chemoradiation regimens is relatively similar, our data suggest that response rates may differ depending on the biological landscape of rectal cancer. Response to neoadjuvant RT in stroma-rich tumors may potentially be improved by the addition of Ox. RSS in preoperative biopsies provides predictive information for response specifically to neoadjuvant RT with 5FU. Significance Rectal cancers with stromal features may respond better to RT and 5FU/Cap with the addition of Ox. Within patients not treated with Ox, high levels of cytotoxic lymphocytes associate with response only in immune and stromal tumors. Our analyses provide biological insights about the outcome by different radiotherapy regimens in rectal cancer.

The aim of this review was to highlight why the use of master protocols trial design is particularly useful for radiotherapy intervention trials where complex-set up pathways (including quality assurance, user training, integrating multiple modalities of treatment) may hinder clinical advances. We carried out a systematic review according to PRISMA guidelines, reviewing the findings using a landscape analysis. Results were summarised descriptively, reporting on trial characteristics highlighting the benefits, limitations, and challenges of developing and implementing radiotherapy master protocols with three case studies selected to explore these issues in more detail. 12 studies were suitable for inclusion (4 platform trials, 3 umbrella trials, and 5 basket trials), evaluating a mix of solid tumour sites in both curative and palliative settings. The interventions were categorised into 1. Novel agent and radiotherapy combinations; 2. Radiotherapy dose personalisation; and 3. Device evaluation, with a case study provided for each intervention. Benefits of master protocol trials for radiotherapy intervention include: protocol efficiency for implementation of novel radiotherapy techniques; accelerating the evaluation of novel agent drug and radiotherapy combinations; and more efficient translational research opportunities, leading to cost savings and research efficiency to improve patient outcomes. Master protocols offer an innovative platform under which multiple clinical questions can be addressed within a single trial. Due to the complexity of radiotherapy trial set up, cost and research efficiency savings may be more apparent than in systemic treatment trials. Use of this research approach may be the change needed to push forward oncological innovation within radiation oncology.

The development of deep learning (DL) models to predict the consensus molecular subtypes (CMS) from histopathology images (imCMS) is a promising and cost-effective strategy to support patient stratification. Here, we investigate whether imCMS calls generated from whole slide histopathology images (WSIs) of rectal cancer (RC) pre-treatment biopsies are associated with pathological complete response (pCR) to neoadjuvant long course chemoradiotherapy (LCRT) with single agent fluoropyrimidine. DL models were trained to classify WSIs of colorectal cancers stained with hematoxylin and eosin into one of the four CMS classes using a multi-centric dataset of resection and biopsy specimens ( n = 1057 WSIs) with paired transcriptional data. Classifiers were tested on a held out RC biopsy cohort (ARISTOTLE) and correlated with pCR to LCRT in an independent dataset merging two RC cohorts (ARISTOTLE, n = 114 and SALZBURG, n = 55 patients). DL models predicted CMS with high classification performance in multiple comparative analyses. In the independent cohorts (ARISTOTLE, SALZBURG), cases with WSIs classified as imCMS1 had a significantly higher likelihood of achieving pCR (OR = 2.69, 95% CI 1.01–7.17, p = 0.048). Conversely, imCMS4 was associated with lack of pCR (OR = 0.25, 95% CI 0.07–0.88, p = 0.031). Classification maps demonstrated pathologist-interpretable associations with high stromal content in imCMS4 cases, associated with poor outcome. No significant association was found in imCMS2 or imCMS3. imCMS classification of pre-treatment biopsies is a fast and inexpensive solution to identify patient groups that could benefit from neoadjuvant LCRT. The significant associations between imCMS1/imCMS4 with pCR suggest the existence of predictive morphological features that could enhance standard pathological assessment.

Introduction Glioblastoma (GBM) is the most common adult primary malignant brain tumour. The condition is incurable and, despite aggressive treatment at first presentation, almost all tumours recur after a median of 7 months. The aim of treatment at recurrence is to prolong survival and maintain health-related quality of life (HRQoL). Chemotherapy is typically employed for recurrent GBM, often using nitrosourea-based regimens. However, efficacy is limited, with reported median survivals between 5 and 9 months from recurrence. Although less commonly used in the UK, there is growing evidence that re-irradiation may produce survival outcomes at least similar to nitrosourea-based chemotherapy. However, there remains uncertainty as to the optimum approach and there is a paucity of available data, especially with regards to HRQoL. Brain Re-Irradiation Or Chemotherapy (BRIOChe) aims to assess re-irradiation, as an acceptable treatment option for recurrent IDH-wild-type GBM. Methods and analysis BRIOChe is a phase II, multi-centre, open-label, randomised trial in patients with recurrent GBM. The trial uses Sargent’s three-outcome design and will recruit approximately 55 participants from 10 to 15 UK radiotherapy sites, allocated (2:1) to receive re-irradiation (35 Gy in 10 daily fractions) or nitrosourea-based chemotherapy (up to six, 6-weekly cycles). The primary endpoint is overall survival rate for re-irradiation patients at 9 months. There will be no formal statistical comparison between treatment arms for the decision-making primary analysis. The chemotherapy arm will be used for calibration purposes, to collect concurrent data to aid interpretation of results. Secondary outcomes include HRQoL, dexamethasone requirement, anti-epileptic drug requirement, radiological response, treatment compliance, acute and late toxicities, progression-free survival. Ethics and dissemination BRIOChe obtained ethical approval from Office for Research Ethics Committees Northern Ireland (reference no. 20/NI/0070). Final trial results will be published in peer-reviewed journals and adhere to the ICMJE guidelines. Trial registration number ISRCTN60524.