The Christie School of Oncology: Christie Research Publications Repository
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Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials
No full textPURPOSE: Over the past 15 years, the landscape of early phase clinical trials (EPCTs) has undergone a remarkable expansion in both quantity and intricacy. The proliferation of sites, trials, sponsors, and contract research organizations has surged exponentially, marking a significant shift in research conduct. However, EPCT operations suffer from numerous inefficiencies, such as cumbersome start-up processes, which are particularly critical when drug safety and the recommended phase II dose need to be established in a timely manner. Networks and consortia may overcome some of these challenges of enrolling suitable patients and streamlining start-up, particularly when distance and disease trajectory come into play. DESIGN: In this article, we provide an overview of EPCT consortia in adult oncology across different continents assembled through systematic review of the literature and snowball sampling methodology. We illustrate their scope, structure, funding, and achievements. RESULTS: Fifteen EPCT consortia were identified including two in the United States, three in Europe, five in Asia-Pacific, two intercontinental consortia, and three within private oncology networks. These consortia vary in their scope, funding, and structure from government-funded models such as the National Cancer Institute Experimental Therapeutics Clinical Trials Networks through charitably funded and private research organizations. EPCT consortia play a role in collaborative research, molecular tumor boards to provide patient-centric biomarker-matched treatments, and streamlining trial conduct to improve timelines and cost efficiency. CONCLUSION: The growth in EPCT activity and complexity has resulted in expansion in the number of EPCT consortia globally. By actively engaging with regulatory bodies and pharmaceutical and contract research organization industries, consortia have an opportunity to address the evolving challenges faced in this field and to accelerate the translation of scientific discoveries into clinical practice
Cone-beam computed tomography reconstruction for a commercial proton beam therapy system
No full textBACKGROUND & PURPOSE: Cone-beam computed tomography (CBCT) images are used in image-guided radiotherapy to track anatomical changes throughout treatment and to set up patients to ensure accurate delivery of therapeutic radiation at each treatment session. An offline method of CBCT reconstruction workflow, operating on 2D projection images and specific to the imaging system in question, is needed for many image optimisation studies. Here we present a methodology to reconstruct CBCT images from these data for a commercial proton beam therapy machine, accounting for the variation in exposure and beam hardening from filtration due to gantry rotation during CBCT acquisition. MATERIALS & METHODS: Projection data of solid water phantoms were acquired to model bow-tie filter motion and beam hardening effects. Projection data and system CBCT reconstructions of a Catphan504 phantom were acquired for validation of the method, as well as a retrospectively accessed patient image. The presented workflow was assessed against the clinical reconstructions using uniformity, signal-to-noise-ratio, and contrast-to-noise-ratio measured in the phantom images. RESULTS: The offline workflow eliminated crescent artefacts due to variable exposure and beam hardening in phantom and patient images. Signal-to-noise and contrast-to-noise ratios were similar compared to system reconstructions, although with slight differences thought to be due to interplay effects in the bow-tie filter. CONCLUSION: A workflow was developed to emulate the CBCT reconstruction process for a commercial proton therapy machine, providing a useful tool for optimised acquisition parameters and novel reconstruction processes using this system
Fractionated radiotherapy for vestibular schwannoma
No full textRadiotherapy (RT) has become an increasingly attractive treatment for vestibular schwannomas (VS) in the last 30 years. Fractionated radiotherapy (FRT) for VS typically involves delivering a dose of 2Gy or less daily over the course of several weeks. With increasing advances in linear accelerator technology, it is now possible to deliver FRT with a stereotactic setup (FSRT) to levels of precision previously only seen in patients receiving stereotactic radiosurgery (SRS) with treatments such as Gamma Knife. FRT can be used where patients cannot tolerate SRS, in situations where treatment-related edema might be a concern, and in patients where hearing preservation is paramount. This chapter outlines the delivery of FRT and FSRT together with outcomes and toxicities from fractionated RT treatment in VS
Enozertinib (ORIC-114), a highly selective, brain penetrant EGFR and HER2 inhibitor, in EGFR Exon 20 mutant NSCLC: randomized dose optimization and CNS activity
No full textA comparison of real-world data on adjuvant treatment in patients with stage III BRAF V600 mutated melanoma - Results of systematic literature research
No full textBACKGROUND: Over the past decade, PD-1-based immune checkpoint inhibitors (ICI) and targeted therapies (TT) with BRAF and MEK inhibitors transformed melanoma treatment. Both are widely used in the adjuvant setting. However, for patients with a BRAF V600 mutation, the optimal adjuvant therapy remains unclear due to the lack of head-to-head comparison studies. METHODS: We conducted a systematic review of real-world data on adjuvant therapy in stage III melanoma to determine the best option for patients with BRAF V600 mutations. Kaplan-Meier curves were generated for TT and ICI using Digitizelt software. RESULTS: Nine publications with 3625 patients were included. TT showed better relapse-free survival (RFS) at 6, 12, 24, and 36 months than ICI. A similar trend was observed for distant metastasis-free survival (DMFS), with no apparent difference in overall survival. CONCLUSION: Real-world data suggest that adjuvant TT may be associated with better RFS and DMFS in stage III BRAF V600-mutated melanoma compared to ICI
Overall survival with maintenance olaparib in platinum-sensitive relapsed ovarian cancer by somatic or germline BRCA and homologous recombination repair mutation status
No full textBACKGROUND: The open-label, single-arm, multicentre ORZORA trial (NCT02476968) evaluated maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) with a germline (g) or somatic (s) BRCA1 and/or BRCA2 mutation (BRCAm) or a non-BRCA homologous recombination repair mutation (non-BRCA HRRm). METHODS: Patients were in response to platinum-based chemotherapy after ≥2 prior lines of treatment and underwent prospective central screening for tumour BRCA status, then central gBRCAm testing to determine sBRCAm or gBRCAm status. An exploratory cohort evaluated non-BRCA HRRm in 13 predefined genes. Patients received olaparib 400 mg (capsules) twice daily until investigator-assessed disease progression. Secondary endpoints included overall survival (OS) and safety. RESULTS: 177 patients received olaparib. At the final data cutoff (25 June 2021), median OS from study enrolment was 46.8 (95% confidence interval [CI] 37.9-54.4), 43.2 (31.7-NC [not calculated]), 47.4 (37.9-NC) and 44.9 (28.9-NC) months in the BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts, respectively. No new safety signals were identified. CONCLUSION: Maintenance olaparib showed consistent clinical activity in the BRCAm and sBRCAm cohorts; exploratory analysis suggested similar activity in the non-BRCA HRRm cohort. These findings highlight that patients with PSR OC, beyond those with gBRCAm, may benefit from maintenance olaparib
Barriers to Cervical Screening and the Potential for Self-Sampling Methods to Improve Screening Uptake in People From Ethnically Diverse Backgrounds Living in the UK: The Alternative CErvical Screening (ACES) Diversity Study
No full textImpact of comorbid anxiety and depression on heart failure diagnosis, hospitalisation, and survival outcomes: an observational study of over 400,000 patients in England
No full textThe importance of standardization and challenges of dosimetry in conventional preclinical radiation biology research
No full textTo fully exploit the prospects presented by the increasing focus on biological approaches for enhancing radiotherapy outcomes, improvements in repeatability and translatability of radiobiological and preclinical studies are required. This requires the development and adoption of appropriate dosimetric standards and reproducible approaches to increase confidence in the studies, enabling inter-laboratory validation and facilitating clinical translation. An Institute of Physics and Engineering in Medicine (IPEM) working party reviewed the current status and challenges associated with dosimetry of medium-energy X-rays and make recommendations with the aim to optimize the potential clinical significance of radiobiological preclinical investigations. The paper discusses the currently available resources with technical recommendations for performing dosimetry in medium-energy X-rays, along with the consequences of lack of standardization and implications of dose inhomogeneity. It is clear that there is still a gap in understanding the needs for standardization of dosimetric aspects of preclinical and radiobiological studies. It is recommended that these radiobiology studies should be conducted in partnership with medical/radiation physicists. This collaboration ensures the correct utilization of suitable dosimetry systems, thus guaranteeing accuracy and consistency of dose delivery. Appropriate calibration and traceability to national/international standards laboratory, along with regular quality assurance of radiation devices, are paramount to reproducibility. Additionally, it is critical that experimental details and associated dosimetry are sufficiently reported to ensure accurate replication that enables reanalysis including evaluation of dose distributions. Increasing awareness among the researchers and the funding bodies was identified as a crucial step to improve translatability and appropriate resources are budgeted to increase the value for money of research proposals. The proposed recommendations will serve as a vital resource for researchers, encouraging uniformity in experimental design and improving the translatability of preclinical research to clinical settings