Biological and Clinical Evaluation of Intensity Modulated Radiotherapy for Brain Tumours

Intensity modulated radiotherapy has gained attention in recent years as a high precision radiation technique, allowing tumour dose escalation and reductions in high dose to adjacent normal organs. IMRT optimises the therapeutic ratio even further than conventional conformal radiation techniques, providing effective dose for tumour control, whilst minimising side effects. Despite these potential benefits, there is concern regarding long term effects from the associated low dose bath, exposing more normal tissue to lower radiation dose as compared to more conventional radiation techniques. However, the effects of this low dose radiation have yet to be established. In this thesis, y-H2AX was used to assess radiation-induced DNA damage within peripheral blood lymphocytes of patients undergoing fixed gantry or static field IMRT (SF-IMRT). The reproducibility and sensitivity of y-H2AX as a comparison of DNA damage following differing radiation techniques has been documented, with significant differences in y-H2AX foci seen following SF-IMRT in comparison to volumetric arc-IMRT and 3D conformal radiation. Efforts have been made to demonstrate a difference in whole body exposure from these techniques and variations in y-H2AX foci distributions seen following techniques may reflect greater whole body exposure following SF-IMRT, which may have impact on long term toxicity. The benefits of IMRT to treat complex shaped meningiomas, often located close to critical dose limiting structures, have been investigated in a clinical phase I/II study. The feasibility of using IMRT to deliver conformal radiation to meningiomas, whilst respecting normal tissue tolerance has been demonstrated here. The preliminary report from this ongoing clinical study documents effective, safe treatment with acceptable toxicity levels and comparable local control, particularly within grade I meningiomas. Prospective data collection has revealed improvements in neurological symptoms and no significant quality of life deterioration. The findings in this thesis provide further information to guide future work, examining the biological and clinical long term effects of new radiation techniques

Cardio-oncology Issues in Lymphoma Patients

Advances in Lymphoma management have resulted in significant improvements in patient outcomes over the last 50 years. Despite these developments, cardiotoxicity from lymphoma treatments remains an important cause of mortality and morbidity in this cohort of patients. We outlined the most common cardiotoxicities associated with lymphoma treatments and their respective investigation and management strategies, including the role of cardiac pre-assessment and late effects monitoring

Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK

\ua9 2024 British Society for Haematology and John Wiley & Sons Ltd.Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes