Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm. All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi + nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity. In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi + nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail. Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipi + nivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients.

To determine the symptomatic and prognostic differences resulting from a novel diagnostic pathway based on cardiac computerized tomography (CT) compared with the traditional exercise stress electrocardiography test (EST) in stable chest pain patients. A prospective randomized controlled trial compared selected patient outcomes in EST and cardiac CT coronary angiography groups. Five hundred patients with troponin-negative stable chest pain and without known coronary artery disease were recruited. Patients completed the Seattle Angina Questionnaires (SAQ) at baseline, 3, and 12 months to assess angina symptoms. Patients were also followed for management strategies and clinical events. Over the year 12 patients withdrew, resulting in 245 in the EST cohort and 243 in the CT cohort. There was no significant difference in baseline demographics. The CT arm had a statistical difference in angina stability and quality-of-life domains of the SAQ at 3 and12 months, suggesting less angina compared with the EST arm. In the CT arm, there was more significant disease identified and more revascularizations. Significantly, more inconclusive results were seen in the EST arm with a higher number of additional investigations ordered. There was also a longer mean time to management. There were no differences in major adverse cardiac events between the cohorts. At 1 year in the EST arm, there were more Accident and Emergency (A&E) attendances and cardiac admission. Cardiac CT as an index investigation for stable chest pain improved angina symptoms and resulted in fewer investigations and re-hospitalizations compared with EST. http://www.controlled-trials.com/ISRCTN52480460.

Radiotherapy is the standard of care treatment for unresectable NSCLC, combined with concurrent chemotherapy and adjuvant immunotherapy. Despite technological advances in radiotherapy planning and delivery, the risk of damage to surrounding thoracic tissues remains high. Cardiac problems, including arrhythmia, heart failure and ischaemic events, occur in 20% of patients with lung cancer who undergo radiotherapy. As survival rates improve incrementally for this cohort, minimising the cardiovascular morbidity of RT is increasingly important. Problematically, the reporting of cardiac endpoints has been poor in thoracic radiotherapy clinical trials, and retrospective studies have been limited by the lack of standardisation of nomenclature and endpoints. How baseline cardiovascular profile and cardiac substructure radiation dose distribution impact the risk of cardiotoxicity is incompletely understood. As Thoracic Oncology departments seek to expand the indications for radiotherapy, and as the patient cohort becomes older and more comorbid, there is a pressing need for cardiotoxicity to be comprehensively characterised with sophisticated oncology, physics and cardio-oncology evaluations. This review synthesises the evidence base for cardiotoxicity in conventional radiotherapy, focusing on lung cancer, including current data, unmet clinical needs, and future scientific directions.

Symptomatic arrhythmia is common following radiotherapy for non-small cell lung cancer (NSCLC), frequently resulting in morbidity and hospitalization. Modern treatment planning technology theoretically allows sparing of cardiac substructures. Atrial fibrillation (AF) comprises the majority of post-radiotherapy arrhythmias, but efforts to prevent this cardiotoxicity have been limited as the causative cardiac substructure is not known. In this study we investigated if incidental radiation dose to the pulmonary veins (PVs) is associated with AF. A single-centre study of patients completing contemporary (chemo)radiation for NSCLC, with modern planning techniques. Oncology, cardiology and death records were examined, and AF events were verified by a cardiologist. Cardiac substructures were contoured on planning scans for retrospective dose analysis. In 420 eligible patients with NSCLC treated with intensity-modulated (70%) or 3D-conformal (30%) radiotherapy with a median OS of 21.8 months (IQR 10.8-35.1), there were 26 cases of new AF (6%). All cases were grade 3 except two cases of grade 4. Dose metrics for both the left (V55) and right (V10) PVs were associated with the incidence of new AF. Metrics remained statistically significant after accounting for the competing risk of death and cardiovascular covariables for both the left (HR 1.02, 95%CI 1.00-1.03, p = 0.005) and right (HR 1.01 (95%CI 1.00-1.02, p = 0.033) PVs. Radiation dose to the PVs during treatment of NSCLC was associated with the onset of AF. Actively sparing the PVs during treatment planning could reduce the incidence of AF during follow-up, and screening for AF may be warranted for select cases.

Cardiac disease is a dose-limiting toxicity in non-small cell lung cancer radiotherapy. The dose to the heart base has been associated with poor survival in multiple institutional and clinical trial datasets using unsupervised, voxel-based analysis. Validation has not been undertaken in a cohort with individual patient delineations of the cardiac base or for the endpoint of cardiac events. The purpose of this study was to assess the association of heart base radiation dose with overall survival and the risk of cardiac events with individual heart base contours. Patients treated between 2015 and 2020 were reviewed for baseline patient, tumour and cardiac details and both cancer and cardiac outcomes as part of the NI-HEART study. Three cardiologists verified cardiac events including atrial fibrillation, heart failure and acute coronary syndrome. Cardiac substructure delineations were completed using a validated deep learning-based autosegmentation tool and a composite cardiac base structure was generated. Cox and Fine-Gray regressions were undertaken for the risk of death and cardiac events. Of 478 eligible patients, most received 55 Gy/20 fractions (96%) without chemotherapy (58%), planned with intensity-modulated radiotherapy (71%). Pre-existing cardiovascular morbidity was common (78% two or more risk factors, 46% one or more established disease). The median follow-up was 21.1 months. Dichotomised at the median, a higher heart base Dmax was associated with poorer survival on Kaplan-Meier analysis (20.2 months versus 28.3 months; hazard ratio 1.40, 95% confidence interval 1.14-1.75, P = 0.0017) and statistical significance was retained in multivariate analyses. Furthermore, heart base Dmax was associated with pooled cardiac events in a multivariate analysis (hazard ratio 1.75, 95% confidence interval 1.03-2.97, P = 0.04). Heart base Dmax was associated with the rate of death and cardiac events after adjusting for patient, tumour and cardiovascular factors in the NI-HEART study. This validates the findings from previous unsupervised analytical approaches. The heart base could be considered as a potential sub-organ at risk towards reducing radiation cardiotoxicity.