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Background: Adjuvant immune checkpoint inhibitors are a new standard of care in melanoma. However, the immune related toxicity associated with these agents can be serious, and the long-term implications are yet to be defined especially in the adjuvant setting. We report, to our knowledge, the first case of anti-PD-1-induced eosinophilic asthma in a melanoma patient treated with adjuvant pembrolizumab. Case Presentation. A 72-year-old man commenced pembrolizumab in the adjuvant setting after resection of a stage IIIB cutaneous melanoma. The patient experienced episodes of breathlessness 4 weeks after cycle 1. These episodes were nocturnal and caused acute respiratory distress and cough, occasionally waking him up. The episodes progressed, and he was admitted after cycle 2 with a productive cough, wheeze, and breathlessness. Observations showed saturations on air of 94% and a respiratory rate of 19/min. The only laboratory abnormality was a raised eosinophil count of 1.1 × 109. Spirometry showed a FEV1 of 2.57 (91% predicted), FVC of 4.04 (108% predicted), and ratio of 64%. Peak expiratory flow rate was 94% predicted, and corrected gas transfer was 6.29 (78% predicted) with KCO 1.18 (93% predicted). FeNO was raised at 129 indicating inflammation of his airways, and peak flow was 422 l/min. CT of the chest did not show pneumonitis or other lung pathology. A diagnosis of acute eosinophilic asthma was made. Treatment with steroids and beclometasone dipropionate and formoterol inhaler produced rapid resolution of symptoms and normalisation of the eosinophil count. Pembrolizumab was safely recommenced once steroids had discontinued and symptoms had resolved. Conclusions: Specialist respiratory input was needed for optimal patient management and is ongoing. Although a safe rechallenge with pembrolizumab was possible, treatment in the adjuvant setting is curative in intent and long-term safety follow-up is required to assess for delayed toxicity and long-term health implications. This is likely to require large regional/national/international databases to detect, monitor, and educate the wider medical community as these patients are followed up in primary care following initial specialist follow-up.
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BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
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Ensayos Clínicos como Asunto/normas , Neoplasias Hepáticas/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Proyectos de Investigación/estadística & datos numéricos , Neoplasias de la Úvea/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/sangre , Benchmarking , Conjuntos de Datos como Asunto , Femenino , Humanos , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/sangre , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Melanoma/sangre , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Factores Sexuales , Factores de Tiempo , Neoplasias de la Úvea/sangre , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/patología , Adulto JovenRESUMEN
BACKGROUND: Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune-related adverse events (irAE) based on tumour type and ICI class. METHODS: Medline, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), χ2 tests and multivariable regression models were used to analyse for effect size and associations. RESULTS: We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8-12.9), hypophysitis (OR 6.5, 95% CI 3.0-14.3) and rash (OR 2.0, 95% CI 1.8-2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2-12.7), hypothyroidism (OR 4.3, 95% CI 2.9-6.3), arthralgia (OR 3.5, 95% CI 2.6-4.8) and vitiligo (OR 3.5, 95% CI 2.3-5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour types in PD-1 mAbs trials [melanoma (n = 2048), non-small-cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis. DISCUSSION: CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.
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Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/inmunología , Antígeno CTLA-4/inmunología , Ensayos Clínicos como Asunto/métodos , Humanos , Enfermedades del Sistema Inmune/inducido químicamente , Enfermedades del Sistema Inmune/inmunología , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
INTRODUCTION: Treatment on a clinical trial is considered to be beneficial to oncology patients. However, supportive evidence for this is scarce. Trial effect describes the phenomenon of improved health outcomes in patients treated with standard of care (SOC) on trial compared to those receiving SOC outside of a clinical trial. We evaluated trial effect in patients with ovarian cancer treated at our tertiary cancer centre. METHODS: We performed a retrospective cohort study of patients with ovarian cancer treated at The Christie National Health Service Foundation Trust. Patients treated on one of three first-line clinical trials: (SCOTROC-4, ICON-5, ICON-7) were matched (for age, International Federation of Gynaecology and Obstetrics stage, surgical status and performance status) with individuals receiving the same SOC off trial. Survival was calculated using Kaplan-Meier methodology. RESULTS: 60 patients were evaluated; 30 on trial and 30 on SOC off trial. The median progression-free survival (PFS) was 21.8â months (control group) and 25.9â months (trial group), median overall survival (OS) was 64.3â months (control group) and 68.9â months (trial group). There was no difference in PFS (log-rank test: HR 0.87 (95% CI 0.48 to 1.54), p=0.6) or OS (log-rank test: HR 0.87 (95% CI 0.46 to 1.64), p=0.7) between groups. CONCLUSIONS: Patient survival was similar regardless if treated on trial or as SOC. Our findings do not support trial effect, at least in a tertiary cancer centre. Clinical trial participation in specialised cancer centres promotes best practice to the benefit of all patients. These findings may impact discussions round consent of patients to trials and organisation of oncology services.
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AIMS: Ovarian cancer is the principal cause of gynaecological cancer death in developed countries, yet overall survival in the UK has been reported as being inferior to that in some Western countries. As there is a range of survival across the UK we hypothesised that in major regional centres, outcomes are equivalent to the best internationally. MATERIALS AND METHODS: Data from patients treated in multicentre international and UK-based trials were obtained from three regional cancer centres in the UK; Manchester, University College London and Leeds (MUL). The median progression-free survival (PFS) and overall survival were calculated for each trial and compared with the published trial data. Normalised median survival values and the respective 95% confidence intervals (ratio of pooled MUL data to trial median survival) were calculated to allow inter-trial survival comparisons. This strategy then allowed a comparison of median survival across the UK, in three regional UK centres and in international centres. RESULTS: The analysis showed that the trial-reported PFS was the same in the UK, in the MUL centres and in international centres for each of the trials included in the study. Overall survival was, however, 45% better in major regional centre-treated patients (95% confidence interval 9-73%) than the median overall survival reported in UK trials, whereas the median overall survival in MUL centres equated with that achieved in international centres. CONCLUSION: The data suggest that international survival statistics are achieved in UK regional cancer centres.
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Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection.
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Biomarcadores de Tumor/sangre , Neoplasias del Ojo/diagnóstico , Melanoma/patología , Células Neoplásicas Circulantes/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias del Ojo/secundario , Humanos , Melanoma/diagnóstico , Neoplasias Cutáneas/secundarioRESUMEN
BACKGROUND: The national confidential enquiry into patient outcomes and death (NCEPOD) set important benchmarks in assessing the quality of care received by patients dying within 30 days of systemic anticancer therapy (SACT). Monthly morbidity and mortality audits conducted to recommendations in the NCEPOD were commenced at the Christie NHS Foundation Trust in 2009, specifically to assess and improve patient outcomes. METHODS: We evaluated the outcomes of patients who died within 30 days of SACT over a 4 year period 2009-2013. We collated audit findings to determine the number of treatment related deaths, clinical characteristics of patients, causes of death and quality of care received. We examined the benefit of the audit in decreasing 30 day mortality during the 4 years and considered factors that may be associated with an increased risk of SACT related death. RESULTS: A total of 31,183 patients were treated at the Christie from 2009 to 2013. Of these 4% died within 30 days of SACT. Death was treatment related in 11%. The decision to treat with SACT was appropriate in 87% of but there was room for improvement in care in 24%. Mortality decreased over the 4 years. Possible factors associated with 30 day mortality post SACT included performance status ⩾2, presence of comorbidities, treatment type and treatment setting. CONCLUSIONS: We demonstrated that our audit process is feasible and robust. Further areas of research to determine predictive scores for patient treatment selection and improve outcomes were highlighted and are ongoing.
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Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Neoplasias/terapia , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Causas de Muerte , Femenino , Humanos , Inmunoterapia/efectos adversos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias/mortalidad , Evaluación de Resultado en la Atención de Salud/métodos , Calidad de la Atención de Salud/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Obtaining tissue for pancreatic carcinoma diagnosis and biomarker assessment to aid drug development is challenging. Circulating tumour cells (CTCs) may represent a potential biomarker to address these unmet needs. We compared prospectively the utility of two platforms for CTC enumeration and characterisation in pancreatic cancer patients in a pilot exploratory study. PATIENTS AND METHODS: Blood samples were obtained prospectively from 54 consenting patients and analysed by CellSearch and isolation by size of epithelial tumour cells (ISET). CellSearch exploits immunomagnetic capture of CTCs-expressing epithelial markers, whereas ISET is a marker independent, blood filtration device. Circulating tumour cell expression of epithelial and mesenchymal markers was assessed to explore any discrepancy in CTC number between the two platforms. RESULTS: ISET detected CTCs in more patients than CellSearch (93% vs 40%) and in higher numbers (median CTCs/7.5 ml, 9 (range 0-240) vs 0 (range 0-144)). Heterogeneity observed for epithelial cell adhesion molecule, pan-cytokeratin (CK), E-Cadherin, Vimentin and CK 7 expression in CTCs may account for discrepancy in CTC number between platforms. CONCLUSION: ISET detects more CTCs than CellSearch and offers flexible CTC characterisation with potential to investigate CTC biology and develop biomarkers for pancreatic cancer patient management.