On examination after admission, she was well and alert; her temperature was 36·7°C, blood pressure 186/105 mm Hg, and pulse rate 83 beats per min. Fluorescence in situ hybridisation analysis found an ...ALK gene rearrangement in 93% of the nuclei, characterised by supernumerary red signals. An 18F-FDG PET/CT confirmed a complete metabolic response (figure).
The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments ...represent a cost that can be harmful to short- and long-term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio-oncology expert panel from the French Working Group of Cardio-Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.
In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the ...spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.
We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC025 (lower end of the IC 95% credibility interval) >0 is deemed significant.
We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 11.6–18.4, IC025 = 3.34), sarcoidosis (n = 94; ROR = 9.6 7.9–11.9; IC025 = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 5.2–9.2; IC025 = 2.24), myositis (n = 465; ROR = 4.9 4.5–5.4; IC025 = 2.12), arthritis (n = 606; ROR = 1.4 1.3–1.5; IC025 = 0.34) and scleroderma (n = 17; ROR = 2.0 1.2–3.2; IC025 = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6–2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1–4.4, p < .05). Median time to onset occurred early for myositis (31 days 19.2–57.8) and was the most delayed for scleroderma (395 days 323.8–457.2, p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to 0–6.7% for other RMS-irAE (p < .0001).
Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.
•We identified over 1000 individual case safety reports related to RMS-irAE induced by ICI.•RMS-irAE encompassed arthritis, myositis, sarcoidosis, polymyalgia rheumatica, Sjogren's syndrome, and scleroderma.•Myositis occurred early within weeks after initiation of ICI therapy and carried a high fatality rate, particularly when concurrent myocarditis was reported; whereas other RMS-irAE had a low mortality burden.
When we first assessed the patient, a transthoracic echocardiogram showed a mass extending from the inferior vena cava into the right atrium causing obstruction of the tricuspid valve (appendix); ...contrast-enhancement showed some opacification of the mass (appendix). After assessment and discussion with the patient—considering firstly his generally good physical state, secondly the response of the disease to immune-checkpoint inhibitors, and thirdly, the obstruction of the tricuspid valve—we excised the right atrial mass during beating-heart surgery with partial cardiopulmonary bypass (appendix). Gross macroscopic evaluation of the excised mass showed a small amount of thrombus with mostly tissue consistent with a metastatic process (appendix); histopathological analysis of a sample of the lesion confirmed mucinous adenocarcinoma.
Abstract
Aims
With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA).
Methods and results
We used the ...international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967–83 to 15 070 in 2014–18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed.
Conclusion
This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements.
Clinical trial registration
NCT03530215.
Graphical Abstract
Graphical Abstract
Evolution of reporting for drug-induced long QT, ventricular arrhythmias, and torsade de pointes associated with anticancer drugs (A) as a function of their classes (B) in VigiBase from inception (1967) to January 2019.
Myocarditis with Immune Checkpoint Blockade Ederhy, Stéphane; Voisin, Anne-Laure; Champiat, Stéphane
The New England journal of medicine,
01/2017, Letnik:
376, Številka:
3
Journal Article
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