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Recommended management of CTCAE-based immune-related adverse events due to immune checkpoint inhibitor (ICI) therapy (Continued) Notes: CTCAE provides grading criteria for peripheral motor neuropathy and sensory motor neuropathy. For all these irAEs, ICI therapy may be continued for grade 1 irAEs. However, ≥ grade 2 events require an ICI hold and referral to neurology. For events of ≥ grade 3 severity, ICI therapy should be permanently discontinued and IV corticosteroids administered.
Source publication
Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs...
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Purpose
To evaluate retrobulbar adipose tissue of patients with active and inactive Graves’ orbitopathy (GO) by shear-wave ultrasound elastography (SWE).
Methods
Followed-up in our ophthalmology clinic due to GO, 72 eyes of 36 patients and 38 eyes of 19 healthy controls were included in this cross-sectional case–control study. Graves’ patients wer...
Citations
... While there is no specific timeline or target ranges for blood glucose assessments, various organisations, including the National Comprehensive Cancer Network (NCCN) and the Japan Endocrine Society, recommend evaluating blood glucose regularly at each treatment cycle or visit (42,43). Furthermore, patients receiving ICIs, particularly anti-PD1 or PD-L1 treatments, should be educated about the acute symptoms of diabetes, such as polyuria, polydipsia, and weight loss, as well as the symptoms of ketoacidosis, including nausea, vomiting, and gastrointestinal disorders (44,45). Our patient was carefully educated about the symptoms to be recognised, and her blood glucose levels were assessed before each cemiplimab infusion. ...
Background
Immune checkpoint inhibitors (ICIs) have revolutionised the cancer treatment landscape in the last decades, improving the outcome of several tumours, such as cutaneous squamous cell carcinoma (cSCC). ICIs are antibodies blocking several immune checkpoint pathways, as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) with its ligand PD-L1. However, the activation of immune response can cause a broad range of side effects, called immune-related adverse events (irAEs). Endocrine irAEs are mainly represented by thyroid dysfunctions (thyrotoxicosis or hypothyroidism) and hypophysitis, while adrenal insufficiency and diabetes mellitus (DM) are less common. Diabetic ketoacidosis (DKA) is a potential life-threatening presentation of ICI-induced insulin-dependent DM (IDDM). This report presents a rare case of DKA and IDDM secondary to anti-PD-1 antibody cemiplimab therapy, and this is the third described in the literature to date.
Case presentation
We describe the case of a 62-year-old female patient with metastatic perianal squamous cell carcinoma who developed DKA and IDDM after the fifth cycle of cemiplimab. Hyperglycemia (1187 mg/dL), metabolic acidosis (pH 7.27) with bicarbonate levels of 11.9 mmol/L, arterial partial pressure of carbon dioxide of 25.7 mmHg with increased anion gap (equal to 25), and hyperketonuria were present. Adequate glycaemic control was difficult to maintain, and intravenously therapy (insulin, sodium bicarbonate, potassium, and fluids) was required for a long time. Subcutaneous basal-bolus insulin treatment was started, but glycaemic control was scarce, also due to the concomitant administration of prednisone for immune-related hepatotoxicity, until the subject’s death.
Conclusion
This report underlines the importance of the awareness on endocrine irAEs with ICIs, particularly life-threatening DKA. A baseline assessment of glycemia and glycated hemoglobin is mandatory, and we recommend a close monitoring of glycemic trend over time during ICIs therapy. Patients and their caregivers should be informed and counselled to recognise DKA signs and symptoms.
... The possibility of dose reduction may have resulted in patients in the IO/TKI group needing less glucocorticoids. However, it is clear that good management of side effects and close monitoring of patients undergoing immunotherapy have a significant impact on the success of treatment and therefore require a high level of interdisciplinary expertise from the treatment team [20,21,[44][45][46]. ...
Introduction
Systemic therapy for advanced renal cell carcinoma (aRCC) has become increasingly diverse. In the 1st-line setting, various combination therapies are available, with little comparative data on the efficacy of the therapies. The aim of this study was to compare the current 1st-line combination therapies under real-life conditions and to investigate risk factors in the patient population.
Methods
Patients with aRCC who started 1st-line IO/IO or IO/TKI combination therapy between 03/2019 and 10/2023 were included. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were time on treatment (ToT), duration of response (DoR), subsequent therapies, the evaluation of risk factors and their influence on PFS and OS. Survival data were analysed using Kaplan–Meier estimates with log-rank tests, risk factors for PFS and OS using Cox regression analysis.
Results
A total of 59 patients, mainly men (79.7%) with a median age of 64.8 years were included. The median follow-up was 21 months. The comparison of IO/IO vs. IO/TKI demonstrated a median PFS of 6 (2.08–9.92) vs. 14 (9.06–18.94) months (47 events; HR IO/TKI vs. IO/IO: 0.53 (0.29–0.99); p = 0.039) and a median OS of 20 (15.07–24.94) vs. 33 (21.68–44.32) months (32 deaths; HR IO/TKI vs. IO/IO: 0.74 (0.36–1.51); p = 0.403). Off all risk factors analysed only synchronous metastases proved to be of independent predictive value for PFS (HR 2.38; 95% CI 1.11–5.11; p = 0.026) and OS (HR 3.47; 95% CI 1.15–10.44; p = 0.027).
Conclusion
An IO/TKI therapy showed a significantly improved PFS in the real-world setting compared to an IO/IO combination. In terms of OS, the improved treatment response of the IO/TKI group did not prevail.
... Depending on the severity of complications, the treatment for hepatotoxicity might include cessation of therapy with immune checkpoint inhibitors. Corticosteroids and immunosuppression (in more severe cases) can be recommended as well [120][121][122][123]. Ursodeoxycholic acid (UDCA) is used to improve the liver function in the case of cholestatic hepatotoxicity, when corticosteroids are ineffective [124][125][126][127]. UDCA has the hepatoprotective and choleretic effects and is considered as the treatment standard for cholestatic liver diseases with the autoimmune component (primary biliary cholangitis, primary sclerosing cholangitis) [128][129][130]. ...
Hyaluronic acid (HA) is the main structure-forming polymer of the extracellular matrix. HA metab-
olism plays an important role in intercellular interaction in healthy organism and in various pathologies.
HA is synthesized by hyaluronan synthase (HAS); mammals have three highly homologous isoforms of this
enzyme: HAS1, HAS2, and HAS3. No highly specific competitive inhibitors of HASs have been described so
far. 4-Methylumbelliferone (4-MU), a natural coumarin compound, is commonly used to inhibit HA synthesis
in vivo and in cell cultures. The review is focused on the molecular mechanisms underlying the therapeutic
effects of 4-MU and discusses results of 4-MU application in tissue cultures and animal disease models, as well
as in first clinical trials of this compound. It was found that along with receptors and transcription factors,
one of the pharmacological targets of 4-MU is HAS2, which is most common isoform of HAS. Moreover, it is
inhibition of HA synthesis that underlies the pharmacological effects of 4-MU in oncological, autoimmune,
degenerative, and hypercompensated regenerative processes (fibrosis, scar formation). New clinical drugs
based on specific HAS2 inhibitors will be the first-in-class compounds to treat a wide range of diseases.
... However, there are inconsistencies in the frequency and timing of cardiac troponin (cTn) measurements across different studies. For instance, Puzanov et al. recommended that the measurement of cTn levels before starting treatment and at regular intervals, which may vary between two weeks and three months after treatment (33). Other researchers recommended regularly checking cTn values weekly during the first six weeks of treatment, in addition to assessing other biomarkers and performing ECG tests (34). ...
Background
Immune checkpoint inhibitors (ICIs), an immunotherapy used in cancer treatment, are associated with potential cardiovascular (CV) toxicity. Monitoring CV issues in non-small cell lung cancer (NSCLC) patients is challenging due to their lower incidence and diversity. Hence, enhancing our understanding of CV toxicities in patients receiving ICIs is required to improve their quality of life and survival. Hence, the main objective of this study is the evaluation of CV side effects in ICI-treated NSCLC patients by assessing the prevalence and hazard of CV events.
Methods
A systematic review was conducted to identify relevant studies, up to November 21st, 2023. A meta-analysis was performed to examine the data extracted from the selected studies. The random-effects model was applied to account for heterogeneity among studies, reporting results as prevalence rates and hazard ratios (HR) alongside their corresponding 95% confidence intervals (CI). Studies meeting inclusion criteria were selected and outcomes were assessed through qualitative analysis.
Results
Twelve observational studies using Real world Data were included, encompassing 23,621 patients with NSCLC. Our findings indicated that patients treated with ICIs exhibited a 3% prevalence of CV events and a significantly higher hazard (HR = 1.78 (95% CI: 1.46, 2.17); p < 0.00001; I2 = 72%) compared to patients treated with other drugs.
Conclusions
The treatment with ICIs caused a higher rate of CV events compared to non-ICI treatments. Nevertheless, further research is required to elucidate the underlying mechanisms and implications for patient care. This calls for continued research efforts to optimize the cardiovascular health of patients undergoing immunotherapy for lung cancer.
... Studies have demonstrated that the presence of LGE is associated with an increased risk of heart failure, arrhythmias, and adverse cardiac events, even after the acute phase of myocarditis has resolved [12]. The persistence of LGE suggests ongoing fibrotic remodeling, which may contribute to ventricular dysfunction and long-term cardiac complications [13]. ...
... The literature suggests that a follow-up MRI at 3 to 6 months post-myocarditis can provide critical insights into disease progression and guide the long-term management. Close monitoring remains essential, particularly in patients with persistent LGE, as they may require further risk stratification and additional cardiac surveillance [12,13]. ...
... Subclinical myocarditis represents an early phase of immune-mediated myocardial injury, in which patients may exhibit elevated cardiac biomarkers or subtle functional impairments detectable through imaging [13]. Over time, chronic inflammation promotes myocardial fibrosis, leading to ventricular dysfunction and increased arrhythmogenic risk [6]. ...
Immune checkpoint inhibitors (ICIs) therapy has revolutionized cancer treatment. However, it is important to acknowledge that ICI therapy can lead to immune-related adverse events (irAEs), including myocarditis. While early-onset myocarditis is well-documented, late-onset cases are increasingly recognized. This case series presents four cases of late-onset ICI-associated myocarditis, emphasizing the need for long-term surveillance of this potentially fatal complication. Patients exhibited a range of cardiac symptoms, including chest pain, shortness of breath, and arrhythmias. The diagnosis was confirmed through cardiac magnetic resonance imaging (MRI) and elevated cardiac biomarkers. Treatment involved the immediate discontinuation of ICI therapy and the initiation of high-dose corticosteroids. In cases with an inadequate response, additional immunosuppressive agents were considered. This case series underscores the importance of prolonged monitoring for late-onset ICI-associated myocarditis. Further research is needed to establish optimal treatment strategies and long-term management approaches for this complex condition.
... A multidisciplinary approach to management is recommended for the treatment of ICI-associated pneumonitis, and classification of severity (Table 1) helps to guide interventions. [50][51][52] It is imperative to involve infectious, pulmonary, and/or oncologic consultants early to determine the most appropriate treatment, especially for complex cases with multiple etiologies. Treatment options generally consist of temporary ICI cessation with regular clinical reassessment, and in more symptomatic cases, systemic immunosuppression may be required. ...
Immune checkpoint inhibitors (ICI), such as pembrolizumab, nivolumab, durvalumab and ipilimumab, have significantly enhanced survival rates for multiple cancer types such as non-small cell lung cancer, melanoma, Hodgkin lymphoma, and breast cancer, and they have emerged as an adjunct or primary therapy for malignant disease. Approximately 40% of patients with cancer on ICI therapy experience side effects called immune-related adverse events (irAE). While not the most common, pulmonary toxicities can be rapidly progressive, potentially fatal, and pose a three-fold increased risk for requiring intensive care unit-level of care. Pneumonitis is a focal or diffuse inflammation of the lung parenchyma, and clinical manifestations may be highly variable. While the onset is generally observed 6–12 weeks after the initiation of therapy, drug toxicity can develop rapidly within days after the first infusion or many months into therapy. Pneumonitis symptoms can be subtle or non-specific; therefore, a thorough and systematic evaluation considering other possible etiologies is crucial. Moreover, extrapulmonary findings, such as skin lesions, colitis, or endocrinopathies, should raise suspicion for irAE as drug toxicity can affect multiple organs simultaneously. Due to the significant overlap of clinical features between ICI-associated pneumonitis and respiratory infections, it can be challenging to differentiate the two conditions based on clinical presentation alone. A multidisciplinary approach to management is recommended for the treatment of ICI-associated pneumonitis, and classification of severity helps to guide interventions. Treatment options in more severe cases include systemic immunosuppression. Given the increased use of ICIs and greater probability that patients with ICI-associated pneumonitis will be seen in the emergency department, we aimed to provide a comprehensive framework for the diagnosis and management. In addition, identifying potential challenges in diagnosis and/or other contributors of respiratory symptoms and radiographic manifestations is highlighted.
... Therefore, it is essential to plan appropriate counseling for patients and effectively manage these concerns. 42 The findings of this study support standardizing the measurements made during physical examination, developing a common language for any findings, and implementing training approaches such as periodic repetition of education programs and highquality simulation to improve nurses' skills. In particular, the authors recommend that oncology and hematology nurses receive extensive training (including theoretical and clinical skills) in skin and edema assessment. ...
OBJECTIVE
To assess the competency of oncology/hematology nurses in evaluating the lower extremities of patients with cancer for skin conditions and edema.
METHODS
This prospective and descriptive observational study was conducted with patients in a university hospital’s 48-bed oncology/hematology service. Patients with cancer admitted to the oncology/hematology service were examined independently by three evaluators (two nurse researchers and the patient’s primary nurse) daily. Interrater reliability for assessing patients’ right and left legs was determined using Fleiss κ statistics for categorical variables.
RESULTS
The study revealed a high degree of agreement among the three evaluators in the assessment of skin surface, skin color, and presence of petechiae and rashes on the right and left leg, as well as itching on the left leg. However, only moderate agreement was found for temperature assessment, ecchymoses edema on the left and right leg, and itching on the right leg. The reliability of the two researcher nurses’ assessment of edema on the right and left legs was excellent.
CONCLUSIONS
Although the agreement between the two researcher nurses was near excellent, only moderate agreement was observed among all evaluators in the edema assessment. The result underscores the importance of healthcare providers’ knowledge and enhancing clinical skills through innovative training strategies.
... These findings are particularly related to anti-CTLA-4 antibodies rather than anti-PD-1/anti-PD-L1 antibodies [97,98]. As mentioned above, however, the diagnosis of IH can also be made in the absence of concomitant specific radiological signs; in this regard, it should be considered that sometimes the pituitary anatomical alterations can precede the biochemical alterations, and imaging is therefore often carried out when this alteration has already regressed [56,69,86,99]. In IH, the gland size returns to baseline size or smaller within months. ...
Immune checkpoint inhibitors (ICIs) have revolutionized oncology, providing a groundbreaking therapeutic option for patients with various advanced-stage cancers. While these treatments can significantly extend survival, they also carry a substantial risk of immune-related adverse events, among which hypophysitis is particularly detrimental to endocrine function. This narrative review synthesizes current knowledge on the pathogenesis, clinical features, diagnosis, and management of ICI-induced hypophysitis (IH) based on an in-depth analysis of the recent literature and clinical trials. The diagnosis of IH presents unique challenges due to its overlap with systemic symptoms commonly associated with the underlying malignancy. These symptoms can include asthenia, anorexia, headache, vomiting, weight loss, hypotension, dizziness, decreased libido, and visual disturbances. Diagnostic evaluation typically combines clinical assessment, hormonal profiling, and findings from magnetic resonance imaging (MRI). Effective management of IH requires a personalized, multidisciplinary approach, focusing on hormone replacement therapy and vigilant monitoring. Long-term care depends on the severity of hypophysitis, and the specific hormonal axes involved. This review aims to enhance awareness of the critical aspects of recognizing and managing IH, underscoring the importance of early diagnosis and timely intervention to reduce its long-term effects on patient quality of life.
... Regular monitoring of liver function tests and clinical status is crucial to assessing treatment response and detecting any progression of liver injury [63]. Consensus recommendations on managing ILICI and other irAEs, and for a safer rechallenge, have been published by the European Society for Medical Oncology (ESMO) [82] and by the Society for Immunotherapy of Cancer (SITC) [83]. ...
Targeted therapies and immunotherapies have shown great promise as best‐in‐class treatments for several cancers with respect to efficacy and safety. While liver test abnormalities are rather common in patients treated with kinase inhibitors or immunotherapy, events of severe hepatotoxicity in these patients are rare in comparison with those associated with chemotherapeutics. The underlying mechanisms and risk factors for severe hepatotoxicity with novel oncology therapies are not well understood, complicating the drug‐induced liver injury (DILI) risk assessment in the preclinical and clinical phases of drug development. The epidemiological and clinical characteristics, as well as mechanisms of liver toxicity, are described here to the current state of knowledge. Tools to study and assess the risk of DILI during drug development are concisely summarised, focusing on caveats thereof for novel oncology treatments. Emerging tools to optimise safety assessments and gather additional mechanistic insights into DILI are introduced. Particularly in oncology, where standard liver signals during drug development are tolerated to a marginally higher degree than in other indications due to the life‐saving, life‐extending and quality‐of‐life improvements for patients with severe or advanced cancers versus previous standard‐of‐care therapeutics, safety assessments must be tailored to the drug and indication. Trends in patient safety‐centred drug development programmes and regulatory approval processes must continually be revisited and streamlined via obtaining an overall greater understanding of DILI and the tools available to assess mechanisms of injury, frequency, severity and prognosis.
... The lack of routine CV monitoring despite guidelines and the inclusion of highly selected and healthier patients in clinical trials suggest that CV irAEs have most likely been underreported throughout the years. [8][9][10][11][12] Although phase III clinical trials play an important role in understanding the effectiveness and safety profiles of ICIs, real-world studies can provide more insight on the risk of cardiotoxicity in a representative patient population. Currently, real-world data on CV events have either been single-center or conducted in non-Caucasian patients, where anti-CTLA-4 has limited availability and different ICIs were used along with different indications, tumor types, and patient characteristics. ...
Background: Immune checkpoint inhibitor (ICI) use may be associated with diverse cardiovascular (CV) adverse events (AEs), but their baseline prevalence and incidence after ICI initiation are poorly known. We aimed to describe CV events using real-world hospital data from Belgian cancer patients. Materials and methods: Electronic health records (EHRs) from patients receiving at least one ICI between March 2017 and August 2022 at three Belgian hospitals were processed into an Observational Medical Outcomes Partnership Common Data Model warehouse. Structured data were enriched with unstructured data that were processed using a natural language processing (NLP) pipeline. We analyzed CV events from first ICI administration until last follow-up, identifying and validating the first detection of a CV event at the patient level. Results: We included 1571 patients (66% male, median age 67 years); CV events were detected in 196 (12.5%) patients [median (min-max) follow-up: 8 (0-63) months]. The CV AEs detected were heart failure (5.3%), atrial fibrillation (4.6%), myocardial infarction (2.0%), atrioventricular block (1.9%), myocarditis (1.2%), vasculitis (0.8%), pericarditis (0.4%), and Takotsubo cardiomyopathy (<0.3%). Median time (min-max) to onset ranged from 109 days (17-849 days) for myocarditis to 529 days (91-967 days) for Takotsubo cardiomyopathy. Conclusions: To our knowledge, this is the first study using a dataset enriched with NLP-processed EHRs that describes the frequency and onset time of CV events. CV event frequencies were higher than those reported in clinical trials, but similar to other real-world studies. However, we observed a later time to onset. Hence, clinicians should note that CV AEs can present in various ways and at any time during or after treatment.
