Troponin or not troponin: What is the impact of regular cardiac monitoring for patients treated with immunotherapy?

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Axel Cailleteau, Elvire Martin-Mervoyer, Mélanie Saint-Jean, Julie Paul, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7820886/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immune checkpoint inhibitors (ICI) have changed cancer treatment, but they also bring a risk of immune-mediated cardiac toxicities (IMCT), such as myocarditis. Given the rarity but high mortality rates of IMCT, early detection is crucial. Objectives This study aimed to evaluate the impact of our cardiac monitoring algorithm, based on troponin and electrocardiogram follow up, on patients undergoing ICI therapy, assessing whether it reduces treatment interruptions and severe cardiac adverse events. Methods A retrospective study was conducted using data from the West Cancer Institute in Saint Herblain, France. Patients treated with ICIs for lung cancer or melanoma were divided into two groups: group A treated in 2019 (pre-algorithm) and group B treated in 2020–2021 (post-algorithm). The primary objective was to assess the impact of monitoring on the number of treatment cycles canceled or delayed. The secondary objective was to assess the rate of grade 3–4 cardiac or associated adverse events. Results 162 patients were included (45 – group A, 117 – group B). There was no significant difference in treatment interruptions (26.7% vs. 24.8%, p = 0.96). Moreover, the rate of grade 3–4 cardiac or associated adverse events was similar between the two groups (p = 0.2). Conclusions The implementation of the cardiac monitoring protocol had no negative impact on treatment administration but without reduction of severe cardiac or associated immune induced adverse event. This implementation demonstrated good adherence to the procedure; however, further efforts are needed to optimize strategies for the early detection of rare but serious adverse events. oncocardiology troponin immunotherapy myocarditis immune checkpoint inhibitors Figures Figure 1 Figure 2 Translational perspective Patients receiving immune checkpoint inhibitors (ICI) are at risk of developing immune-mediated cardiac toxicities (IMCT), which can present as myocarditis, arrhythmias, or other cardiovascular complications. Early identification of IMCT through biomarkers such as troponin, along with systematic ECG and imaging monitoring, may improve patient care by early detection of toxicities. Implementing cardiovascular assessment in cancer patients undergoing ICI therapy could enhance clinical decision-making and reduce morbidity. Further research is needed to refine risk stratification models for IMCT, incorporating clinical, imaging, and biomarker data. Prospective trials should assess the efficacy of early detection or intervention and alternative immunomodulatory treatments in severe cases. Additionally, the development of standardized guidelines for cardiac monitoring in ICI-treated patients could facilitate broader clinical adoption and improve patient safety. Introduction These last years, immune checkpoint inhibitors (ICIs) have changed the practices in oncology, demonstrating remarkable effectiveness in treating malignancies such as melanoma(1) and lung cancer(2). However, these treatments have introduced a new spectrum of immune-mediated toxicities requiring comprehensive evaluation and management. Some of these toxicities are particularly serious, including immune-mediated cardiac toxicities (IMCT), hepatitis, and immune-mediated pneumonitis(3). IMCT include various conditions, from myocarditis(4) and congestive heart failure to acute coronary syndromes, pericardial disorders, dysrhythmias, and even cardiac arrest. Although relatively rare, with an incidence ranging from 0.04% to 1.14%(5), these adverse events have high mortality rates, up to 50% in myocarditis(6). A substantial number of IMCT cases raise up to Grade 3 or 4 severity, highlighting the need for careful monitoring and early detection. Recent reports indicate that while only 0.6% of patients receiving anti-PD-(L)1 immunotherapy experience cardiac adverse events (AE), 77.5% of these events are classified as Grade 3 or higher. Approximately 45% of IMCT cases are attributed to myocarditis, with 65% of IMCT coinciding with other immunotherapy-related toxicities mainly myositis, hepatitis and pneumonitis. Strikingly, 83% of patients afflicted with immunotherapy-associated myocarditis also manifest other immunotherapy-related AE(7). Emerging evidence suggests that cardiac toxicity often manifests early, typically within one to two months or after one to two treatment doses(7) , (8) , (9) Efforts to mitigate IMCT have prompted investigations into the use of biomarkers, particularly troponin, as tools for early detection(10) , (11). However, its utility remains uncertain given the rarity of these events and of the limited specificity of troponin, which may be elevated in numerous other conditions. Elevation in hepatic enzymes appear to have a stronger association with muscular origins and a robust correlation with creatine kinase (CPK) levels, warranting consideration(12). 2022 ESC guidelines have proposed recommendations to classify patients into two risk groups: low and high. High risk is defined by the presence of dual ICI therapy, combination ICI-cardiotoxic therapy, ICI-related non-cardiovascular events, prior cancer therapy-related cardiac dysfunction, or pre-existing cardiovascular disease. For ECG monitoring: In low-risk patients, a baseline ECG (Level I) is recommended, followed by assessments at cycles C2, C3, and C4, then every three cycles (Level IIa), and subsequently every 6 to 12 months (Grade IIb). In high-risk patients, the same schedule is proposed, but with a Grade I recommendation for long-term ECG monitoring every 6 to 12 months. For troponin monitoring: In both low- and high-risk patients, it is recommended at baseline (Grade I), then at cycles 2, 3, and 4, and subsequently every three cycles (Grade II). This recommendation have clarified the cardiac follow up of patient under ICI, however, evidence is missing without prospective or even retrospective external validation(13) Before these guidelines, our institution developed a comprehensive decision algorithm for detecting IMCT (Figure 1), incorporating a baseline cardiac assessment and electrocardiogram and troponin follow up. This study aims to assess the impact of this algorithm on the course of immunotherapy in patients with lung cancer or melanoma. Methods Study design and Participants We used our institutional registry database of chemotherapy (CHIMIO WEB v5.9) to identify and extract data from consecutive patients at the comprehensive cancer center inSaint Herblain, France treated with ICI for melanoma or lung cancer. We divided patients into two groups: those treated in 2019 (before the implementation of our monitoring algorithm) and those treated in 2020-2021 (when the algorithm was implemented). Inclusion criteria encompassed patients aged 18 or older with a histopathologically confirmed diagnosis of lung cancer or melanoma treated with ICI (i.e. antiPD1 or antiPDL1 alone or dual immunotherapy antiPD1 and antiCTLA4) as per standard of care guidelines at the time of the recruitment. Patients in clinical trials, those with concurrent malignancies and those who declined data collection were excluded. Patients treated with chemotherapy or targeted therapy were excluded to minimize confounding factors. The algorithm includes an initial cardiac assessment consisting of clinical evaluation, assessment of cardiovascular risk factors, electrocardiography, baseline echocardiography with measurement of left ventricle ejection fraction and global longitudinal strain, Troponin T and I blood levels, NT proBNP blood level, and patient education on early recognition of cardiac symptoms (Figure 1). Subsequently, patients undergo monthly follow-ups including a clinical and biological assessment (troponin T or I) and electrocardiography for the first three months, followed by evaluations every three months for a year and then annually. A secondary decision algorithm has been implemented based on abnormalities identified during baseline assessment, to separate patients into low-risk and high-risk groups (Figure 1), with risk factors such as double immunotherapy, preexisting cardiopathy, diabetes, and autoimmune diseases. High-risk individuals may undergo additional echocardiography at three months and subsequently annually. The study was approved by the Institutional Ethics Committee of Angers Hospital in France (protocol code 2021-207, date of approval 10 December 2021). Patients were informed about the possible data reuse for research projects during initial data collection. Procedure We collected patients' baseline characteristics, especially cardiologic characteristics, in 2019 (group A) if available, and in 2020-2021 for others patients (group B). The initial characteristics and cardiac follow-up were best conducted by a specialized cardio-oncologist. Evaluation by the attending cardiologist was accepted, provided that the last visit occurred less than one year before the first injection and was conformed to our standard initial cardiac assessment (as precised above). The stage of the disease, the type of immunotherapy (anti-CTLA4, anti-PD(L)1, or association), the number of treatment cycles, and the previous history of autoimmune disease were also collected. For cardiac evaluation, we collected patients’ cardiovascular history: common risk factors (smoking status, body mass index ( BMI), age, hypertension, diabetes, hypercholesterolemia, family history of cardiovascular conditions, preexisting cardiovascular diseases, preexisting cardiac symptoms, cardiovascular medications (beta-blockers, angiotensin-converting enzyme inhibitors, antiarrhythmics, calcium channel blockers, diuretics, antiplatelet, anticoagulant), results of their clinical and biological examinations, the results of the ECG and echocardiography analysis. Patients were classified into LR or HR of immune cardiac adverse events populations according to the previously described criteria.). Preexisting cardiopathy was defined according to ESC guidelines(13) (myocardial infarction, angina, coronary stent, peripheral vascular disease, coronary artery bypass graft, stroke, or transient ischemic attack). Follow-up duration was calculated from the date of baseline cardiac evaluation to the end of immunotherapy. Statistical analysis Categorical variables were described using the number of people and the associated percentage. They were compared using a Pearson Chi-squared test or Fisher’s exact test, whenever appropriate. Quantitative variables were described using median and range (min-max). They were compared using Student’s t-test if the assumption of normality was met; otherwise, non-parametric statistics were made and compared using Wilcoxon’s test. Tests were two-sided and p-values <0.05 were considered significant. All analysis were performed with R software [R Core Team (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: http://www.R-project.org/.]. Outcomes The primary end point was to assess the impact of cardiac monitoring on the number of treatment cycles canceled or delayed. Secondary criteria or end point included evaluating whether our cardiac monitoring approach could prevent Grade 3 or 4 AE by evaluating the percentage of myositis, hepatitis, pneumonitis and myocarditis grade 3 or 4 in each group and to describe the management of these toxicities. Results Population We identified 240 patients treated with immunotherapy between 2019 and 2021. Among them, 53 were treated in 2019, and 187 were treated in 2020-2021. After excluding patients who did not meet inclusion criteria, 45 patients from 2019 (group A) and 117 from the 2020-2021 (group B) were included in the study (Figure 2) (Table 1). The details of histology and stade are available in Table S1 and S2. Baseline Cardiologic Evaluation: Baseline cardiovascular characteristics are summarized in Table 2 and details risk factors in table S3. 12 patients (27%) were considered at high risk of immune-related adverse events in group A (27% ); and 33 in group B, (28%). Cardiac follow up In group B, 84% had the cardiac visit as per the protocol, compared to 42% in group A (p<0.0001) (Table 2). In group A, 35 patients did not undergo troponin T follow-up (77.8%), and 19 did not have ECG follow-up (42%). In group B, 38 patients did not undergo troponin T follow-up (32.5%), and nine did not have ECG follow-up (7.7%). Primary end point: In group A, 11 treatment interruptions (24.4%) occurred for reasons other than disease progression. We observed one case of exacerbation of chronic obstructive pulmonary disease, one of hypereosinophilia, one of grade 2 colitis, one of undocumented fever, one of grade 3 polyarthritis, one of hepatitis, one of sarcoidosis, and four cases of isolated elevated troponin levels. Among these patients, four (36.4%) were able to resume treatment, with an average interruption duration of one month (range 0-4 months). Among the four patients with isolated elevated troponin levels, two experienced a treatment delay of one week, one had a two-week delay, and one permanently discontinued treatment due to this isolated troponin elevation. In group B, 28 treatment interruptions (23.9%) occurred for reasons other than disease progression. These included one case of isolated ECG abnormalities, one of grade 2 pneumonitis, eight cases of hepatitis, one of undocumented fever, five of colitis, one of left-ventricular dysfunction, two of grade 3 polyarthritis, one of pancreatitis, one of grade 3 pneumonitis, one of COVID-19, one of severe hypoglycemia, two of clinical deterioration, one of unexplained chest pain, one of myocarditis, and one of pulmonary embolism. Among these, seven patients (25%) resumed treatment without new toxicities, with an average interruption duration of 1.6 months (range 0-8 months). No patient interrupted treatment due to isolated troponin elevation. Secondary objective: Adverse events Grade 3 or more analysis After a median follow-up of 25.1 months (95%CI : 22.4 ; 27.8) (36.3 months (95%CI : 33.5 ; 37.8) and 20.9 months (95%CI : 19.4 ; 24.0) in group A and B respectively), we observed 19 cases of Grade 3 or higher myositis, myocarditis, hepatitis, or pneumonitis in the entire cohorts (11.7%). Details for each group and by type of adverse event are provided in Table 3, and the analysis without double immunotherapy is provided in Table 4. We also collected data on how Grade 3 or higher adverse events were detected: 8 through regular biological exploration (8 hepatitis), and 11 through clinical symptoms (e.g., diarrhea for colitis, dyspnea for pneumonitis, heart failure for myocarditis). Among the 19 Grade 3 or higher adverse events, 13 were treated with corticosteroids, one with aspirin and colchicine, two with corticosteroids and infliximab, one with corticosteroids and mycophenolate mofetil, one with N-acetyl cysteine, and one showed spontaneous regression. Notably, six adverse events were associated with another immune-related toxicity, including four Grade 3 cases (rash, bicytopenia, renal insufficiency). Overall, the average time to onset Grade 3 or higher adverse events after the first injection was 2.8 months (range 1-11 months), with two months for group A and 3.4 months for group B (range 0-11 months). In group A, among the three patients who experienced relevant toxicity, two had not undergone troponin T follow-up (66.7%), and one had not received follow-up ECG (33.3%). In group B, six of the 16 patients who experienced relevant toxicity had not troponin T follow-up (37.5%), and five had not undergone ECG follow-up (31.3%). Discussion This study is the first to report the impact of implementing a predefined cardiac protocol in patients receiving ICIs.Given the potential severity of myocarditis, several centers have considered a preventive screening strategy based on systematic troponin testing with ECG monitoring,as it is now recommended by the European Society of Cardiology(14). Considering the low specificity of troponin for diagnosing myocarditis and the diagnosis challenges, concerns have been raised regarding a possible increase in false positives and unnecessary immunotherapy interruptions. Different studies have reported significant troponin elevations in patients undergoing immunotherapy. In a prospective observational study by Tamura et al. in Japan, 14% of 129 patients treated with ICIs presented elevated high-sensitivity troponin I (hs-TnI), and 4,7% were diagnosed with ICI-associated myocarditis, with a mortality rate of 16.7%(15). Similarly, a prospective cohort of 164 patients, found that 58% of the patients had elevated high-sensitivity troponin T (hs-TnT) levels (≥ 14ng/mL) during treatment, and 16% experienced level ≥2 times the upper limit of normal (ULN); however, only 5% were diagnosed with ICI-related myocarditis. Most of these troponin elevations were not associated with symptoms or additional evidence of cardiac injury(16). In Waliany et al’ s prospective study, troponin I was monitored every 2 to 4 weeks in 214 patients, leading to the detection of elevated levels in 24 patients. Yet, only 3 of these cases were confirmed as ICI myocarditis. Among the remaining patients, the troponin elevation remain unclear in 19 cases, and led to a delay of ICI treatment in 3 patients(17). All of these studies underscore the high incidence of troponin elevations in patients treated with ICIs, but unfrequently correlated to a define myocarditis. Although troponin is recognized as a sensitive marker for the ICI-associated myocarditis, the concern subsists because of it’s low specificity. Cancer patients are predisposed to both ischemic and nonischemic(18) cardiac-events, and ICIs themselves have been implicated in the development and progression of atherosclerotic plaque therefore amplifying the importance of excluding myocardial ischemia and using additional testing to establish an accurate diagnosis. (19) In our study, despite the lack of specificity and sensibility of troponin monitoring, the rate of treatment interruption solely attributable to troponin elevation remained very low. In fact, the number of delayed or canceled treatment cycles decreased after the implementation of the cardiac monitoring protocol. Four troponin elevations led to treatment interruption in Cohort A, compared to none in Cohort B. This improvement may be due to the availability of cardio-oncologists in our center, allowing for rapid evaluation and reassurance of clinical teams to continue the treatment when no cardiac symptoms were present. In contrast, centers without immediate access to cardio-oncologists, more unintended treatment interruptions could potentially occur. Timely withdrawing the ICI treatment in patients with hs-TnT elevations, could reduce the incidence of severe cardiac complications but it could lead to increased cancer-related morbidity and mortality. Nevertheless, given the long half-life of ICIs, temporarily delaying immunotherapy especially in patients at high risk of immune mediated cardiotoxicity, is likely a safe approach. It is well established that immune-mediated cardiotoxicity is associated to other immune related adverse events such as hepatitis, myositis and pneumonitis. We hypothesized that troponin follow up could lead to detect early immune adverse event associated to cardiac toxicity. However, despite effective implementation of cardiac monitoring in COHORT B, we found no difference in the incidence of grade 3 or more hepatitis, pneumonitis, myositis or myocarditis. Furthermore, all immune-related serious adverse were diagnosed based on clinical symptom or elevated hepatic enzymes : none were identified solely through isolated troponin elevation. This was exemplified by the only case of immune-mediated myocarditis identified in our study: an 84-year-old woman treated with pembrolizumab monotherapy for a locally advanced lung adenocarcinoma (T2bN2M0, PD-L1 60%). After two cycles, the patient presented to the emergency department with dyspnea, Troponin T levels at 4644 ng/L, NT-proBNP at 3850 ng/L, and ASAT reached 7× ULN. Additional findings included T-wave inversion, left bundle branch block on ECG, elevated CPK,. leading to the diagnosis of myocarditis associated with a systemic immune-related events (hepatitis and myositis). This observation supports the potential added value of systematic CPK and ALAT/ASAT measurement alongside troponin testing, to enhance both sensitivity and specificity in detecting ICI-related myocarditis. Indeed, previous studies have highlighted the high sensitivity of CPK, particularly in early or even asymptomatic stages of immune-mediated myocarditis. Furthermore, elevated CPK levels have been associated with more severe outcomes, reinforcing their potential as an early and prognostic biomarker in this setting (20). It is important to notice that clinical symptoms of myocarditis can be nonexistent (the International Cardio-Oncology Society consensus defined myocarditis as new troponin elevation with either positive cardiac magnetic resonance or with the presence of 2 minor clinical criteria)(21). More, symptoms can be very common such as dyspnea, fatigue, and weakness, and can be attributed to malignancy or other treatment related adverse effects such as anemia, infection, or physical deconditioning. As such, diagnosis frequently relies heavily on troponin changes and, in most studies, myocarditis diagnosis was made on the troponin elevation. However in few reported cases, ICI-myocarditis was diagnosed despite negative troponin. In theses cases the troponin assay used was for troponin I (22). Those findings were also reported in Lehrman et al’s study in which 10-20% ICI myocarditis lacked an increase of Troponin I on admission, despite Troponine T being positive(21). In light of all these studies, the key question remains whether troponin monitoring is more effective than a single measurement in cases of suspected myocarditis, given the low rate of early myocarditis detection based on isolated troponin elevation. Although our study did not demonstrate a significant impact of troponin on the detection of subclinical myocarditis, it does not allow us to answer this question definitively. Therefore prospective data in large cohorts of patients receiving ICIs are needed to determine the clinical utility of cardiac biomarkers, the type of cardiac biomarkers, the screening and predicting major adverse cardiovascular events (MACE) and overall outcomes. At last, this retrospective study, conducted under real-world patient care conditions, demonstrated a significant increase in baseline cardiovascular assessments before and after protocol implementation (84% vs. 42%). It also highlights improved awareness among healthcare teams regarding regular biological and ECG monitoring. Only 32.5% and 7.7% of patients, respectively, did not receive this follow-up after protocol implementation, compared to 77.8% and 42% prior. This work underscores the impact of guidelines and internal algorithm implementation on patient care, even though the rates can still be further improved. The primary limitation of this study, in addition to its retrospective nature, is the limited data of a small sample size and lack of power to demonstrate significance, due to the relative rarity of ICI-associated myocarditis. Another limitation is the selection of patients who only received immunotherapy. Currently, many co-administration protocols involve other cardiotoxic treatments which could lead to an increase in MACE. Nonetheless, the study reflects real-world conditions involving patients treated in a tertiary center, all of whom were excluded from any research protocols. Conclusion In conclusion, our study introduced and evaluated the impact of a predefined cardiac monitoring protocol for patients undergoing immune checkpoint inhibitor (ICI) treatment with a strong adherence to the protocol after its implementation. We observed no deleterious impact of troponin T follow up on treatment scheduled. However, this follow up is not associated to a reduction in grade 3 IMCT and other associated toxicity nor to an improvement in detection of early IMCT. Most elevations of troponin did not correspond to clinically relevant cardiac events and rarely led to appropriate early detection of myocarditis in the absence of symptoms. So, while it is safe for the patient it may not be sufficient. Therefore prospective data in large cohorts of patients receiving ICIs are needed to determine the clinical utility of cardiac biomarkers screening and predicting MACE and overall outcomes. Abbreviations ICI : Immune Checkpoint Inhibitors IMCT : Immune-mediated Cardiac Toxicities AE : Adverse Events CPK : Creatine Phosphokinase ECG : Electrocardiogram ESC : European Society of Cardiology BMI : Body Mass Index NT-proBNP : N-terminal pro b-type Natriuretic Peptide CTLA4 : Cytotoxic T-Lymphocyte Associated Protein 4 PD(L)1 : Programmed Death (Ligand) 1 Declarations Disclosures : There is nothing relevant to disclose for any author Funding: None Data availability statement : The data underlying this article will be shared on reasonable request to the corresponding author. Author Contribution A.C., E.M and J.R. design the work, wrote the main manuscript text, drafted the work and substantively revised it, interpretation of the dataM.S. have drafted the work and substantively revised it, interpretation of the dataJ.P. analysis and interpretation of data, substantively revised the work References Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol Off J Am Soc Clin Oncol. 2022 Jan 10;40(2):127–37. Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet Lond Engl. 2019 May 4;393(10183):1819–30. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018 Dec 1;4(12):1721–8. Ansari-Gilani K, Tirumani SH, Smith DA, Nelson A, Alahmadi A, Hoimes CJ, et al. Myocarditis associated with immune checkpoint inhibitor therapy: a case report of three patients. Emerg Radiol. 2020 Aug;27(4):455–60. Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. J Am Heart Assoc. 2020 Jan 21;9(2):e013757. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. The Lancet. 2018 Mar;391(10124):933. Naqash AR, Moey MYY, Cherie Tan XW, Laharwal M, Hill V, Moka N, et al. Major Adverse Cardiac Events With Immune Checkpoint Inhibitors: A Pooled Analysis of Trials Sponsored by the National Cancer Institute—Cancer Therapy Evaluation Program. J Clin Oncol. 2022 Oct 10;40(29):3439–52. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018 Dec;19(12):1579–89. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018 Apr 24;71(16):1755–64. Scard C, Nguyen JM, Varey E, Moustaghfir I, Khammari A, Dreno B. Cardiac adverse events associated with anti-PD-1 therapy in patients treated for advanced melanoma: relevance of dosing troponin T levels. Eur J Dermatol. 2021 Apr;31(2):205–12. Sarocchi M, Grossi F, Arboscello E, Bellodi A, Genova C, Dal Bello MG, et al. Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non‐Small Cell Lung Cancer Patients. The Oncologist. 2018 Aug;23(8):936–42. Mathur T, Manadan AM, Thiagarajan S, Hota B, Block JA. Serum transaminases are frequently elevated at time of diagnosis of idiopathic inflammatory myopathy and normalize with creatine kinase. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2014 Apr;20(3):130–2. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021 Sep 7;42(34):3227–337. Lyon AR, López-Fernández T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022 Nov 1;43(41):4229–361. Tamura Y, Tamura Y, Takemura R, Yamada K, Taniguchi H, Iwasawa J, et al. Longitudinal Strain and Troponin I Elevation in Patients Undergoing Immune Checkpoint Inhibitor Therapy. JACC CardioOncology. 2022 Dec;4(5):673–85. van den Berg PF, Bracun V, Noordman M, van der Meer P, Shi C, Oosting SF, et al. Elevations of Cardiac Troponin in Patients Receiving Immune Checkpoint Inhibitors: Data From a Prospective Study. JACC Adv. 2024 Dec;3(12):101375. Waliany S, Neal JW, Reddy S, Wakelee H, Shah SA, Srinivas S, et al. Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors. JACC CardioOncology. 2021 Mar;3(1):137–9. Fanaroff AC, Sun LL. High-Sensitivity Troponin in Patients With Cancer: Sensitive But Not Specific. JACC CardioOncology. 2023 Oct;5(5):610–2. Suero-Abreu GA, Zanni MV, Neilan TG. Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncology. 2022 Dec;4(5):598–615. Vasbinder A, Ismail A, Salem JE, Hayek SS. Role of Biomarkers in the Management of Immune-Checkpoint Inhibitor-Related Myocarditis. Curr Cardiol Rep. 2023 Sep;25(9):959–67. Herrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D, et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022 Jan 31;43(4):280–99. Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, et al. Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity. Circulation. 2017 Nov 21;136(21):2085–7. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7820886","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":538739530,"identity":"ff9b2b53-0a26-4403-8481-869e6d25fffc","order_by":0,"name":"Axel 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06:35:49","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":107196,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7820886/v1/955cd4697348f6ee33f554f0.html"},{"id":95171788,"identity":"b84ee919-b9db-46a0-a7db-0c3b0e73b93b","added_by":"auto","created_at":"2025-11-05 06:35:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":209727,"visible":true,"origin":"","legend":"\u003cp\u003eComprehensive decision algorithm for detecting IMCT\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7820886/v1/7ce8033d3762289331e46a42.png"},{"id":95171789,"identity":"407792c0-7852-48b7-861d-49759d000c2f","added_by":"auto","created_at":"2025-11-05 06:35:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":124427,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7820886/v1/849fa4daff0596895664763e.png"},{"id":97369102,"identity":"de7cfc1e-fefe-4a55-8ea9-5e263195e05e","added_by":"auto","created_at":"2025-12-03 16:23:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":680807,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7820886/v1/a17a2583-80d4-4cf4-a124-801fecb5eb79.pdf"},{"id":95227492,"identity":"3d484795-7644-48bb-93c9-3e6c986bb7be","added_by":"auto","created_at":"2025-11-05 16:32:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":75207,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7820886/v1/08754b4b1b65e902e6afbc6b.pdf"},{"id":95226885,"identity":"039f0f86-85f8-48bf-8242-e528e4883b2b","added_by":"auto","created_at":"2025-11-05 16:31:50","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":25253,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7820886/v1/96db2eb9452c3f9c10e7fb9c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Troponin or not troponin: What is the impact of regular cardiac monitoring for patients treated with immunotherapy?","fulltext":[{"header":"Translational perspective","content":"\u003cp\u003ePatients receiving immune checkpoint inhibitors (ICI) are at risk of developing immune-mediated cardiac toxicities (IMCT), which can present as myocarditis, arrhythmias, or other cardiovascular complications. Early identification of IMCT through biomarkers such as troponin, along with systematic ECG and imaging monitoring, may improve patient care by early detection of toxicities. Implementing cardiovascular assessment in cancer patients undergoing ICI therapy could enhance clinical decision-making and reduce morbidity.\u003c/p\u003e\u003cp\u003eFurther research is needed to refine risk stratification models for IMCT, incorporating clinical, imaging, and biomarker data. Prospective trials should assess the efficacy of early detection or intervention and alternative immunomodulatory treatments in severe cases. Additionally, the development of standardized guidelines for cardiac monitoring in ICI-treated patients could facilitate broader clinical adoption and improve patient safety.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eThese last years, immune checkpoint inhibitors (ICIs) have\u0026nbsp;changed the practices in oncology, demonstrating remarkable effectiveness in treating malignancies such as melanoma(1)\u0026nbsp;and lung cancer(2). However, these treatments have introduced a new spectrum of immune-mediated toxicities\u0026nbsp;requiring\u0026nbsp;comprehensive evaluation and management. Some of these toxicities are particularly serious, including immune-mediated cardiac toxicities (IMCT), hepatitis, and immune-mediated pneumonitis(3). IMCT include various conditions, from myocarditis(4)\u0026nbsp;and congestive heart failure to acute coronary syndromes, pericardial disorders, dysrhythmias, and even cardiac arrest. Although relatively rare, with an incidence ranging from 0.04% to 1.14%(5), these adverse events have high mortality rates, up to 50% in myocarditis(6).\u003c/p\u003e\n\u003cp\u003eA substantial number of IMCT cases raise up to Grade 3 or 4 severity, highlighting the need for careful monitoring and early detection. Recent reports indicate that while only 0.6% of patients receiving anti-PD-(L)1 immunotherapy experience cardiac adverse events (AE), 77.5% of these events are classified as Grade 3 or higher. Approximately 45% of IMCT cases are attributed to myocarditis, with 65% of IMCT coinciding with other immunotherapy-related toxicities mainly myositis, hepatitis and pneumonitis. Strikingly, 83% of patients afflicted with immunotherapy-associated myocarditis also manifest other immunotherapy-related AE(7). Emerging evidence suggests that cardiac toxicity often manifests early, typically within one to two months or after one to two treatment doses(7)\u003csup\u003e,\u003c/sup\u003e(8)\u003csup\u003e,\u003c/sup\u003e(9)\u003c/p\u003e\n\u003cp\u003eEfforts to mitigate IMCT have prompted investigations into the use of biomarkers, particularly troponin, as tools for early detection(10)\u003csup\u003e,\u003c/sup\u003e(11). However, its utility remains uncertain given the rarity of these events and of the limited specificity of troponin, which may be elevated in numerous other conditions. Elevation in hepatic enzymes appear to have a stronger association with muscular origins and a robust correlation with creatine kinase (CPK) levels, warranting consideration(12). 2022 ESC guidelines have proposed recommendations to classify patients into two risk groups: low and high. High risk is defined by the presence of dual ICI therapy, combination ICI-cardiotoxic therapy, ICI-related non-cardiovascular events, prior cancer therapy-related cardiac dysfunction, or pre-existing cardiovascular disease.\u003c/p\u003e\n\u003cp\u003eFor ECG monitoring: In low-risk patients, a baseline ECG (Level I) is recommended, followed by assessments at cycles C2, C3, and C4, then every three cycles (Level IIa), and subsequently every 6 to 12 months (Grade IIb). In high-risk patients, the same schedule is proposed, but with a Grade I recommendation for long-term ECG monitoring every 6 to 12 months. For troponin monitoring: In both low- and high-risk patients, it is recommended at baseline (Grade I), then at cycles 2, 3, and 4, and subsequently every three cycles (Grade II). This recommendation have clarified the cardiac follow up of patient under ICI, however, evidence is missing without prospective or even retrospective external validation(13)\u003c/p\u003e\n\u003cp\u003eBefore these guidelines, our institution developed a comprehensive decision algorithm for detecting IMCT (Figure 1), incorporating a baseline cardiac assessment and electrocardiogram and troponin follow up. This study aims to assess the impact of this algorithm on the course of immunotherapy in patients with lung cancer or melanoma.\u003c/p\u003e"},{"header":"Methods ","content":"\u003cp\u003e\u003cem\u003e\u003cu\u003eStudy design and Participants\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe used our institutional registry database of chemotherapy (CHIMIO WEB v5.9) to identify and extract data from consecutive patients at the comprehensive cancer\u0026nbsp;center\u0026nbsp;inSaint Herblain, France treated with ICI for melanoma or lung cancer. We divided patients into two groups: those treated in 2019 (before the implementation of our monitoring algorithm) and those treated in 2020-2021 (when the algorithm was implemented). Inclusion criteria encompassed patients aged 18 or older with a histopathologically confirmed diagnosis of lung cancer or melanoma treated with ICI (i.e. antiPD1 or antiPDL1 alone or dual immunotherapy antiPD1 and antiCTLA4) as per standard of care guidelines at the time of the recruitment. Patients in clinical trials, those with concurrent malignancies and those who declined data collection were excluded. Patients treated with chemotherapy or targeted therapy were excluded to\u0026nbsp;minimize\u0026nbsp;confounding factors.\u003c/p\u003e\n\u003cp\u003eThe algorithm includes an initial cardiac assessment consisting of clinical evaluation, assessment of cardiovascular risk factors, electrocardiography, baseline echocardiography with measurement of left ventricle ejection fraction and global longitudinal strain, Troponin T and I blood levels, NT proBNP blood level, and patient education on early recognition of cardiac symptoms (Figure 1). Subsequently, patients undergo monthly follow-ups including a clinical and biological assessment (troponin T or I) and electrocardiography for the first three months, followed by\u0026nbsp;evaluations\u0026nbsp;every three months for a year and then annually. A secondary decision algorithm has been implemented based on abnormalities identified during baseline assessment,\u0026nbsp;to separate\u0026nbsp;patients into low-risk \u0026nbsp; and high-risk groups (Figure 1), with risk factors such as double immunotherapy, preexisting cardiopathy, diabetes, and autoimmune diseases. High-risk individuals may undergo additional echocardiography at three months and subsequently annually.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Ethics Committee of Angers Hospital in France (protocol code 2021-207, date of approval 10 December 2021). Patients were informed about the possible data reuse for research projects during initial data collection.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eProcedure\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe collected patients\u0026apos; baseline characteristics, especially cardiologic characteristics, in 2019 (group A) if available, and in 2020-2021 for others patients (group B). The initial characteristics and cardiac follow-up were best conducted by a specialized cardio-oncologist. Evaluation by the attending cardiologist was accepted, provided that the last visit occurred less than one year before the first injection and was conformed to our standard initial cardiac assessment\u0026nbsp;(as precised above). The stage of the disease, the type of immunotherapy (anti-CTLA4, anti-PD(L)1, or association), the number of treatment cycles, and the previous history of autoimmune disease were also collected. For cardiac evaluation, we collected patients\u0026rsquo; cardiovascular history: common risk factors (smoking status, body mass index ( BMI), age, hypertension, diabetes, hypercholesterolemia, family history of cardiovascular conditions, preexisting cardiovascular diseases, preexisting cardiac symptoms, cardiovascular medications (beta-blockers, angiotensin-converting enzyme inhibitors, antiarrhythmics, calcium channel blockers, diuretics, antiplatelet, anticoagulant), results of their clinical and biological examinations, the results of the ECG and echocardiography analysis. Patients were classified into LR or HR of immune cardiac adverse events populations according to the previously described criteria.). Preexisting cardiopathy was defined according to ESC guidelines(13)\u0026nbsp;(myocardial infarction, angina, coronary stent, peripheral vascular disease, coronary artery bypass graft, stroke, or transient ischemic attack). Follow-up duration was calculated from the date of baseline cardiac evaluation to the end of immunotherapy.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eStatistical analysis\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCategorical variables were described using the number of people and the associated percentage. They were compared using a Pearson Chi-squared test or Fisher\u0026rsquo;s exact test, whenever appropriate. Quantitative variables were described using median and range (min-max). They were compared using Student\u0026rsquo;s t-test if the assumption of normality was met; otherwise, non-parametric statistics were made and compared using Wilcoxon\u0026rsquo;s test. Tests were two-sided and p-values \u0026lt;0.05 were considered significant. All analysis were performed with R software [R Core Team (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: http://www.R-project.org/.].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eOutcomes\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary end point was to assess the impact of cardiac monitoring on the number of treatment cycles canceled or delayed.\u003c/p\u003e\n\u003cp\u003eSecondary criteria or end point included evaluating whether our cardiac monitoring approach could prevent Grade 3 or 4 AE by evaluating the percentage of myositis, hepatitis, pneumonitis and myocarditis grade 3 or 4 in each group and to describe the management of these toxicities.\u003c/p\u003e"},{"header":"Results ","content":"\u003cp\u003e\u003cem\u003e\u003cu\u003ePopulation\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe identified 240 patients treated with immunotherapy between 2019 and 2021. Among them, 53 were treated in 2019, and 187 were treated in 2020-2021. After excluding patients who did not meet inclusion criteria, 45 patients from 2019 (group A) and 117 from the 2020-2021 (group B) were included in the study (Figure 2) (Table 1). The details of histology and stade are available in Table S1 and S2.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eBaseline Cardiologic Evaluation:\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBaseline cardiovascular characteristics are summarized in Table 2 and details risk factors in table S3. 12 patients (27%) were considered at high risk of immune-related adverse events in group A (27% ); and 33 in group B, (28%).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eCardiac follow up\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn group B, 84% had the cardiac visit as per the protocol, compared to 42% in group A (p\u0026lt;0.0001) (Table 2).\u003c/p\u003e\n\u003cp\u003eIn group A, 35 patients did not undergo troponin T follow-up (77.8%), and 19 did not have ECG follow-up (42%).\u003c/p\u003e\n\u003cp\u003eIn group B, 38 patients did not undergo troponin T follow-up (32.5%), and nine did not have ECG follow-up (7.7%).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003ePrimary\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u003cu\u003eend point:\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn group A, 11 treatment interruptions (24.4%) occurred for reasons other than disease progression. We observed one case of exacerbation of chronic obstructive pulmonary disease, one of hypereosinophilia, one of grade 2 colitis, one of undocumented fever, one of grade 3 polyarthritis, one of hepatitis, one of sarcoidosis, and four cases of isolated elevated troponin levels. Among these patients, four (36.4%) were able to resume treatment, with an average interruption duration of one month (range 0-4 months). Among the four patients with isolated elevated troponin levels, two experienced a treatment delay of one week, one had a two-week delay, and one permanently discontinued treatment due to this isolated troponin elevation.\u003c/p\u003e\n\u003cp\u003eIn group B, 28 treatment interruptions (23.9%) occurred for reasons other than disease progression. These included one case of isolated ECG abnormalities, one of grade 2 pneumonitis, eight cases of hepatitis, one of undocumented fever, five of colitis, one of left-ventricular dysfunction, two of grade 3 polyarthritis, one of pancreatitis, one of grade 3 pneumonitis, one of COVID-19, one of severe hypoglycemia, two of clinical deterioration, one of unexplained chest pain, one of myocarditis, and one of pulmonary embolism. Among these, seven patients (25%) resumed treatment without new toxicities, with an average interruption duration of 1.6 months (range 0-8 months). No patient interrupted treatment due to isolated troponin elevation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eSecondary objective: Adverse events Grade 3 or more analysis\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAfter a median follow-up of 25.1 months (95%CI : 22.4 ; 27.8) (36.3 months (95%CI : 33.5 ; 37.8) and 20.9 months (95%CI : 19.4 ; 24.0) in group A and B respectively), we observed 19 cases of Grade 3 or higher myositis, myocarditis, hepatitis, or pneumonitis in the entire cohorts (11.7%). Details for each group and by type of adverse event are provided in Table 3, and the analysis without double immunotherapy is provided in Table 4.\u003c/p\u003e\n\u003cp\u003eWe also collected data on how Grade 3 or higher adverse events were detected: 8 through regular biological exploration (8 hepatitis), and 11 through clinical symptoms (e.g., diarrhea for colitis, dyspnea for pneumonitis, heart failure for myocarditis).\u003c/p\u003e\n\u003cp\u003eAmong the 19 Grade 3 or higher adverse events, 13 were treated with corticosteroids, one with aspirin and colchicine, two with corticosteroids and infliximab, one with corticosteroids and mycophenolate mofetil, one with N-acetyl cysteine, and one showed spontaneous regression. Notably, six adverse events were associated with another immune-related toxicity, including four Grade 3 cases (rash, bicytopenia, renal insufficiency).\u003c/p\u003e\n\u003cp\u003eOverall, the average time to onset Grade 3 or higher adverse events after the first injection was 2.8 months (range 1-11 months), with two months for group A and 3.4 months for group B (range 0-11 months).\u003c/p\u003e\n\u003cp\u003eIn group A, among the three patients who experienced relevant toxicity, two had not undergone troponin T follow-up (66.7%), and one had not received follow-up ECG (33.3%).\u003c/p\u003e\n\u003cp\u003eIn group B, six of the 16 patients who experienced relevant toxicity had not troponin T follow-up (37.5%), and five had not undergone ECG follow-up (31.3%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is the first to report the impact of implementing a predefined cardiac protocol in patients receiving ICIs.Given the potential severity of myocarditis, several centers have considered a preventive screening strategy based on systematic troponin testing with ECG monitoring,as it is now recommended by the European Society of Cardiology(14). Considering the low specificity of troponin for diagnosing myocarditis and the diagnosis challenges, concerns have been raised regarding a possible increase in false positives and unnecessary immunotherapy interruptions.\u003c/p\u003e\n\u003cp\u003eDifferent studies have reported significant troponin elevations in patients undergoing immunotherapy. In a prospective observational study by Tamura et al. in Japan, 14% of 129 patients treated with ICIs presented elevated high-sensitivity troponin I (hs-TnI), and 4,7% were diagnosed with ICI-associated myocarditis, with a mortality rate of 16.7%(15). Similarly, a prospective cohort of 164 patients, found that 58% of the patients had elevated high-sensitivity troponin T (hs-TnT) levels (≥ 14ng/mL) during treatment, and 16% experienced level ≥2 times the upper limit of normal (ULN); however, only 5% were diagnosed with ICI-related myocarditis. Most of these troponin elevations were not associated with symptoms or additional evidence of cardiac injury(16).\u003c/p\u003e\n\u003cp\u003eIn Waliany et al’ s prospective study, troponin I was monitored every 2 to 4 weeks in 214 patients, leading to the detection of elevated levels in 24 patients. Yet, only 3 of these cases were confirmed as ICI myocarditis. Among the remaining patients, the troponin elevation remain unclear in 19 cases, and led to a delay of ICI treatment in 3 patients(17).\u003c/p\u003e\n\u003cp\u003eAll of these studies underscore the high incidence of troponin elevations in patients treated with ICIs, but unfrequently correlated to a define myocarditis. Although troponin is recognized as a sensitive marker for the ICI-associated myocarditis, the concern subsists because of it’s low specificity. Cancer patients are predisposed to both ischemic and nonischemic(18) cardiac-events, and ICIs themselves have been implicated in the development and progression of atherosclerotic plaque therefore amplifying the importance of excluding myocardial ischemia and using additional testing to establish an accurate diagnosis. (19)\u003c/p\u003e\n\u003cp\u003eIn our study, despite the lack of specificity and sensibility of troponin monitoring, the rate of treatment interruption solely attributable to troponin elevation remained very low. In fact, the number of delayed or canceled treatment cycles decreased after the implementation of the cardiac monitoring protocol. Four troponin elevations led to treatment interruption in Cohort A, compared to none in Cohort B. This improvement may be due to the availability of cardio-oncologists in our center, allowing for rapid evaluation and reassurance of clinical teams to continue the treatment when no cardiac symptoms were present.\u003c/p\u003e\n\u003cp\u003eIn contrast, centers without immediate access to cardio-oncologists, more unintended treatment interruptions could potentially occur. Timely withdrawing the ICI treatment in patients with hs-TnT elevations, could reduce the incidence of severe cardiac complications but it could lead to increased cancer-related morbidity and mortality. Nevertheless, given the long half-life of ICIs, temporarily delaying immunotherapy especially in patients at high risk of immune mediated cardiotoxicity, is likely a safe approach.\u003c/p\u003e\n\u003cp\u003eIt is well established that immune-mediated cardiotoxicity is associated to other immune related adverse events such as hepatitis, myositis and pneumonitis. We hypothesized that troponin follow up could lead to detect early immune adverse event associated to cardiac toxicity. However, despite effective implementation of cardiac monitoring in COHORT B, we found no difference in the incidence of grade 3 or more hepatitis, pneumonitis, myositis or myocarditis. Furthermore, all immune-related serious adverse were diagnosed based on clinical symptom or elevated hepatic enzymes : none were identified solely through isolated troponin elevation.\u003c/p\u003e\n\u003cp\u003eThis was exemplified by the only case of immune-mediated myocarditis identified in our study: an 84-year-old woman treated with pembrolizumab monotherapy for a locally advanced lung adenocarcinoma (T2bN2M0, PD-L1 60%). After two cycles, the patient presented to the emergency department with dyspnea, Troponin T levels at 4644 ng/L, NT-proBNP at 3850 ng/L, and ASAT reached 7× ULN. Additional findings included T-wave inversion, left bundle branch block on ECG, elevated CPK,. leading to the diagnosis of myocarditis associated with a systemic immune-related events (hepatitis and myositis). This observation supports the potential added value of systematic CPK and ALAT/ASAT measurement alongside troponin testing, to enhance both sensitivity and specificity in detecting ICI-related myocarditis. Indeed, previous studies have highlighted the high sensitivity of CPK, particularly in early or even asymptomatic stages of immune-mediated myocarditis. Furthermore, elevated CPK levels have been associated with more severe outcomes, reinforcing their potential as an early and prognostic biomarker in this setting (20).\u003c/p\u003e\n\u003cp\u003eIt is important to notice that clinical symptoms of myocarditis can be nonexistent (the International Cardio-Oncology Society consensus defined myocarditis as new troponin elevation with either positive cardiac magnetic resonance or with the presence of 2 minor clinical criteria)(21). More, symptoms can be very common such as dyspnea, fatigue, and weakness, and can be attributed to malignancy or other treatment related adverse effects such as anemia, infection, or physical deconditioning. As such, diagnosis frequently relies heavily on troponin changes and, in most studies, myocarditis diagnosis was made on the troponin elevation. However in few reported cases, ICI-myocarditis was diagnosed despite negative troponin. In theses cases the troponin assay used was for troponin I (22). Those findings were also reported in Lehrman et al’s study in which 10-20% ICI myocarditis lacked an increase of Troponin I on admission, despite Troponine T being positive(21).\u003c/p\u003e\n\u003cp\u003eIn light of all these studies, the key question remains whether troponin monitoring is more effective than a single measurement in cases of suspected myocarditis, given the low rate of early myocarditis detection based on isolated troponin elevation. Although our study did not demonstrate a significant impact of troponin on the detection of subclinical myocarditis, it does not allow us to answer this question definitively.\u003c/p\u003e\n\u003cp\u003eTherefore prospective data in large cohorts of patients receiving ICIs are needed to determine the clinical utility of cardiac biomarkers, the type of cardiac biomarkers, the screening and predicting major adverse cardiovascular events (MACE) and overall outcomes.\u003c/p\u003e\n\u003cp\u003eAt last, this retrospective study, conducted under real-world patient care conditions, demonstrated a significant increase in baseline cardiovascular assessments before and after protocol implementation (84% vs. 42%). It also highlights improved awareness among healthcare teams regarding regular biological and ECG monitoring. Only 32.5% and 7.7% of patients, respectively, did not receive this follow-up after protocol implementation, compared to 77.8% and 42% prior. This work underscores the impact of guidelines and internal algorithm implementation on patient care, even though the rates can still be further improved.\u003c/p\u003e\n\u003cp\u003eThe primary limitation of this study, in addition to its retrospective nature, is the limited data of a small sample size and lack of power to demonstrate significance, due to the relative rarity of ICI-associated myocarditis.\u003c/p\u003e\n\u003cp\u003eAnother limitation is the selection of patients who only received immunotherapy. Currently, many co-administration protocols involve other cardiotoxic treatments which could lead to an increase in MACE. Nonetheless, the study reflects real-world conditions involving patients treated in a tertiary center, all of whom were excluded from any research protocols.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study introduced and evaluated the impact of a predefined cardiac monitoring protocol for patients undergoing immune checkpoint inhibitor (ICI) treatment with a strong adherence to the protocol after its implementation. We observed no deleterious impact of troponin T follow up on treatment scheduled. However, this follow up is not associated to a reduction in grade 3 IMCT and other associated toxicity nor to an improvement in detection of early IMCT. Most elevations of troponin did not correspond to clinically relevant cardiac events and rarely led to appropriate early detection of myocarditis in the absence of symptoms. So, while it is safe for the patient it may not be sufficient. Therefore prospective data in large cohorts of patients receiving ICIs are needed to determine the clinical utility of cardiac biomarkers screening and predicting MACE and overall outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eICI\u003c/strong\u003e : Immune Checkpoint Inhibitors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIMCT\u003c/strong\u003e : Immune-mediated Cardiac Toxicities\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAE\u003c/strong\u003e : Adverse Events\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCPK\u003c/strong\u003e : Creatine Phosphokinase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eECG\u003c/strong\u003e : Electrocardiogram\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eESC\u003c/strong\u003e : European Society of Cardiology\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e : Body Mass Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNT-proBNP\u003c/strong\u003e : N-terminal pro b-type Natriuretic Peptide\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCTLA4\u003c/strong\u003e : Cytotoxic T-Lymphocyte Associated Protein 4\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD(L)1\u003c/strong\u003e : Programmed Death (Ligand) 1\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e: There is nothing relevant to disclose for any author\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e : \u003cem\u003eThe data underlying this article will be shared on reasonable request to the corresponding author.\u003c/em\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.C., E.M and J.R. design the work, wrote the main manuscript text, drafted the work and substantively revised it, interpretation of the dataM.S. have drafted the work and substantively revised it, interpretation of the dataJ.P. analysis and interpretation of data, substantively revised the work\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol Off J Am Soc Clin Oncol. 2022 Jan 10;40(2):127\u0026ndash;37.\u003c/li\u003e\n\u003cli\u003eMok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet Lond Engl. 2019 May 4;393(10183):1819\u0026ndash;30.\u003c/li\u003e\n\u003cli\u003eWang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018 Dec 1;4(12):1721\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eAnsari-Gilani K, Tirumani SH, Smith DA, Nelson A, Alahmadi A, Hoimes CJ, et al. Myocarditis associated with immune checkpoint inhibitor therapy: a case report of three patients. Emerg Radiol. 2020 Aug;27(4):455\u0026ndash;60.\u003c/li\u003e\n\u003cli\u003ePalaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A. Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. J Am Heart Assoc. 2020 Jan 21;9(2):e013757.\u003c/li\u003e\n\u003cli\u003eMoslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. The Lancet. 2018 Mar;391(10124):933.\u003c/li\u003e\n\u003cli\u003eNaqash AR, Moey MYY, Cherie Tan XW, Laharwal M, Hill V, Moka N, et al. Major Adverse Cardiac Events With Immune Checkpoint Inhibitors: A Pooled Analysis of Trials Sponsored by the National Cancer Institute\u0026mdash;Cancer Therapy Evaluation Program. J Clin Oncol. 2022 Oct 10;40(29):3439\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eSalem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018 Dec;19(12):1579\u0026ndash;89.\u003c/li\u003e\n\u003cli\u003eMahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018 Apr 24;71(16):1755\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eScard C, Nguyen JM, Varey E, Moustaghfir I, Khammari A, Dreno B. Cardiac adverse events associated with anti-PD-1 therapy in patients treated for advanced melanoma: relevance of dosing troponin T levels. Eur J Dermatol. 2021 Apr;31(2):205\u0026ndash;12.\u003c/li\u003e\n\u003cli\u003eSarocchi M, Grossi F, Arboscello E, Bellodi A, Genova C, Dal Bello MG, et al. Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non‐Small Cell Lung Cancer Patients. The Oncologist. 2018 Aug;23(8):936\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eMathur T, Manadan AM, Thiagarajan S, Hota B, Block JA. Serum transaminases are frequently elevated at time of diagnosis of idiopathic inflammatory myopathy and normalize with creatine kinase. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2014 Apr;20(3):130\u0026ndash;2.\u003c/li\u003e\n\u003cli\u003eVisseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, B\u0026auml;ck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021 Sep 7;42(34):3227\u0026ndash;337.\u003c/li\u003e\n\u003cli\u003eLyon AR, L\u0026oacute;pez-Fern\u0026aacute;ndez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022 Nov 1;43(41):4229\u0026ndash;361.\u003c/li\u003e\n\u003cli\u003eTamura Y, Tamura Y, Takemura R, Yamada K, Taniguchi H, Iwasawa J, et al. Longitudinal Strain and Troponin I Elevation in Patients Undergoing Immune Checkpoint Inhibitor Therapy. JACC CardioOncology. 2022 Dec;4(5):673\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003evan den Berg PF, Bracun V, Noordman M, van der Meer P, Shi C, Oosting SF, et al. Elevations of Cardiac Troponin in Patients Receiving Immune Checkpoint Inhibitors: Data From a Prospective Study. JACC Adv. 2024 Dec;3(12):101375.\u003c/li\u003e\n\u003cli\u003eWaliany S, Neal JW, Reddy S, Wakelee H, Shah SA, Srinivas S, et al. Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors. JACC CardioOncology. 2021 Mar;3(1):137\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eFanaroff AC, Sun LL. High-Sensitivity Troponin in Patients With Cancer: Sensitive But Not Specific. JACC CardioOncology. 2023 Oct;5(5):610\u0026ndash;2.\u003c/li\u003e\n\u003cli\u003eSuero-Abreu GA, Zanni MV, Neilan TG. Atherosclerosis With Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncology. 2022 Dec;4(5):598\u0026ndash;615.\u003c/li\u003e\n\u003cli\u003eVasbinder A, Ismail A, Salem JE, Hayek SS. Role of Biomarkers in the Management of Immune-Checkpoint Inhibitor-Related Myocarditis. Curr Cardiol Rep. 2023 Sep;25(9):959\u0026ndash;67.\u003c/li\u003e\n\u003cli\u003eHerrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D, et al. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022 Jan 31;43(4):280\u0026ndash;99.\u003c/li\u003e\n\u003cli\u003eEscudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, et al. Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity. Circulation. 2017 Nov 21;136(21):2085\u0026ndash;7.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"oncocardiology, troponin, immunotherapy, myocarditis, immune checkpoint inhibitors","lastPublishedDoi":"10.21203/rs.3.rs-7820886/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7820886/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eImmune checkpoint inhibitors (ICI) have changed cancer treatment, but they also bring a risk of immune-mediated cardiac toxicities (IMCT), such as myocarditis. Given the rarity but high mortality rates of IMCT, early detection is crucial.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eThis study aimed to evaluate the impact of our cardiac monitoring algorithm, based on troponin and electrocardiogram follow up, on patients undergoing ICI therapy, assessing whether it reduces treatment interruptions and severe cardiac adverse events.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA retrospective study was conducted using data from the West Cancer Institute in Saint Herblain, France. Patients treated with ICIs for lung cancer or melanoma were divided into two groups: group A treated in 2019 (pre-algorithm) and group B treated in 2020\u0026ndash;2021 (post-algorithm). The primary objective was to assess the impact of monitoring on the number of treatment cycles canceled or delayed. The secondary objective was to assess the rate of grade 3\u0026ndash;4 cardiac or associated adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e162 patients were included (45 \u0026ndash; group A, 117 \u0026ndash; group B). There was no significant difference in treatment interruptions (26.7% vs. 24.8%, p\u0026thinsp;=\u0026thinsp;0.96). Moreover, the rate of grade 3\u0026ndash;4 cardiac or associated adverse events was similar between the two groups (p\u0026thinsp;=\u0026thinsp;0.2).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThe implementation of the cardiac monitoring protocol had no negative impact on treatment administration but without reduction of severe cardiac or associated immune induced adverse event. This implementation demonstrated good adherence to the procedure; however, further efforts are needed to optimize strategies for the early detection of rare but serious adverse events.\u003c/p\u003e","manuscriptTitle":"Troponin or not troponin: What is the impact of regular cardiac monitoring for patients treated with immunotherapy?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-05 06:35:44","doi":"10.21203/rs.3.rs-7820886/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a06636a9-dfe1-45cb-b29f-938d33e4a987","owner":[],"postedDate":"November 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-02T21:53:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-05 06:35:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7820886","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7820886","identity":"rs-7820886","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}