Abstract
Background
Combination chemotherapy has improved cancer outcomes; however, identifying suspected cardiotoxic chemotherapies can be challenging when multiple chemotherapies are initiated simultaneously.
Case Summary
A 58-year-old woman with endometrial cancer developed heart failure, with a reduced left ventricular ejection fraction of 26%, 10 months after combined pembrolizumab and lenvatinib after doxorubicin. Cardiac magnetic resonance revealed acute myocarditis. Endomyocardial biopsy revealed interstitial fibrosis and scattered CD3-positive T-lymphocyte infiltration without myocytic necrosis. After discontinuation of pembrolizumab and lenvatinib, left ventricular function recovered without steroids. Pembrolizumab monotherapy was resumed for lung metastasis.
Discussion
This case highlights the importance of identifying different cardiotoxic mechanisms. Potential causes of left ventricular dysfunction could overlap with immune checkpoint inhibitor–induced myocarditis from pembrolizumab and reversible cardiotoxicity from lenvatinib, based on myocardial fibrosis caused by doxorubicin cardiotoxicity.
Take-Home Message
Multidisciplinary discussions are crucial for identifying suspected cardiotoxic chemotherapy and exploring additional chemotherapy options, including rechallenging immune checkpoint inhibitors.
Key words: cancer therapeutics–related cardiac dysfunction, cardiotoxicity, heart failure, immune checkpoint inhibitor, immune-related adverse events, myocarditis
Visual Summary
Visual Summary.
Clinical Course and Management of Cancer Therapy-Related Cardiac Dysfunction Following Multiple Combination Chemotherapies
LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction; T2-STIR = T2-weighted short-tau inversion recovery.
History of Presentation
A 58-year-old woman with a history of advanced endometrial cancer presented to the emergency department with fatigue and worsening dyspnea on exertion, persisting over the past several days. She was afebrile, with blood pressure of 140/108 mm Hg and an oxygen saturation of 97% on room air. Physical examination results were unremarkable. Electrocardiography revealed a normal sinus rhythm at a rate of 93 beats/min, along with mild ST-segment depression in leads II, III, aVF, and V4 to V6 (Figure 1A). Chest radiography revealed no signs of cardiomegaly or pulmonary congestion (Figure 1B). Serum high-sensitivity cardiac troponin I level was slightly elevated (66.2 pg/mL), and brain natriuretic peptide level was high (1637.3 pg/mL). Transthoracic echocardiography revealed that left ventricular (LV) wall motion was diffusely hypokinetic, and left ventricular ejection fraction (LVEF) decreased from 55% to 26%. LV outflow tract velocity–time integral decreased to 8.15 cm, indicating a low cardiac output state. No LV wall thickening, thinning, valvular disease, or pericardial effusion was observed (Figure 1C, Video 1).
Take-Home Messages
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It is crucial to recognize the various cardiotoxic mechanisms leading to left ventricular dysfunction when using combination chemotherapy, and multimodal imaging assessment helps identify suspected cardiotoxic chemotherapy.
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Rechallenge of immune checkpoint inhibitors requires a multidisciplinary discussion about the severity of the initial adverse event, the patient's cancer prognosis, and alternative treatment options.
Figure 1.
Electrocardiogram, Chest Radiograph, and Transthoracic Echocardiography on Admission
(A) Electrocardiogram showed mild ST-segment depression in leads II, III, aVF, and V4 to V6. (B) Chest radiograph showed no signs of cardiomegaly or pulmonary congestion. (C) Transthoracic echocardiography revealed a left ventricular ejection fraction of 26% without regional wall motion abnormality, thickening, or thinning.
Past Medical History
The patient had undergone total hysterectomy and bilateral salpingo-oophorectomy for endometrial cancer 8 years before admission. She had previously received paclitaxel and carboplatin chemotherapy from 7 to 3 years before admission, followed by doxorubicin and cisplatin chemotherapy from 3 to 2 years before admission. The cumulative dose of doxorubicin was 578 mg/m2. Combined chemotherapy with pembrolizumab and lenvatinib was initiated for lung metastases from advanced endometrial cancer 10 months before admission. A total of 15 pembrolizumab cycles were administered. After starting lenvatinib, blood pressure increased, and antihypertensive treatment was required with carvedilol (2.5 mg), losartan (25 mg), and spironolactone (25 mg). Otherwise, the patient did not exhibit any cardiovascular risk factors.
Differential Diagnosis
Based on the clinical course, differential diagnoses included heart failure, acute coronary syndrome, and acute myocarditis, which could be because of cancer therapy–related cardiac dysfunction (CTRCD) or immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs).
Investigations
Cardiac magnetic resonance (CMR) demonstrated a high-intensity area in the inferior wall on a T2-weighted short-tau inversion recovery image. Transmural late gadolinium enhancement (LGE) was observed in the inferior wall, and subendocardial LGE was identified in the septum. T1 mapping analysis demonstrated that the native T1 value and extracellular volume fraction (ECV) were remarkably elevated in the areas with LGE. In the area without LGE, native T1 value and ECV were diffusely elevated (Figure 2). Notably, these CMR findings were consistent with those of acute myocarditis. The patient underwent coronary angiography and endomyocardial biopsy. Specifically, coronary angiography revealed no significant stenosis or obstruction. In an endomyocardial biopsy of the right ventricular septum, hematoxylin and eosin staining showed a bizarre arrangement of moderately hypertrophied cardiomyocytes and revealed no evidence of active cardiomyocyte injury. Masson's trichrome staining revealed interstitial fibrosis. CD3 immunostaining showed scattered CD3-positive T-lymphocytes in the interstitium (Figure 3).
Figure 2.
Cardiac Magnetic Resonance on Admission
(A) T2-weighted short-tau inversion recovery image showed a high-intensity area in the inferior wall (red arrowhead). (B) Late gadolinium enhancement (LGE) image showed transmural gadolinium enhancement in the inferior wall (red arrowhead) and subendocardial gadolinium enhancement in the septum (yellow arrowhead), respectively. (C and D) T1 mapping analysis revealed native T1 value and extracellular volume fraction (ECV) to be remarkably elevated in the area with LGE (1,500-1,550 milliseconds [normal: 1182 ± 24 milliseconds] and 55%-58% [normal: 23%-28%]). In the area without LGE, native T1 value and ECV were also diffusely elevated (1,350-1,400 milliseconds and 43%-47%). These findings were compatible with acute myocarditis.
Figure 3.
Endomyocardial Biopsy From the Right Ventricular Side of the Interventricular Septum Obtained 1 Day Before the Cardiac Magnetic Resonance Examination
(A) Hematoxylin and eosin staining showed a bizarre arrangement of the moderately hypertrophied cardiomyocytes and revealed no evidence of active cardiomyocyte injury. (B) Masson's trichrome staining showed interstitial fibrosis. (C) CD3 immunostaining showed scattered CD3-positive T-lymphocytes in the interstitium, with a density of 24 cells/mm2 and 10 cells/HPF in the hot spot.
Management
After discontinuation of the combined pembrolizumab and lenvatinib chemotherapy, dobutamine was initiated for a low cardiac output state. Although LV dysfunction could be attributed to ICI-induced myocarditis from pembrolizumab based on CMR findings, steroid therapy was not initiated because the patient remained hemodynamically stable, and endomyocardial biopsy did not indicate active myocardial inflammation. LV systolic function gradually improved with dobutamine and standard cardioprotective medications for heart failure without the use of steroid therapy. LVEF recovered to 50% by the 13th day, and the patient was discharged on the 17th day. One month after discharge, LVEF improved to 57% (Video 2). Follow-up CMR performed 3 months after discharge indicated that findings suggestive of acute myocarditis, such as T2-weighted short-tau inversion recovery image and LGE, had disappeared. Furthermore, native T1 value and ECV increased slightly, indicating diffuse interstitial fibrosis (Figure 4). Because lung metastasis did not worsen after chemotherapy was discontinued, the patient was followed-up without further chemotherapy. However, 4 months after discontinuation, lung metastasis deteriorated slightly, and no other chemotherapy options were available. After a multidisciplinary discussion among the patient, cardiologists, gynecologists, and oncologists regarding the suspected chemotherapies causing LV dysfunction and treatment options for endometrial cancer, pembrolizumab monotherapy was restarted.
Figure 4.
Cardiac Magnetic Resonance 3 Months After Discharge
(A) T2-weighted short-tau inversion recovery image showed no high-intensity area. (B) LGE image showed no gadolinium enhancement area. (C and D) T1 mapping analysis revealed that native T1 value and ECV remained diffusely slightly increased (1,200-1,300 milliseconds [normal: 1,182 ± 24 milliseconds] and 35% to 40% [normal: 23%-28%]). Abbreviations as in Figure 2.
Outcome and Follow-Up
The patient underwent close follow-up, including blood tests, electrocardiography, and echocardiography. Serum troponin levels were measured every 3 weeks in conjunction with pembrolizumab administration. Echocardiography was performed every 3 months. It took >1 year to restart pembrolizumab monotherapy. Currently, there is no recurrence of troponin elevation, LVEF decline, or heart failure.
Discussion
We encountered a case of CTRCD with LV dysfunction 10 months after combined pembrolizumab and lenvatinib chemotherapy after prior doxorubicin treatment. This case highlights the importance of identifying the different cardiotoxic mechanisms of LV dysfunction caused by combination chemotherapy. Which chemotherapy regimen causes LV dysfunction?
Doxorubicin induces mitochondrial dysfunction, endoplasmic reticulum stress, calcium dysregulation, and DNA damage, which ultimately lead to cardiomyocyte death and dysfunction. This results in myocardial fibrosis caused by vacuolation of myocardial endothelial cells and perivascular fibrosis, impairing cardiac function in a dose-dependent and irreversible manner.1 At cumulative doses of 400 mg/m2, 550 mg/m2, and 700 mg/m2, the risk of heart failure is 3% to 5%, 7% to 26%, and 18% to 48%, respectively.2 Notably, this patient had received a cumulative dose of 578 mg/m2 of doxorubicin. Therefore, subclinical myocardial injuries, such as fibrosis, might have developed before the initiation of pembrolizumab and lenvatinib therapy because myocardial biopsy revealed interstitial fibrosis in this case.
Pembrolizumab is an ICI or a programmed cell death-1 inhibitor. Cardiovascular irAEs include myocarditis, pericarditis, arrhythmia, noninflammatory LV dysfunction, and myocardial infarction. ICI-induced myocarditis is a rare but fatal cardiovascular adverse event that typically occurs within 3 months of ICI administration.3 However, there have been several reports of late-onset ICI-induced myocarditis.4 Treatment for irAE, including ICI-induced myocarditis, mainly requires high-dose steroids. Nonetheless, in the case of lower severity of myocarditis based on endomyocardial biopsy with only mild inflammatory infiltrate but without myocyte necrosis, ICI-induced myocarditis has been reported to recover spontaneously without using steroids.5 Therefore, late-onset low-grade ICI-induced myocarditis could be a possible cause of LV dysfunction in this case.
Lenvatinib is an angiogenesis inhibitor that targets vascular endothelial growth factors and fibroblast growth factor receptors. Cardiovascular adverse events associated with lenvatinib include hypertension, QT prolongation, arterial thrombosis, and heart failure. The mechanism of LV dysfunction caused by lenvatinib has not been thoroughly investigated; however, a preclinical study indicated that lenvatinib induced cardiomyocyte apoptosis through oxidative stress, mitochondrial dysfunction, and damage to the cell nucleus.6 Previous reports indicated that LV dysfunction of tyrosine kinase inhibitor was reversible after its discontinuation.7 Notably, afterload elevation because of hypertension could also cause reversible LV dysfunction. Moreover, CMR and myocardial biopsy findings in cases of lenvatinib-induced cardiotoxicity have never been reported.
Combination chemotherapy is crucial in cancer treatment because of its effectiveness in improving survival rates. However, it might have a potential risk of increasing cardiovascular adverse events compared with conventional monotherapy and synergistic effects on cardiotoxicity in patients with pre-existing cardiovascular risk factors. Traditionally, combinations of cytotoxic chemotherapy agents, such as anthracyclines, with targeted therapies, such as angiogenesis inhibitors, have been associated with an increased risk of cardiotoxicity.8 Moreover, a recent study demonstrated that the combination of ICI and doxorubicin increased LV dysfunction compared with ICI monotherapy.9 The combination of ICI and angiogenesis inhibitors has also been reported to increase cardiovascular adverse events compared with either agent alone.10,11 In cases of combination chemotherapy, identifying the specific cause of suspected cardiotoxicity may be challenging. Given the characteristics of each chemotherapy, the findings of CMR and endomyocardial biopsy, and the treatment course, the possible causes of LV dysfunction could overlap with late-onset low-grade ICI-induced myocarditis caused by pembrolizumab and reversible cardiotoxicity induced by lenvatinib, based on potential myocardial fibrosis caused by cumulative doxorubicin cardiotoxicity. To our knowledge, this is the first report to focus on these distinct cardiotoxic mechanisms and to identify the suspected causative agents through CMR and endomyocardial biopsy.
Furthermore, rechallenge of ICI is not recommended for patients with a history of severe irAE, including ICI-induced myocarditis, because the recurrence rate was relatively high (approximately 30%).12 However, according to a study on the association between ICI-induced myocarditis and endomyocardial biopsy findings, myocarditis could recover spontaneously without stopping ICI in cases of low-grade myocarditis with an inflammatory infiltrate but no myocyte necrosis.5 Therefore, the decision to restart ICI therapy after irAE should be made with extreme caution, considering factors such as the severity of the initial irAE, the patient's cancer prognosis, and alternative treatment options. Restarting pembrolizumab was decided in this case because no other treatment options were available, and the initial ICI-induced myocarditis was considered nonfatal from the viewpoint of endomyocardial biopsy. Careful monitoring of cardiac biomarkers and echocardiographic parameters is essential when considering retreatment.
Conclusions
We observed a case of CTRCD with LV dysfunction in a patient with advanced endometrial cancer treated with a combination of pembrolizumab and lenvatinib after doxorubicin treatment. It is essential to identify the various cardiotoxic mechanisms associated with multiple chemotherapy regimens that lead to LV dysfunction by assessing multimodal imaging and treatment courses. A multidisciplinary discussion is necessary for rechallenge of ICI.
Funding Support and Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgment
The authors thank Dr Yuko Fukuda (Department of Onco-Cardiology, Hyogo Cancer Center, Akashi, Japan) for the helpful discussions.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental videos, please see the online version of this paper.
Appendix
Transthoracic Echocardiography on Admission
Transthoracic Echocardiography 1 Month After Discharge
References
- 1.Narezkina A., Narayan H.K., Zemljic-Harpf A.E. Molecular mechanisms of anthracycline cardiovascular toxicity. Clin Sci (Lond) 2021;135:1311–1332. doi: 10.1042/CS20200301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Von Hoff D.D., Layard M.W., Basa P., et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710–717. doi: 10.7326/0003-4819-91-5-710. [DOI] [PubMed] [Google Scholar]
- 3.Shalata W., Abu-salman A., Steckbeck R., et al. Cardiac toxicity associated with immune checkpoint inhibitors: a systematic review. Cancers (Basel) 2021;13:5218. doi: 10.3390/cancers13205218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Yamaguchi S., Morimoto R., Okumura T., et al. Late-onset fulminant myocarditis with immune checkpoint inhibitor nivolumab. Can J Cardiol. 2018;34:812.e1–812.e3. doi: 10.1016/j.cjca.2018.03.007. [DOI] [PubMed] [Google Scholar]
- 5.Palaskas N.L., Segura A., Lelenwa L., et al. Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy. Eur J Heart Fail. 2021;23:1725–1735. doi: 10.1002/ejhf.2265. [DOI] [PubMed] [Google Scholar]
- 6.Gao X., Zhang J., Dai Z., Luo D., He R., Li M. Anti-tumor drug lenvatinib induced cardiotoxicity via mitochondrial oxidative stress and apoptosis. J Mol Cell Cardiol. 2020;140:25. [Google Scholar]
- 7.Mihalcea D., Memis H., Mihaila S., Vinereanu D. Cardiovascular toxicity induced by vascular endothelial growth factor inhibitors. Life. 2023;13:366. doi: 10.3390/life13020366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Babiker H.M., McBride A., Newton M., et al. Cardiotoxic effects of chemotherapy: a review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system. Crit Rev Oncol Hematol. 2018;126:186–200. doi: 10.1016/j.critrevonc.2018.03.014. [DOI] [PubMed] [Google Scholar]
- 9.Lee S.H., Cho I., You S.C., et al. Cancer therapy-related cardiac dysfunction in patients treated with a combination of an immune checkpoint inhibitor and doxorubicin. Cancers (Basel) 2022;14:2320. doi: 10.3390/cancers14092320. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Wang Y., Cui C., Deng L., Wang L., Ren X. Cardiovascular toxicity profiles of immune checkpoint inhibitors with or without angiogenesis inhibitors: a real-world pharmacovigilance analysis based on the FAERS database from 2014 to 2022. Front Immunol. 2023;14 doi: 10.3389/fimmu.2023.1127128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Crocetto F., Ferro M., Buonerba C., et al. Comparing cardiovascular adverse events in cancer patients: a meta-analysis of combination therapy with angiogenesis inhibitors and immune checkpoint inhibitors versus angiogenesis inhibitors alone. Crit Rev Oncol Hematol. 2023;188 doi: 10.1016/j.critrevonc.2023.104059. [DOI] [PubMed] [Google Scholar]
- 12.Dolladille C., Ederhy S., Sassier M., et al. Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol. 2020;6:865–871. doi: 10.1001/jamaoncol.2020.0726. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Transthoracic Echocardiography on Admission
Transthoracic Echocardiography 1 Month After Discharge