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The Egyptian Journal of Internal Medicine
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A systematic review of epidermal growth factor receptor tyrosine kinase inhibitor-induced heart failure and its management

The Egyptian Journal of Internal Medicine volume 34, Article number: 85 (2022) Cite this article

Abstract

Background

Multiple case reports and case series have been published on heart failure due to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), yet the management and outcome of the said disease have been scarcely discussed in sufficient details. This review is aimed at characterizing the signs, symptoms, laboratory parameters, and outcomes of this entity by analyzing recent published case reports and case series reporting new-onset heart failure in non-small cell lung cancer tumor (NSCLC) patients who are being treated with EGFR TKIs.

Methods

This is a systematic review of case reports and case series for cases of EGFR TKI-induced heart failure. A systematic search was conducted across a number of databases starting with PubMed databases utilizing its MeSH database; after that, a complementary search through Google Scholar was conducted.

Results

In total, 23 cases of epidermal growth factor receptor tyrosine kinase inhibitor-induced heart failure were included. The majority of the reported case were females (20 females and three males) with a male-to-female ratio of 1:6.6. Ages ranged from 47 to 91 years of age with a mean age of 70.73 and a median of 71 years of age. Symptom improvement and being symptom-free from a heart failure perspective after treatment from the acute event were observed in 18 cases (78.26%) while heart failure progressively worsened and led to the death of the patient in only one case (4.3%).

Conclusion

The utilization of EGFR TKIs in NSCLCs has been associated with a better outcome and fewer side effects when compared to classical chemotherapeutic agents. However, cardiotoxic effects, such as heart failure, could be significant for a small proportion of patients. Recent papers have reported heart failure in younger and cardiac risk-free patients. Still, it is only advised to monitor for heart failure in the high-risk group. Treatment should be individualized and based on a case-by-case basis.

Background

The epidermal growth factor receptor (EGFR) which is a member of the tyrosine kinase receptor family is found to be mutated in approximately 12.5% and 50% of non-small cell lung cancer tumors (NSCLCs) of the Caucasian and Asian populations respectively; thus, it is the most established target for NSCLC therapy [1]. Henceforth, multiple drugs have been produced which target the EGFR such as erlotinib, afatinib, gefitinib, and osimertinib. These targeted therapy drugs have drastically changed the treatment of NSCLC and have become the gold standard of care for patients with NSCLC that have the EGFR mutation [2]. Although they are mostly well tolerated when compared to older chemotherapy agents, they might still cause severe side effects in some patients such as cardiotoxicity, hepatotoxicity, and interstitial lung disease [3].

The fact that metastatic cancer patients in general are now surviving for longer has led to the increased recognition of the importance of the cardiotoxicity that is caused by anticancer treatment; with that being said, it is still somewhat disregarded in lung cancer patients due to the dismal survival rate that they used to possess and that highly cardiotoxic anticancer medications such as anthracyclines are not used as much anymore [4]. Anticancer treatment cardiotoxicity is typically classified into two categories; type I cardiotoxicity which is caused by anthracyclines is irreversible and is additive in a dose-dependent manner. On the other hand, type II cardiotoxicity is reversible and is caused by suppression of the HER2 signaling pathway [5].

Multiple case reports and case series have been published on the matter of heart failure due to EGFR TKIs, yet the management and outcome of the said disease have been scarcely discussed in sufficient details. Thus, to help in diagnosing this entity and characterize its signs, symptoms, laboratory parameters, and outcomes leading to successful management for patients, we have conducted this literature review on case reports and case series of “Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors-induced heart failure and its management”. We have reviewed patient demographics, imaging findings, tumor characteristics, acute event management, and outcomes of case reports and series that we have found up to the date of this manuscript writing.

Methods

This is a systematic review of case reports and case series for cases of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)-induced heart failure. A systematic search was conducted across a number of databases starting with PubMed databases utilizing its MeSH database; after that, a complementary search through Google Scholar was conducted. This search was conducted in the period between 22/9/2022 and 3/10/2022 using the keywords: “cardiotoxicity,” “Heart failure,” “EGFR,” “cardiac dysfunction,” “Osimertinib,” “Gefitinib,” “Afatinib,” “Erlotinib.” Following the PRISMA guidelines [6], we presented the flowchart in Fig. 1 demonstrating our search process. In total, we have included 23 cases extracted from 12 case reports, two case series, and two letters to the editor. We have used Microsoft Excel for analyzing the data and measuring the mean, median, and mode of data extracted from the included cases.

Fig. 1
figure 1

PRISMA flow chart demonstrating search steps and article included [6]

Full size image

We have included case reports, case series, and letters to the editor written in English in which the diagnosis of heart failure post-treatment initiation of EGFR TKI medications has been made on the basis of compatible signs and symptoms of heart failure, a reduction in the ejection fraction of more than or equal to 10% of the baseline, or the development of an ejection fraction less than 45% in patients with no baseline echocardiogram using either transthoracic or transesophageal study for ejection fraction calculation with or without an elevated level of brain natriuretic peptide and with no other discernible causes for the reduction in the ejection fraction. We have excluded studies in which the diagnosis was anything other than heart failure and studies in which causes other than the anticancer treatment as a trigger of heart failure could be detected.

Results

In total, 23 cases of epidermal growth factor receptor tyrosine kinase inhibitor-induced heart failure were included. Of which, 12 cases were in separate case reports, two were in letters to the editor, and nine were included from two separate case series. The majority of reported cases were females (20 females and three males) with a male-to-female ratio of 1:6.6. The ages ranged from 47 to 91 years of age with a mean age of 70.73 and a median of 71 years of age. Most of the cases reported to suffer from treatment-induced heart failure were treated using osimertinib (N = 19, 82.6%), two (8.9%) were treated with erlotinib, one case (4.3%) was treated with afatinib, and one case (4.3%) with gefitinib. After the initiation of the treatment, the signs and symptoms of heart failure were appreciated after a period of time that ranged from 2 to 108 weeks with a mean of 25.82 and a median of 20 weeks (Table 1).

Table 1 Cases
Full size table

The most common identified mutation for NSCLC patients in our study is the T790 mutation affecting 11 patients (47.82%) of our study’s population. Other mutations in our study included Exon 21 mutation in seven patients (30.4%) and Exon 19 deletion mutation occurring in six patients (26%),

Most patients (65.2%) had no prior primary cardiac disease while only 34.8% suffered from cardiac disease. The average ejection fraction for patients prior to treatment initiation was 63.9%, the average for the lowest ejection fraction during the treatment was 39.65% with an average drop of the ejection fraction of 21.1 from the baseline, and the average ejection fraction post-treatment termination was 56.05% with an average rise of 15.6. Five patients had a valvular disease prior to therapy initiation and of those patients; four (75%) were reported to have their valvular disease worsen during the treatment period. Two patients developed new-onset valvular disease during treatment.

Only five patients (21.7%) were reported to have a histopathological exam for obtained cardiac tissue sample. Three of the five samples showed no infiltration of the cardiac biopsy with neither inflammatory cells, amyloid deposits, nor necrosis while only one case was reported to have mild fibrosis on histopathological exam and one case was reported to have lymphocytic infiltration of the biopsy.

Treatment of the acute event mostly consisted of regular heart failure exacerbation medications such as angiotensin-converting enzyme inhibitors (ACE-i), loop diuretics, potassium-sparing diuretics, and beta blockers after the patients’ condition had stabilized with all cases being treated using the same regime with some modifications to the drugs within the same class and doses of given drugs. The EGFR TKI drug was discontinued in 20 patients, the dose was reduced in two patients, and the drug was replaced with another drug of the same class but a different generation in five cases.

Symptom improvement and being symptom-free from a heart failure perspective after treatment from the acute event were observed in 18 cases (78.26%). Two patients (8.69%) refused additional therapy and were sent into hospice for supportive care and symptoms of heart failure progressively worsened and led to the death of the patient in one case (4.3%).

Discussion

This systematic review is the first in literature to investigate EGFR tyrosine kinase inhibitor-induced heart failure and we included 1st-generation (gefitinib, erlotinib), 2nd-generation (afatinib, dacomitinib), and 3rd-generation (osimertinib) TKIs. Since osimertinib is the most used drug, most of the published literature have investigated this drug’s induced heart failure. A literature review by Okuzumi et al. showed similar results to our group regarding the median age and male-to-female ratio. [2] However, all the patients investigated in the review had previous cardiovascular comorbidities which may be predisposed to the development of cardiomyopathy. Our review showed 11 patients of the 19 who were on osimertinib were devoid of any cardiovascular comorbidity. In addition, the median time to event was lower in the review (8 weeks) than in our group (20 weeks).

Non-small cell lung cancers account for up to 90% of all primary lung malignancies. Lung cancers in general are the leading cause of death among malignancies in both males and females. Most patients present at advanced stages, hence the dismal 5-year survival rate of only around 7–35% despite the improvements in our understanding of the entity and new introduced treatments. [21] Primary NSCLC histological types include squamous cell carcinoma and adenocarcinoma. Smoking is an established strong risk factor for the development of NSCLC, as well as exposure to carcinogenic substances such as asbestos, radon, and polycyclic hydrocarbons. Additionally, some genetic elements play an important role in NSCLC development, including EGFR mutations, which may even explain the occurrence of NSCLC in never-smoker patients as they harbor EGFR mutations more frequently. [5]

Heart failure (HF) is a clinical syndrome that develops when the heart’s function is impaired and working less efficiently than normal thus it cannot keep up with the metabolic needs of the body [22]. HF has been considered a major public health issue in recent years due to its growing prevalence [23]. With significant rates of morbidity and mortality, patients have a wide array of clinical presentations of HF. However, patients mainly present with symptoms of dyspnea, exercise intolerance, and edema [24]. HF most commonly develops as a result of cardiovascular diseases such as myocardial ischemia or infarction, hypertension, cardiomyopathies, and valvular heart diseases [25]. However, there are less common etiologies like drug-induced heart failure [26], which may arise due to the direct cardiotoxic effects of some drugs or drug-drug interactions. Many studies have shown that tyrosine kinase inhibitors (TKI) are associated with cardiotoxic effects [27]. The current systemic review highlights the reported cases of epidermal growth factor receptor tyrosine kinase inhibitor-induced heart failure and its management.

Epidermal growth factor receptor (EGFR) has been identified as a member of the ErbB family of receptors, which is made up of four distinct types of receptor tyrosine kinases (RTK): the previously mentioned EGFR as ErbB-1, ErbB-2, ErbB-3, and ErbB-4 [28]; it has been recognized that protein kinases contribute to several cellular functions that include proliferation and differentiation through multiple mechanisms [29]. RTK works by the activation of many pathways through a ligand that binds to an extracellular domain of a receptor that is located on the membrane, which activates the intrinsic kinase tyrosine residues and induces activation of downstream signaling pathways [30]. With that being said, EGFR plays a crucial role in the pathogenesis of several malignancies [28].

EGFR tyrosine kinase inhibitors (EGFR TKI) are Food and Drug Administration (FDA) approved for the treatment of many cancers including non-small cell lung cancer (NSCLC); these drugs bind to tyrosine kinase domain by competing with ATP. Thus, inhibiting autophosphorylation [31], this results in the reduction of the proliferation, invasion, and angiogenesis of the tumor [32]. Gefitinib and erlotinib both inhibit the kinase activity reversibly and are considered a first-generation class, while second- and third-generation afatinib, dacomitinib, and osimertinib are irreversible EGFR TKI [31]. Commonly reported side effects of EGFR TKI drugs include diarrhea, rash, acne, and stomatitis [33]. Dose management and supportive care showed a significant reduction in both the intensity and frequency of said side effects [34].

Although EGFR TKI medications have provided massive strides in cancer treatment and are considered to be much safer than classic chemotherapy agents, they have been reported to cause life-threatening side effects including cardiotoxicities [35]. The effect of EGFR TKI medications on the heart ranges from an asymptomatic prolongation of the QT interval to symptomatic heart failure and even cardiovascular collapse [27].

Uncertainty surrounds the detailed mechanism. A signal cascade that has a strong association with the homeostasis of the myocardium might be suppressed by EGFR TKIs. Furthermore, EGFR TKI might inhibit the proper activity of mitochondria and cause their apoptosis and suppress the HER2 receptor, which may also prevent the proper myocardial differentiation [8].

The current systematic review revealed that patients treated with osimertinib were more likely to experience heart failure compared to patients that received erlotinib, afatinib, and gefitinib. There was a comparison between osimertinib cardiotoxicity and other EGFR TKIs (erlotinib, afatinib, gefitinib) that provides supports to these article findings [36]. Data collected retrospectively from 2016 to 2018 indicated a significant increase in the risk of QT prolongation, heart failure, and atrial fibrillation associated with osimertinib when compared to other EGFR TKIs. Out of 8450 reported adverse events related to EGFR TKIs, 2454 were due to the treatment with osimertinib, whereas 5836 were associated with other EGFR TKIs (erlotinib, afatinib, gefitinib) [37]. According to a retrospective review of the FDA side effects reporting system, an incidence of 2.3% of heart failure during the treatment with osimertinib has been reported [36]. In another Japanese report, 2.5% of the patients suffered from heart failure during osimertinib course [38]. A meta-analysis showed that osimertinib had a significant association with QT prolongation and increased hazard for heart failure as well [39].

A female majority treated with osimertinib that suffered from drug-induced heart failure symptoms was observed in the cases included in the analysis. From the total number of adverse events related to osimertinib, 80.3% of patients experienced heart failure and 67.9% of patients suffered from QT prolongation were females [36]. The type of the mutation in the EGFR could be responsible for the apparent difference in the cardiotoxicity side effect. In a study including 33 persons with Del-19 mutation, 23 patients have shown partial response to EGFR TKI comparing to only 7 patients out of 18 patients with other mutations [40]. Moreover, sensitivity to EGFR TKI and increase in survival time were associated with female sex, which could further justify the higher prevalence of cardiotoxicity among the female gender [41, 42].

For early diagnosis and prompt therapeutic intervention, it is advised to screen potential high-risk patients and carefully monitor them using newly proposed echocardiography strain patterns and troponin levels [43]. In the present review, the general management of TKI-induced cardiac toxic effects after the initiation of the treatment depended mainly on overcoming the symptoms of heart failure and improving patients’ treatment outcomes. For that angiotensin-converting enzyme inhibitors (ACE-i), loop diuretics, potassium sparring diuretics, and beta blockers were prescribed based on the stability of patients’ condition. Osimertinib was terminated in 87% of the cases, dose decreased from 80 to 40 mg in two cases, and other EGFR TKIs were either terminated or changed to another drug from the same category in five cases. After treatment modification, the majority of cases experienced an average rise of 15.6% in LVEF. At the end of the treatment, 78.26% of the patients’ heart failure symptoms were improved or became symptoms free, 8.69% of the patients’ symptoms worsened, and one patient passed away.

Given its dose-independency, the discontinuation of osimertinib might aid in the restoration of cardiac function. Kunimasa and colleagues reported three patients whose LVEF recovered at least partially by 1–3 months following the termination of osimertinib [38]. Henceforth, patients receiving osimertinib are recommended to undergo regular echocardiogram monitoring for LVEF at baseline and every 3 months. When the LVEF falls below 50% and by 10% from baseline values, withholding osimertinib is highly considered [44].

Conclusion

In conclusion, the utilization of EGFR TKIs in NSCLCs has been associated with a better outcome and fewer side effects when compared to classical chemotherapeutic agents. Still, however, cardiotoxic effects, such as heart failure, could be significant for a small proportion of patients. It was suggested that EGFR TKI-induced heart failure involves patients with established cardiovascular risks. Nevertheless, recent papers have reported heart failure in patients who do not have these risks. Since these cases are the exception, it is only advised to monitor for heart failure in the high-risk group. Treatment should be individualized, which could involve only symptomatic treatment with medications, changing the TKI to another drug of the same category, reducing the dose, or terminating the offending drug.

Limitations

Due to the fact that this is a systematic review based on case reports, case series, and letters to editors, it is vulnerable to selection bias and is unable to establish a causal relationship between EGFR TKI medications and heart failure since the cases are rare. Many reported cases lacked certain information regarding the clinical features of the case, histopathology results, and procedures performed such as a diagnostic left heart cath.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Authors and Affiliations

  1. Jordan University Hospital, Amman, Jordan

    Mohammad Nawaf AlShatnawi, Rzan Atef Shawashreh & Ali Rezeq Yaghi

  2. Al-Makassed Hospital, Jerusalem, Palestine

    Mohammed Ashraf Sunoqrot

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  1. Mohammad Nawaf AlShatnawi
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  3. Mohammed Ashraf Sunoqrot
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Contributions

1. M.N.S: Idea conception, data collection, data analysis, manuscript writing. 2. R.A.S: data collection, manuscript writing. 3. M.A.S: data collection, manuscript writing. 4. A.R.Y: data collection, manuscript writing. The authors read and approved the final manuscript.

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Correspondence to Mohammed Ashraf Sunoqrot.

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AlShatnawi, M.N., Shawashreh, R.A., Sunoqrot, M.A. et al. A systematic review of epidermal growth factor receptor tyrosine kinase inhibitor-induced heart failure and its management. Egypt J Intern Med 34, 85 (2022). https://doi.org/10.1186/s43162-022-00176-y

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