Table 1 Cases
Reference | Age and sex | Prior primary cardiac disease | Drug used | Duration of treatment before heart failure detection in weeks | mutation | Imaging modalities and findings before medication | Imaging modalities and findings while on medication | Ejection fraction before starting drug (baseline) | Lowest ejection fraction while using the drug | Ejection fraction after discontinuing the drug | Treatment for event | Histopathology report | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
[7] | 67, female | No prior primary cardiac disease | Osimertinib | 28 | –- | Transthoracic echocardiogram (TTE) demonstrated a left ventricular ejection fraction (LVEF) of 70% with left ventricular end-diastolic dimension normal at 35 mm | TTE: global hypokinesis, abnormal global longitudinal strain (− 12%), septal dyssynchrony, and mild biventricular dilation pharmacological nuclear stress test at that time demonstrated a LVEF of 35% with normal perfusion | 70% | 24% | 34% | Lisinopril and metoprolol succinate were initiated, although metoprolol was subsequently discontinued due to fatigue, and lisinopril was replaced by valsartan/sacubitril, Osimertinib was discontinued and replaced by erlotinib | –- | Stable ejection fraction, asymptomatic from a heart failure perspective |
[8] | 74, female | No prior primary cardiac disease | Osimertinib | 108 (i.e., 2Â years) | EGFR gene-positive and T790 mutation-positive | Transthoracic echocardiography demonstrated left ventricular end-diastolic diameter of 43Â mm and left ventricular ejection fraction of 63% | Transthoracic echocardiography presented left ventricular end-diastolic diameter of 62Â mm and left ventricular ejection fraction of 31% | 63% | 31% | 62% | Osimertinib was terminated, Intravenous diuretics, 2.5Â mg of carvedilol. Administration of carvedilol somewhat induced symptomatic hypotension. Termisartan 20Â mg was converted to enalapril 1.25Â mg. Carvedilol was converted to bisoprolol 1.25Â mg, Ivabradine 5.0Â mg was initiated to modulate her heart rate | Percutaneous end-myocardial biopsy revealed slight myocardial fibrosis and atrophy without infiltration of inflammatory cells, The electron microscopy showed hypertrophy and variety in size of the myocardium accompanying smaller mitochondria | Asymptomatic from a heart failure perspective |
[9] | 76, female | No prior primary cardiac disease | Osimertinib | 16 | T790 M EGFR mutation | –- | Echocardiogram indicated an obvious finding of severe hypokinesis, with an ejection fraction of 17% and left ventricular enlargement | –- | 17% | –- | Osimertinib was discontinued. The patient was treated with furosemide, carvedilol, and enalapril | endomyocardial biopsy confirmed non-specific cardiomyopathy, without inflammatory cell infiltration, amyloid deposits, and necrosis | Return of echo parameters back to normal, with the patient being asymptomatic from a heart failure perspective |
[10] | 80, female | No prior primary cardiac disease | Osimertinib | 8 | EGFR exon 19 deletion | Transthoracic ultrasound cardiography (UCG) showed a left ventricular end-diastolic diameter of 47 mm and an LVEF of 65% | Transthoracic UCG showed a dilated and diffusely hypo-contractile left ventricle (left ventricular end-diastolic diameter 56 mm, LVEF 35%) | 65% | 35% | 62% | Osimertinib discontinued, furosemide intravenously on admission and changed to oral azosemide and spironolactone on the sixth hospital day, oral enalapril maleate and bisoprolol fumarate on the fourth hospital day | –- | Asymptomatic from a heart failure perspective, She did not receive any other chemotherapy and died of cancer progression and cachexia at home 15 months after osimertinib discontinuation |
[5] | 91, male | No prior primary cardiac disease | Osimertinib | 6 | EGFR exon 21 L858R point mutation | TTE showed normal wall motion of the left ventricle with an LVEF of 64% and normal chamber calibers | TTE showed diffuse hypokinesis of the left ventricular wall, with a decreased LVEF to 48% | 64% | 48% | 63% | Osimertinib was withheld, furosemide (40 mg daily) was administered for four days. In addition, the dosage of azosemide and tolvaptan was increased to 60 and 7.5 mg, respectively | –- | Asymptomatic from a heart failure perspective |
[11] | 70, female | Mild mitral, and mild tricuspid regurgitation | Osimertinib | 24 | Epidermal growth factor receptor (EGFR) Exon 21 mutation | Transthoracic echocardiogram showed a left ventricular ejection fraction greater than 55%, mild mitral, and mild tricuspid regurgitation | Transthoracic echocardiogram (TTE) showed mild to moderate left ventricular systolic dysfunction with an estimated left ventricular ejection fraction (LVEF) of 40–45%, moderate to severe tricuspid regurgitation, mild to moderate mitral regurgitation, mild aortic regurgitation | 55% | 43% | –- | treated with electrolyte replacement along with parenteral nutrition initially. The potassium level improved to 4.0 mmol/L over the next 24 h. Repeat EKG (Figure-3) with a potassium level of 3.7 mmol/L still showed a prolonged QTc interval of 552 ms. QTc interval normalized in the next 72 h to 408 ms, Osimertinib dose was decreased to 40 mg at the time of discharge, | –- | the patient refused further cancer treatment and decided to go on for hospice management with supportive care |
[12] patient 1 | 78, female | Thoracic aortic aneurysm | Osimertinib | 12 | EGFR L858R, exon 21 | Echocardiography shows a baseline LVEF was 61% and LVIDd/LVIDs were 44/29 mm | Echocardiography revealed severely reduced LVEF at 28% and an increased LVIDd/LVIDs at 44/38 mm, with moderate to severe mitral regurgitation (MR) | 61% | 28% | 48% | Osimertinib was discontinued, and furosemide 40 mg, spironolactone 50 mg, tolvaptan 7.5 mg, carvedilol 5 mg, and candesartan 2 mg, daily | –- | Improvement of the patient’s heart failure symptoms |
[12] patient 2 | 68, male | Moderate aortic regurgitation | Osimertinib | 4 | EGFR Ex.19 del. and T790M mutations | Echocardiogram showed a LVEF of 74% | Echocardiography revealed severe tricuspid valve regurgitation (TR) and mild pulmonary hypertension (estimated pulmonary artery systolic pressure: 45 mm Hg) | 74% | 60% | 72% | Osimertinib was discontinued, and tolvaptan 3.75 mg, and furosemide 40 mg daily | –- | fatigue and edema improved, but severe TR persisted |
[12] patient 3 | 64, female | Moderate mitral regurgitation | Osimertinib | 36 | EGFR L858R and T790M mutations | Echocardiography showed moderate mitral regurgitation | Echocardiography showed a LVEF of 50% | 72% | 50% | 62% | Osimertinib was discontinued, and she was treated with furosemide 20 mg; and spironolactone 25 mg daily | –- | Follow-up showed there were no signs of additional cardiac dysfunction |
[12] patient 4 | 52, female | No prior primary cardiac disease | Osimertinib | 2 | EGFR L858R mutation | Echocardiography revealer a LVEF of 41% | Echocardiography revealed a LVEF of 63% | 63% | 41% | 63% | Osimertinib was discontinued and candesartan 4 mg daily, was initiated | –- | The patient was then treated with afatinib, a second-generation of EGFR-TKI, and her cardiac function remained stable |
[13] | 73, female | No prior primary cardiac disease | Osimertinib | 4 | T790M mutation | –- | Echocardiogram revealed left ventricular akinesis from the apical to the midventricular portion, The left ventricular dimension increased from 34 mm preosimertinib treatment to 46 mm, and left ventricular ejection fraction (LVEF) was 58% | 75% | 58% | 64% | Discontinuing osimertinib and adding treatment for heart failure including spironolactone 25 mg and bisoprolol 1.25 mg | –- | diagnosed with asymptomatic TC, and osimertinib treatment was subsequently stopped |
[14] | 62, female | No prior primary cardiac disease | Osimertinib and ibandronate | 24 | L858R mutation in exon 21 of the EGFR gene | –- | Echocardiogram indicated an obvious severe hypokinesis, with a left ventricular ejection fraction (LVEF) of 36% and the left ventricle was dysfunctioning | –- | 36% | 66% | Discontinue osimertinib, furosemide (20 mg bid), spironolactone (20 mg bid), bisoprolol (20 mg qd), and valsartan (50 mg bid) were given | –- | follow-up treatment that included alternative third-generation EGFR-TKI aumolertinib significantly soothed the condition of a patient with no further complaints of heart discomfort, except fatigue |
[15] | 70, female | No prior primary cardiac disease | Erlotinib | 8 | EGFR deletion mutation in exon 19 | Echocardiogram showed a LVEF of 67% | Echocardiography, the left ventricular ejection fraction (LVEF) 35% | 67% | 35% | 50% | Treated with carperitide, enalapril, spironolactone, carvedilol, and furosemide | endomyocardial biopsy was performed, and showed myocyte disarray with nuclear pleomorphism and mild fibrosis within the myocardium, No inflammatory cell infiltration, amyloid deposits, or necrosis were observed | The patient was able to continue erlotinib treatment for 9Â months without acute exacerbation of chronic heart failure, but due to cancer progression, her anticancer drug was switched to osimertinib, and cardiac function was maintained until the end of the follow-up period |
[16] | 71, female | Asymptomatic left bundle branch block | Erlotinib | 104 | –- | –- | TTE showed dilated cardiomyopathy with a left ventricular ejection fraction (LVEF) of 45% and septal dyskinesia without pericarditis | –- | 25% | 45% | Erlotinib was discontinued, angiotensin-converting enzyme inhibitor, furosemide, bisoprolol and low-salt diet was reinforced | –- | Asymptomatic from a heart failure perspective |
[17] | 71, female | atrial fibrillation | Afatinib | 4 | EGFR-mutated lung cancer exon 19 deletion | Echocardiography showed a left ventricular ejection fraction (LVEF) of 60% | Echocardiography showed a decreased LVEF 40%, diastolic dysfunction, left ventricle enlargement, and pericardial effusion | 60% | 40% | 60% | Afatinib was discontinued and alternative therapy with gefitinib 250 mg/d was started | –- | there was no symptom of cardiac dysfunction and an echocardiography showed no change |
[18] | 56, female | No prior primary cardiac disease | Gefitinib | 28 | EGFR exon 19 deletion | –- | Transthoracic echocardiography showed diffusely depressed left ventricular wall motion (left ventricular ejection fraction: 28%) with minor pericardial effusion. The left ventricular diastolic diameter was 51 mm, with normal wall thickness | –- | 28% | 58% | Gefitinib was discontinued and an angiotensin-conversion enzyme inhibitor and beta-blocker were initiated | myocardial biopsy displayed no cardiac hypertrophy, cardiac fibrosis, myocyte disarray, or inflammatory cell infiltration | After discontinuation of gefitinib treatment, her symptoms gradually improved |
[19] | 84, female | No prior primary cardiac disease | Osimertinib | 34 | EGFR exon 19 deletion and a Thr790Met mutation | –- | Transthoracic echocardiography showed a dilated and diffusely hypocontractile left ventricle (ejection fraction 33%) with minor pericardial effusion. The left ventricular diastolic diameter was 54 mm, with normal wall thickness | –- | 33% | 33% | Osimertinib was discontinued and furosemide, enalapril, and carvedilol were initiated | Pathological examination of a myocardial biopsy specimen revealed no cardiac muscle hypertrophy, cardiac fibrosis, or myocyte disarray; however, there was lymphocyte infiltration and edematization | After 12 weeks, the left ventricular ejection fraction and cardiothoracic ratio had not changed; however, the patient's facial edema had improved |
[20] patient 1 | 70, male | No prior primary cardiac disease | Osimertinib | 12 | EGFR-mutation, T790M mutation on exon 20 | Echocardiographic exam showed a normal left ventricle end-diastolic volume indexed on body surface area (LvVol D/BSA: 49 ml/m2) and a normal ejection fraction (EF: 60%) | echocardiographic re-evaluation was performed and revealed an ejection fraction of 45% | 60% | 45% | 48% | Medical treatment for cardiac failure was prescribed with furosemide, low-dose angiotensin-converting enzyme inhibitor (ACEi), ramipril 2,5 mg, bisoprolol 1,25 mg daily and osimertinib was discontinued | –- | Symptoms and clinical conditions progressively worsened, despite medical treatment and osimertinib withdrawal. And patient past away 4 weeks after drug discontinuation |
[20] patient 2 | 73, Female | intermittent left bundle branch block, mild mitral valve insufficiency due to leaflets fibrosis | Osimertinib | 8 | T790M | Echocardiographic evaluation showed a left ventricle volume at the upper reference limit (LvVol D/BSA: 61 ml/m2) with a small increase in indexed left ventricular mass (LVM/BSA: 104 gr/m2) and a normal systolic function (EF: 62%). A mild mitral valve insufficiency due to leaflets fibrosis was present | Echocardiography showed a global left ventricular dysfunction with an ejection fraction of 50%, mitral valve insufficiency worsened becoming moderate together with an increase in filling pressure | 62% | 50% | 62% | Osimertinib was suspended for 3 weeks and betablocker (bisoprolol1,25 mg per day) was administered | –- | ,osimertinib was restarted at the same dosage without any heart failure symptoms |
[20] patient 3 | 47, Female | No prior primary cardiac disease | Osimertinib | 20 | T790M | Baseline echocardiographic evaluation did not show any pathological finding. With an ejection fraction of | Echocardiogram showed an ejection fraction of 51% | 64% | 51% | 60% | Bisoprolol (5 mg/day) and perindopril (5 mg/day) were administered | –- | 4 weeks after the event osimertinib restarted, the patient underwent a full recovery of the systolic function |
[20] patient 4 | 71, Female | No prior primary cardiac disease | Osimertinib | 36 | T790M | Echocardiographic evaluation showed normal dimensions (LAVol/BSA: 24 ml/m2; LvVol D/BSA: 55 ml/m2) and function (EF: 58%; E/A: 0.6; E/E’: 4) of the left cardiac chambers | Echocardiogram showed an ejection fraction of 45%. Left ventricle and left atrium volumes were both mild dilated (LAVol/BSA: 42 ml/m2; LVVol D/BSA: 83 ml/m2) | 58% | 45% | 54% | Bisoprolol 2,5 mg/daily, furosemide 12,5 mg/daily, and perindopril 2,5 mg/daily | –- | Fifteen days after interruption,osimertinib therapy was resumed along with cardiologic therapy prosecution. Clinical and echocardiographic controls showed a stabilization of the cardiac function |
[20] patient 5 | 80, Female | No prior primary cardiac disease | Osimertinib | 44 | T790M | Echocardiographic evaluation did not show any pathological findings. And an ejection fraction of 62% | Echocardiogram showed an ejection fraction of 43% and an increase in left ventricle mass and left atrial volume | 62% | 43% | 55% | . Osimertinib was temporarily suspended and enalapril therapy titrated from 2,5 mg to 5 mg per day | –- | Reduced osimertinib dose at 40 mg/die with a stable echocardiographic monitoring until the treatment was permanently discontinued for progressive disease |