Acute reversible left ventricular systolic dysfunction associated with 5-fluorouracil therapy: a rare and increasingly recognised cardiotoxicity of a commonly used drug

Abstract

5-Fluorouracil (5-FU) is the third most common chemotherapeutic agent for treating solid cancers and the second most common to cause cardiotoxicity. We present a rare case of acute reversible severe left ventricular systolic dysfunction associated with 5-FU. A 54-year-old woman with a history of stage IV gastric cancer presented with features of transient ischaemic attack after receiving the first dose of FLOT (5-FU, leucovorin, oxaliplatin and docetaxel). During the diagnostic workup, it was found that her ejection fraction was severely reduced to 15% with features of global hypokinesis, which later improved back to 65% within 13 days. These cases challenge our current understanding of the underlying mechanisms of this cardiotoxicity. Additionally, even though the patient did not experience any cardiac symptoms, it is important to monitor these patients closely as they are at high risk for fatal complications like arrhythmia and thrombus formation.

Background

5-Fluorouracil (5-FU) belongs to a class of medications called fluoropyrimidines, which is the third most commonly used chemotherapeutic agent for solid malignancies,^{1 2} and is the second most common chemotherapy agent associated with cardiotoxicity.^{3 4} The antitumor potential of this drug was first described in the 1950s, and the first description of cardiotoxicity associated with it can be seen from the late 1960s.⁵ Since then, our understanding of the full spectrum of the cardiotoxic manifestations and the possible underlying mechanism is still evolving. We describe a case of cardiotoxicity related to 5-FU use, in which the patient did not experience any features of cardiac decompensation but had severe global systolic dysfunction which reversed in a span of 13 days. Such cases have been rarely described in the literature, and they challenge our current understanding of the most commonly accepted underlying mechanism of cardiotoxicity. Furthermore, during these episodes of systolic dysfunction, these patients are at an increased risk of cardiac arrhythmia and thrombus formation; thus, it is important to recognise them for increased monitoring.

Case presentation

A 54-year-old female patient with a history of stage IV gastric cancer and no prior history of coronary artery disease presented 1 day after initiation of FLOT regimen (5-FU, leucovorin, oxaliplatin and docetaxel) with sudden onset expressive aphasia. The patient received 2600 mg/m² of 5-FU as a short-term infusion over 48 hours. She did not experience any arm or leg weakness and denied any chest pain, dyspnea, headache, blurry vision or palpitations. Examination revealed normal vital signs and no signs of any neurological deficits or cardiac decompensation including elevted jugular venous pulsation, crackles on lung auscultation, S3/S4, murmurs or pedal oedema. Her speech spontaneously improved within hours of hospitalisation. During the course of her hospital stay, she experienced chemotherapy-related vomiting, and her blood pressure (BP) dropped to 80/50 mm Hg with a heart rate of 120/min, which resolved with gentle fluid replacement.

Investigations

Chest X-ray at the time of admission did not reveal signs of pulmonary oedema. An extensive cardioembolic workup for a possible cerebrovascular accident was done. Neurological workup including CT angiogram of head and neck did not reveal any significant vessel stenosis or narrowing. Electrocardiogram (EKG) showed non-specific T-wave inversions with no ST-segment changes (figure 1). Transthoracic Echocardiogram (TTE) revealed an ejection fraction (EF) of 15%–20% with global hypokinesia and absence of cardiac thrombi, valvular pathology or changes in left ventricular (LV) wall thickness (figure 2A and B). She was found to have elevated troponin at 0.17 ng/mL (reference range: normal <0.040 ng/mL) and elevated BNP at 1582 pg/mL. She underwent cardiac catheterisation, which revealed normal coronaries (figure 3).

Figure 1.

EKG at the time of presentation.

Figure 2.

Echocardiographic findings. (A,B) End diastolic (left) and end systolic (right) frames at the time of presentation, respectively. (C,D) End diastolic (left) and end systolic (right) frames 2 weeks after presentation, respectively.

Figure 3.

Normal right (A) and left coronary (B) arteries on coronary angiography.

Differential diagnosis

Given the acute drop in EF, with no previous cardiac history and no signs of cardiac dysfunction, the primary aetiology which was considered was 5-FU related cardiotoxicity. Although docetaxel is known to be associated with cardiotoxicity, it is not reported to cause acute reversible systolic dysfunction.^{6 7} Additionally, oxaliplatin is known to increase the incidence of cardiotoxicity in fluoropyrimidines, but by itself, it is not known to cause such a presentation as well.⁸ Other etiologies that were considered included coronary artery disease due to an acute drop in EF and stress cardiomyopathy (SCM) due to the presence of normal coronaries.

Treatment

The patient was managed conservatively during the course of hospitalisation. She was initiated on Carvedilol 6.25 two times per day and Lisinopril 2.5 two times per day and discharged with a Life vest. Since the patient presented with severely reduced EF along with global hypokinesis indicating low likelihood of vasospastic aetiology, the agents like calcium channel blockers and nitrates were not preferred.

Outcome and follow-up

The patient followed up in 1 week postdischarge, and a repeat TTE showed a completely improved EF of 65%. Figure 2 compares the patient’s EFs at presentation (figure 2A,B) versus the recovered EF 1 week later (figure 2C,D). Due to the absence of previous cardiac history, temporal association of 5-FU administration with the onset of LV dysfunction, the absence of coronary occlusion and reversibility of LV dysfunction, the aetiology of this episode was thought to be secondary to 5-FU use. The patient’s subsequent chemotherapy regimen was switched to carboplatin/paclitaxel.

Discussion

The patient presented with features of a transient ischaemic attack for which she had a thorough neurological workup done including a CT angiogram of head and neck, which showed essentially normal vessels without signs of stenosis or narrowing. Links of 5-FU use and stroke-mimic symptoms like confusion and aphasia have been reported in the literature.^9–11 The incidence of this neurological complication is not clearly described. Due to the inability to timely differentiate this presentation from a true stroke, these patients frequently are administered with tissue plasminogen activator.¹² The underlying cause for this stroke-mimic is poorly understood, and various possible mechanisms have been proposed, including ammonia accumulation, 5-FU induced thiamine deficiency, and dihydropyrimidine dehydrogenase deficiency.¹¹

As a part of the workup for this transient ischaemic attack, the patient was incidentally found to have severely reduced EF and the patient did not have overt clinical signs of decompensated heart failure. The presence of mild elevation in troponin levels could be related to LV systolic dysfunction or as a part of the presentation of stroke-mimic. Of note, the role of troponin elevation in screening for chemotherapy-associated cardiotoxicity and LV dysfunction has been explored in literature.¹³

This case brings our attention to acute reversible global LV systolic dysfunction, which is an increasingly recognised 5-FU-related cardiotoxicity. 5-FU is a commonly used chemotherapy, and our understanding of possible presentations and underlying mechanisms is still evolving.

Incidence and risk factors

The reported incidence of 5-FU cardiotoxicity has been variable across multiple studies. Initial studies reported the incidence to be around 1%–2%,3 4 14 15 although later studies have recorded incidence to be as high as 19%.^16–19 The incidence varies with the mode of administration used viz bolus versus short infusional bolus versus continuous infusion. The bolus regimen is reported to have an incidence of around 1.6%.⁴ Kosmas et al reported the incidence of cardiotoxicity associated with a continuous infusional regimen to be 6.7%, compared with 2.3% with the short-term infusional regimen.²⁰ The association of dose with the incidence of cardiotoxicity has been suggested in some studies,²¹ but multiple other studies have found no such association.^{14 22}

The presence of previous cardiac disorders and risk factors has not been consistently associated with cardiotoxicity incidence. Some studies do report an increased incidence of cardiotoxicity with preexisting cardiac disease,¹⁴ while various other studies have shown no significant association.^{19 23} All the reported cases of reversible LV dysfunction in the setting of 5-FU use, including the case we are describing, did not have significant cardiac risk factors or history of cardiac disease (table 1).

Table 1.

Previously described cases of acute reversible left ventricular systolic dysfunction with global hypokinesis associated with 5-FU use

	Fakhri et al	Dechant et al	Calik et al	Dalzel et al	Mayden et al patient 1	Mayden et al patient 6	Rajeshwar et al
Age/gender	69/F	51/M	55/F	54/M	56/M	59/M	35/F
Prior cardiac history	None	None	None	None	None	None	None
Cardiac risk factors	NR	A*	NR	None	NR	NR	NR
Cancer	Colorectal cancer	Rectal cancer	Colon adenocarcinoma	Colon adenocarcinoma	Pancreatic cancer	Nasopharyngeal	Breast cancer
Additional chemotherapy	Oxaliplatin, leucovorin	NR	NR	Oxaliplatin, leucovorin	Gemcitabine	Carboplatin	Cyclophosphamide, methotrexate
Mode of infusion	Bolus + infusion	Bolus + infusion	Bolus	Infusion	Bolus + infusion	Bolus + infusion	Bolus
Dose	B*	B*	Not reported	Not reported	C*	C*	600 mg/sqmt
Symptoms	Dyspnea, hypotension	Typical chest pain	Atypical chest pain	Typical chest pain	Typical chest pain, palpitations, dyspnea, hypotension	Typical chest pain, dyspnea	Dyspnea, orthopnea, hypotension
Timing of onset of symptoms	Day 3	Day 2	10 hours	20 hours into the infusion	Day 2	Day 2	18 hours
EKG	Anterolateral ST-segment depression and T wave inversions (I, aVL and V2–V6)	Significant ST elevations and prominent T waves in almost all leads (I–III, aVF and V2–V6)	Diffuse ST-segment elevation in all derivations except aVR and V1	Lateral ST elevation with reciprocal change alternating with intermittent left bundle branch block	I, II, III, V1–6 ST elevation	T-wave inversions D1, aVL, V1–6	<2 mm ST depression in inferior leads
Trop	Elevated	NR	Elevated	Elevated	Elevated	Normal	NR
Echo	EF 25%, GH*	EF 24%, GH	EF 20%, GH	EF 30%, GH	EF 25%, GH	EF 31%, GH, MR, TR	EF 35%, GH
Cath	Normal coronaries	D*	Normal coronaries	Normal coronaries	NR	NR	NR
Intevention	ACEi, BB, spironolactone	ACEi, CCB, diuretics	ACEi, BB	ACEi, BB	ACEi, aspirin	Aspirin, warfarin	Inotropic support, DC shock
Timing of evidence of recovery since symptom onset	9 days, normal EF	2 days, normal EF	2 months, normal EF	2 months, normal EF	No recovery reported	NR. E*	2 days

A* Hypertension, Hyperlipidemia, 80 pack-year smoking history, PAD.

B* 400 mg/m² intravenous bolus followed by 2400 mg/m² intravenous infusion.

C* 2-hour intravenous infusion of leucovorin (calcium leucovorin DBL, Orna, Turkey) 200 mg/m², followed by an intravenous bolus of 5-FU 400 mg/m² and then an intravenous infusion of 600 mg/m² for 22 hours on days 1 and 2, biweekly.

D* Generally reduced coronary flow (TIMI II–III), with an ostial stenosis of the left main coronary artery, multiple focal stenoses in the circumflex artery, the left anterior descending coronary artery and the diagonal branch, and an ostial stenosis of the right coronary artery.

E* Patient survived for 20 months and was alive at the time of completion of study.

GH*, global hypokinesis.

5-FU, 5-fluorouracil; ACEi, angiotensin converting enzyme inhibitors; BB, beta blockers; DC, Direct Current Cardioversion; EF, ejection fraction; NR, not reported; MR, mitral regurgitation; PAD, peripheral artery disease; TIMI, Thrombolysis in Myocardial Infarction; TR, tricuspid regurgitation.

Presenting features

There is a wide array of presenting features of 5-FU cardiotoxicity. Saif et al studied 377 patients undergoing 5-FU chemotherapy, the majority of which received continuous infusion. Angina was reported in 45% of patients, and signs of myocardial ischemia were found in 22%; arrhythmia, acute pulmonary oedema, cardiac arrest and pericarditis were reported in 23%, 5%, 1.4% and 1.4% of cases, respectively.²⁴ Also, the changes in EKG are noted to be highly variable in various studies.^{17 25–27} Furthermore, it is important to note that patients can be completely asymptomatic from the therapy, but have EKG changes, arrhythmia and BNP elevation.^{19 23 28} The usual timing of onset of cardiomyopathy is between 3 and 18 hours following initiation of chemotherapy.²⁵ The unique and concerning feature about our case was that, while the patient had severe ventricular dysfunction, she was completely asymptomatic from a cardiac standpoint throughout the phase of cardiomyopathy.

The exact incidence of TTE changes and heart failure has not been studied thoroughly. There have been multiple reports of patients presenting with reversible cardiomyopathies, without evidence of coronary artery occlusion, consistent with features of SCM.^29–35 Although our case did have non-obstructive coronaries and complete reversibility of LV dysfunction, the presence of global hypokinesis pattern is not a part of Mayo clinical criteria³⁶ and is not commonly described in SCM.³⁷ Additionally, the presence of these features in the setting of drug use, excludes the diagnosis of SCM, per Gothenburg Criteria.³⁸ A similar presentation of reversible global hypokinesis associated with 5-FU has been previously described,^39–45 and these cases do not meet the strict definition of SCM (table 1). Thus, these reports of 5-FU-related global hypokinesia, make us think about our current understanding of the underlying mechanism for this cardiotoxicity.

Current understanding of the underlying mechanism

The common implicated mechanisms in 5-FU cardiotoxicity are (1) coronary artery vasospasm, (2) direct endothelial damage leading to increased thrombosis, (3) oxidative stress and (4) reduced RBC oxygen transfer capacity.^{16 46} Coronary vasospasm is a leading mechanism as reported by various authors including Iskander et al,^{16 47} and is a reasonable explanation for cases with ST-elevation, troponin elevation along with reversible myocardial dysfunction. However, vasospasm should lead to a more localised wall motion abnormality, rather than global hypokinesia.

However, various studies challenge that vasospasm can be the sole aetiology. For instance, during the episodes of cardiotoxicity, the vasospasms have not been documented consistently and the reintroduction of 5-FU has failed to reproduce the vasospasm.^48–50 For the presentation of cases like ours, we agree with Fakhri et al that the depletion of high energy phosphate compounds would be a plausible explanation for global hypokinesis of the LV wall. This hypothesis of energy reserve depletion has mostly been studied in animals,^51–53 and to the best of our knowledge, their potential role of this mechanism in human subjects has not been explored. For the evaluation of this hypothesis in cases of global LV systolic dysfunction, non-invasive methods like myocardial 31P MR spectroscopy could be of use, but this imaging technique is not available readily.

Management

5-FU cardiotoxicity is reversible in most of the cases and the management includes discontinuation of the drug and using guideline-directed medical therapy.²⁴ This diagnosis is based on the right clinical setting and not any single test. This clinical setting would include the absence of significant cardiac history and the temporal association of drug administration with the onset of clinical features.

It is imperative to establish the right association since a false attribution of the cause of cardiac dysfunction to this chemotherapy can lead to the use of a relatively less effective second-line chemotherapeutic agent, and thus compromise cancer cure. On the other hand, failure to recognise the right association can be catastrophic, and fatality has been reported in around 13% of the cases.²⁴

An important point to emphasise from our case is that even though the patient can be asymptomatic, the dysfunction of the LV is severe. Although the dysfunction is reversible and temporary in most cases,^{39 40 54} during the acute phase of cardiac dysfunction, the patient is at increased risk for grave complications like thrombus formation and fatal arrhythmia. Thus, it is warranted that patients be monitored closely for cardiac complications at least during the acute phase following 5-FU therapy.

Learning points.

• 5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent, and our understanding of the full spectrum of its cardiotoxicity is still evolving. The reports of global dysfunction in cases like ours challenge the predominant role of vasospastic aetiology and warrants exploration for other possible mechanisms.

• The presentation of cardiotoxicity associated with 5-FU can be highly variable, and even asymptomatic, as demonstrated in our case. Thus, it can be challenging to identify these patients.

• During the acute postchemotherapy phase, patients are at risk for severe complications like arrhythmia and thrombus formation. Therefore, they should be closely monitored.