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Cardiotoxicity and Neurotoxicity of High-Dose Continuous Fluorouracil As a Result of Degradation Compounds in the Drug Vials

Stadtspital Triemli, Zürich, Switzerland
Stadtspital Triemli, Zürich, Switzerland, Groupe de Resonance Magnétique Nucléaire Biomédicale (RMN) Biomédicale, Laboratoire de Synthèse et Physico-Chimie des Molécules d’Intérêt Biologique (SPCMIB), Université Paul Sabatier, Toulouse Cedex, France

To the Editor:

Cardiotoxicity and neurotoxicity are rare but serious adverse effects of fluorouracil (FU) treatment.^1,2 The presentation of these toxicities is variable. Several cases of severe, yet generally reversible, global left ventricular failure have been reported.³ Yeh and Cheng⁴ observed a 5.7% incidence of FU-induced encephalopathy associated with hyperammonemia and lactic acidosis in patients receiving high-dose continuous FU. The mechanism of cardiotoxicity and neurotoxicity is not fully understood. It has been attributed by some authors to the conversion of alpha-fluoro-beta-alanine, the major metabolite of FU, into fluoroacetate (FAC), which is known as a cardiotoxic and neurotoxic poison.^5,6 Lemaire et al^7,8 and Arellano et al⁹ postulated that two degradation products in commercially available FU preparations, namely fluoromalonic acid semialdehyde (FMASAld) and fluoroacetaldehyde (Facet), may be responsible, at least partly, for cardiotoxicity because these two compounds are highly cardiotoxic on the isolated perfused rabbit heart model, and Facet is also transformed to FAC in vivo.^7-9

Between March 2002 and September 2002, we observed one case of lethal hyperammoniemic encephalopathy and two cases of severe, reversible left ventricular failure in patients receiving high-dose continuous FU. Alerted by the accumulation of these unusual toxic events within 6 months, we reviewed the records of our pharmacy. Two FU preparations (lot No. 94 2445 from Biosyn Arzneimittel GmbH, Fellbach, Germany, and batch No. 101410 from ICN-Pharmaceuticals, Barcelona, Spain) were used in this time period in our institution. The two FU solutions were analyzed for the presence of possible toxic degradation products with fluorine-19 nuclear magnetic resonance (¹⁹F NMR).

Case 1:

A 53-year-old, otherwise healthy female patient was diagnosed with locally advanced rectal cancer (uT3, uN1). Neoadjuvant combined chemoradiotherapy, consisting of continuous FU (1,000 mg/m²/d for 4 days in weeks 1 and 5) and radiotherapy over 5 weeks (45 Gy), was started. On days 2 and 3 of the first week, the patient had severe nausea and vomited repeatedly. On day 4, she became disoriented and somnolent. There were no focal neurologic deficiencies. Liver function tests were normal. The EEG showed slow waves and theta waves, which was consistent with metabolic or toxic encephalopathy. Brain magnetic resonance imaging and lumbar puncture were normal. Plasma ammonia level was 354 µmol/L (normal, < 35 µmol/L), lactate was 14 mmol/L (normal, < 2.44 mmol/L), arterial blood gas analysis showed hypocapnia (pCO₂: 3.3 kPa), and the pH was 7.34. Sudden apnea and ventricular fibrillation developed. Resuscitation was not successful, and the patient died.

Case 2:

A 64-year-old male patient was diagnosed with squamous cell carcinoma of the esophagus (uT2, uN1). Combined chemoradiotherapy, consisting of continuous FU (1,000 mg/m²/d for 4 days in weeks 1 and 5), cisplatin (75 mg/m² divided on 2 days, days 2 and 3), and radiotherapy over 5 weeks (55.8 Gy), was started. On day 4 of week 1, oliguric cardiogenic shock developed. An echocardiography showed a severely depressed left ventricular ejection fraction of 20% to 25% with global hypokinesis. There was no chest pain. Chemotherapy was stopped. Cardiac enzymes remained normal. The patient needed hemodynamic support with high doses of catecholamines. He recovered rapidly during the next days, and left ventricular ejection fraction improved to near normal (55%) 1 week later.

Case 3:

A 65-year-old female patient was diagnosed with locally advanced rectal cancer (uT3, uN1). The same neoadjuvant chemoradiotherapy as in patient 1 was started. Echocardiography and ECG were normal. Chemotherapy was tolerated well in week 1. On day 4 of the second FU cycle (week 5 of radiotherapy), left ventricular failure developed. FU was stopped. Echocardiography showed a severely depressed left ventricular ejection fraction of 25% with diffuse hypokinesis. In the ECG, there were T-wave inversions and ST-segment elevations in the precordial leads. Cardiac enzymes remained normal. ECG findings returned to normal 5 days later. Left ventricular function normalized, as shown by echocardiography 2 weeks later.

Patients 1 and 2 received FU from Biosyn. Patient 3 received FU from ICN Pharmaceuticals in cycle 1 (which was tolerated well) and FU from Biosyn in cycle 2. The Biosyn solution contained FU dissolved in a Tris [tris(hydroxymethyl)aminomethane; Trometamol] buffer as shown by ¹H and ¹³C NMR spectra because the manufacturer did not indicate the vehicle. The ¹⁹F NMR spectrum of the solution revealed the presence of FU and about 100 fluorinated impurities representing 7.7 mole% with respect to FU (Table 1). Fluoride ion (F^–), the two diastereoisomeric oxazolidines formed from FMASAld and Tris (FMASAld-Tris), and the oxazolidine formed from Facet and Tris (Facet-Tris) were already observed when we analyzed the FU-Tris Roche (Produits Roche, Neuilly, France) solutions commercialized in France before 1994.^8,10 The number of impurities and their total percentage were higher in FU Biosyn than in FU-Tris Roche (7.7 v 1.5 mole%, respectively; Table 1). The amount of FMASAld-Tris plus Facet-Tris was also slightly superior in FU Biosyn compared with FU-Tris Roche (1.6 v 1.3 mole%, respectively).

We were surprised that the Biosyn vial contained FU dissolved in Tris. Indeed, we thought that Tris was not used anymore to dissolve FU because we reported several years ago that FU degradation in Tris leads to the two cardiotoxic compounds Facet-Tris and FMASAld-Tris.^8,10 We also showed that the solutions of FU dissolved in a NaOH solution at pH 9.2, which contains lesser amounts of Facet and FMASAld, were much less cardiotoxic on the isolated perfused rabbit heart model than the FU-Tris solutions.^8,10 Thus, the formulation in Tris commercialized in France was withdrawn in 1994 and replaced by a formulation with NaOH solution.

The evidence of the higher cardiotoxicity of FU-Tris solutions from studies in humans was incomplete until now. Even if we know that Facet and FMASAld are not the sole cause of cardiotoxicity because FU itself is metabolized to FAC in the isolated perfused rat liver model,⁹ the present retrospective study clearly shows that FU from ICN was less toxic than FU from Biosyn. The incidence of severe cardiotoxicity or neurotoxicity was 9% (three of 34 treatment cycles with Biosyn FU formulation in 23 patients) over a period of 6 months, whereas none of the patients receiving ICN FU (22 treatment cycles in 17 patients) experienced cardiotoxicity or neurotoxicity.

The difference between these two formulations is the vehicle, Tris buffer for the former and basic water for the latter. Tris blocks the aldehydes (Facet and FMASAld) formed during the degradation of FU as oxazolidines (Facet-Tris and FMASAld-Tris), depot forms that are stable in basic medium but release free Facet and FMASAld at physiologic pH. On the other hand, when the aldehydes are formed in basic water, their high chemical reactivity leads to their extensive transformation into a variety of other fluorinated compounds, which are probably noncardiotoxic.

In conclusion, we showed that the patients were all being treated with the FU-Tris Biosyn formulation when they experienced cardiotoxicity or neurotoxicity, which contains more toxic compounds than the FU ICN solution. Cardiotoxic and neurotoxic syndromes in patients treated with FU are, at least in part, caused by these toxic compounds. Therefore, we suggest that the FU-Tris formulation should be withdrawn and no longer be commercialized.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Acknowledgment

Dedicated to Dr Marcel de Forni in memoriam. J.L. and M.M.-M. contributed equally to this article.

REFERENCES

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10. Lemaire L, Malet-Martino MC, Martino R, et al: The Tris formulation of fluorouracil is more cardiotoxic than the sodium salt formulations. Oncol Rep 1:173-174, 1994

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lukaschek, J. Articles by Martino, R. Search for Related Content PubMed PubMed Citation Articles by Lukaschek, J. Articles by Martino, R. Social Bookmarking                            What's this?