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Fluorouracil


See also Cytotoxic and immunosuppressant drugs

General information

Fluorouracil is a fluorinated pyrimidine, which is converted intracellularly to the active form, fluorodeoxyuridine monophosphate, which inhibits thymidylate synthetase and hence reduces the production of thymidylic acid, the deoxyribonucleotide of thymine (5-methyluracil), a DNA pyrimidine base, blocking DNA synthesis. In addition, intracellular conversion to 5-fluorouridine monophosphate results in incorporation of the activated antimetabolite into RNA and consequent RNA dysfunction.

Fluorouracil is specific to the S phase of the cell cycle. It is primarily used intravenously to treat carcinoma of the breast and adenocarcinomas of the gastrointestinal tract [ ]. In addition, topical fluorouracil is used to treat actinic keratoses.

General adverse effects and adverse reactions

The dose-limiting toxic effects of fluorouracil vary with the dose and mode of administration.

  • With five consecutive daily bolus injections of 450–600 mg/m 2 , the dose-limiting effects are myelosuppression, mucositis, and diarrhea.

  • With weekly injections of 450–600 mg/m 2 , myelosuppression is dose-limiting.

  • With continuous five-day infusion of 1000 mg/m 2 /day, mucositis and diarrhea are dose-limiting.

  • With protracted continuous infusion of 200–400 mg/m 2 /day, mucositis and palmar–plantar erythrodysesthesia syndrome are the most common dose-limiting adverse reactions [ ].

Some very high-dose, short-exposure studies have been reported, including 14 g over 24 hours [ ] and 2.6 g/m 2 weekly [ ]; in the latter study, neurotoxicity was dose-limiting; with 24-hour infusion of 2.6 g/m 2 weekly, palmar–plantar erythrodysesthesia syndrome is a major adverse reaction.

Relation of toxicity to pharmacokinetics

The pharmacokinetics of fluorouracil have been determined in 19 patients receiving fluorouracil by protracted intravenous infusion of 190–600 mg/m 2 /day [ ]. The steady-state fluorouracil plasma concentration and AUC were significantly lower in the nine patients who had grade 2 toxicity or less compared with the nine patients who had greater than grade 2 toxicity. In contrast, there was no difference in fluorouracil plasma concentrations between the 10 responders and the nine patients who had no evidence of a clinical response. These investigations confirm previous observations that correlations can be drawn between fluorouracil pharmacokinetics and clinical toxicity [ ]. Furthermore, the data suggest that pharmacokinetic monitoring might permit identification of patients at increased risk of toxicity.

Organs and systems

Cardiovascular

Fluorouracil can cause anginal chest pain, with non-specific ST–T electrocardiographic changes, during infusion [ ]. The outcome is favorable if the drug is withdrawn. Re-introduction of the drug has been associated with occasional fatal outcomes and is not recommended [ ]. The cardiotoxicity of 5-fluorouracil in 135 reported cases has been reviewed [ ].

Presentation

More frequent use of fluorouracil by continuous infusion, increased awareness of the problems, and more sophisticated monitoring have increased the reported incidence. By 1990, more than 67 clinical cases had been described [ ] and an incidence ranging up to 68% of silent ischemic electrocardiographic changes was identified in patients monitored by continuous 24-hour ambulatory electrocardiography during fluorouracil infusion [ ]. The clinical features include the following:

  • Precordial pain (both non-specific and anginal) [ ].

  • Electrocardiographic ST–T wave changes (non-specific and ischemic) [ , ].

  • Acute myocardial infarction (rare) [ , ].

  • Atrial dysrhythmias (including atrial fibrillation) and less often, ventricular extra beats (including refractory ventricular tachycardia and fibrillation) [ ].

  • Ventricular dysfunction (usually global, less frequently segmental).

  • Cardiac failure, pulmonary edema, and cardiogenic shock (with and without ischemic symptoms) [ ].

  • Sudden death, presumed to be caused by ventricular fibrillation [ , , ].

In most patients with chest pain, with or without electrocardiographic changes, the creatinine kinase MB fraction remained normal [ , , ].

Acute dilated cardiomyopathy with left ventricular dysfunction related temporally to fluorouracil and cisplatin infusion, with subsequent complete recovery, has been tentatively linked to fluorouracil [ ]. Other similar events have been reported [ , , ]. The association is more striking in patients who receive a continuous infusion of fluorouracil and in patients who receive concomitant cisplatin [ ]. For example, myocardial ischemia and infarction occur in about 10% of patients who receive fluorouracil by infusion and sudden death has occurred [ ].

Five cases of paroxysmal atrial fibrillation and sinus bradycardia attributed to fluorouracil have been reported [ ].

Acute pulmonary edema leading to lethal cardiogenic shock has been reported with fluorouracil. This occurred despite the fact that the patient had received eight infusions of leucovorin 100 mg/m 2 at weekly intervals [ ].

Most often, cardiotoxicity develops during the second or later course of treatment, but some patients have problems during the first course [ ]. Those who develop cardiac toxicity and recover usually have symptoms again when re-challenged with another infusion [ , ].

Fluorouracil has also been associated with a number of vascular effects, particularly thromboembolic or circulatory in nature [ ]. Although Raynaud’s phenomenon has been reported after cisplatin-based chemotherapy, the first case of digital ischemia and Raynaud’s phenomenon has been reported with fluorouracil given in a De Gramond type schedule [ ].

Mechanisms and pathophysiology

The mechanisms of fluorouracil cardiotoxicity are not known. Those that have been suggested include:

  • direct uncoupling of electromechanical myocardial function at the level of ATP generation [ ];

  • an immunoallergic reaction following sensitization by a complex of fluorouracil and cardiac cells;

  • vasospasm secondary either to fluorouracil or to released products;

  • a direct toxic effect of the drug on the myocardium.

Most reports have attributed chest pain to vasospasm [ ]. Certainly, the ischemic-like pains and electrocardiographic findings, lack of changes in creatine kinase, and frequent responses to nitrates and at times to calcium antagonists in the setting of anatomically normal coronary angiography, plus reversible contractility defects suggest coronary vasospasm as a mechanism of fluorouracil cardiotoxicity. However, global dysfunction possibly due to stunned myocardium and the lack of universal response to coronary vasodilators leaves some questions about this hypothesis. Some investigators have postulated myocarditis or myocardiopathy [ ]. In 43 patients it did not interfere with the electrical properties of myocardial fibers [ ].

Findings on autopsy and endomyocardial biopsy have shown diffuse, interstitial edema, intracytoplasmic vacuolization of myocytes, and no inflammatory infiltrate [ ]. Acute myocardial infarction has been demonstrated pathologically in some, but not all, patients with clinical infarction [ ].

In patients with fluorouracil cardiotoxicity endothelin plasma concentrations were raised [ ].

Susceptibility factors

With regard to susceptibility factors for cardiotoxicity with fluorouracil, there was no effect of age or sex on incidence [ ]. Symptoms have been reported in a 38-year-old man [ ] and in several women in their forties [ , ] with no prior cardiac history. Cardiac findings have occurred when fluorouracil was given by infusion or bolus as a single agent or with cisplatin and other drugs [ , ]. Although some felt that cardiac irradiation and pre-existing heart disease were susceptibility factors [ , ], others did not [ , ]. Several investigators have documented normal coronary arteries in patients with severe symptoms [ , ].

Frequency

The cardiotoxicity of fluorouracil was first identified in 1975 [ ]. Of 140 patients treated with intravenous 5-fluorouracil, four developed ischemic chest pain within 18 hours of either the second or third dose. In three of these patients the pain recurred after subsequent doses. Predose electrocardiograms in two cases were normal. None of the four patients had a history of ischemic heart disease, although all had received left ventricular irradiation [ ].

A 5% incidence of cardiotoxicity-complicating high-dose infusion of fluorouracil 1000 mg/m 2 /day for 4 days has been reported and correlated with plasma fluorouracil concentrations in excess of 450 mg/ml [ ].

In 910 patients toxicity was life-threatening in 0.55% [ ]. A combination of cisplatin, fluorouracil, and etoposide given for advanced non-small cell cancer of the lung caused only the expected amount of hematological toxicity, but was associated with a higher than expected incidence of cardiac, pulmonary, and cerebrovascular toxicity, including two myocardial infarctions, two cases of congestive heart failure, one pulmonary embolus, and one cerebrovascular accident in a study of 35 patients [ ].

In 1083 patients there was cardiotoxicity in 1.1% of all patients and in 4.6% of patients with prior evidence of heart disease [ ].

Management

Some investigators have reported success in preventing cardiotoxicity with calcium antagonists, such as nifedipine and diltiazem [ ], while others had less success [ , ]. Two patients with proven fluorouracil cardiotoxicity did not have cardiotoxicity when treated with the specific thymidylate synthase inhibitor raltitrexed 3 mg/m 2 every 3 weeks [ ]. The authors commented that fluorouracil cardiotoxicity is therefore not mediated via thymidylate synthase.

In most cases, fluorouracil-induced dysrhythmias were treatable and the ischemic-like symptoms and electrocardiographic changes disappeared if the infusion was discontinued or responded to nitrates, allowing the infusion to continue. The abnormalities of segmental and global ventricular function reverted to normal within days to weeks of withdrawal. In some patients intravenous inotropic and vasodilator support was needed during the initial period [ , ].

However, in one case, both oral nitrates and calcium antagonists failed to prevent chest pain associated with 5-fluorouracil [ ].

  • About 48 hours after starting her first course of 5-fluorouracil (1000 mg/m 2 /day) a woman developed anginal chest pain and electrocardiographic changes that eventually normalized. She was readmitted for her second cycle whilst taking amlodipine 10 mg/day and isosorbide dinitrate 40 mg/day, and after 42 hours into the second cycle had the same chest pain and electrocardiographic changes. These were controlled only by withdrawal of the 5-fluorouracil and the intravenous administration of glyceryl trinitrate.

Respiratory

Pulmonary toxicity in the form of fibrosing alveolitis has been attributed to fluorouracil.

  • A 55-year-old man with gastric adenocarcinoma received fluorouracil 1 g intravenously each week for 9 weeks and mitomycin 10 mg intravenously every 3 weeks [ ]. After 12 treatments he developed severe dyspnea.

Although mitomycin C was most probably the agent responsible for pulmonary toxicity in this patient, combined use with fluorouracil as a contributing factor cannot be ruled out. Necropsy confirmed that the patient had interstitial fibrosis [ ].

Nervous system

Fluorouracil can cause neurotoxicity [ ], with an incidence of 5–15% and with all schedules of administration in common use [ , ]. The toxicity is acute in onset and cumulative dose-dependency has not been observed.

Acute cerebellar dysfunction, with gait ataxia, nystagmus, dysmetria, and dysarthria, is the most common form of neurotoxicity [ , ]. A rare problem is optic neuropathy and impaired vision [ ].

The acute cerebellar syndrome is considered to be associated with peak concentrations of fluorouracil [ , , ]. Continuous 5-day infusions appear not to cause neurological toxicity, even when the total dose is higher, although high-dose infusions can cause encephalopathy, with symptoms varying from lethargy to coma [ ].

Cerebral demyelination has been reported in a patient receiving fluorouracil and levamisole [ ].

Two patients with some of the classic neurological complications of fluorouracil have been reported. One had a cerebellar syndrome in association with global motor weakness and bulbar palsy and the other a bilateral third cranial nerve palsy [ ].

Peripheral neuropathy, possibly caused by fluorouracil, has been reported [ ].

Five patients developed ischemic stroke within 2–5 days of finishing a 4-day course of fluorouracil plus low-dose cisplatin by continuous infusion [ ]. Whilst cisplatin has been implicated as having produced central ischemic events, most commonly in combination with vindesine and bleomycin, there has only been one other report involving fluorouracil. Although the causal link was not conclusive, the circumstantial evidence was strong.

The cause of neurotoxicity is not well understood. Acute neurological symptoms, including somnolence, cerebellar ataxia, and upper motor neuron signs, are primarily seen in patients receiving intracarotid infusions for head and neck tumors and also in patients receiving fluorouracil monotherapy in high doses. This syndrome has been reproduced in animals by a neurotoxic metabolite of fluorouracil, fluorocitrate, which has been believed to cause neurotoxicity [ , ]. However, several patients have developed severe toxic symptoms due to deficiency of dihydropyrimidine dehydrogenase, the enzyme that is mainly responsible for metabolizing fluorouracil [ ]. This toxicity appears to be due to the parent compound and not metabolites. Patients with complete or partial deficiency of the enzyme are particularly subject to fluorouracil neurotoxicity.

The neurotoxicity is usually reversible by withdrawing fluorouracil. Since there is no cumulative effect, therapy can be resumed later if desired, usually with either a lower dose or a less frequent dosing schedule to prevent recurrence.

Sensory systems

Fluorouracil-containing regimens have been linked with several ocular adverse reactions, including marked lacrimation, ocular pruritus, and a burning sensation in the eyes [ ].

Striate melanokeratosis of the retina has been associated with 5-fluorouracil in reports from a number of centers; there has been no consistent explanation of the pathogenesis of this adverse reaction [ ].

Excessive lacrimation and other ocular disturbances have been reported secondary to intravenous fluorouracil [ ]. In a review of this subject, blurred vision, excessive lacrimation, excessive nasal discharge, and conjunctivitis were the most commonly reported ocular effects of fluorouracil [ ]. The symptoms, eye irritation and excessive tear production, can be aggravated by cold weather. The onset of symptoms varies from 15 minutes to 14 months after the start of treatment [ ]. The symptoms usually resolve 2–3 weeks after withdrawal of therapy, with or without the use of topical antibiotic–glucocorticoid combinations [ , ].

More severe toxic effects, including tear duct fibrosis and eversion of the lower eye lid, have been reported [ ]. Tear duct fibrosis develops in one of six patients with excessive lacrimation from fluorouracil [ ]. The eversion of the lower eyelid is reversible with conservative managementwhile the tear duct fibrosis may not be [ ]. Persistent lacrimation has been described in six patients receiving intravenous fluorouracil weekly for 6–10 months [ ]. Lacrimation persisted in five patients after the withdrawal of fluorouracil, suggesting an irreversible dacryostenosis. Lacrimal duct stenosis has also been reported [ ]. Bilateral cicatricial ectropion was also reported in a patient after topical administration of fluorouracil for the treatment of multiple facial actinic keratoses [ ]. If ectropion and tear duct stenosis progress, surgical correction may be required.

Three women developed lacrimal outflow obstruction while receiving fluorouracil, cyclophosphamide, and methotrexate for breast cancer [ ]. The authors commented on both the high incidence of excessive tearing in patients given fluorouracil, a probable precondition, and the rarity of permanent damage (12 patients reported worldwide), but counselled on the need for vigilance and early referral to an ophthalmologist. Others have suggested that the prevalence of tearing and canalicular fibrosis in patients receiving fluorouracil is related to total dose and duration of treatment, and that the risks become significant at 20–60 weeks of therapy and a total fluorouracil dose of 20–50 g [ ].

  • Ankyloblepharon (adherence of the eyelids resulting in narrowing of palpebral apertures) was reported in a 59-year-old man during fluorouracil therapy for metastatic adenocarcinoma of the stomach [ ]. It appeared that bilateral conjunctival ulcers, secondary to fluorouracil and ulcerative blepharitis, resulted in ankyloblepharon. Withdrawal of chemotherapy resulted in improvement and re-initiation of therapy resulted in recurrence of ocular lesions.

Transient, non-infectious, crystalline, intrastromal corneal deposits have been reported after subconjunctival administration of 5-fluorouracil [ ]. The deposits were treated with glucocorticoids and completely resolved in 4 days.

Psychological, psychiatric

Confusion and cerebral cognitive defects have been attributed to fluorouracil [ , ].

Metabolism

Patients with poorly controlled diabetes are at risk of greater or more severe fluorouracil toxicity, causing hyperglycemia, which has been fatal. This effect seems to be independent of previous diabetic control and or fluorouracil dosage schedules [ ].

There have been attempts to unravel the mechanism of fluorouracil-induced hyperammonemia, lactic acidosis, and encephalopathy, a rare adverse reaction associated with high-dose therapy. The cause is not known, although Krebs cycle metabolism is almost certainly involved [ , ].

Hematologic

The hematological toxicity of fluorouracil is dose- and schedule-related [ ]. Leukocytes and platelets are affected, although the latter less so. Myelosuppression begins 4–7 days after the first dose, with recovery usually 14 days after the last dose [ ]. With continued treatment, anemia can develop in 3–4 months [ ]. Severe bone marrow depression causing death has been reported [ ].

Leukopenia is the most common blood dyscrasia secondary to fluorouracil and usually occurs after every course. The lowest white cell counts are usually seen at 9–14 days after the first course of treatment, but can be delayed for up to 20 days [ , ]. Leukopenia usually resolves after drug withdrawal. Leukopenia is often followed by megaloblastic anemia [ ]. Agranulocytosis has been reported during fluorouracil therapy [ ].

Thrombocytopenia has occurred during fluorouracil therapy but is much less frequent than leukopenia [ ].

The following summarizes the dose-relatedness of the hematological effects of fluorouracil [ , ]:

  • with a daily bolus of 12 mg/kg for 5 days, leukopenia (under 4 × 10 9 /l) occurred in all of 70 patients; 31% had marked leukopenia (under 2 × 10 9 /l);

  • with a continuous infusion of 30 mg/kg/day for 5 days, the leukopenia was mild and occurred in only 12% of patients;

  • a protracted continuous infusion of 300 mg/m 2 /day caused one case of moderate leukopenia and four cases of mild/moderate thrombocytopenia;

  • with a daily bolus of 500 mg/m 2 for 5 days there was a 38% incidence of leukopenia (with 20% below 2 × 10 9 /l and an 8% incidence of thrombocytopenia (1% severe).

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