Therapeutic response is unlikely to occur without some evidence of toxicity. The major toxic effects of 5-FU are on the normal, rapidly proliferating tissues particularly of the bone marrow and lining of the GI tract. Toxicity is schedule-dependent: reducing the rate of injection to a slow infusion is associated with less hematological toxicity but does not decrease GI toxicity.
Anorexia, nausea and vomiting are common. Stomatitis and esophagopharyngitis are common signs of toxicity. Esophagitis, proctitis, GI ulceration and bleeding have been reported, and paralytic ileus occurred in two patients who received excessive doses.
Leukopenia (predominantly granulocytopenia), thrombocytopenia and anemia are common. Pancytopenia, agranulocytosis and hemolytic anemia have also occurred. Leukopenia and thrombocytopenia may be less frequent during maintenance therapy.
Allergic reactions including anaphylaxis, bronchospasm, urticaria, and pruritus have been reported. If anaphylactic shock occurs, the usual countermeasures should be employed.
Hair loss occurs frequently with 5-FU therapy, and cosmetically significant alopecia has occurred in a substantial number of patients. Regrowth of hair has been reported even in patients receiving repeated courses of the drug. Partial loss of nails has occurred rarely, and diffuse melanosis of the nails has been reported. The most common type of dermatologic toxicity is a pruritic maculopapular rash which usually appears on the extremities and less frequently on the trunk. This rash is generally reversible and usually responsive to symptomatic treatment.
An erythematous, desquamative rash involving the hands and feet has been reported in patients receiving 5-FU (in some cases, prolonged infusions of high doses of the drug were administered). The rash may be accompanied by tingling of painful hands and feet, swollen palms and soles and phalangeal tenderness. These adverse effects, referred to as palmar-plantar erythrodysesthesia or hand-foot syndrome, may gradually disappear over 5 to 7 days after discontinuance of 5-FU therapy.
Other dermatologic manifestations of 5-FU toxicity have included dry skin and fissuring, diffuse erythema and scaling. Exposure to strong sunlight may intensify skin reactions to the drug. Seborrheic dermatitis has been reported in a few patients, but could not always be definitely attributed to 5-FU. Recall phenomenon and photosensitivity manifested by erythema or increased pigmentation can occur with 5-FU therapy.
Disorientation, confusion, euphoria, ataxia, dysarthria, nystagmus, headache, slurred speech, dizziness, unsteadiness, muscular weakness, vertigo, Parkinson-like symptoms, pyramid signs, aphasia, convulsions, coma, optic neuritis, peripheral neuropathy and acute cerebellar syndrome (which may persist after therapy is discontinued) have occurred rarely in patients receiving 5-FU. Oculomotor disturbances have occurred occasionally. Extrapyramidal or cortical dysfunction (usually reversible) and isolated cases of leucoencephalopathy have also been reported. These symptoms may persist after therapy is discontinued.
Conjunctivitis was commonly reported. Excessive lacrimation, dacryostenosis, visual changes, photophobia, diplopia, blepharitis, and ectropion have been uncommon. Lacrimal duct stenosis (canalicular fibrosis) associated with prolonged administration of 5-FU has been rarely reported. This condition is reversible upon reduction or temporary cessation of 5-FU therapy, but on occasion may necessitate surgical intervention.
There have been reports of chest pain, tachycardia, breathlessness, ECG changes (ST segment changes), myocardial ischemia, angina (including Prinzmetal variant angina), precordial pain, cardiac arrhythmias, dilatative cardiomyopathy, ischemia and heart failure resulting rarely in death. Vasculitis, Raynaud's phenomenon and thromboembolism have been rarely reported.
Hepatocellular damage and in very rare cases, fatal hepatic necrosis have been observed.
Due to immunosuppression, infections (sometimes serious), may develop in patients treated with 5-FU. Sepsis was uncommon.
Fever that occurred during the end of the 2nd
week following the first dose of 5-FU, and was usually not accompanied by demonstrable infection, has been reported. Epistaxis, thrombophlebitis, vein pigmentation, and dehydration have also been reported. Hyperuricemia was uncommon.