FLUOROURACIL

Fetal Risk Summary

Fluorouracil was embryotoxic and teratogenic in mice, rats, and hamsters given parenteral doses equivalent to the human dose (1). Although not teratogenic in monkeys, divided doses above 40 mg/kg resulted in abortions. Animal reproduction studies with topical fluorouracil have not been conducted (1).

When applied topically in patients with actinic keratoses, the amount of fluorouracil absorbed systemically is approximately 6% (1). The amount absorbed from mucous membranes is unknown. One manufacturer reported an infant with cleft lip and palate from a woman who appropriately used topical fluorouracil and a second infant with a ventricular septal defect from a woman who used the drug topically on mucous membranes (1). In addition, spontaneous abortions (SABs) have been reported following use on mucous membrane areas (1). It is not known if there is a causative relationship between the topically applied drug and these outcomes.

Following systemic therapy in the 1st trimester (also with exposure to 5 rad of irradiation), multiple defects were observed in an aborted fetus: radial aplasia; absent thumbs and three fingers; hypoplasia of lungs, aorta, thymus, and bile duct; aplasia of esophagus, duodenum, and ureters; single umbilical artery; absent appendix; imperforate anus; and a cloaca (2).

A 33-year-old woman with metastatic breast cancer was treated with a modified radical mastectomy during her 3rd month of pregnancy followed by oophorectomy at 13 weeks' gestation (3). Chemotherapy, consisting of 5-fluorouracil, cyclophosphamide, and doxorubicin, was started at approximately 11 weeks' gestation and continued for six 3-week cyclic courses. Methotrexate was substituted for doxorubicin at this time and the new three-drug regimen was continued until delivery by cesarean section at 35 weeks of a 2260-g female infant. No abnormalities were noted at birth, and continued follow-up at 24 months of age revealed normal growth and development. Toxicity consisting of cyanosis and jerking extremities has been reported in a newborn exposed to fluorouracil in the 3rd trimester (4).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 14 newborns had been exposed to fluorouracil (includes nonsystemic administration) during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (7.1%) major birth defect was observed (one expected). No anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.

In a brief 1997 report, three pregnant women with breast cancer were successfully treated with two or three courses of vinorelbine (20–30 mg/m2) and fluorouracil (500–750 mg/m2) at 24, 28, and 29 weeks' gestation, respectively (5). Delivery occurred at 34, 41, and 37 weeks' gestation, respectively. One patient also required six courses of epidoxorubicin and cyclophosphamide. Her infant developed transient anemia at 21 days of age that resolved spontaneously. No adverse effects were observed in the other two newborns. All three infants were developing normally at about 2–3 years of age (5).

A 1999 report from France described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (6). The first cycle of chemotherapy occurred at a mean gestational age of 26 weeks with delivery occurring at a mean 34.7 weeks. A total of 38 cycles were administered during pregnancy with a median of two cycles per woman. None of the women received radiation therapy during pregnancy. The pregnancy outcomes included two SABs (both exposed in the 1st trimester), one intrauterine death (exposed in the 2nd trimester), and 17 live births, one of whom died at 8 days of age without apparent cause. The 16 surviving children were developing normally at a mean follow-up of 42.3 months (6). Fluorouracil (F), in combination with various other agents (cyclophosphamide [C], doxorubicin [D], epirubicin [E], mitoxantrone [M], or vinorelbine [V]) was administered to 16 of the women at a mean dose of 535 mg/m2 (range 300–750 mg/m2). The outcomes were one SAB (FCE; 1st trimester), one neonatal death (one cycle of FCE 32 days before birth), and 14 surviving liveborn infants (five FEC, four FV, two FAC, two FCM, and one FD in the 2nd or 3rd trimesters). One of the infants, exposed to two cycles of FCE with the last at 25 days before birth, had transient leukopenia and another was growth retarded (1460-g, born at 33 weeks' gestation after two cycles of FCM) (6).

Amenorrhea has been observed in women treated with fluorouracil for breast cancer, but this was probably caused by concurrent administration of melphalan (see also Melphalan) (7,8). The long-term effects of combination chemotherapy on menstrual and reproductive function have been described in two 1988 reports (9,10). In one report, only 2 of the 40 women treated for malignant ovarian germ cell tumors received fluorouracil (9). The results of this study are discussed in the monograph for cyclophosphamide (see Cyclophosphamide). The other report described the reproductive results of 265 women who had been treated from 1959–1980 for gestational trophoblastic disease (10). Single-agent chemotherapy was administered to 91 women, including 54 cases in which fluorouracil was the only agent used; sequential (single agent) and combination therapies were administered to 67 and 107 women, respectively. Of the total group, 241 were exposed to pregnancy and 205 (85%) of these women conceived, with a total of 355 pregnancies. The time interval between recovery and pregnancy was 1 year or less (8.5%), 1–2 years (32.1%), 2–4 years (32.4%), 4–6 years (15.5%), 6–8 years (7.3%), 8–10 years (1.4%), and more than 10 years (2.8%). A total of 303 (4 sets of twins) liveborn infants resulted from the 355 pregnancies, 3 of whom had congenital malformations: anencephaly, hydrocephalus, and congenital heart disease (one in each case). No gross developmental abnormalities were observed in the dead fetuses. Cytogenetic studies were conducted on the peripheral lymphocytes of 94 children, and no significant chromosomal abnormalities were noted. Moreover, follow-up of the children, more than 80% of the group older than 5 years of age (the oldest was 25 years old), revealed normal development. The reproductive histories and pregnancy outcomes of the treated women were comparable to those of the normal population (10).

Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).

[*Risk Factor X according to manufacturers Allergan and ICN Pharmaceuticals, 2000.]

Breast Feeding Summary

No reports describing the use of fluorouracil during lactation have been located. The low molecular weight (about 130) probably indicates that the drug is excreted into milk. Because of the potential for severe toxicity in a nursing infant, women should not breast feed while receiving fluorouracil.

References

1. Product information. Efudex. ICN Pharmaceuticals, 2000.
2. Stephens JD, Golbus MS, Miller TR, Wilber RR, Epstein CJ. Multiple congenital anomalies in a fetus exposed to 5-fluorouracil during the first trimester. Am J Obstet Gynecol 1980;137:747–9.
3. Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988;61:435–440.
4. Stadler HE, Knowles J. Fluorouracil in pregnancy: effect on the neonate. JAMA 1971;217:214–5.
5. Cuvier C, Espie M, Extra JM, Marty M. Vinorelbine in pregnancy. Eur J Cancer 1997;33:168–9.
6. Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy. Cancer 1999;86:2266–72.
7. Fisher B, Sherman B, Rockette H, Redmond C, Margolese K, Fisher ER. L-Phenylalanine (L-PAM) in the management of premenopausal patients with primary breast cancer. Cancer 1979;44:847–57.
8. Schilsky RL, Lewis BJ, Sherins RJ, Young RC. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:109–14.
9. Gershenson DM. Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 1988;6:270–5.
10. Song H, Wu P, Wang Y, Yang X, Dong S. Pregnancy outcomes after successful chemotherapy for choriocarcinoma and invasive mole: long-term follow-up. Am J Obstet Gynecol 1988;158:538–45.