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Motherisk Update 2014
Fetal Alcohol Canadian Expertise (FACE) Satellite Meeting,
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Current Studies at Motherisk
Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
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Cancer in Pregnancy: Etoposide
Etoposide (Vepesid; VP-16) is a podophyllotoxin derivative used in antineoplastic therapy, including gestational trophoblastic disease 1. This agent appears to interfere with normal mitosis, probably through inhibition of DNA synthesis. The embryotoxic potential of this agent has been utilized to terminate ectopic pregnancy 2.
|In vitro studies||Peripheral lymphocytes||Patients receiving etoposide (as well as cisplatin) show an increase in chromosomal aberrations 3.|
|Rat embryos in vitro||1-5 uM concentration||Rat embryos grown in culture with etoposide did not show adverse effects at concentrations of 1 uM. At 2 uM malformations began to appear and all embryos were malformed at 5 uM 4. Abnormalities included hypoplasia and edema of brain and eyes.|
|Animal studies *||rats and mice||3-4 and <1 times the human therapeutic dose||Increased frequencies of congenital anomalies, fetal death, and fetal growth retardation were observed among the offspring of rats and mice treated with etoposide during pregnancy 5-7. The most frequent structural anomalies observed involved the brain, eyes, and skeleton.|
|rabbits||No teratogenic effect was observed among the offspring of pregnant rabbits treated with etoposide in doses similar to those used in humans 8.|
|Human studies||Case reports||1st and 3rd trimesters||No epidemiological studies of congenital anomalies among infants born to women treated with etoposide during pregnancy have been reported. Anecdotal observations of at least 11 infants whose mothers were treated with etoposide during gestation have been reported 9-13. None of these babies, including at least two born to mothers treated during the first trimester of pregnancy, had malformations. Leukopenia and hearing loss were observed in one child who was born at 27 weeks gestation and transient pancytopenia occurred in another infant born at 32 weeks gestation after maternal treatment with etoposide and other chemotherapeutic agents during the third trimester of pregnancy 10,13.|
|Breast feeding||Case reports||Based on a report involving one lactating mother, etoposide is excreted in breast milk in small amounts 14. After receiving etoposide for five days, the maximum concentration of this agent in breast milk was 0.8 ug/mL. Etoposide was undetectable in breast milk within 24 h of each administration. Based on the typical elimination half-life of 4 to 11 h for etoposide in adults, breastfeeding should be delayed for at least 55 h after the last dose of etoposide if avoidance of neonatal exposure to this agent is desired 15.|
- Jones WB: Gestational trophoblastic disease: what have we learned in the past decade? Am J Obstet Gynecol 162: 1286-95, 1990.
- Segna RA, Mitchell DR, Misas JE: Successful treatment of cervical pregnancy with oral etoposide. Obstet Gynecol 76: 945-7, 1990.
- Tominaga K et al: Cytogenetic effects of multiagent chemotherapy on the peripheral lymphocytes of patients with small cell lung cancer. Jpn J Cancer Res 77:1241-8, 1986.
- Mirkes PE, Zwelling LA: Embryotoxicity of the intercalating agents, m-AMSA and o-AMSA and the epipodophyllotoxin VP-16 in postimplantation rat embryos in vitro. Teratology 41:679-88, 1990.
- Sieber SM, Whang-Peng J, Botkin C, Knutsen T: Teratogenic and cytogenetic effects of some plant-derived antitumor agents (vincristine, colchicine, maytansine, VP-16-213 and VM-26) in mice. Teratology 18:31-48,1978.
- Hiramatsu Y, Suzuki T, Okada K, et al.: Safety study of etoposide (NK 171). Oral administration in pre and post implantation period in rats. Kiso To Rinsho (Clin Rep)19:3885-3896, 1985.
- Takahashi N, Kai S, Kohmura H, et al.: Reproduction studies of VP16-213. II. Oral administration to rats during the period of fetal organogenesis. J Toxicol Sci 11(Suppl 1):195-225, 1986.
- Takahashi N, Kai S, Kohmura H, et al.: Reproduction studies of VP16-213. III. Oral administration to rabbits during the period of fetal organogenesis. J Toxicol Sci 11(Suppl 1):227-239, 1986.
- Choo YC, Chan SYW, Wong LC, Ma HK: Ovarian dysfunction in patients with gestational trophoblastic neoplasia treated with short intensive courses of etoposide (VP-16-213). Cancer 55(10):2348-2352, 1985
- Raffles A, Williams J, Costeloe K, Clark P: Transplacental effects of maternal cancer chemotherapy. Case Report. Br J Obstet Gynaecol 96:1099-1100, 1989.
- Aviles A, Diaz-Maqueo JC, Talavera A, et al.: Growth and development of children of mothers treated with chemotherapy during pregnancy: Current status of 43 children. Am J Hematol 36:243-248,1991.
- Brunet S, Sureda A, Mateu R, Domingo-Albos A: Full-term pregnancy in a patient diagnosed with acute leukemia treated with a protocol including VP-16. Med Clin (Barc) 100:757-8, 1993.
- Murray NA, Acolet D, Deane M, Price J, Roberts IAG: Fetal marrow suppression after maternal chemotherapy for leukaemia. Arch Dis Child71:F209-10, 1994.
- Azuno Y, Kaku K, Fujita N, Okubo M, Kaneko T: Mitroxantrone and etoposide in breast milk. Am J Hematol 48:131-2, 1995.
- Briggs GG, Freeman RK, Yaffe SJ: Etoposide. Drugs in pregnancy and lactation: update. 9:27-29, 1996.