Drugs in Pregnancy and Lactation: Tenth Edition

ETOPOSIDE

Antineoplastic

PREGNANCY RECOMMENDATION: Human and Animal Data Suggest Risk

BREASTFEEDING RECOMMENDATION: Contraindicated

PREGNANCY SUMMARY

Etoposide is a potent animal teratogen and potentially may be a teratogen in humans, but exposure during organogenesis has not been reported. Five cases of maternal exposure to this agent and other antineoplastics during the 2nd and 3rd trimesters resulted in growth restriction and/or severe myelosuppression in three fetuses–newborns, two of whom were delivered prematurely, and one had reversible alopecia. Successful pregnancies, commencing after etoposide treatment, have also been reported.

FETAL RISK SUMMARY

Etoposide (VP-16, VP-16-213) is a semisynthetic derivative of podophyllotoxin used as an antineoplastic agent. Low doses of the drug, 1/20th–1/2 of the recommended clinical dose based on BSA, are teratogenic and embryocidal in rats and mice (1). A dose-related increase in the occurrence of embryotoxicity and congenital malformations was observed in these animals. Defects included decreased weight, skeletal anomalies, retarded ossification, exencephaly, encephalocele, and anophthalmia. The drug is also mutagenic in mammalian cells and, although not tested in animals, should be considered a potential carcinogen in humans (1).

When etoposide was administered intraperitoneally to pregnant mice during organogenesis, various anomalies were observed, including exencephaly, encephalocele, hydrocephalus, gastroschisis (including abnormal stomach or liver), microphthalmia or anophthalmia, dextrocardia (including missing lung lobe), and axial skeleton defects (2). In whole-embryo rat culture, a concentration of 2 micro-M (no-observed-adverse-effect-level 1.0 micro-M; embryotoxic range 2–5 micro-M) produced growth restriction and brain anomalies (hypoplasia of prosencephalon and edema of rhombencephalon) and microphthalmia (3).

Reported use of etoposide during human pregnancy is limited to five cases (48). A 21-year-old woman with a dysgerminoma was treated surgically at 26 weeks’ gestation, followed 6 days later with etoposide (100 mg/m2) and cisplatin (20 mg/m2), daily for 5 days at 3- to 4-week intervals (4). Four cycles of chemotherapy were given. Because of oligohydramnios and probable intrauterine growth restriction, labor was induced and she delivered a healthy, 2320-g female infant at 38 weeks. The hematologic profile of the newborn was normal, as was her development at 9 months of age.

A 36-year-old woman at 25 weeks’ gestation was treated for acute myeloid leukemia with combination chemotherapy consisting of two courses of etoposide (400 mg/m2/day, days 8–10), cytarabine (1 g/m2/day, days 1–3), and daunorubicin (45 mg/m2/day, days 1–3) (5). No fetal growth was observed during serial ultrasound examinations from 30 to 32 weeks. An emergency cesarean section was performed because of fetal distress at 32 weeks’ gestation, 11 days after the second course of chemotherapy. The pale, 1460-g (10th percentile) female infant required resuscitation at birth. Analysis of the cord blood revealed anemia and leukopenia, and profound neutropenia and thrombocytopenia were discovered at 30 hours of age. Following successful therapy, the child, at 1 year of age, was no longer receiving any treatment, had normal peripheral blood counts, and was apparently progressing normally.

A 32-year-old woman at 26 weeks’ gestation presented with an unknown primary, poorly differentiated adenocarcinoma of the liver and with a mass in the posterior chamber of the right eye (6). She was treated with daily doses of etoposide (165 mg), bleomycin (30 mg), and cisplatin (55 mg), for 3 days. The patient became profoundly neutropenic, developed septicemia, and went into premature labor. A 1190-g female infant was born with Apgar scores of 3 and 8 at 1 and 5 minutes, respectively. Severe respiratory distress was successfully treated over the next 10 days. Although the antineoplastics were chosen because they are highly protein bound (etoposide, 97%; cisplatin, 90% of plasma platinum; bleomycin, no data) and less likely to cross the placenta, marked leukopenia with neutropenia developed in the infant on day 3 (10 days after in utero exposure to the chemotherapy). Scalp hair loss and a rapid loss of lanugo were observed at 10 days of age. By 12 weeks of age, substantial hair regrowth had occurred, and at 1 year follow-up, the child was developing normally, except for moderate bilateral sensorineural hearing loss. The investigators could not determine if the deafness was due to the in utero exposure to cisplatin or to the maternal and/or neonatal aminoglycoside therapy. The alopecia and bone marrow depression in the infant were attributed to etoposide.

Treatment of nonlymphoblastic acute leukemia, diagnosed at 18 weeks’ gestation, was described in a brief 1993 report (7). Therapy consisted of two courses of etoposide (100 mg/m2/day) and daunorubicin (60 mg/m2/day) on days 1–3, and cytarabine (100 mg/m2/day) on days 1–7. Follow-up therapy consisted of mitoxantrone, cytarabine, and amsacrine. The patient eventually delivered a term, 2930-g, healthy male infant who was developing normally.

Non-Hodgkin’s lymphoma, diagnosed in a 36-year-old woman at 22 weeks’ gestation, was treated with a 12-week chemotherapy course consisting of etoposide (125 mg/m2), vincristine (1.4 mg/m2), and bleomycin (9 mg/m2) in weeks 2, 4, 6, 8, 10, and 12, and cyclophosphamide (375 mg/m2) and doxorubicin (50 mg/m2) in weeks 1, 3, 5, 7, 9, and 11 (8). Prednisolone was given during the entire 12-week period. A healthy, 3200-g male infant, delivered 3 weeks after the completion of therapy, was alive and well at 21 months of age. At this time also, the mother had just delivered another healthy male infant.

Seven reports, including the one above, have described women who became pregnant following treatment with etoposide (814) and one report described the return of normal menstrual function after etoposide therapy (15). One woman delivered a normal term infant following treatment for choriocarcinoma with nine courses of etoposide (100 mg/m2/day), cisplatin, dactinomycin, and intrathecal methotrexate 2 years prior to conception (9). Pregnancies occurred, about 6–7 years after treatment, in 3 women from a group of 128 who had been previously treated with high-dose chemotherapy for refractory or relapsed Hodgkin’s disease (10). The current chemotherapy regimen consisted of etoposide (600–900 mg/m2), cyclophosphamide, and carmustine, followed by either autologous bone marrow or peripheral progenitor cell transplantation. One of the women conceived after receiving a donated ovum and delivered a healthy child. A second one became pregnant with twins after receiving ovulatory stimulating agents, but aborted both at 5 1/2 months’ gestation. The third woman spontaneously conceived and delivered a healthy child.

Two women had normal pregnancies and babies after treatment with high-dose chemotherapy for relapsed Hodgkin’s disease and non-Hodgkin’s lymphoma, respectively (11). The first patient was treated with etoposide (800 mg/m2), carmustine, and melphalan, followed by autologous stem cell transplantation (ASCT). She conceived 19 months after completion of treatment. The second woman received etoposide (1000 mg/m2), cyclophosphamide, and carmustine, followed by ASCT. She became pregnant 33 months later.

Of 33 women (>18 years old) treated with multiple courses of chemotherapy for ovarian germ cell tumors and fertility conserving surgery, 14 (42%) had successful pregnancies (12). No congenital abnormalities in their offspring were observed. The chemotherapy consisted of etoposide (100 mg/m2 × 3 days/course), bleomycin, cisplatin, cyclophosphamide, dactinomycin, methotrexate, vincristine, and folinic acid.

A 1993 report described return of ovulation in 25 women under 40 years of age from a group of 34 patients treated with etoposide for gestational trophoblastic disease (13). Nine apparently healthy infants were delivered from the group. In another study, 12 women with methotrexate-resistant gestational trophoblastic disease were treated with etoposide (100 mg/m2/day × 5 days every 10 days) (14). Two of the women had successful pregnancies, 3 and 4 years, respectively, after treatment.

Etoposide (200 mg/m2/day × 5 days) was successfully used to treat a cervical pregnancy in one woman (15). Her baseline menstrual function returned 60 days after completion of therapy, but it was not stated if she attempted to conceive. A man, who had received etoposide for acute nonlymphoblastic leukemia in a cumulative dose of 3193 mg/m2, fathered two children, one of whom had a unspecified birthmark (16). There is no evidence that the treatment, that also included irradiation to the brain and lumbar spine, vincristine, thioguanine, doxorubicin, cyclophosphamide, and cytarabine, resulted in the birth defect.

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).

BREASTFEEDING SUMMARY

Etoposide is excreted into breast milk (17). After delivery of a healthy, 2960-g female at 34 weeks’ gestation, a 28-year-old woman with acute promyelocytic leukemia in remission (see Mitoxantrone for details of treatment during gestation) was treated with a second consolidation course of cytarabine and mitoxantrone followed by a third consolidation course consisting of etoposide (80 mg/m2, days 1–5), mitoxantrone (6 mg/m2, days 1–3), and cytarabine (170 mg/m2, days 1–5). She maintained milk secretion by pumping her breasts during the chemotherapy courses. The peak milk concentrations of etoposide measured on days 3, 4, and 5 of therapy were approximately (exact concentrations or times of sample collections were not specified) 0.6, 0.6, and 0.8 mcg/mL, respectively. Milk concentrations of etoposide were undetectable within 24 hours of drug administration on each day. The rapid disappearance of etoposide from the milk is compatible with the lack of plasma accumulation and an elimination half-life of 4–11 hours in adults (1). Against medical advice, the mother began breastfeeding 21 days after drug administration (see Mitoxantrone).

Because of the potential for severe toxicity in a nursing infant, such as bone marrow depression, alopecia, and carcinogenicity, breastfeeding should be stopped for at least 55 hours after the last dose of etoposide to account for the elimination half-life range noted above. However, if other antineoplastic agents have also been administered, breastfeeding should be withheld until all of the agents have been eliminated from the mother’s system.

References

1.Product information. VePesid. Bristol-Myers Squibb Oncology, 2000.

2.Sieber SM, Whang-Peng J, Botkin C, Knutsen T. Teratogenic and cytogenic effects of some plant-derived antitumor agents (vincristine, colchicine, maytansine, VP-16-213 and VM-26) in mice. Teratology 1978;18:31–47.

3.Mirkes PE, Zwelling LA. Embryotoxicity of the intercalating agents in m-AMSA and o-AMSA and the epipodophyllotoxin VP-16 in postimplantation rat embryos in vitro. Teratology 1990;41:679–88.

4.Buller RE, Darrow V, Manetta A, Porto M, DiSaia PJ. Conservative surgical management of dysgerminoma concomitant with pregnancy. Obstet Gynecol 1992;79:887–90.

5.Murray NA, Acolet D, Deane M, Price J, Roberts IAG. Fetal marrow suppression after maternal chemotherapy for leukaemia. Arch Dis Child 1994;71:F209–10.

6.Raffles A, Williams J, Costeloe K, Clark P. Transplacental effects of maternal cancer chemotherapy. Case report. Br J Obstet Gynaecol 1989;96:1099–1100.

7.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) 1993;100:757–8.

8.Rodriguez JM, Haggag M. VACOP-B chemotherapy for high grade non-Hodgkin’s lymphoma in pregnancy. Clin Oncol (R Coll Radiol) 1995;7:319–20.

9.Bakri YN, Pedersen P, Nassar M. Normal pregnancy after curative multiagent chemotherapy for choriocarcinoma with brain metastases. Acta Obstet Gynecol Scand 1991;70:611–3.

10.Bierman PJ, Bagin RG, Jagannath S, Vose JM, Spitzer G, Kessinger A, Dicke KA, Armitage JO. High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin’s disease: long term follow-up in 128 patients. Ann Oncol 1993;4:767–73.

11.Brice P, Pautier P, Marolleau JP, Castaigne S, Gisselbrecht C. Pregnancy after autologous bone marrow transplantation for malignant lymphomas. Nouv Rev Fr Hematol 1994;36:387–8.

12.Bower M, Fife K, Holden L, Paradinas FJ, Rustin GJS, Newlands ES. Chemotherapy for ovarian germ cell tumours. Eur J Cancer 1996;32A: 593–7.

13.Matsui H, Eguchi O, Kimura H, Inaba N, Takamizawa H. The effect of etoposide on ovarian function in patients with gestational trophoblastic disease. Acta Obstet Gynaecol Jpn 1993;45:437–43.

14.Mangili G, Garavaglia E, Frigerio L, Candotti G, Ferrari A. Management of low-risk gestational trophoblastic tumors with etoposide (VP-16) in patients resistant to methotrexate. Gyn Oncol 1996;61:218–20.

15.Segna RA, Mitchell DR, Misas JE. Successful treatment of cervical pregnancy with oral etoposide. Obstet Gynecol 1990;76:945–7.

16.Green DM, Zevon MA, Lowrie G, Seigelstein N, Hall B. Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. N Engl J Med 1991;325:141–6.

17.Azuno Y, Kaku K, Fujita N, Okubo M, Kaneko T. Mitoxantrone and etoposide in breast milk. Am J Hematol 1995;48:131–2.