Antineoplastic
PREGNANCY RECOMMENDATION: Human and Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Typical of many chemotherapeutic agents, carmustine is carcinogenic, mutagenic, clastogenic, embryotoxic, and teratogenic in experimental animals. However, only two reports have described the use of carmustine in human pregnancy. In one of these, a woman was treated with carmustine before and during the first two trimesters. She gave birth to a normal infant. In the other case, a woman who was not treated until late in the 2nd trimester was electively delivered prematurely because of her disease. Her infant was growth restricted 17 months after birth but had apparently normal mental and motor development. As with other cancer chemotherapeutic agents, treatment after the 1st trimester does not appear to result in newborn toxicity, although bone marrow suppression has been reported when multiple agents were used close to delivery (e.g., see Cyclophosphamide). Several alkylating agents are thought to be human teratogens (e.g., busulfan, chlorambucil, and cyclophosphamide), but few infants have been exposed to these drugs in the 1st trimester. Until proven otherwise, carmustine should be considered a potential teratogen if used during the period of organogenesis. Therefore, a woman whose condition requires treatment during organogenesis, or who conceives while under treatment, should be informed of the potential risk to her embryo.
FETAL RISK SUMMARY
Carmustine (BCNU) is an alkylating agent that is chemically classified as a nitrosourea. Other antineoplastics in this group include lomustine (CCNU) and streptozocin. Carmustine is indicated for the palliative therapy of certain brain tumors, multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphoma. The drug alkylates deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), in addition to inhibiting some enzymes by carbamoylation of amino acids in proteins. Carmustine undergoes rapid degradation in the plasma with a terminal half-life of 22 minutes after an IV dose. The antineoplastic and toxic properties of carmustine are thought to be secondary to metabolites. The most severe toxicities are delayed bone marrow suppression and pulmonary toxicity (1,2).
Carmustine is carcinogenic in mice and rats at doses less than the recommended human dose based on BSA (RHD). The agent was mutagenic in in vitro assays and clastogenic in both in vivo and in vitro tests (2). Reproduction studies have been conducted with carmustine in pregnant rats and rabbits (1,2). A dose about 0.17 times the RHD in rats caused embryotoxicity and fetal malformations (anophthalmia, micrognathia, and omphalocele). In rabbits, increased embryolethality was observed at approximately 1.2 times the RHD (1,2). In another animal study, pregnant rats were given an intraperitoneal dose of 20 mg/kg on embryonic day 15 (3). (Note: This dose is approximately 3.4 times the RHD.) Exposed offspring had histologic alterations suggestive of cortical dysplasia (laminar disorganization, cytomegalic neurons, and neuronal heterotopias). Of interest, cortical dysplasia is associated with epilepsy in children and adults (3).
It is not known if carmustine or its metabolites crosses the placenta. The molecular weight (about 214) is low enough that exposure of the embryo or fetus should be expected. Two characteristics of carmustine, its high lipid solubility and its relatively lack of ionization at physiologic pH, will promote transfer of the drug across the placenta. The very short plasma half-life may lessen the transfer of the parent drug, but the pharmacology and pharmacokinetics of the active metabolites have not been fully elucidated.
A 1984 report described a 21-year-old woman with diffuse histiocytic lymphoma who received carmustine and procarbazine for 5 months before conception and throughout the first 24 weeks of pregnancy (4). A second nitrosourea agent, streptozocin, replaced carmustine and procarbazine in the 2nd trimester. Before pregnancy, the patient had received multiple courses of chemotherapy, including cyclophosphamide, doxorubicin, vincristine, bleomycin, methotrexate, cytarabine, and etoposide, in addition to radiation therapy to the neck. Because of the failure of the previous therapy, she was started on carmustine 110 mg IV on day 1 and procarbazine 100 mg orally for 10 days every 4 weeks. She conceived after five monthly cycles of this latter therapy. The woman refused pregnancy termination and received five more cycles of therapy at 4-week intervals starting at 4 weeks’ gestation. Three courses of streptozocin, 800 mg IV for 3 days every 4 weeks, were started at 24 weeks’ gestation because of disease progression. She received the last dose of streptozocin 2 weeks before delivery at 35 weeks’ gestation. The woman’s normal- appearing male infant weighed 2.34 kg with a head circumference of 32.5 cm and a length of 51.5 cm. The Apgar scores were 7 and 9 at 1 and 5 minutes, respectively. The initial blood test revealed a normal hemoglobin, white blood cell and platelet counts. All other clinical tests were within normal limits, including electrolytes, multiple chemistry, urinalysis, renal ultrasound, and chromosome studies (4).
In a second case report, a 27-year-old woman with a history of malignant melanoma was admitted to the hospital at 14 weeks’ gestation for progressive weight loss and persistent headache (5). Approximately 9 months earlier an enlarged nevus had been removed from her left shoulder and the pathology had revealed the melanoma. The work-up for metastatic disease was negative and she was discharged home. Two months later, the woman was readmitted for severe back pain, which was attributed to diffuse metastatic disease of the spine. At 23 weeks’ gestation, she was started on chemotherapy consisting of carmustine 150 mg/m2 IV on day 1, tamoxifen 80 mg orally twice daily for 7 days, cisplatin 25 mg/m2 IV on days 1 to 3, and dacarbazine 220 mg/m2 on days 1 to 3. Approximately 3 weeks later, she received a second course of these agents. Corticosteroids were administered for fetal lung maturity and as an antiemetic for chemotherapy. Because the woman continued to deteriorate, a 1520-g female infant was delivered by cesarean section at 30 weeks’ gestation. The 325-g placenta had malignant melanoma in the intervillous space and melanin pigment granules in villous Hofbauer cells and syncytial trophoblasts. The mother died 1 month later. At 17 months of age the child’s weight was 6.6 kg (5th percentile), length 74.5 cm (<5th percentile), and head circumference 47 cm (10th percentile). Examination revealed age-appropriate evaluations for mental age, motor age, and language scores (5).
A number of reports have described pregnancy outcomes after the use of carmustine before conception (6–11). In four studies, the outcomes of 16 pregnancies (12 women) were 14 normal newborns, one stillbirth (twins), and one elective abortion (6–9). In one case, a man treated earlier with carmustine fathered a normal infant (7). A 2000 study analyzed the pregnancy outcomes of 340 cancer survivors who had one or more pregnancies after treatment with carmustine and 11 other alkylating agents (10). The cases were divided into five mutually exclusive treatment groups: nonsterilizing surgery, chemotherapy with alkylating agents, abdominal–pelvic radiation, alkylating agents plus abdominal–pelvic radiation, and all other treatments. The study found no evidence of an increased risk of birth defects or spontaneous abortions (10). In a 2002 study, 1915 women had 4029 pregnancies after chemotherapy with or without radiation (11). No statistical differences in pregnancy outcomes (live births and spontaneous abortions) by treatment group were found, including the 126 pregnancies in women treated with carmustine.
BREASTFEEDING SUMMARY
No reports describing the use of carmustine during lactation have been located. The low molecular weight (about 214), high lipid solubility, and relative lack of ionization at physiologic pH suggest that carmustine will be excreted into breast milk. The short elimination half-life in the plasma may limit the amount of parent drug in milk, but the pharmacology and pharmacokinetics of the active metabolites have not been adequately characterized. Because there is substantial risk of harm for a nursing infant, women who are being treated with carmustine should not nurse.
References
1.Product information. BiCNU. Bristol-Myers Squibb, 1998.
2.Product information. Gliadel Wafer. Guilford Pharmaceuticals, 2003.
3.Benardete EA, Kriegstein AR. Increase excitability and decreased sensitivity to GABA in an animal model of dysplastic cortex. Epilepsia 2002;43:970–82.
4.Schapira DV, Chudley AE. Successful pregnancy following continuous treatment with combination chemotherapy before conception and throughout pregnancy. Cancer 1984;54:800–3.
5.DiPaola RS, Goodin S, Ratzell M, Florczyk M, Karp G, Ravikumar TS. Chemotherapy for metastatic melanoma during pregnancy. Gynecol Oncol 1997;66:526–30.
6.Blatt J, Mulvihill JJ, Ziegler JL, Young RC, Poplack DG. Pregnancy outcome following cancer chemotherapy. Am J Med 1980;69:828–32.
7.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.
8.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.
9.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.
10.Chiarelli AM, Marrett LD, Darlington GA. Pregnancy outcomes in females after treatment for childhood cancer. Epidemiology 2000;11:161–6.
11.Green DM, Whitton JA, Stovall M, Mertens AC, Donaldson SS, Ruymann FB, Pendergrass TW, Robison LL. Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor study. Am J Obstet Gynecol 2002;187:1070–80.