With little information in the literature, pharmacists and oncologists may feel insecure about the use of chemotherapy in a pregnant patient. Attendees at the Hematology/Oncology Pharmacy Association 10th Annual Conference received some guidance from Erica Hochard, PharmD, hematology/oncology clinical pharmacist at the University of Kansas Hospital, Kansas City.
Hochard sought to “clarify the conundrum” regarding the safety of chemotherapy during pregnancy, she said, by outlining what is known about risks—which drugs to avoid and which can be safely given. The information should help pharmacists “make good clinical recommendations for these patients,” she explained.
Cancer During Pregnancy
Approximately 6000 pregnant women are diagnosed with cancer each year—an estimated 1 in 1000 pregnancies. As more women delay childbearing, this number is expected to increase. These cancers are most likely to be cervical, followed by breast, melanoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.
Since suboptimal doses of chemotherapy may predispose patients to recurrence, weight-based dosing is recommended, with doses adjusted for continued weight gain as pregnancy progresses, Hochard advised.
Most chemotherapy agents are rated as Category D in terms of fetal risk, indicating there is positive evidence of human fetal risk based on adverse reaction data; nevertheless, the potential benefits may warrant the use of the drug during pregnancy. Almost all agents have been found to be teratogenic in animals, but in humans it has been difficult to interpret retrospective data since most drugs are used in combination, she pointed out.
“In general, the teratogenicity of a drug depends on the timing of exposure, dose, and drug characteristics,” Hochard said.
During the first 4 weeks, when the embryo is undifferentiated, there is an “all or none phenomenon,” wherein either the fetus aborts or the pregnancy continues. The first trimester, when organogenesis occurs, carries a risk of spontaneous abortion, fetal death, and congenital malformation as high as 20%. The main concern during the second and third trimesters is the risk that chemotherapy imposes on intrauterine growth restriction; however, the risk of fetal malformation diminishes to only 1.3%.
“Malformations and toxicity to the fetus are really a reflection of gestational age,” Hochard noted.
Treatment considerations should include maternal prognosis, trimester of pregnancy, feasibility of delaying chemotherapy until after the first trimester, timing of chemotherapy to avoid delivery during the maternal nadir, and chemotherapy after 35 weeks, as well as the potential effect of treatment on future fertility. It is best to have a multidisciplinary team on board for these decisions, she added.
What Agents to Avoid?
In a nutshell, there are about half a dozen agents that should strictly be avoided during all trimesters: bevacizumab, trastuzumab, high-dose chemotherapy (ie, preparative regimens for transplant), idarubicin (and possibly epirubicin), methotrexate, and tamoxifen. Many other agents are considered relatively safe in the second and third trimesters, but most should be avoided in the first trimester whenever possible, she said.
Hochard also shared her list of preferred agents for the common cancers that occur in the pregnant population (Table).
With bevacizumab, there is a theoretical concern regarding angiogenesis inhibition. With trastuzumab, oligohydramnios has been observed in more than 50% of cases; however, there have been no reports of congenital anomalies or cardiac events.
With tamoxifen, reported birth defects have included ambiguous genitalia, Goldenhar syndrome (associated with incomplete development of the ear, nose, soft palate, lip, and mandible), and Pierre Robin sequence (smaller-than-normal lower jaw, tongue that falls back in the throat, and difficulty breathing).
Idarubicin has been associated with transient and permanent cardiomyopathy and congenital abnormalities. With methotrexate, there have been cases of aminopterin-like syndrome, skeletal abnormalities, ambiguous genitalia, spontaneous abortion, low birth weight, and pancytopenia.
Discussing the taxanes, she noted 12 exposures of which 92% resulted in a healthy newborn. It is theorized that placental P-glycoprotein could prevent transplacental transfer of the drug. Use in the treatment of breast cancer in the second and third trimesters, however, is controversial. Regarding the platinums, cisplatin is preferred over carboplatin.
In addition to trastuzumab and bevacizumab on the “do not give” list, Hochard discussed other targeted agents.
She noted that rituximab is believed to be relatively safe but may suppress B cells; no cases of fetal morbidity or mortality have been reported. Alemtuzumab has shown no adverse reproductive effects in animal studies. Patients receiving cetuximab and panitumumab have shown some increased risk of weight loss and spontaneous abortion.
Imatinib should not be the drug of choice for initiating therapy for chronic myelogenous leukemia, but if patients become pregnant while on this therapy, it should be continued due to the risk of disease progression, Hochard indicated.
Hochard E. The use of chemotherapy during pregnancy: clarifying the conundrum. Presented at: 10th Annual Conference of the Hematology/Oncology Pharmacy Association; March 26-29, 2014; New Orleans, LA.