Antineoplastic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Docetaxel, always in combination with other antineoplastics, has been reported in eight pregnancies, two of which involved the 1st trimester but only one during organogenesis. Both of the 1st trimester exposures had normal infant outcomes. Mild hydrocephalus, which resolved spontaneously, was observed in one fetus exposed in the 2nd and 3rd trimesters; the cause is unknown. In another case, multiple anomalies were identified before chemotherapy was started and the infant died shortly after birth. The animal reproduction data suggest risk at doses that were a small fraction of the human dose, but maternal toxicity also was evident. Based on the very limited human pregnancy experience, docetaxel, if indicated, should not be withheld because of pregnancy, but avoiding organogenesis should be considered.
FETAL RISK SUMMARY
Docetaxel is an antineoplastic with antimitotic activity. It is in the same antineoplastic subgroup of taxoids as cabazitaxel and paclitaxel. Docetaxel is indicated either alone or in combination with other antineoplastics for the treatment of breast cancer, non-small-cell lung cancer, prostate cancer, gastric adenocarcinoma, and head and neck cancer. Plasma protein binding of the highly lipophilic drug is about 94%, mainly to α1-acid glycoprotein, albumin, and lipoproteins. The terminal half-life is 11.1 hours (1).
Reproduction studies have been conducted in rats and rabbits. In these species, doses given during organogenesis, which were 1/50 and 1/300 the daily maximum recommended human dose based on BSA, were embryotoxic and fetotoxic, manifested as intrauterine death, increased resorption, reduced fetal weight, and fetal ossification delay. These doses also caused maternal toxicity (1).
Long-term studies for carcinogenic potential have not been conducted. The drug was clastogenic in several tests but did not induce mutagenicity in assays. No impairment of fertility was noted in rats, but decreased testicular weights did occur. In a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs, testicular atrophy or degeneration was observed (1).
It is not known if docetaxel crosses the human placenta. The molecular weight (about 862), highly lipophilic nature, and the long terminal half-life suggest that the drug will cross to the embryo–fetus. However, the plasma protein binding might limit the transfer.
The first case of docetaxel use in pregnancy was reported in 2000 (2). A 34-year-old woman presented at 15 weeks’ gestation with recurrent breast cancer. Approximately 1 year before presentation, she had undergone a modified radical mastectomy followed by chemotherapy for treatment of breast cancer. Chemotherapy at that time had been epirubicin, cyclophosphamide, fluorouracil, and methotrexate. At 19 weeks’, vinorelbine was given, but, because of rapid disease progress, that agent was discontinued and docetaxel was given every 3 weeks for 3 cycles. A planned cesarean section was performed at 32 weeks’ that delivered a normal, 1620-g female infant with Apgar scores of 8 and 9 presumably at 1 and 5 minutes, respectively. The infant did well and her psychophysical development was normal at 20 months of age.
In a 2006 report, a 35-year-old woman at 13 weeks’ gestation with breast cancer was treated with four 21-day cycles of fluorouracil, doxorubicin, and cyclophosphamide (3). No response was noted and at 25 weeks’ her therapy was changed to 21-day cycles of docetaxel. She gave birth at 39 weeks to a healthy, 3.09-kg, length 51-cm male infant with normal Apgar scores and blood counts (3). No other information on the infant was provided.
A second 2006 report described two cases of docetaxel exposure in pregnancy (4). In the first case, a 29-year-old woman at 12 weeks’ gestation was diagnosed with breast cancer. Treatment with doxorubicin and cyclophosphamide every 2 weeks for four cycles was started at 14 weeks’. At 17 weeks’, a fetal ultrasound revealed hydrocephalus (dilated lateral and third ventricle). A modified radical mastectomy and axillary node dissection was conducted at 24 weeks’, followed by docetaxel every 2 weeks between 26 and 32 weeks’ gestation for four cycles. At 34 weeks’, she gave birth to an infant with mild hydrocephalus that regressed spontaneously over several months. The child’s development at 28 months was normal (no other details of the infant were provided). The second case involved a 38-year-old woman who was diagnosed with breast cancer at 10 weeks’ gestation. At 14 weeks’, docetaxel and doxorubicin every 3 weeks for six cycles was started. She developed preeclampsia and a cesarean section was conducted at 35 weeks’ to deliver a healthy infant with no detectable malformations. The infant was developing normally at 9 months of age (no additional details were provided) (4).
A brief case report described a 44-year-old woman with advanced-stage breast cancer (5). She was treated with fluorouracil, epirubicin, and cyclophosphamide before undergoing a mastectomy before she became pregnant. During pregnancy, she was treated with five weekly doses of docetaxel because of symptomatic bone metastases starting at about 35 weeks’ gestation. She gave birth at 40 weeks to a normal male infant who was doing well and developing normally at 15 months of age (5).
A 2007 case report described a 28-year-old woman with a history of radical mastectomy, chemotherapy, and radiotherapy 1 year before pregnancy (6). Because of metastases, she was treated with docetaxel and trastuzumab at 23 and 26 weeks’ gestation, trastuzumab alone at 27 weeks’, and docetaxel alone at 30 weeks’. Trastuzumab was omitted at 30 weeks’ because an ultrasound revealed anhydramnios and fetal growth at the fifth percentile. The anhydramnios was thought to be due to trastuzumab. At 33 weeks’, oligohydramnios was noted. An elective cesarean section was conducted at 36 weeks’ to deliver a 2.23-kg male infant with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. No evidence of positional deformations or respiratory abnormalities from the prolonged low amniotic fluid was noted and the neonatal urine output was normal. The development of the infant also was normal (6).
A 35-year-old woman with metastatic non-small-cell lung cancer was treated in the 1st and 2nd trimesters with chemotherapy of an unknown pregnancy (7). After undergoing a craniotomy to remove the metastatic tumor and whole brain irradiation early in pregnancy, she was treated with docetaxel and cisplatin on days 1 and 8 every 21 days for four cycles (gestational weeks 9–18). Because of lack of response, treatment was changed to two cycles of gemcitabine and cisplatin (gestational weeks 19 and 22). About 2 months after the last dose her pregnancy was diagnosed. At 33 weeks’, a cesarean section delivered a normal 1490-g female infant (normal karyotype 46,XX) with Apgar scores of 8, 9, and 10 at 1, 5, and 10 minutes, respectively, and normal blood counts. An extensive examination of the infant failed to find any abnormalities. The infant was developing normally at 10 months of age (7).
A 32-year-old woman underwent surgery at 20 weeks’ gestation (from in vitro fertilization) for a ruptured ovarian cyst (8). Ovarian cancer was diagnosed and she was given four cycles of docetaxel and cisplatin before a cesarean section at 34 weeks. The 2245-g female infant had Apgar scores of 3 and 6 at 1 and 10 minutes, respectively. The infant died at 5 days of age from multiple congenital anomalies that had been diagnosed before starting chemotherapy (8).
BREASTFEEDING SUMMARY
No reports describing the use of docetaxel during human lactation have been reported. The molecular weight (about 862), highly lipophilic nature, and the long terminal half-life (11.1 hours) suggest that the drug will be excreted into breast milk, although the plasma protein binding (about 94%) might limit the excretion. The effect of this exposure on a nursing infant is unknown, but serious toxicities (e.g., bone marrow depression, allergic reactions, nausea, vomiting, and diarrhea) have been reported in adults and are a potential complication. If a mother is receiving this drug, she should not breastfeed.
References
1.Product information, Taxotere. Sanofi-Aventis, 2008.
2.De Santis M, Lucchese A, De Carlos S, De Carolis S, Ferrazzani S, Caruso A. Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer Care (Engl) 2000;9:235–7.
3.Nieto Y, Santisteban M, Armendia JM, Fernandez-Hidalgo O, Garcia-Manero M, Lopez G. Docetaxel administered during pregnancy for inflammatory breast carcinoma. Clin Breast Cancer 2006;6:533–4.
4.Potluri V, Lewis D, Burton GV. Chemotherapy with taxanes in breast cancer during pregnancy: case report and review of the literature. Clin Breast Cancer 2006;7;167–70.
5.Gainford MC, Clemons M. Breast cancer in pregnancy: are taxanes safe? Clin Oncol (R Coll Radiol) 2006;18:159.
6.Sekar R, Stone PR. Trastuzumab use for metastatic breast cancer in pregnancy. Obstet Gynecol 2007;110:507–10.
7.Kim JH, Kim HS, Sung CW, Kim KJ, Kim CH, Lee KY. Docetaxel, gemcitabine, and cisplatin administered for non-small cell lung cancer during the first and second trimester of an unrecognized pregnancy. Lung Cancer 2008;59:270–3.
8.Rouzi AA, Sahly NN, Sahly NF, Alahwal MS. Cisplatinum and docetaxel for ovarian cancer in pregnancy. Arch Gynecol Obstet 2009;280:823–5.