Annals of Oncology Advance Access originally published online on October 5, 2007
Annals of Oncology 2008 19(4):607-613; doi:10.1093/annonc/mdm460
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Emerging therapeutic options for breast cancer chemotherapy during pregnancy
1 Department of Medical Oncology
2 Department of Clinical Pharmacology
3 Department of Obstetrics, Université Paris Descartes—Faculté de Médecine, Hôpital Cochin, Assistance Publique—Hôpitaux de Paris, Paris
4 Department of Obstetrics, Hôpital André Mignot, Versailles, France
* Correspondence to: Dr O. Mir, Department of Medical Oncology, Université Paris Descartes—Faculté de Médecine, Hôpital Cochin, Assistance Publique—Hôpitaux de Paris, 27, rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France. Tel: +33-630-739-079; Fax: +33-158-411-745; E-mail: olivier.mir{at}cch.aphp.fr
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Abstract |
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 Top Abstract introductionsearch strategy and selection...resultsdiscussionconclusionsReferences |
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Background: Breast cancer is the commonest solid tumor observed during pregnancy. Anthracycline-based chemotherapy is feasible during the 2nd and 3rd trimesters of pregnancy, but few data are available on recent and highly active drugs taxanes, vinorelbine and anti-HER-2 agents in this setting.
Patients and methods: We carried out a comprehensive review of reports documenting the use of taxanes, vinorelbine, trastuzumab and lapatinib during pregnancy in the English literature, in order to evaluate their safety profile in pregnant patients.
Results: Twenty-four pregnancies are described, in which no grade 3–4 maternal toxicity nor malformation in the offspring was reported. Whereas only one report studied the pharmacokinetics of paclitaxel (Taxol) during pregnancy, several preclinical reports indicate that the placental P-glycoprotein could prevent the transplacental transfer of taxanes and vinorelbine. The use of trastuzumab was associated with the occurrence of anhydramnios in three of six cases.
Conclusion: The administration of recent drugs taxanes and vinorelbine seems feasible during the 2nd and 3rd trimesters of pregnancy, with a favorable toxicity profile. In contrast, anti-HER-2 agents may obscure the normal development of the fetal kidney, and should be avoided during pregnancy.
Key words: breast cancer, docetaxel, paclitaxel, pregnancy, vinorelbine
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introduction |
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TopAbstractintroductionsearch strategy and selection...resultsdiscussionconclusionsReferences |
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Breast cancer is the most frequent solid cancer observed during pregnancy, and its incidence is expected to increase, given the trend for women to postpone childbearing [1, 2]. We and others established the feasibility of anthracyclines during the 2nd and 3rd trimesters of pregnancy with minimal risk to the developing fetus [3, 4], providing a rationale for recent international recommendations [2].
Antimicrotubule agents paclitaxel (TaxolTM; Bristol-Myers-Squibb, New York, NY), docetaxel (TaxotereTM; Sanofi-Aventis, Paris, France) and vinorelbine display a high activity against breast cancer [5]. Most recently, two agents targeting HER-2 were introduced: trastuzumab, an IgG1 monoclonal antibody and lapatinib, a tyrosine kinase inhibitor. Breast cancer in young patients (
35 years) overexpress HER-2 in up to 35% of cases [6], stressing the need for information on the safety of anti-HER-2 agents during pregnancy.
We carried out a comprehensive review of the English literature in order to evaluate the maternal and embryo–fetal safety of these recent drugs.
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search strategy and selection criteria |
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Data for this review were identified by search of Pubmed, and references from relevant articles using the search terms ‘drug name and pregnancy’, the drug names being ‘paclitaxel’, ‘docetaxel’, ‘vinorelbine’, ‘trastuzumab’ and ‘lapatinib’. Only papers published in English from 1990 to 1 August, 2007 were included.
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results |
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A total of 17 publications [7–23] documenting the use of taxanes and vinorelbine during pregnancy were identified: nine patients received paclitaxel, five received docetaxel, five received vinorelbine and one received both docetaxel and vinorelbine. Six patients received trastuzumab (concomitantly with paclitaxel or docetaxel in two cases) [11, 20, 23–26], and only one report of lapatinib administration during pregnancy was found [27].
paclitaxel and pregnancy
Nine reports documenting the use of paclitaxel during pregnancy [7–15] are summarized in Table 1. Median maternal age was 36 years (range: 30–42). The malignancy was ovarian in five cases (four carcinomas and one dysgerminoma) or mammary in four cases. Paclitaxel was started during the 2nd trimester in four cases, and during the 3rd trimester in five cases. Paclitaxel was administered as a single agent in two of nine cases. Data concerning maternal hematologic toxicity were not available in most cases. Eight out of nine patients underwent caesarean section. No malformation was reported. The offspring seemed healthy with a median follow-up of 16 months (range: 3–36).
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docetaxel and pregnancy
To date, six pregnancies were described [16–20] (Table 2). All patients were treated for breast carcinomas. The median maternal age was 34.5 years (range: 28–44). Docetaxel was administered as a single agent in only one case. Chemotherapy was initiated during the 2nd (three cases) or the 3rd (three cases) trimesters. Again, the toxicity in the mother, especially hematologic was not detailed and, grade 3–4 maternal toxicity was reported. One fetus developed hydrocephalia before treatment with docetaxel, which remained stable thereafter; the baby developed normally and was considered healthy at 28 months [18]. No other malformation was reported, and the offspring appeared healthy with a median follow-up of 17.5 months (range: 9–28).
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vinorelbine and pregnancy
Six cases were identified [16, 21–23] (Table 3). Five patients were treated for breast carcinomas, and one for non-small-cell lung cancer. The median maternal age was 32 years (range: 28–34). Vinorelbine was associated with other cytotoxic drugs (5-fluorouracil, csiplatin or trastuzumab) in five of six cases, and started during the 2nd (three cases) and 3rd (three cases) trimesters. Neither grade 3–4 maternal toxicity nor malformation was reported, and the offspring seemed healthy with a median follow-up of 23 months (range: 6–35). One patient [22] underwent a caesarean section 4 days after her first cycle of chemotherapy, due to tumor progression and respiratory failure.
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anti-HER-2 agents and pregnancy
Trastuzumab or lapatinib administration during pregnancy were reported in six and one cases, respectively [23–27] (Table 4). All patients were treated for breast carcinomas. The median maternal age was 30 years (range: 28–44). Whereas the pregnancy under lapatinib was unremarkable, an anhydramnios was reported in three of six pregnant patients receiving trastuzumab. In one case, anhydramnios was found reversible at trastuzumab withdrawal [24].
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No grade 3–4 maternal toxicity nor neonatal malformation was reported, and the offspring seemed healthy with a median follow-up of 6 months (range: 2–18).
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discussion |
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TopAbstractintroductionsearch strategy and selection...resultsdiscussionconclusionsReferences |
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We retrospectively reviewed 21 reports [7–27] documenting the use of taxanes, vinorelbine and anti-HER-2 agents during 24 pregnancies.
maternal safety
No grade 3–4 hematological toxicity was reported. However, the frequency of hemograms was not precised. It is important to underline that to indicate in case reports the nadir and duration of hematologic toxicity would be a valuable pharmacodynamic end point to discuss whether, due to pharmacokinetics changes during pregnancy, the dose should be adjusted or not. In the lack of such information, we may only indicate to start at the standard dose and to secondarily adjust the dose to hematologic toxicity. The use of granulocyte-colony stimulating factor, if needed, is feasible during the 2nd and 3rd trimesters of pregnancy [13]. One report assessed the pharmacokinetics of paclitaxel (175 mg/m2 IV over 3 h) in a pregnant patient at 34 and 36 weeks of gestation [13]. The Cmax: maximal plasmatic concentration (Cmax) and area under the curve of paclitaxel were decreased compared with nonpregnant patients [28], suggesting a plasmatic underexposure during pregnancy. The estimated clearance, half-life and volume of distribution were within the ranges previously reported in nonpregnant patients. However, given the lack of data on large series of patients, the impact of pregnancy-induced pharmacokinetics changes on taxanes and vinorelbine safety remains uncertain.
Finally, 14 of 24 patients underwent caesarean section. The reasons for this obstetrical management were scarcely reported (Tables 1–3) but the most likely cause is to prevent neonatal infection in the context of neutropenia. However, two cases of preeclampsia were reported, in patients receiving respectively paclitaxel and docetaxel [10, 18].
embryo–fetal safety
In all cases, taxanes or vinorelbine were started during the 2nd or 3rd trimesters, after organogenesis was completed. The neonates exhibited normal physical examinations, except for two of them who had transitory respiratory distress (at 32 and 35 weeks, which could be due to prematurity) [11, 14]. Low birth weights (30th percentile [29]) were observed in 16 neonates.
In two cases, an anhydramnios was reported during the concomitant administration of taxanes and trastuzumab [11, 20]. A third case of anhydramnios during trastuzumab therapy in pregnancy was reported, and was found reversible at trastuzumab withdrawal [24]. Transplacental transfer of maternal IgG1 is well documented, and was already demonstrated for both monoclonal IgG1 antibodies rituximab and infliximab [30]. Hence, one may expect that trastuzumab could also cross the placental barrier. Moreover, HER-2 plays an important role in renal development [11]. Thus, the causative link between the use of trastuzumab and the development of anhydramnios is possible.
No malformation was noticed in the 25 newborns, and their development appeared normal with an overall median follow-up of 18 months (range: 3–36). Two babies had mild anemia, and grade 4 neutropenia in another case [14, 21, 22]. In all cases, the mother had received chemotherapy during the last 3 weeks before delivery (epirubicin, paclitaxel–carboplatin and vinorelbine–cisplatin, respectively), raising the hypothesis of a late transplacental transfer of these drugs. This leads to the pragmatic recommendation to avoid taxanes or vinorelbine in the weeks preceding delivery to prevent febrile neutropenia in the neonate.
transplacental transfer of taxanes and vinorelbine
Vinorelbine, paclitaxel and docetaxel are mainly metabolized by cytochrome P450 isoforms CYP3A4, CYP2C8 and CYP3A4 and CYP3A4/5, respectively [5]. The maturation of these cytochromes mostly occur in the first weeks of neonatal life [31]. Hence, fetuses are unable to metabolize these drugs and are therefore highly susceptible to their toxic effects when a transplacental transfer occurs.
Taxanes and vinorelbine would be expected to cross the placenta since they have a relatively low molecular weight, are highly lipophilic (Table 5) [5]. By contrast, they are highly bound to plasma proteins (Table 4) [5]. Plasma protein binding is increased during pregnancy [28], potentially leading to a decreased unbound (active) fraction of these drugs.
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Moreover, taxanes and vinorelbine are substrates for the P-glycoprotein (Pgp, MDR-1) [5], an efflux transporter for various xenobiotics which is highly expressed on the maternal compartment of the placenta [32]. One report [9] mentioned a high placental expression of the Pgp assessed by immunochemistry, raising the hypothesis of a protective role of the Pgp against these drugs. Hence, Pgp displays a major role in the protection of the fetus against a broad range of xenobiotics, including paclitaxel [33]. We hypothesize that the placental Pgp reduces the transplacental transfer of taxanes and vinorelbine, making their clinical use possible during the 2nd and 3rd trimesters of pregnancy. However, as previously described for other drugs [4, 28], we consider that the administration of these drugs during the last 3 weeks preceding delivery should be avoided, in order to preserve the neonate from chemotherapy-induced medullar toxicity.
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conclusions |
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TopAbstractintroductionsearch strategy and selection...resultsdiscussionconclusionsReferences |
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This review of the literature indicates the feasibility of treating pregnant cancer patients with taxanes and vinorelbine during the 2nd and 3rd trimesters of pregnancy. By contrast, anti-HER-2 agents were associated with an increased risk of anhydramnios, and should be avoided during pregnancy. Reports of taxanes or vinorelbine use during pregnancy with more details on the severity and kinetics of recovery of hematologic toxicity are warranted, to confirm their safety, to discuss the possible requirement of increased doses in comparison to nonpregnant patients as well as to better handle these recent agents in the obstetrical setting.
Received for publication August 10, 2007. Revision received August 16, 2007. Accepted for publication August 21, 2007.
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References |
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