Paul Berveiller1, 2, 3 and Olivier Mir3, 4
(1)
Department of Gynecology and Obstetrics, CHI Poissy Saint-Germain, 10 rue du champ Gaillard, Poissy, F78300, France
(2)
EA7404 – Gamètes, implantation, gestation, Université de Versailles Saint-Quentin en Yvelines, Montigny Le Bretonneux, France
(3)
French Group CALG “Cancers Associés à La Grossesse”, Paris, France
(4)
Department of Cancer Medicine, Gustave Roussy Cancer Institute, Université Paris Sud, Villejuif, France
Paul Berveiller
Email: paulberveiller@yahoo.fr
Keywords
CancerPregnancyAnticancer agentsPlacentaPharmacokinetics
Introduction
Systemic treatment with chemotherapy has a crucial role in pregnancy-associated cancers since it appeared to improve the overall survival, for instance, in breast cancer patients [1, 2]. Moreover, delaying anticancer agent administration as a result of pregnancy may adversely affect maternal survival [2]. In this complex medical and ethical situation, clinicians need to balance embryo-fetal well-being with maternal prognosis. Recent clinical data indicate that systemic treatment in cancer patients during the second and third trimesters of pregnancy is feasible and should be as close as possible to that used in nonpregnant patients [3–6]. Conversely, some other anticancer agents such as trastuzumab should be avoided given their potential fetal toxicity [3, 7].
Despite these general findings, the optimal use of cytotoxic drugs in pregnant patients remains undefined, particularly regarding molecule selection, dosing, dose intensity (standard or dose-dense regimens), and their potential repercussions of transplacental transfer. Indeed, both physiological changes in pharmacokinetics and pharmacodynamics play a critical role in drug safety (differential transplacental transfer) in one hand and in drug efficacy in the other hand. We herein focus on the pharmacokinetic data, the pharmacological changes occurring during pregnancy, and the subsequent potential changes in drug dosing and transplacental transfer that may be considered for selected drugs considered for the treatment of solid tumors during pregnancy.
Firstly, plasma concentrations should be in the optimal therapeutic window in order to display a favorable efficacy profile (to be above the minimum effective concentration) and must be below the maximum tolerated concentration. However, anticancer drugs are characterized by a narrow therapeutic index, i.e., their therapeutic concentration is very close to their concentration leading to significant toxicity. Hence, for these types of drugs, even minor changes in drug concentrations may lead to significant consequence represented by toxicity if concentration exceeds toxicity threshold and of inefficacy if concentration is below efficacy concentration level.
Conversely, regarding drugs that display a wide therapeutic index, moderate changes in drug concentration will not lead to significant clinical effects.
Finally, given the crucial physiological changes occurring during pregnancy and potentially leading to significant alterations of anticancer drug pharmacokinetics, physicians have to treat their patients carefully taking into account updated data that are listed below:
Physiological Changes During Pregnancy
Pregnant patients exhibit significant variations of pharmacokinetic parameters potentially altering drug metabolism in comparison with nonpregnant patients [8]. Physicians have to take into account that during pregnancy, these parameters may add their effects or cancel it and lead to no change in drug concentration.
Clearance
Drug clearance represents how the administered drug is metabolized and subsequently eliminated by the body. Thus, clearance affects directly total drug exposure and is used in order to determine maintenance dosing. Clearance is dependent on hepatic/renal blood flow, protein binding of studied drugs, and the activity of hepatic drug-metabolizing enzymes.
Hence, an increased blood flow may lead to an increase hepatic/renal clearance. Conversely, some factors inducing decreased hepatic/renal blood flows may subsequently decrease hepatic/renal clearances and lead to a drug overexposure. For example, during pregnancy, renal clearance is increased by 45 % at the beginning of gestation and reached 150 % at mid-gestation versus nonpregnant patients. Thus, physicians have to take into account these elements by making dosing adjustments (by increasing drug dosage or decreasing in some cases).
Drug Metabolism
Drug metabolism represents the fact that a xenobiotic is biotransformed in another one or many (one or many metabolites). Drug metabolism enzymes allow one molecule to be transformed in active or inactive metabolites. Many drug-metabolizing enzymes are involved in either phase I (often precedes phase II) or phase II metabolism, or in both phases. Thus, isoforms of cytochrome P450 (CYP1A2, CYP3A4, CYP3A5, CYP2D6) and alcohol dehydrogenase are involved in phase I reactions. UD-glucuronyltransferase (UGT), sulfotransferase, glutathione S-transferase (GST), etc. are involved in phase II [8].
Notably, the activity of cytochrome P450 isoform CYP3A4 increases by 50–100 % during the third trimester of pregnancy [9], potentially leading to a lower maternal exposure to drugs metabolized by this isoenzyme. Conversely, CYP1A2 activity appears to decrease during pregnancy, subsequently resulting in greater maternal plasma concentrations [9].
Finally, in case of cancer diagnosed during pregnancy, some other therapeutics such as ondansetron or codeine may be used, and these ones are also metabolized by cytochromes and potentially altered by the pregnancy setting (CYP1A2 and CYP2D6, respectively).
To conclude, many anticancer drugs are metabolized by metabolism enzymes; some of them are listed in Table 5.1 [10].
Table 5.1
Metabolism enzymes involved in anticancer drugs and supportive drug pharmacokinetics
|
Anticancer drugs |
P450 cytochrome |
Effect |
|
Cyclophosphamide |
CYP2B6, CYP3A4 |
Activation |
|
Ifosfamide |
CYP2B6, CYP3A4 |
Activation |
|
Doxorubicin |
CYP3A4 |
Inactivation |
|
Docetaxel |
CYP3A4 |
Inactivation |
|
Paclitaxel |
CYP2C8, CYP3A4 |
Inactivation |
|
Etoposide |
CYP3A4 |
Inactivation |
|
Erlotinib |
CYP1A2, CYP3A4 |
Inactivation |
|
Gefitinib |
CYP3A4 |
Inactivation |
|
Vinorelbine |
CYP3A4 |
Inactivation |
|
Supportive treatment |
P450 cytochrome |
Effect |
|
Codeine |
CYP1A2 |
Inactivation |
|
Morphine |
Activation? |
|
|
Paracetamol |
Activation? |
|
|
Metoclopramide |
CYP2D6 |
|
|
Ondansetron |
CYP1A1, 1A2, CYP2D6 |
Activation? |
Adapted from Scripture et al. [10]
The Area Under the Concentration-Time Curve
AUC represents the overall systemic drug exposure and is dependent on the dose, clearance, and bioavailability of the considered anticancer drug. For many drugs, AUC is well correlated with outcomes whereas for others drugs, minimum/maximum concentrations are better correlated.
Protein Binding
Protein-binding levels are dramatically involved in targeted concentration of various treatments such as anticancer agents. As an example, serum albumin levels significantly decrease during the second and third trimesters of pregnancy (approximately 13 % at 32 weeks), potentially resulting in elevated unbound drug levels and subsequent potential fetal toxicity [11, 12]. In pathologic conditions, these albumin levels may even be lower. Interestingly, albumin is not the only drug-binding protein; other plasma proteins such as alpha, beta, or gamma globulins and orosomucoid also play a significant role in protein binding (Table 5.2). Of note, physicians have to be extremely precautious in using, for example, drugs highly bound to plasma protein and displaying a narrow therapeutic range.
Table 5.2
Protein binding and unbound fraction of frequently used anticancer drugs
|
Anticancer drugs |
Unbound fraction (%) |
Binding protein |
|
Bleomycin |
>99 |
Plasma |
|
Carboplatin |
1 |
Albumin |
|
Cisplatin |
<5 |
Albumin, transferrin, gamma globulins |
|
Cyclophosphamide |
87 |
Plasma |
|
Docetaxel |
<2 |
Albumin, orosomucoid, HDL |
|
Doxorubicin |
15–25 |
Albumin |
|
Etoposide |
4 |
Albumin |
|
5-fluorouracil |
>95 |
Albumin, alpha, beta, and gamma globulins |
|
Ifosfamide |
45 |
Plasma |
|
Irinotecan (CPT-11) |
65 |
Albumin |
|
Methotrexate |
54 |
Albumin |
|
Oxaliplatin |
13–21 |
Albumin, gamma globulins |
|
Paclitaxel |
2–8 |
Albumin, orosomucoid, HDL |
|
SN38 (active metabolite of CPT-11) |
2 |
Albumin, orosomucoid |
|
Tamoxifen |
<2 |
Albumin, beta globulins |
|
Topotecan |
79 |
Albumin |
|
Vinorelbine |
12 |
Orosomucoid |
Volume of Distribution
Volume of distribution (Vd) is not a physical space but a pharmacological theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in the blood plasma.
Some drugs display a small Vd (0.1–1 L/kg) whereas some other drugs display larger Vd (1–10 L/kg). The volume of distribution is used to determine the loading dose needed to achieve the targeted concentration. Many physiological changes will occur during pregnancy and that may subsequently lead to an altered Vd.
Hence, plasmatic volume significantly increases during pregnancy (30–45 %) and peaks between 28 and 34 weeks of gestation, and the total body water will increase up to 8 l at term. These crucial physiological changes will lead to a decreased concentration peak and a higher trough concentration and subsequently to an increased distribution volume [13, 14].
Half-Life
Half-life corresponds to the period necessary for the drug concentration to be divided by two. This parameter is helpful to determine the administration frequency. Half-life directly depends on distribution volume and clearance. If the distribution volume of a drug is increased during pregnancy (or if clearance is decreased), its half-life will subsequently be longer and the interval between two administrations will have to be extended. Conversely, when the distribution volume is decreased and/or if the clearance is increased, the interval between two administrations will have to be shortened. In some cases, changes in distribution volume and in clearance do not lead to substantial changes in interval dosing.
Placental Metabolism and Placental Transfer
Although the placenta acts as a biologic barrier, the placenta also plays major role such as an endocrine organ and a metabolizing organ. Even if placental metabolizing activities have been described as relatively moderated, in some cases, their role may lead to potential consequences. This placental metabolism has to be taken into account when prescribing anticancer drugs.
The impact of pregnancy setting of the expression/activity of placental cytochromes is listed in Table 5.3 [15]. Interestingly, placental metabolizing activities may not only be altered in the pregnancy setting but also in patients who abuse tobacco, alcohol, or drugs or are exposed to polluted air.
Table 5.3
Cytochrome P450 (CYP) expression and activity in the first trimester and term human placentas
|
CYP isoenzyme |
CYP subtype |
First trimester |
Term |
|
CYP1 |
CYP1A1 |
+1,2,3 |
+1,2,3 |
|
CYP1A2 |
+1 |
−1,2 |
|
|
CYP2B1 |
+1 |
+1 |
|
|
CYP2 |
2A6 |
−1 |
−1 |
|
2A7 |
−1 |
−1 |
|
|
2A13 |
−1 |
−1 |
|
|
2B6 |
−1 |
−1 |
|
|
2B7 |
−1 |
−1 |
|
|
2C |
+1 |
−1 |
|
|
2D6 |
? (+1, −3) |
−1,3 |
|
|
2E1 |
? (+1,2, −/+3) |
? (+1, −/+2,3) |
|
|
2 F1 |
+1 |
+1 |
|
|
CYP3 |
3A3 |
? |
? (+1, −2) |
|
3A4 |
+1,2 |
? (+1, +/−2, −3) |
|
|
3A5 |
+1,2 |
? (+1, +/−2) |
|
|
3A6 |
+1,2 |
? (+1, −2) |
|
|
3A7 |
+1,2 |
? (+/−1,2) |
|
|
CYP4 |
4B1 |
+1 |
+1,2 |
Adapted from Syme et al. [15]
1: mRNA expression +: detectable
2: protein expression −: undetectable
3: enzyme activity ?: unknown or controversial results
Besides, all anticancer drugs can cross the placental barrier, but placental transfer may considerably vary [16]. Historically, three major mechanisms of placental transfer have been described: passive diffusion, facilitated diffusion, and active transport [16]. Chemical properties of drugs that influence their placental transfer are molecular weight, lipophilia, ionization at physiological pH, and plasma protein binding (see above). Grossly, low molecular weight drugs, weakly bound to plasma proteins, highly lipophilic, and nonionized at physiologic pH, may theoretically cross the placenta more easily [16].
Nevertheless, these concepts remain highly theoretical and many other factors may contribute to make the placental transfer varying. Thus, some drugs sharing these characteristics may be substrates of maternal-faced placenta proteins (efflux transporters) such as the P-glycoprotein (P-gp, MDR1, ABCB1) or the breast cancer resistance protein (BCRP, ABCG2) [15, 17]. These transporters are expressed in human placenta all along pregnancy and therefore may protect the fetus from various xenobiotics such as paclitaxel [18, 19] and may thereby counterbalance the unfavorable chemical properties of the drugs. Hence, physiological changes of pharmacology during pregnancy, placental metabolism, and the differential expression of placental transporters may subsequently alter transplacental transfer. Thus, we will provide below available data regarding the resulting transplacental transfer of various systemic anticancer therapies.
Placental Transfer of Selected Drugs: Preclinical and Clinical Data
Cyclophosphamide
Regarding in vivo data, no study documenting maternal pharmacokinetic parameters or amniotic fluid/neonatal blood cord dosage after cyclophosphamide administration was found. Regarding human ex vivo studies, only one study documented maternofetal passage of cyclophosphamide [20]. The authors described the case of a 33-year-old woman diagnosed with stage IVB Hodgkin’s lymphoma treated with a combination therapy with cyclophosphamide (400 mg/m2) started at 29th gestational week. At 34th gestational week, an amniocentesis was performed 1 h after the last dose of cyclophosphamide concomitantly with maternal blood sample analyses (second course). Interestingly, the level of cyclophosphamide in amniotic fluid was 25 % of the plasma level at the first hour post-administration of cyclophosphamide.
Interestingly, in animals such as baboons, transplacental transfer was obviously evidenced using ex vivo studies, with 25 and 63 % of maternal concentration of 4-hydroxy-cyclophosphamide found in fetal plasma and cerebrospinal fluid [21].
Cisplatin and Carboplatin
To our knowledge, only two ex vivo studies investigated the cisplatin transport from the maternal to the fetal circulation in human perfused placental cotyledon. In the first one [22], the authors found a transport fraction of cisplatin roughly reaching 13 % of reference marker value (antipyrine). Thus, the authors assumed that cisplatin transport remains negligible in the human placenta at term and may be used with minimal risk in pregnant patients [22]. In the second one, the authors found that carboplatin does cross the placental barrier, especially at higher concentrations in a placental perfusion model [23]. The placental transfer of carboplatin was concentration dependent. The concentration of carboplatin in fetal compartment ranged from 2.2 % up to 23.7 % of the total drug concentration crossing the placenta across all experiments. The authors concluded that doses of carboplatin up to an area under the curve of 7.5 were not associated with significant placental transfer, fetal exposure, or fetal toxic effects.
An animal ex vivo study described transplacental transfer of labeled cisplatin used as a tracer in pregnant mice at different times of gestation [24]. Interestingly, very small amounts of radioactivity were detected in the embryos during the first days of gestation, whereas increasing amounts of radioactivity were evidenced during the late days of gestation. These data suggest that placental transfer may be gestational age dependent, and progressive transporters expression may influence drug transfer along with placental maturation. Another animal study confirmed the transplacental transfer of carboplatin in baboons with fetal concentrations reaching up to 57.5 % of maternal concentration [25].
Two human in vivo reports highlighted a significant cisplatin transplacental transfer with detection of cisplatin in umbilical cord blood of two neonates exposed to cisplatin during pregnancy [26, 27]. These neonatal cisplatin levels were 40 μg/ml at the third day post-chemotherapy (first day of life) [27] and 0.82 μm/L versus 1.10 μm/L for the mother [26].
Another in vivo report described the case of a 40-year-old pregnant woman with ovarian cancer, in whom cisplatin 100 mg/m2 was initiated at 20 weeks of gestation, followed by carboplatin 300 mg/m2 [28]. Platinum-DNA adducts were detected in amniotic fluid (after amniocentesis), placental tissues, blood cord, and maternal blood (at delivery). Platinum-DNA adducts were not detected any more 3 months after delivery.
Koc et al. reported the detection of platinum-DNA adducts after carboplatin 400 mg/m2 administration at 22 weeks of gestation [29]. Platinum-DNA adducts were detected in blood cord lymphocytes 9 weeks after the last administration of carboplatin.
Interestingly, Marnitz et al. studied cisplatin concentration in amniotic fluid after a second cycle of cisplatin (20 mg/m2) dose for cervical cancer in a 35-year-old patient with twin pregnancy [30]. Cisplatin maternal serum concentrations were 293.8 mg/L before and 1148.8 mg/L 30 min after cisplatin administration. At the same time, cisplatin amniotic fluid concentration was 106.7 mg/L. Hence, cisplatin amniotic fluid concentration reached approximately 10 % of maternal concentration. At delivery, cisplatin concentrations were studied in the twin neonate blood cords and in amniotic fluid. The blood cord concentrations were 57.1 mg/L for the first neonate and 61.2 mg/l for the second. Amniotic fluid concentration was roughly one third of blood cord concentrations. Moreover, maternal pharmacokinetic parameters were studied after the third cycle of cisplatin-based chemotherapy and were comparable to nonpregnant patients.
In very recent study, Köhler et al. investigated the transplacental transfer of platinum [31]. Twenty-one patients with cervical cancer diagnosed in the second trimester were treated with neoadjuvant cisplatin chemotherapy, started between the 17th and the 25th week at the dose of 20 mg/m2 on days 1–3 every 3 weeks. At the time of delivery by cesarean delivery, synchronous samples from maternal blood, umbilical cord blood, and amniotic fluid were taken and analyzed for cisplatin concentrations. Cisplatin concentrations in umbilical cord blood and amniotic fluid were 23–65 % and 11–42 % of the maternal blood, respectively.
All these data confirm an obvious transplacental transfer of platinum salts through the placental barrier.
Doxorubicin
Only one ex vivo study using human perfused placental cotyledon model documenting transplacental transfer of doxorubicin was found [32]. The authors investigated passage of maternal doxorubicin concentrations of 3, 30 and 150 mg/l through the cotyledon. The global transfer value was 2.96 % and did not seem to be dose dependent.
Regarding in vivo data, several reports documented the transplacental transfer of doxorubicin in humans. In a pregnant patient receiving 60 mg/m2 [33]. 3 weeks after the last infusion of doxorubicin, no doxorubicin was detectable, neither in neonate blood nor in the placental tissues.
In another case report, the authors investigated the transplacental transfer of doxorubicin 20 mg/ m2 started at 32 weeks of gestational age [34]. After four courses of chemotherapy, an amniocentesis was performed (96 h after the last doxorubicin administration). Accordingly with the previous case report, doxorubicin and its metabolite were not detectable in amniotic fluid.
Karp et al. [35] reported two cases of transplacental transfer of doxorubicin. The first patient received 45 mg/m2 of doxorubicin-based treatment. At delivery (2 days after the last administration), doxorubicin levels in the placental-maternal side, placental-fetal side, and umbilical cord were at 1.186, 0.786, and 0.083 nmol/g of tissues, respectively. Interestingly, doxorubicin was not detectable in blood cord. The second patient received 45 mg/m2doxorubicin-based treatment. Sixty hours after the last administration, the mother delivered a stillborn baby. Noteworthy, no doxorubicin could be detected in any fetal tissue; however metabolite was highly detected in fetal spleen and was also present in lower concentrations in fetal liver, lung, kidney, muscle, heart, and duodenum.
Another case report available documented the use of 30 mg/m2 doxorubicin for myeloblastoma diagnosed at 20 weeks of gestational age [36]. Four and 16 h after doxorubicin administration, amniocentesis were performed. Interestingly, no doxorubicin could be detected in amniotic fluid.
Conversely, D’Incalci et al. investigated 15 h after a 40 mg doxorubicin infusion (therapeutic abortion) transplacental passage in fetal tissues [37]. Doxorubicin reached high concentrations in the lung, liver, and fetal kidneys (ten times the maternal concentration), whereas no doxorubicin was detected in the amniotic fluid, brain, intestine, and gastrocnemius muscle. The authors explained the undetectable doxorubicin in the amniotic fluid by important distribution volume during pregnancy.
To our knowledge, no in vivo data were available in the literature regarding transplacental transfer of pegylated liposomal doxorubicin. However, a very recent article studied its transfer in human placental cotyledon [38]. Interestingly, the pegylated doxorubicin did not cross the placenta whereas liposomal doxorubicin crossed the placental barrier (12 % of the maternal concentration maximum).
Paclitaxel
Three human ex vivo studies documented transplacental transfer of paclitaxel [17].
Firstly, the authors investigated placental transfer of paclitaxel 85 ng/ml using perfused placental cotyledon model (seven placentas). The final fetal concentration of paclitaxel was 3.7 ng/ml, which represented roughly 4.3 % of initial maternal concentration.
Noteworthy, as paclitaxel is known to be a substrate of the P-glycoprotein (P-gp, MDR1, ABCB1) [39], the authors investigated the role of P-gp administration on transplacental transfer rate of paclitaxel with six placentas. Fetal concentrations with P-gp inhibitors were found to be two times higher than without P-gp inhibitors (7.5 ng/ml), representing 8.8 % of initial maternal concentration. Thus, transfer of paclitaxel through the placenta was significantly higher with P-gp inhibitors, reinforcing the role of protecting fetus against drugs such as paclitaxel.
Secondly, using the same model with the same concentrations of paclitaxel (12 placentas), Nanovskaya et al. found similar results [40]. Fetal concentrations of paclitaxel with and without P-gp inhibitor were 3.97 and 6.56 % of initial maternal concentration, respectively.
Finally, we have recently documented a low transplacental transfer rate of paclitaxel (close to 5 %) with however an important inter-patient variability [41].
An ex vivo study investigated with another model (cellular culture of Caco-2 cells) the efflux permeability of paclitaxel with and without P-gp inhibitor [42]. Using a P-gp inhibitor, the authors confirmed the fact that paclitaxel is a P-gp substrate by documenting a significant increase in influx permeability (roughly three times higher).
Docetaxel
We have recently studied the transplacental transfer rate of docetaxel (close to 5 %) in an ex vivo cotyledon perfusion model [41]. Similarly to what was found with paclitaxel, inter-patient variability was important.
No other ex vivo nor in vivo data documenting the transplacental transfer of docetaxel in humans was found in the literature, neither in summary of pharmaceutical product.
However, in baboons, Van Calsteren et al. investigated the transplacental transfer of docetaxel [21]. Interestingly, although they did not find significant level of docetaxel in fetal blood samples after administration of 100 mg/m2of docetaxel, they detected 5–50 % in fetal tissues of maternal tissue concentration after 3 h. Interestingly, fetal and maternal tissue concentrations were similar after 26–76 h.
To conclude, physicians have to pay attention to the physical properties of the administered drugs, the term of pregnancy, and the available data in the literature to better handle these drugs during pregnancy and potentially change drug dosing.
Recent Clinical Pharmacokinetic Data
Although clinical data indicate a good tolerability of anthracyclines and taxanes during the late trimesters of pregnancy [43–46], the existence of physiological variations in drug pharmacokinetics during pregnancy raises important concerns regarding the optimal drug dosing in pregnant patients [8, 47]. Indeed, the favorable toxicity profile of these agents during the late trimesters of pregnancy questions whether pregnant patients could achieve suboptimal plasma concentrations (underdosing) compared to that observed in nonpregnant patients, potentially leading to a decreased antitumor efficacy [47]. Recent data summarized as follows provide some information that may help clinicians to better handle anticancer agents during pregnancy:
· Most anticancer agents are empirically prescribed according to the body surface area (BSA), resulting in large inter-patient variability (even outside the pregnancy setting). To date, when a pregnant patient is diagnosed with a cancer, no data are available to support the use of alternative dosing methods [4]. Thus, dosing based on the BSA, using the current patient’s weight (prior to every course), remains a standard [48]. Conversely, the use of target-AUC-based dosing, used, for example, for carboplatin (in platinum-sensitive diseases such as triple negative breast cancer), cannot be currently recommended in pregnant patients [48]. Indeed, the formula (Calvert or Chatelut) used to calculate carboplatin dose according to the target AUC was obtained from population pharmacokinetic models that did not include pregnant patients, and the impact of physiological changes associated with pregnancy on these models is unknown.
· In addition, an increased activity of major enzymes involved in the metabolism of taxanes and anthracyclines (such as cytochrome P450 isoforms CYP3A4 or CYP2C8) is observed during the late trimesters of pregnancy [49], potentially resulting in decreased drug exposure. Moreover, given the fact that albumin concentrations significantly vary during pregnancy and taxanes being highly protein bound, these may lead to significant changes in taxane pharmacokinetics [47].
· Furthermore, very recent pharmacokinetic data comparing the use of anthracyclines and taxanes in pregnant versus nonpregnant patients highlighted the fact that exposure to taxanes was significantly decreased during pregnancy, especially for paclitaxel [47]. Conversely, exposure to anthracyclines such as doxorubicin and epirubicin was not significantly modified [47], confirming recent additional data [50].
Thus, anthracycline dosing method should probably be remained unchanged during pregnancy, whereas physicians should be aware of potential suboptimal exposure while using taxanes (paclitaxel and docetaxel) in this particular setting. However, whether doses should be increased in this population is uncertain because such increases could result in severe thrombocytopenia, neutropenia, and infection, with potentially serious consequences for both mother and neonate [4]. Although granulocyte-colony stimulating factor (G-CSF) support can reduce the occurrence of febrile neutropenia in nonpregnant patients, its effectiveness and safety profile during pregnancy are not clearly established [8, 46, 51].
· Finally, platinum salts may have a role in gynecologic, lung, and triple negative breast cancer, especially carboplatin. Although the use of platinum salts may be considered during the late trimesters of pregnancy, significant transplacental transfer was demonstrated and long-term effects remain unknown [52]. Little is known regarding the platinum salt displaying the best toxicity profile, but carboplatin might have a less global toxicity compared to cisplatin [6].
· Otherwise, although maternal drug exposure is a concern in terms of treatment efficacy, the transplacental transfer of anticancer agents is critical for fetal safety. Data on transplacental transfer rates indicate similar and reassuring data on doxorubicin, epirubicin, and taxanes [32, 41, 53], still with major inter-patient variability, particularly marked with docetaxel [41]. As a consequence, from the fetal safety point of view, paclitaxel should probably be preferred to docetaxel in the setting of pregnancy [54].
· Some other therapies such as targeted anticancer agents may be indicated in specific cases, notably in breast cancer, for instance, trastuzumab. Initiating trastuzumab therapy as early as possible is associated with a better long-term outcome in nonpregnant patients with HER-2-positive breast cancer [55]. Regarding the use of trastuzumab during pregnancy, in a recent review, some authors retrospectively collected data from numerous reports [56]. Thus, oligo-/anhydramnios was described as the most frequent adverse outcome. Interestingly, this adverse outcome was in general limited when trastuzumab therapy was discontinued [56]. However, the rate of prematurity was found to be high, sometimes leading to neonatal deaths mainly caused by respiratory failures. Indeed, trastuzumab is an IgG1, the subclass of antibodies that is the most actively transferred across the placenta during the second and third trimesters of pregnancy, and HER-2-signaling pathway is critical for fetal renal development [57].
Although trastuzumab use is currently not recommended during pregnancy [8], short inadvertent fetal exposure to trastuzumab therapy should not systematically lead to termination of pregnancy.
Regarding other targeted agents such as bevacizumab, pertuzumab, or trastuzumab emtansine, to our knowledge, no data is available on their use during pregnancy [8].
· Moreover, physicians have to deal with the timing of systemic therapy, taking into account anticancer molecule, drug dosing, and potential fetal consequences according with gestational age. In order to summarize, systemic therapy should be avoided during the first trimester due to the embryologic organogenesis period [3]. During the late trimesters (second and third), taking into account parameters such as disease stage and gestational age, various anticancer agents may be used with a favorable safety profile as abovementioned [6].
During the end of the third trimester, to allow the bone marrow to recover and minimize the hematological consequences (risk of maternal and fetal neutropenia), delivery should be postponed at least 3 weeks after the last course of chemotherapy [3, 58].
· Finally, some authors introduced the potential use of dose-dense chemotherapy during pregnancy [59]. Among ten patients who received dose-dense chemotherapy, there was no significant difference regarding neonatal outcomes (birth weight, congenital anomalies, neutropenia, and preterm births) and maternal outcomes (neutropenia, recurrence, time to recurrence, survival) [59]. Although a very small sample of patients was treated, these data suggest that dose-dense chemotherapy might be used in some particular cases. Nevertheless, further studies on dose-dense chemotherapy are mandatory in order to encourage or not the use of dose-dense chemotherapy regimen during pregnancy.
Conclusion
To conclude, various systemic anticancer agents such as anthracyclines and taxanes using standard protocols are feasible during the last trimesters, whereas monoclonal antibodies such as trastuzumab should be avoided along the pregnancy. Given the major pharmacokinetic changes during pregnancy and given recent published data, a potential dose increase could be useful especially for taxanes, but further studies remain necessary to confirm these preliminary results and to confirm that transplacental transfer is not subsequently increased.
Anthracycline-based chemotherapy might be preferred in the first intention due to concerns regarding paclitaxel and docetaxel exposure and efficacy during pregnancy. Platinum salts might be used (using the BSA-based dosing method) in particular settings, even though their transplacental transfer has been established as significant, and potential long-term outcomes remain unknown.
As a consequence, although very recent studies provided highly interesting data, further pharmacokinetic studies are warranted before changing our chemotherapy protocols during pregnancy.
Conflict of Interest
Dr. Mir has acted as a consultant for Astra-Zeneca, Amgen, Bayer, BMS, Novartis, and Pfizer, and Roche. Dr. Berveiller declares no conflict of interest.
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