Pharmacology of antineoplastic agents in pregnancy

Critical Reviews in

ONCOLOGY/ HEMA TOLOG Y ELSEVIER SCIENCE IRELAND

Critical

Pharmacology

Reviews

I6 (1994) 75-112

in Oncology/Hematology

of antineoplastic

agents in pregnancy

Valerie J. Wiebe*“, Pirkko E.H. Sipilab “Department of Medicine, Division of Oncology. University of Texas Health Science Center, San Antonio. TX. USA ‘Department of Obstetrics and Gynecology, University of Oulu. Oulu. Finland

(Accepted

10 August

1993)

Contents .

76

.

1.

Introduction

2.

Clinical

3.

Radiation induced 3.1. Radiation

4.

Antineoplastic agents 4.1. Alkalating agents 4. I .I. Busulfan 4.1.1.1. Clinical pharmacology 4.1.1.2. Pharmacokinetics 4.1.1.3. Adverse effects on fetus 4.1.2. Cisplatin . 4.1.2. I. Clinical pharmacology 4.1.2.2. Pharmacokinetics 4.1.2.3. Adverse effects on fetus 4.1.3. Cyclophosphamide 4. I .3. I. Clinical pharmacology 4. I .3.2. Pharmacokinetics 4.1.3.3. Adverse effects on fetus 4.2. Antimetabolites 4.2.1. Ara-C . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. I. I. Clinical pharmacology 4.2. I .2. Pharmacokinetics . 4.2.1.3. Adverse effects on fetus 4.2.2. 5-Fluorouracil 4.2.2.1. Clinical pharmacology 4.2.2.2. Pharmacokinetics 4.2.2.3. Adverse effects on the fetus 4.2.3. Methotrexate 4.2.3. I. Clinical pharmacology 4.2.3.2. Pharmacokinetics 4.2.3.3. Adverse effects on the fetus 4.3. Natural products (plant alkaloids and antibiotics) 4.3.1. Daunorubicin and doxorubicin 4.3. I. 1. Clinical pharmacology 4.3.1.2. Pharmacokinetics 4.3.1.3. Adverse effects on the fetus 4.3.2 Vinblastine and vincristine 4.3.2.1. Clinical pharmacology

* Corresponding

author,

pharmacology

7703 Floyd

of antineoplastics birth

during

77

pregnancy

78 78

defects

Curl Drive, San Antonio,

1040~8428/94/526.00 0 1994 Elsevier Science Ireland SSDI 1040-8428(93)00096-X

TX 78284-7884

Ltd. All rights reserved.

USA

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78 78 78 78 79 79 79 79 81 81 82 82 82 87 85 85 85 86 86 91 91 91 91 92 92 92 92 92 93 93 95 95 Yb

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76

4.4.

Rev. Oncol. Hematol. 16 (1994)

4.3.2.2. Vinca alkaloids: pharmacokinetics ................................. 4.3.2.3. Adverse effects on the fetus ....................................... Miscellaneous .................................................................... Procarbazine ............................................................. 4.4.1. 4.4.1.1. Clinical pharmacology ............................................ 4.4. I .2. Pharmacokinetics ................................................ 4.4.1.3. Adverse effects on the fetus .......................................

96 100 100 100

100 105 105

5.

Discussion

............................................................................

106

6.

Biographies

............................................................................

108

7.

Reviewer

8.

References

.............................................................................. ............................................................................

The use of antineoplastic agents in pregnant women poses obvious risks to both the patient and the developing fetus, particularly during organogenesis. While the use of antineoplastics during pregnancy is often unavoidable, the physician may limit the risks by having a clear knowledge of the pharmacology and teratogenic potential of individual agents. Specific physiologic changes in the pregnant patient, such as enhanced renal excretion of drugs, increased or decreased hepatic function, altered gastrointestinal absorption and enterohepatic circulation, altered plasma protein binding, an increase in plasma volume (50%), and creation of a fluid filled 3rd compartment (amniotic fluid) for water soluble drugs may all significantly influence the pharmacology of antineoplastic agents. These physiological changes may effect the pregnant patients ability to absorb orally administered drugs, metabolize drugs to either active or inactive metabolites, and eliminate cytotoxically active drugs. A resulting reduction in concentration x time (C x T) for drug exposure to the maternal system may reduce the efficacy of the antineoplastic agents, while an increase in C x T may expose the patient and her fetus to undue toxicity. The timing of drug administration to gestational age is also a critical factor for some drugs. While many drugs result in adverse effects on the fetus regardless of gestational age, others appear to pose less of a threat if administered beyond the first trimester. This review addresses the pharmacology, pharmacokinetics and the teratogenic potential of individual antineoplastic agents that are commonly used in pregnant patients. The aim of this review’is to help the physician select, on a patient specific basis, antineoplastic agents that avoid at least some of the fetal risk involved while maintaining efficacy in the treatment of the patient. 1. Introduction In 1970, Potter and Schoeneman reported that the incidence of all cadncers occurring during pregnancy was low (1 in 1008 pregnancies), with breast and cervical

75-I I2

108 108

cancers accounting for more than 50% of all cases [l]. However, the decision to delay pregnancy until the later reproductive years for many women is expected to increase the number of patients presenting with cancer during pregnancy. Therefore, the clinician may be confronted more frequently about the issues surrounding the use of chemotherapy in pregnancy, including both moral and therapeutic dilemmas. To date, there is little information available concerning the therapeutic treatment of these patients. A number of recently published reviews have provided some information that may be useful to a clinician approached with the difficult decision of using antineoplastics in pregnancy [2-51. However, these reviews primarily address the therapeutic approach to specific cancers including breast, lymphoma, leukemia and malignant melanoma, but do not provide information about specific antineoplastic agents and their use during pregnancy. Unfortunately, prospective, controlled studies examining the adverse effects of specific antineoplastics during pregnancy are not available and cannot be performed in many instances for obvious ethical and moral reasons. Furthermore, extrapolation of data from studies performed on pregnant animals to humans has also been shown to have many limitations as evidenced by the thalidomide disaster of 1960- 1962. Although many anecdotal reports suggest that antineoplastics can be used safely in pregnancy, these agents do pose obvious risks to the growing fetus. The use of chemotherapy during pregnancy has been associated with both immediate and delayed effects on the fetus. Fetal death, miscarriage, premature birth, low birth weight, teratogenesis, organ toxicity, hematopoietic depression, immunosuppression and hormonal alterations are immediate effects that may occur after intrauterine exposure to chemotherapeutic agents. Potential long term complications may also involve carcinogenesis, physical or mental retardation, sterility and teratogenesis in subsequent generations. Although many chemotherapeutic agents such as aminopterin are known to result in both immediate and delayed adverse

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effects to the fetus, not all agents appear to have such devastating effects. The safe use of antineoplastics in pregnancy appears to be largely dependent on the specific drug used, its mechanism of action, total exposure of the fetus to drug, and timing of exposure to gestational age. Selectivity of the drug for rapidly growing tissues, penetration across the blood placental barrier, pharmacokinetics and systemic toxicities vary between agents and may ultimately dictate the risk to the fetus from antineoplastics. A thorough understanding of the pharmacologic properties of antineoplastics may ultimately aid in the rational design of antineoplastic therapy during pregnancy. At least three criteria must be addressed in selecting an agent including (i) the pharmacology of the agent, (ii) the pharmacokinetics and (iii) the potential for adverse effects on the fetus. 2. Clinical pharmacology of antineoplastics during pregnancy In a review of 53 cases where antineoplastics were used during the first trimester pregnancy, Nicholson et al. report 4 cases (7.5%) of fetal malformation [6]. Further review of their work by Willemse et al. suggest that radiation administered during pregnancy may have contributed to the development of fetal abnormalities in many of these patients [7]. In a more recent review of the use of cytotoxic agents during first trimester pregnancy, Doll et al. report that 24 of 139 (17%) of fetuses exposed to chemotherapy developed fetal malformation [8]. However, radiation therapy was also used in many of these patients during the same period, confusing the degree to which chemotherapy was involved in the induction of birth defects. Radiation is a known inducer of birth defects and is often used in combination with chemotherapy in certain malignancies common in pregnant patients. A variety of case reports using full doses of chemotherapy alone without the use of radiation during pregnancy have resulted in normal fetal development lending support to the theory that radiation significantly contributes to the induction of birth defects in pregnant patients receiving chemotherapy in combination with radiation [4,9- 131. The selectivity of antineoplastic agents for cancer cells is largely dependent on the agents ability to inhibit actively dividing cells. Therefore the fetus is highly sensitive to antineoplastics particularly during the first trimester when cells are rapidly dividing. Most authors suggest that antineoplastics be avoided during the first trimester. This is especially true for the antimetabolites methotrexate and aminopterin. However, other agents such as doxorubicin have been used successfully during the first trimester with limited fetal abnormalities [14]. Since not all agents will produce fetal malformation when administered during first trimester, withholding

77

Table 1 Phannacokinetic factors effected during pregnancy Pharmacokinetic factor

Effect

Volume of distribution Peak drug concentration Halflife Concentration x time (AUC) Drug absorption Enterohepatic circulation Protein binding Renal clearance Hepatic clearance

Increased Decreased Increased Increased Increased Increased Increased Increased Increased

or or or or

decreased decreased decreased decreased

or decreased

treatment during the first trimester to a patient severely in need of treatment should be carefully considered [7]. There are many pharmacologic factors that must be considered in the selection of agents to be used during pregnancy. The pharmacokinetfcs of some drugs may be significantly altered in pregnant patients (Table 1). The pharmacokinetics (volume of distribution, peak drug concentrations, halflife of administration, AUC and maternal clearance) of antineoplastics have not been well studied in pregnant patients. Unfortunately, pharmacokinetic parameters established in other patient populations may not be easily applied in pregnancy due to a variety of metabolic alterations in the pregnant patient. Changes in gastrointestinal function may alter drug absorption. Enterohepatic circulation of drugs may be increased resulting in an increase in bioavailability (F) of drugs. The volume of distribution may be altered by changes in the hemodynamic compartments and may result in a dilutional effect on some drugs. Pregnant patients have an increase in plasma volume by almost 50% and the development of a fluid compartment (amniotic fluid) which may behave as a 3rd space for water soluble drugs [ 15,161. An increase in the volume of distribution may lead to a decrease in the peak concentrations of drugs and a prolongation of the halflife of some agents unless the excretion or elimination of the drug is also increased [ 17,181. The development of a third space can result in delayed elimination and increased exposure to drug, resulting in maternal and potentially fetal toxicity. Plasma albumin concentrations decrease, but there is an overall increase in plasma proteins as a result of high estrogen concentrations. This may lead to a decrease in unbound drug fractions (the active fraction). Drug elimination may also be altered due to changes in renal and hepatic function. Renally excreted drugs may be enhanced and hepatically cleared drugs may be increased or decreased [19]. An increase in the glomerular filtration rate and an increase in creatinine clearance may lead to rapid clearance of renally excreted drugs. The hepatic mixed function oxidase system is also

78

faster in pregnant patients so that drugs metabolized by this route would be expected to be cleared much more rapidly [20]. The result of increased drug clearance from the body may lead to reduced area under the concentration x time curve (AUC) of agents. A reduced AUC can drastically alter the chemotherapeutic efficacy of drugs. In addition to altered maternal metabolism during pregnancy, fetal metabolic pathways also differ from adults. While most agents are eliminated primarily by oxidative metabolism in adults, other pathways may be the major metabolic pathway in preterm infants [21]. Fetal exposure or the area under the concentration x time curve (C x T) of the antineoplastic agent may be the most important factor in determining risk to the fetus. Fetal exposure involves many factors including physiochemical properties of the antineoplastic agent, dose and schedule of the drug, and pharmacokinetics of the drug in both the maternal and fetal system. The blood-placental barrier is easily penetrated by most agents, however, physiochemical properties of the drug may limit the extent of fetal exposure. Drug diffusion across the placenta is dependent on the molecular weight, degree of protein binding, lipophilicity and degree of ionization. Agents which are noted to penetrate the blood-placental barrier are generally low in molecular weight, have low plasma protein binding, are lipophilic and remain in the unionized state [21]. The dose, route and scheduling of the agent is also important in determining fetal exposure. Short infusions may produce high peak levels which increase the likelihood of toxic drug concentrations. The route of administration may also be important. While intravenous therapy poses obvious risks to the fetus, inallow direct traperitoneal administration may transuterine absorption [22]. Topically applied cytotoxic agents have also been associated with fetal toxicity 123,241.Orally administered agents may have altered absorption since the stomach empties at a slower rate in pregnancy [25]. This review will address the available information on the pharmacology, pharmacokinetics and potential adverse effects on the fetus of individual antineoplastic agents. In addition, since radiation is perhaps the most commonly administered antineoplastic therapy that has been associated with severe birth defects, it is briefly summarized. 3. Radiation induced birth defects 3.1. Radiation The effects of radiation on the developing fetus are well known. In humans, radiation exposure during pregnancy can result in either embryonic death, congenital malformations or intrauterine growth retardation. The

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extent and type of effect on the fetus is dependent on the time and dose of radiation received. Irradiation consisting of small doses (< 5 rad or 0.05 Gy) does not appear to be associated with growth retardation or fetal malformations. However, small doses of radiation received from diagnostic procedures (l-2 rad) have been associated with an increased risk of childhood malignancies, particularly leukemia [26]. The increased risk of cancer associated with exposure to small doses of radiation remains to be established since many other factors may also contribute to the elevated risk. In fetuses exposed to acute doses of radiation (> 50 rad or 0.5 Gy), microcephaly with mental retardation, hydrocephaly, growth retardation and eye malformations (microphthalmia, pigmentary changes in the retina, cataracts) are commonly seen [27,28]. Other malformations noted at these doses include intrauterine growth retardation, hypoplastic genitalia, cleft palate, and abnormalities of the large toe and ear. The effects of radiation on the growing fetus are also dependent on the time in which the exposure occurred. In the early blastocyst stage, an embryo exposed to radiation will experience only lethal effects from radiation. The lethal effects at this stage are generally considered all or nothing, since any surviving embryo will generally not experience any teratogenic effects [29]. However, during early organogenesis the developing embryo is very sensitive to the lethal, teratogenic and growth retarding effects of irradiation [30]. In humans, the period in which the embryo is highly sensitive to multiple system malformations is from the 9th to the 11th week of gestation. In later stages of development, exposure of the fetus to radiation may not result in severe deformities, but can result in permanent cell depletion in organs or tissues exposed to radiation [3 11. Exposure to radiation after the 20th week of gestation has resulted in epilation, dermal erythema and hematologic depression. 4. Antineoplastic agents 4. I. Alkalating agents 4. I. I. Bust&an 4.1. I. 1. Clinical pharmacology.

Busulfan is commonly used in the treatment of chronic myelogenous leukemia which is noted in women of child bearing years. Busulfan inhibits cell division by interacting with DNA and thiol groups on proteins [32,33]. Busulfan is an orally administered drug that actively inhibits cells with a low growth fraction. Busulfan is metabolized to at least 12 metabolites which have not been fully characterized. The biological activity appears to be associated with the parent compound rather than its metabolites. Busulfan is approximately 55% protein bound in the nonpregnant patient [34]. Although it is not known which

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specific proteins bind busulfan, an overall increase in plasma proteins may potentially lead to a small decrease in the active fraction of this compound. Busulfan undergoes first pass metabolism and clearance in the liver [35]. Since this agent is orally administered its absorption may be significantly altered in pregnancy. Since the maternal stomach empties at a slower rate the passage of a tablet may be extended from a few minutes to as long as several hours for passage through the pylorus. The results of the prolonged exposure time of busulfan to the highly acidic environment in the stomach are unknown but will most likely have a significant effect on the dissolution rate and the amount of active drug absorbed. Following absorption busulfan rapidly distributes into most tissues and plasma compartments including the cerebral spinal fluid (CSF). CSF concentrations are roughly equivalent to plasma concentrations after dosing [34]. The rapid and efficient distribution of busulfan across the blood brain barrier suggests that busulfan most likely also penetrations across other membranes including the blood-placental barrier. No information is available on busulfan penetration into breast milk, but it should be assumed to readily penetrate into breast milk in significant concentrations. Since busulfan has significant antihematopoietic effects even at low concentrations, mothers should be advised to avoid breast feeding while taking this drug. 4.1.1.2. Pharmacokinetics. Absorption of oral busulfan in the non-pregnant patient is complete with a lag time of 0.5-2.0 h, occurring before busulfan is detected in plasma [36]. This may be significantly extended in the pregnant patient due to the slowed gastric emptying time. Busulfan steady state concentrations of 83 1- 1480 ng/ml have been reported following a 1 mg/kg dose given every 6 h in non-pregnant patients [34]. However, delayed absorption in pregnant patients may result in significant variability in plasma concentrations. Following oral administration both monophasic and biphasic elimination patterns have been observed. The halflife of the parent compound is short (1.8-5.6 h) [34], but terminal halflives that include the metabolites may be as long as 5 days [37,38]. The halflife of both the parent compound and its metabolites may be significantly altered in the pregnant patient with altered liver metabolism and increased renal elimination of drugs. Metabolites are slowly eliminated in urine with approximately IO-50% of the dose excreted within a 24 h period in non-pregnant adults. Since liver metabolism and excretion of busulfan metabolites may be increased in the maternal system, the AUC of the parent compound and its metabolites may be effectively decreased. 4.1.1.3. Adverse effects on fetus. Busulfan has been used in a number of patients with chronic mylogenous leukemia during pregnancy. In most cases it has had few

79

adverse effects on the fetus. Used in doses of l-6 mg/day it has been used with few adverse effects in lst, 2nd, and 3rd trimester pregnancy (Table 2). However, there have been a number of reports of fetal anomalies following the use of busulfan in combination with known teratogenic agents. Diamond et al. present a case involving busulfan in which multiple anomalies were reported, but the mother also received radiation (200 rads) at approximately one month gestation and 6-mercaptopurine ( 100 mg/day) prior to conception until two months gestation and was not initiated on busulfan (4-6 mg/day) until the 8th week of gestation [47]. The female infant (1.08 kg) was born with bilateral microphthalmia, cleft palate, and cornea1 opacities. The infant died at 10 weeks of age and autopsy demonstrated further abnormalities including thoracic kyphosis, hypoplasia of the thyroid and ovaries, acute bronchopneumonia, glossitis, gastritis, entero-colitis, and lymphadenitis. Focal nephritis, glomerulitis, adrenal cortical degeneration, and skeletal muscle degeneration were also noted. The authors contributed the anomalies to busulfan. However, the contribution of both radiation and 6-mercaptopurine to these birth defects cannot be ruled out. At least one other author has also reported anomalies following the use of busulfan during first trimester pregnancy. Abramovici et al. report fetal anomalies including myeloschisis (dysraphia-persistence of the neural groove beyond the neurula stage) in a six-week old embryo following the use of busulfan 2 mg/day (total dose = 90 mg) in a 39-year old women treated for chronic lymphatic leukemia 1481. Although these case studies suggest a possible role of busulfan in the development of several types of birth defects, there is clearly not enough information available to conclude that busulfan cannot be used safely in pregnancy. Since anomalies occurred in both cases following the use of busulfan in the first trimester, avoidance of busulfan during this period may help to reduce the risk of birth defects. 4.1.2. Cisplatin 4.1.2.1. Clinical pharmacology. Cisplatin is an eleven atom inorganic cis-isomer of platinum which is commonly used in the treatment of ovarian cancer. It is also active in other malignancies noted in women of child bearing age including cervical cancer and melanoma. Cisplatin inhibits the growth of cancer cells by inducing interstrand crosslinks in DNA. administration, Following cisplatin rapidly distributes into most tissues [49-511. It also distributes into 3rd spaces including ascites and pleural fluid [52,53]. Amniotic fluid may therefore act as a reservoir for drug retention extending the elimination halflife of the drug. Cisplatin is excreted in both its unchanged and

80

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Table 2 Summary of busulfan use in pregnancy Disease Reference

Patient age (years)

Gestational age (weeks)”

Drugs used during gestation dose/schedule/(T, total dose)

Maternal outcome

Fetal outcome

Infant followup

CML [39]

28

Conception

Busulfan 6mg/day, weeks l-4, Busulfan 2 mg/day x 8 days (week 5). Post delivery chemo.

Remission (time - N.S.)

Normal, M 2.3 kg, S.D. at 38 weeks

Diarrhea, fever, anorexia at 4 weeks, death at I month from staph. infection

CML [40]

24

Conception

Busulfan 2 mg/day x 3 weeks (weeks l-3), Busulfan 2 mg EOD (weeks 4-27)

Remission (time - N.S.)

Normal ‘fullterm’

N.S.

CML [4l]

34

N.S.

Busulfan (doses radiation

N.S.).

Remission > 5 years

Spontaeous abortion at 4 months

N.S.

CML [41]

27

N.S.

Busulfan (doses radiation

N.S.), &MP,

Death 3 days post-partum

Premature 4.5lbs

N.S.

CML [41]

21

N.S.

Busulfan (doses radiation

N.S.),

Living 4 years post-partum

Normal S.D. at 40 weeks

N.S.

CML 1411

32

N.S.

Busulfan (doses - N.S.), radiation, (*I st pregnancy)

Living

Normal S.D. at 39 weeks

N.S.

CML [41]

32

N.S.

Busulfan (doses - N.S.), radiation, (*2nd pregnancy of above patient)

Death 4 years post-partum

Normal S.D. at 38 weeks

N.S.

CML [92]

31

lst, 3rd trimester

Busulfan 4-6 mg/day in Ist, 3rd trimester

N.S.

Normal, M 2.44 kg S.D.

Normal at I year

CML [43]

31

Conception

Busulfan 1 mg twice weekly, (conception to 5 months)

Complete remission

Normal, M 3.49 kg SD.

Normal at I I months

Chronic granulocytic leukemia 1441

29

8 weeks

Busulfan 2-4 mg/day throughout pregnancy

Death 5 weeks post-patrum

Normal, M 2. I8 kg, C-set, Mild anemia, neutropenia

Monocytosis x 2 months. Normal partum at 4 months

Chronic granulocytic leukemia [45]

27

Conception to 8 weeks

Busulfan 2-6 mg/day (T = 204 mg)

Remission (time - N.S.)

Normal F 3.9 kg S.D.

Normal at 4 months

Chronic granulocytic leukemia 146)

29

Conception

Busulfan l-6 mg/day throughout pregnancy

Death 5 months postpartum

Normal S.D. at 39 weeks M - 2.4 kg

Slow growth at 39 months

Chronic granulocytic leukemia [47]

39

1st. 2nd, 3rd trimester

Busulfan 4-6 mg/day at 8 weeks, radiation 200 rads at 4 weeks, 6-MP 100 mg/day x 1 month, (conception to 1st trimester), 6-MP 125 m&day at 9 months gestation

Death 2 months postpartum

Multiple anomalies, - 1.08 kg, C-sec., microphthalmia, cleft palate

Death at 2 months

N.S., not stated; SD., spontaneous delivery; M, male; F, female; CML, chronic myelogenous leukemia; 6-MP, bmercaptopurine. “Gestational age at which time mother received chemotherapy.

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chemically altered form by glomerular filtration and renal tubular secretion (541. The increase in glomerular filtration rates seen in pregnant patients may have the effect of increasing platinum elimination. Cisplatin has been reported to penetrate into breast milk (551. However, it does not appear to readily penetrate into the cerebrospinal fluid or brain [56,57]. Although penetration of platinum across the bloodplacental barrier has not been evaluated in humans, animal studies indicate that cisplatin readily penetrates the blood-placental barrier, and can be measured in a variety of fetal tissues. Studies performed in mice demonstrate that platinum crosses the blood-placental barrier in a gestational stage dependent manner [58]. Following intraperitoneal administration of radiolabeled cisplatin (10 mg/kg) to mice on days 10, 11, and 12 of gestation, only small amounts of platinum are initially detected in embryos (< 1%). However, if administered at 13 days of gestation approximately (14%) of the applied radiolabel was noted in fetal tissues with increasing amounts of cisplatin detected in the fetal compartment with time up to day 17. At day 17 more drug is found in the fetus then maternal liver and kidneys. The authors suggest that the increased penetration of cisplatin across the more mature placenta may be due to a carrier mediated transport process [58]. 4.1.2.2. Pharmacokinetics. The pharmacokinetics of platinum remain to be evaluated in pregnant patients. In non-pregnant patients the terminal halflife is 58-73 h. The prolonged terminal halflife of platinum is probably associated with release of protein bound drug. Clearance of the unbound drug is dependent on a variety of factors including renal clearance, degree of tissue and protein binding, and the presence of third spaces. Residual unbound platinum concentrations have been detected following high dose cisplatin administration which may represent prolonged (> 24 h) elimination of active platinum species in humans [59]. Cisplatin is approximately 90% protein bound with the active fraction being maintained in the non-protein bound fraction (601.The increase in plasma proteins noted in pregnancy may have the effect of reducing the amount of unbound active drug available to the tumor. Due to the significant influence of protein binding and renal clearance on cisplatin pharmacokinetics the kinetics may be substantially altered in pregnant patients with both increased renal clearance of compounds, altered protein binding and third spacing due to the amniotic fluid compartment. 4.1.2.3. Adverse effects on fetus. Cisplatin is teratogenie in a number of animal species. In mice and rats it causes skeletal malformations and fetal resorptions [61,62]. Gestational stage dependent neuroepithelium necrosis has also been reported in mice [63]. In chicken embryos, cisplatin frequently produces microphthalmia if administered in the early stages (days 4-6) of develop-

81

ment. Brain necrosis, liver damage and destruction of the germ cell line occurs with cisplatin exposure in later stages [64]. Little information exists regarding the use of cisplatin during pregnancy in humans. Several case reports are available. Jacobs et al. report the use of a single intravenous dose of cisplatin 50 mg/kg, in a pregnant patient at 10 weeks gestation for the treatment of carcinoma of the cervix [65]. Two weeks following chemotherapy a radical hysterectomy was performed with no apparent abnormalities noted in the fetus. However, the time between cisplatin administration and surgery (2 weeks) may not have been sufficient to conclude that cisplatin had no effects on the fetus. Malfetano et al. report a normal infant born following administration of a cisplatin containing regimen in a 28-year old pregnant patient diagnosed at 16 weeks gestation with ovarian carcinoma. The patient received seven cycles (every 21 days) of cisplatin (50 mg/m2) and cyclophosphamide (750 mg/m2) until the induction of labor at 37-38 weeks gestation. A healthy 3275 g male was delivered without any neurodevelopmental or organ abnormalities [66]. In a third case report, Malone et al. report the use of cisplatin in combination with vinblastine and bleomycin in a 25-year old pregnant patient with endodermal sinus tumor at 25 weeks gestation. Following two courses of chemotherapy, a healthy male infant was delivered by C-section at 32 weeks which was found to be normal at a 12 month followup 1671. King et al. also report the use of cisplatin (100 mg/m2) in combination with cyclophosphamide (600 mg/m2) (5 courses) for the treatment of epithelial ovarian carcinoma in a 24-year old female starting after 15.5 weeks gestation [68]. During admission for her 6th course of chemotherapy at 36.5 weeks gestation, spontaneous rupture of her membranes occurred, and she delivered a 3060 g male infant. No myelosuppression or apparent anomalies were reported. The infant required respiratory support at 24 h of age but continued to develop normally without evidence of physical or mental impairment. Although these case reports suggest that cisplatin has been administered safely in second and third trimester pregnancy, the risk of cisplatin-induced toxicities and teratogenic effects is still unknown; The stage dependent teratogenic effects of this agent in animals suggests that teratogenic effects begin to occur during the 12th day of gestation which corresponds to the end of neurulation (day 9), and the beginning of active morphogenesis (day 7-19) (69,701. In humans, neurulation occurs during the third week of gestation and morphogenesis occurs during the 1l-12th week 1711,until further experience has been obtained using this drug in pregnancy, institution of cisplatin particularly during these stages of pregnancy should be carefully considered.

82

4.1.3. Cyclophosphamide 4.1.3.1. Clinical pharmacology. Cyclophosphamide

is used in the treatment of breast cancer, leukemia, ovarian cancer, Hodgkin’s and non-Hodgkin’s lymphoma, neoplasms which are often found in young women. Cyclophosphamide is an inactive prodrug which must undergo enzymatic activation. The inactive parent drug is converted by hepatic microsomal enzymes to reactive intermediates (4-hydroxycyclophosphamide, phosphoramide mustard and nornitrogen mustard). 4-Hydroxycyclophosphamide plays a major role in the antineoplastic effects of cyclophosphamide [72]. The reduced oxidative metabolism capacity of the fetus may limit the conversion of the inactive parent compound to the active 4-hydroxy metabolite. The cyclophosphamide parent compound may therefore accumulate in fetal tissues or may be metabolized by alternative metabolic routes. Plasma protein binding of cyclophosphamide is low (12-24%). However, the alkalating metabolites are bound more tightly (50%) [73]. The elevated plasma protein concentration in maternal blood is not expected to have much of an effect on cyclophosphamide protein binding since both it and its metabolites are only moderately protein bound. Following administration to non-pregnant patients, cyclophosphamide distributes into a volume roughly equivalent to 60% body weight (0.4-0.5 l/kg) [74]. Cyclophosphamide easily penetrates most membranes and has been measured in CSF, ascites fluid and other fluids; CSF concentrations are 43 to 85% of plasma concentrations, although alkalating activity is only 28% of that noted in plasma (751. Although it has not been measured in fetal tissues or amniotic fluids it should be assumed to readily penetrate into these tissues. Although placental transfer has not been evaluated in humans it has been examined in mice. In mice, cyclophosphamide crosses the placenta more readily than its alkalating metabolites [76]. The induction or inhibition of cytochrome P450 oxidative enzymes has a profound effect on the placental transfer of the parent compound but not the metabolites. When P450 inhibitors are given prior to cyclophosphamide administration there is an increase in the placental transfer of cyclophosphamide. On the other hand, P450 inducers decreased the concentration of cyclophosphamide found in embryos. Cyclophosphamide has also been reported to cross into breast milk in significant concentrations. Wiernik et al. report that cyclophosphamide may be detected in breast milk up to 6 h after a single 500 mg intravenous dose [77]. Cyclophosphamide has also been reported to produce neutropenia and thrombocytopenia in breast fed infants [78,79]. 4.1.3.2. Pharmacokinetics. The pharmacokinetics of cyclophosphamide have not been examined during pregnancy. The halflife of elimination of cyclophosphamide

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is approximately 9 h in non-pregnant patients [80]. In general, liver dysfunction may significantly prolong the halflife of cyclophosphamide and decrease total body clearance, leading to drug accumulation [81]. However, patients with liver dysfunction may experience fewer side effects suggesting that impaired metabolic pathways may reduce toxic metabolite production [81]. In pregnant patients, the effects and degree of altered liver metabolism of cyclophosphamide are unknown. However, increased renal elimination of cyclophosphamide would be expected in pregnancy resulting in an increased clearance rate of drug. 4.1.3.3. Adverse effects on fetus. Cyclophosphamide is highly teratogenic in a number of animal models including mice, rats, and rabbits [82,83]. In rats cyclophosphamide (7-10 mg/kg) administered on the 1lth or 12th day of gestation produces predictable teratogenic effects including exencephaly, cleft palate and appendage malformations [83]. In mice multiple skeletal defects, exencepathy and aphakia have been reported [82]. Interestingly, the teratogenic effects of cyclophosphamide in mouse embryos is increased following P450 inhibition, suggesting that the parent compound may exert its own teratogenic effects by mechanisms other than alkalation or that cyclophosphamide may be metabolized to other non-detectable metabolites that are teratogenic. The teratogenic effects of a number of cyclophosphamide metabolites have been studied and appear to differ in spectrum to those noted following cyclophosphamide administration [76]. In humans, cyclophosphamide has unpredictable effects on the fetus (Table 3). The extent to which cyclophosphamide has been directly associated with teratogenic effects is complicated by the concurrent use of other teratogenic agents such as radiation in many cases. Greenberg et al. report multiple congenital anomalies in an infant born to a patient receiving cyclophosphamide single agent therapy for the treatment of Hodgkin’s disease. The 21-year old mother had received radiation therapy (3182 rads to the mediastinum and 3690 rads to the neck) just prior to conception. The patient then received cyclophosphamide 50 mg orally twice daily for 43 days, starting about the time of conception. She then received cyclophosphamide 162 mg (2.5 mg/kg) intravenously for 5 days and an additional 1000 mg on the sixth day. One week later she began cyclophosphamide 100 mgday which she continued through the entire pregnancy. At 38 weeks gestation she spontaneously delivered a male infant (1.93 kg) with anomalies including; four toes on each foot with varying sizes, a groove extending to the uvula on each side of the hard palate, flattened nasal ridge, abdominal skin tags, hypoplastic middle phalanx of the fifth finger, bilateral inguinal hernia sacs and wide heals. At a one year followup the child had incomplete ossification of the

V.J. Wiebe, P. E.H. Sipila / Crit. Rev. Oncol. Hematol. 16 (1994)

75-I I2

83

Table 3 Summary of cyclophosphamide use in pregnancy Disease (reference)

Patient age (years)

Gestational age (wceks)a

Drugs used during gestation dos&chedule/(T, total dose)

Maternal outcome

ALL [84]

18

12.5

CY 100 mgm2/day x 2 weeks, (T = 1.4 g/m2), VCR 2 mg x 4 weeks (T = 8 mg), MTX IO mg IT x 2 (T = 20 mg) ~-Asp 6000 u/m2 3/week x 5 weeks, (T = 90 000 u/m2), Dauno 60 mg/m2/day x 2 days (T = 120 mg/m2), PDN 60 mg/m2/day x 4 weeks (T = 1.68 g/m2), 6MP 60 mg/m2/day x 4 weeks (T = 1.68 mg/m2) CNS radiation 2400 rads

Remission x 20 months

Fetal outcome

development. F-2.4 kg Severe bone marrow hypoplasia plasia

Infant followup

Normal at 12 months

ALL [SS]

32

I7

CY 300 mgweek (T = 4.8 g). VCR 2 mgweek x 4 (T = I6 mg), PDN 40 mgday x 4 weeks (T = 2.24 g), ~-Asp 14 000 u, EOD x 7 (T = 196 Ooo u), Dox 50 mg, day I (T = 100 mg), MTX 30 mgweek (T = 480 mg), 6-MP 75 mgday (T = 8.325 g)

Remission x 8 months

Normal, F 3.2kg, S.D. at 38 weeks

Normal development at 40 months

ALL [86]

24

1,2,3rd trimester

CY (T = 25 g), VCR (T = 48 mg), MTX (T = I g), 6-MP (T = 18.3 g), PDN (T = 7.6 g), Ara-C (T = 3.5 g)

Partial remission, died I6 months after childbirth

Normal, F 2.3 kg S.D. at 40 weeks

Alive at 6 years

ALL [86]

18

I ,2,3rd trimester

CY (T = 5 g), Ara-C (T = 1.6 g), PDN (T = 3.8 g), 6-MP (T = 250 mg), VCR (T = 24 mg), MTX(T = 600 mg)

No response to treatment, died 5 months after childbirth

Pancytopenic, C-set at 34 weeks

Died from septicemia at 21 days, normal karyotype

ALL (861

28

1,3rd trimester

CY(T=3.15g),MTX(T=725 mg), 6-MP (T = 3.15 g)

Complete remission

Normal, M 3.0 kg, induced labor

Alive at 7 years

ALL [87]

34

22

CY 650 mg/m2; days 29,43,57, Ara-C 75 mg/m2 4 x day x 4 days, Dauno 25 mg/m2, VCR 1.5 mg/m2; days 1,8,15,22, PDN 60 mg/m2/day; days l-28, ~-Asp 5000 ulm2/day; days 15-28, MTX 20 mg/m2/week, MTX IO mg/m2; days 31,38,45,52, 6-MP 60 mg/m2; days 29-56; then q week, Crania1 radiation (24 Gy)

Complete remission (time, N.S.)

Normal F, S.D. at 40

Chromasomal gaps and rings found on karyotyping

ALL [88]

32

I6

VCR Dox (doses - N.S.) PDN ~-Asp Maintenance: CY&MP,MTX VCR,PDN, discontinued 2 weeks prior to delivery

ALL [IZ]

29

1st trimester

CY q month x 9 months, PDN q month x 9 months, (doses N.S.)

F-3.8 kg. slight leukopenia

Remission, death at 21 months postdelivery

Twins F 1.49 kg, M 1.30 kg, S.D. at 37 weeks, multiple anomalies in male

Normal, development, wbc counts normal at 2 weeks

Female normal at 17 years, male with multiple anomalies

V.J. Wiebe, P.E.H. Sipila/Crit.

84

Rev. Oncol. Hematol. 16 (1994)

7.5-112

Table 3 (Continued) Disease (reference)

Patient age (years)

Gestational age (weeks)’

Drugs used during gestation dose/schedule/(T, total dose)

Maternal outcome

Fetal outcome

Infant followup

AML (121

30

18

Doxo (doses - N.S.) 3 cycles, Ara-C 3 cycles, maintenance: monthly; CY, Ara-C, VCR

Complete remission

Normal, M 2.51 kg. S.D. at 34 weeks

Normal development, growth, at 7 years

AML 1121

32

23

Dauno (doses - N.S.) 2 courses, Ara-C 2 courses, PDN 2 courses, Maintenance: CY, VCR, 6TG. PDN x 3 months

Partial remission

Normal, M 3.43 kg, induced labor at 39 weeks

Normal growth intellect at 12 years

Non-Hodgkin’s lymphoma [89]

25

Conception

CY 700 mg/m*)(T = 1.4 g/m*), Dox 45 mg/m2 (T = 90 mg/m*), VCR 2 mg, day 1 (T = 4 mg), PDN 100 mg, day l-5 (T = 500

N.S.

Normal, M 3.4 kg, SD. at 38 weeks

Normal at 2 months

mg) Non-Hodgkins lymphoma [90]

26

18

CY, Doxo, VCR, MTX, bleomycin, PDN, (full MACOP-B doses given weekly)

Excellent response

Normal twin males, C-set at 28 weeks

N.S.

Hodgkins lymphoma [91]

21

18

CY 1 g days 1 + 8 (T = 7 g). VCR 21 mg days 1 + 8 (T = 14 mg), Procarbazine 150 mg days I-14, (T= 7.35 g), PDN 74 mg days 15-28 (T = 3.15 g)

Relapse at one year

Normal, F 2 kg S.D. at 37 weeks

Normal at 1 year, normal karyotype

Hodgkins lymphoma [92]

21

1st trimester

CY 50 mg bid x 43 days, CY 162 mg/day x 5 days, CY 1000 mg x 1, CY 100 mg/day - continued through out pregnancy

Partial remission, death at 8 months postdelivery

Multiple anomalies, M 1.93 kg, SD. at 37 weeks

Incomplete ossification of the phalanges bilaterally

Hodgkin’s disease [93]

23

1st trimester

CY (560 mg/day x 4 days), CY (100-150 mg/day x 2 months), Radiation to chest, abdomen, pelvis

N.S.

Multiple anomalies M - 470 g, Elected abortion at 6 months

Toe and cardiac anomalies on autopsy

Breast cancer

33

10.5

CY (T = N.S.), Dox (T = 420 mg), 5-FU (T = N.S.), 6 courses q 3 weeks, then: CY, MTX, 5-FU (T = N.S.)

Remission x 2.5 years

Normal, F 2.26 kg, C-set at 34.5 weeks

Normal develop ment at 24 months

33

2.0

CY (T = 2.1 g), Dox (T = 325 mg), Radiation (T = 8800 rads)

N.S.

Multiple anomalies F 2.98 kg S.D. at 39 weeks

Small in size, no other anomalies at 1.5 years

Ewings sarcoma (961

21

25

CY (T = N.S.), dactinomycin (T = N.S.), Dox, bleomycin, VCR (T = N.S.), Post-delivery chemotherapy, radiation

Remission > 4 years

Premature, F - 1.75 kg, Cset at 34 weeks

Respiratory support, calcium, required after birth, normal at I month

Endodermal tumor of the ovary 1971

24

17

CY 600 mg/m2 q 4 weeks x 5, VCR2mgq4weeksx5+2 mg x 3, Dox 45 mg/m2 q 4 weeks x 5, post-delivery chemotherapy

Remission (time N.S.)

Normal, F, induced labor 37 weeks

Normal at 1 year

P4

Breast cancer

I951

V.J. Wiebe, P. E. H. Sipila / Crit. Rev. Oncol. Hemarol. 16 (1994)

85

75-112

Table 3 (Continued) Disease (reference)

Patient age (years)

Gestational age (weeks)a

Drugs used during gestation dose/schedule/(T, total dose)

Maternal outcome

Fetal outcome

Infant followup

Endodermal sinus tumor t981

25

16

CY 200 mglday x 5 day q 4 weeks (T = 6 g), VCR weekly x 12 weeks (T = 26.4 mg), actinomycin D 0.5 mg q 4 weeks, - post-delivery chemotherapy

Complete response > 33 months

Normal, M 2.85 kg SD. at 37 weeks

N.S.

N.S., Not stated, S.D., spontaneous delivery; C-set, cesarean section; M, male; F, female; ALL, acute lymphocytic leukemia; AML, acute myelocytic leukemia; Ara-C, cytarabine; CY, cyclophosphamide; VCR, vincristine; MTX, methotrexate; ~-Asp, L-asparaginase; Dauno, daunorubicin; Dox, doxorubicin; PDN, prednisone; 6-MP, 6-mercaptopurine. aGestational age at which time mother received chemotherapy.

phalanges bilaterally, but development was otherwise normal. The child also had a normal karyotype [92]. Toledo et al. also report anomalies of the toes, in addition to cardiac anomalies in a fetus whose mother received cyclophosphamide for Hodgkin’s disease [93]. The 23-year old, mother had received roentgenologic procedures to the chest, abdomen and pelvis at 2-5.5 weeks gestation and cyclophosphamide starting at 6.5 weeks gestation. She received cyclophosphamide 560 mg iv. daily for 4 days, then lOO- 150 mg/day for a 2-month period. At 6 months gestation an elected abortion was performed with hypertonic saline with the passage of a male fetus. The fetus weighed 470 g and had absence of toes on both feet, although metatarsals were present. In addition, autopsy showed only a single left coronary artery. The anomalies in this case may have resulted from radiation, although the contribution of cyclophosphamide to these anomalies remains unknown. In a third case report multiple anomalies including imperforate anus and rectovaginal Iistula were reported in a female infant born following maternal exposure to cyclophosphamide (total dose 2100 mg), radiation (total dose 8800 rad) and doxorubicin (total dose 325 mg) starting at 2 weeks gestation for breast cancer [95]. In addition, the infant had a P2 heart sound and holosystolic murmur 6 days after delivery. Followup at 1.5 years found the infant to be small in size but without further anomalies. Reynoso et al. report the use of cyclophosphamide in three pregnant patients [12]. In both cases where cyclophosphamide combination chemotherapy was administered after the 1st trimester of pregnancy the infants were normal [ 121. However, administration during the first trimester resulted in anomalies in a twin pregnancy. In this case, the mother had received monthly courses of oral cyclophosphamide and prednisone for 9 months starting in the first trimester of pregnancy for acute lymphocytic leukemia. She had previously achieved complete remission two months prior to this therapy with

aminopterin, 6-mercaptopurine, vincristine and prednisone. A normal female infant (1.49 kg) and a male infant (1.3 kg) with multiple anomalies were spontaneously delivered at 37 weeks gestation. The male infant had multiple anomalies including deformities of the upper extremity (paraaxial hemimelia, absent thumb, hyperflexion of the wrist), esophageal atresia, and an anomalous inferior vena cava, undescended testicles and duplication of the collecting systems of both kidneys. At an 11-year followup he had learning problems, a low intelligence quotient and a cold thyroid nodule. At 14 years of age he was diagnosed with a neuroblastoma arising from the adrenal gland and at 16 years biopsy disclosed metastatic papillary thyroid cancer. Although many other case reports have resulted in normal infants born to mothers exposed to cyclophosphamide there appears to be enough evidence to suggest that cyclophosphamide may at least in part be associated with a risk of teratogenic effects in human fetuses. The use of concurrent or prior radiation exposure during the first trimester of pregnancy may increase the risk. Large doses and daily dosing for extended periods may also increase the associated risk. The use of P450 inhibitors which further suppress the oxidative metabolism of the growing fetus should also be avoided prior to cyclophosphamide administration. 4.2. Antimetabolites 4.2.1. Ara-C 4.2. I. 1. Clinical pharmacology. Cytosine arabinoside (Ara-C) is commonly used in remission induction therapy for acute leukemia and lymphoma. Both diseases are found in women of child bearing age. Ara-C is an inactive arabinoside nucleoside derivative that undergoes intracellular activation to its 5’ triphosphate (ara-CTP) metabolite. Three enzymes have been reported to be involved in this conversion including deoxycytidine kin-

86

ase, deoxycytidylate kinase and nucleoside diphosphate kinase. At this time little is known concerning the activity of these enzymes in the fetus. Ara-C uptake into cells uses the same carrier mediated process used in the cellular uptake of deoxycytidine. It would therefore be assumed that Ara-C would also be readily taken up by fetal cells. Ara-C is metabolized in the liver, kidneys and red blood cells by cytidine deaminase to uracil arabinoside. In addition, it is metabolized by deoxycytidine kinase to Ara-CMP which is further metabolized into Ara-UMP, Ara-CDP and ultimately to Ara-UTP and Ara CTP. Ara-CTP inhibits DNA synthesis by competitive inhibition of DNA polymerases [99]. Cytotoxic activity of Ara-C is dose and schedule dependent. High concentrations of ara-C (1 &ml) are lethal to cells, while concentrations of < 0.1 &ml inhibit DNA synthesis but are much less cytotoxic [loo]. 4.2.1.2. Pharmacokinetics. Following administration in normal patients ara-C distributes into intracellular of distribution with a volume compartments approximately equal to total body water [loll. Its volume of distribution should therefore be substantially increased in the pregnant patient. Ara-C is rapidly cleared from plasma, however the active ara-CTP metabolite is retained intracellularly. Approximately 13-42% of ara-CTP is retained intracellularly 4 h after ara-C administration. Accumulation of ara-C does not appear to occur even after successive doses in nonpregnant patients, suggesting no saturation of deaminase enzymes occurring within the dose range of l-3 g/m2. However, since the deaminase activity of the fetus is unknown, saturation of the enzyme system with a resulting accumulation of drug may or may not occur in fetal tissues. Initial and terminal halflives (7.6- 15.6 min and 2.3-2.6 h, respectively) are approximately the same at low dose (100 mg!m2) and high dose (3 g/m2). Approximately 80% of an ara-C dose is eliminated 36 h after administration with the majority of the dose being excreted as ara-U [ 102). Ara-C is’approximately 13% protein bound and readily penetrates the blood brain barrier. CSF concentrations rise linearly with increasing doses (l-3 g/m2) and are 6-22% of the corresponding ara-C plasma concentrations. CSF concentrations of 0.35-1.07 &ml have been reported with a halflife of 2 h (1031. Although placental transport of ara-C has not been measured in the human fetus, ara-C would be expected to readily penetrate the blood-placental barrier. Concentrations reaching the fetus may also be dose dependent although it remains to be studied. 4.2.1.3. Adverse effects on fetus. Ara-C inhibits DNA synthesis and may cause chromasomal breaks. It has been shown to be highly teratogenic in animals. Following administration of Ara-C (10 mg/kg) to pregnant rats (days 9-12 of gestation) it produced a high fetal mortali-

V.J. Wiebe, P.E. H. Sipila / Crir. Rev. Oncol. Hemalol. 16 (1994) 75-112

ty and anomaly rate (1041. Fetal limb malformations have been noted following its use in animals. In an in vitro mouse limb development assay, ara-C was shown to alter ectodermal-mesenchymal interactions of limb buds resulting in adactylous limbs [105,106]. Ara-C has been used extensively in combination chemotherapy for the treatment of leukemia in pregnancy (Table 4). It has been used safely in second and third trimester pregnancy, but has resulted in several cases of fetal anomalies when used during the first eight weeks of gestation [10&l 161. In addition, chromasomal aberrations have been reported following its use throughout pregnancy [87,123]. Both chromasomal damage and teratogenic effects appear to be unpredictable. This is best demonstrated by several cases where pregnancies in the same patient resulted in variable outcomes after receiving similar cytotoxic treatment in consecutive pregnancies. Maurer et al. noted trisomy C in one aborted fetus following the use of ara-C (100 mg/m2, i.v.) and thioguanine (2.5 mg/kg, p.o.) during a second trimester pregnancy, however, following abortion of a second fetus in the same patient 6 months later there was no sign of chromasomal abnormalities, although the patient had continued to receive maintenance doses of both ara-C and thioguanine [123]. Schafer et al. report multiple skeletal anomalies in an infant born following the continuous use of ara-C (80 mg SQ bid) and thioguanine (60 mg bid x 5 days/month) in a 22-year old pregnant patient with acute myelocytic leukemia, but a second pregnancy using the same drugs and doses given in the first two months of pregnancy resulted in a normal infant [116] (Table 4). Birth defects in the first infant included absence of the medial digits on both feet and absence of the distal phalanges of both thumbs with a hypoplastic remnant of the right thumb. However, upon chromosome analysis, growth and development were found to be normal at 16 months. Plow et al. report fetal toxicity in one of two pregnancies following ara-C and thioguanine administration. In the first pregnancy, a 25year old female at 22 weeks gestation was given ara-C (200 mg q 12 h x 8 days) and 6thioguanine (160 mg q 12 h x 8 days). Intrauterine fetal death occurred 14 days after chemotherapy. Spontaneous delivery of a lacerated fetus occurred 6 days later, although the fetus was otherwise normal. In the second pregnancy the mother received ara-C (200 mg/day x 5 days; at week 16), ara-C (300 mgday x 5 days; week 32) and thiognanine and a normal female (3.13 kg) was delivered by caesarean section at 39 weeks gestation. Again suggesting the unpredictable effects of this combination on the fetus [119]. Although thioguanine is also known to be teratogenic and may be a factor in the teratogenic and toxic effects in the cases above, ara-C has also been reported to produce teratogenic effects as a single agent. Wagner et al.

V.J. Wiebe, P.E. H. Sipila / Crit. Rev. Oncol. Hematol. 16 (1994)

87

75-11.2

Table 4 Summary of cytosine arabinoside use in pregnancy Disease (reference)

Patient age (years)

Gestational age (weeks)”

Drugs used during gestation dose/schedule/ (T, total dose)

Maternal outcome

Fetal outcome

Infant followup

ALL [IO?]

24

15

Ara-C 100 m&m2 bid, days l-7, 6-TG 100 mg/m2 bid, days l-7 Dauno 60 mg/m2/day, days 5.6.7 allopurinol 100 mg TID, postdelivery chemo.

Remission > 6 months

Death following preeclamptic toxemia

No congenital abnormalities at autopsy

ALL 1871

34

22

Ara-C 75 mg/m2 4 x day x 4 days, MTX IO mg/m2; days 31,38,45,52, Dauno 25 mgm’. VCR 1.5 mg/m2; days 1,8,15,22. PDN 60 mg/m?day; days l-28, ~-Asp 5000 u/m2/day; days 15-28, CY 650 mg/m2; days 29,43,57 MTX 20 mg/m2/week, 6MP 60 mg/m2; days 29-56; then q week, cranial radiation (24 Gy)

Complete remission (time - N.S.)

Normal, F, SD. at 40 weeks

Chromasomal gaps and rings found on karyotyping

ALL (108)

19

4.8 weeks

Ara-C x 4 days q months at 4.8 weeks (T = N.S.)

Continued remission (time - N.S.)

Multiple anomalies, M - 2.86 kg S.D. at 39 weeks, ear. appendage anomalies

Normal motor development at 10 months. normal karyotype

ALL [lO9]

21

Conception

Maintenance: 6-MP 150 mg/day, paramethasone 18 mgday, at 8 weeks gestation: weekly Ara-C. VNC, PND. Dauno, (dose = N.S.)

No response, death at 23 weeks gestation

Normal placenta, fetus at autopsy

N.S.

ALL (861

37

2.3rd trimester

Ara-C (T = 1.4 g), VCR (T = 16 mg). PDN (T = 3 g). 6-MP (T=4 g). MTX (T = 600 mg)

Complete remission, death at 5 months postdelivery

Normal. F 2.4 kg, S.D. at 38 weeks

Death at 90 days of age from gastroenteritis

ALL [86]

24

1,2,3rd trimester

Ara-C (3.5 g), MTX (T = 1.0 g), CY (T = 25 g), 6-MP (T = 18.3 g), PDN (7.6 g), VCR (T = 48 mg)

Partial remission, death 16 months postdelivery

Normal. F 2.3 kg, S.D. at 40 weeks

Normal at 6 years

ALL 186)

18

1,2,&d trimester

Ara-C (T = 1.6 g), VCR (T = 24 mg), PDN (T = 3.8 g). 6-MP (T = 250 mg). MTX (T = 600 mg), CY (T = 5 g)

Active disease, death 5 months postdelivery

Pancytopenic, M-l.Okg C-W at 34 weeks, septicemia

Death at 2) days of age from septicemia

AML 1861

27

3rd trimester

Ara-C(T=1.2g),PDN(T=lso mg), VNC (T = 2 mg)

Partial remission, death 2 months postdelivery

Normal. F 3 kg, S.D. at 38 weeks

Normal at 2 months

AML [I 10)

20

30

Ara-C 100 mgIm?day x 10 days (T = 3 g). VNC day I, PND 100 mg/day x IO days (T = 3 g),

Remission > 30 months

Normal, M 2.97 kg, induced labor at 39 weeks

Normal development at 30 months, normal karyotype

3 courses

V.X Wiebe. P. E.H. Sipila / Crit. Rev. Oncol. Hemarol. 16 (1994) 75-112

88 Table 4 (Continued) Disease (reference)

Patient age (years)

Gestational age (weeks)’

Drugs used during gestation dose/schedule/ (T, total dose)

AML [12]

21

25

Ara-C (doses - N.S.) Dauno, maintenance: 6-TG Ara-C, BMT at 13 months

Maternal outcome

Fetal outcome

Infant followup

x I3 months, death at I6 months

Premature M - I.0 kg, S.D. at 29 weeks, iris adhered to cornea

Normal growth, at 3 years

AML [IO91

23

26

Ara-C 80 mgday x 3/week (3 cycles), Dauno 40 mg/day/week (3 cycles), Ara-C 160 mgday x 3/week

Death 4 months postdelivery

Normal, M 2.66 kg, S.D. at 39 weeks

Normal at 9 years, normal karyotype

AML 112)

32

23

Ara-C (dose - N.S.) 2 courses, Dauno (dose - N.S.) 2 courses. PDN (dose - N.S.) 2 courses, maintenance: CY, VCR, 6TG, PDN x 3 months (dose - N.S.)

Partial remission (time N.S.)

Normal, M 3.43 kg, induced labor at 39 weeks

Normal growth, intellect at I2 years

AML [I I I]

23

17

Ara-C 100 mg/m’/day x 7 days, (T = 2.2 g), 6-TG 100 mg/m2/day x 5 days, (T = 1.5 g/m’), Dauno 45 mgrn’, days 1-3 (T = 135 mg/m2), given every 4 weeks

Remission

Normal, M 2.9 kg, induced labor at 40 weeks

Normal development, bone marrow, cytogenetic analysis, ECG

AML [I121

36

24

Ara-C 60 mg bid x 5 days, (T = 1.2 g), Dauno 90 mg (T = 180 mg), DOX 90 mg (T = 180 mg), 6-TG 160 mg bid x 7 days (T = 4.5 g)

N.S.

Normal, F 2.0 kg, SD. at 32 weeks

Normal development at 13 months

AML (851

16

16

Ara-C 160 mgday x 4 days, (T = 640 mg), VCR 2 mgweek (T = 2 mg), PDN 100 mg/day (T = 1.2 g), Dox 65 mg day I (T = 65 mg)

Death I week after chemotherapy, no response to treatment

Spontaneous abortion prior to maternal death at 18 weeks

N.S.

AML [IO71

34

27

Ara-C 100 mg/m2 bid. l-7 days, (T= 1 g/m’) 6-TG 100 mg/m’ bid, l-7 days (T = I p/m2), Dauno 60 mg/m2/day, days 5-7 (T = 360 mg/m2), Allopurinol 100 mg tid, 3 courses at 21-day intervals

Remission > 6 months

Normal, M 5 kg, S.D. at 40 weeks

Normal development, blood count, karyotype at 6 months

AML [I131

24

24

Ara-C 160 mglday x 7 days (T = 2.24 g), Dauno 50 mgday x 3 days (T = 300 mg), 2 courses, post-delivery chemotherapy

Remission months

Normal, F 1.4 kg, C-set at 29 weeks

Perinatal seizures. pneumothorax, normal at 14 months

AML [I 141

27

12

Ara-C 140 mg24 h x 240 h (T = 700 mg), Dox 80 mg, day I (T = 400 mg) VCR 2 mg, day 1 (T=lOmg)PDN IOOmgdays l-5 (T = 2.5 g), 5 courses

N.S.

Normal, F 2.86 kg S.D. at 28 weeks

Normal development, karyotype at 6 weeks

x

x

7

2

V.J. Wiebe. P.E.H.

Table 4

Sipila / Crit.

Rev. Oncol.

Hemarol.

I6 (1994)

89

75-112

(Continued)

Disease (reference)

Patient age (years)

Gestational age (weeks)”

Drugs used during gestation dose/schedule/ (T, total dose)

Maternal outcome

Fetal outcome

Infant followup

AML [I 141

22

18

Ara-C 170 mg/24 h x 240 h. VNC 2 mg day I, PDN 100 mg/day x 5 days, consolidation: Ara-C 40 mg q 6 h x 5 days VNC 1 mg, day I PDN 100 mg x 5 days

Complete remission > 3 years

Normal, M 3.46 kg, C-set at 39 weeks

Normal at 4 years, normal karyotype

AML [I 151

23

27

Ara-C 100 mg/m* q 12 h x 5 days, (T = 4 g/m’) TG 80 mpim? q 12 h x 5 days (T = 3.2 g/m*). 4 cycles, post-delivery chemotherapy

Remission x 8 months. death II months post-delivery

Normal, F 1.43 kg, SD. at 35 weeks

Normal at I year, normal karyotype

AML [I 161

22

Conception

Ara-C 80 mg SQ bid, 6-TG 60 mg bid x 5 days q month. continued throughout pregnancy

Continued remission (time - N.S.)

Anomalies M - 2.21 kg. Cset at 38 weeks, multiple skeletal anomalies

Normal karyotype, development at I6 months

AML [I 161

23

Conception

Ara-C 80 mg SQ bid 6-TG 60 mg bid x 5 days q month, 2 cycles in 1st two months of pregnancy, Note: Same patient as above, same doses given in 1st. 2nd months

Continued remission (time - N.S.)

Normal. F 2.91 kg, C-see at ‘term’

Normal at 4 months

AML [I 171

22

26

Ara-C 200 mglday x 14 days. 6TG 160 mg/day x 14 days, maintenance: Ara-C 200 mg q week, 6-TG 120 mg/day x 5 days/week

Complete remission (time - N.S.)

Normal, M 3.54 kg. SD. at 39 weeks

Normal at I year, normal karyotypc

AML [IIS]

22

17

Ara-C 90 mp/m’ bid x 7 days, (T = 1.26 g/m*), Hydroxyurea 8 g (T = 8 g), Dauno 70 mg/m2/day X 3 days, (T = 210 mg/m2). VCR 1 mg/m*/day, days 1 + 7 (T = 2 mg/m2), 6-TG 90 mgim2 bid x 7 days, (T = 1.26 mg/m’). PDN 40 mg/m2/day x 7 days, (T = 280 mg) post-delivery chemotherapy, bone marrow transplant

Remission > 2 years

Elective abortion at 21 weeks

Normal fetus. 307.8 g, enlarged spleen

AML [I IS]

28

27

Ara-C 90 mp/m* bid x 7 days (T = 2. 52 g/m*), Dauno 70 mg/m2/day x 3 days. (T = 483 mg/m2), VCR 1 mgim*, day I + 7 (T = 4.6 mg/m2). 6-TG 90 mg/m? bid x 7 days (T = 2.9 g/m*). PDN 40 mg/m2/day x 7 days (T = 644 mplm2), 2 courses, 2nd course with 30”/~increase in doses

Disease progression, death 9 days postdelivery

Normal. M 2.13 kg, S.D. at 31 weeks, anemia, electrolyte imbalances

Normal development at 13.5 months. depressed growth

AML [12]

30

I8

Ara-C (dose - N.S.), Dox (dose - N.S.), maintenance: VCR, CY, Ara-C monthly cycles

Death 5 months post BMT

Normal. M 2.51 kg, S.D. at 34 weeks

Normal at 7 years

90

V.J. Wiebe, P. E. H. Sipila / Cd.

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Table 4 (Continued) Disease (reference)

Patient age (years)

AML [109]

20

AML [I 191

Gestational age (weeks)”

Drugs used during gestation dose/schedule/ (T, total dose)

Maternal outcome

Fetal outcome

Infant followup

8

Ara-C 480 mg x 3 (T = 1.44 g). Dox 40 mg (T = 40 mg), Dauno 40 mg x 3, VCR 2 mg x 4 (T = 8 mg), post-delivery chemotherapy

Complete remission X I I months, death I4 months post-delivery

Normal, F 2.8 kg, S.D. at 38 weeks

Normal at 7 years

25

22

Ara-C 200 mg q 12 h x 8 days, 6-TG 160 mg q I2 h x 8 days

Remission year

Fetal death I4 days post chemotherapy

No fetal abnormalities at autopsy

AML [I 191

25

I6

Ara-C 200 mgday x 5 days (week 16). Ara-C 300 mg/day x 5 days (week 32). Note: second pregnancy of above patient

Remission x I year, death 14 months postdelivery

Normal, F 3. I3 kg, C-set at 39 weeks

N.S.

ANLL [IO!?]

26

20

Ara-C (dose 6-TG

No response

Normal, M I.5 kg, S.D. at 32 weeks

N.S.

APL [I201

I8

21

Ara-C 100 mg/m2, days 1-9, Dox 70 mg/m2, days l-3, 6-TG 100 mgIm2, days l-9, PDN 40 mg/m2, days l-9, VCR I mg/m2, day I + 9, post-delivery chemotherapy

Remission > 4 months

Normal, M 1.32 kg, C-set at 30 weeks, respiratory

Normal at 70 days, normal karyotype distress

APL [I211

38

28

Ara-C 160 mg x 2, 80 mg x 2, (T = 480 mg), Dauno 60 mg x 4, (T = 240 mg), Methyl-PDN (T = 160 mg), post-delivery chemotherapy

Remission (time - N.S.)

Normal, F I.85 kg, C-set at 34 weeks

N.S.

Acute monocytic leukemia [I221

38

23

Ara-C 160 mgday x 5 days (T = 5.76 g), Dauno 120 mg, day I, (T = 960 mg), 7-8 courses, then: 6-TG 160 mgday x 5 aysd x 2 (T = I .6 g), Ara-C 160 mg/day x 5 days x 2, (T = 1.6 g)

Short remission (time N.S.)

Normal, M 2.88 kg, SD. at 37 weeks.

Normal development at I6 months

Acute myelomonocytic leukemia 11091

24

1,2,3rd

Remission x 3 months, death 4 months postdelivery

Normal M 2.75 kg, S.D. at 38 weeks

Normal develop ment at 7 years

CML [I21

35

29 6-TG

Maintenance: 6-MP, M7X (doses - N.S.) during lst, 2nd trimester, Ara-C 160 mgday x 3, (T = 480 mg) during 3rd trimester, post-delivery chemotherapy Ara-C (dose - N.S.) remission, Dauno, I cycle, post-delivery chemotherapy

Partial, M 2.29 kg, death at 13 months post-delivery

Normal platelets, S.D., thrombocytopenia

Normal at I I days, development at 18 months

Erythroleukemia [SS]

28

24

Ara-C 100 mg bid x 5 aysd (T = 3 g), Dox 50 mg, day I (T = I50 mg), 6-TG 80 mg bid x SD. (T = 2.4 g). 3 courses, post-delivery chemotherapy

Remission > I year

Normal, F 2.98 kg, S.D. at 35 weeks

N.S.

trimester

N.S.), Dauno.

x

I

N.S., not stated; SD., Spontaneous delivery; C-set, Cesarean section; M, male; F, female; ALL, acute lymphocytic leukemia; AML, acute myelocytic leukemia; ANLL, acute non-lymphocytic leukemia; APL, acute promyelocytic leukemia; Ara-C, cytarabine; CY, cyclophosphamide; VCR, vincristine; MTX, methotrexate; ~-Asp, t_-asparaginase; Dauno, daunorubicin; Dox, doxorubicin; 6-MP, 6-mercapatopurine; 6-TG, 6thioguanine; PDN, prednisone. “Gestational age at which mother received chemotherapy.

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report severe deformities including bilateral microtia and bilateral atresia of the external auditory canals, a lobster claw deformity of the right hand with only three digits, a short, bowed right femur, bitid left femur, a single bone in the lower legs, and each foot composed of a OScalcis and only two ‘metatarsals [108]. The mother had received extensive chemotherapy prior to conception but was maintained only on ara-C (dose not stated) 4 days a month to maintain her remission during pregnancy. Ara-C was estimated to be administered at 4 and 8 weeks gestation. Limb buds in humans occur by the fourth week of gestation and the limbs and external ears become differentiated during the sixth week, suggesting that the administration of ara-C during these times correlated well to the anomalies noted. Other fetal toxicities following combination chemotherapy with ara-C have included premature, low birth weight infants ]12,120], perinatal seizures, pneumothorax [ 1131, anemia, thrombocytopenia [ 12,118], septicemia and pancytopenia [86], and one case of congenital adherence of the iris to the cornea [12]. 4.2.2. 5Fluorouracil 4.2.2.1. Clinical pharmacology. 5Fluorouracil

is used in the treatment of breast and colorectal cancer which are malignancies commonly found in women of childbearing age. 5-Flourouracil is a fluorinated pyrimidine analog which inhibits thymidine formation and blocks DNA and protein synthesis. 5-Fluorouracil rapidly distributes into most tissues and is quickly metabolized. 5-Flourouracil transport across membranes is rapid and pH dependent [124]. Penetration of 5-fluorouracil and its metabolites across the bloodplacental barrier would therefore be expected. 5-Fluorouracil is rapidly metabolized in non-pregnant patients to 5,6 dihydro-Muorouracil (fluorouracil-H2), alpha-fluoro-beta-ureido-propionic acid (FUPA) and alpha-fluoro-beta-guanido-propionic acid (FBAL). Fluorouracil-H2 is an active fluoropyrimidine metabolite (1251. 5-Fluorouracil is eliminated by renal and hepatic routes. Increased renal elimination of 5flourouracil in pregnant patients may increase the elimination rate. Dose reduction in mild hepatic disease is not required in non-pregnant patients and is probably not necessary in the case of pregnancy [126]. In patients with concurrent extensive liver metastasis dose reduction should be considered. 4.2.2.2. Pharmacokinetics. 5-Fluorouracil distributes into a volume of approximately 9 l/m2 [127], and its volume of distribution may be significantly increased in the pregnant patient. It distributes into extracellular 3rd spaces such as ascites and pleural fluids and most likely the amniotic fluid compartment. It readily penetrates the blood-brain barrier with peak CSF concentrations of 60-80 nmol/l measured following a 15 mg/kg intrave-

91

nous bolus dose [ 1281. The halflife of elimination in non-pregnant patients is 12-37 min 11291. Little is known about the placental transfer of 5flourouracil in humans, however it has been examined in a rat model. Boike et al. examined the maternal and fetal pharmacokinetics of increasing intravenous doses of 5flourouracil. 5-Flourouracil crossed the placenta in a dose dependent manner. Fetal pharmacokinetics were non-linear with increased halflife and area under the curve concentrations (AUC) at increasing doses [1301. Other authors have also shown that the rat fetal/maternal exposure (AUC) to 5-floururacil is approximately 28.7% [ 131). Although analysis of 5-flourouracil in human placental and fetal tissues has not been performed to our knowledge, it is expected to cross the placenta and distribute into breast milk based on animal studies and its physiochemical properties. 4.2.2.3. Adverse effects on the fetus. 5-Flourouracil is considered to be highly teratogenic. It has been reported to be teratogenic in rats, *monkeys and humans [132,133]. In rats, 5-flourouracil crosses the placenta in significant amounts and is embryotoxic at doses easily tolerated in the maternal rat. The fetal 5-flourouracil LDs,, is 50 mgkg while the maternal LDso is 230 mg/kg [131]. Saturation of fetal elimination processes has been suggested as a potential mechanism for this observed toxicity difference [ 1301. In rats, teratogenic effects have included; cleft palate, microphthalmus, omphalocele, and deformed appendages. In monkeys, abortion of embryos and fetal growth retardation have been reported [124,135]. The use of 5-flourouracil during human pregnancy is limited to a few case reports. Stephens et al. report multiple congenital anomalies in an aborted fetus following exposure to 5-flourouracil in a first trimester pregnancy [133]. The mother, 41 years of age was diagnosed with cancer of the bowel and had undergone radiological evaluation (fetal exposure < 5 rads) and laparotomy at 8 weeks gestation. 5-Flourouracil (600 mg i.v., 5 x week) was administered during the 11 to 12th week of gestation. Therapeutic abortion at 16 weeks resulted in a male fetus (465 g) with multiple anomalies including; bilateral radial aplasia, absent thumbs and fingers, hypoplastic aorta, pulmonary hypoplasia, hypoplastic thymus, esophageal aplasia, aplasia of the first part of the duodenum, biliary hypoplasia, absent appendix, imperforate anus, common bladder and rectum, renal dysplasia and aplastic ureters. In this case, the maternal age and radiation exposure may have contributed to the anomalies, limiting the extent to which the teratogenic effects can be attributed to 5-flourouracil [133]. Due to the limited experience with the use of 5flourouracil in human pregnancy and the overriding teratogenic and embryotoxic effects seen in animal studies, the use of this agent during pregnancy should be

92

should be avoided if possible particularly in 1st trimester pregnancy. 4.2.3. Methotrexate 4.2.3.1. Clinical pharmacology. Methotrexate is used in a variety of cancers in women of child bearing age including leukemia, breast cancer and invasive mola chorion cancer. Methotrexate is a folic acid antagonist which competitively inhibits the enzyme dihydrofolate reductase. This results in reduced production of tetrahydrofolate from dihydrofolate. Tetrahydrofolate is involved in the de novo synthesis of purines to pyrimidines, which is vital for cell replication particularly in the newly developing fetus. Methotrexate is only 50% protein bound in human serum, and can easily penetrate membranes. Methotrexate is therefore expected to cross the blood placental barrier. It is metabolized in a variety of maternal tissues including the liver, gastrointestinal tract, bone marrow, fibroblasts and cultured human breast cancer cells. In the maternal liver it is metabolized by hepatic aldehyde oxidase to 7-hydroxymethotrexate 11361.The enzyme is not saturable in the maternal system, however reduced oxidative capacity in the fetus may limit the rate of methotrexate elimination following placental transfer. The 7-hydroxy metabolite is approximately 200-fold less active then methotrexate [137]. Methotrexate is also metabolized to several polyglutamate derivatives. While these metabolites are not detected in human serum they are taken up by cells and appear to be active [ 1381.It has been suggested that these metabolites may act to prolong the elimination phase of methotrexate by acting as an intracellular reservoir. Methotrexate is eliminated by both renal and hepatic metabolism, Biliary concentrations of methotrexate exceed plasma concentrations by a factor of 100 to 10 000-fold [139]. However, enterohepatic circulation reabsorbs the majority of the drug so that only 2-10% of a dose remains in feces [140]. Increased enterohepatic circulation in the pregnant patient may slightly increase the absorption of the remaining drug in feces, however a corresponding increase in renal elimination during pregnancy may significantly increase the elimination of methotrexate. Renal excretion accounts for as much as 90% of methotrexate elimination. 4.2.3.2. Pharmacokinetics. Methotrexate distributes rapidly after intravenous administration into a volume approximately equivalent to total body water [ 1411.The volume of distribution is approximately 0.28-0.77 l/kg at steady state [142]. Due to the significant increase in plasma volume during pregnancy (50% increase) there may be a dilutional effect on plasma concentrations of methotrexate. Absorption of orally administered methotrexate may also be altered in the pregnant patient were stomach emptying is slower, therefore intravenous routes would be preferable. Methotrexate also

V.J. Wiebe, P. E. H. Sip& / Crit. Rev. Oncol. Hemarol. 16 (1994)

7S- I I2

distributes into pleural and ascites fluids and would be expected to distribute into other fluid tilled 3rd compartments such as amniotic fluid. Clearance of methotrexate is highly variable 1.86 to 12 l/h in non-pregnant patients and may be significantly increased in pregnant patients with enhanced renal function. Following intravenous bolus doses of methotrexate (100 mg/m2) a terminal halflife on the order of 8- IO h is noted in patients with normal renal function [143]. Penetration of methotrexate into cerebrospinal fluid (CSF) increases with prolonged infusions; however, ratios of CSF to plasma concentrations remain low (1:40) [144]. Overall methotrexate may be significantly influenced by a variety of physiological alterations in the pregnant patient including altered plasma volume, increased renal clearance and accumulation of drug in 3rd compartment spaces. Few studies have examined transplacental passage of methotrexate. In a case report by Schleuning et al, the authors detected methotrexate in serum and red blood cells of a fetus from a patient receiving weekly methotrexate administration. The patient was receiving mercaptopurine (60 mg/m2/day) and methotrexate 20 mg/m2/weekly until delivery at 40 weeks gestation for consolidation of acute lymphoblastic leukemia. Assessment of chord blood at this time demonstrated a fetal methotrexate serum concentration of 1.86 x 10e9 M and RBC concentration of 2.6 x 10m9M/g of hemoglobin. The drug was primarily in the form of methotrexate with 29% noted to be in the polyglutamate form [87]. Methotrexate has also been shown to be excreted into breast milk. Concentrations of 6 nmol/l were measured after a 22.5 mg dose, with a milk to plasma ratio of 0.08 11451. 4.2.3.3. Adverse effects on the fetus. The use of folic acid antagonists in pregnancy is associated with both embryotoxic and teratogenic effects. In a review of chemotherapeutic agents administered during the first trimester of pregnancy, Doll et al. report that single agent chemotherapeutics resulted in fetal abnormalities in 17% of patients, but when folate antagonists were eliminated from the evaluation the incidence dropped to only 6% [8]. The incidence of fetal malformations due to methotrexate in chemotherapeutic doses and schedules is difficult to assess. Fetal death, spontaneous abortion and numerous congenital malformations including oxycephaly, webbing and absence of digits, low set ears and other cranial anomalies have been reported following single agent methotrexate in pregnancy [146,147]. However, these reports are primarily from patients in which methotrexate was used unsuccessfully to induce abortion or for the treatment of psoriasis. Milunsky et al. report multiple congenital defects in an infant born to a patient following the unsuccessful use of methotrexate (2.5 mg/day x 5 days; total 12.5

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mg) as an abortifacent during weeks 8-10 of gestation (1471. Oxycephaly, absence of coronal and lambdoid sutures, wide posterior fontanel, low-set ears, skin folds, absence of toes, rib anomalies, growth retardation and unexplained tachypenia were noted. However, karyotype and mental and motor development were found to be within normal limits at 15 months. Powell et al. also report multiple abnormalities including oxycephaly, wide frontal metopic suture, large anterior fontanelle, widely separated eyes, low set ears, webbed fingers and skin tags in an infant born to a mother receiving methotrexate for psoriasis. The mother who was 40 years of age received methotrexate 5 mg daily from conception to the second month of pregnancy [1461. A variety of case reports have been published using methotrexate in combination chemotherapy for acute leukemia (Table 5). In the majority of cases, pregnancy has resulted in a normal outcome, however, a number of cases have resulted in infants with fatal pancytopenia, septicemia, gasteroenteritis and one case of chromasomal damage (chromatid lymphocyte breakage causing gaps and rings). However, in all cases multiple agents had been administered so that these effects could not be attributed to a particular drug. In the case where chromasomal damage was noted, the mother had received numerous agents including daunorubicin, vincristine, prednisolone, Asp, cytoxan, Ara-C, mercaptopurine, methotrexate and radiation. After 18 weeks of chemotherapy (40 weeks gestation) she delivered a healthy female infant with a normal karyotype (46Xx) but with several gaps. A ring chromosome was also noted in metaphase following methotrexate synchronization [87]. While the incidence of teratogenic effects induced by methotrexate alone in antineoplastic regimens is difficult to access, the risk of congenital anomalies following antimetabolite use is particularly high when these agents are used in early pregnancy. The use of high doses, continuous administration, or delayed elimination of methotrexate may all contribute to an increased incidence of teratogenic effects. The pharmacokinetic monitoring of maternal methotrexate plasma concentrations with dose adjustments of further doses or leukovorin rescue should be considered carefully as a means of reducing fetal exposure. 4.3. Natural products (plant alkaloids and antibiotics) 4.3.1. Daunorubicin and doxorubicin 4.3. I. I. Clinical pharmacology. Anthracyclines

(doxorubicin and daunorubicin) are active in several types of cancers in women of child bearing age including lymphoma, leukemia, breast and ovarian cancers [149]. These agents are potent inhibitors of nucleic acid synthesis and are cell cycle-phase non-specific agents. Anthracyclines are large, water soluble compounds which

93

can be actively taken up into cells. Once inside cells they intercalate between DNA base pairs producing a blockade of RNA synthesis [150]. Anthracyclines are metabolized by cytoplasmic enzymes to several active metabolites. Metabolism of anthracyclines to their alcohol and free radical metabolites involves a number of flavin dependent oxidoreductases including P450 reductase, xanthine oxidase and NADH dehydrogenase. Doxorubicinol and daunorubicinol are the major metabolites in tissues and are the product of intracellular aldo-keto reductases. These metabolites are more polar than the parent compounds and are also active inhibitors of nucleic acid metabolism [ 151,152]. Anthracyclines have also been reported to bind cell membrane phospholipids, particularly cardiolipin [ 1531. Metabolism of membrane bound anthracyclines may potentially cause localized free-radical production resulting in tissue damage. Both free radical formation and lipid peroxidation occur through redox-cycling of the anthracyclines [ 1541. Redox recycling has been evaluated in human fetal tissues with regard to age of gestation. Human adrenal and hepatic reductase activities increase after the 7th week of gestation [155], suggesting that free radical formation and lipid peroxidation can occur in fetal tissues beyond the 1st trimester. Further metabolism by liver microsomal enzymes to inactive aglycones, sulfate conjugates and demethylated glucuronides also occurs. Incomplete recovery of an administered dose may suggest retention of doxorubicin in tissues or extensive metabolism into non-identifiable metabolites. Elimination of maternal metabolites is primarily through biliary (50%) and renal (10%) routes [ 156,157l. Increased bilirubin concentrations especially above (120 mg/l) are associated with increased plasma concentrations of doxorubicin and doxorubicin induced toxicities [ 1571.Pregnant patients with elevated bilirubin concentrations receiving anthracyclines are therefore at greater risk of anthracycline induced fetal toxicities. Transplacental passage of anthracyclines has been examined by a number of authors. Roboz et al. report that neither doxorubicin or its major metabolite, doxorubicinol could be detected in amniotic fluid 4 and 16 h after a 30 mg/m* dose to a women at 20 weeks gestation (1581. However, D’Incalci et al. report that while doxorubicin concentrations could not be detected in fetal amniotic fluid, brain, intestine, or muscle tissue 15 h after a single (40 mg) dose of doxorubicin, concentrations were almost 10 times the maternal serum concentration in the liver, kidney, and lung of a 17-week old fetus [159]. Karp et al. report that doxorubicin was also measured in placental tissue distant from the umbilical chord and in the placenta proximal to the chord following a single dose of doxorubicin (45 mg/m*) to a pregnant patient at 34 weeks gestation. An unknown metabolite in fetal

V.J. Wiebe. P.E.H. Sipila/ Crir. Rev. Oncol. Hemalol. 16 (1994)

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Table 5 Summary of methotrexate use during pregnancy Disease (reference)

Patient age (years)

Gestational age’ (weeks)

Drugs used during gestation dose/schedule/ (T, total dose)

ALL [94]

17

18

MTX 15 mg x 5 days q 2 weeks, VCR2mgx4(T=> 8mg), PDN 80 mg/day ~-Asp 10 000 u 2 x /week (T = 10’ u) 6-MP 350 mg X 5 days q 2 weeks, Dauno (T = 220 mg)

Maternal outcome

x 2.5 years

Fetal outcome

Infant followup

Normal twins, M - 2.5 kg, F - 2.4 kg, Cset at 37 weeks

Diarrhea at 24 h, normal immune function tests, normal development at 54 months

ALL [86]

24

12

MTX (T = 150 mg), VCR (T = 16 mg), PDN (T = 3.0 g), Dox (T = 80 mg), 6-MP (T = 1.0 mg)

Partial remission x 7 months

Normal, F 1.9 kg, C-see at 33 weeks

Normal at 16 months

ALL [85]

32

17

MTX 30 mgiweek (T = 480 mg), VCR2mg/weekx4(T=16 mg), PDN 40 mg/day x 4 weeks (T = 2.24 g), ~-Asp 14 000 u, EOD x 7 (T= 196000 u), CY 300 mg/week (T = 4.8 g), Dox 50 mg, day 1 (T = 100 mg), 6-MP 75 mg/day (T = 8.3 g)

Remission x 8 months

Normal, F 3.2 kg, S.D. at 38 weeks

Normal development at 40 months

ALL 1861

24

1,2,3rd trimester

MTX (T = 1 g), VCR (T = 48 mg), CY (T = 25 g). 6-MP (T = 18.3 g), PDN (T = 7.6 g), Ara-C (T = 3.5 g)

Partial remission, died 16 months after childbirth

Normal, F -

Alive at 6 years

2.3 kg, S.D. at 40 weeks

ALL [86]

18

1,2,3rd trimester

MTX (T = 600 mg), Ara-C (T = 1.6 g), PDN (T = 3.8 g), 6-MP (T = 250 mg), VCR (T = 24 mg), CY (T = 5 g)

No response to treatment died 5 months after childbirth

Pancytopenic, M - 1.0 kg, C-set at 34 weeks

Died from septicemia at 21 days of age, normal karyotype

ALL [86]

37

2rd,3rd trimester

MTX (T = 600 mg), Ara-C (T = 1.4 g), PDN (T = 3 g), 6-MP (T = 4 g), VCR (T = 16 mg)

Complete remission, died 5 months after childbirth

Normal, F 2.4 kg, S.D. at 38 weeks

Died from gastroenteritis at 90 days of age, normal karyotype

ALL [86]

28

lst,3rd trimester

MTX (T = 725 mg), 6-MP (T = 15.8 g), CY (T = 3.15 g)

Complete remission

Normal, M 3.0 kg, induced labor

Alive at 7 years

ALL [148]

26

Conception

MTX 30 mg/week (T = 180 mg), 6-MP 100 mg/day x 6 weeks (T = 4 g), VCR (T = N.S.) PDN (T = N.S.), reinduction: Dox 45 mg/m2, EOD (T = N.S.), VCR weekly (T = N.S.), PDN daily, maintenence: Ara-C, MTX

Remission > 6 months

Normal, M 2.4 kg C-set at 36 weeks, polycythemia, hyperbilirubinemia

Normal development at 6 months

ALL (841

I8

12.5

MTX 10 mg intrathecal x 2, (T=20mg),VCR2mgx4 weeks (T = 8 mg), Dauno 60 mg/m*/day x 2 days (T = 120 mg/m*) ~-Asp 6000 u/m* 3/week x 5 weeks (T = 90 000 u/m3 CY 100 mg/m2/day x 2 weeks, (T = 1.4 g/m*), PDN 60 mg/m*/day x 4 weeks, (T = 1.68 g/m*), 6-MP 60 mg/m*/day x 4 weeks, (T = 1.68 mp/m*), CNS radiation 2400 rads

Normal development, F - 2.4 kg, severe bone marrow hypoplasia

Normal at 12 months

x 20 months

V.J. Wiebe, P.E. H. Sipila / Crit. Rev. Oncol. Hematol. 16 (1994)

95

75-1 I2

Table 5 (Continued) Disease (reference)

Patient age (years)

Gestational agea (weeks)

Drugs used during gestation dose/schedule/ (T, total dose)

Maternal outcome

Fetal outcome

Infant followup

ALL (871

34

22

MTX 20 mg/m2/week MTX 10 mg/m*; days 31,38,45,52, Dauno 25 mg/m2, VCR 1.5 mg/m2; days 1,8,15,22 PDN 60 mg2/day; days l-28 ~-Asp 5000 cJm2/day; days 15-28, CY 650 mg/m*; days 29,43,57, Ara-C 75 mg/m24 x/day 4 days, 6-MP 60 mg/m2; days 29-56; then q week, cranial radiation (24 Gy)

Complete remission (time - N.S.)

Normal, F, SD. at 40 weeks

Chromasomal gaps and rings found on karyotyping

AML [I181

37

32

MTX 2.5 mg q 12 h, VCR I mg, 6-MP 50 mg q 12 h, PDN 20 mg q 12 h x 7 days

Remission x 6 months, death 13 months postpartum

Normal, F 2.35 kg, SD. at 34 weeks, cushingoid

Normal development at 8 weeks

N.S., not stated; SD., spontaneous delivery; C-set, Cesarean section; M, male; F, female; ALL, acute lymphocytic leukemia; AML. acute VCR, vincristine; MTX, methotrexate; ~-Asp. t-asparaginase; Dauno, daunorubicin; Dox, doxorubicin; 6-MP, 6-mercapatopurine; PDN, prednisone. “Gestational age at which mother received chemotherapy.

myetqtic leukemia; Ara-C, cytarabine; CY,= cyclophosphamide;

tissue was also noted. The metabolite was found in high concentrations in fetal spleen and was also present in fetal liver, lung, kidney, heart, muscle and duodenum [ 1601.These studies suggest that doxorubicin does cross the placenta and is able to distribute into fetal tissues. High doxorubicin concentrations noted in fetal liver, kidney and lung may reflect the binding of doxorubicin to metabolizing enzymes present in these organs. 4.3.1.2. Pharmacokinetics. Following administration, anthracyclines are extensively bound to tissue and plasma proteins (50-90%). The halflife of anthracyclines in non-pregnant patients is triphasic with a long terminal halflife of approximately 25-50 h [161]. Anthracyclines have a very large distribution volume (400-1400 l/m2) [ 1561.The volume of distribution is expected to increase in pregnancy due to a significant increase in plasma volume. An increase in protein binding in the pregnant patient may also have the effect of reducing the nonprotein bound active fraction of drug. Doxorubicin also accumulates in fluid filled compartments such as ascitis fluid, where its slow release may increase total body exposure and toxicity. The amniotic fluid compartment may therefore behave as a 3rd space for these water soluble anthracycline compounds, potentially increasing both maternal and fetal exposure. Doxorubicin and its aglycol metabolite have been measured in breast milk in low concentrations [55], suggesting that women should avoid breast feeding if receiving doxorubicin. 4.3.1.3. Adverse effects on the fetus. The teratogenic effects of the anthracyclines have been examined in a number of animal models including rats and mice. Both

doxorubicin and daunorubicin are teratogenic in rats with doxorubicin being more teratogenic than daunorubicin [162]. However, a variety of case reports have described the successful use of anthracyclines in combination therapy in human pregnancy, with minimal fetal risk. Unfortunately, the evaluation of doxorubicin as a single agent in pregnancy is limited to only a number of case reports. Daunorubicin was used as a single agent in one reported case of pregnancy complicated by acute promyelocytic leukemia [163]. In this case, a 26-year old patient with newly diagnosed APL and disseminated intravascular coagulation (DIC) was administered daunorubicin (2 mg/kg/day for 4 days) in her 28th week of gestation. A premature, but normal male (1.8 kg) was delivered by Csection at 34 weeks gestation. Although delivery was uneventful in this case, the infant developed acute respiratory distress syndrome with congestive heart failure on day one which resolved with treatment after 6 days. The authors suggest that the ARDS and CHF were due to the premature nature of the infant. They further suggest that the infant may have been premature due to a severe placental involution which they believe was secondary to daunorubicin. The placenta was found to be small in size (200 g) and had numerous necrotic areas. Membrane binding and free radical formation by the anthracyclines could potentially be a factor in necrosis of the placental tissues. Tissue necrosis following anthracycline extravasation begins to occur late after exposure (> 1 week) and in this case it had been approximately 5 weeks following anthracycline exposure.

96

The laboratory and chromosomal analysis of the infant were found to be normal except for hypoprothrombinemia. The hypoprothrombinemia may have been related to heparin therapy. The mother was receiving heparin 1.5 mg/kg/day x 7 days concurrently with daunorubicin for her DIC. Since DIC is commonly associated with acute leukemia and anticoagulation with heparin or warfarin is often required, one must also be aware of the potential embryotoxic effects of these agents. Warfarin is a known teratogenic (10%) and embryotoxic (10%) agent, particularly during exposure in the first trimester of pregnancy. Heparin has also been associated with a high incidence of stillbirths ( > 1O%), spontaneous abortions (1.5%) and premature births (24%) [164]. A variety of other case reports have described normal infants born to mothers receiving anthracycline containing chemotherapy for leukemia, Ewings sarcoma and breast cancer (Table 6). However, the use of combination chemotherapy complicates the evaluation of fetal toxicity due to a specific agent. A review of case reports demonstrates that anthracyclines have been used in all trimesters of pregnancy with few adverse effects on the fetus. Congenital defects were not present in any of the reports reviewed and in those cases where karyotyping was performed it was found to be normal. A number of fetal deaths were reported. There was only one intrauterine death resulting in a stillborn infant directly following chemotherapy (36 h after chemotherapy) and in this case the mother had also received radiation (900 rads), dexamethasone, vincristine and prednisolone in combination with doxorubicin [ 1601. Radiation is known to be a substantial risk to the fetus and while the fetus appeared normal in this case the placenta was immature, with infarcted areas, extensive endothelial damage, thrombosis and occlusion of chorionic vessels. The overall risk of teratogenicity from anthracycline use in pregnancy appears minimal, however long term effects have not been established. Aviles et al. report that long term followup (4-22 years) of I1 children exposed in utero to anthracycline containing combination therapy showed no difference to age matched controls or siblings in cytogenetic studies, bone marrow exams and scholastic performance [ 131. While anthracyclines have not been reported to cause teratogenic effects they do cross the placenta and may be associated with some degree of embryotoxicity, as evidenced by the high incidence of premature births noted. Fetal death following pre-eclamptic toxemia in one patient and maternal death resulting in fetal death from disease progression in two other cases have also occurred [85,107,158]. Fetal toxicities primarily involve hematologic effects including marrow hypoplasia, leukopenia, polycythemia, anemia and an enlarged spleen [84,88,118,148]. Premature or low birtliweight children were common as were the complications associ-

V.J. Wiebe, P.E. H. Sipila / Crir. Rev. Oncol. Hematd

16 i 1994) 75-112

ated with premature births, particularly respiratory distress. Electrolyte imbalances, diarrhea, hyperbilirubinemia, perinatal seizures and infections were also reported but subsided with supportive measures. 4.3.2. Vinblastine and vincristine 4.3.2.1. Clinical pharmacology. The vinca alkaloids including vinblastine and vincristine are antimitotic agents which inhibit microtubule formation and produce arrest of the cell cycle in metaphase. Both agents are similar in their mechanism of action, although they differ in clinical activity and have distinct pharmacological and toxicological properties. These agents are commonly used in breast cancer and Hodgkin’s disease, malignancies that are often found in women of child bearing years. Liver metabolism and biliary excretion account for the majority of vincristine and vinblastine elimination. Vinblastine is metabolized in the liver to desacetylblastine, which has greater activity than the parent compound. Metabolites of vincristine have not been fully characterized [166]. The majority of both drugs (70%) is eliminated via the feces, however, a small amount appears in urine, Dose reduction may be necessary in hepatobiliary disease since the majority of a dose is excreted via bile. The vinca alkaloids are highly protein bound (> 99%) which may limit their penetration across barriers such as the blood-placental barrier. An increase in plasma proteins in pregnancy may also reduce the free fraction of drug available to the tumor. Both agents have very poor penetration across the blood-brain barrier, resulting in non-cytotoxic concentrations. It is unknown whether these agents or their metabolites cross the placenta or penetrate into breast milk. Both vincristine and vinblastine have been found to enhance cellular accumulation of methotrexate through blockade of methotrexate efflux from cells [167,168], although the interaction has not been shown to be therapeutically significant (1691, small changes in MTX concentrations may be significant in the case of fetal toxicity. 4.3.2.2. Vinca alkaloids: pharmacokinetics. Little is known about the pharmacokinetics of the vine alkaloids in pregnant patients. In non-pregnant patients the vinca alkaloids are rapidly taken up by tissues and follow a triphasic distribution and elimination model. Both agents have long terminal halflifes (vincristine, 85 h; vinblastine, 25 h) which may reflect extensive tissue binding with slow release of drug from tissue binding sites. The distribution of both vincristine and vinblastine has not been fully elucidated, however they have very large volumes of distribution. The volume of distribution of vincristine has been reported to be 97 l/m2 [170]. This may significantly increase in the pregnant patient. Peak vincristine and vinblastine plasma concentrations following an intravenous dose are between 10e7 and

97

V.J. Wiebe, P. E.H. Sipila / Crit. Rev. Oncoi. h’ematol. 16 (19941 75-112

Table 6 Summary of anthracycline use during pregnancy Disease (reference)

Patient age (years)

Gestational age (weeks)”

Drugs used during gestation dose/schedule/ (T, total dose)

ALL 1941

I7

18

Dauno (T = 220 mg), VCR 2 mgx4(T=>8mg),PDN80 mg/day, ~-Asp IO 000 u 2 x Iwk (T = IO* u), 6-MP 350 mg x 5 days q 2 weeks, MTX I5 mg x 5 days q 2 weeks

Maternal outcome

x 2.5 years

Fetal outcome

Infant followup

Normal twins, M - 2.5 kg, F - 2.4 kg, Cset at 37 weeks

Diarrhea at 24 h, normal immune function tests, normal development at 54 months

ALL [86]

24

I2

Dox (T = 80 mg), VCR (T = I6 mg), PDN (T = 3000 mg), MTX (T = I50 mg), 6MP (T = 1000 mg)

Partial remission X 7 months

Normal, F 1.9 kg, C-set at 33 weeks

Normal at I6 months

ALL [84]

I8

12.5

Dauno 60 mglm*/day x 2 days, PDN 60 mg/m2, VCR 2 mg MTX 10 mg IT x 2, ~-Asp WI0 u/m*, 3/week x 5 weeks, CY 100 mg/m*/day x I4 weeks

Remission x 20 months

Normal development, F - 2.4 kg, severe bone marrow hypoplasia

Normal at I2 months

ALL [85]

32

I7

Dox 50 mg, day I (T = 100 mg), VCR 2 mg/week (T = I6 mg), PDN 40 mg/day x 4 weeks (T = 2.24 g), ~-Asp I4 000 u, (T = I96 000 u) CY 300 mg/week, (T = 4800 mg), MTX 30 mg/week (T = 480 mg) 6-MP 75 mg/day (T = 8325 mg)

Remission x 8 months

Normal, F 3.2 kg SD. at 38 weeks

Normal development at 40 months

ALL [85]

I7

34

Dox 75 mg, day I (T = 75 mg), VCR 2 mg/week (T = 6 mg), PDN 60 mg/day (T = 1.3 g)

Remission x 4 months

Normal, M 3.3 kg, S.D. at 37 weeks

Normal growth and development at 32 months

ALL [SS]

I6

35

Dox 40 mg, day I (T = 40 mg), VCR 2 mg/week (T = 8 mg), PDN 60 mg/day (T = 1.7 g)

Remission x I year

Normal, M 2.9 kg, SD. at 39 weeks

Normal development at 29 months

ALL [88]

32

I6

Dox (N.S.), VCR, PDN, ~-Asp, maintenance:CY, 6-MP, MTX, VCR, PDN

Remission (N.S.)

Normal, F 3.8 kg, slight leukopenia

Normal development, normal whc counts at 2 weeks

ALL (I071

24

I5

Dauno 60 mg/m’/day, 6-TG 100 mg/m’ q I2 h, days l-7, Ara-C 100 mg/m* q I2 h, day l-7

Remission > 6 months

Death following preeclamptic toxemia at 29 weeks

No congenital abnormalities at autopsy

ALL [I481

26

Conception

6-MP 100 mg/day (T = 4g), MTX 30 m&week (T = 180 mg), VCR (T = N.S.), PDN (T = N.S.), reinduction: Dox 45 mgIm* (T = N.S.), VCR weekly (T = N.S.), PDN daily, maintenence: Ara-C, MTX

Remission > 6 months

Normal, M 2.4 kg, C-set at 36 weeks, polycythemia, hyperbilirubinemia

Normal development at 6 months

ALL [I601

30

21

Dox (T = 214 mg/m*), VCR (T = N.S.), PDN (T = N.S.), LAsp (T = N.S.), MTX (T = N.S.), cranial radiation

Remission x 30 months

Normal, M 2.08 kg, C-see at 34 weeks

Normal development at 30 months, Dox in placental tissues

98

Table 6

V.J. Wiebe. P. E. H. Sipila / Cd.

Rev. Oncol. Hema~ol. 16 (IYWI

75-112

(Continued)

Disease (reference)

Patient age (years)

Gestational age (weeks)”

Drugs used during gestation dose/schedule/ (T, total dose)

Maternal outcome

Fetal outcome

Infant followup

AML [ill]

23

17

Dauno 45 mg/m2 (T = 135 mdm2), Ara-C 100 mg/m*/day (T = 2.2 g), 6-TG 100 mdm2/day (T = 1.5 g/m’)

Remission x 7 months

Normal, M 2.9 kg, induced labor at 40 weeks

Normal development, bone marrow, cytogenetic analysis, ECG

AML [I121

36

24

DOX90 mg (T = 180 mg), Dauno 90 mg (T = 180 mg), Ara-C 60 mg bid x 5 days (T = 1.2 g), 6TGl6Omgbidx7days (T = 4.5g)

N.S.

Normal, F 2.0 kg, S.D. at 32 weeks

Normal development at 13 months

AML 1851

16

16

Dox 65 mg day 1 (T = 65 mg), VCR 2 mgweek (T = 2 mg), PDN 100 mg/day (T = 1.2 g), Ara-C 160 mg/day (T = 640 mg)

Death 1 week after chemotherapy. No response to treatment

Spontaneous abortion prior to maternal death at 18 weeks

-

AML [107]

34

27

Dauno 60 mg/m2/day (T = 360 mg/m2), 6-TG day l-7 (T = 1 g/m*), Ara-C 100 mg/m2 q 12 h (T = 1 g/m*), allopurinol 100 mg tid, courses at 21-day intervals

Remission > 6 months

Normal, M 5 kg, SD. at 40 weeks

Normal development, blood count, karyotype at 6 months

AML [113]

24

24

Dauno 50 mglday x 3 days (T = 300 mg), Ara-C 160 mglday x 7 days (T = 2.24 g), 2 courses, post-delivery

Remission months

Normal, F 1.4 kg, C-set at 29 weeks

Perinatal seizures, pneumothorax, normal at 14 months

AML [114]

27

12

Dox 80 mg, day I (T = 400 mg), Ara-C 140 mg/24 h x 240 h (T = 700 mg), VCR 2 mg, day 1 (T = 10 mg), PDN 100 mg days l-5 (T = 2.5 g), 5 courses

N.S.

Normal, F 2.86 kg, SD. at 28 weeks

Normal development, karyotype, at 6 weeks

AML [118]

22

17

Dauno 70 mg/m*/day x 3 days (T = 210 mg/m2), hydroxyurea 8 g (T = 8 g). Ara-C 90 mg/m2 bid x 7 days (T = 1.26 g/m’), VCR 1 mg/m2/day, days 1 + 7 (T = 2 mg/m2), 6-TG 90 mg/m2 bid x 7 days (T = 1.26 mdm2), PDN 40 mg!m2/day x 7 days (T = 280 mg), post-delivery chemotherapy, bone marrow transplant

Remission > 2 years

Elective abortion at 21 weeks

Normal fetus, 307.8 g, enlarged spleen

AML [118]

28

27

Dauno 70 mplm2/day x 3 days (T = 483 m%/m2), Ara-C 90 mg/m2 bid x 7 days (T = 2.52 g/m*), VCR 1 mg/m*, days I + 7 (T = 4.6 mglm2), 6-TG 90 mp/m2 bid x 7 days (T = 2.9 g/m’), PDN 40 mp/m2/day x 7 days (T = 644 mg/m2), 2 courses, 2nd course with 30% increase in doses

Disease progression, death 9 days postdelivery

Normal, M 2. I3 kg, SD. at 31 weeks anemia, electrolyte imbalances

Normal development at 13.5 months, depressed growth

APL [163]

26

28

Dauno 2 mg/kg/day x 4 days (T = 8 mg&g), post-delivery chemotherapy

Remission (time - N.S.)

Normal, M 1.8 kg, C-set at 34 weeks, placental necrosis

ARDS, CHF, hypoprothrombinemia at birth, normal at 10 months

x

2

V.J. Wiebe. P.E.H. Sipila /Crit. Rev. Oncol. Hematol. 16 (1994)

99

7S-112

Table 6 (Continued) Disease (reference)

Patient age (years)

Gestational age (weeks)”

Drugs used during gestation dose/schedule/ (T, total dose)

APL [165]

22

Conception

Dauno 30 mg/m*/day, days 1,2 (T-60 mg/m2), methylglyoxalbisguanyl-hydrazone 250 mg/m*. days 3,5,8 (T = 750 mg/m2)

Maternal outcome

(time -

N.S.)

Fetal outcome

Infant followup

Normal, F 2.2 kg, S.D. at 34 weeks

Normal growth

APL [120]

18

21

Dox 70 mg/m2, day 1-3, Ara-C 100 mgIm2, days l-9 6-TG 100 mg/m*, days 1-9, PDN 40 mg/m*, days l-9, VCR 1 mg/m*, day 1 + 9, post-delivery chemotherapy

Remission > 4 months

Normal, M 1.32 kg, C-see at 30 weeks respiratory distress

Normal at 70 days, normal karyotype

APL (1211

38

28

Dauno 60 mg x 4 (T = 240 mg), Ara-C 160 mg x 2, 80 mg x 2 (T = 480 mg), methyl-PDN (T = 160 mg), post-delivery chemotherapy

Remission (time - N.S.)

Normal, F 1.85 kg, C-set at 34 weeks

N.S.

Acute monocytic leukemia [122)

38

23

Dauno 120 mg, day 1 (T = 960 mg), Ara-C 160 mgday x 5 days (T = 5.76 g), 7-8 courses, then: 6-TG 160 mg/day x 5 days x 2 (T = 1.6 g), Ara-C 160 mg/dayx5daysx2(T=1.6g)

Short remission

Normal, M 2.88 kg, S.D. at 37 weeks.

Normal development at 16 months

Erythroleukemia (851

28

24

Dox 50 mg, day 1 (T = 150 mg). Ara-C 100 mg bid x 5 days. (T = 3 g), 6-TG 80 mg bid x 5 days. (T = 2.4 g), 3 courses. post-delivery chemotherapy

Remission > I year

Normal, F 2.98 kg, SD. at 35 weeks

N.S

Non-Hodgkin’s lymphoma 1891

25

Conception

Dox 45 mg/m* (T = 90 mgim*), CY 700 mgim* (T = 1.4 g/m*), VCR 2 mg, day 1 (T = 4 mg) PDN 100 mg, day 1-S (T = 500 mg) l-2 courses

N.S.

Normal, M 3.4 kg, SD. at 38 weeks

Normal at 2 months

Hodgkin’s lymphoma 11591

22

17

Dox (T = 40 mg), bleomycin (T = 15 mg), vinblastine (T = 9 mg), dacarbazine (T = 600 mg)

N.S.

Therapeutic abortion 15 h after chemotherapy

Dox measured in fetal tissues

T-cell lymphoma 11601

28

25

Dox 45 mg/m* (T = N.S.), radiation 900 rads in 3 fractions over 36 h, (fetal dose = 9-18 rads). dexamethasone (T = N.S.)

N.S.

Stillborn, F 1.2 kg, fetal death 36 h after chemotherapy

Normal fetus, placental thrombosis, Dox metabolites in fetal tissues

Myoblastoma H561

26

20

Dox 30 mg/m* mp/m2)

Death at 26 weeks due to severe respiratory distress

Normal growth prior to maternal death at 26 weeks

Autopsy denied

Breast cancer [I121

25

22

Dox40mg,day1=8(T=160 mg), VCR 1.5 mg, day 1 + 8 (T = 6 mg). PDN 20 mg, day 1-14 (T = 280 mg), 2 courses

N.S.

Normal, M 1.99 kg, SD. at 31 weeks

Normal growth at 4 months

Breast cancer [941

33

10.5

Dox (T = 420 mg), CY (T = N.S.), 5-FU (T = N.S.), 6 courses q 3 weeks, then: CY, MTX, 5-FU (T = N.S.)

Remission x 2.5 years

Normal, F 2.26 kg, C-set at 34.5 weeks

Normal development at 24

x

3 days (T = 90

100

V.J.

Wiebe. P.E.

H.

Sipila / Crir. Rev. Oncol. Hetnarol. /6 (1994)

75-112

Table 6 (Continued) Disease (reference)

Patient age (years)

Gestational age (weeks)”

Drugs used during gestation doseischedulei(T = total dose)

Maternal outcome

Fetal outcome

Infant followup

Ewings sarcoma [96]

21

25

Dox (T = N.S.), dactinomycin (T = N.S.), CY, bleomycin, VCR (T = N.S.), post-delivery chemotherapy, radiation

Remission > 4 years

Premature, F - 1.75 kg, C-see at 34 weeks

Respiratory support, calcium, required after birth, normal at 1 month

Endodennal sinus tumor of ovary 197)

24

17

Dox45mg/m2q4weeksx5, VCR2mgq4weeks x S+2 mgX3,CY600mg/m2q4 weeks x 5, post-delivery chemotherapy

Remission N.S.

Normal, F N.S. induced labor 37 weeks

Normal at I year

N.S., not stated; S.D., spontaneous delivery; C-see, Cesarean section; M, male; F, female; ALL, acute lymphocytic leukemia; AML, acute myelocytic leukemia; APL, acute promyelocytic leukemia; Ara-C, cytarabine; S-FU, 5-fluorouracil; CY, cyclophosphamide; VCR, vincristine; MTX, methotrexate; ~-Asp, L-asparaginase; Dauno, daunorubicin; Dox, doxorubicin; 6-MP, 6-mercapatopurine; PDN, prednisone; 6-TG, 6thioguanine. *Gestational age at which mother received chemotherapy,

10e9 mol/l [171,172]. Peak concentrations may be significantly reduced in pregnant patients due to dilutional effects from the increased volume of distribution. 4.3.2.3. Adverse effects on the fetus. The teratogenic effects of the vinca alkaloids have been examined in a variety of animal models. In mice, rats and hamsters these agents are known to be teratogenic [ 173- 1751. Ferm et al. report that administration of vinblastine to hamsters on the eighth day of gestation increased both the number of congenital malformations and the mortality rate of fetuses (1751. However, numerous case reports in humans have established the relative safety of the use of these agents in pregnancy, indicating that the human fetus may be less sensitive to the teratogenic effects of these agents than animals. Vinblastine has been used in all trimesters of pregnancy without producing teratogenic effects. As a single agent it has been used without any deleterious effects on the fetus even when used during the entire gestational period. Rosenzweig et al. report a normal infant born to a mother who had received a total of 67 mg vinblastine during the first three months of pregnancy for the treatment of Hodgkin’s disease. She then received bimonthly intravenous vinblastine (10 mg) injections for the remainder of her pregnancy. At 40 weeks gestation she spontaneously delivered a normal female infant (2.7 kg) [176]. Other case reports utilizing single agent, continuous dose vinblastine (5 mg orally, 5 x /week) throughout pregnancy have resulted in normal infants [177,178]. Vincristine is commonly employed in combination chemotherapy for the treatment of cancer during pregnancy. It has been used safely in the doses and schedules used for leukemia and has not been directly associated with any teratogenic effects. Of 31 cases reviewed, only

2 cases of teratogenic effects in infants receiving combination chemotherapy with vincristine were reported ]179,180], Atria1 anomalies following 1st trimester exposure to vincristine, vinblastine and procarbazine were noted in one infant [ 1791, and renal anomalies were reported in another infant after 1st trimester exposure to vincristine, nitrogen mustard, procarbazine and prednisolone [180] (Table 7). In both cases the dose of vincristine was relatively small (< 10 mg) compared to the other agents used, and in both cases procarbazine was used. In fact, the only cases of teratogenic effects following the use of the vinca alkaloids have involved the use of either procarbazine or nitrogen mustard either subsequent to or during 1st trimester pregnancy. The use of this combination of agents should perhaps be avoided during pregnancy, particularly during the 1st trimester. 4.4. Miscellaneous 4.4.1. Procarbazine 4.4.1.1. Clinical pharmacology. Procarbazine is a methylhydrazine which is commonly employed in the

treatment of Hodgkin’s disease. The antineoplastic effects of this agent are not fully understood but it appears to inhibit both RNA, DNA and protein synthesis. Following administration procarbazine distributes into most tissues including the liver, kidney, intestine and skin. Procarbazine must undergo metabolic activation to become cytotoxic (1821. The parent compound undergoes hepatic oxidation by the cytochrome P450 system to active azo, azoxy and hydroxy derivatives. The capacity for activation of procarbazine by the fetal tissues is unknown, but may likely occur. Further metabolism results in several N-isopropyl metabolites

101

V.J. Wiebe, P. E. H. Sipila / Crit. Rev. Oncol. Hematol. 16 (1994) 75-112 Table 7 Summary of vinca alkaloid use during pregnancy Disease (reference)

Patient age (years)

Gestational age (weeks)a

Drugs used during gestation dose/schedule/(T = total dose)

Maternal outcome

Fetal outcome

Infant followup

Hodgkin’s lymphoma

22

17

VLB (T = 9 mg), bleomycin (T = 15 mg), Dox (T = 40 mg), dacarbazine (T = 600 mg)

N.S.

Therapeutic abortion 15 h after chemotherapy

Dox measured in fetal tissues

Hodgkin’s lymphoma 11791

25

3

VLB (T = 10 mg), VCR (T = 2 mg), procarbazine (T = 1050 mg)

N.S.

Dysmature M - 1.8 kg, S.D. at 26 weeks, acute respiratory distress

Death day 2 atrial septal defect at autopsy

Hodgkin’s lymphoma 11811

27

1st trimester

VLB (doses - N.S.), nitrogen mustard, procarbazine, 6 courses prior to conception and booster course given at 2 months gestation

N.S.

Spontaneous abortion at 24 weeks, M fetus

Multiple anomalies webbed toes, cerebral hemorrhage

Hodgkin’s lymphoma [I761

23

1,2,3rd trimester

VLB (T = 67 mg-1st trimester), VLB IO mg bimonthly, throughout 2,3rd trimester

Partial response (time - N.S.)

Normal, F 2.3 kg, S.D. at 40 weeks

N.S.

Hodgkin’s lymphoma 11771

18

1,2,3rd

VLB (5 mg 5 x/week x II months)

Remission x 13 months

Normal, M 3.6 kg, S.D. at 1I months

Normal at 2 months

Hodgkin’s lymphoma 11781

22

7th month

VLB (0.1 mg/kg/week x 9 weeks) (T = 47.8 mg), radiation (C 27 rads)

Sustained remission (time - N.S.)

Normal, M 3.2 kg, S.D. at IO months

Normal at 7 months

Hodgkin’s lymphoma 11781

32

18

VLB 0.1 mgkgweek (T = 111 mg), CY 1 mg/kg iv x I, CY 50 mg/day orally x 8 days, CY 100 mg/day orally x 10 days, (T = 1480 mg)

Disease progression

Normal, M 3.1 kg, C-see at 37 weeks

Normal at 1 year, normal karyotype

Hodgkin’s lymphoma 11801

20

I st trimester

VCR 1.5 mg iv x 1, nitrogen mustard 4 mg, procarbazine 100 mgday x 7 days, PDN 60 mgday x 7 days

N.S.

Elective abortion at 92 days, M 89.2 g

Renal and cardiac abnormalities at autopsy

Hodgkin’s lymphoma [91]

21

18

VCR 2 mg days 1 + 8 (T = 14 mg), CY 1 g days 1 + 8 (T = 7 g), procarbazine 150 mg days I-14, (T = 7.35 g), PDN 74 mg days 15-28 (T = 3.15 g)

Relapse at 1 year

Normal, F 2.0 kg, S.D. at 37 weeks

Normal at 1 year, normal karyotype

Non-Hodgkin’s lymphoma [90]

26

18

VCR (doses - N.S.), MTX, Dox, CY, PDN, bleomycin, weekly intensive MACOP-B x 13 weeks

Excellent response, subsequent BMT

Normal male twins, C-set at 28 weeks

N.S.

Non-Hodgkin’s lymphoma [89]

25

Conception

VCR 2 mg, day I (T = 4 mg). CY 700 mg/m2(T = 1.4 g/m2), Dox 45 mg/m2 (T = 90 mg/m2), PDN 100 mg, day l-5 (T= 500 mg), l-2 courses

N.S.

Normal, M 3.4 kg, S.D. at 38 weeks

Normal at 2 months

T-ceil lymphoma 0601

28

25

VCR (T = N.S.), radiation 900 rads in 3 fractions over 36 h, (fetal dose 9-18 rads), dexamethasone (T = N.S.), Dox 45 mg/m* (T = N.S.), PDN (T = N.S.)

N.S.

Stillborn, F 1.2 kg, fetal death 36 h after chemotherapy

Normal fetus, placental thrombosis, dox metabolites in fetal tissues

11591

trimester

102

V.J. Wiebe. P. E. H. Sipila / Crit. Rev. Oncol. Hemafol. 16 (1994)

75-112

Table 7 (Conhued) Disease (reference)

Patient age (years)

Gestational age (weeks)a

Drugs used during gestation dose/schedule/(T = total dose)

Maternal outcome

Fetal outcome

Infant followup

ALL [12]

22

16

VCR monthly (doses - N.S.), PDN monthly, maintenance throughout remainder of pregnancy

Disease progression death at 1 month post-delivery

Normal, M 2.96 kg, C-set at 37 weeks

Normal at 4 years

ALL [94]

17

18

VCR2mgx4(T=> 8mg), Dauno (T = 220 mg), PDN 80 mg/day, ~-Asp 10000 u 2 x/week (T = IO5 u) 6-MP 350 mg x 5 days q 2 weeks, MTX 15 mg x 5 days q 2 weeks

Remission X 2.5 years

Normal twins, M - 2.5 kg, F - 2.4 kg, C-set at 37 weeks

Diarrhea at 24 h, normal immune fxn tests, normal development at 54 months

ALL [86]

24

12

VCR (T = 16 mg), Dox (T = 80 mg), PDN (T = 3.0 g), MTX (T = 150 mg), 6-MP (T = 1.0 mg)

Partial remission x 7 months

Normal, F 1.9 kg, C-set at 33 weeks

Normal at 16 months

ALL [86]

24

~23 trimester

VCR (T = 48 mg), MTX (T = 1.0 g), CY(T = 25 g), 6-MP (T = 18.3 g). PDN (7.6 g), Ara-C (3.5 g)

Partial remission, death 16 months postdelivery

Normal, F 2.3 kg, SD. at 40 weeks

Normal at 6 years

ALL 186)

18

1,233

VCR (T = 24 mg), Ara-C (T = 10.6 g), PDN (T = 3.8 g), 6MP (T = 250 mg), MTX (T = 600 mid,CY (T= 5 g)

Active disease, death 5 months postdelivery

Pancytopenic, M - 1.0 kg, C-set at 34 weeks, septicemia

Death at 21 days of age from septicemia

ALL [86]

37

2,3 trimester

VCR (T = 16 mg), Ara-C (T = 1.4 g), PDN (T = 3 g), 6-MP (T = 4 g), MTX (T = 600 mg)

Complete remission, death at 5 months postdelivery

Normal, F 2.4 kg, SD. at 38 weeks

Death at 90 days of age from gastroenteritis

ALL 1841

18

12.5

VCR2mgx4weeks(T=8 mg), Dauno 60 mg!m2/day x 2 days (T = 120 mg/m’), MTX 10 mg IT x 2 (T = 20 mg), ~-Asp 6000 u/m2 3iweek x 5 weeks (T=90000u/m2)CY 100 mg/m*/day x 2 weeks (T = 1.4 g/m2), PDN 60 mglm’/day x 4 weeks (T = 1.68 g/m2), 6-MP 60 mgfm2/day x 4 weeks (T = 1.68glm2), CNS radiation 2400 rads

Remission x 20 months

Normal development, F - 2.4 kg, severe bone marrow hypoplasia

Normal at 12

ALL [85]

32

17

VCR 2 mg/week x 4(T= 16 mg), Dox 50 mg, day I (T = 100 mg), PDN 40 mg/day x 4 weeks (T = 2.24 g), ~-Asp 14 000 u EOD x 7 (T = 196 000 u) CY 300 m&week (T = 4.8 g). MTX 30 mg’week (T = 480 mg), 6-MP 75 mg/day (T = 8.325 g)

Remission x 8 months

Normal, F 3.2 kg, S.D. at 38 weeks

Normal development at 40 months

ALL (851

17

34

VCR 2 mg/week (f = 6 mg), Dox 75 mg day 1 (T = 75 mg), PDN 60 mg/day (T = 1.26 g), Postdelivery chemotherapy

Remission x 4 months

Normal, M 3.3 kg, S.D. at 37 weeks

Normal growth and development at 32 months

V.J. Wiebe, P.E.H. Sipila/Crit.

103

Rev. Oncol. Hematol. 16 11994) 7.5-112

Table I (Continued) Disease (reference)

Patient age (years)

Gestational age (weeks)a

Drugs used during gestation dose/schedule/(T = total dose)

Maternal outcome

Fetal outcome

Infant followup

ALL [SS]

16

35

VCR 2 mtiweek (T = 8 md, Dox 40 mg, day 1 (T = 40 mg),?DN 60 mgday (T = 1.68 g), postdelivery chemotherapy

Remission x I year

Normal, M 2.9 kg, S.D. at 39 weeks

Normal development at 29 months

ALL [88]

32

16

VCR (doses - N.S.) Dox, PDN, ~-Asp, maintenance: CY, 6-MP, MTX, VCR, PDN, discontinued 2 weeks prior to delivery

Remission

Normal, F 3.8 kg, slight leukopenia

Normal development, normal wbc counts at 2 weeks

ALL [148]

26

Conception

VCR (dose - N.S.), MTX 30 mgweek (T = 180 mg), 6-MP 100 mg/day x 6 weeks (T = 4 g), PDN (dose - N.S.), reinduction: Dox 45 mgim*, EOD (T = N.S.), VCR weekly (T = N.S.), PDN daily, maintenance: Ara-C, MTX

Remission > 6 months

Normal M 2.4 kg, C-set at 36 weeks, polycythemia, hyperbilirubinemia

Normal development at 6

ALL [160]

30

21

VCR (dose - N.S.) , Dox (T = 214 mg/m*), PDN, ~-Asp, MTX, crania1 radiation

Remission x 30 months

Normal. M 2.08 kg, C-set at 34 weeks

Normal development at 30 months, Dox in placental tissues

AML [85]

16

16

VCR 2 mg/week (T = 2 mg), Dox 65 mg day 1 (T = 65 mg), PDN 100 mg/day (T = 1.2 g), Ara-C 160 mg/day x 4 days (T = 640 mg)

Death 1 week after chemotherapy, no response to treatment

Spontaneous abortion prior to maternal death at 18 weeks

N.S.

AML [I 141

21

12

VCR 2 mg, day 1 (T = 10 mg), Ara-C 140 mg/24 h x 240 h (T = 700 mg), Dox 80 mg, day I (T = 400 mg), PDN 100 mg days l-5 (T = 2.5 g), 5 courses

N.S.

Normal, F 2.86 kg, SD. at 28 weeks

Normal development, karyotype at 6 weeks

AML [I181

22

17

VCR 1 mgIm*/day, days 1 + 7, (T = 2 mgim*), Hydroxyurea 8 g (T = 8 g), Ara-C 90 ms/m* bid x 7 days, (T = 1.26 g/m*), Dauno 70 mglm*/day x 3 days (T = 210 mg/m*), 6-TG 90 mg/m* bid x 7 days (T = 1.26 mp/m*), PDN 40 mg/m*/day x 7 days (T = 280 mg), post-delivery chemotherapy, bone marrow transplant

Remission > 2 years

Elective abortion at 21 weeks

Normal fetus, 307.8 g, enlarged spleen

AML (1181

28

27

VCR 1 mg/m*, day 1 + 7, (T = 4.6 mgIm*), Ara-C 90 mg/m* bid x 7 days, (T = 2.52 g/m*), Dauno 70 mg/m’/day x 3 days, (T = 483 mg/m*) 6-TG 90 mg/m’ bid x 7 days (T = 2.9 g/m*), PDN 40 mg/m2/day x 7 days (T = 644 mgIm*), 2 courses, 2nd course with 30% increase in doses

Disease progression, death 9 days postdelivery

Normal, M 2.13 kg, S.D. at 31 weeks, anemia, electrolyte imbalances

Normal development at 13.5 months, depressed growth

104

Table 7

V.J. Wiebe. P. E. H. Sipila / Crir. Rev. Oncol. Hematol.

16 (1994)

75-11-7

(Conhued)

Disease (reference)

Patient age (years)

Gestational age (weekQa

Drugs used during gestation dose/schedule/(T = total dose)

AML [118]

37

3rd trimester

VCR 1 mg x 1 (T= 1 mg), MTX 2.5 mg bid x 3 days (T = 15 mg), 6-MP 50 mg bid po x 3 days (T = 300 mg), PDN 60 mg/day x 3 days (T = 180 mg), PDN 20 mg bid x 7 days (T = 280 mg)

AML 1121

30

18

AML [109]

20

APL (1201

Fetal outcome

Infant followup

Partial remission, death at 13 months post-delivery

Normal, F 2.35 kg, SD. at 34 weeks, cushingoid appearance

Normal at 8 weeks

Dox (doses - N.S.), Ara-C, maintenance: VCR, CY, Ara-C, monthly cycles

N.S. death 5 months post BMT

Normal, M 2.51 kg, S.D. at 34 weeks

Normal at 7 years

8

VCR2mgx4(T=8mg),Dox 40 mg (T = 40 mg), Daunoblastin 40 mg x 3, Ara-C 480 mg x 3 (T = 1.44 g), post-delivery chemotherapy

Complete remission x 11 months, death 14 months postdelivery

Normal, F 2.8 kg, S.D. at 38 weeks

Normal at 7 years

18

21

VCR 1 mg/m’, day 1 + 9, Ara-C 100 mg/m*, days 1-9, 6-TG 100 ms/m*, days 1-9, PDN 40 mg/m2, days l-9, Dox 70 mg/m*, days l-3, post-delivery chemotherapy

Remission > 4 months

Normal, M 1.32 kg, C-set at 30 weeks, respiratory distress

Normal at 70 days, normal karyotype

Breast cancer 11121

25

22

VCR 1.5mg, day I +8 (T=6 mg) N.S., Dox 40 mg, day 1 + 8 (T = 160 mg), PDN 20 mg, day 1- 14 (T = 280 mg), 2 courses

N.S.

Normal, M 1.99 kg, S.D. at 31 weeks

Normal growth at 4 months

Breast cancer 171

42

25

VCR2mgx2(T=4mg),MTX 40 mg/m* at week 30.33. Dox 60 mg/m* at week 30.33. postdelivery chemotherapy

Partial response, death at 1 year post delivery

Normal, F 2.00 kg, S.D. at 33 weeks, apnea, asystole at dehvery

Normal at 2 years

Endodermal tumor of the ovary 1971

24

17

Dox 45 mgIm* q 4 weeks x 5, VNC2mgq4weeks x 5+2 mgx3.CY600mg/m2q4 weeks x 5, post-delivery chemotherapy

Remission (time - N.S.)

Normal, F, induced labor at 37 weeks

Normal at 1 year

Endodermal sinus tumor

25

16

VCR weekly x 12 weeks, CY 200 mg/day x 5 days q 4 weeks (T = 6 g), Actinomycin D 0.5 mg q 4 weeks, post-delivery chemotherapy

Complete response > 33 months

Normal, M 2.85 kg, SD. at 37 weeks

N.S.

l981

Maternal

outcome

N.S., not stated; S.D., spontaneous delivery; C-see, Cesarean section; M, male; F, female; ALL, acute lymphocytic leukemia; AML, acute myelocytic leukemia; APL, acute promyelocytic leukemia; Ara-C, cytarabine; 5-FU, 5-fluorouracil; CY, cyclophosphamide; VCR, vincristine; VLB, vinblastine; MTX, methotrexate; ~-Asp, L-asparaginase; Dauno, daunorubicin; Dox, doxorubicin; 6-MP, 6mercapatopurine; PDN, prednisone; 6-TG, dthioguanine. Qestational age at which mother received chemotherapy.

V.J. Wiebe, P.E.H. Sipila/Cril.

Rev. Oncol. Hematol. 16 (1994)

7.5-112

(N-isopropyl-p-formylbenzamide, N-isopropyl-p-hydN-isopropylterephthalamic roxymethyl benzamide, acid). In vivo hydrolysis and autooxidative processes are also believed to result in free radical formation. Procarbazine is almost entirely converted to an azo metabolite. The procarbazine parent compound is highly polar, while the metabolites are non-polar. Procarbazine is renally eliminated primarily in the form of N-isopropylterephthalamic acid. The increased renal elimination of drugs in pregnancy may significantly increase the elimination of procarbazine. The parent compound and its metabolites readily penetrate the blood brain barrier [ 1831. Procarbazine concentrations in CSF are roughly equivalent to plasma concentrations by OS-l.5 h after administration. Penetration of procarbazine across the blood placental barrier has not been measured to our knowledge but it is very likely that procarbazine and its active non-polar metabolites penetrate into fetal tissues as well as breast milk. 4.4.1.2. Pharmacokinetics. Following oral administration of procarbazine peak plasma concentrations are seen in approximately 1 h. Plasma concentrations of the azo metabolite are low (< 100 nM/ml) however, this may only reflect the larger distribution of this lipophilic primary metabolite. Both the azo and azoxy metabolites can be measured in the CSF lo-30 min after procarbazine administration suggesting rapid penetration across membranes [ 1841. Procaribazine is rapidly cleared from plasma after intravenous dosing, with an elimination halflife of approximately 7 min. Conversion to active alkalating intermediates is subject to alterations in liver function. Agents which induce liver metabolizing enzymes, such as phenobarbital and phenytoin, result in an increase in procarbazine clearance and decrease in plasma azo concentrations [185]. Plasma clearance of procarbazine may therefore be altered in pregnancy where oxidative metabolism may be increased or decreased. In non-pregnant patients approximately 25-42% of a dose is excreted within 24 h after administration [ 1841. 4.4.1.3. Adverse effects on the fetus. Procarbazine has been shown to be teratogenic in rats at doses ranging from S-550 mg/kg. Appendicular defects, cleft palate and shortened jaws are noted in offspring. Single doses of 25, 50, and 75 mg/kg procarbazine are lethal or teratogenic given on days 5-12 of gestation but had no effect when given on days 14-17 [ 1861. Therefore the teratogenic effects are noted when the drug is given during the processes of neurulation and early morphogenesis. The use of single agent procarbazine during first trimester pregnancy has been described in a number of patients. Wells et al. report an infant born to a 18-year old woman who became pregnant while taking procarbazine loo-150 mg/m*/day for treatment of Hodgkin’s

105

disease. The drug was discontinued following diagnosis of pregnancy on approximately the 38th day after conception. A male infant (4096 g) with a number of abnormalities was delivered. Abnormalities included a verrucose, serpentive erythematous hemangioma on the forearm and several small hemangiomas on the trunk and extremities. Followup over a 13 month period reported normal growth and development with stabilization of the hemangiomas [ 1871. Daw et al., also report a normal infant born to a 22year old pregnant patient who mistakenly took procarbazine (50 mg/day) in place of a vitamin supplement for 30 days starting in her twelfth week of pregnancy. A normal 3.575 kg boy was delivered at term. No reference was made to followup of the infant [ 1881. The use of procarbazine in combination therapy has also been described in first trimester pregnancy. A 27year old pregnant patient with a prior history of Hodgkin’s disease treated with six courses of combination chemotherapy including nitrogen mustard, vinblastine sulfate and procarbazine, received a booster course at 2 months gestation. A male child with multiple abnormalities was delivered in the 24th week of gestation. Abnormalities included oligodactyly of both feet with webbing of the third and fourth toes, bowing of the right tibia, abnormal right pinna, and a large hemorrhage of the right cerebral hemisphere [181]. Thomas et al. report fetal abnormalities including a dysmature infant (1.88 kg) with a small secundum atria1 septal defect following combination therapy which consisted of nitrogen mustard (105 mg), vinblastine (140 mg); vincristine (2 mg) and procarbazine (12.6 g) (total doses received). Although the exact fetal exposure to chemotherapy was not mentioned at least one course of nitrogen mustard, vincristine and maintenance procarbazine were received during the first trimester of gestation [182]. Similarly, Mennuti et al. report several abnormalities in a fetus exposed to nitrogen mustard (4 mg), vincristine (1.5 mg), prednisone (60 mg/day x 7 days) and procarbazine (100 mg/day x 7 days) during the first 6 weeks of pregnancy in a 20-year old female with Hodgkin’s disease. Following termination of pregnancy at 92 days gestation, examination of the fetus showed no external abnormalities. However, on internal examination the kidneys were markedly reduced in size and malpositioned. Both kidneys were located just above the pelvic inlet, and the bifracation of the aorta was cephalad to their upper poles. Amniotic fluid cell culture revealed a normal 46XY chromosome analysis [ 1801. The role of procarbazine in the induction of these teratogenic effects is unknown. However, the use of nitrogen mustard which is known to be teratogenic complicates the assessment of teratogenic effects due to procarbazine. There have been reports of normal infants

106

born following the use of procarbazine in combination with other agents. Daly et al report the use of cyclophosphamide (650 mg/m2; day 1 + 8), vincristine (1.4 mg/m2; day 1 + 8), procarbazine (100 mg/m2; days 1- 14) and prednisone (50 mg/m2; days 15-28) in a 21year old pregnant patient with Hodgkin’s disease at 18 weeks gestation. A normal child which was slightly low in birth weight (2 kg) was delivered following total doses of cyclophosphamide (7000 mg), vincristine (14 mg), procarbazine (7350 mg) and prednisone (3150 mg). One year followup and chromosomal analysis were also normal [91]. The use of procarbazine in early pregnancy, particularly during the period of fetal neurulation and morphogenesis (3-12th weeks in humans) does appear to be associated with the risk of teratogenic effects. Although the agent has been used safely in some instances its use during the critical developmental stages of neurulation and morphogenesis is best avoided.

V.J. Wiebe. P.E.H. Sipila / Crit. Rev. Oncol. Hematol. 16 (1994)

Table 8 Pharmacologic variables that increase fetal risk during pregnancy Pharmacologic variable

Avoidance of risk

Stage of fetal development during drug exposure

Avoid exposure during 1st trimester, particularly weeks 3-12 Avoid high dose, long term therapy Avoid high dose, long term therapy Avoid using agents known to cause birth defects (folic acid antagonists, purine and pyrimidine antagonists, and alkylating agents) Allow sufficient time between delivery and last dose of chemotherapy, provide enough lime for maternal and fetal blood counts to recover Avoid using peritoneal and orally administered agents, whose absorption may be increased or decreased in late pregnancy Avoid drugs that are known to accumulate in fluid tilled compartments such as methotrexate, particularly late in pregnancy

High concentration x time (AW Extent of placental penetration by drug Mechanism of action of drug

Timing of delivery to last dose of chemotherapy

Route of drug administration

5. Discussion The decision to use antineoplastics in pregnancy is complicated by many ethical, emotional and religious issues. Fortunately the risk of developing cancer during pregnancy is low (< 0.1%) [189,190]. However, the current trend toward delaying child birth until a women is in her later reproductive years may bring with it an increased risk of cancer in pregnancy and the increased necessity to use antineoplastics in pregnancy. The use of antineoplastics in pregnancy is obviously not without risks to the fetus. However, if agents, doses and schedules are carefully selected the risk to the fetus may be substantially reduced (Table 8). What is known about the clinical pharmacology, pharmacokinetics and toxicology must be evaluated for each agent (Table 9). Although there is limited information about the pharmacology and pharmacokinetics of antineoplastics in pregnancy, some conclusions can still be drawn from the little information that is available. In general, where fetal tissues or blood samples have been evaluated for the presence of drug either the parent compound or metabolites have been noted. This suggests that many drugs can easily penetrate the maternal/fetal placental barrier. However, fetal exposure to drug does not necessarily imply that teratogenesis or fetal toxicity will occur. In the case of doxorubicin its presence has been detected in a variety of fetal tissues, but it has not been directly associated with significant teratogenic or toxicologic effects on the fetus. Drug induced fetal anomalies may therefore be more related to each agents mechanism of action, the ability of the fetus to metabolize the drug and the total exposure time and concentration (AUC) of the drug. Drugs that interfere with the biosynthesis of DNA, RNA and proteins appear to be particularly teratogenic. These

75-112

Pharmacologic 3rd spacing of drugs

include; folic acid antagonists (methotrexate, aminopterin), purine antagonists (6-mercaptopurine, 6-thioguanine), and pyrimidine antagonists (5-fluorouracil, FUdR, ftorafur, Ara-C, 5-azacytidine, 6-azauridine, hydroxyurea, guanazole). Alkalating agents including nitrogen mustard and cyclophosphamide are also considered highly teratogenic. At this point very little is known concerning fetal metabolism of antineoplastic agents. Fetal liver metabolism appears to be significantly different from that of the maternal liver. In general, the fetus has reduced oxidative/reductase capacity compared to the maternal liver. However, fetal adrenal and hepatic enzyme activities increase after the 7th week of gestation [ 1551. The effect of reduced fetal metabolism of drug may increase or decrease the risk of drug induced fetal toxicity. If agents require metabolism to their active or toxic species then reduced fetal exposure to cytotoxically active drug may result. On the other hand, if the parent compound is cytotoxically active and the fetus is unable to metabolize the drug increased exposure and toxicity is likely to result. Furthermore, if the drug is excreted in active form by the fetus into the amniotic fluid, oral ingestion of the drug in the amniotic fluid may occur causing further fetal exposure to drug. Increased fetal exposure to cytotoxic drugs may also be the result of a variety of factors including large total

107

V.J. Wiebe. P.E. H. Sipila I Crit. Rev. Oncol. Hematol. 16 (19941 75-112

Table 9 The pharmacology and pharmacokinetics of chemotherapeutic

drugs in non-pregnant patients

Drug

Route given

Metabolism

Activity of metabolites

T1/2”

Protein bindingb

Membrane penetration

Anthracyclines

IV

Active

25-50 h

50-90%

High

Ara-C Busulfan Cisplatin Cyclophosphamide SFluorouracil Methotrexate

IV Oral IV IV, Oral IV IV

Active Unknown Active Active Active Active

2.3-2.6 h 1.8-5.6 h 58-73 h 9h 12-37 min 2-4 h

13% 55x, 90°K 50”/1, 50%

High High High High High High

Procarbazine Vinblastine Vincristine

Oral IV, Oral IV

Intracellular, liver, kidneys Liver, RBC’s kidneys Liver Renal Liver Liver, kidneys Liver, GI, bone marrow Liver Liver Liver

Active Active Unknown

7 min 25 h 85 h

Unknown 99%” 99%

High Low Low

aThe halflife may be significantly altered in pregnancy, an increased volume of distribution and decreased peak concentration will result in a longer Tl/2, unless metabolism and/or excretion are also increased. bProtein binding will be increased for those drugs that are significantly bound to plasma proteins; IV, Intravenous.

doses of drug, prolonged infusions of drug, intraperitoneal administration of antineoplastics, coadministration of drugs that allow the accumulation of one drug (vine alkaloids and MTX), or delayed elimination of drug from the maternal system (such as third spacing with methotrexate). The amniotic fluid may itself behave as a 3rd compartment and may act as a sink, where the slow release of drug over time may increase the exposure time of the fetus to drug. This may be particularly true if high dose methotrexate is administered to the pregnant patient. In this case, methotrexate levels should be monitored and calcium leucovorin rescue should be considered. In general, the maternal system is geared up in pregnancy with most renally excreted drugs being rapidly metabolized and eliminated. There is an increase in renal plasma flow, glomerular filtration rate, and creatinine clearance. Increased protein binding of some drugs may also reduce the non-protein bound active fraction of the drug. These factors may tend to reduce maternal exposure (AUC) of drugs and potentially reduce the efficacy of cytotoxic agents. However increasing the dosage of drug may risk fetal toxicity and is not advised. Avoidance of any other variables that may also alter the pharmacokinetics of the antineoplastics may be beneficial. For example, since the stomach empties more slowly and gastrointestinal motility is decreased in pregnancy it is best to avoid the use of oral agents since their absorption may be significantly altered. The timing of delivery with respect to the administration of the antineoplastic agents is also crucial. Although the halflife of most chemotherapy drugs is variable (hours to weeks) typically the majority of drug will be sufficiently eliminated from the maternal system

after 2-3 weeks following therapy. Since surgery or delivery should never be planned when a patients blood count remains low from the cytotoxic effects of chemotherapy and the nadir is generally around 2 weeks, a period of 3-4 weeks following the last course of chemotherapy should be the minimum time between chemotherapy and delivery. Delayed nadirs may indicate delayed elimination of drug and the need for more time to recover from the cytotoxic effects of chemotherapy before delivery. Since elimination of drug from the fetus is also dependent on the maternal system, prior to full recovery delivery may not only predispose the mother to bleeding problems and infection but may also put the fetus at increased risk of cytotoxic effects from drugs which may not be easily eliminated by the immature infant liver and kidneys. Close monitoring of the infant’s blood counts and potential danger of hemorrhage should be assessed carefully. In the first trimester it is best to avoid the use of antineoplastics altogether, however, if the situation arises where chemotherapy must be used, both doxorubicin and the vinca alkaloids appear to be somewhat less teratogenic than other agents used in first trimester pregnancy. In the second and third trimester, single agent antineoplastics or combination chemotherapy has been given successfully with little damage to the fetus. However, careful fetal monitoring, evaluating intrauterine growth and fetal stress should be performed routinely. When using combination chemotherapy each agent should be selected carefully and the benefits must be weighed against the risks. Furthermore, radiation is a known teratogenic agent and its use during pregnancy should be discouraged. However, if radiation has been administered to a patient where the physician was unaware of the patient being

108

V.J. Wiebe, P. E.H.

pregnant this does not always imply that therapeutic abortion be suggested. The physician should first try to establish the stage when radiation was administered, the extent of embryonic exposure and other ethical considerations. The patient should be counseled as to the increased risk of fetal malformations and should be offered the use of diagnostic procedures such as amniocentesis, placental villusbiopsy and ultrasound to help evaluate the situation. Breast feeding should also be discouraged in any patient receiving chemotherapy. Many drugs do appear to penetrate into breast milk and the long term effects of low doses of antineoplastics are unknown. Significant concentrations of cyclophosphamide resulting in neutropenia in infants have been reported (Amato 77). In addition, doxorubicin, cisplatin, methotrexate and hydroxyurea have all been identified in significant concentration in breast milk.

5 6 7

8 9

IO II

12

I3

6. Biographies 14

Valerie J. Wiebe received her B.A. and M.S. from the University of California, Santa Barbara, and her Pharm.D. from the University of California, San Francisco. She completed a fellowship in the Section of Oncology at Yale University. She is currently an Assistant Professor in the Departments of Medicine and Pharmacy at the University of Texas Health Science Center in San Antonio, TX. Pirkko Sipila received her B.A. and M.D. from the University of Turku, Finland. She completed a Fellowship in the Department of Gynecological Oncology at the University Hospital of Oulu. She served as Chief of the Department of Gynecological Oncology at the University Hospital of Oulu and the University Central Hospital of Oulu. She was a visiting Assistant Professor in the Department of Medicine at the University of Texas Health Science Center in San Antonio, TX, and is currently doing research at Oulu University, Department of PubIic Health Science.

I5 I6 I7 I8 19 20

21 22

23 24

7. Reviewer 25

This paper was reviewed by David Gandara, M.D., Oncology Division, University of California, School of Medicine, Davis, CA, USA.

26

8. References

27

Potter JF, Schoeneman M. Metastasis of maternal cancer to the placenta and fetus. Cancer 25:380-388, 1970. Gallenberg MM, Loprinzi CL. Breast cancer and pregnancy. Semin Oncol 16:369-376, 1989. Ward FT, Wiess RB. Lymphoma and pregnancy. Semin Oncol 16:397-409, 1989. Caligiuri MA, Mayer RJ. Pregnancy and leukemia. Semin Oncol 16:388-396, 1989.

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