Part 13 (1/2)

Antibiotics 137.

Dactinomycin Dactinomycin (Cosmegen), also known as actinomycin-D, is one of a group of antibiotics produced by various species of streptomyces called the actinomycins. It is FDA-approved to treat choriocarcinoma, Ewing's and Wilms' tumors, rhabdomyosarcoma, and cancers of the testis and uterus. Primary indication for dactinomycin in obstetrics is to treat gestational trophoblastic tumors.

No studies are available regarding dactinomycin use during pregnancy, but it is an FDA category C drug. Four normal infants (one set of twins) were born to mothers who received dactinomycin in the second and/or third trimesters of pregnancy as part of combination therapy in two pregnancies (Gililland and Weinstein, 1983), but there was no exposure during embryogenesis. The manufacturer of dactinomycin reported that malformations were increased in frequency in various animals whose mothers were given doses of the drug several times those normally used in humans, but the information is unpublished and no details were provided.

Mitomycin Mitomycin (Mitomycin-C) is an antibiotic with ant.i.tumor activity that acts by blocking DNA synthesis. It is isolated from the broth of Streptomyces caespitosus Streptomyces caespitosus, similar to dactinomycin. It is FDA-approved as part of combination therapy for pancreatic and stomach cancers. Occasionally, it is used to treat hypercalcemia secondary to malignancy.

No reports have been published regarding the use of mitomycin during pregnancy and infant outcome. Congenital anomalies were increased in several mouse teratology studies that employed several times the usual human therapeutic dose of the drug during pregnancy (Friji and Nahatsuka, 1983; Gregg and Snow, 1983; Snow and Tam, 1979). In an experimental animal model, approximately 6 percent of mitomycin crossed the placenta in pregnant rats (Boike et al et al., 1989). One investigator conducted embryo studies in mice that suggest that as early as the four-cell embryo stage, mitomycin has a genetic imprint-ing effect acting at the proliferative DNA level (Snow, personal communication).

Anthracycline antibiotics Anthracycline antibiotic antineoplastics (daunorubicin or Cerubidine; doxorubicin or Adriamycin, Rubex) are potent inhibitors of nucleic acid synthesis and are nonspecific cell cycle-phase agents. Daunorubicin is FDA-approved for neuroblastoma and acute leukemias. Doxorubicin is FDA-approved for acute leukemias, lymphomas, Wilms'

tumor, and sarcomas, as well as a variety of carcinomas (bladder, breast, ovary, gastric, thyroid, and small-cell cancers).

No studies are available of either of these agents during pregnancy, but there are a number of case reports. In reviews from 18 reports of 28 pregnancies that were exposed to one of the anthracyclines at various stages of gestation, eight of the pregnancies were at 16 weeks' gestational age or less at exposure. All but one received polytherapy chemotherapy.

There were 24 normal infants (one set of twins), two spontaneous abortions, one therapeutic abortion, and two fetal deaths (Turchi and Villasis, 1988; Wiebe and Sipila, 1994).

Fetal deaths were secondary to maternal deaths. One infant was reported with multiple 138 138 Antineoplastic drugs during pregnancy abnormalities, similar to BallerGerold syndrome; was exposed in utero in utero at conception to combination therapy containing doxorubicin and daunorubicin (Artlich at conception to combination therapy containing doxorubicin and daunorubicin (Artlich et al et al., 1994).

Among 43 infants published in 26 reports, the frequency of birth defects was not increased, with two malformed infants (Friedman and Polifka, 2006).

The cytotoxic nature of these drugs suggests that embryonic exposure may not be without risk, depending upon the timing of the exposure. Adverse fetal effects do appear to be appreciably increased. The manufacturer of daunorubicin reported multiple defects in rabbits; prematurity and low birth weight was found in mice exposed to the drug in utero, in utero, but this information has not been published. Published data indicate increased frequencies of birth defects (heart, digestive system, eye, genitourinary (GU) defects) in rats, but not rabbits. but this information has not been published. Published data indicate increased frequencies of birth defects (heart, digestive system, eye, genitourinary (GU) defects) in rats, but not rabbits.

PLANT ALKALOIDS.

Vinblastine (Velban) and vincristine (Oncovin) are antimitotic Vinca Vinca alkaloids and they act through inhibition of microtubule formation, and this produces arrest of the cell cycle in metaphase (Box 7.6). The mechanism of action of etoposide is probably similar. alkaloids and they act through inhibition of microtubule formation, and this produces arrest of the cell cycle in metaphase (Box 7.6). The mechanism of action of etoposide is probably similar.

Box 7.6 The plant alkaloid antineoplastics Vinblastine (Velban, Velsar) Vincristine (Oncovin, Vincasar, Vincrex) Etoposide (VePesid) Vinblastine Vinblastine (Velban, Velsar) is FDA-approved to treat lymphoma, Hodgkin's disease, chronic myelocytic leukemia, and several carcinomas: breast, bladder, lung, and testis (Jacobs et al et al., 1981). A review from five separate reports of pregnant women with Hodgkin's disease gave details of 13 normal infants following maternal vinblastine therapy. Eleven of these infants had first-trimester exposure and two had second-trimester exposure. Among the offspring of five pregnant women who used vinblastine during the first trimester, congenital anomalies were observed in two infants, there was one spontaneous abortion and two normal neonates (Metz et al et al., 1989). No anomalies were reported in 27 infants, 17 of whom were exposed during the first trimester (Aviles and Neri, 2001; Wiebe and Sipila, 1994). One normal infant was reported who was exposed following maternal vinblastine, bleomycin, and cisplatin therapy for a malignant ter-atoma during the second trimester (Christman et al et al., 1990). It should be noted that there is considerable overlap in the published reports included in the different reviews.

Vinblastine was a.s.sociated with an increased frequency of congenital anomalies in rats, mice, hamsters, and rabbits exposed during embryogenesis.

Vincristine (Oncovin) Vincristine is FDA-approved to treat leukemia (acute and chronic), lymphomas, Hodgkin's disease, neuroblastoma, rhabdomyosarcoma, and Wilms' tumor. It is also used to treat Miscellaneous agents Miscellaneous agents 139.

melanoma, trophoblastic tumors, and some carcinomas (breast, cervical, ovarian, and lung). The cytotoxic nature of vincristine suggests high potential to cause birth defects in exposed embryos, although no published studies doc.u.ment this. Among 35 infants born to women who received vincristine as part of polydrug antineoplastic regimens at various stages of gestation, there were two spontaneous and three therapeutic abortions, two intrauterine deaths (without anomalies), and 29 live-born infants with no gross anomalies (Caliguri and Mayer, 1989). It is important to note that only 11 of 29 infants were exposed to vincristine in the first trimester, and none were malformed. However, all vincristine-polytherapy-exposed newborns had significant transient pancytopenia, and one infant had polydactyly (most probably not drug-related). Among 31 infants exposed to antineoplastic agents during gestation in another review, two major birth defects occurred among those exposed to vincristine polytherapy regimens (Wiebe and Sipila, 1994). Of five infants born to women who sustained exposure to the drug during the first trimester, one had a major congenital anomaly (Metz et al et al., 1989). Vincristine and vinblastine were a.s.sociated with an increased frequency of congenital anomalies in nonhuman primates and in rat studies (Courtney and Valenio, 1968; Demeyer, 1964, 1965).

Etoposide Etoposide (VePesid, VP-16VPP) is a semisynthetic derivative of podophyllotoxin that inhibits DNA synthesis. Its related sister molecule, podophyllum, is used to treat condylomas. It is approved for use against testicular and small-cell lung cancer. Acute leukemia, lymphomas, gestational trophoblastic tumors, and a variety of carcinomas are also treated with etoposide. No anomalies were reported in one infant exposed whose mother was treated with an etoposide-containing polytherapy during pregnancy (Rodriguez and Haggag, 1995). One infant was born with cerebral atrophy following first trimester exposure to etoposide (Elit et al et al., 1999), but 16 infants in other case reports were found to have no congenital anomalies. According to the manufacturer of the drug, this agent was teratogenic in animals, but these studies have not been subjected to peer review.

MISCELLANEOUS AGENTS.

Other antineoplastic agents that do not belong to the categories previously discussed are cla.s.sified as miscellaneous in this text (Box 7.7).

Asparaginase Asparaginase (Elspar) contains the enzyme L-asparagine amidohydrolase (derived from Escherichia coli Escherichia coli), and is FDA-approved to treat acute lymphocytic leukemia. Occasionally, this agent is used to treat chronic leukemias and lymphomas. The mode of action is thought Box 7.7 Miscellaneous antineoplastic agents Box 7.7 Miscellaneous antineoplastic agents Asparaginase (Elspar) Hydroxyurea (Hydrea) Altretamine (Hexalen) Pac.l.i.taxel (Taxol) Cisplatin (Platinol) Procarbazine (Matulane) 140.

Antineoplastic drugs during pregnancy to be asparagine catabolism. No studies have been published regarding use of this drug during the first trimester of pregnancy. Treatment during the second and third trimesters was a.s.sociated with pancytopenia. It is cla.s.sified as FDA fetal risk category C. In a review of seven infants whose mothers were given L-asparaginase as part of polydrug therapy for leukemia, all were live-born and none had congenital anomalies (Caliguri and Mayer, 1989).

Importantly, only one of these infants was exposed to the drug during the first trimester.

Asparaginase was a.s.sociated with an increased frequency of congenital anomalies in the offspring of pregnant rats, rabbits, and mice (Adamson and Fabro, 1970; Lorke and Tettenborn, 1970; Ohguro et al et al., 1969).

Cisplatin Cisplatin (Platinol) is a heavy-metal complex that inhibits growth of cancer cells by inducing interstrand crosslinks in DNA. It is FDA-approved for the treatment of testicular, ovarian, and bladder cancers. Cisplatin is also used to treat a number of carcinomas: adrenal, head and neck, lung, neuroblastoma, osteosarcoma, prostate, stomach, cervical, endometrial, and breast.

No studies of this agent have been published, but there are case reports. A review of case reports suggested that cisplatin has been administered in the second and third trimesters without untoward fetal effects (Christman et al et al., 1990; King et al et al., 1991), but case reports cannot adequately address safety. Caution is recommended for its use in the first trimester because platinol interferes with neurolation (complete development of the neural tube) in experimental animals. This corresponds to the 3rd to 4th weeks postconception in humans (Wiebe and Sipila, 1994). In animal teratology studies, investigators found growth r.e.t.a.r.dation but no malformations following exposure during embryogenesis to cisplatin in mice, rats, and rabbits (Anabuki et al et al., 1982; Kopf-Maier et al et al., 1985; Nagaoka et al et al., 1981).

Carboplatin Carboplatin (Paraplatin) is a platinum compound whose action is similar to cisplatin, producing predominantly interstrand DNA crosslinks rather than DNA protein crosslinks. Its FDA-approved indications are for the primary and secondary treatment of advanced ovarian cancer. It is also used to treat other types of cancer: bladder, brain, breast, endometrium, head and neck, lung, neuroblastoma, testis, and Wilms' tumor. No studies have been published of use of this agent during pregnancy in humans. One case report of carboplatin treatment during the second trimester stated that subsequent fetal and neonatal development was normal (Henderson et al et al., 1993). Manufacturer package inserts report that carboplatin is embryotoxic and teratogenic in rats. In one study, in offspring of rats exposed to carboplatin during embryogenesis, fetal weight was reduced, but there were no congenital anomalies (Kai et al et al., 1988).

Procarbazine Procarbazine (Matulane) is a hydrazine derivative that inhibits RNA, DNA, and other protein synthesis. It is FDA-approved for treatment of Hodgkin's disease.

Miscellaneous agents 141.

Procarbazine is also used to treat lymphomas, lung and brain carcinoma, and melanoma.

No studies have been published of infants born to women who were exposed to this drug during embryogenesis. A clinical series of six pregnancies were published following exposure to procarbazine in the first trimester (four in combination with other agents). Among these infants two were normal, one infant had hemangiomas on its extremities, one elective abortion occurred, and two miscarriages were reported. Of the miscarriages, one had malpositioned, hypoplastic kidneys and the other had four toes on each foot, with bilateral webbing (Gililland and Weinstein, 1983). In a review of collected cases, the authors summarized their findings, stating that procarbazine use 'in early pregnancy, particularly during the period of fetal neurolization and morphogenesis (3rd to 12th weeks menstrual in humans) does does appear to be a.s.sociated with the risk of teratologic effects' (Wiebe and Sipila, 1994) (emphasis added). Congenital anomalies were increased in frequency among rats whose mothers were treated with procarbazine during embryogenesis (Chaube and Murphy, 1968; Tuchmann-Duplessis and Mercier-Parot, 1967). Notably, both animal studies found an increased frequency of eye defects. appear to be a.s.sociated with the risk of teratologic effects' (Wiebe and Sipila, 1994) (emphasis added). Congenital anomalies were increased in frequency among rats whose mothers were treated with procarbazine during embryogenesis (Chaube and Murphy, 1968; Tuchmann-Duplessis and Mercier-Parot, 1967). Notably, both animal studies found an increased frequency of eye defects.

Hydroxyurea Hydroxyurea (Hydrea) inhibits DNA synthesis and is FDA-approved for chronic myelocytic leukemia, ovarian carcinoma, head and neck cancers, and melanoma. No studies have been published on the use of hydroxyurea during pregnancy in humans. A case report of two infants exposed to hydroxyurea during the second and third trimesters as part of polydrug therapy had no congenital anomalies in the fetus (therapeutic abortion) or the live born infant (Caliguri and Mayer, 1989). Three subsequent case reports of fetuses exposed in the first and second trimesters revealed no anomalies (Fitzgerald and McCann, 1993; Jackson et al et al.; 1993; Patel, 1991). Among seven women treated from conception to delivery, one stillborn premature infant and one fetal death occurred (Koh et al et al., 2002). Five apparently normal infants were born after exposure to hydroxyurea throughout gestation. Importantly, hydroxyurea is suspected to be a human teratogen based upon its mechanism of inhibitory action on DNA and essential proteins.

Altretamine Altretamine (hexamethylmelamine, Hexalen) was used early (1964) as an antineoplastic and is FDA-approved to treat epithelial ovarian cancer (Moore et al et al., 1991). The mechanism of action is unknown. No studies of congenital anomalies in infants whose mothers used this agent during pregnancy have been published. Offspring of rats and rabbits exposed to hexamethylmelamine during embryogenesis had an increased frequency of congenital anomalies (Thompson et al et al., 1984).

Pac.l.i.taxel Pac.l.i.taxel (Taxol) is a natural plant product derived from the bark of the Pacific yew tree. It promotes a.s.sembly and stabilization of microtubules by preventing depolymer-ization, and subsequently halting mitosis. It is FDA-approved for the treatment of 142 142 Antineoplastic drugs during pregnancy ovarian and breast cancer. It is also used against endometrial and non-small-cell lung cancer. No studies of pac.l.i.taxel in pregnant women have been published. Unpublished data from the manufacturer states that pac.l.i.taxel has been shown to be embryo- and feto-toxic in rats and rabbits.

SPECIAL CONSIDERATIONS.

Nongenital cancers Breast carcinomas and melanoma appear to be the most frequently occurring of several forms of nongenital cancers that may occur in the pregnant patient (Table 7.1).

Breast carcinoma Breast carcinoma is the most common malignancy that occurs in women, and affects approximately 10 percent of all women at some time during their lives. Breast carcinoma occurs in approximately one to seven per 10 000 pregnancies (3 percent of all breast carcinomas) (Parente et al et al., 1988).

Apparently, pregnancy per se per se has little, if any, adverse effect on the course or prognosis of breast cancer when a.n.a.lyzed stage for stage (Marchant, 1994). Pregnant women seem to be more likely to have: (1) advanced lesions when diagnosed, and (2) estrogen-receptor-negative tumors (Is.h.i.+da has little, if any, adverse effect on the course or prognosis of breast cancer when a.n.a.lyzed stage for stage (Marchant, 1994). Pregnant women seem to be more likely to have: (1) advanced lesions when diagnosed, and (2) estrogen-receptor-negative tumors (Is.h.i.+da et al et al., 1992; Elledge et al et al., 1993). Both of these factors are a.s.sociated with a worse prognosis than less advanced lesions and estrogen-receptor-positive tumors. The average delay in the diagnosis of breast carcinoma in pregnancy is from 1.56 months longer than diagnosis in nonpregnant women (Barnavon and Wallack, 1990). Delays in diagnosis of 36 months significantly diminish the chances of survival in both pregnant and nonpregnant patients. As part of family history collected, any genetic relative of the patient who has had breast cancer should trigger a simple screening for breast carncinoma.

Treatment strategy depends upon (1) stage of the carcinoma and (2) gestational age of the pregnancy. Surgery can generally be performed throughout gestation (see Chapter 6). If the procedure is done close to term, risk to the fetus can be eliminated if the infant is delivered first (Bloss and Miller, 1995). The usual accepted surgical technique for breast carcinoma in the pregnant patient is modified radical mastectomy with axillary node dissection (Marchant, 1994). 'Lumpectomy' and sampling of axillary nodes followed by radiotherapy has not been satisfactorily evaluated in the pregnant patient.

Moreover, radiotherapy may present a significant risk to the fetus (Petrek, 1994). These guidelines are consistent with the recommendations made in 2005 (Pentheroudakis and Pavlidis, 2006).

Chemotherapy is frequently recommended for either adjunctive therapy or treatment in advanced cases. Women with axillary lymph node metastases appear to be the best candidates for adjunctive chemotherapy (Barnavon and Wallack, 1990). As detailed previously in this chapter, chemotherapy with currently available antineoplastic agents carries an increased risk of congenital anomalies with first-trimester exposure, and fetal growth r.e.t.a.r.dation is the major risk in the latter two-thirds of pregnancy, although long-term effects are unknown.

Special considerations 143.

The efficacy of breast carcinoma treatment during pregnancy appears to be enhanced little, if at all, by therapeutic abortion and prophylactic ooph.o.r.ectomy (Donegan, 1986). Therapeutic abortion might be a consideration if radiotherapy is deemed necessary or if chemotherapy is necessary during the first trimester. However, with proper s.h.i.+elding and focused radiotherapy above the maternal diaphram, it may be possible to minimize the adverse effects of radiation on the fetus (Pentheroudakis and Pavlidis, 2006).

Leukemia Acute leukemia is extremely rare during pregnancy, occurring in approximately one in 100 000 pregnancies. However, it is among the most common neoplasms in young women (Caliguri and Mayer, 1989; Catanzarite and Ferguson, 1984; Koren et al et al., 1990). Review of 72 cases of leukemia during pregnancy (13 separate reports), 64 (89 percent) women had acute leukemia and eight (11 percent) had chronic or other forms of leukemia (Caliguri and Mayer, 1989). Acute myelocytic leukemia (AML) was the most common malignancy encountered, and most cases were recognized in the latter half of pregnancy (see Table 7.4). The survival rate was approximately 75 percent in one report of 45 pregnant women with acute leukemia (Reynoso et al et al., 1987), which is similar to the rate among nonpregnant patients with acute leukemia (Caliguri and Mayer, 1989). Therefore, pregnancy per se per se does not affect the course of leukemia. does not affect the course of leukemia.

Antineoplastic drugs most commonly used to treat chronic leukemia include antimetabolites (methotrexate, thioguanine, mercaptopurine, and cytarabine), anthracycline antibiotics (daunorubicin and doxorubicin), and plant alkaloids (vincristine).

Alkylating agents are also used as antileukemic drugs. Notably, all of these drugs are cytostatic, although their methods of accomplis.h.i.+ng this differs (cyotoxicity, DNA, and protein synthesis suppression). Therefore, all antineoplastics have a very high potential for production of birth defects during embryogenesis because this period is characterized by the highest rate of cell division (hyperplasia) in a human's life.

The prognosis for survival in the untreated woman is extremely poor, with life expectancy of less than 3 months (Catanzarite and Ferguson, 1984; Hou and Song, Table 7.4 Table 7.4 Cases (n = 72) of leukemia in pregnancy, 19751988 Cases (n = 72) of leukemia in pregnancy, 19751988 n %.

Trimesters First 16.22.Second 26.36.Third 30 42.

Types of leukemia Acute lymphoblastic 20.28.Acute myelocytic 44.61.Chronic myelocytic 5.7.Hairy cell 1.1.3.

Not specified 2.2.7.