Cancer in Pregnancy: Cisplatin

Cisplatin "Platinol;"cis-diamminedichloroplatinum; also called cis-platinum is a platinum-containing complex which may act similarly to the alkylating agents. This antineoplastic agent has been used in the treatment of a variety of solid tumors, including those of the urogenital system, in men and women. In most animal experiments cisplatin caused an increase in embryolethality but teratogenic effects were not seen ^1-4.

	Setting	Treatment	Outcomes
In vitro studies	chicks embryo	single dose	A study in chicks, found microphthalmia associated with single-dose cisplatin injection of the egg ⁵.
	Species studied
Animal studies *	mouse	before organogenesis administration	One mouse study, reported in abstract, found that cisplatin induced digital and tail malformations when administered before the onset of organogenesis of these tissues ⁶.
		pharmacokinetics, placental transport	Animal data (mouse) indicate that as the placenta matures the drug is transferred more efficiently ⁷. This would protect the early developing embryo from toxic effects but would permit toxic effects of cisplatin on the more developed fetus. This observation is supported by the available clinical reports ^8,9.
	mice	after embryogenesis administration	Degenerative changes in the brain tissue of fetal mice were found when cisplatin was given after the embryo genesis period ². The developing embryo may be protected from exposure to this agent by poor placental transfer of cisplatin ^3,7.
	rats	9 weeks treatment	Treating male rats with cisplatin for a period of nine weeks increases the incidence of preimplantation and post implantation loss as well as the incidence of omphalocele and growth retardation of their offspring ^10,11.Data were not collected on the possible direct transfer of cis-platinum, or its metabolites, in the semen of exposed animals, although some of the investigators suggested this direct transfer was unlikely ¹¹.
		intraperitoneally, in maximum daily doses of 0.5 mg/kg	In rats treated before mating and during the first 7 days of gestation, resorptions were increased at 0.25 mg/kg and above ¹. At the highest dose, some lethality and growth retardation was seen when rats were treated during organogenesis. Postnatal studies showed decreased viability and exploratory behavior in rat offspring exposed to 0.25 and 0.5 mg/kg.
	mice	intraperitoneally, 10-20 mg on individual days	This treatment during organogenesis produced growth and osseous retardation but no gross malformations ¹². Some increase in slight hydrocephalus was seen but no dose response was present. At doses of 20 mg/kg the embryos were resorbed.
	rats and rabbits	intravenously, 0.54 and 0.3 mg/kg	Nagaoka et al. (1981) gave this antineoplastic agent intravenously to rats and rabbits in maximum doses of 0.54/kg and 0.3 mg/kg, respectively ⁴. No ill effects were found in the rabbit fetuses exposed during organogenesis. In the rat, some embryolethality and decreased body weight occurred at 0.375 mg/kg during organogenesis and in the perinatal period.
	rats and mice	prenatal exposure	One group of investigators have found that mice or rats prenatally exposed to cisplatin had an increased risk of later tumor formation in various tissues ^13,14. Although it is not known if this finding has relevance for the use of cisplatin clinically, the authors recommend that infants exposed to this agent during gestation be monitored for preneoplastic and neoplasticlesions in later life ¹³.
	Study Design
Human studies	pharmacokinetics	12 vs 26 weeks of exposure	In a report involving fetal exposure to cisplatin at 12 weeks gestation, adverse effects on fetal development were not detected ⁸. However, the administration of cisplatin at 26 weeks gestation was associated with neutropenia, hair loss, and some hearing impairment in the premature neonate that was delivered six days after being exposed ⁹.
	Case reports	2nd- 3rd trimester exposure combination with cyclophosphomide	The clinical course of a 40-year-old primigravida with ovarian cancer at 17 weeks of gestation has been described ¹⁵. The patient received initial chemotherapy with cisplatin 100 mg/m2 and cyclophosphamide 600 mg/m2 at 20 weeks of gestation. Following 2 courses of this therapy, carboplatin was substituted for cisplatin and therapy was continued. At 36 weeks, a normal-appearing 3600 gram infant was delivered (APGAR scores of 9/9). Cisplatin-DNA adducts were found in amniotic cells and in placental tissue, but not in the infant's blood at 3 or 12 months of age. Growth, neurologic findings, hematologic parameters, and renal function were normal in the infant at 12 months of age. There are two others case reports of women who received a complete course of chemotherapy, including cisplatin, for the successful control of neoplastic disease and subsequently had a normal pregnancy ^16,17.
	Occupational study (survey)		One study that examined the occupational exposure of health care personnel to cisplatin did not find significant absorption of the drug ¹⁸.
Breast feeding	Case reports	cisplatin infusions	Although an older study did not detect cisplatin in breast milk ¹⁹, two more recent studies have reported the excretion of platinumin milk ^20,21.In one report, the breast milk from a woman who had received cisplatin infusions on the previous 3 days showed a milk: plasma ratio of 1.1 for platinum ²⁰. A second group reported a milk:plasma ratio of 0.1 based on milk samples collected over 18 hours after cisplatin administration ²¹.
			Cisplatin passes into breast milk in substantial quantities and is inherently toxic. A suckling infant would ingest in a day 34.7% of the weight-adjusted maternal daily dose ²². Breastfeeding during treatment is contraindicated.

* - None of the animal studies reported in this table were conducted at The Hospital for Sick Children, Toronto, or by Motherisk.

References

Anabuki K et al: Reproductive studies oncisplatin. Yakuri to Chiryo 10:659-701, 1982.
Keller KA, Aggarawal SK: Embryotoxicity of cisplatin in rats and mice. Toxicol Appl Pharmacol 69:245-56, 1983.
Kopf-Maier, P, Merker HJ: Effects of the cytostatic drugcis-platinum on the developing neocortex of the mouse. Teratology28:189-99, 1983.
Nagaoka T et al: Reproductive studies on cisplatin. Kiso to Rinsho 15:5769-808, 1981.
Narbaitz R, Marino I: Experimental induction of microphthalmia in the chick embryo with a single dose of cisplatin. Teratology 37:127-34,1988.
Muranaka R, Fukiishi Y, Tsuiki H, Hasegawa Y: Teratogenic characteristics by single dosing of antineoplastic platinum complexes in rats. Teratology 44:7B-8B, 1991.
Koph-Maier, P: Stage of pregnancy-dependent transplacental passage of 195mPt after cis-platinum treatment. Eur J Cancer Clin Oncol19:533-536, 1983.
Jacobs AJ et al: Oat cell carcinoma of the uterine cervix in a pregnant woman treated with cis-diamminedichloroplatinum. Gynecol Oncol9:405-10, 1980.
Raffles A et al: Transplacental effects of maternal cancer chemotherapy. Case report. Br J Obstet Gynaecol 96:1099-1100, 1989.
Seethalakshmi L, Flores C, Kinkead T et al: Effects of subchronic treatment with cis-platinum on testicular function, fertility, pregnancy outcome, and progeny. J Andrology 13:65-74, 1992.
Kinkead T, Flores C, Carboni AA, Menon M, Seethalakshmi L: Short term effects of cis-platinum on male reproduction, fertility and pregnancy outcome. J Urol 147: 201-6, 1992.
Meistrich ML, Finch M, de Cunha MF, Hacker U, Au WW: Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. CancerRes 42:122-31, 1982.
Diwan BA, Anderson LM, Rehm S, Rice JM: Transplacental carcinogenicity of cisplatin: initiation of skin tumors and induction of other preneoplastic and neoplastic lesions in SENCAR mice. Cancer Res 53:3874-6, 1993.
Diwan BA, Anderson LM, Ward JM, Henneman JR, Rice JM:Transplacental carcinogenesis by cisplatin in F344/NCr rats: Promotion of kidney tumors by postnatal administration of sodiumbarbital. Fundam ApplToxicol 132:115-21, 1995.
Henderson CE, Elia Giovanni E, Garfinkel D et al: Platinum chemotherapy during pregnancy for serous cystadenocarcinoma of the ovary. Gynecol Oncol 1993; 49:92-94.
Bakri YN, Given FT: Normal pregnancy and delivery following conservative surgery and chemotherapy for ovarian endodermal sinus tumor. Gynecol Oncol 19, 222, 1984.
Curtin JP et al: Pregnancy following treatment of endodermal sinus tumor of the ovary with combination chemotherapy,including cis-platinum.Gynecol Oncol 24:268-270, 1986.
Venitt S et al: Monitoring exposure of nursing and pharmacy personnel to cytotoxic drugs: urinary mutation assays andurinary platinumas markers of absorption. Lancet 1:74-7, 1984.
Egan PC et al: Doxorubicin and cisplatin excretion into human milk. Cancer Treat Rep 69:1387-89, 1985.
de Vries EG et al: Excretion of platinum into breast milk. Lancet1:497, 1989.
Ben-Baruch G, Menczer J, Goshen R, Kaufman B, Gorodetsky R: Cisplatin excretion in human milk. J Natl Cancer Inst 84: 451-2, 1992.
The WHO Working Group, Bennet PN (ed).: Drugs and Human Lactation. Elsevier, Amsterdam, New York, Oxford, 1996. pp. 271.

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