Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated (1st Trimester)
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The human pregnancy experience is limited and the animal data in one species suggest risk. Although two infants exposed in utero had no complications attributable to oxaliplatin, both were exposed only in the 2nd and 3rd trimesters. Exposure during organogenesis and/or in any portion of the 1st trimester has the potential for causing embryo–fetal harm and should be avoided.
FETAL RISK SUMMARY
Oxaliplatin is indicated, in combination with infusional fluorouracil/leucovorin (5-FU/LV), for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of 5-FU/LV and irinotecan. The drug undergoes rapid and extensive nonenzymatic biotransformation to several reactive oxaliplatin derivatives. Preceded by two relatively short distribution phases (0.43 and 16.8 hours), the terminal elimination half-life is 391 hours (about 16 days). Following a 2-hour infusion, only about 15% of the dose is in the systemic circulation, with the remaining 85% in tissues or eliminated in the urine. Plasma protein binding (>90%) primarily to albumin and γ-globulins is irreversible (1).
Reproduction studies have been conducted in rats. In this species, a dose <0.1 times the recommended human dose based on BSA (RHD) given before implantation and before and during organogenesis was associated with early resorptions, decreased body weight, and delayed ossification (1).
Long-term carcinogenicity studies have not been conducted. The drug was mutagenic and clastogenic in animal and human assays. A dose <1/7th the RHD in male and female rats did not affect pregnancy rates, but did cause increased early resorptions, decreased live fetuses, decreased live births, and decreased fetal weight. In dogs, a dose about 1/6th the RHD given for 5 days every 28 days for three cycles caused testicular damage (characterized by degeneration, hypoplasia, and atrophy) (1).
It is not known if oxaliplatin or any of its reactive derivatives cross the human placenta. The molecular weight of oxaliplatin (about 397 and about 309 without the oxalate ligand) and the long terminal half-life suggest that the parent drug and/or its derivatives will cross to the embryo–fetus. However, the relatively small amount of the dose in the systemic circulation and the irreversible binding to albumin and γ-globulins should limit the amount transferred.
A 2009 case report described the use of oxaliplatin at 20 weeks’ gestation in a 25-year-old woman with metastatic rectal cancer (2). Therapy involved a modified FOLFOX-6 regimen consisting of oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, and 5-fluorouracil 400 mg/m2 bolus followed by a 5-fluorouracil 2400 mg/m2 46-hour infusion given biweekly. After six biweekly courses, the woman gave birth vaginally at 33.6 weeks’ gestation to a normal, about 2440-g (5 pounds, 6 ounces), female infant with Apgar scores of 8 and 8 at 1 and 5 minutes, respectively. At 3.5 years of age, the child was growing normally with her height and weight at the 60th and 45th percentile, respectively (2).
A 40-year-old woman (gravida 4, para 3) was diagnosed at 23 weeks’ gestation with advanced metastatic colorectal cancer (3). At 27 weeks’, treatment was begun with the same FOLFOX-6 regimen described above at 2-week intervals except that the oxaliplatin dose was 100 mg/m2. The woman received four treatments before a planned cesarean section was performed at 31.5 weeks’ to give birth to a small-for-gestational-age 1175-g female infant. In addition to the typical complications associated with prematurity, the infant also was hypothyroid. At 11.75 months of age, the infant’s height, weight, and head circumference were at the 50th, 80th, and 90th percentiles (corrected for prematurity), respectively. The infant had a flaky red spot on the top of her head but no other abnormalities. Except for gastroesophageal reflux (treated with lansoprazole) and hypothyroidism (treated with levothyroxine), the infant was developing normally (3).
BREASTFEEDING SUMMARY
No reports describing the use of oxaliplatin during human lactation have been located. The molecular weight of oxaliplatin (about 397 and about 309 without the oxalate ligand) and the long terminal half-life (391 hours) suggest that the parent drug and/or its derivatives will be excreted into breast milk. However, the relatively small amount of a dose in the systemic circulation and the irreversible binding to albumin and γ-globulins should limit the amount excreted. The effect of the potential exposure on a nursing infant is not known. However, the safest course for the infant is to not breastfeed if the mother is receiving this antineoplastic.
References
1.Product information. Eloxatin. Sanofi-Synthelabo, 2002.
2.Gensheimer M, Jones CA, Graves CR, Merchant NB, Lockhart AC. Administration of oxaliplatin to a pregnant woman with rectal cancer. Cancer Chemother Pharmacol 2009;63:371.
3.Kanate AS, Auber ML, Higa GM. Priorities and uncertainties of administering chemotherapy in a pregnant woman with newly diagnosed colorectal cancer. J Oncol Pharm Pract 2009;15:5–8.