Persistence of Oxaliplatin Transfer into Human Milk: A Case Report

Introduction

Exclusive breastfeeding is recommended for the first 6 months of an infant's life, then complemented by solid nutrition until the child is 2 years of age or older.^1,2 Breastfeeding offers numerous short- and long-term health benefits for both baby and mother. There are very few contraindications to breastfeeding. ³ However, cytotoxic chemotherapy presents a valid risk to the infant that must be contemplated and is often considered an absolute contraindication to breastfeeding.

Currently, little guidance addresses the safety of breastfeeding during or after the completion of chemotherapy treatments. A report by the American Academy of Pediatrics Committee on Drugs acknowledges that chemotherapy is a contraindication to breastfeeding; however, it does not specify recommendations for whether and when a return to breastfeeding is possible. ⁴ A clinical protocol produced by the Academy of Breastfeeding Medicine (ABM) advises against providing infants chemotherapy-contaminated milk and recommends minimum waiting periods between the last drug administration and the resumption of breastfeeding for seven chemotherapy agents, all of which are specific to breast cancer. ⁵

Oxaliplatin, a mainstay of treatment for colorectal cancer, is not included on this list. It is an alkylating chemotherapeutic agent that forms inter- and intrastrand platinum-DNA cross-links. Cross-linkage inhibits DNA replication and transcription, producing cell cycle nonspecific cytotoxicity.

The ABM Clinical Protocol recommendations are specific to breast cancer, leaving a considerable gap in clinical knowledge for the care of postpartum women with common malignancies receiving other chemotherapeutic agents. In the absence of evidence, the estimated distribution of drugs in milk depends upon multiple variables such as lipid solubility, molecular size, ionization, elimination half-life, and maternal dosage.^6,7 Certain drugs are considered more toxic due to their longer half-lives that would make breastfeeding between cycles unsafe, whereas shorter half-lives may allow mothers to safely pursue breastfeeding if desired.

The collection and analysis of breast milk during and after drug treatments will allow for data to be accumulated for future guidance. Medical professionals must be highly informed on the safety and management of medications during lactation to best advise their patients.

Case Report

We present a 37-year-old patient (50 kg) diagnosed with stage 3a colorectal cancer requiring treatment with chemotherapy, radiation, and surgery. At the time of diagnosis, she was breastfeeding a 7-month-old infant. Of note, the patient is a survivor of breast cancer, for which she received radiation, docetaxel, carboplatin, and trastuzumab (doses unknown) in 2008. As a consequence of radiation, lactation was only successful in the right breast. Owing to the limited availability of data on safe breastfeeding during chemotherapy, she contacted the InfantRisk Center at Texas Tech University Health Sciences Center for information on pharmacovigilance while breastfeeding.

The first phase of treatment was limited to pelvic radiation; during this phase, breastfeeding was safely continued. The second phase consisted of a 12-week chemotherapy regimen of oxaliplatin and capecitabine. Four cycles of oxaliplatin 130 mg/m² were infused every 3 weeks, and capecitabine was prescribed twice daily by mouth for the first 2 weeks of 21-day cycles at 1,000 mg/m².

The estimated duration of oral infant exposure to a medication from residues in breast milk is often determined by using the serum half-life of the drug as a proxy for the drug's half-life in breast milk. Standard recommendations for breastfeeding postchemotherapy include a washout period of 5 to 10 half-lives before resuming breastfeeding. Oxaliplatin was determined to be the drug with the highest infant risk due to the long platinum terminal elimination half-life (392 hours) and lack of data in lactation. ⁸

For oxaliplatin, the waiting period is estimated at a minimum of 81 days (5 half-lives) to be verified by the analysis of milk platinum concentrations before the resumption of infant feeding. Similarly, the manufacturer recommends that lactating women not breastfeed for at least 3 months after receiving their final dose of oxaliplatin. This extended withholding period would effectively prohibit breastfeeding after oxaliplatin treatment in most cases.

At the initiation of chemotherapy, the patient began formula feeding but continued to express milk. Whole milk samples were obtained by expressing the breast until empty. The patient reported a significant drop in milk supply during chemotherapy and radiation treatments.

The patient's breast milk samples were tested for total platinum levels at two points at the referral laboratory, Lactation Lab, Inc., in Santa Monica, CA, in 2020 and 2021 through a previously published inductively coupled plasma mass spectrometry (ICP-MS) method. ⁹ Reported total platinum levels using ICP-MS include undifferentiated active platinum species and inactive platinum species (platinum bound to macromolecules). Toxic active platinum species represent a small portion of total measured platinum. ¹⁰

Thirty-four days after her fourth infusion of oxaliplatin, platinum levels were 0.0078 mg/L. Sixty-five days after the fourth infusion, platinum levels were 0.0103 mg/L. The patient required an extension of chemotherapy at that time, which prompted her to discontinue breastfeeding entirely. A representation of the timeline is shown in Figure 1. At the time of publication, the patient is in remission; mother and child are doing well.

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FIG. 1.

Timeline of oxaliplatin dosing and platinum milk residues.

Discussion

Chemotherapy options for colorectal cancer are limited. Most regimens include oxaliplatin due to its superior efficacy in colorectal malignancies. ¹¹ Oxaliplatin toxicity is proportional to the oxaliplatin dose administered. Residual oxaliplatin and its active platinum species in breast milk have the potential to significantly impair infant cell growth and contribute to adverse effects. Adult adverse effects are extensive, including anemia, diarrhea, nausea, elevated liver enzymes, fatigue, peripheral neuropathy, and more. An exposed infant may experience these effects as well as myelosuppression (particularly thrombocytopenia or neutropenia).

With a molecular weight of 397 daltons, oxaliplatin has the potential to directly transfer into breast milk. Drug transfer should be somewhat mitigated by high protein binding (>90%) and large volume of distribution (440–582 L). Oxaliplatin is nonenzymatically converted to active platinum metabolites and differs from other platinum analogues due to a bulky carrier ligand (1,2-diaminocyclohexane [DACH]), designed to enhance tissue penetration. ¹² Dichloro(DACH) platinum complexes are pharmacologically active and more readily penetrate cell membranes to improve cytotoxicity along with reactive unbound platinum. ¹³

Unbound platinum after oxaliplatin administration has triphasic pharmacokinetics. ¹⁴ The extended terminal elimination phase is concerning, and it has precluded lactation with oxaliplatin treatment. However, the long terminal half-life (t_1/2: 392 hours) most likely represents the inactive platinum conjugates, while the first two phases (t_1/2: 0.28 and 16.3 hours) represent active platinum. ¹² However, until a profile can be determined for bound versus reactive platinum, all platinum is assumed to be reactive.

The oral bioavailability of platinum species is unknown. Chronic infant gastrointestinal exposure to oxaliplatin through breast milk may result in adverse cytotoxic local effects. There are no known standards for “safe” platinum serum or milk levels. Still, inferences might be made from this case. Comparisons against platinum exposure from other sources are given in Table 1. The platinum exposure due to breast milk for this case was the same at day 34 versus day 65.

Sixty-five days after oxaliplatin treatment, platinum levels remained detectable and fell within the range of published platinum exposures due to carboplatin and cisplatin found in the weeks after dosing.^10,15 However, the platinum exposure to an infant from an intravenous chemotherapeutic oxaliplatin dose is >1,500-fold greater than the infant's daily exposure through breast milk (Table 1).

Conclusions are limited by the lack of robust data. Oxaliplatin has triphasic elimination that cannot be observed with two samples. A relative infant dose also cannot be calculated with only two milk concentration values. Furthermore, this patient received carboplatin 13 years before this report, and there were no baseline platinum concentrations. Platinum persists in tissue and serum at low levels for decades after chemotherapy. ¹⁶ Residual levels are expected to be negligible compared with recent dosing, but they could contribute to an overestimate of platinum exposure from oxaliplatin.

Conclusion

The prevalence of colorectal cancer in women of reproductive age is increasing, as is an understanding of the maternal and infant benefits of breastfeeding. Oxaliplatin is a mainstay of treatment for colorectal cancer, but most breastfeeding guidelines address chemotherapeutic drugs specific to breast cancer. Addressing the question of infant safety when treating a breastfeeding mother with oxaliplatin remains challenging. In this case, platinum breast milk concentrations 1 and 2 months after oxaliplatin treatment were found to be similar to the platinum levels of other platinum analogues in the weeks after their administration, suggesting that the equivalent platinum exposure risk persists for longer with oxaliplatin than with cisplatin or carboplatin.

The impact on a breastfeeding infant is unknown but potentially severe; it could result in adverse events, including myelosuppression. These risks may be moderated by low oral bioavailability and the proportion of reactive platinum available; platinum exposure from breast milk is distinctly less than therapeutic doses administered to infants. However, unless more evidence becomes available, the result from this case supports current recommendations to cease breastfeeding after oxaliplatin administration.