Treating any cancer in pregnancy is complex and a carefully tailored treatment plan is required at all stages, with consideration to the needs of the mother and risks to the foetus. 

Every case of pregnancy-associated cancer should be discussed in multidisciplinary team meetings for series and sequence of treatments, such as surgery, chemotherapy, adjuvant radiotherapy and endocrine therapy, etc. It is very important to discuss the side-effects of chemotherapy, as well as antiemetics for chemotherapy-induced nausea and vomiting, for the mother as well as the foetus in the short- and long-term. 

Available clinical data suggest that foetuses exposed to chemotherapy initiated in the second trimester do not experience significant long-term complications. Nevertheless, these pregnancies should be regarded as high risk and it is therefore reasonable to consider regular foetal monitoring during gestation. ESMO guidelines recommend targeting full-term delivery (ie. ≥⊇37 weeks) whenever possible, since subtle but significant cognitive impairment has been described in preterm babies who have been exposed to chemotherapy in utero.¹ Early or very early pregnancy (ie. between 34-37 weeks and < 34 weeks respectively) should be discouraged, unless maternal and/or foetal health are endangered by the postponement of delivery until term. 

Chemotherapy 

The incidence of newly diagnosed cancer in pregnancy is 1 in every 1000 pregnant women. Breast, melanoma and cervical cancers are those most commonly diagnosed during pregnancy followed by haematological malignancies. In this article, we will focus on prescribing supportive medication during pregnancy in a patient with any active cancer in general, and breast cancer in particular. 

Doxorubicin and cyclophosphamide are the most commonly prescribed chemotherapeutic agents for breast cancer in pregnancy as there is considerable experience of using this regimen during the second and third trimesters. No significant complications have been reported for the foetus and infant treated with these agents. The use of paclitaxel during pregnancy should only be considered if anthracyclines are contraindicated. In this case, weekly paclitaxel is preferred as it facilitates close monitoring and has a better overall toxicity profile.

If a patient is diagnosed with breast (or any other) cancer in her first trimester then initiation of chemotherapy should be delayed until the second trimester as this is a prime period of organogenesis with the risk of fetal malformation at 10-20% with monotherapy, rising to 25% with combination chemotherapy.² Termination of pregnancy should be considered if chemotherapy needs to be administered on urgent basis. 

Apart from steroids, no other antiemetics are safe in first trimester of pregnancy. Most chemotherapies can be prescribed from the second trimester with the exception of those that have a teratogenic effect. 

Prescribing supportive medication

Nausea and vomiting

Chemotherapy-induced nausea and vomiting is a common treatment-related adverse effect and has a detrimental impact on the quality of life of patients with cancer, potentially leading to dose reductions in or discontinuation of chemotherapy. Several neurotransmitters, such as dopamine, serotonin and substance P, and their receptors are involved in mediation of chemotherapy-induced emesis.³ Until the late 1970s, dopamine receptor antagonists, including metoclopramide, prochlorperazine and haloperidol, were standard antiemetics. However, after the Food and Drug Administration (FDA) approved the highly emetogenic chemotherapy cisplatin in 1978, metoclopramide was not considered as effective to control nausea and vomiting, and research found the combination of dexamethasone and high-dose metoclopramide effective as antiemetics in this setting. 

In the early 1990s, serotonin (5-HT3) receptor antagonists proved to be a landmark in the treatment of acute chemotherapy-induced emesis. The first 5-HT3 receptor antagonist, ondansetron, was approved by the FDA and was immediately incorporated into routine oncology practice. Ondansetron-dexamethasone was found to be superior to high-dose metoclopramide-dexamethasone for protection from chemotherapy-induced emesis in patients receiving highly emetogenic chemotherapy, and had a much better side-effect profile. Ondanstron has been used traditionally to manage severe nausea and vomiting (hyperemesis) in pregnancy after the first trimester. 

Two additional 5-HT3 receptor antagonists were approved by the FDA – granisetron (1993) and dolasetron (1997) – as prophylaxis for chemotherapy-induced emesis. Granisetron is commonly used as a first-line antiemetic but its safety data in pregnancy is not well established. A retrospective study, which compared 100 granisetron-exposed pregnancies to 108 granisetron-unexposed pregnancies, gave some reassurance for the use of granisetron in pregnancy.⁴ Researchers found that the miscarriage rate was significantly lower among granisetron-exposed patients compared to controls (0 vs 5.5%, respectively). Three major malformations were identified prenatally or postnatally in each of the groups (2.77% vs 2.83%). The rate of major malformations was similar between exposed and unexposed fetuses even after excluding second trimester exposure (3.2% vs 2.83 %, respectively). 

In 2003, two new antiemetics were introduced – palonosetron and aprepitant. Palonosetron is a second-generation 5-HT3 receptor antagonist that has a prolonged half-life, a receptor binding affinity higher than that of other antiemetic agents, and positive co-operativity when binding to the 5-HT3 receptor. This binding triggers 5-HT3 receptor internalisation, leading to the inhibition of the 5-HT3/neurokinin-1 (NK-1) receptor and 5-HT3/NK-1 receptor crosstalk. As a result of these characteristics, palonosetron has increased efficacy in preventing both acute and delayed chemotherapy-induced emesis. Aprepitant – the first NK-1 receptor antagonist to be approved – when combined with dexamethasone, was found to be effective at preventing chemotherapy-induced emesis in patients receiving highly emetogenic chemotherapy. In 2008, the FDA approved fosaprepitant, a prodrug and intravenous form of aprepitant, on the basis of a phase 3 noninferiority trial.

Between 2013 and 2015, phase 2 and phase 3 trials of two new NK-1 receptor antagonists – netupitant (administered as an oral fixed-dose combination of netupitant [300mg] and palonosetron [0.5mg], [Akynzeo]) and rolapitant – were completed and led to a substantial improvement in prophylaxis for chemotherapy-induced emesis, especially during the delayed phase (one to four days after chemotherapy). 

All above NK-1 receptor antagonists are very promising in preventing nausea from high emetogenic chemotherapy but extreme caution is required for their use in pregnancy. There are no controlled data describing the use of aprepitant in human pregnancy. The animal data suggest low risk, even though low doses relative to the human dose were studied. Use of higher doses was not possible because of saturation of absorption in the animals. The absence of human pregnancy experience prevents a full assessment of the risk. 

Until the additional data are available, the use of aprepitant, if indicated, should be restricted to the second and third trimesters. Adverse events were observed in some animal reproduction studies using netupitant and palonosetron. Information related to the use of netupitant and palonosetron during pregnancy is limited.

Neutropenia 

Granulocyte colony-stimulating factor (GCSF) support is used in chemotherapy regimens that can cause potential neutropenia and can subsequently delay the scheduled treatments. Usually, long-acting GCSF agents (pegfilgrastim, lipefilgrastim) are administered to patients for convenience – due to the fact that they only need to be administered once following chemotherapy – but no reports describing the use of these in human pregnancy have been found. Although animal data do not suggest foetal risk, the absence of human pregnancy experience prevents a better assessment of the embryo-foetal risk. Filgrastim (Neupogen) has been used during pregnancy without apparent foetal harm. Therefore, until human data are available, filgrastim should be preferred over pegfilgrastim in pregnancy. 

Diarrhoea/constipation

Diarrhoea and constipation are also potential symptoms in patients receiving cytotoxic agents. The most commonly used antidiarrhoeal agent in our centre is loperamide (Imodium), and ideally its use should be prohibited in the first trimester of pregnancy as there is some evidence to suggest that there is a possible increase in foetal cardiac malformation with first trimester use.⁵ Two studies of approximately 750 pregnant women taking loperamide did not show that they had a higher risk of having a pre-term birth or a low birth weight baby. However, information from larger numbers of women is required before firm conclusions can be drawn.^6,7 As far as the safety of taking laxatives during pregnancy is concerned, data available to date are very encouraging and no safety issues have been reported for most commonly used laxatives, including Lactulose, Movicol, Dulcolax, Denokot and Dioctyl.

Conclusion

In summary, for prevention of chemotherapy-induced nausea and vomiting, ondansetron is relatively safe as compared to granisetron, aprepitant, and netupitant/palonosetron, from the second trimester on. Steroids can safely be used in pregnancy. Filgrastim is the preferred choice for use in pregnancy to prevent a fall in white blood cell count. Loperamide is safe to use from second trimester onwards, and laxatives can be used safely in pregnancy. 

It is crucial to discuss all pros and cons with the patient and her partner, including possible implications for the unborn baby. Wherever possible, delivery should be targeted at full-term and chemotherapy should not be administered beyond week 33 of gestation, as spontaneous delivery can occur at any time after week 34. Ongoing, registry-based studies will help guide chemotherapy prescribing during pregnancy. 

Our experience to date highlights the important collaborative role of pharmacy staff in safe prescribing in this complex situation where the potential of transgenerational treatment-associated toxicity exists. We would also recommend downloading and placing in the patient chart pertinent, recent guidelines and literature reviews to demonstrate contemporaneous safe practice. 

References

1. Peccatori FA, et al. Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 Suppl 6): vi60-vi70
2. Eastwood-Wilshere N, et al. Cancer in Pregnancy. Asia-Pacific Journal of Clinical Oncology 2019; 15(6): 296-308
3. Janelsins MC, et al. Current Pharmacotherapy for Chemotherapy-Induced Nausea and Vomiting in Cancer Patients. Expert Opin Pharmacother 2013; 14(6): 757-766
4. Shapira M, et al. The safety of early pregnancy exposure to granisetron. Euro J of Obs & Gyne and Repro Bio 2019; 245: 35-388, 
5. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 5th ed. Baltimore: Williams & Wilkins, 1998: 577-8, 627-8
6. Einarson A, Mastroiacovo P, Arnon J, et al. Prospective, controlled, multicentre study of loperamide in pregnancy. Can J Gastroenterol 2000; 14(3): 185-7
7. https://www.medicinesinpregnancy.org/Medicine--pregnancy/Loperamide/