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Cancer in Pregnancy: Pharmacological and non-pharmacological treatment of chemotherapy-induced nausea and vomiting

Professional Summary
The most common cause of nausea and vomiting (NV) in patients with cancer is chemotherapy. Many agents are available to treat nausea and emesis. However, little is known about their safety when used in human pregnancy.

Ondansetron is probably the 5HT3 antagonist of choice, given reassuring (albeit) limited data on teratogenicity. If indicated, concomitant therapy with corticosteroids should be regarded as safe for the fetus after 10 weeks' gestation; maternal blood pressure and blood sugar should be monitored. Although limited data suggest that metoclopramide is not teratogenic, doses studied have been substantially lower than those advocated for relief of acute or delayed chemotherapy-induced NV; extrapyramidal side effects in the fetus/neonate would remain a concern. Phenothiazines (such as prochlorperazine) are not teratogenic, but their use near term may be associated with extrapyramidal side effects in the newborn. Benzodiazepine use for anticipatory NV, should be avoided early in gestation, given the possible association with oral clefting.

Although there are limited data on the safety of potent antiemetics in human pregnancy, any theoretical risks would certainly be outweighed by those of the cancer and/or chemotherapy themselves. Given the importance in oncology of controlling nausea and emesis, especially chemotherapy-induced NV, potential risks of antiemetic therapy would certainly be outweighed by the demonstrable benefits.

Introduction
Patients with cancer may experience nausea and vomiting (NV) for many reasons. NV is usually multifactorial in etiology, resulting from the disease process itself (e.g., gastric involvement, raised intracranial pressure, hypercalcemia), drug therapy (e.g., opioids), and/or radiotherapy, chemotherapy, or surgery. Nausea and vomiting may lead to undernutrition and/or dehydration, refusal of future courses of chemotherapy, and/or impairment of health-related quality of life . Therefore, control of NV remains a priority among oncologists.

Chemotherapy-induced NV
Among patients with cancer, NV is most commonly caused by chemotherapy. NV occurs in 70% of patients who receive chemotherapy, especially among women. Chemotherapy-induced NV may be acute (i.e., within 4 hours post-chemo), delayed (i.e., one to several days post-chemotherapy, especially with cisplatin) or anticipatory (in 10-44% of patients) . The latter may be a conditioned response to external stimuli (e.g., sights, sounds, odours, presence of physician and/or nurse) associated with chemotherapy.

Different chemotherapeutic regimes have different emetogenic potential; cisplatin is highly emetogenic whereas methotrexate-containing regimes are less so. Although activation of the chemoreceptor trigger zone (CTZ) is thought to be the most common single mechanism by which chemotherapy causes NV, most agents at different and/or multiple sites.

Management of emesis in the patient with cancer
A variety of anti-emetics have been used for the treatment of various causes of NV associated with cancer and its treatment. Choices have been based on the variety of pathways involved in the pathophysiology of nausea and emesis: CTZ (which is richly innervated with receptors for dopamine, histamine, acetylcholine and serotonin), vestibular apparatus (where cholinergic and histaminergic fibres are thought to be involved in transmission), visceral afferents (e.g., dopamine receptors mediate motor reflexes in the stomach), and vagal afferents (e.g., serotonin receptors (specifically 5-HT3) located in close proximity to enterochromaffin cells in the intestinal tract).

The list of effective anti-emetic agents has grown beyond only the phenothiazines which were available in the 1970s. This is an area of active research given that no single agent is effective in all patients. The agents used most commonly, especially for acute chemotherapy-induced NV, are antagonists of the type 3 serotonin (5-HT3) receptor, such as ondansetron, granisetron and azasetron. To date, none has been proven to be more effective than another. All are well-tolerated, and equally effective when given orally or parenterally. Metoclopramide is a dopamine (DA2) receptor antagonist, which at high doses (1-3 mg/kg iv every 2 hours), probably acts by blocking 5-HT3 receptors. Metoclopramide is at least as effective, and certainly cheaper, than 5-HT3 antagonists in preventing delayed NV . However, metoclopramide is associated with an excess of side effects, particularly extrapyramidal reactions which may require diphenhydramine treatment. Concomitant corticosteroid therapy can improve the efficacy of 5-HT3 antagonists for acute NV, such that more than 75% of patients have complete control of NV; glucose intolerance is a predictable side effect. Steroids have also been used as monotherapy for delayed NV, although some experts advocate the addition of metoclopramide. Other antiemetic agents such as phenothiazines and cannabinoids are less effective and associated with more side effects (e.g., orthostatic hypotension) than 5-HT3 antagonists or high-dose metoclopramide.

Anti-anxiety agents have little if any antiemetic efficacy when given alone, and add only a minor effect when given with more active agents. However, they may have a role in amelioration of anticipatory emesis, for which other antiemetics are ineffective. No studies have addressed this issue.

Antagonists of the type 1 histamine (H1) receptor are not effective for chemotherapy-induced emesis.

Treatment of chemotherapy-induced NV in pregnancy
There are no data on the efficacy of anti-emetic therapy for NV in the pregnant patient with cancer. Therefore, what has been reviewed is the safety data in human pregnancy, for antiemetics used commonly to treat NV in non-pregnant cancer patients.

5-HT3 antagonists
Information about reproductive toxicity was available only for ondansetron and granisetron. Reproductive toxicology studies of ondansetron in rats, at doses of 20-80 times the recommended dose in humans, failed to produce developmental toxicity. However, there was evidence of fetotoxicity, as doses of 10-30 times the recommended dose in humans were associated, in rats and rabbits, with intrauterine fetal growth restriction. Use of ondansetron in human pregnancy has been limited. No malformations were reported in three case reports or in the setting of a randomized controlled trial of fifteen patients exposed during the first trimester of pregnancy 24 (J.C. Morrison, personal communication, October 23, 1996) . Animal studies in rats and rabbits administered granisetron, in doses up to 200 times that recommended in humans, failed to produce teratogenic or fetotoxic effects. However, there have been no reports of granisetron in human pregnancy.
Metoclopramide
Animal reproductive toxicology studies could not detect malformations in pregnant mice, rats or rabbits treated with doses of 17-330, 17-330, and 3-17 times the recommended human doses (respectively) . Studies of the teratogenic potential of metoclopramide in human pregnancy are limited. No malformations were reported among two cases of first trimester exposure. No association was found between the occurrence or pattern of malformations, and metoclopramide use in early pregnancy, in either i) a prospective cohort study of 120 women receiving metoclopramide for treatment of hyperemesis gravidarum , or ii) a retrospective record linkage study (i.e., 10/192 (5.2%) malformations)46.
Corticosteroids
Steroids used for chemotherapy-induced nausea and vomiting include dexamethasone and prednisone. Preliminary animal data suggested that first-trimester exposure to steroids was associated with an increased risk for cleft palate. A recent meta-analysis of 6 cohort and one case-control study found a trend towards an increased risk of major malformations following first trimester exposure to corticosteroids (RR = 1.23, 95% CI 0.96 - 1.58) 33-39, 53. The risk of oral clefting was significantly increased (RR = 1.59, 95% CI 1.16 - 2.18), although individual trials were not consistent 53. Prolonged therapy with steroids throughout pregnancy, for prevention of recurrent fetal loss, has been associated with premature delivery, hypertension and gestational diabetes. However, short-term use (i.e., high dose dexamethasone) is commonly administered to accelerate fetal pulmonary maturity, without maternal morbidity. Therefore, it would be expected that similar short courses of steroids for management of chemotherapy-induced NV would not represent a fetal risk if administered after 10 weeks' gestation. It would be prudent to monitor matenal blood pressure and blood sugar.
Phenothiazines
Although anecdotal case reports have tried to associate phenothiazines exposure in early pregnancy with major malformations, prospective and retrospective cohort, and record linkage studies of various phenothiazines have failed to demonstrate an increased risk for major malformations, particularly when used infrequently 46. When used late in gestation, the newborn may experience self-limited extrapyramidal effects.
Cannabinoids
Tetrahydrocannabinol (delta 9-THC) ingested as
  1. the active agent in inhaled marijuana,
  2. alone as dronabinol, or
  3. as a semisynthetic agents (e.g., nabilone and levonantradol)

appear to be of low and equivalent efficacy for relief of chemotherapy-induced NV. Autonomic side effects (e.g., dry mouth, hypotension, dizziness) are frequent.


Safety data
Obviously, the medico-legal implications of cannabinoids and their derivatives and the potential maternal and fetal risks of inhaled substances during pregnancy would preclude the potential benefits for treatment of chemotherapy-induced nausea and emesis.

Benzodiazepines
Although a number of drugs are available in this class, the one recommended for prevention of anticipatory NV is lorazepam. A recent meta-analysis of the available cohort (N=4) and case-control studies (N=7) of first trimester exposure to benzodiazepines, including lorazepam, found no increase in major malformations (cohort studies: OR of 0.92, 95% CI [0.62,1.37]; case-control studies: 2.27 [0.95,5.45]), but a marginally increased risk for oral clefts among case-control studies (cohort studies: OR of 1.19 [0.34,4.15]; case-control studies: 1.66 [1.00,2.75]).

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