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