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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]).
- Coates A, Abraham S, Daye SB, Sowerbutts T, Frewin C, Fox RM, Tattersall MHN. On the receiving end-patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983;19:203-208.
- Morrow GR. Chemotherapy-related nausea and vomiting: etiology and management. Cancer J Clin 1989;39:89-104.
- Roila F, Tonato M, Asurto C. Antiemetic activity of high doses of metoclopramide in cisplatin treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 1988;5:141-149.
- Fiore JJ, Gralla RJ. Pharmacologic treatment of chemotherapy-induced nausea and vomiting. Cancer Investigation 1984;2:351-61.
- Andrykowski MA. Definitional issues in the study of anticipatory nausea in cancer chemotherapy. J Behav Med 1986;9:33-41.
- Wickham R. Managing chemotherapy-related nausea and vomiting: the state of the art. Oncol Nurs Forum 1989;16:563-74.
- Coons HL, Levanthal H, Nerenz DR, Love RR, Larson S. Anticipatory nausea and emotional distress in patients receiving cisplatin-based chemotherapy. Oncol Nurs Forum 1987;14(4):31-5.
- Gralla RJ, Tyson LB, Kris MG, Clark RA. The management of chemotherapy-induced nausea and vomiting. Med Clin North Am 1987;71(2):289-301.
- Stewart DJ. Nausea and vomiting in cancer patients. In: Kucharczyk J, Stewart DJ, Miller AD, eds. Nausea and vomiting: Recent research and clinical advances. CRC Press 1991:177.
- DeMulder PHM, Seynaeve C, Vermorker JB, et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: multicenter, randomized, double-blind, crossover study. Ann Intern Med 1990;113:834.
- Roila F, DeAngelis V, Cognetti F, et al. Ondansetron vs. granisetron, both combined with dexamethasone in the prevention of cisplatin induced emesis: the Italian Group for antiemetic research. Proc ASCO 1995;14:523.
- Rittenberg CN, Gralla REJ, Lettow LA, Cronin MD, Kardinal CG. New approaches in preventing delayed emesis: altering the time of regimen initiation and use of combination therapy in a 109 patient trial. Proc Am Soc Oncol 1995;14:526.
- Kris MG, Gralla RJ, Clark RA, et al. Antiemetic control and prevention of side effects of anticancer therapy with lorazepam or diphenhydramine when used in conjunction with metoclopramide plus dexamethasone: a double-blind, randomized trial. Cancer 1987;69:1353.
- Kaneko Y, Kuwagata M, Hashimoto Y, Miszutani M, Ezaki H, Yokoyama S, Tokado H. Reproduction study (seg I) of ondansetron hydrochloride in rats by intravenous route. Yakuri to Chiryo 1992;20:s1119-11130.
- Sutherland MF, Adams MJ, Parkinson MM, Sparrow SJ, Fluck PA, Ezaki H, Yokoyama S, Tokado H. Reproductive study (seg I) of ondansetron hydrochloride in rats by oral route. Yakuri to Chiryo 1992;20:s1131-1141.
- Shimizu M, Ohta T, Kato M, Kobayashi Y, Yamashita Y, Asano M, Mori K, Koike T, Ezaki H, Yokoyama S, Takeda K. Reproduction study (seg II) of ondansetron hydrochloride in rats by intravenous route. Yakuri to Chiryo 1992A;20:s1145-1164.
- Shimizu M, Ohta T, Kato M, Kobayashi Y, Yamashita Y, Asano M, Mori K, Fujimura T, Ezaki H, Yokoyama S, Takeda K. Reproduction study (seg II) of ondansetron hydrochloride in rats by oral route. Yakuri to Chiryo 1992B;21:s1165-1185.
- Secker RC, Parkinson MM, Kelly JA, Sparrow SJ, Libretto SE, Ezaki H, Yokoyama S, Tokado T. Reproduction study (seg III) of ondansetron hydrochloride in rats by intravenous route. Yakuri to Chiryo 1992A;20:s1197-s1209.
- Secker RC, Parkinson MM, Kelly JA, Sparrow SJ, Libretto SE, Ezaki H, Yokoyama S, Tokado T. Reproduction study (seg III) of ondansetron hydrochloride in rats by oral route. Yakuri to Chiryo 1992B;20:s1211-s1226.
- Ezaki H, Yokoyama S, Takahashi N, Takamatsu M, Tokado H, Takeda K. Reproduction study (seg II) of ondansetron hydrochloride in rabbits by oral route. Yakuri to Chiryo 1992;20:s1187-s1196.
- Guikontes E, Spantideas A, Kiakakis J. Ondansetron and hyperemesis gravidarum. The Lancet 1992;340:1223.
- World MJ. Ondansetron and hyperemesis gravidarum. The Lancet 1993;341:185.
- Tincello DG, Johnstone MJ. Treatment of hyperemesis gravidarum with the 5-HT3 antagonist ondansetron (Zofran). Postgraduate Medical Journal 1996;72(853):688-9.
- Sullivan CA, Johnson CA, Roach H, Martin RW, Stewart DK, Morrison JC. A pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet Gynecol 1996;174(5):1565-68.
- Baldwin JA, Davidson EJ, Goodwin J, Pritchard AL, Ridings JE. Intravenous administration study during organogenesis in rats and rabbits. Kiso to Rinsho 1990;24:5043-53.
- Baldwin JA, Davidson EJ, Goodwin J, Pritchard AL, Ridings JE. Fertility and general reproductive performance and peri- and post-natal toxicity studies with subcutaneous administration in rats. Kiso to Rinsho 1990;24:5055-69.
- Baldwin JA, Caton FD, Davidson EJ, Goodwin J, Pritchard AL, Ohta M, Yasuda E, Nishioka Y. Toxicity study of granisetron hydrochloride: reproduction studies in rats by oral administration. Yakuri to Chiryo 1993;21:1753-69.
- Watanabe N, Iwanami K, Nakahara N. Teratogenicity of metoclopramide. Jpn J Pharmacy Chem 1968;39:92-106.
- Lyonnet R, Lucchini G. Metoclopramide in obstetrics. J Med Chir Prat 1967;138:352-5.
- Milo R, Neuman M, Klein C, Caspi E, Arlazoroff A. Acute intermittent porphyria in pregnancy. Obstet Gynecol 1989;73:450-2.
- Sidhu MS, Lean TH. The use of metoclopramide (Maxolon) in hyperemesis gravidarum. Proc Obstet Gynaecol Soc Singapore 1970;1:43-46.
- Fainstat T. Cortisone-induced congenital cleft palate in rabbits. Endocrinology 1954;55:502.
- Mogadam M, Dobbins WO, Korelitz BI, Ahmed SW. Preganncy in inflammatroy bowel disease: effect of sulfasalazine and cortiosteroid on fetal outcome. Gastroenterology 1981;80(1):72-6.
- Propert AJ. Pregnancy and adrenocortical hormones. British Medical Journal 1962; :967-72.
- Warrell DW, Taylor R. Outcome for the fetus of mothers receiving prednisolone during pregnancy. Lancet 1968;1(534):117-8.
- Jacobson SJ, Pastuszak A, Koren G. Effects of prenatal exposure to prednisone: a prospective study. Pediatric Research 1997;41(4 Pt 2):348.
- Richards ID. A retrospective enquiry into possible teratogenic effects of drugs in pregnancy. IN: Drugs and teratology development. 1971:441-55.
- Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JWK, Farewell V, Farine D, Spitzer K, Fielding L, Soloninka CA, Yeung M. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. New Eng J Med 1997;337(3):148-53.
- Ho CK, Kaufman RL, McAlister WH. Congenital malformations. Cleft palate, congenital heart disease, absent tibiae, and polydactyly. Am J Dis Child 1975;129:714-716.
- Farag RA, Ananth J. Thanatophoric dwarfism associated with prochlorperazine administration. NY State J Med 1978;78:279-282.
- Freeman R. Limb deformities: possible association with drugs. Med J Aust 1972;1:606-607.
- Hall G. A case of phocomelia of the upper limbs. Med J Aust 1963;1:449-450.
- Rafla N. Limb deformities associated with prochlorperazine. Am J Obstet Gynecol 1987;156:1557.
- Brambati B, Lanzani A, Sanchioni L, Tului L. Conjoined twins and in utero early exposure to prochlorperazine. Reprod Toxicol 1990;4:331-2.
- Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
- Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation, 5th ed. Baltimore: Williams and Wilkins, 1998.
- Hill RM, Desmond MM, Kay JL. Extrapyramidal dysfunction in an infant of a schizophrenic mother. J Pediatr 1966;69:589-95.
- Ayd FJ Jr, ed. Phenothiazine therapy during pregnancy-effects on the newborn infant. Int Drug Ther Newslett 1968;3:39-40.
- Tamer A, McKay R, Arias D, Worley L, Fogel BJ. Phenothiazine-induced extrapyramidal dysfunction in the neonate. J Pediatr 1969;75:479-80.
- Levy W, Wisniewski K. Chlorpromazine causing extrapyramidal dysfunction in newborn infant of psychotic mother. NY State J Med 1974;74:684-5.
- O'Connor M, Johnson GH, James DI. Intrauterine effect of phenothiazines. Med J Aust 1981;1:416-7.
- Dolovich LR, Addis A, Vaillancourt JMR, Power JDB, Koren G, Einarson TR. Benzodiazepines in pregnancy and major malformations, oral cleft or neurodevelopment: A meta-analysis. BMJ (in press).
- Diav-Citrin O., L. Park, A. Pastuszak, L. Beique, L. Hunnisett, M.H. Friesen, S. Jacobson, S. Kasapinovic, D. Chang, T.R. Einarson, and G. Koren. Pregnancy outcome following maternal exposure to corticosteroids: a prospective controlled cohort study and a meta-analysis of epidemiological studies. Teratology 1998; 57: 188.