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Nausea and vomiting


Table of Contents

INTRODUCTION
NEUROPHYSIOLOGY
INCIDENCE AND ETIOLOGY
PHARMACOLOGIC MANAGEMENT
Single Agents
Combination Therapy
NONPHARMACOLOGIC MANAGMENT
MANAGEMENT OF ANTICIPATORY NAUSEA AND VOMITING

INTRODUCTION

Prevention and control of nausea and vomiting are paramount in the treatment of cancer patients, as they can result in serious metabolic derangements, nutritional depletion and anorexia, deterioration of patients' physical and mental status, esophageal tears, fractures, wound dehiscence, withdrawal from potentially useful and curative antineoplastic treatment, and degeneration of self-care and functional ability.[1-4]

Nausea is a subjective phenomenon of an unpleasant, wavelike sensation experienced in the back of the throat and/or the epigastrium that may or may not culminate in vomiting. Vomiting is the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching is gastric and esophageal movements of vomiting without expulsion of vomitus and is also referred to as "dry heaves." Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting remain two of the side effects most distressing to cancer patients and their families.[5,6]

Some studies suggest that nausea and vomiting are distinct entities with different components.[2,7,8] Patients indicate that nausea is far more distressing than vomiting.[8-10]

Nausea and vomiting are commonly classified as anticipatory, acute, or delayed when referring to chemotherapy-induced symptoms. Anticipatory nausea and vomiting (ANV) may occur prior to or during chemotherapy administration, but earlier than is consistent with the characteristic onset of symptoms associated with a particular emetogenic drug or drug combination. Anticipatory symptoms may also appear in patients who receive radiation therapy. Acute nausea and vomiting occur with a variable period of latency from the time of drug administration to onset of nausea and vomiting (within a few minutes to several hours) but, by definition, within 24 hours after drug administration. Delayed (or late) nausea and vomiting occur after the acute phase, i.e., more than 24 hours after chemotherapeutic drugs are given, and may persist for several days. Cisplatin and other drugs (e.g., cyclophosphamide, doxorubicin, and ifosfamide) given at high doses or on two or more consecutive days are associated with delayed nausea and vomiting.[11] Delayed emesis has been associated with high levels of morbidity and there are few treatment options with proven efficacy.[12-15]

References:

  1. Richardson JL, Marks G, Levine A: The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. Journal of Clinical Oncology 6(11): 1746-1752, 1988.

  2. Laszlo J, Ed.: Antiemetics and Cancer Chemotherapy. Baltimore: Williams & Wilkens, 1983.

  3. Ingle RJ, Burish TG, Wallston KA: Conditionability of cancer chemotherapy patients. Oncology Nursing Forum 11(4): 97-102, 1984.

  4. Mitchell EP: Gastrointestinal toxicity of chemotherapeutic agents. Seminars in Oncology 19(5): 566-579, 1992.

  5. Coates A, Abraham S, Kaye SB, et al.: On the receiving end - patient perception of the side-effects of cancer chemotherapy. European Journal of Cancer and Clinical Oncology 19(2): 203-208, 1983.

  6. Craig JB, Powell BL: The management of nausea and vomiting in clinical oncology. American Journal of the Medical Sciences 293(1): 34-44, 1987.

  7. Gralla RJ: Antiemetic therapy. In: DeVita VT, Hellman S, Rosenberg SA, Eds.: Cancer: Principles and Practice of Oncology. Philadelphia: JB Lippincott Company, 4th Edition, 1993, pp 2338-2348.

  8. Rhodes VA, Watson PM, Johnson MH, et al.: Patterns of nausea, vomiting, and distress in patients receiving antineoplastic drug protocols. Oncology Nursing Forum 14(4): 35-44, 1987.

  9. Rhodes VA, Watson PM, Johnson MH: Association of chemotherapy related nausea and vomiting with pretreatment and posttreatment anxiety. Oncology Nursing Forum 13(1): 41-47, 1986.

  10. Rhodes VA, Watson PM, Johnson MH: Patterns of nausea and vomiting in chemotherapy patients: a preliminary study. Oncology Nursing Forum 12(3): 42-48, 1985.

  11. Moreno I, Rosell R, Abad A, et al.: Comparison of three protracted antiemetic regimens for the control of delayed emesis in cisplatin-treated patients. European Journal of Cancer 28A(8/9): 1344-1347, 1992.

  12. Gandara DR, Harvey WH, Monaghan GG, et al.: The delayed-emesis syndrome from cisplatin: phase III evaluation of ondansetron versus placebo. Seminars in Oncology 19(4, Suppl 10): 67-71, 1992.

  13. Kris MG, Tyson LB, Clark RA, et al.: Oral ondansetron for the control of delayed emesis after cisplatin: report of a phase II study and a review of completed trials to manage delayed emesis. Cancer 70(4, Suppl): 1012-1016, 1992.

  14. Louvet C, Lorange A, Letendre F, et al.: Acute and delayed emesis after cisplatin-based regimen: description and prevention. Oncology 48(5): 392-396, 1991.

  15. Passalacqua R, Cocconi G, Bella M, et al.: Double-blind, randomized trial for the control of delayed emesis in patients receiving cisplatin: comparison of placebo vs. adrenocorticotropic hormone (ACTH). Annals of Oncology 3(6): 481-485, 1992.


NEUROPHYSIOLOGY

Progress has been made in understanding the neurophysiologic mechanisms that control nausea and vomiting. Both are controlled or mediated by the central nervous system but by different mechanisms. Nausea is mediated through the autonomic nervous system. Vomiting results from the stimulation of a complex reflex that is coordinated by a putative true vomiting center, which may be located in the dorsolateral reticular formation near the medullary respiratory centers. The vomiting center presumably receives convergent afferent stimulation from several central neurologic pathways, including the following:[1-4]

The CTZ is located in the area postrema, one of the circumventricular regions of the brain on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle. Unlike vasculature within the blood-brain diffusion barrier, the area postrema is highly vascularized with fenestrated blood vessels, which lack tight junctions (zonae occludentes) between capillary endothelial cells. The CTZ is anatomically specialized to readily sample elements present in the circulating blood and cerebrospinal fluid (CSF).[1,5]

Currently, evidence indicates that acute emesis following chemotherapy is initiated by the release of neurotransmitters from cells that are susceptible to the presence of toxic substances in the blood or CSF. Area postrema cells in the CTZ and enterochromaffin cells within the intestinal mucosa are implicated in initiating and propagating afferent stimuli that ultimately converge on central structures corresponding to a "vomiting center." The relative contribution from these multiple pathways culminating in nausea and vomiting symptoms is complex and is postulated to account for the variable emetogenicity (intrinsic emetogenicity and mitigating factors, i.e., dosage, administration route, exposure duration) and emetogenic profile (i.e., time to onset, symptom severity, and duration) of agents.

References:

  1. Andrews PL, Hawthorn J: The neurophysiology of vomiting. Baillieres Clinical Gastroenterology 2(1): 141-168, 1988.

  2. Andrews PL, Rapeport WG, Sanger GJ: Neuropharmacology of emesis induced by anti-cancer therapy. Trends in Pharmacological Sciences 9(9): 334-341, 1988.

  3. Cubeddu LX: Mechanisms by which cancer chemotherapeutic drugs induce emesis. Seminars in Oncology 19(6, Suppl 15): 2-13, 1992.

  4. Borison HL, McCarthy LE: Neuropharmacology of chemotherapy-induced emesis. Drugs 25(Suppl 1): 8-17, 1983.

  5. Miller AD, Leslie RA: The area postrema and vomiting. Frontiers in Neuroendocrinology 15(4): 301-320, 1994.


INCIDENCE AND ETIOLOGY

Not all cancer patients will experience nausea and/or vomiting. The most common causes are emetogenic chemotherapy drugs and radiation therapy to the gastrointestinal tract, liver, or brain. Other possible causes include fluid and electrolyte imbalances such as hypercalcemia, volume depletion, or water intoxication; tumor invasion or growth in the gastrointestinal tract, liver, or central nervous system, especially the posterior fossa; constipation; certain drugs such as opioids; infection or septicemia; uremia; and psychogenic factors. Clinicians treating nausea and vomiting must be alert to all potential causes and factors, especially in cancer patients who may be receiving combinations of several treatments and medications.

Anticipatory nausea and vomiting (ANV) occur prior to treatment as a classically conditioned response to specific environmental stimuli (i.e., certain objects, odors, and tastes). For example, a chemotherapy agent is an unconditioned stimulus (UCS) that may be paired or associated with the smell of an alcohol swab, the neutral stimulus (NS), at the time of chemotherapy administration. Then, the individual experiences nausea and vomiting as an unconditioned response (UCR). In the future, the smell of alcohol alone becomes the conditioned stimulus (CS) that can lead to nausea and vomiting as a conditioned response (CR). There is some evidence that the environmental triggering stimuli in anticipatory nausea may be predominantly odors, while the triggering stimuli in anticipatory vomiting may be contemplation of the treatment.[1] Approximately 10%-44% of patients receiving chemotherapy experience nausea and/or vomiting prior to or during chemotherapy infusions.[2-5] While the onset of ANV varies among patients, the pattern is frequently apparent by the fourth or fifth course of treatment. No single factor is characteristic of the development of ANV symptoms. Recent evidence indicates that certain variables may predict which patients will develop ANV. These variables include treatment with a drug regimen high in emetogenic potential, symptom and psychosocial distress, mood disturbances, and limited ability to cope with treatment stress.[6] There have been a number of theoretical explanations and empirical investigations as to possible causes of ANV [7] although some studies report contradictory findings. Many variables have been correlated with the development of ANV.[2,5,7-25]

Chemotherapy-associated variables:

Psychosocial variables:

Although anxiety may not be the sole factor, it may facilitate the development of ANV in the presence of other identified factors. State- and trait-anxiety levels have been observed to be significantly higher in patients with anticipatory nausea, and increased anxiety has been found to decrease the patient's ability to develop coping strategies in the event of nausea and vomiting.[9] One review of the relationship between anxiety and ANV found that state anxiety exacerbates delayed nausea and vomiting, thereby increasing the risk of ANV.[26]

The direct effect of age on the development of ANV has not been clearly demonstrated. It has been suggested that younger adults are more susceptible to ANV because they receive more aggressive chemotherapy treatments than their older counterparts, and subsequently experience more severe post-treatment nausea and vomiting.[2]

Nonpharmacological approaches, such as hypnosis, relaxation, and behavioral modification techniques may reduce ANV. Also, some anxiolytic drugs, e.g., benzodiazepines, especially lorazepam (Atiran), may be helpful in ANV.[27]

Chemotherapy is the most common treatment-related cause of nausea and vomiting. The incidence and severity in persons receiving chemotherapy varies according to many factors, including the particular drug, dose, schedule of administration, route, and individual patient variables. In the vast majority of cancer patients, these symptoms can be prevented or controlled.

Although every chemotherapy drug in use has the potential for causing nausea and vomiting, drugs are generally classified based on their emetogenic potential. These classifications vary from study to study.[11]

Severe emetogenic potential drugs (more than 90% of persons will experience nausea and vomiting) include the following:

High emetogenic potential drugs (60%-90% of persons will experience nausea and vomiting) include the following:

Moderate emetogenic potential drugs (30%-60% of persons will experience nausea and vomiting) include the following:

Low emetogenic potential drugs (10%-30% of persons will experience nausea and vomiting) include the following:

Finally, very low emetogenic potential drugs (fewer than 10% of persons will experience nausea and vomiting) include the following:

In addition to emetogenic potential, the dose and schedule used are also extremely important factors. For example, a drug with a low emetogenic potential given in high doses may cause a dramatic increase in the potential to induce nausea and vomiting. Standard doses of cytarabine rarely produce nausea and vomiting, but these are often seen with high doses of this drug. Another factor to consider is the use of drug combinations. Because most patients receive combination chemotherapy, the emetogenic potential of all of the drugs combined and individual drug doses needs to be considered.

Radiation therapy:

Although patients receiving radiation therapy can experience ANV, in general, patients receiving radiation to the GI tract or brain have the greatest potential for nausea/vomiting as a side effect. Because cells of the GI tract are dividing quickly, they are quite sensitive to radiation therapy. Radiation to the brain is believed to stimulate the brain's vomiting center or CTZ. Similar to chemotherapy, radiation dose factors also play a role in determining the possible occurrence of nausea and vomiting. In general, the higher the daily fractional dose and the greater the amount of tissue that is irradiated, the higher the potential for nausea and vomiting.

In addition, the larger the amount of GI tract irradiated (particularly for fields that include the small intestine and stomach), the higher the potential for nausea and vomiting. Total-body irradiation before bone marrow transplant, for example, has a high probability of inducing nausea and vomiting as acute side effects.

Nausea and vomiting from radiation may be acute and self-limiting, usually occurring one half to several hours after treatment. Patients report that symptoms improve on days that they are not being treated. There are also cumulative effects that may occur in patients receiving radiation therapy to the GI tract.

References:

  1. Boakes RA, Tarrier N, Barnes BW, et al.: Prevalence of anticipatory nausea and other side-effects in cancer patients receiving chemotherapy. European Journal of Cancer 29A(6): 866-870, 1993.

  2. Morrow GR, Lindke J, Black PM: Predicting development of anticipatory nausea in cancer patients: prospective examination of eight clinical characteristics. Journal of Pain and Symptom Management 6(4): 215-223, 1991.

  3. Nesse RM, Carli T, Curtis GC, et al.: Pretreatment nausea in cancer chemotherapy: a conditioned response? Psychosomatic Medicine 42(1): 33-36, 1980.

  4. Wilcox PM, Fetting JH, Nettesheim KM, et al.: Anticipatory vomiting in women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant chemotherapy for breast carcinoma. Cancer Treatment Reports 66(8): 1601-1604, 1982.

  5. Carey MP, Burish TG: Anxiety as a predictor of behavioral therapy outcome for cancer chemotherapy patients. Journal of Consulting and Clinical Psychology 53(6): 860-865, 1985.

  6. Pickett M: Determinants of anticipatory nausea and anticipatory vomiting in adults receiving cancer chemotherapy. Cancer Nursing 14(6): 334-343, 1991.

  7. Andrykowski MA, Redd WH, Hatfield AK: Development of anticipatory nausea: a prospective analysis. Journal of Consulting and Clinical Psychology 53(4): 447-454, 1985.

  8. Nerenz DR, Leventhal H, Easterling DV, et al.: Anxiety and drug taste as predictors of anticipatory nausea in cancer chemotherapy. Journal of Clinical Oncology 4(2): 224-233, 1986.

  9. Andrykowski MA, Redd WH: Longitudinal analysis of the development of anticipatory nausea. Journal of Consulting and Clinical Psychology 55(1): 36-41, 1987.

  10. Chin SB, Kucuk O, Peterson R, et al.: Variables contributing to anticipatory nausea and vomiting in cancer chemotherapy. American Journal of Clinical Oncology 15(3): 262-267, 1992.

  11. Chase JL, Staggs RJ: Outpatient treatment of chemotherapy induced nausea and vomiting. Outpatient Chemotherapy 3(3): 4, 1990.

  12. Gandara DR, Harvey WH, Monaghan GG, et al.: The delayed-emesis syndrome from cisplatin: phase III evaluation of ondansetron versus placebo. Seminars in Oncology 19(4, Suppl 10): 67-71, 1992.

  13. Morrow GR: The effect of a susceptibility to motion sickness on the side effects of cancer chemotherapy. Cancer 55(12): 2766-2770, 1985.

  14. Morrow GR: Clinical characteristics associated with the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy treatment. Journal of Clinical Oncology 2(10): 1170-1176, 1984.

  15. Challis GB, Stam HJ: A longitudinal study of the development of anticipatory nausea and vomiting in cancer chemotherapy patients: the role of absorption and autonomic perception. Health Psychology 11(3): 181-189, 1992.

  16. Morrow GR: Methodology in behavioral and psychosocial cancer research: the assessment of nausea and vomiting: past problems, current issues, and suggestions for future research. Cancer 53(10, Suppl): 2267-2278, 1984.

  17. Fetting JH, Wilcox PM, Iwata BA, et al.: Anticipatory nausea and vomiting in an ambulatory medical oncology population. Cancer Treatment Reports 67(12): 1093-1098, 1983.

  18. Altmaier EM, Ross WE, Moore K: A pilot investigation of the psychologic functioning of patients with anticipatory vomiting. Cancer 49(1): 201-204, 1982.

  19. Lerman C, Rimer B, Blumberg B, et al.: Effects of coping style and relaxation on cancer chemotherapy side effects and emotional responses. Cancer Nursing 13(5): 308-315, 1990.

  20. Carey MP, Burish TG: Etiology and treatment of the psychological side effects associated with cancer chemotherapy: a critical review and discussion. Psychological Bulletin 104(3): 307-325, 1988.

  21. Nerenz DR, Leventhal H, Love RR: Factors contributing to emotional distress during cancer chemotherapy. Cancer 50(5): 1020-1027, 1982.

  22. Andrykowski MA, Jacobsen PB, Marks E, et al.: Prevalence, predictors, and course of anticipatory nausea in women receiving adjuvant chemotherapy for breast cancer. Cancer 62(12): 2607-2613, 1988.

  23. Nicholas DR: Prevalence of anticipatory nausea and emesis in cancer chemotherapy patients. Journal of Behavioral Medicine 5(4): 461-463, 1982.

  24. Redd WH, Jacobsen PB, Andrykowski MA: Behavioral side effects of adjuvant chemotherapy. Recent Results in Cancer Research 115: 272-278, 1989.

  25. Burish TG, Carey MP: Conditioned aversive responses in cancer chemotherapy patients: theoretical and developmental analysis. Journal of Consulting and Clinical Psychology 54(5): 593-600, 1986.

  26. Andrykowski MA: The role of anxiety in the development of anticipatory nausea in cancer chemotherapy: a review and synthesis. Psychosomatic Medicine 52(4): 458-475, 1990.

  27. Grunberg SM, Hesketh PJ: Control of chemotherapy-induced emesis. New England Journal of Medicine 329(24): 1790-1796, 1993.


PHARMACOLOGIC MANAGEMENT


Single Agents

Antiemetic agents are the most common intervention in the management of treatment-related nausea and vomiting. The basis for antiemetic therapy is the neurochemical control of vomiting. Although the exact mechanism is not well understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, histamine (H1 and H2), dopamine, acetylcholine, opioids, and numerous other endogenous neurotransmitters.[1,2] Many antiemetics act by competitively blocking receptors for these substances, thereby inhibiting stimulation of peripheral nerves at the CTZ, and perhaps at the "vomiting center." Most drugs with proven antiemetic activity can be categorized into one of the following groups: competitive antagonists at dopaminergic (D2 subtype) receptors or serotonergic (5-hydroxytryptamine-3 or 5-HT3 [subtype]) receptors, corticosteroids, or cannabinoids. Examples of dopaminergic antagonists include the phenothiazines, substituted benzamides, and butyrophenones.

Prochlorperazine is perhaps the most frequently (and empirically) used antiemetic and, in low doses, is generally effective in preventing nausea associated with radiation therapy and in treating nausea and vomiting attributed to very low to moderately emetogenic chemotherapeutic drugs. It is a phenothiazine and can be given orally, intramuscularly, intravenously, and rectally. It is usually given in the 10-50 mg dose range (pediatric dose: 6 mg every 4-6 hours). Higher prochlorperazine doses (e.g., 0.2-0.6 milligrams per kilograms per dose) are also used intravenously for chemotherapy with high emetogenic potential.[3-5] Phenothiazines may be of particular value in treating patients who experience delayed nausea and vomiting (post-acute phase symptoms) on cisplatin regimens.[6]

As with other dopaminergic antagonists, the most common side effects of prochlorperazine are extrapyramidal reactions (acute dystonias, akathisias, neuroleptic malignant syndrome [uncommon], and rarely, akinesias and dyskinesias), and sedation. Marked hypotension may also result if intravenous prochlorperazine is administered rapidly at high doses. Administration over at least 30 minutes appears adequate to prevent hypotensive episodes.[7-11]

Phenothiazines act on dopaminergic receptors at the CTZ, and perhaps at other CNS centers, and peripherally. With the exception of thioridazine, many phenothiazines possess antiemetic activity, including chlorpromazine given in the 10-50 mg dose range orally, intramuscularly, intravenously, and rectally (pediatric dose for older than 12 years old: 10 mg every 6-8 hours; for younger than 12 years old: 5 mg every 6-8 hours); thiethylperazine given in the 5-10 mg dose range orally, intramuscularly, and intravenously; and perphenazine. The primary consideration in selecting among phenothiazines are differences in their adverse effect profiles, which substantially correlate with their structural classes. Generally, aliphatic phenothiazines (e.g., chlorpromazine, methotrimeprazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine, thiethylperazine, perphenazine, and fluphenazine) are associated with less sedation but greater incidence of extrapyramidal reactions.

Metoclopramide is a substituted benzamide, which, prior to the introduction of serotonin (5-HT3) receptor antagonists, was considered the most effective single antiemetic agent against highly emetogenic chemotherapy such as cisplatin. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given intravenously at high doses (e.g., 0.5-3 milligrams per kilograms per dose), probably because it is a weak competitive antagonist (relative to other serotonin antagonists) at 5-HT3 receptors. It may act on the CTZ and the periphery. Metoclopramide also increases lower esophageal sphincter pressure and enhances the rate of gastric emptying, which may factor into its overall antiemetic effect. It can be administered intravenously at the FDA-approved dose of 1-2 mg/kg every 2 hours (or less frequently) for 3-5 doses. Metoclopramide has also been safely given by intravenous bolus injection at higher single doses (up to 6 mg/kg) and by continuous intravenous infusion, with or without a "loading" bolus dose, with efficacy comparable to multiple intermittent dosing schedules.[12-15] Metoclopramide is associated with akathisia and dystonic extrapyramidal effects, with the latter seen more commonly in persons under the age of 30 years, and the former seen more frequently in patients over 30 years of age. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize extrapyramidal reactions (EPRs).[7,16] While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia, the subjective sense of restlessness or inability to sit still, is best treated by: 1) switching to a lower potency neuroleptic for emesis, if possible; 2) lowering the dose, or; 3) adding a benzodiazepine (i.e., lorazepam) or beta blocker (i.e., propranolol).

Droperidol and haloperidol represent the butyrophenones, a third class of dopaminergic (D2 subtype) receptor antagonists that are structurally and pharmacologically similar to the phenothiazines. While droperidol is used primarily as an adjunct to anesthesia induction, haloperidol is indicated as a neuroleptic antipsychotic drug; however, both agents have potent antiemetic activity. Droperidol is administered intramuscularly or intravenously, typically from 1-2.5 mg every 2-6 hours, but higher doses (up to 10 mg) have been safely given.[17-19] Haloperidol is administered intramuscularly, intravenously, or orally, typically from 1-4 mg every 2-6 hours.[20] Both agents may produce extrapyramidal reactions, akathisia, hypotension, and sedation.

Two serotonin receptor antagonists, ondansetron and granisetron are available in the United States. Agents in this class are thought to prevent nausea and vomiting by preventing serotonin, which is released from enterochromaffin cells in the gastrointestinal mucosa, from initiating afferent transmission to the CNS via vagal and spinal sympathetic nerves.[21,22] 5-HT3 antagonists may also block serotonin stimulation at the CTZ and other CNS structures.

Several studies have demonstrated that ondansetron produces an antiemetic response that equals or is superior to high doses of metoclopramide, but ondansetron has a superior toxicity profile compared to dopaminergic antagonist agents.[23-33] Ondansetron (0.15 mg/kg) is given intravenously 15-30 minutes prior to chemotherapy and is repeated every 4 hours for two additional doses. Alternatively, for patients older than 18 years of age, a large multicenter study determined that a single 32-mg dose of ondansetron is more effective in treating cisplatin-induced nausea and vomiting than a single 8-mg dose, and is as effective as the standard regimen of three 0.15 mg/kg doses given every 4 hours starting 30 minutes before chemotherapy.[34] There are, however, some areas of controversy among clinicians related to the optimal role for serotonin receptor antagonists. Because they are better tolerated than previously available antiemetics and are effective, serotonin antagonists have the potential to be overused as prophylaxis in situations that do not present a very substantial emetogenic challenge, i.e., when less expensive agents would suffice. It is also worth noting that during its clinical development, ondansetron was effective at doses of 0.06-0.48 mg/kg given by a variety of intermittent and continuous administration schedules.[35-41] However, neither dose-limiting toxicity nor a maximally tolerated dose were encountered and the optimal dose and schedule for ondansetron have not yet been defined.[34,42,43] Higher (0.30 mg/kg) or lower (0.015 mg/kg) doses of ondansetron have not been shown to be superior to the 0.15 mg/kg dose,[44] and it is unclear whether a single 32-mg dose is necessary to achieve the results reported by Beck, et al.[34] or whether an intermediate dose (between 8 and 32 mg) would be equally effective.

Currently, the oral and injectable ondansetron formulations are approved for use without dosage modification in patients older than 4 years of age, including the elderly and patients with renal insufficiency. Oral ondansetron is given 3 times daily starting 30 minutes before chemotherapy and continuing for up to 2 days after chemotherapy is completed. Patients older than 12 years of age should receive 4 mg/dose. Ondansetron is not approved for use in children under 4 years of age. Ondansetron clearance is diminished in patients with severe hepatic insufficiency, therefore, such patients should receive a single injectable or oral dose not greater than 8 mg. There is currently no information available evaluating the safety of repeated daily ondansetron doses in patients with hepatic insufficiency.

Other effective dosing schedules, such as a continuous intravenous infusion (e.g., 1 mg/hr for 24 hours) or oral administration have also been evaluated.[34,45-50] The major adverse effects include headache (which can be treated with mild analgesics), constipation or diarrhea, fatigue, dry mouth, and transient asymptomatic elevations in liver function tests (alanine [ALT] and aspartate [AST] transaminases), which may be related to concurrent cisplatin administration.[51] Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events.[52] In addition, a few case reports have implicated ondansetron in causing EPRs. However, it is not clear in some cases whether the events described were in fact extrapyramidal reactions, and in other reports the evidence is confounded by concurrent use of other agents that are known to produce EPRs. Nevertheless, the greatest advantage of serotonin receptor antagonists over dopaminergic receptor antagonists is that they have fewer adverse effects.

Granisetron has demonstrated efficacy in preventing and controlling nausea and vomiting at a broad range of doses (e.g., 10-80 micrograms per kilogram and empirically, 3 mg/dose). In the United States, granisetron injection and oral tablets are approved for initial and repeat prophylaxis for patients receiving emetogenic chemotherapy, including high-dose cisplatin. Granisetron is pharmacologically and pharmacokinetically distinct from ondansetron; however, clinically it appears equally efficacious and equally safe.[53-59] Both granisetron formulations are given before chemotherapy, as either a single intravenous dose of 10 micrograms per kilogram (0.01 mg/kg) or 1 mg orally (1- mg tablets) every 12 hours.

Both granisetron formulations and ondansetron injection share the same indication against highly emetogenic chemotherapy. In contrast, the oral ondansetron formulation has been approved only for use against nausea and vomiting associated with moderately emetogenic chemotherapy.

Currently, granisetron injection is approved for use without dosage modification in patients older than 2 years of age, including the elderly and patients with hepatic and renal insufficiency. Oral granisetron has not yet been approved for use in pediatric patients.

Clinicians should note that there are no published reports prospectively comparing antiemetic response rates to prophylaxis with oral ondansetron and granisetron at FDA-approved dosages. Also, preliminary evidence suggests that patients who fail to achieve complete antiemetic control with either ondansetron or granisetron during chemotherapy may achieve adequate control with the alternative agent.[60]

Although ondansetron and granisetron are superior to other antiemetics, neither agent provides continuously high response rates throughout treatments that are administered over two or more consecutive days nor during the post-acute, delayed symptom phase.[61-66] Both granisetron and ondansetron demonstrate greater antiemetic efficacy in combination with corticosteroids (see the COMBINATION THERAPY section).[28,50,67-82]

Other serotonin antagonists, e.g., dolasetron, batanopride, and tropisetron, are currently under evaluation.[35,53,83-88] Thus far, serotonin antagonists have not demonstrated efficacy in treating delayed (post-acute; greater than 24 hours after emetogenic treatment) phase symptoms. In addition, they are expensive to administer and some patients may not be able to afford this treatment.[52,54,89]

Other agents commonly used as prophylaxis and treatment for chemotherapy-induced nausea and vomiting, alone or in combination antiemetic regimens, include corticosteroids (dexamethasone, methylprednisolone) and a cannabinoid (dronabinol). Benzodiazepines (lorazepam, midazolam, alprazolam, diazepam) are also valuable adjuncts in combination with acute antiemetic regimens.

Steroids are sometimes used as single agents against mild to moderately emetogenic chemotherapy, but are more often used in antiemetic drug combinations.[90-95] Their antiemetic mechanism of action is not fully understood, but they may affect prostaglandin activity in the brain. Clinically, steroids quantitatively decrease or eliminate episodes of nausea and vomiting and may improve patients' mood, thus producing a subjective sense of well-being or euphoria (although they also can cause depression and anxiety). In combination with high-dose metoclopramide, steroids may mitigate adverse effects, such as the frequency of diarrheal episodes.

Steroids are often given intravenously before chemotherapy and may or may not be repeated. Dosages and administration schedules are selected empirically. Dexamethasone is often the treatment of choice in treating nausea and vomiting in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally, intramuscularly, or intravenously in the dose range of 8-40 mg (pediatric dose: 0.25-0.5 mg/kg).[96-100] Methylprednisolone is also administered orally, intramuscularly, or intravenously at doses and schedules that vary from 40-500 mg every 6-12 hours for up to 20 doses.[95,101]

Dexamethasone is also used orally for delayed nausea and vomiting. However, long-term corticosteroid use is inappropriate and may cause substantial morbidity, including immunosuppression, proximal muscle weakness (especially involving the thighs and upper arms), aseptic necrosis of the long bones, cataract formation, hyperglycemia and exacerbation of preexisting diabetes or escalation of subclinical diabetes to clinical pathology, adrenal suppression with hypocortisolism, lethargy, weight gain, GI irritation, insomnia, anxiety, mood changes, and psychosis. As had previously been shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT3 blocking agents.[50,68,69,102-104] If given intravenously, dexamethasone should be given over 10-15 minutes, since rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perineal and/or rectal pain.[99,105-109]

Prednisone and adrenocorticotropic hormone (ACTH) given concomitantly with other active antiemetic agents have also demonstrated efficacy against cisplatin-containing chemotherapy during the acute phase (within 24 hours after receiving chemotherapy).[110-113] In a double-blind randomized study of metoclopramide and dexamethasone with or without ACTH 1 mg, patients receiving ACTH prophylaxis for cisplatin-containing chemotherapy experienced a significantly decreased incidence and severity of delayed emesis for up to 72 hours after treatment.[113]

Cannabinoids also presumably target higher CNS structures to prevent nausea and vomiting.[114,115] Dronabinol (delta-9-tetrahydrocannabinol) is one of the psychoactive substances present in crude marijuana. Because of cultural and societal constraints and a low therapeutic index at clinically useful dosages, cannabinoids are often not among agents that are first selected for clinical use, but may be accepted and useful in selected patients. Dronabinol is administered orally at 5-15 milligrams per square meter 1-3 hours before chemotherapy, then every 2-4 hours for up to 6 doses/day.[116-120]

Adverse effects experienced along with the pharmacologic and psychogenic effects of cannabinoids include an acute withdrawal syndrome, sedation, dry mouth, orthostatic hypotension, dizziness, and ataxia. The effects dronabinol produces on the CNS at minimally effective dosages include euphoria or dysphoria; feelings of detachment, depression, anxiety, paranoia, and panic; decreased cognitive function; memory loss; increased tendencies toward impulsive and compulsive behaviors; altered perceptions, such as a distorted sense of time; other sensory distortions; hallucinations; and, rarely, a psychotic organic brain syndrome.[121-124] Cardiovascular adverse effects typically manifest at dosages somewhat greater than those recommended for antiemetic effect and include tachycardia, vasodilation with variable effects on blood pressure, orthostatic symptoms, and decreased body temperature. With chronic administration, tolerance to cardiovascular and subjective effects may occur within days to weeks after treatment onset.[115]

Benzodiazepines, such as lorazepam, midazolam, and alprazolam, have become recognized as valuable adjuncts in the prevention and treatment of anxiety and anticipatory nausea and vomiting symptoms associated with chemotherapy, especially with the highly emetogenic regimens given to children.[125-127] It is important to note that benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents. Therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents.[128] Benzodiazepines presumably act on higher CNS structures, the brainstem, and spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic effects. In addition, they markedly decrease the severity of EPRs, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.

Lorazepam may be administered orally, intramuscularly, intravenously, and sublingually.[129-133] Dosages range from 0.5-3 mg (alternatively, 0.025-0.05 mg/kg, or 1.5 milligrams per square meter, but not greater than 4 mg/dose) in adults and 0.03-0.05 mg/kg in children every 6-12 hours.[125,134-139] Midazolam produces mild to marked sedation for 1-4.5 hours at doses equal to 0.04 mg/kg given intravenously over 3-5 minutes.[140-142] Alprazolam has been shown to be effective when given in combination with metoclopromide and methylprednisolone.[143]

The adverse effects of benzodiazepine include sedation, perceptual disturbances, disorders of micturition and/or defecation, visual disturbances, hypotension, anterograde amnesia, psychological dependence, confusion, ataxia, and depressed mental acuity with intoxication.[144]

Several authors have published comprehensive overviews of antiemetic drugs and their actions, doses, and possible side effects.[105,145-148]


Combination Therapy

Combination antiemetic regimens have become increasingly popular with highly emetogenic chemotherapy treatment programs. A combination of several drugs can be used to attack nausea and vomiting from several sites and mechanisms of action. Most combination regimens combine a dopamine antagonist with agents having no dopamine-blocking effect. An example of a combination regimen is the inpatient administration of metoclopramide, dexamethasone, and lorazepam for a cisplatin-containing regimen, as follows:

metoclopramide 2 mg/kg IV before chemotherapy
dexamethasone 20 mg IV before chemotherapy
lorazepam 1-2 mg IV before chemotherapy (2 mg if over 170 lbs.)
metoclopramide 1 mg/kg IV every 3 hours for 3 doses
dexamethasone 10 mg IV
lorazepam 1 mg IV every 4 hours prn

Diphenhydramine (50 mg IV before chemotherapy; pediatric dose: 1 mg/kg) is usually given with the above regimen to prevent dystonic reactions.

Several studies compared certain drugs in antiemetic drug
combinations.[6,149-151] The combination of intravenous ondansetron and dexamethasone has been shown to be superior to the combination of intravenous metoclopramide, dexamethasone, and diphenhydramine.[152-155] The combination of ondansetron, dexamethasone, and chlorpromazine was superior to ondansetron and dexamethasone.[156] However, the use of oral ondansetron was not as effective as oral metoclopramide and intravenous dexamethasone in a group of breast cancer patients receiving a moderately emetogenic chemotherapeutic regimen.[153] The combination of a serotonin antagonist (ondansetron) and a dopamine D2 antagonist (metopimazine) may prove to be an effective and safe regimen for patients receiving moderate emetogenic therapy.[154] As the diversity of agents with different mechanisms of action expands, the success of combinations of agents will potentially increase the effectiveness of managing nausea and vomiting.

In the selection of antiemetics, there are general factors that should be considered. These include dose, route of administration, and schedule. Patients receiving high emetogenic potential chemotherapy, for example, may require higher doses of antiemetics. Patients receiving highly emetogenic chemotherapy on an outpatient basis (returning home without continued intravenous access, for example) may do best with sublingual or rectal antiemetic routes of delivery. Since the duration of action of drugs differs greatly, the schedule of antiemetics will directly impact on their success. Metoclopramide has a short duration of action (2-3 hours) and therefore should be given frequently. Lorazepam, on the other hand, has a longer duration of action (4-8 hours) and should not be given as frequently as metoclopramide. The same consideration holds for combination antiemetic regimens. Each drug must be considered separately. Maintaining adequate blood levels of a particular drug to prevent nausea and vomiting from occurring is essential to the success of any antiemetic program.

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  110. Colbert N, Izrael V, Lotz J, et al.: Adrenocorticotropic hormone in the prevention of cisplatin-induced nausea and vomiting. Journal of Clinical Oncology 1(10): 635-639, 1983.

  111. Senn HJ, Glaus A, Bachmann-Mettler I, et al.: Effective control of chemotherapy-induced nausea and vomiting with oral prednisone and metoclopramide. Journal of Clinical Oncology 2(4): 320-322, 1984.

  112. Passalacqua R, Cocconi G, Bella M, et al.: Double-blind, randomized trial for the control of delayed emesis in patients receiving cisplatin: comparison of placebo vs. adrenocorticotropic hormone (ACTH). Annals of Oncology 3(6): 481-485, 1992.

  113. Passalacqua R, Cocconi G, Silingardi V, et al.: Double-blind randomized trial for the control of delayed emesis: comparison of placebo vs two different doses of adrenocorticotropic hormone (ACTH). Proceedings of the American Society of Clinical Oncology 12: A-1513, 438, 1993.

  114. Vincent BJ, McQuiston DJ, Einhorn LH, et al.: Review of cannabinoids and their antiemetic effectiveness. Drugs 25(Suppl 1): 52-62, 1983.

  115. Dewey WL: Cannabinoid pharmacology. Pharmacological Reviews 38(2): 151-178, 1986.

  116. Sallan SE, Zinberg NE, Frei E: Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. New England Journal of Medicine 293(16): 795-797, 1975.

  117. Chang AE, Shiling DJ, Stillman RC, et al.: Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate: a prospective, randomized evaluation. Annals of Internal Medicine 91(6): 819-824, 1979.

  118. Sallan SE, Cronin C, Zelen M, et al.: Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. New England Journal of Medicine 302(3): 135-138, 1980.

  119. Gralla RJ, Tyson LB, Bordin LA, et al.: Antiemetic therapy: a review of recent studies and a report of a random assignment trial comparing metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treatment Reports 68(1): 163-172, 1984.

  120. McCabe M, Smith FP, Macdonald JS, et al.: Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy. Investigational New Drugs 6(3): 243-246, 1988.

  121. Frytak S, Moertel CG, O'Fallon JR, et al.: Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy: a comparison with prochloperazine and a placebo. Annals of Internal Medicine 91(6): 825-830, 1979.

  122. Dow GJ, Meyers FH, Stanton W, et al.: Serious reactions to oral delta-9-tetrahydrocannabinol in cancer chemotherapy patients. Clinical Pharmacology and Therapeutics 3(1): 14, 1984.

  123. Lane M, Smith FE, Sullivan RA, et al.: Dronabinol and prochlorperazine alone and in combination as antiemetic agents for cancer chemotherapy. American Journal of Clinical Oncology 13(6): 480-484, 1990.

  124. Lane M, Vogel CL, Ferguson J, et al.: Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. Journal of Pain and Symptom Management 6(6): 352-359, 1991.

  125. Kris MG, Gralla RJ, Clark RA, et al.: Consecutive dose-finding trials adding lorazepam to the combination of metoclopramide plus dexamethasone: improved subjective effectiveness over the combination of diphenhydramine plus metoclopramide plus dexamethasone. Cancer Treatment Reports 69(11): 1257-1262, 1985.

  126. Greenberg DB, Surman OS, Clarke J, et al.: Alprazolam for phobic nausea and vomiting related to cancer chemotherapy. Cancer Treatment Reports 71(5): 549-550, 1987.

  127. Hockenberry-Eaton M, Benner A: Patterns of nausea and vomiting in children: nursing assessment and intervention. Oncology Nursing Forum 17(4): 575-584, 1990.

  128. Triozzi PL, Goldstein D, Laszlo J: Contributions of benzodiazepines to cancer therapy. Cancer Investigation 6(1): 103-111, 1988.

  129. Gram-Hansen P, Schultz A: Plasma concentrations following oral and sublingual administration of lorazepam. International Journal of Clinical Pharmacology, Therapy and Toxicology 26(6): 323-324, 1988.

  130. Calis KA, Mitsch RA: Sublingual use of benzodiazepines. Drug Intelligence and Clinical Pharmacy 19(11): 839-840, 1985.

  131. Caille G, Spenard J, Lacasse Y, et al.: Pharmacokinetics of two lorazepam formulations, oral and sublingual, after multiple doses. Biopharmaceutics and Drug Disposition 4(1): 31-32, 1983.

  132. Greenblatt DJ, Divoll M, Harmatz JS, et al.: Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. Journal of Pharmaceutical Sciences 71(2): 248-252, 1982.

  133. Gale GD, Galloon S, Porter WR: Sublingual lorazepam: a better premedication? British Journal of Anaesthesia 55(8): 761-765, 1983.

  134. Bauer J, Perey L, Douglas P, et al.: Is sublingual lorazepam beneficial for patients on emetogenic chemotherapy? a double-blind randomized and cross-over study. Proceedings of the American Society of Clinical Oncology 8: A-1306, 335, 1989.

  135. Bishop JF, Olver IN, Wolf MM, et al.: Lorazepam: a randomized, double-blind, crossover study of a new antiemetic in patients receiving cytotoxic chemotherapy and prochlorperazine. Journal of Clinical Oncology 2(6): 691-695, 1984.

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NONPHARMACOLOGIC MANAGMENT

Nonpharmacologic strategies to manage nausea and vomiting are also employed. These include dietary alterations, hypnosis, and guided imagery, which may positively alter a patient's perception of the chemotherapy experience, but does not necessarily alter emetic episodes.[1] These strategies are perhaps more useful in treating anticipatory nausea and vomiting but may also enhance a pharmacologic treatment program as well (see MANAGEMENT OF ANTICIPATORY NAUSEA AND VOMITING).

References:

  1. Troesch LM, Rodehaver CB, Delaney EA, et al.: The influence of guided imagery on chemotherapy-related nausea and vomiting. Oncology Nursing Forum 20(8): 1179-1185, 1993.


MANAGEMENT OF ANTICIPATORY NAUSEA AND VOMITING

Anticipatory nausea and vomiting (ANV) is often refractory to standard antiemetic treatment. Because the chemoreceptor trigger zone (CTZ) is probably not directly stimulated in ANV, antiemetics, which block receptors in this zone, theoretically would yield poor results. In some studies, drugs with anxiolytic effect have demonstrated a degree of efficacy in controlling anticipatory symptoms. Lorazepam, a benzodiazepine that has also demonstrated anxiolytic and amnesiac activity, may be effective in the treatment of ANV by blocking the memory of post-treatment nausea and vomiting. As a single agent, lorazepam (0.05 mg/kg IV) has been given one hour before cisplatin and every 4 hours as needed following chemotherapy.[1] Lorazepam has also been given as a single sublingual dose 30 minutes prior to chemotherapy, in conjunction with prochlorperazine suppositories (25 mg every 6 hours).[2] The antihypertensive clonidine decreases anxiety by reducing noradrenergic activity and has been suggested as a possible intervention for ANV, but the relationship between noradrenergic activity and anticipatory symptoms requires further evaluation in controlled clinical trials.[3] No other major classes of drugs used as antiemetics have demonstrated efficacy in the management of ANV.

Some nonpharmacologic approaches to treat ANV include cognitive and behavioral interventions, such as systematic desensitization, distraction, elimination of consistently repeating patterns, manipulation of the setting and personnel associated with chemotherapy administration, biofeedback, and blocking taste sensation with another strong taste (e.g., lemon).[4-9]

Guided imagery or relaxation is used to distract the attention of the patient away from the aversive stimuli. Competing stimuli to the emetic center block the reception of nausea- and vomiting-inducing stimuli. Relaxation techniques promote autonomic responses that inhibit contraction of the gastrointestinal and abdominal musculature thereby blocking the physiological chain of events that leads to nausea and vomiting.[9-14]

Studies suggest that an orientation program educating patients about chemotherapy procedures and the medical environment can reduce conditioned side effects and other distress associated with chemotherapy and can improve patients' ability to cope.[15,16] Such programs can be implemented in many different clinical settings.

In counterconditioning, the patient is first taught to identify existing stimulus-response pairs and then to purposely alter either the stimulus or the response to the stimulus with a new behavior. The techniques that have been studied include hypnosis, relaxation, imagery, and systematic desensitization. The desensitization process uses relaxation training and progressive muscle relaxation in conjunction with chemotherapy stimuli-related guided imagery to gradually decrease anxiety associated with the situation. These techniques are particularly useful because they provide effective relief of nausea and restore a sense of control to the patient. They also require minimal personnel training, little patient effort, and no special equipment.

Approximately 25% of pediatric patients will experience ANV. Hypnosis, relaxation, and distraction (such as playing video games) have been found to be effective in reducing chemotherapy-induced distress in children and adolescents.[17-22]

References:

  1. Laszlo J, Clark RA, Hanson DC, et al.: Lorazepam in cancer patients treated with cisplatin: a drug having antiemetic, amnesic, and anxiolytic effects. Journal of Clinical Oncology 3(6): 864-869, 1985.

  2. Bishop JF, Olver IN, Wolf MM, et al.: Lorazepam: a randomized, double-blind, crossover study of a new antiemetic in patients receiving cytotoxic chemotherapy and prochlorperazine. Journal of Clinical Oncology 2(6): 691-695, 1984.

  3. Fetting JH, Sheidler VR, Stefanek ME, et al.: Clonidine for anticipatory nausea and vomiting: a pilot study examining dose-toxicity relationships and potential for further study. Cancer Treatment Reports 71(4): 409-410, 1987.

  4. Greene PG, Seime RJ: Stimulus control of anticipatory nausea in cancer chemotherapy. Journal of Behavior Therapy and Experimental Psychiatry 18(1): 61-64, 1987.

  5. Burish TG, Shartner CD, Lyles JN: Effectiveness of multiple muscle-site EMG biofeedback and relaxation training in reducing the aversiveness of cancer chemotherapy. Biofeedback and Self Regulation 6(4): 523-535, 1981.

  6. Burish TG, Carey MP, Redd WH, et al.: Behavioral relaxation techniques in reducing the distress of cancer chemotherapy patients. Oncology Nursing Forum 10(3): 32-35, 1983.

  7. Carey MP, Burish TG: Providing relaxation training to cancer chemotherapy patients: a comparison of three delivery techniques. Journal of Consulting and Clinical Psychology 55(5): 732-737, 1987.

  8. Morrow GR, Asbury R, Hammon S, et al.: Comparing the effectiveness of behavioral treatment for chemotherapy-induced nausea and vomiting when administered by oncologists, oncology nurses, and clinical psychologists. Health Psychology 11(4): 250-256, 1992.

  9. Morrow GR, Morrell C: Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. New England Journal of Medicine 307(24): 1476-1480, 1982.

  10. Redd WH, Andrykowski MA: Behavioral intervention in cancer treatment: controlling aversion reactions to chemotherapy. Journal of Consulting and Clinical Psychology 50(6): 1018-1029, 1982.

  11. Jacobsen PB, Redd WH: The development and management of chemotherapy-related anticipatory nausea and vomiting. Cancer Investigation 6(3): 329-336, 1988.

  12. Redd WH, Andreson GV, Minagawa RY: Hypnotic control of anticipatory emesis in patients receiving cancer chemotherapy. Journal of Consulting and Clinical Psychology 50(1): 14-19, 1982.

  13. Burish TG, Lyles JN: Effectiveness of relaxation training in reducing the aversiveness of chemotherapy in the treatment of cancer. Journal of Behavioral Medicine 4(1): 65-78, 1981.

  14. Lyles JN, Burish TG, Krozely MG, et al.: Efficacy of relaxation training and guided imagery in reducing the aversiveness of cancer chemotherapy. Journal of Consulting and Clinical Psychology 50(4): 509-524, 1982.

  15. Burish TG, Tope DM: Psychological techniques for controlling the adverse side effects of cancer chemotherapy: findings from a decade of research. Journal of Pain and Symptom Management 7(5): 287-301, 1992.

  16. Burish TG, Snyder SL, Jenkins RA: Preparing patients for cancer chemotherapy: effect of coping preparation and relaxation interventions. Journal of Consulting and Clinical Psychology 59(4): 518-525, 1991.

  17. Zeltzer L, Kellerman J, Ellenberg L, et al.: Hypnosis for reduction of vomiting associated with chemotherapy and disease in adolescents with cancer. Journal of Adolescent Health Care 4(2): 77-84, 1983.

  18. Zeltzer L, LeBaron S, Zeltzer PM: Paradoxical effects of prophylactic phenothiazine antiemetics in children receiving chemotherapy. Journal of Clinical Oncology 2(8): 930-936, 1984.

  19. Zeltzer LK, Dolgin MJ, LeBaron S, et al.: A randomized, controlled study of behavioral intervention for chemotherapy distress in children with cancer. Pediatrics 88(1): 34-42, 1991.

  20. Kolko DJ, Rickard-Figueroa JL: Effects of video games on the adverse corollaries of chemotherapy in pediatric oncology patients: a single-case analysis. Journal of Consulting and Clinical Psychology 53(2): 223-228, 1985.

  21. Redd WH, Jacobsen PB, Die-Trill M, et al.: Cognitive/attentional distraction in the control of conditioned nausea in pediatric cancer patients receiving chemotherapy. Journal of Consulting and Clinical Psychology 55(3): 391-395, 1987.

  22. Dolgin MJ, Katz ER, McGinty K, et al.: Anticipatory nausea and vomiting in pediatric cancer patients. Pediatrics 75(3): 547-552, 1985.

  23. LeBaron S, Zeltzer L: Behavioral intervention for reducing chemotherapy-related nausea and vomiting in adolescents with cancer. Journal of Adolescent Health Care 5(3): 178-182, 1984.

Date Last Modified: 06/1997



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