Kelbvli I’endergrass,m Options in the
`Treatment of
`
`Chemotherapy-
`Induced Emesis
`
`therapy, nursing, hospitalimtion, and reduced patient/care
`giver productivity.‘
`Severe chemotherapy-induced emesis may result in
`malnutrition, aspiration pneumonia, and esophageal rup-
`ture.” In addition, electrolyte imbalance and dehydration
`mayoccur,whichcandelaydrugclearanceandincrease
`the overall risks of toxicity from cytotoxic agents. In some
`cases, toxicity from chemotherapy may be severe enough
`to require or extend hospitalization.’
`Many patients have cited nausea and vomiting as their
`primary concern regarding chemotherapy."‘ These con-
`cerns about chemotherapy-induced emesis can become a
`formidable obstacle to optimal cancer treatment.’ Reports
`suggest that from 10% to 50% of patients may refuse or
`delay chemotherapy treatments because of fears about nau-
`sea and vomiting.‘''’ In addition, inadequate control of eme-
`sis during the
`course of chemotherapy can predis
`pose patients to anticipatory nausea and vomiting, resulting
`in refusal of further cancer treatment.3
`For patients with cancer who may be cured by or sig-
`nificantly benefit from chemotherapy, premature with-
`drawal or cessation of treatment may have life-threatening
`consequences.7 Effective control of emesis has, therefore,
`become a major objective for physicians administering che-
`motherapy because it not only maintains the best quality of
`life for the patient but enables the
`to administer
`potentially life-saving treatment.
`
`cllnlcal characterlstlcs
`
`The incidence and severity of chemotherapy-induced
`emesis depend on several factors, including the intrinsic
`emetogenicity of the particular drug, dosage used, and
`route of administration (Table 1).‘ High-dose cisplatin, for
`example, induces emesis in virtually all patients, whereas
`bleomycin seldom produces this effect.’ Similarly, low
`doses or extended infusions of cyclophosphamide or cis-
`
`KellyB.Pcndergrass,MD,Chief,Sectionof0ncoIogy,Re-
`search Medical Center, Kansas City,
`Addressforcorrcspondence:KellyB.Pendagrass,Chid,Sec-
`tion of Oncology, Research Tower, Suite T—l0l, 6420 Prospect
`Ave, Kansas City, MO 64132.
`
`canon: l||IAc"l'IcE Septeuubeductober 1998, Vol. 6, No. 5
`© American Cancer Sodety 1065-4074/98/$10.50/276 276-281
`
`Helsinn Healthcare Exhibit 2039
`
`ausea and vomiting are among the most common and
`distressing side effects of cancer chemotherapy. Inad-
`equate control of emesis reduces the quality of life and
`functional status of cancer patients and jeopardizes the de-
`livery of optimal treatment.‘ The economic impact of
`poorly controlled chemotherapy-induced emesis is seen not
`only in intangible costs, such as patient distress and suffer-
`ing,butalsointhosecostsassociatedwithrescuedrug
`
`276
`
`Page 1 of 7
`
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`

`
`Table 1. Emetogenicity of Chemotherapeutic Agents*
`
`Frequency of
`Emesis (%)
`
`>90
`
`60–90
`
`30–60
`
`10–30
`
`<10
`
`Agent
`
`Carmustine >250 mg/m2
`Cisplatin ⱖ50 mg/m2
`Cyclophosphamide >1500 mg/m2
`Dacarbazine
`Mechlorethamine
`Streptozocin
`
`Carboplatin
`Carmustine ⱕ250 mg/m2
`Cisplatin <50 mg/m2
`Cyclophosphamide >750 mg/m2 ⱕ1500 mg/m2
`Cytarabine >1 g/m2
`Doxorubicin >60 mg/m2
`Methotrexate >1000 mg/m2
`Procarbazine (oral)
`Cyclophosphamide ⱕ750 mg/m2
`Cyclophosphamide (oral)
`Doxorubicin 20–60 mg/m2
`Epirubicin ⱕ90 mg/m2
`Hexamethylmelamine (oral)
`Idarubucin
`Ifosfamide
`Methotrexate 250–1000 mg/m2
`Mitoxantrone <15 mg/m2
`
`Docetaxel
`Etoposide
`5-Fluorouracil <1000 mg/m2
`Gemcitabine
`Methotrexate >50 mg/m2 <250 mg/m2
`Mitomycin
`Paclitaxel
`
`Bleomycin
`Busulfan
`Chlorambucil (oral)
`2-Chlorodeoxyadenosine
`Fludarabine
`Hydroxyurea
`Methotrexate ⱕ50 mg/m2
`L-phenylalanine mustard (oral)
`Thioguanine (oral)
`Vinblastine
`Vincristine
`Vinorelbine
`
`*Reprinted from Hesketh et al.9 Used with permission.
`
`platin may cause only mild or moderate emesis compared
`with the severe nausea and vomiting encountered with
`high drug doses or bolus administration.6 Combination che-
`motherapy with more emetogenic agents appears to be
`additive.
`Individual patient characteristics also play a role in che-
`motherapy-induced emesis. Age, gender, and alcohol con-
`sumption appear to be determining factors. At increased
`
`Chemotherapy-Induced Emesis / Pendergrass
`
`277
`
`risk are women, younger patients, those with a low alcohol
`intake, and those who experienced nausea and vomiting
`during previous chemotherapy treatments.6,10
`Chemotherapy-induced emesis may take one of several
`forms: acute, delayed, or anticipatory. Acute nausea and
`vomiting within 24 hours of treatment have been reported
`in 50% and 27% of outpatients, respectively.7 In a study by
`Kris et al,11 93% of patients who received high-dose cisplat-
`in experienced delayed emesis (nausea and/or vomiting be-
`tween 24 and 120 hours after starting therapy). Anticipa-
`tory nausea and vomiting, a learned response, may affect
`as many as 50% of cancer chemotherapy patients whose
`emesis was poorly controlled during previous courses of
`chemotherapy.12
`
`Pathways and Pathophysiology
`
`Emesis serves as a protective reflex against the inges-
`tion of various toxins.13 Chemotherapy may induce emesis
`by damaging enterochromaffin cells in the gastrointestinal
`(GI) tract or by acting directly on medullary centers in the
`brain.6 Much of the current understanding of the emetic
`response comes from the work of Borison and Wang,14 who
`proposed that emesis is controlled by two distinct central
`nervous system sites in the brain: the chemoreceptor trig-
`ger zone (CTZ) and the vomiting center.
`The CTZ, considered the primary mediator of chemo-
`therapy-induced emesis,3 is found in the area postrema,
`which is located on the surface of the brain in the floor of
`the fourth ventricle.6 The CTZ lies outside the blood-brain
`barrier and is therefore accessible to stimuli borne in either
`the blood or cerebral spinal fluid.5 The CTZ acts by stimu-
`lating the vomiting center, which is located in the lateral
`reticular formation of the medulla oblongata.3,6 The vomit-
`ing center also receives input from the pharynx and GI tract
`via the vagus nerve, with some input from splanchnic
`nerves.6
`Progress made in the management of chemotherapy-
`induced emesis is the result in part of an increased under-
`standing of the role of various neurotransmitters. Early stud-
`ies focused on the dopamine receptor, and in fact D2
`receptors are abundant in the area postrema, where dopa-
`mine appears to act as an excitatory transmitter.6
`In recent years there has been substantial evidence to
`link the process of chemotherapy-induced emesis with se-
`rotonin (5-hydroxytryptamine, or 5-HT), specifically the
`type 3 receptor (5-HT3).3,6,13 Serotonin receptors are abun-
`dant on vagal afferent neurons and other neurons in the GI
`tract and have been identified in the area postrema, in the
`nucleus tractus solitarii, and on vagal afferent terminals in
`the medulla.6,13 Cytotoxic agents stimulate the release of
`serotonin from enterochromaffin cells in the GI mucosa.
`The released serotonin binds to 5-HT3 receptors in the gut,
`triggering impulses that travel up the vagus nerve to 5-HT3
`receptors in the brain.3,6 The CTZ receives these signals and
`sends impulses to the vomiting center,3 which coordinates
`these messages and activates a series of responses, includ-
`ing gastric stasis accompanied by nausea, increased saliva-
`tion, and finally, rhythmic retching that culminates with
`vomiting.
`
`Page 2 of 7
`
`

`
`278
`
`CANCER PRACTICE September/October 1998, Vol. 6, No. 5
`
`Substance P, one of the four mammalian tachykinins,
`may function as a sensory neurotransmitter in the nucleus
`tractus solitarii. Neurokinin-1 (NK1) receptor antagonists
`appear to block one of the sites of action of substance P and
`have the ability to block retching and vomiting induced by
`cisplatin and other emetogenic agents.15–18 These NK1 an-
`tagonists may block both acute and delayed emesis and are
`currently being investigated in human clinical trials.
`Also, high levels of histamine H1 and muscarinic cho-
`linergic receptors have been found in the nucleus tractus
`solitarii.6 However, further investigations are required to
`determine whether these neurotransmitters play a role in
`chemotherapy-induced emesis.
`
`Antiemetic Agents
`
`Several classes of drugs are used to treat and, hopefully,
`prevent chemotherapy-induced emesis (Table 2). Their ac-
`tivity can be explained by their affinity for certain neuro-
`transmitter receptors. Treatment with two or more anti-
`emetics may improve efficacy and/or reduce drug toxicity
`(extrapyramidal reactions).
`
`DopamineReceptorAntagonists
`
`Metoclopramide appears to suppress chemotherapy-
`induced emesis by antagonizing dopamine receptor activity
`in the CTZ and by enhancing gastric motility.19,20 In high
`
`Table 2. Potency of Antiemetic Agents*
`
`Potency
`
`Agent
`
`Effective against
`highly emetogenic
`chemotherapy
`
`Effective against
`moderately or
`mildly emetogenic
`chemotherapy
`
`Minimally effective
`
`Dopamine receptor antagonist
`(metoclopramide)
`Serotonin receptor antagonist
`(ondansetron, granisetron, dolasetron,
`tropisetron, azasetron, itasetron)
`Butyrophenone
`(haloperidol, droperidol)
`Corticosteroid
`(dexamethasone, methylprednisone,
`prednisone)
`Cannabinoid
`(tetrahydrocannabinol, dronabinol,
`nabilone)
`Phenothiazine
`(prochlorperazine, thiopropazate,
`promethazine)
`Anticholinergic
`(scopolamine)
`Antihistamine
`(diphenhydramine)
`Benzodiazepine
`(lorazepam, alprazolam)
`
`*Adapted from Grunberg and Hesketh.6 Used with permission.
`
`concentrations, metoclopramide also blocks 5-HT3 recep-
`tors.13 However, the use of high-dose metoclopramide is
`limited by antidopaminergic side effects that include extra-
`pyramidal reactions, restlessness, and anxiety.21 In clinical
`practice, the use of high-dose metoclopramide is accompa-
`nied by the coadministration of diphenhydramine to mini-
`mize central nervous system side effects. The incidence of
`dystonic reactions is highest in children and young adults.
`Dopaminergic antagonistic effects also may cause hyperpro-
`lactinemia, which can result in impotence, galactorrhea,
`and amenorrhea.22 Although antihistamines have only weak
`antiemetic action, they have been useful in reducing the
`incidence of extrapyramidal reactions associated with high-
`dose metoclopramide.6 Anticholinergics, such as scopol-
`amine, may also help to decrease metoclopramide toxicity.6
`The antiemetic effect of the phenothiazines is primarily
`via dopamine D2 receptor antagonism.22 Phenothiazines,
`such as prochlorperazine, thiopropazate, and prometha-
`zine, are considered to be relatively effective in patients
`treated with chemotherapeutic agents that are only mini-
`mally or moderately emetogenic, such as fluorouracil and
`doxorubicin.6
`In patients treated with highly emetogenic drugs, such
`as high-dose cisplatin, moderate doses of phenothiazines
`appear to be no better than placebo in preventing emesis.
`Antiemetic activity is enhanced by increasing the dose;
`however, high doses may be contraindicated (especially in
`children) because of dopamine antagonist activity, which
`can cause extrapyramidal reactions and side effects such as
`hypotension and restlessness.6
`The butyrophenones haloperidol and droperidol, po-
`tent D2 receptor antagonists, are used primarily to control
`postoperative vomiting and to reduce anticipatory nausea
`and vomiting in cancer patients. Extrapyramidal side effects
`may occur, and tolerance may develop with repeated use.13
`Domperidone, also a potent D2 receptor antagonist,
`has been used to relieve the nausea and vomiting often
`associated with Parkinson’s disease and diabetes. Studies to
`date suggest that domperidone effectively controls vomit-
`ing associated with moderately emetogenic cytotoxic
`drugs.23 The antiemetic and pharmacodynamic profiles of
`domperidone are similar to those of metoclopramide. How-
`ever, the antiemetic effects of domperidone are mediated
`by peripheral versus central D2 antagonism, so this drug
`does not readily cross the blood-brain barrier and rarely
`causes extrapyramidal side effects.13,22,23 Adverse events
`include headache, diarrhea, and prolactin-related effects
`such as galactorrhea.22,23
`
`SerotoninReceptorAntagonists
`
`The 5-HT3 antagonists, the most recently approved an-
`tiemetic drugs, inhibit the emetic response by preventing
`serotonin released in the GI mucosa from binding to 5-HT3
`receptors.10 These agents are effective against highly
`emetogenic chemotherapy.6 Their single-agent efficacy in
`completely preventing acute cisplatin-induced emesis is ap-
`proximately 40% to 50%.6,24 Ondansetron, granisetron, and
`dolasetron are available in the United States; complete re-
`sponse rates in patients receiving high-dose cisplatin are
`
`Page 3 of 7
`
`

`
`comparable. Tropisetron and azasetron are marketed out-
`side the United States. Itasetron is in phase III clinical trials
`in the United States. Current clinical practice is to combine
`a 5-HT3 antagonist with a corticosteroid, a regimen with
`complete response rates of more than 70% in patients re-
`ceiving moderately to highly emetogenic chemotherapy.25
`Side effects associated with the 5-HT3 antagonists tend
`to be mild and transient and include headache, constipa-
`tion, fatigue, dry mouth, and diarrhea.6,21 Electrocardio-
`gram abnormalities have been observed but do not appear
`to be clinically significant.
`These agents appear to be similar in activity and are
`equally effective in oral or parenteral form.26 The 5-HT3
`antagonists share a modest dose-response curve with a
`threshold effect and subsequent plateau phase. They are
`most effective in acute emesis; most treatment failures oc-
`cur after 16 hours, which may actually signal the start of
`delayed emesis. Repetitive dosing, multiple dosing, or con-
`tinuous infusion is of no added benefit.27,28
`The approved dose of ondansetron for highly emeto-
`genic chemotherapy is a single 32-mg intravenous dose in
`the United States versus 8 mg in Europe. For granisetron the
`opposite is true, with a 10-µm/kg dose in the United States
`versus a 40-µm/kg dose in Europe. This paradox arose from
`the doses chosen in early trials and may be explained by the
`dose-response curve/plateau phase; it supports the use of
`lower doses as a cost-saving measure and speaks against
`higher and/or repetitive dosing in patients who experience
`chemotherapy-induced emesis within the first 24 hours.
`
`Cannabinoids
`
`The use of tetrahydrocannabinol, the active agent in
`marijuana, and the synthetic cannabinoids dronabinol and
`nabilone has been shown to be effective in patients receiv-
`ing moderately emetogenic chemotherapy.6 Side effects
`can be severe, however; they include dysphoria, hallucina-
`tions, sedation, vertigo, dry mouth, and disorientation. Can-
`nabinoids are seldom used as first-line therapy but may be
`useful in patients who have a low tolerance or minimal
`response to other antiemetic agents. They are generally
`poorly tolerated by the elderly and/or tetrahydrocannabi-
`nol-naı¨ve individuals.
`
`Corticosteroids
`
`Corticosteroids, such as dexamethasone, methylpred-
`nisone, and prednisone, have been shown to be effective
`against chemotherapy-induced emesis.6 Their antiemetic
`action, however, is not clearly understood. Proposed theo-
`ries include blocking of prostaglandin formation (doubtful)
`and changes in cellular permeability.6,13 Steroids may have
`a role in altering endorphin release. Because corticosteroids
`may cause psychotic reactions and affect glucose metabo-
`lism, they must be used with caution in patients with dia-
`betes mellitus and those with certain psychiatric disorders.
`Corticosteroids are the agents used most often in com-
`bination antiemetic regimens. Dexamethasone plus on-
`
`Chemotherapy-Induced Emesis / Pendergrass
`
`279
`
`dansetron is used widely for both acute and delayed emesis.
`A marked decrease in emesis has been reported in patients
`receiving corticosteroids plus high-dose metoclopramide or
`a serotonin antagonist (ondansetron, granisetron, dolas-
`etron).6,29 The combination of 200 mg of oral dolasetron
`and 20 mg of dexamethasone given only once was shown
`to prevent acute emesis in 76% of patients who received 70
`mg/m2 or greater doses of cisplatin.30 A second dose of
`dexamethasone did not reduce the number of emetic epi-
`sodes or time to onset of emesis significantly.
`Improved antiemetic efficacy has also been demon-
`strated when corticosteroids are combined with a pheno-
`thiazine, butyrophenone, cannabinoid, or benzodiazepine.6
`
`Benzodiazepines
`
`Benzodiazepines, such as lorazepam and alprazolam,
`have been used as antiemetic agents but have low anti-
`emetic potency. Their beneficial effects may be the result of
`their anxiolytic, sedative, and amnesic properties.6 These
`drugs are most useful in alleviating anticipatory nausea and
`vomiting and in reducing anxiety.6
`
`Clinical Implications
`
`EconomicChallenges
`
`Chemotherapy-induced emesis reduces the quality of
`life and functional status of patients with cancer and in-
`creases direct and indirect costs of managing the disease.1
`These factors have dramatic implications for the healthcare
`system, given that 40% of all newly diagnosed cancer pa-
`tients in the United States each year are expected to be
`candidates for chemotherapy.1 The direct costs of poorly
`controlled emesis include increased hospitalization and the
`increased nursing and medical staff costs of managing ad-
`verse events.1 Indirect costs include lost or reduced patient
`and/or care giver productivity and income.1
`Another financial concern is that the use of oral 5-HT3
`antagonists is not reimbursed by Medicare (and other third-
`party payers), except with oral chemotherapy agents. Med-
`icare rules concerning coverage for oral drugs are expected
`to change in 1998, however.
`
`QualityofLife
`
`Nausea and vomiting have been cited by cancer pa-
`tients as the most troubling side effects of chemotherapy.
`Fear or experience of these debilitating side effects may
`interfere with the completion of prescribed courses of po-
`tentially beneficial chemotherapy.1,3,4,7 Fortunately, the de-
`velopment of effective antiemetics has improved dramati-
`cally the tolerability of cancer treatment. As noted by
`Grunberg and Hesketh only 5 years ago, patients receiving
`cisplatin for the first time had a median of 12 vomiting
`episodes over the first 24 hours.6 Today, more than 50% of
`
`Page 4 of 7
`
`

`
`280
`
`CANCER PRACTICE September/October 1998, Vol. 6, No. 5
`
`Table 3. Recommended Antiemetic Regimens for Patients Receiving Highly Emetogenic Cancer Chemotherapy
`
`Goal
`
`Regimen
`
`Timing
`
`To prevent acute emesis
`
`To prevent delayed emesis
`
`*Not available in the United States.
`
`5-HT3 antagonist
`(granisetron, 10 µg/kg intravenously or 1 mg total dose
`or
`ondansetron, 8 mg intravenously
`or
`dolasetron, 1.8 mg/kg intravenously or 100 mg total dose
`or
`tropisetron, 5 mg intravenously*)
`plus
`Corticosteroid
`(dexamethasone, 8–10 mg intravenously)
`
`Metoclopramide, 20 mg po bid for 3 days
`plus
`Dexamethasone, 16 mg po on day 1 with breakfast,
`8 mg po on day 2, and 4 mg po on day 3
`
`Administer before cancer chemotherapy
`
`Start administration the morning after chemotherapy,
`with meals
`
`patients experience no vomiting at all, with most treat-
`ments being administered in an outpatient setting.
`Selecting and administering appropriate antiemetic
`agents can improve the cancer patient’s quality of life and
`functional status significantly. Doing so may also facilitate
`the acceptance of potentially life-saving therapy and affect
`favorably the overall cost of managing the disease.
`
`Recommendations
`
`Currently, for outpatients receiving highly emetogenic
`chemotherapy (high-dose cisplatin) outside of a clinical
`trial, a single intravenous dose of a 5-HT3 antagonist plus a
`corticosteroid before chemotherapy is recommended to
`prevent acute emesis. The combination of oral metoclo-
`pramide plus dexamethasone the following morning is rec-
`ommended to prevent delayed emesis (Table 3).
`
`References
`
`1. Plosker GL, Benfield P. Granisetron: a pharmacoeconomic
`evaluation of its use in the prophylaxis of chemotherapy-
`induced nausea and vomiting. PharmacoEconomics. 1996; 9:
`357–374.
`2. Lee M, Feldman M. Nausea and vomiting. In: Sleisenger MH,
`Fordtran JS, eds. Gastrointestinal Disease: Pathophysiology/
`Diagnosis/Management. Philadelphia, Pa: W.B. Saunders;
`1993;1:509–523.
`3. Perez EA, Gandara DR. Advances in the control of chemo-
`therapy-induced emesis. Ann Oncol. 1992;3(suppl 3):47–50.
`4. Coates A, Abraham S, Kaye SB, et al. On the receiving end:
`patient perception of the side effects of cancer chemotherapy.
`Eur J Cancer Clin Oncol. 1983;19:203–208.
`5. Sitzia J, Huggins L. Side effects of cyclophosphamide, metho-
`trexate, and 5-fluorouracil (CMF) chemotherapy for breast
`cancer. Cancer Practice. 1998;6:13–21.
`
`6. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced
`emesis. N Engl J Med. 1993;329:1790–1796.
`7. Lindley CM, Bernard S, Fields SM. Incidence and duration of
`chemotherapy-induced nausea and vomiting in the outpatient
`oncology population. J Clin Oncol. 1989;7:1142–1149.
`8. Laszlo J. Emesis as limiting toxicity in cancer chemotherapy.
`In: Laszlo J, ed. Antiemetics and Cancer Chemotherapy. Bal-
`timore, Md: Williams & Wilkins; 1983:1–5.
`9. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classi-
`fying the acute emetogenicity of cancer chemotherapy. J Clin
`Oncol. 1997;15:103–109.
`10. Perez EA. Review of the preclinical pharmacology and com-
`parative efficacy of 5-hydroxytryptamine-3 receptor antago-
`nists for chemotherapy-induced emesis. J Clin Oncol. 1995;
`13:1036–1043.
`11. Kris MG, Gralla RJ, Clark RA, et al. Incidence, course, and
`severity of delayed nausea and vomiting following the admin-
`istration of high-dose cisplatin. J Clin Oncol. 1985;3:
`1379–1384.
`12. Andrykowski MA. The role of anxiety in the development of
`anticipatory nausea in cancer chemotherapy: a review and
`synthesis. Psychosom Med. 1990;52:458–475.
`13. Mitchelson F. Pharmacological agents affecting emesis: a re-
`view (part I). Drugs. 1992;43:295–315.
`14. Borison HL, Wang SC. Physiology and pharmacology of vom-
`iting. Pharmacol Rev. 1953;5:193–230.
`15. Tattersall FD, Rycroft W, Hill RG, Hargreaves RJ. Enantioselec-
`tive inhibition of apomorphine-induced emesis in the ferret by
`the neurokinin1 receptor antagonist CP-99,994. Neurophar-
`macology. 1994;33:259–260.
`16. Watson JW, Gonsalves SF, Fossa AA, et al. The antiemetic
`effects of CP-99,994 in the ferret and the dog: role of the NK1
`receptor. Br J Pharmacol. 1995;115:84–94.
`17. Gardner CJ, Twissel DJ, Dale TJ, et al. The broad-spectrum
`antiemetic activity of the novel nonpeptide tachykinin NK1
`receptor antagonist GR203,040. Br J Pharmacol. 1995;116:
`3158–3163.
`18. Gonsalves S, Watson J, Ashton C. Broad spectrum antiemetic
`effects of CP-122,721, a tachykinin NK1 receptor antagonist,
`in ferrets. Eur J Pharmacol. 1996;305:181–185.
`
`Page 5 of 7
`
`

`
`Chemotherapy-Induced Emesis / Pendergrass
`
`281
`
`19. Albibi R, McCallum RW. Metoclopramide: pharmacology and
`clinical application. Ann Intern Med. 1983;98:86–95.
`20. Alphin RS, Proakis AG, Leonard CA, et al. Antagonism of cis-
`platin-induced emesis by metoclopramide and dazopride
`through enhancement of gastric motility. Dig Dis Sci. 1986;
`31:524–529.
`21. DeMulder PHM, Seynaeve C, Vermorken JB, et al. Ondansetron
`compared with high-dose metoclopramide in prophylaxis of
`acute and delayed cisplatin-induced nausea and vomiting: a
`multicenter, randomized, double-blind, crossover study. Ann
`Intern Med. 1990;113:834–840.
`22. Kendall BJ, McCallum RW. Gastroparesis and the current use
`of prokinetic drugs. Gastroenterologist. 1993;1:107–114.
`23. Brogden RN, Carmine AA, Heel RC, et al. Domperidone: a
`review of its pharmacological activity, pharmacokinetics, and
`therapeutic efficacy in the symptomatic treatment of chronic
`dyspepsia and as an antiemetic. Drugs. 1982;24:360–400.
`24. Hainsworth J, Harvey W, Pendergrass K, et al. A single-blind
`comparison of intravenous ondansetron, a selective serotonin
`antagonist, with intravenous metoclopramide in the preven-
`tion of nausea and vomiting associated with high-dose cisplat-
`in chemotherapy. J Clin Oncol. 1991;9:721–728.
`25. Hesketh PJ, Beck T, Uhlenhopp M, et al. Adjusting the dose of
`intravenous ondansetron plus dexamethasone to the emeto-
`
`genic potential of the chemotherapy regimen. J Clin Oncol.
`1995;13:2117–2122.
`26. Cubeddu LX, Pendergrass K, Ryan T, et al. Efficacy of oral
`ondansetron, a selective antagonist of 5-HT3 receptors, in the
`treatment of nausea and vomiting associated with cyclophos-
`phamide-based chemotherapies. Am J Clin Oncol. 1994;17:
`137–146.
`27. Pendergrass K, Audhuy B, Hesketh P, et al. Analysis of optimal
`dose from eight pooled clinical trials assessing the acute anti-
`emetic efficacy of IV dolasetron mesylate (DM) after emeto-
`genic chemotherapy (ECT). Proc Am Soc Clin Oncol. 1996;
`15:547(abstr).
`28. Beck TM, Hesketh PJ, Madajewicz S, et al. Stratified, random-
`ized, double-blind comparison of intravenous ondansetron ad-
`ministered as a multiple-dose regimen versus two single-dose
`regimens in the prevention of cisplatin-induced nausea and
`vomiting. J Clin Oncol. 1992;10:1969–1975.
`29. Perez EA. Comparative efficacy of oral and intravenous granis-
`etron for the prevention of acute chemotherapy-induced eme-
`sis. Clin Ther. 1996;18:578–590.
`30. Kris MG, Pendergrass KB, Navari RM, et al. Prevention of acute
`emesis in cancer patients following high-dose cisplatin with
`the combination of oral dolasetron and dexamethasone. J Clin
`Oncol. 1997;15:2135–2138.
`
`Bulletin Board
`
`Symposia
`October 8–9, 1998. Baltimore, Maryland. Program Evaluation and
`Outcomes Measurement: A Necessity for the 21st Century. Contact:
`Kim Bell, Johns Hopkins Oncology Center Postgraduate Program, 1910
`East Jefferson Street, Baltimore, MD 21205 (phone, 410-614-3995; fax,
`410-614-3991).
`
`Contact: Jaclyn Silverman, Division of Neoplastic Diseases, Box 1178,
`Mount Sinai School of Medicine, One Gustave Levy Place, New York,
`NY 10029 (phone, 212-241-6772; fax, 212-996-5787).
`
`November 13–15, 1998. Dallas, Texas. Oncology Nursing Society Fall
`Institute. Contact: ONS, 501 Holiday Drive, Pittsburgh, PA 15220
`(phone, 412-921-7373; fax, 412-921-6565).
`
`October 8–10, 1998. Boston, Massachusetts. Urological Cancer
`Course. Contact: Harvard Medical School (phone, 617-432-1525).
`
`October 15–16, 1998. Baltimore, Maryland. Skills for Enhancing Pa-
`tient Self-Control: Cognitive-Behavioral and Other Complementary
`Approaches in Oncology. Contact: Kim Bell, Johns Hopkins Oncology
`Center Postgraduate Program, 1910 East Jefferson Street, Baltimore,
`MD 21205 (phone, 410-614-3995; fax, 410-614-3991).
`
`October 16–18, 1998. Bethel, Maine. The Northeast Regional Oncol-
`ogy Nursing (NERON) Conference: Cancer Care, Managing in the
`New Millenium. Contact: Judi Floyd (phone, 203-630-5298; e-mail,
`jdfloyd@worldnet.att.net).
`
`November 5–6, 1998. Baltimore, Maryland. The Caring Continuum:
`Transitioning from Acute Care Interventions to Palliation and End
`of Life. Contact: Kim Bell, Johns Hopkins Oncology Center Postgradu-
`ate Program, 1910 East Jefferson Street, Baltimore, MD 21205 (phone,
`410-614-3995; fax, 410-614-3991).
`
`November 11–13, 1998. New York, New York. Chemotherapy Foun-
`dation Symposium XVI, Innovative Cancer Therapy for Tomorrow.
`
`American Cancer Society
`Scholarships and Grants*
`Scholarships in Cancer Nursing 1999. To provide support for study in
`a doctoral degree program in nursing or a related area or in a master’s
`degree graduate program with demonstrated integration of cancer
`nursing content. Includes subsistence and tuition expenses for $8000
`each year. Applications are due by December 15, 1998 for September
`1, 1999 scholarships.
`
`Research Project Grant. To support research projects initiated by in-
`vestigators in their first 8 years of independent research. Deadline:
`October 15, 1998.
`
`Targeted Research Project Grant. To provide one-time support for
`research projects involving psychosocial, behavioral, quality of life,
`health policy, or outcomes research as related to prostate cancer.
`Deadline: October 15, 1998.
`
`*For more information, contact your local grants administra-
`tion office, or the American Cancer Society (phone, 404-329-7558;
`fax, 404-321-4669; e-mail, grants@cancer.org). Funding amounts
`and eligibility vary from program to program.
`
`Page 6 of 7
`
`

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`
`Page 7 of 7