A Single-Blind Comparison of Intravenous Ondansetron, a Selective Serotonin Antagonist, With Intravenous Metoclopramide in the Prevention of Nausea and Vomiting Associated With High-Dose Cisplatin Chemotherapy By John Hainsworth, Walter Harvey, Kelly Pendergrass, Basil Kasimis, David Oblon, Greg Monaghan, David Gandara, Paul Hesketh, Ali Khojasteh, Graydon Harker, Martin York, Tariq Siddiqui, and Andrew Finn Ondansetron (GR 38032F), a selective antagonist of serotonin subtype 3 receptors, is effective in the prevention of emesis associated with cisplatin as well as other chemotherapeutic agents. In this randomized, singleblind, multicenter, parallel group study, we compared the efficacy and safety of intravenous (IV)ondansetron with IV metoclopramide in the prevention of nausea and vomiting associated with high-dose (> 100 mg/ m') cisplatin chemotherapy. Three hundred seven patients receiving their first dose of cisplatin, either alone or in combination with other antineoplastic agents, were randomized to receive ondansetron 0.15 mg/kg IVevery 4 hours for three doses or metoclopramide 2 mg/kg IV every 2 hours for three doses, then every 3 hours for three additional doses. The study prohibited the concurrent administration of other antiemetics or dexamethasone. Patients receiving ondansetron had a higher rate of complete protection from emesis (40%v

C

ISPLATIN is a widely used chemotherapeutic agent that produces emesis in virtually all patients not treated with an adequate antiemetic regimen.! Patients who receive cisplatin at a dose of 100 mg/m 2 have a minimum of five and a median of more than 10 emetic episodes within 24 hours if they receive either no antiemetics or prochlorperazine alone. 2 At present, high-dose metoclopramide is considered to be the most effective agent in preventing cisplatin-induced emesis. When administered at a dose of 2 mg/kg every 2 hours for five doses, metoclopramide provided complete antiemetic protection during the first 24-hours in 38% of patients receiving high-dose cisplatin.2 Originally, the antiemetic effect of metoclopramide was thought to be mediated by dopamine receptor blockade. Recent data suggest that the antiemetic properties are due to a serotonin antagonist activity that occurs at doses higher than those associated with the dopamine receptor blockade. 4 Ondansetron (GR 38032F) is a selective antagonist of serotonin subtype 3 receptors, and is a potent antiemetic agent when used in patients

30%, P = .07), a higher complete plus major response rate (65% v 51%, P = .016), a lower rate of failure (21% v 36%, P = .007), and a lower median number of emetic episodes (one v two, P = .005) than did those receiving metoclopramide. The median time to the first emetic episode was longer on ondansetron (20.5 v 4.3 hours, P < .001). Adverse events occurred in 48% of patients receiving ondansetron and 69% of those receiving metoclopramide (P < .001). Akathisia and acute dystonic reactions occurred only on metoclopramide; headache (controlled with acetaminophen) was significantly more frequent with ondansetron. Ondansetron is more effective, produces fewer adverse events, and is easier to administer than metoclopramide for the prevention of emesis associated with high-dose cisplatin chemotherapy. J Clin Oncol 9:721-728. © 1991 by American Society of ClinicalOncology.

receiving cancer chemotherapy.5 8 Preliminary data suggest that ondansetron is at least as effective as metoclopramide in the management of cisplatininduced emesis and has excellent activity both in single-day and multiple-day cisplatin schedules." 9 In addition, ondansetron has been extremely well tolerated by patients. The acute dystonic reactions

From Vanderbilt University, Nashville, TN; University of Texas Medical Branch, Galveston, TX; Research Medical Center,Kansas City; Ellis FischelCancer Center; Hematology! OncologyAssociates, Columbia, MO; VeteransAdministration Medical Center, East Orange, NJ; University of Florida, Gainesville; UniversityHospital,Jacksonville, FL; Universityof California, Davis/Veterans Administration Medical Center, Martinez, CA; Boston University Medical Center, Boston, MA; Veterans Administration Medical Center, Salt Lake City, UT; Emory University Hospital, Atlanta, GA; and Glaxo Inc, Research Triangle Park NC. SubmittedJuly 19, 1990; acceptedNovember 16, 1990. Supported by a grantfrom Glaxo Inc. Address reprint requests to John Hainsworth, MD, Division of Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 37232. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0905-0009$3.00/0

Journal of Clinical Oncology, Vol 9, No 5 (May), 1991: pp 721-728

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HAINSWORTH ET AL

that sometimes limit the use of metoclopramide

Treatment

have not been observed with ondansetron. Here we report on the superior efficacy and safety of intravenous (IV) ondansetron compared with IV metoclopramide in the prevention of nausea and vomiting induced by high-dose cisplatin (> 100 mg/m2) chemotherapy.

Patients at each institution were randomized (1:1) according to a computer-generated scheme from the Department of Biostatistics at Glaxo Inc. The treatment schedule was sealed in an envelope and given to the pharmacy at each institution. To prevent bias in assignment, investigators were blinded from knowledge of treatment until after patients were enrolled. Treatment was either ondansetron 0.15 mg/kg every 4 hours for a total of three doses or metoclopramide 2.0 mg/kg every 2 hours for the first three doses, and then every 3 hours for three additional doses (total of six doses). Each dose of study drug was admixed with 80 mL of normal saline and infused IV over a 15-minute period. The first dose of study drug was given 30 minutes before the start of the cisplatin infusion. Cisplatin was administered IV at a dose of at least 100 mg/mn over a period of 3 hours or less. Patients who developed extrapyramidal reactions were to be given 50 mg of diphenhydramine either IV or intramuscularly every 6 hours as needed to control symptoms. Patients with inadequate control of nausea and vomiting (see below) or patients who requested additional antiemetic drugs were considered study failures, removed from the study, and received antiemetics at the choice of the individual investigator.

PATIENTS AND METHODS This study was a randomized, single-blind, parallel group trial involving 24 medical centers. Three hundred seven patients, 151 treated with ondansetron and 156 with metoclopramide, entered the study between June 1988 and June 1989.

Eligibility Criteria All patients in this study had histologically proven cancer and were to receive chemotherapy with cisplatin at a single dose of at least 100 mg/m2. All patients were at least 18 years of age and had a Karnofsky performance status of at least 60%. All patients were hospital inpatients during treatment. The protocol excluded patients with the following findings: (1) a history of any previous chemotherapy, (2) evidence of uncontrolled cardiovascular disease, (3) significant cerebrovascular disease, (4) significant psychiatric disease requiring chronic medication, (5) serum creatinine greater than 2.0 mg/dL, (6) serum alanine aminotransferase (ALT) (SGPT) greater than twice the upper limit of the normal range, (7) uncontrolled nausea and vomiting due to organic etiologies, (8) any vomiting within 24 hours before the initiation of the study, (9) any treatment with radiotherapy to the abdomen within 48 hours before or during the study period, (10) use of any drug with possible antiemetic effects during the 24 hours preceding the trial or during the trial including antidepressants, phenothiazines, butyrophenones, lorazepam, cannabinoids, metoclopramide, domperidone, corticosteroids, trimethobenzamide, and anticholinergics, (11) patients receiving other strongly emetogenic antineoplastic agents during the 24-hour study period including mechlorethamine, dacarbazine, or cyclophosphamide at a dose of greater than 1,100 mg/m2, and (12) patients receiving an investigational antineoplastic agent. Patients were permitted to receive triazolam for sleep during the 24 hours before cisplatin administration, but this drug was not allowed during the 24-hour study period. The institutional review board at each participating institution approved the protocol, and each patient signed informed consent. Before study entry, a complete history was obtained and a physical examination performed on all patients. In addition, patients had the following laboratory studies performed within 48 hours of cisplatin administration and again 24 hours after the administration of cisplatin: complete blood count, differential, serum electrolytes, Sequential Multiple Analysis-12, and serum ALT (SGPT). Abnormal posttreatment laboratory parameters were repeated within 2 weeks of study completion.

Evaluation of Response The primary efficacy parameter was the number of emetic episodes occurring during the 24-hour study period. An episode of vomiting was defined as expulsion of any stomach contents through the mouth. Each episode of vomiting was considered an emetic episode. An episode of retching was an attempt to vomit that was not productive of any stomach contents. One to five retches within a 5-minute period was considered an emetic episode. A research nurse monitored and evaluated each patient for 24 hours following cisplatin therapy. Monitoring was accomplished through direct observation and patient interviews. The research nurse recorded the number of vomits and retches and the time of each on a bedside record form. Monitoring for efficacy ended 24 hours after cisplatin administration; therefore, no data concerning delayed emesis were collected. The response of each patient to the treatment was defined as follows: complete response, no emesis over the 24-hour study; major response, one to two episodes of emesis in the 24-hour study; minor response, three to five episodes of emesis in the 24-hour study; treatment failure, more than five episodes of emesis, requirement of rescue antiemetic therapy, or withdrawal from the study during the study period. In addition to the number of emetic episodes, several other efficacy parameters were monitored including severity of nausea, level of appetite, and global assessment of satisfaction with the control of nausea and vomiting during the study period. Patients completed visual analog scales (0 to 100 mm) to assess the severity of nausea (0, no nausea; 100, nausea as bad as it could be) and global satisfaction of nausea and vomiting control (0, not at all satisfied; 100, totally satisfied). Each patient was assisted in completing

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723

ONDANSETRON FOR CISPLATIN-INDUCED EMESIS the nausea analog scale before administration of the study drug and both scales 24 hours after cisplatin therapy. The change in nausea was calculated by subtracting baseline from posttreatment score. Appetite during the study period was noted by the patient as follows: appetite better than usual, appetite as usual, appetite less than usual (some solids), liquids only, and nothing by mouth. Two potential treatment-related toxicities, sedation (0, not at all sleepy; 100, very sleepy), and restlessness (0, not at all restless; 100, very restless), were also measured with 100 mm visual analog scales. The patients completed these scales before administration of the study drug and 24 hours after the cisplatin infusion. Other treatment-related toxicities were recorded by the research nurse. Akathisia and restlessness were sometimes difficult to differentiate, but were separated because we felt that the nonspecific complaint of restlessness did not always indicate extrapyramidal toxicity. In this study, patients were considered to have akathisia only if they described the typical disorder characterized by the inability to sit or lie quietly, while less specific complaints were categorized as restlessness.

StatisticalAnalysis Ondansetron and metoclopramide were compared with regard to number of emetic episodes using the Wilcoxon 0 rank-sum test (Van Elteren stratified by center).' For this analysis, patients who reported more than five episodes or who were rescued or withdrawn for any reason were assigned the same arbitrarily high value for number of emetic episodes. Treatments were also compared with respect to the proportion of patients with no emetic episodes (complete response), proportion with complete plus major response, and the proportion of failures. The MantelHaenszel test (Cochran-Mantel-Haenszel test stratified by center) was used for these comparisons." The treatments were compared with respect to time to first emetic episode (hours from the start of cisplatin infusion) using the Wilcoxon rank-sum test (Van Elteren stratified by center). Patients with zero emetic episodes were assigned the same arbitrary time greater than 24 hours. The Wilcoxon rank-sum test (Van Elteren stratified by center) was also used to compare treatments with respect to severity of nausea, global satisfaction with control of nausea and vomiting, and severity of treatment-related sedation and restlessness. Appetite assessments were not analyzed statistically because the categories were not mutually exclusive.

RESULTS

Three hundred seven patients were randomized; 151 received ondansetron and 156 received

metoclopramide. Thirty-three patients (15 ondansetron, 18 metoclopramide) were either ineligible or nonassessable for treatment efficacy due to protocol violations. Table 1 lists the reasons for exclusion of these 33 patients. Two hundred seventy-four patients were assessable for efficacy. All

Table 1. Protocol Violations Resulting in Patient Exclusion No. of Patients Violation

Entry violations Received other antiemetic during 24-hours before study Previous chemotherapy Radiotherapy given within 48 hours Emesis within 24 hours of study entry During-study violations Received other antiemetic during 24-hour study period Study drug administered incorrectly Total

Ondonsetron

Metoclopromide

3 0

5 1

1

1

1

0

6

8

4 15

3 18

307 patients received one or more doses of study drug and were therefore assessable for safety. Patient Characteristics

The clinical characteristics of the 274 assessable patients are summarized in Table 2. Distributions of patients with respect to age, sex, race, and alcohol use were similar in the two study groups. The study included patients with a wide variety of cancer types. The majority of patients had either head and neck or lung primaries. The incidence of head and neck cancer was similar in the two study groups. A larger percentage of patients with lung cancer was treated in the metoclopramide group, while the ondansetron group contained more patients with gastrointestinal and gynecologic cancers. Eighty-six patients (31%) received treatment with cisplatin as a single agent, while the remainder received cisplatin combined with one or more additional cytotoxic agents. Of the 188 patients

receiving combination regimens, 133 (71%) received cisplatin in combination with either fluorouracil or etoposide, both of which have mild to moderate emetogenic potential. The distribution of chemotherapy regimens was similar in the two treatment groups. Antiemetic Response The antiemetic efficacy data are summarized in Table 3. Fifty-four (40%) patients receiving ondansetron had a complete response to therapy,

compared with 41 (30%) patients receiving meto-

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724

HAINSWORTH ET AL Table 2. Efficacy Population Characteristics Ondansetron Characteristic

No.

No. of patients Sex Male Female Race White Black Other Age (years) Median Range Alcohol use Nonuser < 4 drinks/day > 5 drinks/day Prior heavy use Type of cancer Head and neck Lung Gastrointestinal Genitourinary Gynecologic Other Chemotherapy Cisplatin alone Cisplatin plus other agents

136 71 29

92 46

67 33

106 25 5

78 18 4

101 32 5

73 23 4

59

58 22-80 32 29 7 32

48 46 10 34

35 33 7 25

35 47 17 8 18 11

26 35 13 6 13 8

33 61 9 11 14 10

24 44 7 8 10 7

39 97

29 71

47 91

34 66

Table 3. Summary of Antiemetic Efficacy P

54 (40%) 34 (25%) 19 (14%)

41 (30%) 30 (22%) 18 (13%)

.070

29 (21%)

49(36%)

.007

1.0

2.0

.005

20.5

4.3

< .001

26

37

.107

85

63

.001

38 (28%)

27 (20%)

*Posttreatment-pretreatment nausea score. tMedian scores.

25-81

44 39 10 43

24-hour study period compared with 71 patients

Metoclopromide (N 138)

%

96 40

receiving ondansetron had < two emetic episodes (ie, complete plus major responses) during the

Treatment response Complete, 0 episodes Major, 1-2 episodes Minor, 3-5 episodes Failure, > 5 episodes/rescued Median no. emetic episodes Median time to onset of emesis (hours) Median nausea score difference* Global satisfaction with control of nausea and vomitingt No. with normal appetite

No. 138

clopramide (P = .07). Eighty-eight patients (65%)

Ondansetron (N= 136)

Metoclopramide %

(51%) receiving metoclopramide (P = .016). In addition, there were fewer treatment failures with ondansetron than with metoclopramide (21% v 36%, P = .007). Patients receiving ondansetron had fewer emetic episodes than patients who received metoclopramide (median emetic episodes one v two, respectively, P = .005). The time to onset of emesis after chemotherapy also differed significantly between the two treatment groups (Fig 1). Patients receiving metoclopramide had a median time to the first emetic episode of 4.3 hours following cisplatin chemotherapy as compared with a median of 20.5 hours in the ondansetron group (P < .001). In the first 6 hours after chemotherapy, 80 (58%) of the metoclopramide patients had emesis and 22 were removed from the study as failures. In contrast, only 12 (9%) of the patients receiving ondansetron had emesis during the first 6 hours, and none of these was removed from the study. In addition to its superiority in the control of emesis, ondansetron was also superior to metoclopramide in most of the other tests of efficacy (Table 3). Most importantly, overall patient satisfaction

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725

ONDANSETRON FOR CISPLATIN-INDUCED EMESIS

I

Ondwebwmr

20.5

I 4.;

Fig 1. Median time to first emetic episode.

I

I

I

I

I

a

I

I

0

2

4

0

8

10

12

14

Mui

with control of nausea and vomiting was significantly greater in the ondansetron group (P = .001). Patient assessment of nausea was not significantly different in the two groups (P = .107). Twentyeight percent of ondansetron patients had no change in appetite over the study period compared with 20% of metoclopramide patients. Twentyfour percent of ondansetron patients and 37% of metoclopramide patients did not eat solid food during the study period. Safety The adverse events reported in this trial are summarized in Table 4. Overall, 141 adverse events were reported by 73 (48%) patients in the ondansetron group, compared with 213 adverse events by 107 (69%) patients in the metoclopramide group (P < .001). Akathisia and acute dystonic reactions were reported only on metoclopraTable 4. Safety

Total no. of patients with any adverse event Neurologic events Restlessness Akathisia Acute dystonic reaction Headache Diarrhea/loose stools Liver function abnormalities* AST ALT

Ondansetron (N - 151)

Metoclopramide (N = 156)

P

73 (48%)

107 (69%)

< .001

5 0

19 10

.004 .002

0 24 37

8 11 68

.005 .015 < .001

11 (8%) 8 (6%)

3 (2%) 0 (0%)

.051 .003

*Rise in enzyme level to more than twice the upper limit of normal. Only patients with initially normal values included in this analysis.

I 16

I 1

I

I

20

22

24

PMV 0&A0

mide. Restlessness and diarrhea were reported significantly more frequently in patients receiving metoclopramide. Metoclopramide patients had higher sedation scores than ondansetron patients, but the difference was not statistically significant (28 v 20, P = .088). Headache, which was usually mild, was reported more frequently in ondansetron patients (16% v 7%, P = .015). Elevations in serum aspartate aminotransferase (AST) and ALT occurred more frequently in the ondansetron group. In patients with normal baseline enzyme levels, AST values increased to more than twice the upper limit of normal in 8% (11 of 133) of ondansetron patients compared with 2% (three of 130) of metoclopramide patients (P = .051). Similarly, ALT values increased in 6% (eight of 127) of ondansetron patients compared with no metoclopramide patients (P = .003). In those patients with elevated baseline AST or ALT values, AST values doubled in six of 15 (40%) patients receiving ondansetron and zero of 18 (0%) patients receiving metoclopramide (P = .005). Serum ALT doubled in two of 16 (13%) ondansetron patients and in one of 12 (8%) metoclopramide patients (P > .05). All patients with elevations in serum transaminases were asymptomatic, and enzyme levels returned to baseline within 2 weeks for all patients with follow-up measurements. Three patients receiving metoclopramide were removed from the study due to adverse events (severe dystonic reaction, two; allergic reaction, one). One patient was removed because an overdose (145 mg) of ondansetron was administered. Five additional patients (two receiving ondansetron, three receiving metoclopramide) experienced adverse events thought to be related

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HAINSWORTH ET AL

either to the underlying malignancy or the chemotherapy, rather than the study drug (pulmonary edema, two; acute myocardial infarction, one; acute renal failure, one; deep vein thrombosis, one). Two patients inadvertently received overdoses of ondansetron. The first of these patients received a single dose of 1.5 mg/kg (10 times the prescribed dose), and complained of generalized hot flashes, and a sensation of heat where her skin touched the bedsheets. Nine hours after the overdose, the patient reported subjective sensations of leg twitching and ear popping; no objective muscular twitching was noted by observers. All of these side effects resolved 24 hours later. The second patient received three doses of ondansetron 1.5 mg/kg (10 times the prescribed dose), and experienced pruritus, restlessness, nervousness, and hot flashes, which were treated with diphenhydramine and resolved within 12 hours.

DISCUSSION Major improvements have been made in the control of chemotherapy-induced nausea and vomiting over the past decade. Antiemetics in standard use during the 1970s had limited efficacy in controlling nausea and vomiting produced by highly emetogenic chemotherapeutic agents such as cisplatin. Patients receiving cisplatin with no antiemetic therapy, or with standard doses of prochlorperazine alone, had severe nausea and vomiting (median, 11 emetic episodes), which began within 2 hours after cisplatin administration. 2 Gralla et al2 reported that high-dose metoclopramide resulted in substantial reduction of nausea and vomiting after cisplatin therapy. Eight of the initial 21 (38%) patients reported had complete antiemetic protection, and 56% experienced fewer than three emetic episodes. Subsequent reports by Gralla and other investigators substantiated the efficacy of high-dose metoclopramide in controlling emesis following high-dose cisplatin administration; complete control of vomiting has been Control reported in 20% to 38% of patients. 2"12-14 of nausea and vomiting has been further improved by administering metoclopramide with other agents, notably dexamethasone or lorazepam. At present, optimum combination antiemetic regimens can be expected to provide major antiemetic

control (< two emetic episodes) in 60% to 80% of patients."1516 In spite of these marked improvements in antiemetic therapy, several problems remain unsolved. First, 25% to 40% of patients continue to have poor control of nausea and vomiting even with optimum combination antiemetic regimens. Second, the use of high-dose metoclopramide is frequently associated with unpleasant neurologic side effects including restlessness, akathisia, and acute dystonic reactions. These side effects are worse when the drug is used in younger patients, or in patients receiving multiple-day cisplatin regimens. Finally, combination antiemetic regimens require multiple doses of medication and are often time-consuming and difficult to administer. A selective antagonist of serotonin subtype 3 receptors, ondansetron has shown excellent antiemetic activity in phase I and II clinical trials. In patients receiving cisplatin, a three-dose regimen of ondansetron provided antiemetic protection when given every 4 hours at doses ranging from 0.06 mg/kg to 0.48 mg/kg, with no increase in efficacy seen above a dose level of 0.18 mg/kg.7 In a large phase II study, ondansetron (0.18 mg/kg IV every 6 or 8 hours for three doses) provided major antiemetic control in 75% of patients receiving high-dose cisplatin (55% complete responses).' Ondansetron also showed excellent antiemetic activity in patients receiving multiple-day cisplatin regimens; on a daily basis, 64% to 93% of patients had major protection, and 33% had complete protection throughout the entire study period. 9 In addition to its impressive efficacy, ondansetron was a remarkably safe drug in all the phase I and II studies. Extrapyramidal signs and symptoms were not observed in any patient, and the most common side effects were mild headache and transient elevation of serum transaminase levels. This prospective, randomized trial demonstrates that ondansetron is superior to metoclopramide in the control of cisplatin-induced emesis. Patients receiving ondansetron had a higher complete response rate, a lower drug failure rate, and a lower median number of emetic episodes during the study than did patients receiving metoclopramide. In this study, metoclopramide was administered at a dose and schedule that has produced a high level of antiemetic protection in previous reports. 12" The complete response and major re-

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727

ONDANSETRON FOR CISPLATIN-INDUCED EMESIS

sponse rates achieved with metoclopramide in this 1 -14 study are similar to those previously reported.2, 2 Similarly, the antiemetic efficacy of ondansetron observed in this randomized study is consistent with the results in nonrandomized phase II studies.6"8

Ondansetron and metoclopramide also differed markedly with respect to the median time to first emesis (20.5 hours v 4.3 hours, respectively). Patients receiving cisplatin without antiemetics experience the most intense emesis during the first 6 hours after treatment.' 7 Twenty-two patients receiving metoclopramide experienced severe emesis and were withdrawn from treatment during the first 6 hours, indicating inadequate protection during this critical early period. In contrast, none of the ondansetron patients were withdrawn for lack of efficacy during the first 6 hours. Instead, 17 of 23 patients failing ondansetron were removed during the last 8 hours of the study period. In an attempt to prevent these late failures, a prolonged schedule of ondansetron (0.18 mg/kg IV every 4 hours for six doses) was recently tested.' 8 However, results were similar to those achieved with the three-dose regimen used in this study. Delayed nausea and vomiting following high-dose cisplatin is a well-recognized problem, and may be produced by a different mechanism than the acute emesis."' Delayed treatment failure with ondansetron despite excellent early control supports this hypothesis and suggests that other approaches may be necessary to control delayed emesis. In addition to increased efficacy, the lower incidence of adverse events with ondansetron makes it far more attractive than metoclopramide for routine use. Ondansetron eliminates the concerns of severe extrapyramidal reactions seen primarily in young patients and patients receiving multiple-day metoclopramide. The most common symptom frequently associated with ondansetron was headache, which was usually mild, transient, and controlled with acetaminophen. Elevations in serum transaminase values seen in 8% of patients receiving ondansetron were clinically insignificant and returned to normal within 2 weeks.

The results of this study strengthen and extend the findings of a recently reported European trial comparing ondansetron and metoclopramide.2 0 Both studies demonstrate superior efficacy and reduced toxicity with ondansetron when compared with metoclopramide. However, several differences in study design allow clarification of ambiguities remaining after the European study. First, and most importantly, we used metoclopramide in a dose and schedule that have previously produced optimal antiemetic results. 2 In contrast, in the European study, metoclopramide was administered by continuous infusion following a loading dose, a cumbersome and seldom-used method of administration. Ondansetron was also used in a more convenient and clinically applicable schedule in our study. Second, the crossover design used in the European study is not considered optimal in antiemetic trials due to the problem of anticipatory nausea and vomiting in previously treated patients. Only 76 patients receiving their first dose of cisplatin were included in the European study (41 received ondansetron, 35 received metoclopramide), as compared with 274 assessable patients in our study.

In summary, ondansetron is more effective and less toxic than metoclopramide for the prevention of emesis associated with high-dose cisplatin chemotherapy. A three-dose regimen of ondansetron is also easier to administer than the six-dose regimen of metoclopramide recommended by the manufacturer. Ondansetron represents a major advance in the supportive care of cancer patients receiving chemotherapy. Further improvements in efficacy are likely when this drug is combined with other antiemetic agents with different mechanisms of action. ACKNOWLEDGMENT The authors gratefully acknowledge the following investigators for patient recruitment: Stephen Bernard, MD, Orlando Martelo, MD, Fred Meyers, MD, Douglas Reding, MD, Charlotte Jacobs, MD, Alan Rosenblum, MD, Gerald Kallas, MD, Efstathios Tapazoglou, MD, Kurt Tauer, MD,

Peter Wiernik, MD, Ronald Lawson, MD, and William Knight, MD.

REFERENCES 1. Von Hoff D, Schilsky R, Reicher CM, et al: Toxic effects of cis-Dichlorodiammineplatinum (II) in man. Cancer Treat Rep 63:1527-1531, 1979 2. Gralla RJ, Itri LM, Pisko SE, et al: Antiemetic efficacy

of high-dose metoclopramide; Randomized trials with placebo and prochlorperazine in patients with chemotherapyinduced nausea and vomiting. N Engl J Med 305:905-909, 1981

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HAINSWORTH ET AL

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A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy.

Ondansetron (GR 38032F), a selective antagonist of serotonin subtype 3 receptors, is effective in the prevention of emesis associated with cisplatin a...
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