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Journal of Clinical Oncology, Vol 19, Issue 7 (April), 2001: 2091-2097
© 2001 American Society for Clinical Oncology

Ondansetron Plus Metopimazine Compared With Ondansetron Plus Metopimazine Plus Prednisolone as Antiemetic Prophylaxis in Patients Receiving Multiple Cycles of Moderately Emetogenic Chemotherapy

By T. Sigsgaard, J. Herrstedt, J. Handberg, M. Kjær, P. Dombernowsky

From the Department of Oncology, Herlev Hospital, and Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, and Department of Oncology, Aalborg Hospital, Aalborg, Denmark.

Address reprint requests to Tine Sigsgaard, MD, PhD, Department of Internal Medicine F, Copenhagen University Hospital Gentofte, Niels Andersens Vej 65, 2900 Hellerup, Denmark; email: sigsgaar@ post5.tele.dk.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To compare the antiemetic efficacy and tolerability of ondansetron plus metopimazine with ondansetron plus metopimazine plus prednisolone during nine cycles of moderately emetogenic chemotherapy.

PATIENTS AND METHODS: A total of 221 women with stage I or II breast cancer and no prior chemotherapy who were scheduled to receive adjuvant chemotherapy with intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin, and fluorouracil given every 3 weeks were included in a double-blind parallel trial. Patients were randomized to 3 days of oral treatment with ondansetron plus metopimazine, or ondansetron plus metopimazine plus prednisolone. Ondansetron was administered as 8 mg bid, metopimazine as 30 mg qid, and prednisolone as 50 mg qd.

RESULTS: In all, 216 patients (97.7%) were assessable for efficacy during a total of 1,462 cycles. In cycle 1, complete protection from emetic episodes/nausea day 1, days 2 through 5, and days 1 through 5 was achieved in 84.4%/51.4%, 82.6%/41.3%, and 79.8%/34.9% with ondansetron plus metopimazine and in 84.1%/57.0%, 86.8%/53.8%, and 79.4%/43.0% with ondansetron plus metopimazine plus prednisolone, respectively. In cycle 1, the three-drug combination was superior only in the treatment of nausea on days 2 through 5 (P = .0497). The cumulative emetic protection rate after nine cycles was 0.52 with ondansetron plus metopimazine and 0.75 with ondansetron plus metopimazine plus prednisolone. Side effects were generally few and mild with both treatments. Constipation was the only adverse event significantly more frequent with the three-drug combination (P = .029).

CONCLUSION: Ondansetron plus metopimazine plus prednisolone is highly effective and superior to ondansetron plus metopimazine during nine cycles of moderately emetogenic chemotherapy.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE EFFICACY OF antiemetic treatment during multiple cycles of chemotherapy is of great clinical importance. Despite this, only a few trials have evaluated the efficacy of antiemetic treatments during repeated cycles of chemotherapy.

Trials that investigated patients during the first one or two cycles of chemotherapy showed that corticosteroids used as single agents are superior to placebo1 and are equal or superior to metoclopramide.2-4 The dopamine D2 antagonist metopimazine is superior to placebo5,6 and is equal to prochlorperazine.5 In patients who received moderately emetogenic chemotherapy, the serotonin antagonist ondansetron is superior or equal to metoclopramide7-9 and the serotonin antagonist granisetron is superior to prednisolone plus metopimazine.10

Interpretation of the results from trials following patients during multiple cycles are complicated by the use of different methodology and different statistical analyses, and conclusions are not concordant. Some studies demonstrated a decrease in antiemetic efficacy,11,12 whereas others found sustained efficacy.13-17 In a previous study we showed that during nine cycles of moderately emetogenic chemotherapy, granisetron was superior to prednisolone plus metopimazine, but the antiemetic efficacy of both treatments declined from cycles 1 through 9. Only 25.7% of patients treated with granisetron and 16.5% treated with prednisolone plus metopimazine completed all nine cycles.10

In patients refractory to antiemetic treatment with granisetron or prednisolone plus metopimazine, the three-drug combination of granisetron plus prednisolone plus metopimazine is highly effective.18 Furthermore, the efficacy of ondansetron is improved by the addition of metopimazine in patients with refractory emesis,19 and in chemotherapy-naive patients the efficacy of both ondansetron and granisetron is improved by the addition of a corticosteroid.20 The efficacy and tolerability of a 5-HT3 antagonist plus a dopamine D2 antagonist versus a 5-HT3 antagonist plus a dopamine D2 antagonist plus a corticosteroid has not previously been investigated in a randomized trial.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Women with histologically confirmed stage I or II breast cancer who were scheduled to receive nine cycles of adjuvant chemotherapy were eligible. Other inclusion criteria were age >= 18 and < 70 years and a performance status of 0 to 2 as defined by the World Health Organization.21

Patients were excluded if they had previously received chemotherapy, had a peptic ulcer or diabetes, gastrointestinal obstruction, nausea or vomiting within 24 hours before the first cycle of chemotherapy, received antiemetic therapy (including steroids) during the week before entry, or were not capable of filling in the diary cards. The use of benzodiazepines for night-time sedation was allowed.

Chemotherapy
Chemotherapy consisted of cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 (CMF) or cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) given intravenously every 3 weeks and planned for nine cycles. Patients treated with radiotherapy to the chest wall and axillary lymph nodes received single-agent cyclophosphamide 850 mg/m2 during that period (usually cycles 2 and 3).

Study Design
A randomized, double-blind, placebo-controlled parallel design was used. Patients were randomized in blocks of 10 and stratified for center and chemotherapy (CMF or CEF).

Antiemetic Treatment
Patients were randomly assigned to a 3-day oral treatment with ondansetron plus metopimazine or ondansetron plus metopimazine plus prednisolone. Ondansetron was given as 8 mg bid, metopimazine as 30 mg tid on day 1 and qid on days 2 through 3, and prednisolone (or an identical appearing placebo tablet) as one daily dose of 50 mg. The first dose of ondansetron, metopimazine, and prednisolone (or placebo) was given at least 30 minutes before the start of chemotherapy. The second dose of metopimazine was given 30 minutes before dinner, and the third dose together with the second dose of ondansetron was given just before bedtime. On days 2 and 3, metopimazine was given 30 minutes before breakfast, lunch, and dinner and just before the patient went to bed. Ondansetron was given together with the first and third dose of metopimazine and prednisolone (or placebo) together with the first dose of metopimazine. The study medication was given in a plastic container with a separate compartment for each dose. The container was returned at the next chemotherapy cycle and the number of unused study tablets counted. If, for any reason, the patients did not take one or more tablets, they were asked to explain the reasons on their diary card.

Assessment of Antiemetic Efficacy
After chemotherapy, patients recorded on days 1 through 5 on diary cards the number of vomiting episodes and dry retches and the severity of nausea and other adverse events. Any vomit productive of liquid or a dry retch was considered a single emetic episode. The severity of nausea and other adverse events were assessed on a graded scale as "none," "mild," "moderate," or "severe." Complete response (CR) was defined as no emetic episodes, major response (MR) as one emetic episode, minor response (mR) as two to four emetic episodes, and failure as five or more emetic episodes.

On the diary card day 5 after each cycle of chemotherapy, patients were instructed to check off one of the following two possibilities: "I have been satisfied with the antiemetic treatment and want the same antiemetic treatment during the next cycle of chemotherapy" or "I have not been satisfied with the antiemetic treatment and want another antiemetic treatment during the next cycle."

During cycles 1 and 2, and thereafter only when necessary, a research nurse called patients on days 2 and 5 to ensure that the study medication was taken and the diary cards completed. To assess the frequency of anticipatory nausea and vomiting, patients were again called 3 days before the next cycle of chemotherapy and reminded to record the number of vomiting episodes and dry retches, and grade nausea days 1 through 3 before the next course. The diary card was returned at the following visit.

Patients were withdrawn from the study if they had had five or more emetic episodes on one or more days during the study period, or if they had checked off on the diary card that they were not satisfied with the antiemetic treatment. Patients receiving rescue medication were also withdrawn. If chemotherapy was changed, eg, because of progressive disease, the patients were also withdrawn.

Ethical Considerations
All patients gave written informed consent. The study was conducted according to the Helsinki II Declaration and was approved by the local Scientific Ethics Committees and by the Danish Medical Health Authorities.

Statistical Analysis
The sample size was calculated on the assumption that after nine cycles of chemotherapy 50% of patients treated with ondansetron plus metopimazine and 75% of patients treated with ondansetron plus metopimazine plus prednisolone would still be "at risk." Using a two-sided 5% test level and a power of 0.8, it was estimated that 100 assessable patients in each treatment arm would be required to detect this difference (log-rank test). To ensure that at least 100 patients were assessable for each of the two treatments, 220 patients were included.

The Mann-Whitney U test was used to compare the number of patients obtaining CR, MR, mR, and failure on day 1 (acute), days 2 through 5 (delayed), and days 1 through 5 (overall) in cycle 1. For days 2 through 5 and days 1 through 5 the analyses were based on the severity of nausea recorded on the worst day within the period and, for emesis, both on the number of emetic episodes on the worst day in the period and on the total number of emetic episodes in the period.

Maintenance of emetic control during cycles 1 through 9 (not failure, satisfied with the antiemetic treatment, and no rescue medication) was calculated by the Kaplan-Meier method (cumulative emetic control) and compared with the log-rank test. Patients going off study because of other reasons were regarded as censored. The number of completed cycles was compared using the log-rank test. The maintenance of emetic control was also calculated based on conditional probabilities.22 The condition was that failure of antiemetic treatment did not occur in the previous cycles.

The number and severity of side effects were analyzed with the Mann-Whitney U test. All tests were two-tailed, using a 5% level of significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In all, 221 consecutive patients were included, and one patient was lost to follow-up before cycle 1. Therefore, 220 patients were assessable according to the intention-to-treat principle; 110 received ondansetron plus metopimazine, and 110 received ondansetron plus metopimazine plus prednisolone. Patient characteristics are listed in Table 1. A total of 216 patients were assessable for response, and four were not eligible because they used benzodiazepines during the daytime. The results presented here represent the 216 assessable patients and did not differ from those obtained in the intention-to-treat analysis of all 220 patients.


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  		Table 1. Patient Characteristics (N = 220)
 
During the cycles with concomitant radiotherapy, 54 patients in the ondansetron plus metopimazine group and 56 in the ondansetron plus metopimazine plus prednisolone group received cyclophosphamide as a single agent.

Table 2 shows the number of patients "at risk" and the number of patients withdrawn during each cycle of chemotherapy. Twelve patients terminated chemotherapy before completing all nine cycles of chemotherapy and 10 more patients went off study during courses 1 through 9 for reasons other than being failures and/or not satisfied with the antiemetic treatment: one patient received concomitant medication with metopimazine the day before cycle 2 and one by mistake received ondansetron plus metopimazine plus prednisolone instead of ondansetron plus metopimazine in cycles 4 through 6. Thus, the efficacy of antiemetic treatment was only assessable in cycles 1 through 3. Four patients (two on each treatment) went off study because of toxicity (three experienced skin rash and one experienced skin rash and dyspnea). Three patients were erroneously withdrawn, and one was lost to follow-up after cycle 8.


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  		Table 2. Off Study Reasons, Cumulative Protection Rates, and Conditional Protection Rates Among 216 Patients Receiving Adjuvant Chemotherapy and Treated With Ondansetron Plus Metopimazine or Ondansetron Plus Metopimazine Plus Prednisolone During Cycles 1–9
 
The 216 patients were assessable for nausea and vomiting in 694 cycles of ondansetron plus metopimazine (n = 109) and 768 cycles of ondansetron plus metopimazine plus prednisolone (n = 107). The dose of chemotherapy during cycles 2 through 9 was reduced in 76 (11.0%) cycles in the first group and in 105 (13.7%) in the second group.

In only two cycles did patients not return the plastic container and/or not record the number of unused tablets. Overall, all tablets were taken in 645 (93.2%) cycles with ondansetron plus metopimazine and in 722 (94.0%) with ondansetron plus metopimazine plus prednisolone. One or more tablets were forgotten during 36 (5.2%) cycles with ondansetron plus metopimazine and during 44 (5.7%) cycles with ondansetron plus metopimazine plus prednisolone. During seven (1.0%) and two (0.3%) cycles, respectively, patients did not take all tablets because of nausea and vomiting. In the ondansetron plus metopimazine group, patients did not take all tablets in four (0.6%) cycles because of side effects (palpitation, rash, dizziness, and constipation).

Efficacy of Antiemetic Treatment Cycle 1
The antiemetic response in cycle 1 is listed in Table 3. Of the 216 assessable patients, three patients treated with ondansetron plus metopimazine and seven treated with ondansetron plus metopimazine plus prednisolone were failures at day 1. Of these, one patient receiving the three-drug combination went off study at day 1, leaving 215 assessable for delayed nausea and vomiting. There was no significant difference in antiemetic response during cycle 1 between ondansetron plus metopimazine and ondansetron plus metopimazine plus prednisolone. Complete protection from vomiting at day 1, days 2 through 5, and days 1 through 5 was achieved in 84.4%, 82.6%, and 79.8% with ondansetron plus metopimazine and in 84.1%, 86.8%, and 79.4%, respectively, with ondansetron plus metopimazine plus prednisolone. Treatment failures at days 1 through 5 were observed in 5.5% and 7.5% of the patients, respectively.


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  		Table 3. Antiemetic Response Cycle 1 in 216 Patients Treated With Ondansetron Plus Metopimazine or Ondansetron Plus Metopimazine Plus Prednisolone
 
The severity of nausea is listed in Table 4. There were no significant differences at day 1 and days 1 through 5, but at days 2 through 5 nausea was significantly better controlled with ondansetron plus metopimazine plus prednisolone than with ondansetron plus metopimazine (P = .0497).


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  		Table 4. Severity of Nausea in Cycle 1 in 216 Patients Treated With Ondansetron Plus Metopimazine or Ondansetron Plus Metopimazine Plus Prednisolone
 
Complete protection from nausea at days 2 through 5 was achieved in 41.3% of the patients treated with ondansetron plus metopimazine and in 53.8% treated with ondansetron plus metopimazine plus prednisolone. This difference was not statistically significant (Fisher’s exact test, P = .0895).

Efficacy of Antiemetic Treatment During Multiple Cycles
Ondansetron plus metopimazine plus prednisolone was significantly superior to ondansetron plus metopimazine during multiple cycles of chemotherapy ( Fig 1, P = .0014). The cumulative emetic protection rate after nine cycles was 0.75 and 0.52, respectively (Table 2 and Fig 1).



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  		Fig 1. Maintenance of emetic control in patients treated with ondansetron plus metopimazine (-•-;, OND+MPZ) or ondansetron plus metopimazine plus prednisolone (–{blacktriangleup}–, OND+MPZ+PRED) during nine cycles of adjuvant chemotherapy. P = .0014 (log-rank test).

 
The number of assessable patients starting each new cycle of chemotherapy and the number who were failures, not satisfied with the antiemetic treatment, or went off study because of other reasons during the nine cycles are given in Table 2.

Of the 109 patients treated with ondansetron plus metopimazine and of the 107 patients in the three-drug treatment group, 50 (45.9%) and 68 (63.6%), respectively, completed all nine cycles with fewer than five emetic episodes on any day and were still satisfied with the treatment.

Anticipatory Nausea and Vomiting
Days 1 through 3 before the next cycle of chemotherapy no emetic episodes were observed in 621 (97.6%) cycles with ondansetron plus metopimazine and in 682 (98.4%) with ondansetron plus metopimazine plus prednisolone. The corresponding figures for no nausea were 584 (91.8%) and 637 (91.9%) cycles, respectively. Data for anticipatory nausea and vomiting were missing in three cycles in both regimens.

Safety
The most frequently reported adverse events included headache, dizziness, constipation, tiredness, and palpitations ( Table 5). Constipation was significantly more frequent with the three-drug combination (P = .029). No other statistically significant differences were seen.


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  		Table 5. Most Frequent Adverse Events Based on the Worst Day Among 220 Patients Receiving Adjuvant Chemotherapy and Treated With Ondansetron Plus Metopimazine or Ondansetron Plus Metopimazine Plus Prednisolone
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first double-blind randomized study to compare the combination of a 5-HT3 antagonist plus a dopamine D2 antagonist with a 5-HT3 antagonist plus a dopamine D2 antagonist plus a corticosteroid. There were no differences in patients characteristics (Table 1). Specifically, no differences in known risk factors of emesis such as age (median age 47 years in both groups), sex (all women), and exposure to previous chemotherapy (all chemotherapy-naive) were seen. There was no difference in the effect on acute emesis during the first cycle of moderately emetogenic chemotherapy, but the three-drug combination of ondansetron plus metopimazine plus prednisolone was significantly superior to the two-drug combination in the treatment of delayed nausea. In concordance with other trials,7-10,20,23-25 the protection against emesis was higher with both treatments than was the protection against nausea. It is not clear why antiemetic treatments protect better against emesis than against nausea, but it has been suggested that there may be two kinds of nausea, one related to vomiting and another independent of vomiting.26 These two kinds of nausea may differ in their responsiveness to antiemetic treatment.26

The complete protection of acute nausea and vomiting with ondansetron plus metopimazine plus prednisolone during the first cycle of chemotherapy was lower, whereas the complete protection of delayed nausea and vomiting was slightly higher than that observed with granisetron plus dexamethasone by Roila et al20 This might be explained by differences in chemotherapy, antiemetic treatment, patient populations, and duration of antiemetic treatment. In the study by Roila et al,20 both females and males were included, which predisposes to higher response rates than in studies such as ours, which included only women. Furthermore, higher and divided doses of corticosteroids were used. The slightly inferior protection against delayed nausea and vomiting seen in the Italian Study20 is explained by the fact that patients received antiemetics on the day of chemotherapy only.

During the first cycle of chemotherapy, only treatment of delayed nausea was significantly improved by the addition of prednisolone to ondansetron plus metopimazine, but the three-drug regimen was significantly superior to ondansetron plus metopimazine in the maintenance of antiemetic effect during multiple cycles of chemotherapy. After nine cycles, the cumulative emetic control was 0.75 with three drugs and 0.52 with two drugs. The study clearly demonstrates that differences in the efficacy of different antiemetic treatments might appear only if patients are followed during multiple cycles of chemotherapy.

In patients receiving platinum-based chemotherapy, a 5-HT3 antagonist plus dexamethasone27-32 or metopimazine33 provides better antiemetic control than a 5-HT3 antagonist alone. A three-drug combination of a serotonin antagonist plus a corticosteroid plus a dopamine antagonist was effective in an uncontrolled trial in patients naive to cisplatin,34 but the efficacy of such a three-drug combination needs to be investigated in a randomized trial that follows patients during multiple cycles of platinum-based chemotherapy.

In conclusion, this study showed that the three-drug combination of ondansetron plus metopimazine plus prednisolone was highly effective and superior to ondansetron plus metopimazine during multiple cycles of moderately emetogenic chemotherapy.


   ACKNOWLEDGMENTS
 
Supported by Glaxo Wellcome a/s, Rhone-Poulenc Rorer A/S, and the Danish Cancer Society, Denmark.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Pollera CF, Nardi M, Marolla P, et al: Effective control of CMF-related emesis with high-dose dexamethasone: Results of a double-blind crossover trial with metoclopramide and placebo. Am J Clin Oncol 12: 524-529, 1989[Medline]

2. Markman M, Sheidler V, Ettinger DS, et al: Antiemetic efficacy of dexamethasone. Randomized, double-blind, crossover study with prochlorperazine in patients receiving cancer chemotherapy. N Engl J Med 311: 549-552, 1984[Abstract]

3. Ibrahim EM, Al-Idrissi HY, Ibrahim A, et al: Antiemetic efficacy of high-dose dexamethasone: Randomized, double-blind, crossover study with high-dose metoclopramide in patients receiving cancer chemotherapy. Eur J Cancer Clin Oncol 22: 283-288, 1986[Medline]

4. Fox SM, Einhorn LH, Cox E, et al: Ondansetron versus ondansetron, dexamethasone, and chlorpromazine in the prevention of nausea and vomiting associated with multiple-day cisplatin chemotherapy. J Clin Oncol 11: 2391-2395, 1993[Abstract/Free Full Text]

5. Moertel CG, Reitemeier RJ: Controlled studies of metopimazine for the treatment of nausea and vomiting. J Clin Pharmacol 13: 283-287, 1973[Abstract]

6. Israel L, Rodary C: Treatment of nausea and vomiting related to anti-cancerous multiple combination chemotherapy: Results of two controlled studies. J Int Med Res 6: 235-240, 1978[Medline]

7. Bonneterre J, Chevallier B, Metz R, et al: A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy. J Clin Oncol 8: 1063-1069, 1990[Abstract]

8. Kaasa S, Kvaløy S, Dicato MA, et al: A comparison of ondansetron with metoclopramide in the prophylaxis of chemotherapy-induced nausea and vomiting: A randomized, double-blind study. Eur J Cancer 26: 311-314, 1990

9. Marschner NW, Adler M, Nagel GA, et al: Double-blind randomised trial of the antiemetic efficacy and safety of ondansetron and metoclopramide in advanced breast cancer patients treated with epirubicin and cyclophosphamide. Eur J Cancer 27: 1137-1140, 1991

10. Sigsgaard T, Herrstedt J, Andersen LJ, et al: Granisetron compared with prednisolone plus metopimazine as antiemetic prophylaxis during multiple cycles of moderately emetogenic chemotherapy. Br J Cancer 80: 412-418, 1999[Medline]

11. Martin M, Diaz-Rubio E, Casado A, et al: Progressive loss of antiemetic efficacy during subsequent courses of chemotherapy. Eur J Cancer 28: 430-432, 1992

12. Soukop M, McQuade B, Hunter E, et al: Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer. Oncology 49: 295-304, 1992[Medline]

13. Blijham HG: Does granisetron remain effective over multiple cycles? Eur J Cancer 28a: S17-S21, 1992 (suppl 1)

14. de Wet M, Falkson G, Rapoport L: Repeated use of granisetron in patients receiving cytostatic agents. Cancer 71: 4043-4049, 1993[Medline]

15. Kaizer L, Warr D, Hoskins P, et al: Effect of schedule and maintenance on the antiemetic efficacy of ondansetron combined with dexamethasone in acute and delayed nausea and emesis in patients receiving moderately emetogenic chemotherapy: A phase III trial by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 12: 1050-1057, 1994[Abstract/Free Full Text]

16. Italian Group for Antiemetic Research: Persistence of efficacy of three antiemetic regimens and prognostic factors in patients undergoing moderately emetogenic chemotherapy. J Clin Oncol 13: 2417-2426, 1995[Abstract/Free Full Text]

17. Silva RR, Bascioni R, Giorgi F, et al: Granisetron plus dexamethasone in moderately emetogenic chemotherapy: Evaluation of activity during three consecutive courses of chemotherapy. Support Care Cancer 4: 287-290, 1996[Medline]

18. Sigsgaard T, Herrstedt J, Christensen P, et al: Antiemetic efficacy of combination therapy with granisetron plus prednisolone plus the dopamine D2 antagonist metopimazine during multiple cycles of moderately emetogenic chemotherapy in patients refractory to previous antiemetic therapy. Support Care Cancer 8: 233-237, 2000[Medline]

19. Herrstedt J, Sigsgaard T, Boesgaard M, et al: Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy. N Engl J Med 328: 1076-1080, 1993[Abstract/Free Full Text]

20. The Italian Group for Antiemetic Research: Dexamethasone, granisetron, or both for the prevention of nausea and vomiting during chemotherapy for cancer. N Engl J Med 332: 1-5, 1995[Abstract/Free Full Text]

21. World Health Organization: Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979

22. De Wit R, Schmitz PIM, Verweij J, et al: Analysis of cumulative probabilities shows that the efficacy of 5HT3 antagonist prophylaxis is not maintained. J Clin Oncol 14: 644-651, 1996[Abstract/Free Full Text]

23. Jones A, Hill AS, Soukop M, et al: Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy. Lancet 338: 483-487, 1991[Medline]

24. Marty M: A comparative study of the use of granisetron, a selective 5-HT3 antagonist, versus a standard anti-emetic regimen of chlorpromazine plus dexamethasone in the treatment of cytostatic-induced emesis. Eur J Cancer 26: S28-S32, 1990 (suppl 1)

25. Warr D, Willan A, Fine S, et al: Superiority of granisetron to dexamethasone plus prochlorperazine in the prevention of chemotherapy-induced emesis. J Natl Cancer Inst 83: 1169-1173, 1991[Abstract/Free Full Text]

26. Italian Group for Antiemetic Research: On the relationship between nausea and vomiting in patients undergoing chemotherapy. Support Care Cancer 2: 171-176, 1994[Medline]

27. Roila F, Tonato M, Basurto C, et al: Protection from nausea and vomiting in cisplatin-treated patients: High-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: A study of the Italian Oncology Group for Clinical Research. J Clin Oncol 7: 1693-1700, 1989[Abstract]

28. Smyth JF, Coleman RE, Nicolson M, et al: Does dexamethasone enhance control of acute cisplatin induced emesis by ondansetron? BMJ 303: 1423-1426, 1991

29. Smith DB, Newlands ES, Rustin GJS, et al: Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy. Lancet 338: 487-490, 1991[Medline]

30. Hesketh PJ, Harvey WH, Beck TM, et al: A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis. J Clin Oncol 12: 596-600, 1994[Abstract]

31. Latreille J, Stewart D, Laberge F, et al: Dexamethasone improves the efficacy of granisetron in the first 24 H following high-dose cisplatin chemotherapy. Support Care Cancer 3: 307-312, 1995[Medline]

32. Sorbe B, Högberg T, Himmelmann A, et al: Efficacy and tolerability of tropisetron in comparison with a combination of tropisetron and dexamethasone in the control of nausea and vomiting induced by cisplatin-containing chemotherapy. Eur J Cancer 30a: 629-634, 1994

33. Herrstedt J, Sigsgaard T, Handberg J, et al: Randomized, double-blind comparison of ondansetron versus ondansetron plus metopimazine as antiemetic prophylaxis during platinum-based chemotherapy in patients with cancer. J Clin Oncol 16: 1690-1696, 1997

34. Depierre A, Lebeau B, Chevallier B, et al: Efficacy of ondansetron (O), methylprednisolone (M) plus metopimazine (MPZ) in patients previously uncontrolled with dual therapy in cisplatin containing chemotherapy. Ann Oncol 7: 134a, 1996 (abstr)

Submitted July 7, 2000; accepted December 14, 2000.


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Employment of Substandard Antiemetic Prophylaxis in Recent Trials of Chemotherapy-Induced Nausea and Vomiting
Ann. Pharmacother., November 1, 2005; 39(11): 1903 - 1910.
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R. de Wit, J. Herrstedt, B. Rapoport, A.D. Carides, G. Carides, M. Elmer, C. Schmidt, J.K. Evans, and K.J. Horgan
Addition of the Oral NK1 Antagonist Aprepitant to Standard Antiemetics Provides Protection Against Nausea and Vomiting During Multiple Cycles of Cisplatin-Based Chemotherapy
J. Clin. Oncol., November 15, 2003; 21(22): 4105 - 4111.
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S. Goodin and R. Cunningham
5-HT3-Receptor Antagonists for the Treatment of Nausea and Vomiting: A Reappraisal of Their Side-Effect Profile
Oncologist, October 1, 2002; 7(5): 424 - 436.
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