483

CLINICA L PRACTICE

Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy

A multicentre, randomised, double-blind, cross-over

on

trial was done to compare the efficacy and safety of a serotonin receptor antagonist—ondansetron—and dexamethasone in the prophylaxis of acute and delayed emesis and nausea induced by moderately emetogenic non-platinum-containing chemotherapy regimens. Patients were treated as outpatients and received intravenous ondansetron 4 mg or dexamethasone 8 mg before chemotherapy and oral maintenance (ondansetron 4 mg every 6 h and dexamethasone reducing from 4 mg to 1 mg 6-hourly between days 1 and 5) for 5 days. 112 patients were treated (38 men, 73 women, 1 with no gender recorded; age range 30-73 years) and 100 were evaluable for cross-over analysis. Patients taking ondansetron or dexamethasone reported no significant difference in complete and major control of acute (83% vs 79%, p=0·46) or delayed (82% vs 88%, p=0·214) emesis (vomiting

tractus

plus retches). Significantly more patients on dexamethasone (87%) than on ondansetron (72%) reported control of delayed nausea (days 2-5) (p=0·003). Both drugs were well tolerated with no significant difference in the number of adverse events, and this is reflected by similar patient preference for ondansetron (40%) and dexamethasone (30%) (p=0·244). Both drugs offer adequate out-patient control of however, emesis; chemotherapy-induced dexamethasone has an advantage in the control of delayed nausea, and also in terms of cost and resource

allocation.

Introduction Nausea and vomiting are the most distressing side-effects of chemotherapy.1 These symptoms have an adverse effect on quality of life and may result in non-compliance and the curtailment of potentially curative treatment. The serotonin receptor is recognised as an important component of the emetic response. After administration of cytotoxic drugs, serotonin is thought to be released by enterochromaffm cells in the proximal gut, and this acts on serotonin receptors

vagal afferents in the gut2 and on the nucleus solitarius3 an area in the midbrain close to the chemoreceptor trigger zone. Chemotherapy with cisplatin has been shown to increase urinary excretion of 5-hydroxyindole acetic acid, a metabolite of serotonin,4 suggesting a rationale for use of serotonin antagonists as antiemetics. Selective serotonin-receptor antagonists have been used successfully in uncontrolled clinical trials as antiemetic agents in patients receiving cisplatin chemotherapy and in patients with chemotherapy-induced emesis refractory to conventional antiemetics.5-7 Ondansetron, a serotoninreceptor antagonist, was superior to high-dose metoclopramide against cisplatin-induced emesis in a controlled trial.8Although many chemotherapy regimens use relatively less emetogenic drugs than cisplatin, up to 40 % of patients still experience nausea and vomiting despite the use of conventional antiemetic therapy.9,10 Serotoninreceptor antagonists are effective antiemetic agents against such moderately emetogenic chemotherapy regimens. S,6,11 However, no comparison has been made of a serotonin antagonist with dexamethasone, a widely used antiemetic that is notably more effective than metoclopramide, domperidone, and prochloperazine against moderately

emetogenic non-platinum-containing chemotherapy regimens.-14 The mechanism of dexamethasone’s antiemetic activity is not fully understood, but may involve central inhibition of prostaglandin synthesis.1s There remains a need to identify an effective, safe, and economic oral schedule for prophylaxis of emesis in the many cancer patients receiving moderately emetogenic chemotherapy as outpatients. We have done a multicentre, randomised, double-blind, cross-over trial with two treatment periods separated by 21 days comparing the efficacy and safety of ondansetron with ADDRESSES: Section of Medicine, Institute of Cancer Research and The Royal Marsden Hospital, Sutton, Surrey SM2 5PT. UK (A. L. Jones, MRCP, A S Hill, SRN, D Cunningham, FRCP); Department of Medical Oncology, The Royal Infirmary, Glasgow (M. Soukop, FRCP); Aberdeen Royal Infirmary, Foresterhill, Aberdeen (A. W. Hutcheon, FRCP); Beatson Oncology Centre, Glasgow (J Cassidy, MRCP, Prof S B. Kaye, MD); Department of Clinical Oncology, Hammersmith Hospital, London (Prof K. Sikora, MD); and Department of Medical Oncology, Mater Hospital, Dublin, Ireland (D. N. Carney, MD). Correspondence to Dr David

Cunningham.

484

dexamethasone in the prophylaxis of acute and delayed emesis induced by moderately emetogenic non-platinum-

TABLE I-PATIENT CHARACTERISTICS

containing chemotherapy regimens. Patients and methods Patients Patients were eligible for the study provided they were aged at least 18 years, had histologically confirmed cancer and had not received previous chemotherapy, and were designated to receive two identical courses of chemotherapy separated by 21 days. Patients with severe concurrent illness, clinical jaundice, or other evidence of hepatic dysfunction were excluded. Also excluded were patients in whom glucocorticosteroids were contraindicated, and those who had experienced emesis within 12 h or received antiemetics within 24 h before starting the study. Approval for the study was obtained from the ethical committees of the participating hospitals. Patients gave informed consent before the start of the study, and they were free to withdraw from the study at any time without prejudice to further treatment but remained within the study for follow-up purposes. Patients entered the study consecutively, and were assigned randomly to receive either ondansetron or dexamethasone with their first course of chemotherapy crossing over to the other antiemetic with their second course of identical chemotherapy after about 21 days. The trial design allowed an interim analysis after 50 evaluable patients so that the study could be terminated if there was strong evidence that one of the drugs was superior. Randomisation was generated with a computer program, with treatment sequences balanced in blocks of 10 patients. Matching injections were prepared by the hospitals’ pharmacies according to the randomisation code, and matching capsules were supplied in separate packs for each day to allow the dose of dexamethasone to be reduced over a 5-day period. The investigator and the patient were blinded to the treatment given. Either 4 mg ondansetron (Glaxo) or 8 mg dexamethasone (Organon) was given to patients by slow intravenous injection immediately before chemotherapy. At the same time 4 mg (1 capsule) of the same drug was given orally and further doses of 4 mg were given every 6 h on day 1. From days 2-5 the same drug was given orally every 6 h. The dose of ondansetron (4 mg) was constant over the 5-day study period, but the 6-hourly dose of dexamethasone was reduced from 4 mg on day 2 to 2 mg on days 3 and 4 and 1 mg on day 5. Patients failing to achieve antiemetic control were given alternative antiemetics.

Chemotherapy receiving cisplatin or regimens that included oral alkylating agents, or single-agent vinca alkaloids were excluded. Most patients received a combination chemotherapy regimen including an intravenous anthracycline, and/or cyclophosphamide;and/or etoposide, and all patients Patients

glucocorticosteroids,

received identical

chemotherapy on each course.

*No gender listed for 1 patient.

Each day patients recorded on diary cards the severity of nausea and the number of episodes of vomiting or retching during the preceding 24 h of antiemetic treatment. Patients also recorded any other adverse symptoms and the number of study capsules taken. A research nurse telephoned each patient 24 h after treatment to check progress and to document the number of vomits/retches and the grade of nausea. Patients were interviewed by the research nurse after 1 week (outpatient clinic or home visit) to check the diary cards, document adverse events, and to check the number of capsules taken to monitor compliance. Routine haematological and biochemical tests were done before the study and at the 1 week assessment visit. Assessments were the same for study periods 1 and 2. At the 1 week visit after study period 2, patients were asked to indicate their preference, if any, for either study treatment.

Statistical analysis

Analyses of nausea and vomiting were done separately for day 1 (acute), days 2-5 (delayed), and days 1-5 (overall) for each drug. For days 2-5 and 1-5 analysis was based on the worst grade of emesis or nausea on a single day within the period. Patients were only included in a cross-over analysis of a response variable if they provided data from both courses of treatment on that variable. For emetic response and nausea grade the four possible outcomes in consecutive courses (success and failure) were analysed by log-linear models for binary cross-over data.16 This procedure includes the Hills-Armitage test for interaction between treatment and course number and Prescott’s test for a treatment difference. There was evidence of interaction between treatment and course number in the analysis of complete and major response when emesis was assessed by vomits only on day 1, and the proportion of successes were compared between treatments by the MantelTABLE II-NUMBER OF PATIENTS REPORTING EACH GRADE OF CONTROL OF EMESIS BY ONDANSETRON AND DEXAMETHASONE

Assessment of response An emetic episode was defined as a vomit or a retch. Control of emesis was graded as: complete response-no emetic episodes; major response--one or two emetic episodes; minor responsethree to five emetic episodes; and failure-more than five episodes or patient given rescue medication. Patients achieving complete or major response were regarded as a "success" and patients with a minor response or failure of control were regarded as a "failure" for the cross-over analysis. Nausea was assessed by patients as none, mild, moderate, or severe, and also by a visual analogue scale (VAS) on which a score of 0 mm denoted absence of nausea and a score of 100 mm denoted "worst ever feeling of sickness". The difference between the post-treatment and baseline scores was used to assess overall nausea. Patients reporting no or mild nausea were regarded as a "success" and those reporting moderate or severe nausea were regarded as a "failure".

*Report of response based

on

number of vomits

or

retches

on worse

day.

485

TABLE III-NUMBER OF PATIENTS REPORTING EACH GRADE OF CONTROL OF NAUSEA BY ONDANSETRON AND DEXAMETHASONE

The efficacy of ondansetron and dexamethasone in the control of emesis on day 1, days 2-5, and days 1-5 is shown in table 11. There was no significant difference in success (ie, complete or major control) between ondansetron and dexamethasone on day 1 (=0-55 with 1 df, p = 046), although there were significantly less failures (more than five emetic episodes or rescue) with ondansetron than with dexamethasone on day 1 (X2 = 1091 with 1 df, p < 0-001). The overall median number of vomits and retches was 0 for both ondansetron and dexamethasone. There was no significant difference between ondansetron and dexamethasone in control of delayed emesis on days 2-5 (X2 = 1.54 with 1 df p = 0-214). There was also no significant difference between the treatments in overall control of emesis (days 1-5 inclusive) (X2 0- 13 with 1 df, p 0-717). The apparent difference in number of failures over days 1-5 (Prescott’s test: X2 5-22 with 1 df, p 0-022) (table n) can be explained by the significant difference between the treatment groups in the failure rate on day 1. There was no significant difference between the treatment group for control of acute emesis (&khgr;2=0.04, p = 0842) or delayed emesis (X2 0-51, p 0-476) when analysis for a treatment difference was based on emesis assessed by vomiting only. Control of nausea is summarised in table ill. There was no significant difference in reports of none or mild posttreatment nausea on day 1 for patients receiving ondansetron or dexamethasone (X2=0-65 with 1 df, p =0-421). Severe nausea on day 1 was reported by 8% of patients taking ondansetron and 13% of those taking dexamethasone (p>0.l). Delayed nausea (days 2-5) was significantly better controlled by dexamethasone than by ondansetron with 76 of 87 (87%) and 63 of 87 (72%) patients, respectively, reporting none or mild nausea (&khgr;2 = 8.68 with 1 df, p = 0003). The incidence of severe nausea during days 2-5 was 3% for dexamethasone and 8% for ondansetron (p > 0-1). Nausea was also assessed by VAS comparing the highest increase in VAS with baseline scores. There was no difference between dexamethasone (1mm) and ondansetron (0 mm) on day 1. The overall median increase in VAS for days 2-5 was 2 mm for dexamethasone and 4 mm for ondansetron. Cross-over analysis gave an estimated difference (dexamethasone-ondansetron) of -5-8 (approximate 95% confidence limits - 12-0 to —0-5). This increase in nausea score was significantly less for dexamethasone compared with ondansetron (Z=2-95, =

=

=

*Based

on worst

grade reported on

any

day.

Haenszel chi-squared test with data from the first course only. The numbers of emetic episodes were analysed by non-parametric methods for the cross-over design!7 with the Wilcoxon rank-sum test. The analysis included a test for interation between treatment and course number. A similar non-parametric analysis was done on the nausea score-ie, the difference between the VAS nausea score and the nausea grade recorded at baseline and at the end of day 1 and days 2-5.

Results 112 patients (38 men, 73 women, 1 no gender recorded) entered into the study. Characteristics of the patients are given in table 1. There were no significant differences in characteristics between patients in the ondansetron/ dexamethasone treatment sequence and those in the dexamethasone/ondansetron sequence. 12 patients were not evaluable in the cross-over analysis of day 1 emesis because of protocol violation, and were excluded before the randomisation code was broken. Of these 12 patients, 2 had received concurrent steroids and 1 had received concurrent prochlorperazine (in error), 1 had received intravenous diazepam on day 1 of the first study period, 3 had inappropriate chemotherapy for the protocol (single agent or different drugs in study period 1 and 2), 1 died before the second course, 1 was withdrawn because of a stroke, 1 had concurrent subacute bowel obstruction, and 2 had incorrect dosing of study drug. Of the 100 patients included in the cross-over analysis, 14 were not evaluable for effects on emesis and 13 for effects on nausea for days 2-5 because of failure to achieve emetic control on day 1 (9) or because of missing diary card information on emesis (5) or nausea (4). Except for 1 patient who received additional antiemetic on days 2-4 of the second study period in error, all 100 patients were included in the overall analysis of efficacy (day 1-5), which is a measure of any failure to achieve control of either acute or delayed emesis. All 112 patients were included in the analysis of safety. were

TABLE IV-PREFERENCES OF PATIENTS FOR ANTIEMETIC AGENTS ACCORDING TO SEQUENCE

=

=

=

=

p = 0-003).

evidence of an interaction between and course number for emesis assessed by vomiting alone on day 1 (X2 3 04, p 0-081). There was no other evidence of any interaction between treatments and course number or between treatments and investigators for emesis or nausea. The subsequent analysis of control of emesis assessed by vomiting alone was based on a parallel group comparison of treatments for the first course only. The preferences of patients for treatments in relation to the cross-over sequence is shown in table IV. There was no significant difference in expressed preference for ondansetron or dexamethasone (X2 =1 -36, p 0244); 29 patients expressed no preference. There was no evidence of an interaction between treatments. Minor adverse events were reported in 16 (14%) patients (20 events) during or after ondansetron treatment and in 18 (16%) patients (26 events) during or after dexamethasone treatment. These events were assessed as possibly, probably, or almost certainly related to the drug and are There

was some

treatment

=

=

=

486

TABLE V-NUMBER OF PATIENTS REPORTING SIDE-EFFECTS ASSOCIATED WITH ONDANSETRON AND DEXAMETHASONE

*Examples of side-effects listed as miscellaneous include tiredness and sluggishness.

detailed in table v. Headache was the most common side-effect and occurred in 8 patients (3 moderate, 5 mild) receiving ondansetron and 7 patients (11headaches: 3 severe, 1 moderate, and 7 mild) receiving dexamethasone. Some side-effects that may be attributed to glucocorticosteroid administration were reported in patients receiving dexamethasone. These included 1 patient diagnosed as having a moderate psychosis after 5 days of dexamethasone, and a further 5 patients who reported hyperactivity, tingling or burning sensations. 3 patients receiving dexamethasone reported dyspepsia or heartburn and 1 patient receiving ondansetron reported severe dyspepsia. 2 patients (1dexamethasone and 1 ondansetron) were withdrawn from the study because of dyspepsia. There were no changes in any parameter of the full blood count for either treatment. 1 patient had transient elevation of aspartate transaminase on both drugs; however, this patient had abnormal liver function before treatment.

Discussion Both ondansetron and dexamethasone were highly effective in the control of acute emesis. However, significantly fewer patients taking ondansetron reported failure to control acute emesis. There is no evidence that modifying the schedule of ondansetron or dexamethasone therapy would improve antiemetic efficacy. 5,18 Delayed emesis has been recognised as a problem that may persist for at least 48 h after chemotherapy9,10,19,20 and that necessitates continuation of antiemetics for several days after chemotherapy, even when adequate control of acute emesis has been achieved. In this trial there was no difference between ondansetron and dexamethasone with respect to delayed vomiting and retching. However, there was an advantage for dexamethasone over ondansetron in the control of delayed nausea. This may in part reflect the relative superiority of dexamethasone in the control of delayed emesis (88% of patients reporting success) compared with acute emesis (79% of patients reporting success). These results are consistent with experience in a ferret model in which dexamethasone was shown to successfully suppress nausea but had less efficacy in the control of vomiting.21 Both study drugs were given for an

adequate period (5 days) to control delayed nausea, and the apparent advantage for dexamethasone may indicate a separate mechanism for mediation of delayed nausea. Although a cross-over design is attractive in antiemetic studies because using patients as their own controls reduces the variance in results for a given sample size,12 there is a potential problem if the relative efficacy of treatments varies with the two treatment sequences due to anticipatory vomiting, altered clinical status, or loss of patients after the first treatment period.22 In this study 86 of 100 patients were evaluable for cross-over analysis, and there was no evidence

of interaction between treatments and course with the possible exception of emesis as judged by vomiting alone on day 1. Since the cross-over analysis was invalidated, this parameter was compared by a parallel group analysis for the first treatment period only. Ondansetron and dexamethasone were well tolerated with a low incidence of treatment-related side-effects despite prolonged therapy. In particular, we did not observe any extrapyramidal reactions or sedation which may be a problem with dopamine antagonists. 3 patients on dexamethasone reported side-effects of mood change/ twitching/hyperactivity that are normally attibuted to long-term therapy with steroids;23 however, there was no evidence in terms of patient preference for the sense of "well being" that has been associated with steroid therapy. It could be argued that in a non-trial situation the reducing dose of steroids is more complex for patients than a fixed drug dose over 5 days, but this is unlikely to be a real problem for most patients. Moreover, our current clinical practice is to give dexamethasone 4 mg orally every 6 h for 3-4 days. Ondansetron and dexamethasone provide safe, effective antiemetic prophylaxis against moderately emetogenic nonplatinum-containing chemotherapy regimens and are suitable for out-patient use. At current prices in the UK, the antiemetic schedules of these drugs would cost L135.50 for ondansetron and k3.45 for dexamethasone. Although the current relative costs favour dexamethasone, and this has implications for resource allocation, the situation may change as a wider range of serotonin antagonists become available. Ondansetron has been added to dexamethasone with improved antiemetic control in subsequent courses of chemotherapy in patients with refractory emesis. 23 It may, therefore, be possible to devise a combination or alternating schedule using both drugs to further improve control of acute and delayed emesis and nausea in selected patients. We thank Glaxo Group Research for financial support, data management, statistical analysis, and for supplying ondansetron. Miss Peta Heatley kindly prepared the typescript.

REFERENCES 1. Coates A, Abraham S, Kaye SB, et al. On the receiving end-patients perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983; 19: 203-08. 2. Humphrey PPA. Peripheral 5-hydroxytryptamine receptors and their classification. Neuropathy 1984; 23: 1503-05. 3. Kilpatrick GJ, Jones BJ, Tyers MB. Identification and distribution of 5HT3 receptors in rat brain using radiological binding. Nature 1987; 330: 746-48. 4. Cubeddu LX, Hoffman IS, Feunmayor NT, Finn AL. Efficacy of ondansetron (GR38032F) and the role of serotonin in cisplatin induced nausea and vomiting. N Engl J Med 1990; 322: 810-16. 5. Cunningham D, Hawthorn J, Pople A, et al. Prevention of emesis in

patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist. Lancet 1987; i: 1461-63. 6. Kris MG, Gralla RJ, Clarke RA, Tyson LB. Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients

receiving anticancer chemotherapy. J Clin Oncol

1988; 6: 659-62. 7. Hesketh PJ, Murphy WK, Lester EP, et al. GR38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatin-induced emesis. J Clin Oncol 1989; 7: 700-05. 8. Marty M, Pouillant P, Scholl S, et al. Comparison of the 5hydroxytryptamine (serotonin) antagonist ondansetron (GR38032F) with high-dose metaclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990; 322: 816-21. 9. Cunningham D, Evans C, Gazet JC, et al. Comparison of anti-emetic efficacy of domperidone, metaclopramide and dexamethasone in patients receiving outpatient chemotherapy regimens. Br Med J 1987; 295: 250.

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10. Morran C, Smith DC, Anderson DA, McArdle CS. Incidence of nausea and vomiting with cytotoxic chemotherapy in a prospective randomised trial of antiemetics. Br Med J 1979; i: 1323-25. 11. Schmoll HJ. The role of ondansetron in the treatment of emesis induced by non-cisplatin-containing chemotherapy regimens. Eur J Cancer Clin Oncol 1989; 25 (suppl): 535-39. 12. Aapro M, Plezzia PM, Alberts D S, et al. Double-blind crossover study of the anti-emetic efficacy of high dose dexamethasone versus high dose metaclopramide. J Clin Oncol 1983; 2: 466-71. 13. Markman M, Sheilder V, Ettinger DS, et al. Anti-emetic study of dexamethasone. Randomised double-blind, crossover study with high dose metoclopramide in patients receiving cancer chemotherapy. N Engl J Med 1984; 331: 549-22. 14. Ibrahim EM, Al-Idrissi HY, Ibrahim A, et al. Anti-emetic efficacy of high dose dexamethasone: randomised double-blind crossover study with high dose metoclopramide in patients receiving cancer chemotherapy. Eur J Cancer Clin Oncol 1986; 22: 283-88. 15. Rich WM, Abdulhayoglu G, Disaia PJ. Methylprednisolone as an antiemetic during cancer chemotherapy: a pilot study. Gynaecol Oncol 1980; 9: 193-98. 16. Kenward MG, Fleming TR. A log-linear model for binary crossover data. Appl Statistics 1987; 36: 192-204.

17. Koch GG. The use of non-parametric methods in the statistical analysis of the two-period change-over design. Biometrics 1972; 28: 577-84. 18. Drapkin RL, Sokol GH, Paladino WJ, et al. The antiemetic effect and dose response of dexamethasone in patients receiving cisplatinum. Proc Am Soc Clin Oncol 1982; 1: C236. 19. Kris MG, Gralla RJ, Tyson LB, et al. Incidence, course and severity of delayed nausea and vomiting following the administration of high dose cisplatin. J Clin Oncol 1985; 3: 1379-84. 20. 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: 1142-49. 21. Hawthorn J, Cunningham D. Dexamethasone can potentiate the anti-emetic action of a 5HT3 receptor antagonist on cyclophosphamide-induced vomiting in the ferret. Br J Cancer 1990; 61: 56-60. 22. Olver IN, Simon RH, Aisner J. Anti-emetic studies: a methodological discussion. Cancer Treat Rep 1976; 70: 555-63. 23. Eisman JA. Long term corticosteroid therapy-managing side-effects. Concurrent Therapy 1986; 27: 42-46. 24. Cunningham D, Turner A, Hawthorn J, Rosin RD. Ondansetron with

and without dexamethasone Lancet 1989; i: 1323.

to treat

chemotherapy-induced

emesis.

Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy

Ondansetron,

serotonin antagonist, is effective in controlling the emesis associated with cancer chemotherapy; however, emesis in patients receiving high-dose cisplatin is poorly controlled by ondansetron alone. Dexamethasone is an effective antiemetic with no known interaction with serotonin receptors and was thus chosen for study in combination with ondansetron. 31 patients (30 male, 1 female; median age 28·5 a

range 18-49) receiving a 4-day course of a chemotherapy regimen containing cisplatin (100120 mg/m2) for metastatic germ-cell tumours were

years,

entered in a randomised, double-blind, cross-over trial comparing oral ondansetron plus placebo with oral ondansetron plus dexamethasone as antiemetic prophylaxis. Ondansetron (8 mg every 8 h) was given to all patients for 8 days from the start of chemotherapy. Patients were given 8 mg of dexamethasone or placebo every 8 h starting 2 h before cisplatin (on day 4) and continuing for six doses (ie, for 2 days only). A second course of chemotherapy began 14 days after the start of the first, during which patients crossed over to the alternative antiemetic regimen. Results were available from 27 patients. In the 24-48 h after cisplatin 78% of patients taking ondansetron plus dexamethasone reported complete or major control of emesis compared with 30% of those taking ondansetron plus placebo (p=0·001). Cross-over analysis showed a significant advantage for ondansetron plus dexamethasone in the control of nausea (p=0·013) and emesis (p