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Journal of Clinical Oncology, Vol 18, Issue 19 (October), 2000: 3409-3422
© 2000 American Society for Clinical Oncology

Contribution of Dexamethasone to Control of Chemotherapy-Induced Nausea and Vomiting: A Meta-Analysis of Randomized Evidence

By John P. A. Ioannidis, Paul J. Hesketh, Joseph Lau

From the Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece, and St Elizabeth Medical Center and Division of Clinical Care Research, New England Medical Center, Boston, MA.

Address reprint requests to Joseph Lau, MD, Division of Clinical Care Research, New England Medical Center, 750 Washington St, Box 63, Boston, MA 02111; email JLau1{at}Lifespan.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Studies Rejected After...
 APPENDIX Cont’d
 REFERENCES
 
PURPOSE: To synthesize the available randomized evidence on the efficacy of dexamethasone when used for protection against acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic cancer chemotherapy.

MATERIALS AND METHODS: A meta-analysis was performed using trials identified through MEDLINE (1966 to April 1999), Embase, Derwent Drug File, and the Cochrane Library’s Database of Controlled Trials. Data on acute and delayed emesis and nausea were collected. All randomized studies comparing dexamethasone to placebo, no treatment, or other antiemetics qualified, including cross-over trials providing first-cycle data.

RESULTS: Of 1,200 citations screened, 32 studies with 42 pertinent comparisons and 5,613 patients were included in the meta-analysis. Dexamethasone was superior to placebo or no treatment for complete protection from acute emesis (odds ratio, 2.22; 95% confidence interval [CI], 1.89 to 2.60) and for complete protection from delayed emesis (odds ratio, 2.04; 95% CI, 1.63 to 2.56). The results were similar for complete protection from nausea. The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively). The beneficial effect was similar in subgroups defined by various study design parameters. No trial addressed the efficacy of dexamethasone in the delayed phase without having administered dexamethasone for acute-phase protection as well.

CONCLUSION: Dexamethasone is clearly effective in protecting from emesis both in the acute and delayed phases, with emesis avoided in one patient out of six treated. Future trials should determine whether the delayed-phase effect is independent of the acute-phase benefit.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Studies Rejected After...
 APPENDIX Cont’d
 REFERENCES
 
CHEMOTHERAPY-INDUCED nausea and vomiting are among the most common significant side effects of cancer chemotherapy and can be major problems for cisplatin-based as well as other chemotherapeutic regimens. During the last decade, several agents have been studied in randomized trials in order to establish their efficacy in controlling chemotherapy-induced emesis.1-4 Dexamethasone was one of the first agents to be introduced and it is currently used extensively, especially in combination with other antiemetics, such as type 3 serotonin (5-HT3) receptor antagonists. Despite the extensive use of this agent, there is limited insight on its overall efficacy as inferred from data collected in randomized trials. Most trials of single-agent dexamethasone have been relatively small in sample size. The dispersion of the evidence across several small trials leaves several important questions unanswered regarding the exact therapeutic role of dexamethasone in chemotherapy-induced emesis. Specifically, how effective is dexamethasone compared with placebo or no treatment? Is the effect different for protection of acute emesis (first 24 hours) versus protection for delayed emesis (24 hours to about 7 days)? What evidence exists for the relative efficacy of dexamethasone when used in combination with different additional antiemetics (5-HT3 receptor antagonists, metoclopramide, and others) or without any such background therapy? Finally, is there evidence of variability in the reported efficacy of dexamethasone in studies of different study design or methodologic quality or in different patient populations?

In order to help answer these questions, it would be important to examine in its totality the evidence concerning the efficacy of dexamethasone in cancer patients receiving emetogenic chemotherapy. Therefore, in this article, we report the results of a systematic review and meta-analysis of randomized controlled trials (RCTs) addressing the efficacy of dexamethasone in reducing chemotherapy-induced nausea and vomiting.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX Studies Rejected After...
 APPENDIX Cont’d
 REFERENCES
 
Literature Search
The MEDLINE database was searched (1966 to April 1999) to identify RCTs assessing the use of dexamethasone in controlling chemotherapy-induced nausea and vomiting. The literature search was also extended to include Embase, Cancerlit, and Derwent Drug File. The Cochrane Library’s Database of Controlled Trials Registry (Issue 1, 1999), which contains over 218,000 controlled clinical trials including results from hand searching of clinical journals, was also perused. In addition, the bibliography of retrieved RCTs, meta-analyses, and narrative review articles was reviewed. The results of these searches were combined to yield a common set of citations from which the titles and abstracts were screened for potential qualifying studies.

Inclusion Criteria
All RCTs of human subjects that allowed the evaluation of the efficacy of dexamethasone (compared with placebo, no-treatment control, or another active agent, or in combination with another active agent v that active agent alone) to reduce chemotherapy-induced nausea and/or vomiting and reported relevant clinical outcome data qualified for the meta-analysis. Both acute- and delayed-phase protection qualified, and we included trials in which patients had received regimens of high or moderate emetogenicity.5,6 In addition to English-language studies, we also decided a priori to examine studies if they were published in Chinese, French, German, Greek, or Italian, based on the translating abilities of the authors. Because of the high likelihood of carry-over effects,6 cross-over studies qualified only if they reported extractable first-period data.

Definition of Outcomes
Nausea and vomiting are main problems of chemotherapy and both of these outcomes were considered. We placed more emphasis on vomiting because it is more objective to determine, but data on nausea control were also collected, as well as data on control of both nausea and vomiting, wherever available. Control of emesis (complete protection from emesis) was defined as no vomiting or retches in the defined emesis phase (acute or delayed). Acute emesis was defined as vomiting or retching occurring within the first 24 hours after chemotherapy. Delayed emesis was defined as vomiting or retching occurring more than 24 hours after chemotherapy and up to 5 to 8 days (as defined by authors in each study). We allowed minor variations in studies that reported emesis control on slightly differently defined periods, ranging from days 2 to 5 to days 2 to 8. In a few cases, data were not available for the complete period of days 2 to 7 but were given separately for each specific day. Since the data on specific days are not independent, we cannot simply combine these rates. We agreed a priori to select the rates of the worst day for inclusion to the meta-analysis calculations.

Data Extraction
Data extraction was performed on studies that met the inclusion criteria for meta-analysis. Data extraction was conducted in duplicate and independently by two investigators (J.P.A.I. and J.L.). Discrepancies were handled through consensus. In addition to the main outcomes, the following information was searched for in each study: method of random allocation and adequacy of concealment, adequacy of blinding of the investigators and patients to the investigational drug, definition of the condition of interest and of the outcome of interest, type and dosage of chemotherapy (we categorized chemotherapy into highly emetogenic [level 5 per Hesketh et al5 ], eg, cisplatin >= 50 mg/m2 or cyclophosphamide > 1,500 mg/m2, and moderately emetogenic [level 3 to 4 per Hesketh et al5 ], eg, cyclophosphamide < 1,500 mg/m2 or cisplatin < 50 mg/m2), the cycle of chemotherapy in which dexamethasone was being tested (first cycle v later cycles), previous chemotherapy and history of chemotherapy-induced emesis, possible preselection of patients on the basis of prior antiemetic response, patient demographics such as the average age and sex ratio in the study, comparator treatment (placebo, no treatment, other regimen), and concurrent background antiemetics given to all patients.

Data Synthesis
Outcome data for each of the study questions were combined using both fixed-effects and random-effects models.7 In general, the fixed-effects and random-effects models give similar estimates, although the random-effects model is more conservative and gives wider confidence intervals when heterogeneity is present and is therefore less likely to be misleading. Heterogeneity was always tested by the Q statistic and was considered significant if P was less than .10.7 For completeness, we included calculations for the odds ratio, the risk ratio, and the risk difference. The odds ratio may be substantially inflated compared with the risk ratio, when the event rates in the compared arms are higher than 10% and less than 90%. The odds ratio is considered to have more attractive statistical properties, but the risk ratio is more clinically relevant. The inverse of the risk difference provides the metric number needed to treat (NNT), which may be useful for the clinical interpretation of the results.8

We also performed various types of sensitivity analyses to examine the robustness of the results. The effect of the methodologic quality of the studies was assessed by subgroups comparing unblind studies with single-blind and double-blind designs. The adequacy of randomization concealment was assessed similarly. Subgroup and metaregression analyses were performed to explore possible relationships between covariates and treatment effects.9 In particular, control-rate metaregressions assessed possible relationships of the dexamethasone benefit (as expressed by the risk difference or natural logarithm of odds ratio) with the baseline risk of the study populations (as expressed by the control group event rate, ie, the complete emesis protection rate in the comparator arm). Since simple linear regressions may overestimate such relationships, we used instead hierarchical models, which account for random error.10

Cumulative meta-analyses with studies ordered by dexamethasone dosage were used to identify possible relationship between the magnitude of treatment effect and dexamethasone dosage.11 Finally, inverted funnel plots were used to evaluate whether the magnitude of the treatment benefit was related to the sample size of the included trials, which might be suggestive of publication bias, ie, the lack of publication of small trials with unfavorable results.12


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 APPENDIX Studies Rejected After...
 APPENDIX Cont’d
 REFERENCES
 
Twelve hundred citations were reviewed. There were many overlaps among the results of the three search strategies. Screening of the titles and abstracts identified 82 potentially useful clinical trials. There were four non–English-language publications: one Italian study and one French study were retrieved, but did not qualify for analysis; two Japanese language studies could not be retrieved. Three publications indexed by Embase were not found in MEDLINE and only one of these three articles qualified for analysis. Search of the Cancerlit database and Derwent Drug File and examination of review articles, meta-analyses, and retrieved trials did not identify any additional useful RCTs.

Excluded Studies
From the 80 retrieved articles, 48 were rejected from the meta-analysis (see Reference Appendix). All of these studies were of small sample size and many were also of doubtful quality. Twenty-four of the rejected studies were cross-over trials with no extractable first-period data. Other reasons for exclusion included nonanalyzable data and/or purely pharmacokinetic information (n = 2), data from multiple cycles with or without randomization for the second cycle based on previous response (n = 3), a comparison of different timing for giving the same regimen (n = 1), comparison of one versus multiple doses of the same drugs (n = 1), comparison of dexamethasone and adrenocorticotropic hormone (n = 1), comparisons involving dexamethasone together with other drugs (n = 2), lack of randomization (n = 2), and duplicate publications or publications with some additional data that were not pertinent to the meta-analysis (n = 12).

Only two of the rejected studies had more than 100 patients, and one of these two was not a comparison involving dexamethasone, but dexamethasone in combination with metoclopramide and lorazepam versus a 5-HT3 receptor antagonist. The other excluded trial with more than 100 patients (a cross-over design with no reported first-cycle data)13 may be more important because, with 112 patients, it is only one of two studies that compared dexamethasone with a 5-HT3 receptor antagonist. Therefore, data on the direct comparison of dexamethasone and 5-HT3 receptor antagonists should be interpreted cautiously. The other 23 trials with no extractable first cycle were overall of small sample size, and they had a total of only 890 patients. Moreover, most of their findings were in concordance with the results of the meta-analysis. Therefore, the inclusion of these multiple-cycle data would not have altered the main findings of the meta-analysis.

Characteristics of Included Studies
A total of 32 studies14-45 with 42 pertinent comparisons were included in the meta-analysis (Tables 1 and 2). Twenty studies with 26 comparisons were published in 1994 or later. The total number of patients was 5,613, and the number of assessable patients was 5,457. There were 17 multicenter trials, and all of them were published in 1991 or later (all early studies were single-center trials). With few exceptions, research had been sponsored by pharmaceutical companies, or the source of funding was not stated (Table 1). Patients were preselected in three studies on the basis of poor or partial antiemetic response during the first cycle. With few exceptions, most studies addressed patients with various types of neoplastic diseases. With one exception, the mean (median) age was fairly similar, between 48 and 63 years. The proportion of male patients in each study is also given in Table 1. Alcohol consumption data were given only in recent studies, but the information was not standardized across trials to allow meaningful interpretation. In the majority of cases, patients had not been exposed to the chemotherapy before. In 12 comparisons, patients who had previously received some chemotherapy (not necessarily the regimen given during the trial) were included (Table 1). In another case,36 patients had already been given 1 day of low-emetogenic chemotherapy before being randomized to the compared regimens on the day of receiving cisplatin.


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  		Table 1. Characteristics of Studies Included in the Meta-Analysis and Their Patient Populations
 

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  		Table 2. Characteristics of Study Design and Chemotherapy Regimens
 
Seven studies used cross-over designs with extractable first-period data (Table 2). Most studies were double-blind, although there were also four open-label and three single-blind studies. Some information on randomization methods was reported in nine studies (10 pertinent comparisons), and supporting documentation for robust allocation concealment was reported in seven studies (10 pertinent comparisons). Seven of the 42 comparisons involved randomization performed after the acute phase (at 24 hours after receiving chemotherapy). In all of these studies, patients had received a standard antiemetic regimen to cover the acute phase (dexamethasone and a 5-HT3 receptor antagonist in four cases, or dexamethasone [or methylprednisolone] along with metoclopramide or also lorazepam in three cases). There were no studies at all in which corticosteroids had not been given during the acute phase and were then only given for delayed-phase coverage. Thirty-seven of the 42 comparisons evaluated dexamethasone versus placebo or no-treatment controls. In 34 of the 37 these comparisons, other antiemetics were commonly prescribed to both arms, whereas in three of the 37 comparisons, no other common antiemetics were prescribed (a practice that would be unethical by current standards). There were also four qualifying comparisons of dexamethasone and metoclopramide (with a background of no other therapy [three studies] or tropisetron [one study]) and one comparison of dexamethasone and ondansetron (with no other antiemetics given) (Table 2).

Most comparisons involved highly emetogenic chemotherapy (typically based on cisplatin at doses of at least 50 mg/m2 or higher). However, there were seven cases in which only moderately emetogenic regimens were considered (including three comparisons in which cisplatin was used at doses of 20 to 50 mg/m2) and one study with four pertinent comparisons in which a wide range of emetogenicity potential existed (Table 2).

The dosage of dexamethasone used in the acute phase varied between 8 mg and 100 mg. Half of the studies used 20 mg. The mean total dosage for studies that used dexameth- asone in both the acute and delayed phases was 56 mg. All studies administered dexamethasone intravenously in the acute phase, but oral dexamethasone was also added to the intravenous dose by Aapro et al14 and the Italian Group for Antiemetic Research study,26 which actually was conducted with patients receiving moderately emetogenic chemotherapy. With two exceptions (Dreschler et al20 and Ahn et al16 ) dexamethasone was given orally during the delayed phase.

Data Synthesis
The data on the end points of complete protection from emesis, nausea, and both events combined, including a breakdown by acute or delayed phase, are listed in Table 3. Thirty-five comparisons had some pertinent data available for protection during the acute phase, 18 had some pertinent data on delayed-phase control, and 26 comparisons addressed the delayed phase either alone or in combination with the acute phase.


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  		Table 3. Data on Main Outcomes
 
Acute Phase
Twenty-nine (4,176 patients) of the 35 pertinent comparisons (4,761 patients) had data on complete protection from acute emesis. The remaining six comparisons had data on complete protection from both vomiting and nausea in the acute phase. The results were very similar when only the 29 comparisons were considered or the six additional comparisons were added. There was no significant heterogeneity for any of the treatment effect metrics (P > .10 for all). There was even less heterogeneity when the analysis was limited to the 31 (of the 35) and 25 (of the 29) comparisons in which dexamethasone was compared with placebo or no treatment, respectively. For all metrics and for all modes of analysis, the benefit from dexamethasone was highly statistically significant (P < .0001) (Table 4).


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  		Table 4. Complete Protection From Emesis in the Acute Phase: Meta-Analysis
 
In the summary estimates, dexamethasone increased the chance of no vomiting by about 25% to 30% and offered an additional 15 out of 100 patients a vomit-free first 24 hours after receiving chemotherapy. The random-effects weighted vomit-free rate across the 25 placebo/no-treatment trials was 48% (95% confidence interval [CI], 40% to 55%).

Three studies with a total of 189 patients14,20,39 compared dexamethasone with metoclopramide. The pooled result of these three studies was largely driven by the largest of them20 to show a superiority of dexamethasone in the acute phase (risk ratio, 1.11; 95% CI, 1.00 to 1.24), but there was significant heterogeneity for the odds ratio and risk difference metrics. The only qualifying trial comparing dexamethasone with a 5-HT3 receptor antagonist26 showed no difference in the acute-phase efficacy between the two treatments.

In a separate analysis of data on the 22 comparisons of dexamethasone and placebo/no treatment in which a 5-HT3 receptor antagonist had been given to both arms, the results were practically identical. Among 3,791 patients, the pooled odds ratio was 2.29, the pooled risk ratio was 1.25, and the pooled risk difference was 16.5% (P < .0001 for all metrics), with no evidence of heterogeneity across trials.

Data on complete protection from acute nausea were available in 23 of the 35 pertinent comparisons, and another seven comparisons gave data for complete protection from both nausea and vomiting. Five pertinent studies offered no data on nausea control or offered data in different metrics (typically visual analogs). Although the data are not as complete (Table 3), the same results are discernible as for the more objective emesis end points (not shown).

Delayed Phase
Of the 26 comparisons that addressed the delayed phase (4,054 patients), 20 gave data on the specific end point of complete protection from emesis (2,772 patients). The other six offered data on either complete control of emesis during the acute and delayed phases combined (rates of protection were expected to be lower than rates of protection during the delayed phase only) or complete control of both nausea and emesis during the acute and delayed phases combined (rates of protection were also expected to be somewhat lower). There were 22 comparisons using placebo or no treatment (3,560 patients), and 16 of them (2,278 patients) used the strict end point of complete emesis protection during the delayed phase.

Regardless of the metric used and which end point definitions were allowed in the analysis, dexamethasone showed a clear protective benefit in the delayed phase (P < .0001 for all comparisons), and there was no evidence of statistical heterogeneity (Table 5). The magnitude of the treatment effect for all metrics is very similar to what was observed for the acute phase.


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  		Table 5. Complete Protection From Delayed Emesis: Meta-Analysis
 
In the summary estimates, dexamethasone increased the chance of no vomiting during the delayed phase by approximately 25% to 30% and offered an additional 15 out of 100 patients a vomit-free delayed period. The random-effects weighted vomit-free rate across the 16 placebo/no-treatment trials with strict emesis protection end points was 49% (95% CI, 42% to 57%).

There were three studies with a total of 189 patients that compared dexamethasone with metoclopramide. The results were largely driven by the largest study20 to show a trend for superiority of dexamethasone (risk ratio, 1.16; 95% CI, 0.75 to 1.80), but there was significant heterogeneity for all three (odds ratio, risk ratio, and risk difference) metrics across these studies. The sparseness of the data does not allow us to probe into reasons for this heterogeneity. The only qualifying trial to compare dexamethasone with a 5-HT3 receptor antagonist showed a superiority of dexamethasone (risk ratio, 1.20; 95% CI, 1.06 to 1.36).26

In a separate analysis of data on the 18 comparisons of dexamethasone and placebo/no treatment in which a 5-HT3 receptor antagonist had been given to both arms, the results were practically identical. Among 3,276 patients, the pooled odds ratio was 2.03, the pooled risk ratio was 1.34, and the pooled risk difference was 15.9% (P < .0001 for all metrics), with no evidence of heterogeneity across trials.

Data on complete protection from delayed-phase nausea were available in 16 of the 26 pertinent comparisons, and another one gave data for complete protection from both nausea and vomiting. Five pertinent comparisons offered nausea or vomiting/nausea data from the combined acute and delayed phases, and four comparisons had no data on nausea control or offered data in different metrics (typically visual analogs). Although the data are not complete and similar in terms of end points, the same results are discernible as for the more objective emesis end points (Table 3).

Evaluation of Potential Variability in Antiemesis Efficacy
In cumulative meta-analyses of studies ordered by increasing dexamethasone dosages, no obvious trend was seen, indicating the lack of a strong dose-response relationship among these studies. This was true for both acute-phase vomiting (Fig 1) and delayed-phase vomiting (Fig 2). We cannot rule out the possibility that a subtle dose-response relationship may exist for total doses less than 20 mg, with saturation of dexamethasone receptors at higher doses. Nevertheless, even low doses show clear efficacy.



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  		Fig 1. The left panel depicts a meta-analysis for complete protection from emesis in the acute phase. The odds ratios and 95% CIs of the studies and the combined result are shown. No significant dose effect was observed in the cumulative meta-analysis (right panel) ordered by increasing dexamethasone dosage.

 


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  		Fig 2. The left panel depicts a meta-analysis for complete protection from emesis in the delayed phase. The odds ratios and 95% CIs of the studies and the combined result are shown. No significant dose effect was observed in the cumulative meta-analysis (right panel) ordered by increasing dexamethasone dosage.

 
Control rate metaregressions showed no statistically significant relationship between the treatment effects and the control rates of acute- or delayed-phase emesis. Moreover, other subgroup analyses showed consistent patterns across subgroups. For complete protection from acute emesis, the random effects odds ratio (and 95% CI) was 2.30 (1.45 to 3.66) in trials of moderately emetogenic chemotherapy and 2.18 (1.85 to 2.58) in trials of highly emetogenic chemotherapy, 2.22 (1.90 to 2.59) in double-blind studies and 1.72 (1.18 to 2.51) in single-blind and unmasked trials, 2.05 (1.50 to 2.79) in adequately concealed trials and 2.23 (1.88 to 2.65) in inadequately concealed trials, and 2.19 (1.85 to 2.60) in trials with 5-HT3 concurrent antiemetics and 2.08 (1.40 to 3.11) in trials with concurrent metoclopramide or no concurrent coverage. For complete protection from delayed emesis, the random effects odds ratio (and 95% CI) was 2.16 (1.64 to 2.86) in trials of moderately emetogenic chemotherapy and 1.93 (1.58 to 2.34) in trials of highly emetogenic chemotherapy, 1.95 (1.59 to 2.38) in double-blind studies and 2.20 (1.62 to 2.99) in single-blind and unmasked trials, and 2.04 (1.56 to 2.66) in adequately concealed trials and 2.02 (1.66 to 2.45) in inadequately concealed trials.

Only three trials recruited only patients who had a history of vomiting secondary to chemotherapy. The results of these trials were consistent with the remaining evidence: the random effects odds ratios (and 95% CIs) for complete protection from vomiting and from both nausea and vomiting in the acute phase were 3.18 (1.63 to 6.20) and 1.76 (1.21 to 2.57), respectively; the respective odds ratios (and 95% CIs) for the delayed phase were 2.55 (1.19 to 5.45) and 2.83 (1.16 to 6.92). Similarly, dexamethasone efficacy was seen in trials with both chemotherapy-naïve and nonnaïve patients.

Reporting of Safety Data
Most of the studies provided some reporting of adverse events, but these data were often incomplete and the quality of the reporting varied greatly. Most studies concluded that the side effects are mild and tolerable. Since most of the trials used a 5-HT3 compound concurrently, many of the reported side effects could have been due to the use of concurrent antiemetics. Several studies reported increases in hiccups and various gastrointestinal symptoms among patients given dexamethasone, but the definitions vary. Only one case of hematemesis attributed to dexamethasone was reported among all the considered studies.

Potential Bias
Publication bias could be an issue in this area where there are several studies of small sample size supported by the industry. Nevertheless, several studies of moderate sample size were included in the meta-analysis (200 to 600 patients qualifying in a comparison), and all of them showed results similar to those of smaller studies. Inverse funnel plots of the acute (Fig 3) and delayed (Fig 4) data do not suggest strong evidence for publication bias, although in the case of acute-phase protection, the largest study showed a more conservative effect. Nevertheless, the largest study on delayed-phase protection showed a more pronounced than average effect (Fig 4).



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  		Fig 3. Funnel plot for studies of acute emesis protection.

 


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  		Fig 4. Funnel plot for studies of delayed emesis protection.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
APPENDIX Studies Rejected After...
 APPENDIX Cont’d
 REFERENCES
 
This meta-analysis shows that dexamethasone offers a clear advantage over placebo or no treatment for protection against emesis in both the acute and delayed phases. Approximately six patients need to be treated to prevent one patient from experiencing emesis in either phase. The absolute magnitude of the benefit was similar in both phases, and there was no strong evidence for statistical heterogeneity among the individual studies. An incremental benefit was also seen and was of identical magnitude in studies in which patients were specifically given a 5-HT3 receptor antagonist as background therapy. There was more limited evidence when other background therapy was used and very limited data on the efficacy of dexamethasone alone without other background therapy. There was also rather limited evidence comparing dexamethasone directly with metoclopramide or a 5-HT3 receptor antagonist. The available data suggest a superiority of dexamethasone over a 5-HT3 receptor antagonist in direct comparison for protection against delayed emesis, but more evidence is required for more firm conclusions on these comparisons.

Bias is unlikely to influence substantially the magnitude of the reported protective effect. Several subgroup analyses, cumulative meta-analyses, and inverted funnel plots failed to identify signs of bias or strong heterogeneity. It is possible that dexamethasone may be less effective in patients at very high risk of vomiting, and newer agents may need to be tested, in addition to dexamethasone, in this population. The dose of dexamethasone varied substantially across studies, but this was not related to variability in the treatment effect, which suggests that perhaps relatively low doses may be adequate for achieving the protective effect. The available evidence does not suggest that there are major safety concerns with the use of dexamethasone for antiemetic purposes. Nevertheless, reporting of safety information from trial reports could definitely be improved and standardized.46 Finally, the large number of duplicate publications is of some concern for the quality of the literature,47 although the careful conduct of the meta-analysis should have obviated any bias on the pooled effects. The phenomenon seems to be similar to the duplication of publications which was previously described for antiemetics after surgery.47

In this meta-analysis, we did not include studies of corticosteroid agents other than dexamethasone. The efficacy of corticosteroids may be the same regardless of the specific agent used, but it may be prudent to suggest that other corticosteroids should be compared with the reference standard of dexamethasone. There is substantial evidence that methylprednisolone also provides effective antiemetic coverage when compared with placebo/no treatment, both as a single agent48 and with a background of metoclopramide49 or a 5-HT3 receptor antagonist.50-52 In one randomized trial, a combination of dexamethasone and metoclopramide showed better efficacy than a combination of methylprednisolone and metoclopramide, but the metoclopramide was used at different dosages in the two arms and the dexamethasone arm was also given diphenhydramine as well.53 Thus, this is not a true comparison of the two corticosteroid agents.

The current meta-analysis finally suggests several issues that could help improve the design of future trials in the field.6 We identified a large number of small cross-over trials in which no data were reported on the first cycle. Due to the high probability of carry-over effects with these regimens, such designs should not be favored; if they are pursued, first-cycle data should at least be presented. Furthermore, information on parameters that are likely to modify the incidence of emesis and possibly also the treatment effect should be carefully recorded and analyzed.5,6 In that regard, the provided information was sometimes suboptimal, especially as far as a history of ethanol consumption or predisposition to motion sickness was concerned.

Finally, it is interesting to note that the efficacy of dexamethasone was established as adjunctive treatment to 5-HT3 receptor antagonists, while very limited data were ever assembled on its efficacy against placebo, without any background therapy. This is probably due in good part to the catalytic role of the pharmaceutical industry in promoting combination trials with 5-HT3 receptor antagonists. There was probably more limited interest in dexamethasone alone. As the current evidence stands, there is no rationale for pursuing further trials in which dexamethasone would be compared with placebo with a background of 5-HT3 receptor antagonists, since the evidence is already more than convincing, regardless of its relatively minor shortcomings. Finally, there is no randomized evidence from trials in which dexamethasone has been administered only at the delayed phase. Given the design of prior trials, it is hard to tell the extent to which the efficacy of reducing delayed emesis is related to carry-over effects from the administration of dexamethasone to cover acute emesis. Such evidence would be important to accumulate, but given the current data, dexamethasone needs to be given as part of the standard antiemetic treatment in the acute phase. Separating the acute phase from the delayed-phase effects would be feasible only if newer antiemetics were found with similar efficacy or superiority to dexamethasone for acute-phase coverage.

The current meta-analysis has implications for future antiemetic studies. Although dexamethasone is not approved as an antiemetic in the United States, its demonstrated efficacy would strongly argue for its incorporation into studies evaluating new antiemetic approaches. The use of dexamethasone would undoubtedly complicate trial design. Nevertheless, the current meta-analysis strengthens the scientific and ethical imperative to incorporate dexamethasone into future trials evaluating new antiemetic approaches for patients receiving moderately or highly emetogenic chemotherapy.


   APPENDIX Studies Rejected After Screening
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Studies Rejected After...
APPENDIX Cont’d
 REFERENCES
 
1. Aapro MS, Alberts DS: High-dose dexamethasone for prevention of cis-platin-induced vomiting. Cancer Chemother Pharmacol 7:11-14, 1981

2. Al-Ghamdi MS, Ibrahim EM, al-Idrissi HY, et al: Antiemetic efficacy of cimetidine randomized, double-blind, crossover study with dexamethasone in cancer patients receiving emetogenic chemotherapy. Ann Oncol 2:517-518, 1991

3. Allan SG, Cornbleet MA, Warrington PS, et al: Dexamethasone and high dose metoclopramide: Efficacy in controlling cisplatin induced nausea and vomiting. BMJ (Clin Res Ed) 289:878-879, 1984

4. Allan SG, Farquhar DF, Harrison DJ, et al: Anti-emetic efficacy of dexamethasone in combination for out-patients receiving cytotoxic chemotherapy. Cancer Chemother Pharmacol 18:86-87, 1986


   APPENDIX Cont’d
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Studies Rejected After...
 APPENDIX Cont’d
REFERENCES
 
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10. Cassileth PA, Lusk EJ, Torri S, et al: Antiemetic efficacy of dexamethasone therapy in patients receiving cancer chemotherapy. Arch Intern Med 143:1347-1349, 1983

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APPENDIX Cont’d
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40. Sismondi P, Danese S, Giardina G, et al: Antiemetic efficacy of granisetron in patients with gynecological malignancies. Anticancer Drugs 8:225-230, 1997

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

42. Sorbe BG: Tropisetron (Navoban) alone and in combination with dexamethasone in the prevention of chemotherapy-induced emesis: The Nordic experience. Semin Oncol 21:20-26, 1994 (5 suppl 9)

43. Sorbe BG, Hogberg T, Glimelius B, et al: Navoban (tropisetron) alone and in combination with dexamethasone in the prevention of chemotherapy-induced nausea and vomiting: The Nordic experience—The Nordic Antiemetic Trial Group. Anticancer Drugs 6:31-36, 1995 (suppl 1)

44. Sumer T, Abu-Melha A, Maqbool G, et al: Dexamethasone as an antiemetic in children receiving cisplatinum. Am J Pediatr Hematol Oncol 10:126-128, 1988

45. Tonato M: Ondansetron plus dexamethasone: An effective combination in high-dose cisplatin therapy. Eur J Cancer 27:S12-S14, 1991 (suppl 1)

46. Van Belle SJ, Cocquyt VF, Bleiberg H, et al: Optimal combination therapy with Navoban (tropisetron) in patients with incomplete control of chemotherapy-induced nausea and vomiting: The Belgian Navoban Group. Anticancer Drugs 6:22-30, 1995 (suppl 1)

47. Williams CJ, Davies C, Raval M, et al: Comparison of starting antiemetic treatment 24 hours before or concurrently with cytotoxic chemotherapy. BMJ 298:430-431, 1989

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   ACKNOWLEDGMENTS
 
Supported in part by an unrestricted grant from Pfizer, Inc, New York, NY.

We thank Christopher H. Schmid, PhD, for performing the hierarchical model control-rate metaregression analyses.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Studies Rejected After...
 APPENDIX Cont’d
 REFERENCES
 
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Submitted February 9, 2000; accepted June 6, 2000.




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