1 Institut Multidisciplinaire dOncologie, Clinique de Genolier, Vaud; 2 Department of Medicine C, Kantonsspital, Sankt Gallen; 3 Istituto Oncologico Cantonale, Ospedale San Giovanni, Bellinzona; 4 Division dOncologie, Hôpital Cantonal Universitaire, Genève; 5 Swiss Institute for Applied Cancer Research Coordinating Centre, Bern, Switzerland
Received 4 March 2002; revised 20 September 2002; accepted 22 October 2002
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Abstract |
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The prophylactic use of 5-HT3 receptor antagonists (setrons), after the first 24 h (acute phase) of exposure to emetic chemotherapy, to decrease the incidence of delayed phase emesis increases costs. We designed a study to evaluate the efficacy of a setron (granisetron) in the delayed phase, compared with metoclopramide, each combined with a corticosteroid.
Patients and methods:
Patients on their first course of single-day emetic chemotherapy (cisplatin, carboplatin, doxorubicin, cyclophosphamide and others) received granisetron 2 mg p.o. and dexamethasone 8 mg p.o. on day 1, followed for 5 days by dexamethasone 4 mg p.o. od combined with either metoclopramide 20 mg p.o. tds or granisetron 1 mg bd in a double-blinded double-dummy protocol. Patients evaluated the results using a diary card. Randomization was stratified by institution, sex, emetic chemotherapy naïve versus previous, alcohol consumption and platinum versus non-platinum regimen.
Results:
131 evaluable patients received granisetron in the delayed phase, and 127 received metoclopramide. Control of acute emesis in both arms was similar (86% granisetron; 85% metoclopramide). The 35 patients experiencing acute emesis had poor control in the delayed phase, with only four granisetron and three metoclopramide patients having no or mild nausea and no vomiting.
Conclusions:
In daily practice, a combination of oral dexamethasone and oral granisetron achieves an extremely high control of acute emesis (86% protection). Our data suggest that routine prescription of setrons for delayed phase control is not advisable as it increases costs without any benefit for the majority of patients. Delayed emesis in the rare patients with acute phase emesis remains an unsolved problem.
Key words: acute, delayed, dexamethasone, granisetron, nausea, vomiting
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Introduction |
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With this background, the Swiss Group for Clinical Cancer Research (SAKK) designed a study to evaluate the efficacy of a setron in the delayed emesis phase, compared with metoclopramide, both agents being combined with a corticosteroid. Patients receiving moderately to highly emetic cytotoxic agents were given oral granisetron and oral dexamethasone on the day of chemotherapy and then randomly assigned to one of two oral treatments for the prevention of delayed emesis: dexamethasone with either granisetron or metoclopramide. This trial was activated on 28 May 1996 and closed for patient accrual on 30 April 1999. The main end point of the trial was to compare the clinical efficacy and safety of granisetron and metoclopramide in combination with dexamethasone in the prophylaxis of delayed nausea and vomiting induced by emetic cancer chemotherapy. This final report gives a complete analysis, and is based on information from all 267 randomized patients.
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Patients and methods |
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The main end point of the trial was control of emesis, defined as only the most mild nausea (not interfering with normal daily life) and no vomiting over the period of 5 days after emetic chemotherapy. The primary evaluation of this main end point was restricted to the group of patients with control of acute emesis (for 1824 h after treatment), but an intention-to-treat analysis irrespective of control of acute emesis was also planned.
Randomization by the minimization method was stratified by institution; sex; chemotherapy naïve versus previous chemotherapy; regular alcohol consumption (daily intake of >2 dl wine and/or >5 dl beer and/or >1 measure of spirits), yes versus no; and chemotherapy regimen, cisplatin or carboplatin versus others.
Statistics
The trial was planned to have a size that would be sufficient to detect an absolute difference of 20% in the rates of control between the two arms for the patients without acute phase emesis. It was calculated that a maximum of 270 patients without emesis in the acute phase was necessary to test such a difference with a two-sided significance level of 5% and 90% power. This number could be lower if the rate of control was markedly >50%. In order to account for 25% of patients having acute emesis, the sample size was raised to 360 patients. The analysis of the main end point was to be by intention-to-treat.
No formal interim analysis was planned in the protocol. Nevertheless, the trial team decided to perform one in March 1999, after randomization of 257 patients, because of a problem with the trial medication: the expiry date was 29 April 1999. The intention was to determine whether there was sufficient need to continue the trial to the planned accrual goal of 360 patients. If the chance of reaching a significant difference in the main outcome was remote, then there would not have been sufficient reason for investing more resources in the trial by preparing new trial medication.
The interim analysis showed that the differences between the two treatments were minimal and the formal interim test showed clearly that the continuation of the trial would have been extremely unlikely to lead to a difference of 20% between the treatment arms in terms of control, which could be detected with a power of 90%. After seeking the opinion of independent experts who concurred with our analysis, this led to the conclusion that the trial could be stopped safely without incurring any loss of information with regard to the research question posed in the protocol.
A second consideration justified stopping the trial at that time. The overall rate of control (~80%) was higher than anticipated at the time of planning the trial (6070%). This meant that the cautious approach to sample size estimation in the protocol could be revised, clarifying that not more than 230 evaluable patients without acute emesis were needed to test for a difference of 20% in control. Furthermore, taking into account that only 14% of all patients experienced acute emesis (not 25% as estimated in the protocol), the revised sample size would have been 267 fully evaluable patients [230 x 1/(10.14)], a number which was almost reached. In reality, 230 evaluable patients without acute emesis is a slight under-estimate, because only one interim analysis was carried out. The exact number would have been 238.
Several statistical tests were performed in a descriptive way. However, the primary evaluation of the main end point by the chi-square test was carried out in a formal way and took into account that interim testing affects the significance level of the final analysis. An -spending function was chosen according to the OBrienFleming procedure [5] with LandeMets boundaries [6]. This is a very conservative procedure and leads to early stopping only in a case with strong evidence that continuation is not warranted. The calculation was performed with the statistical package EaSt (1995, Cytel Corp, Cambridge, MA). Specifically, a post-hoc trial design was generated with EaSt allowing for one interim evaluation with early stopping in the case of either a statistically significant difference between the treatment arms or sufficient evidence that no statistical significance will be reached by proceeding up to the original target sample size. A significance level of 5% and a power of 90% for a chi-square test for the comparison of two proportions (80% versus 60%) were chosen as the basis for the evaluation of the main end point. The P value for partial control of delayed emesis in patients without acute emesis was 0.54, it was therefore concluded that the likelihood of reaching a statistically significant difference by including more patients was extremely small. It was therefore decided to stop the trial at the end of April 1999.
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Results |
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Patient characteristics
The distribution of parameters for stratification at randomization is shown in Table 1. Two patients were stratified wrongly because their chemotherapy regime was incorrectly specified on the eligibility form. Despite the exclusion of nine patients who had no data about delayed emesis, the stratification parameters were well balanced between the two treatment arms. Other patient characteristics are shown in Table 2.
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Diary cards
Out of the 258 patients, 250 (97%) returned the diary card to the Coordinating Center. The diary card of one patient had to be discarded because the patient did not fill in the card himself. From the remaining 249 patients, 58 did not answer all the questions, and 191 (77%) returned a complete diary.
Acute emesis
Table 3 shows the rate of acute emesis on day 1, as reported by the patients on the diary card (one patient provided no information). Thus the rate of acute emesis (14% severe nausea or vomiting) was lower than the 2025% anticipated in the protocol, confirming the high degree of protection from acute emesis obtained with a setron and a corticosteroid combination previously reported by others [1].
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Discussion |
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Our study does not allow one to conclude with confidence regarding a lack of difference between the approaches in patients who had nausea and vomiting on day 1, as the numbers are small. However, other studies have not shown any superiority of the addition of a setron to dexamethasone for these patients [7, 8]. The Italian Group for Antiemetic Research has shown that for patients receiving cisplatin-based chemotherapy who have no acute emesis metoclopramide and ondansetron are of similar efficacy during the delayed phase [7]. In those patients who had acute emesis ondansetron prevented delayed emesis in only 29% of cases, compared to 4% for metoclopramide. However, if one accounts for severe nausea, no difference is observed between the arms during the delayed phase.
In patients undergoing moderately emetic chemotherapy who experienced acute emesis the Italian Group compared oral placebo to oral ondansetron 8 mg, both combined with dexamethasone 4 mg p.o. bd, on days 25 after the start of chemotherapy [8]. The delayed complications were prevented in 18 of the 44 patients taking the combination of the two drugs (41%) and in 10 of the 43 patients on dexamethasone alone (23%). The authors concluded, as we do, that the best choice for preventing delayed nausea and vomiting in patients at high risk for these complications remains to be identified. Other papers offer contradictory results in the field, but they were not prospectively designed to take into account the influence of acute emesis on the rate of control of delayed emesis [1, 9].
Many patients in our study had moderately emetic chemotherapy and an excellent rate of acute control with granisetron 2 mg and dexamethasone. However, emerging data indicate that a 1 mg granisetron oral dose may be sufficient for such patients [10]. The 8 mg dose of dexamethasone used in this study for acute emetic control might be too low for patients receiving cisplatin-based chemotherapy, where 20 mg has been suggested as a standard [11]. However, for the majority of our patients this combination was excellent, with an 84% acute control rate. The doses of dexamethasone and metoclopramide used in this study are not those suggested by other authors for use with cisplatin-based chemotherapy [12]. They are based on a clinical practice consensus, but may be less effective than the doses others have suggested. Should this be the case, it would only reinforce our main message: setrons are of very limited value in control of delayed nausea and vomiting.
The routine prescription of setrons for delayed phase control is not advisable as it increases costs without any benefit for the majority of patients. Patients should be offered a combination of a corticosteroid and metoclopramide, for a duration which has not yet been firmly established as it varies from 3 to 5 days among the available studies. Delayed emesis in the rare patients with acute phase emesis remains an unsolved problem. The development of neurokinin-1 receptor antagonists might be of major importance in this setting [13].
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Acknowledgements |
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Footnotes |
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References |
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3. Perez EA, Hesketh P, Sandbach J et al. Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study. J Clin Oncol 1998; 16: 754760.[Abstract]
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