Preventing Delayed Nausea with Continued Dexamethasone and Ondansetron
ABSTRACT & COMMENTARY
Synopsis: Delayed nausea and/or vomiting after chemotherapy remains a problem for cancer patients. This is particularly true for those who experience nausea and vomiting within the first 24 hours after chemotherapy. In this clinical trial, dexamethasone, alone or in combination with ondansetron, was shown to reduce the delayed onset of nausea and vomiting in patients in whom initial control (i.e., during the first 24 hours after chemotherapy) had been successful. It is also suggested that these drugs reduced nausea and vomiting in higher risk patients (those who experienced nausea and vomiting during the first 24 hours after chemotherapy), but this approach was not effective for the majority of patients. Clearly, the best way to prevent delayed nausea and vomiting is to effectively prevent these symptoms from occurring initially (within the first 24 hours after chemotherapy). Sustained ondansetron and dexamethasone treatment may provide additional benefit.
Source: The Italian Group for Antiemetic Research.N Engl J Med 2000;342:1554-1559.
Optimal treatment to prevent delayed nausea and vomiting 2-5 days after chemotherapy remains to be established. To address this question, the Italian Group for Antiemetic Research performed a randomized prospective trial in which 705 patients were treated with either dexamethasone, ondansetron, both, or neither (placebo) during days two through five after chemotherapy.
The research design was as follows: patients receiving moderately emetogenic chemotherapy (e.g., cyclophosphamide, doxorubicin, epirubicin, or carboplatin) were studied during their first treatment cycle. If the chemotherapy included more highly emetogenic agents, such as cisplatin or dacarbazine, they were not eligible. Enrolled patients were treated with ondansetron (8 mg, IV) and dexamethasone (8 mg, IV) just prior to chemotherapy. In addition, patients received oral dexamethasone (4 mg) prior to and every six hours after chemotherapy for a total of four doses. The effectiveness of this regimen was determined at 24 hours and, based upon this determination, patients were divided into two groups: those without moderate-severe nausea or vomiting (low risk for delayed nausea and vomiting) and those who had developed moderate to severe nausea or vomiting (high risk for delayed nausea and vomiting).
Those in the low-risk group (n = 618) were randomly assigned to one of three treatment arms to prevent delayed nausea or vomiting. For days two through five after chemotherapy, they received either 4 mg of dexamethasone twice daily, a combination of 4 mg dexamethasone and 8 mg ondansetron twice daily, or placebo. Patients in the high-risk group (n = 87) received either the dexamethasone or the dexamethasone/ondansetron combination at the same doses, but there was no placebo arm. Episodes of nausea and vomiting were recorded on daily diary cards for a total of nine days.
Among the 618 patients in the low-risk group, there was a complete absence of moderate-severe nausea or vomiting in 91.8% for those receiving the combination of ondansetron and dexamethasone, and in 87.4% of those receiving the dexamethasone alone. Both treatments resulted in significantly less delayed nausea and/or vomiting when compared to placebo, in which there was no nausea or vomiting present in 76.8% (P < 0.001 and P < 0.02, respectively). Of the 87 patients in the high-risk group, complete protection was achieved in 40.9% in those treated with ondansetron and dexamethasone and in 23.3% of those treated with dexamethasone alone. The difference between the two treatment groups was not statistically significant.
The authors conclude that the best way to prevent delayed nausea and vomiting is to effectively control those symptoms in the first 24 hours. Thereafter, for those who did not experience first-day nausea or vomiting, delayed nausea and vomiting can be reduced significantly by dexamethasone alone.
COMMENT BY WILLIAM B. ERSHLER, MD
Oncologists have not reached consensus on the optimal pharmacologic regimen to prevent delayed nausea and vomiting after chemotherapy. This report from the Italian Group for Antiemetic Research published in the widely read New England Journal of Medicine may be useful in helping us standardize our approach. It will be recalled that this same group demonstrated the effectiveness of the ondansetron/dexamethasone combination in preventing acute (first-day) nausea and vomiting.1 The success of this initial treatment is critical. For those who escape the first 24 hours without nausea or vomiting, it appears that 75% (e.g., those on the placebo arm) will not develop delayed nausea or vomiting. However, this means that in 25%, delayed nausea and vomiting develop even though prevented in the immediate post-chemotherapy period. It appears that treatment with either ondansetron/dexamethasone or dexamethasone alone can reduce this occurrence by 50% or more.
For those in whom initial nausea prophylaxis was unsuccessful, delayed nausea and/or vomiting developed in the majority, despite ondansetron and/or dexamethasone. In fact, because there was no placebo group, it cannot be concluded from the current study that treatment with these agents was successful at all in reducing delayed nausea. A larger study might have demonstrated superiority of the ondansetron/dexamethasone combination compared to dexamethasone alone, but such a conclusion is not possible from this report. Hopefully, new agents or approaches will become available that will improve the success rate. As these are developed, they probably should be compared in a careful clinical trial, such as this one, with ondansetron/dexamethasone as it remains unlikely that a placebo arm could be ethically introduced into such a clinical design. Until new agents or combinations are proven better, the ondansetron/dexamethasone combination may be considered standard therapy in this clinical setting.
Reference
1. The Italian Group for Antiemetic Research.N Engl J Med 1995;332:1-5.
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