Controlling delayed vomiting: double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin.

Summary This randomized, double-blind, double-dummy parallel study compared the anti-emetic efficacy and tolerability of the serotonin antagonist granisetron with prednisolone plus the dopamine D 2 antagonist metopimazine during nine cycles of moderately emetogenic chemotherapy. Chemotherapy naive women with stage I or II breast cancer scheduled to intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin and fluorouracil every 3 weeks were included. Patients received a single intravenous dose of granisetron 3 mg or a 3-day oral treatment with prednisolone 25 mg once a day plus metopimazine 30 mg four times a day. A total of 223 women were enrolled and 218 patients (97.8%) were evaluable for efficacy. Granisetron (n = 109) was superior to prednisolone plus metopimazine (n = 109) in the prophylaxis of acute nausea and vomiting during the first cycle of chemotherapy (P < 0.001) and prednisolone plus metopimazine was superior on days 2-5 (P = 0.002). Overall, granisetron was superior on days 1-5 (P = 0.009). The median number of cycles completed with granisetron was five (95% confidence interval 4-6) compared with two (95% confidence interval 2-2) for prednisolone plus metopimazine (P = 0.0019). Constipation and rash were reported more frequently with granisetron (P < 0.001 and P = 0.043 respectively) and palpitations more frequently with prednisolone plus metopimazine (P = 0.015). In conclusion, the number of cycles completed with granisetron was significantly higher than the number completed with prednisolone plus metopimazine, but the anti-emetic efficacy of both treatments declined during multiple cycles of moderately emetogenic chemotherapy.

Section: Discussionsupporting

confidence: 80%

Granisetron compared with prednisolone plus metopimazine as anti-emetic prophylaxis during multiple cycles of moderately emetogenic chemotherapy

Sigsgaard

Herrstedt

et al. 1999

“…Furthermore, they have an improved safety profile. There is now evidence indicating that the addition of a corticosteroid to ondansetron further enhances its efficacy in the acute phase (Roila, 1991;Smyth, 1991), although to date there are no similar data for granisetron.The management of delayed emesis, however, remains less than satisfactory with existing therapies, with around 50% of patients remaining uncontrolled (Kris, 1989). The combination of metoclopramide and dexamethasone has been shown to be better than either dexamethasone or placebo (Kris, 1989;Moreno, 1992).…”

mentioning

confidence: 99%

“…The management of delayed emesis, however, remains less than satisfactory with existing therapies, with around 50% of patients remaining uncontrolled (Kris, 1989). The combination of metoclopramide and dexamethasone has been shown to be better than either dexamethasone or placebo (Kris, 1989;Moreno, 1992).…”

mentioning

confidence: 99%

Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis

Carmichael

Bessell²,

Harris³

et al. 1994

Summary Two hundred and seventy-eight adult chemonaive patients receiving moderately emetogenic chemotherapy were randomly allocated to receive either intravenous (i.v.) granisetron 3 mg plus i.v. dexamethasone 8 mg or i.v. granisetron 3 mg plus i.v. placebo dexamethasone prior to chemotherapy. Eighty-two per cent of all patients recruited were female, and 91% of all patients consumed less than 10 units of alcohol per week, suggesting a study population with an increased risk of nausea and vomiting. In the first 24 h 85% of patients who received granisetron plus dexamethasone were complete responders compared with 75.9% of the patients receiving granisetron alone (P = 0.053). There were statistically significant improvements in complete response over 7 days (P = 0.029) and in the numbers of patients receiving rescue antiemetic (P = 0.0004). Toxicity was minimal with no significant differences between treatment groups. These results confirm the antiemetic activity of granisetron and show that it has an additive effect in combination with dexamethasone.As single agents the 5HT3 antagonists granisetron (Marty, 1992;Chevallier, 1993) ondansetron (De Mulder, 1990) and tropisetron (De Bruijn, 1992) have been shown to be at least as effective as conventional treatments in controlling the acute nausea and vomiting experienced by patients receiving highly emetogenic chemotherapeutic regimens. Furthermore, they have an improved safety profile. There is now evidence indicating that the addition of a corticosteroid to ondansetron further enhances its efficacy in the acute phase (Roila, 1991;Smyth, 1991), although to date there are no similar data for granisetron.The management of delayed emesis, however, remains less than satisfactory with existing therapies, with around 50% of patients remaining uncontrolled (Kris, 1989). The combination of metoclopramide and dexamethasone has been shown to be better than either dexamethasone or placebo (Kris, 1989;Moreno, 1992). However, the place of 5HT3 antagonists in the management of delayed emesis is as yet unclear. Indeed, oral ondansetron alone has not been demonstrated to be superior to either dexamethasone (Jones, 1991) or metoclopramide (De Mulder, 1990). The objective of this study was therefore to compare the safety and efficacy of intravenous granisetron plus dexamethasone phosphate with that of intravenous granisetron alone in the prevention of both acute and delayed emesis induced by moderately emetogenic cytotoxic chemotherapy. Patients and methods Study designThe study was a double-blind, randomised, parallel group study carried out at 18 centres in the UK. Patients gave their witnessed written or verbal informed consent to participate in the study and were informed that they were free to withdraw at any time. The Cytotoxic chemotherapy regimens Patients received at least one of the following cytotoxic drugs: carboplatin > 300 mg m2, cisplatin 20-50 mg dacarbazine 350-500 mg m-2, cyclophosphamide > 500 mg m 2 (in combination), doxorubicin>40 mg m2 (single agent), doxoru...

“…During highly emetogenic chemotherapy, there is a synergistic antiemetic effect of corticosteroids and metoclopramide or 5-hydroxytryptamine (5-HT3) receptor antagonists (Kris et al, 1989;Smith et al, 1991). Recently we reported that nausea during chemotherapy with low emetic potential was inversely related to urinary cortisol excretion (Fredikson et al, 1992 Patients rated their nausea during the past 24 h at the morning of the first and second day after the cisplatin infusion by choosing one of four alternatives ranging from none to severe nausea.…”

mentioning

confidence: 99%

Endogenous cortisol exerts antiemetic effect similar to that of exogenous corticosteroids

Hursti

Fredrikson²,

Steineck³

et al. 1993

Summary Lower pre-chemotherapy night time cortisol excretion predicted more severe cisplatin induced nausea and vomiting in 42 ovarian cancer patients receiving ondansetron as a single antiemetic agent. Dexamethasone administration added to the antiemetic effect of ondansetron principally in patients who had low excretion of cortisol.Corticosteroids as single antiemetic agents have a well documented effect on mild to moderate chemotherapy induced emesis (Cassileth et al., 1983). During highly emetogenic chemotherapy, there is a synergistic antiemetic effect of corticosteroids and metoclopramide or 5-hydroxytryptamine (5-HT3) receptor antagonists (Kris et al., 1989;Smith et al., 1991). Recently we reported that nausea during chemotherapy with low emetic potential was inversely related to urinary cortisol excretion (Fredikson et al., 1992 Patients rated their nausea during the past 24 h at the morning of the first and second day after the cisplatin infusion by choosing one of four alternatives ranging from none to severe nausea. At the first morning patients also used a 100 mm visual analog scale (VAS) to report the severity of nausea. A zero score is anchored at the left end with 'no nausea at all' and a maximum score of 100 'worst possible nausea'. Emetic episodes (vomiting or retching) were recorded by patients during both days.In the statistical analyses patients responding with 'no' or 'mild' nausea were treated as one group and those responding 'moderate' or 'severe' nausea formed the other group. Regarding the emetic episodes, patients with complete or major response ( <2 emetic episodes) formed one group whereas minor response and failure (> 3 emetic episodes) formed the other group. A median split approach was used to form groups with relatively high and low cortisol excretion. Relative risk was used to describe the association between urinary cortisol levels and nausea and vomiting. Relative risk was calculated as the ratio between the proportions of patients with moderate or severe nausea, or > 3 emetic episodes in respective groups of interest. Calculation of 95% confidence intervals was performed as described by Greenland & Robins (1985). Student's t-test with one-tailed P-values was used to analyse VAS-ratings of nausea and the total number of emetic episodes. ResultsThe median used to form groups high and low in cortisol excretion was 23.2pmolmin-'. The high and low excretion group had a mean (standard error of the mean) of 38.7 (2.5) and 16.5 (0.9) pmol min-', respectively. The groups did not differ concerning the percentage of 1-vs 2-day chemotherapy course (chi2 = 0.12, P = 0.73). The mean cortisol excretion in patients receiving dexamethasone was 28.8 pmol min-' and in those receiving placebo 25.8 pmol min-' (t (40) = 0.68, P = 0.50). Evaluating the importance of age for the studied variables, patients were categorised by their median age (50 years). No significant association was found between patient's age, cortisol excretion, nausea intensity or emetic episodes (t (40)<1.12, chi2 (1)<0.54, ...