Efficacy of Oral Ondansetron, A Selective Antagonist of 5-HT3 Receptors, in the Treatment of Nausea and Vomiting Associated with Cyclophosphamide-Based Chemotherapies

Different cytotoxic drugs induce different patterns of emesis. This is relevant to clinical practice since we often see in the medical literature oversimplifications in the recommendation for management of chemotherapy-induced emesis, so that the same guidelines are given for cisplatin and non-cisplatin-containing chemotherapy. In particular, cisplatin induces a biphasic pattern of emesis which is characterized by an acute immediate phase and a delayed phase. These two phases are clearly different, especially when cisplatin is given in short i.v. administration (e.g. over 20 min to 1 h) and in high doses (100–120 mg/m²). On the other hand, cyclophosphamide and carboplatin induce a quite different pattern of emesis, characterized by a monophasic curve which, although more intense in the first 24 h, may continue for a number of days. The antiemetic response to 5-HT₃ receptor antagonists on days 2–5 is good in the case of carboplatin and cyclophosphamide and poor in the case of cisplatin (delayed emesis after cisplatin). This firmly suggests that the pathogenesis of cisplatin-induced emesis may differ from that induced by other cytotoxic drugs, especially in the delayed phase of emesis. We think that we should reserve the term ‘delayed emesis’ for the late emesis induced by cisplatin, while ‘prolonged emesis’ could be a better denomination for the late emesis induced by cyclophosphamide and carboplatin. The main clinical implication of these observations is that 5-HT₃ receptor antagonists should be administered over 3–5 days in the case of carboplatin and cyclophosphamide, while a short treatment during the first day could be sufficient to control the acute phase of cisplatin-induced emesis.

Section: Cyclophospham Ide-induced Em Esismentioning

confidence: 83%

The Severity and Pattern of Emesis following Different Cytotoxic Agents

Martín¹

1996

“…In the absence of prophylactic therapy, emesis and nausea which may be prolonged over several days are a problem in 70-90% of patients [5], The introduction of the first 5HTi receptor antagonist, ondansetron, has significantly improved the control of emesis and consequent QOL in this patient group [8][9][10][11], More recently, the introduction of other 5HTi receptor antagonists such as granisetron has provided the clinician with a choice of agents. However, until now, comparative data in patients receiving non-cisplatin chemotherapy have been limited to open, crossover studies in heteroge neous groups of patients [15][16][17], The open study designs in particular may have led to bias in subjective assess ments such as patient preference.…”

Section: Discussionmentioning

confidence: 99%

“…Associated emesis is a problem in 70-90% of patients [5] and prolonged emesis may persist for several days [6], adversely affecting the quality of life (QOL). In addition, poorly controlled emesis and nausea often lead to patients experiencing anticipatory emesis during subse quent chemotherapy courses and may result in premature termination of potentially curative treatment [7], Ondansetron, the first serotonin (5HT-0 receptor an tagonist to be approved for use throughout Europe and North America, is effective in controlling the emesis asso ciated with cyclophosphamide over a period of up to 5 days, both during the first course of treatment and over a series of treatment courses [8][9][10][11], Granisetron, another 5HTy receptor antagonist, is also effective in the control of non-cisplatin-chemotherapyinduced emesis [12,13], However, until recently, it was available only in intravenous (i.v.) form and oral therapy in the prophylaxis of prolonged emesis (beyond the first 24 h) in out-patients following non-cisplatin chemothera py remains to be established.…”

Section: Introductionmentioning

confidence: 99%

Ondansetron Compared with Granisetron in the Prophylaxis of Cyclophosphamide-lnduced Emesis in Out-Patients: A Multicentre, Double-Blind, Double-Dummy, Randomised, Parallel-Group Study

Stewart

McQuade²,

Cronje

et al. 1995

This is the first double-blind clinical trial in a homogenous group of patients to compare the recommended dosing schedules of ondansetron and granisetron in the control of prolonged emesis after cyclophosphamide-containing chemotherapy (48% CMF, 35% EC) for breast cancer. A total of 514 patients were recruited. Of the 488 patients included in the intent-to-treat analyses, 167 were randomised to group A [8 mg ondansetron intravenously (i.v.) + placebo by mouth (p.o.) before chemotherapy + 8 mg ondansetron p.o. twice daily (b.d.) until day 5], 155 to group B (placebo i,.v. + 8 mg ondansetron p.o. before chemotherapy + 8 mg ondansetron p.o. b.d. until day 5) and 166 to group C (3 mg granisetron i.v. + placebo p.o. before chemotherapy + placebo p.o. b.d. until day 5). On study day 1, the groups were comparable with respect to the proportion of patients experiencing up to 2 emetic episodes (group A: 89%; B: 86%; C: 91%) and in the severity of nausea (no nausea; group A: 51%; B: 55%; C: 54%). Over the 5-day study period significantly more patients were rescued or withdrawn due to lack of response after the granisetron regimen (26%) than after the i.v. + p.o. ondansetron regimen (11%; p < 0.001). Since there was no difference in these parameters on day 1, this reflects differences on days 2-5 and was also reflected in the all-oral ondansetron group over this period (group B: 12%; C: 22% on days 2-5). A significant difference in the severity of nausea after i.v. and p.o. ondansetron compared with granisetron was also observed over the 5-day study period (p = 0.009). This was reflected in a numerical difference in favour of the all-p.o. ondansetron regimen compared with the granisetron regimen (no nausea; group A: 33%; B: 34%; C: 25%). Again these differences reflected differences in nausea control on days 2-5, since no differences were observed on day 1. Logistic regression analyses adjusted for prognostic factors also revealed a significant difference (p = 0.011) in favour of the i.v. + ondansetron group compared with the granisetron group when complete plus major response was compared over days 2–5. No significant differences in the safety profiles of the three treatment groups were observed. There were no severe or unexpected drug-related adverse events and as is well established for the serotonin receptor antagonists, mild constipation (mean 8%) and mild headache (mean 8%) were most commonly reported.

“…Two randomized, double-blind, placebo-controlled oral ondansetron dose finding studies (ondansetron 1, 4 or 8 mg 3 times/day) in patients receiving intravenous cyclophosphamide-based chemotherapy have recently been published [14,15]. Patients received cyclophospha mide plus either doxorubicin or methotrexate with or without additional low to moderately emetogenic chemo therapy.…”

Section: Standard Intravenous Dose Cyclophosphamidementioning

confidence: 99%

Optimal Control of Cyclophosphamide-lnduced Emesis

Stewart¹

1996

Cyclophosphamide induces moderate to severe emesis. The severity of emesis is dependent on the dose of cyclophosphamide and on the addition of other cytotoxic drugs. A review of the literature dividing studies according to the dose of cyclophosphamide and the specific cytotoxic combination shows that ondansetron plus dexamethasone provides optimal antiemetic therapy in patients receiving standard or high-dose cyclophosphamide ( ≥450 mg/m²). These studies also show that it is important to give antiemetic therapy to cover the prolonged duration emesis and nausea induced by these regimens, e.g. intravenous CMF/(F)AC/(F)EC. For continuous ‘oral’ (low-dose) CMF chemotherapy, oral ondansetron or oral metoclopramide plus intravenous (or possibly oral) dexamethasone are effective antiemetic therapies.