Jul 24, 1996 - Maurie Markman 9 Alexander Kennedy. Kenneth Webster 9 Gertrude Peterson 9 Barbara Kulp. Jerome Belinson. Low-dose intravenous ...
J Cancer Res Clin Oncol (1997) 123:224-226
9 Springer-Verlag 1997
Maurie Markman 9 Alexander Kennedy K e n n e t h W e b s t e r 9 G e r t r u d e P e t e r s o n 9 B a r b a r a Kulp Jerome Belinson
Low-dose intravenous ondansetron (8 mg) plus dexamethasone: an effective regimen for the control of carboplatin-induced emesis
Received: 24 July 1996 ! Accepted: 29 January 1997 A b s t r a c t Twenty-nine patients with gynecologic malignancies were treated with a fixed low dose of intravenous ondansetron (8 mg) plus dexamethasone (20 mg) in an effort to develop an effective and less expensive antiemetic regimen for the control of carboplatin-induced emesis. Twenty-six (90%) of the women participating in this trial experienced complete control of both acute nausea and vomiting (developing within the first 24 h after chemotherapy administration), while 27 (93%) patients exhibited either complete or major control (--250 mg/m2 or a calculated AUC (area-under-the concentration-versus-time curve) of -- 4.
225 Antiemetic regimen
(range: 4 9 - 1 2 9 kg). Five patients (17%) weighed ->90 kg at the time of trial initiation.
Patients treated on this trial received the following antiemetic regimen: (a) ondansetron 8 mg intravenously over 15 minutes, and (b) dexamethasone 20 mg intravenously over at least 5 min, given together 30 min prior to the initiation of the carboplatin infusion. All individuals participating in this study were evaluated during Antiemetic efficacy only a single course of chemotherapy.Patients were requested to record the number of emetic episodes (both vomiting and retching) which Twenty-six individuals (90%) treated on this trial experiwere experienced during the 24 hours following the completion of enced complete control of both nausea and vomiting. chemotherapy. Twenty-seven patients (93%) demonstrated either complete Approximately 24 h after treatment the patient received a telephone call from a research nurse inquiring as to the number of emetic events or major control emesis. In contrast, only two patients (7%), and the severity of nausea. Treatment-related side effects were also were noted to have achieved inadequate control of nausea documented during this telephone call. In addition, patients were asked and vomiting during the first 24 h after chemotherapy about their requirement for "breakthrough" antiemetic medications administration. One individual did experience some degree (e. g., prochlorperazine) during the 24-h period following chemoof delayed emesis (either nausea or vomiting) which began therapy. > 24 h after completion of chemotherapy. Antiemetic response criteria Complete control of vomiting/nausea: No episodes of vomiting or nausea over 24 h following chemotherapy. Major control of vomiting: -- 2 episodes of vomiting or 2 episodes of vomiting or >5 episodes of retching (without vomiting) over 24 h following chemotherapy. Inadequate control of nausea: Major interference with eating (as judged by the patient) over 24 h following chemotherapy.
Results Patient population A total of 29 women (median age: 66; range 38-80) with gynecologic cancers (18 ovary, 4 endometrial, 1 cervix, 6 primary papillary carcinoma of the peritoneum) participated in the evaluation of this ondansetron/dexamethasone antiemetic program. Of the 29 patients, 16 (55%) were previously unexposed to cytotoxic chemotherapy, while 13 women had received prior therapy (9 cisplatin-based and 4 carboplatin-based). For the patients who had previously received chemotherapy the median duration off treatment was 16 months (range 4 - 1 0 6 months) before entry onto this protocol. All but one individual participating in this trial had their carboplatin dose calculated based on AUC, rather than body surface area. Thirteen patients (45%) received a calculated AUC of 4, while 15 (52%) women were treated with a carboplatin AUC of 5. One individual was treated with a dose of carboplatin of 300 mg/m a. Ten patients received single agent carboplatin, while 19 women were treated with a carboplatin-paclitaxel combination regimen. Six and 13 patients received paclitaxel at a dose of 135 mg/m 2 or 175 mg/m 2, respectively. As a fixed dose of ondansetron was employed in this study, it is important to note the weights of the women participating in this study. The median weight was 65 kg
Antiemetic regimen side effects In the 29 patients participating in this phase 2 trial, there were no reported side effects for which the antiemetic regimen could be considered directly responsible. In particular, headache was not noted by any patient.
Discussion The emetogenic potential of carboplatin is well established, both in animal models (Rose and Schurig 1985), and in patients (Calvert et al. 1982; Alberts et al. 1992; Swenerton et al. 1992; Martin et al. 1990). In the initial trials of carboplatin the majority of patients administered the drug at dose levels > 120 mg/m 2 demonstrated some level of nausea or vomiting, even though antiemetic treatment (lorazepam and metoclopromide) was provided (Calvert et al. 1982). In a more recent report involving 28 patients (Martin et al. 1990), the potential severity of carboplatin-induced emesis was stressed. In this study, where prophylactic antiemetic therapy was not provided, 82% and 89% of these patients developed vomiting or nausea, respectively. However, of interest, the nausea and vomiting caused by carboplatin is generally acute, and delayed emesis has been observed to be less of a problem with this cytotoxic drug than its parent compound, cisplatin (Calvert et al. 1982). As the serotonin receptor antagonists have been shown to be principally effective in the prevention of the acute nausea and vomiting associated with cisplatin administration (Grunbert and Hesketh 1993; DeMulder et al. 1990), they are potentially ideal agents to employ in the management of emesis induced by carboplatin. The clinical utility of this approach in patients treated with carboplatin has been demonstrated in a limited number of prior studies (Harvey et al. 1991; Markman et al. 1996). This favorable experience has been extended by the results of the current trial in which > 9 0 % of treated women experienced either complete or major control of acute
226 emesis, with no evidence of significant side effects o f the antiemetic regimen. Unfortunately, the serotonin receptor antagonists are quite expensive, and concern has been raised about the cost o f antiemetic therapy when relatively high doses o f these drugs are e m p l o y e d (Chapman and Pruemer 1993; Peters et al. 1993). In the current trial We have shown that a regimen of dexamethasone plus a low dose o f intravenous ondansetron (8 mg) is effective antiemetic prophylaxis for carboplatin-based chemotherapy. At retail pharmacies in Northeast Ohio, 8 m g of intravenous ondansetron currently (July 1996) costs $ 47.00. As 20 m g o f dexamethasone only costs $ 1.00, this combination antiemetic regimen will cost < 50.00. Pharmacy preparation, treatment administration solutions, and nursing time charges will increase the expenses associated with this treatment program. However, considering the actual costs of the chemotherapy drugs, the expenditure for this antiemetic program would appear to be quite reasonable. It is unknown at present if an even lower dose of ondansetron ( 4 - 6 mg) might provide equivalent antiemetic protection, at even lower cost, for patients receiving carboplatin-based chemotherapy. It would be appropriate for a future clinical trial to examine such an antiemetic treatment strategy. It might even be reasonable to test single agent dexamethasone alone in this clinical setting.
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