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'." Br. J. Cancer (I991), 63, 942 944 Br. J. Cancer (1991), 63, 942-9~~~~~~~~~ Macmillan Press Ltd., 1991 © Macmillan Press Ltd., 1991~~~~~~ Reduction of carboplatin induced emesis by ondansetron V.J. Harvey', B.D. Evans', P.L.R. Mitchell', D. Makl, L.M. Neave', G.B. Langley2 & D.S.P. Dickson2 'Department of Clinical Oncology, Auckland Hospital, Auckland; 2Glaxo New Zealand Ltd, Palmerston North, New Zealand. Summary Ondansetron is a selective 5-HT3 antagonist with significant antiemetic properties in patients receiving cytotoxic chemotherapy. Patients who had suffered severe vomiting on carboplatin alone (23 patients with ovarian carcinoma) or in combination (two patients with testicular cancer) despite intensive antiemetic regimens were treated with ondansetron, given as 8 mg immediately prior to carboplatin followed by 8 mg orally, 8 hourly for 5 days. Twenty-five patients received 58 courses of ondansetron. In the first 24 h after the first course of chemotherapy with ondansetron, 17 patients (68%) experienced no vomiting, five patients (20%) had almost complete control and the other three patients had partial control. During the subsequent 4 days slightly lesser control was achieved. Nausea was similarly controlled in most patients. Twenty-two patients stated a preference for ondansetron with future chemotherapy. Fourteen patients received additional chemotherapy with ondansetron and in only three patients did the efficacy of therapy lessen. Toxicity was mild and transient with headache and constipation predominant. No extrapyramidal reaction was seen. Sedation was absent. Ondansetron is highly effective in refractory vomiting associated with carboplatin chemotherapy. It may be particularly beneficial when an extrapyramidal reaction has occurred on previous antiemetics and when sedation is unacceptable. Although carboplatin is significantly less emetogenetic than cisplatin, most patients experience some nausea and/or vomiting. For a proportion of patients emesis is severe, despite aggressive antiemetic regimens. Most such antiemetic regimens are based on moderate or high dose metoclopramide, often with dexamethasone and lorazepam in addition. These regimens may themselves cause distressing side effects, including extrapyramidal reactions and sedation. (Roila et al., 1989). Ondansetron, a selective 5-HT3 receptor antagonist, has shown considerable antiemetic activity in uncontrolled studies (Cunningham et al., 1987; Kris et al., 1988; Hesketh et al., 1989; Einhorn et al., 1990). In randomised studies it has been proven superior to both placebo (Cubeddu et al., 1990) and high dose metoclopramide (Marty et al., 1990) in controlling cisplatin induced emesis. In non-cisplatin containing chemotherapy regimens it has been shown superior to metoclopramide in four randomised studies (Schmoll, 1989; Kaasa et al., 1990). Vomiting after most chemotherapeutic agents tends to start within a couple of hours of treatment. The onset of vomiting after carboplatin, however, is often delayed for 6-1O h (Calvert et al., 1982) and there is no previous study of the effect of ondansetron on carboplatin induced vomiting. This paper reports our initial experience with ondansetron in patients treated with carboplatin, who had proven refractory to a previous aggressive antiemetic regimen. Patients and methods Patients Adult patients receiving carboplatin chemotherapy were eligible for treatment with ondansetron if they had vomited three times or more in the first 24 h of the previous course of chemotherapy. However, patients were excluded if they had a severe concurrent illness other than neoplasia, had hepatic dysfunction other than due to metastases or were receiving any other antiemetic medication, including benzodiazepines. Twenty-three women with ovarian cancer receiving carboplatin alone (300-400 mg m-2) and two men with testicular germ cell tumours receiving carboplatin (300 mg m2) with Correspondence: V.J. Harvey. Received 28 September 1990; and in revised form 2 January 1991. etoposide (120 mg m-2 days 1-3) were entered on protocol. The median age was 52 years (rane 24-68 years). All patients had multiple episodes of vomiting during the first 24 h of their previous course of chemotherapy (Table I), with 18 patients having > 10 episodes. Nine patients had experienced an extrapyramidal reaction and three patients found this intolerable. The previous exposure to antiemetic regimens is shown in Table I. Twenty-one patients had three or more antiemetic drugs in their previous protocol. Treatment Ondansetron was given as 4 mg intravenously and 4 mg orally immediately prior to chemotherapy with 8 mg orally 6 h and 12 h later. All patients received 8 mg TDS for' a further 4 days. No other antiemetic medication was permitted. This restriction included benzodiazepines, except when these had been taken regularly by the patient as night sedation prior to the study. Patients, who vomited on more than five occasions, were considered to have failed ondansetron therapy and were eligible for rescue antiemetic medication. Assessment of vomiting A vomit was defined as any single vomit or retch or any series of vomiting or retching within a 5 min period without pause. Control of vomiting was recorded as; complete control (no episode) almost complete control (1-2 episodes) partial control (three to five episodes) or failure (>five episodes). Nausea, as estimated by the patient, was recorded Table I Details of previous antiemetic therapy and emetic episodes (A) Vomiting during previous antiemetic regimen 3-9 Episodes 7 pts 10-19 Episodes l0pts 20 + Episodes 8 pts (B) Antiemetic drugs given during previous chemotherapy cycle High dose metoclopramide 22 pts (2 mg kg- ' 2-hourly x 3 - 5 doses) Moderate dose metoclopramide 3pts (0.5 -1 mg kg-' 2-hourly x 4 doses) Lorazepam 16 pts (1 -2 mg PO pre-chemotherapy) Dexamethazone 1 3pts (8 mg i.v. 6-hourly x 2 doses) Haloperidol 8 pts (2.5 mg i.v. 4-hourly PRN) 'Scopaderm' patch 15 pts (1 patch pre-chemotherapy) REDUCTION OF CARBOPLATIN INDUCED EMESIS BY ONDANSETRON as none, mild (not interfering with normal life) moderate (interfering with normal daily life) or severe (bedridden due to nausea). All patients were treated as out-patients and were contacted at 24h by a research nurse to assess number of vomits and grade of nausea experienced. Patients used a diary card to record any nausea, vomiting or side effects of therapy for the first 5 days. Each patient was reviewed by the research nurse at 1 week, when diary cards were checked and a pill count of unused ondansetron was made to assess compliance. At the end of each course of the treatment the patient was asked to state their preferred antiemetic regimen for future courses of treatment. Statistics Student's paired t-test was used to compare the incidence of vomiting and nausea in the first 24 h with that in the subsequent 4 days during the first cycle of ondansetron therapy. Ethical considerations The proposed study was reviewed and approved by the Research Ethics Committee of Auckland Hospital. The study was conducted according to the principles of the Declaration of Helsinki. All patients gave written informed consent in the presence of an independent witness, prior to entry. Results Twenty-five patients received 58 cycles of chemotherapy with ondansetron (median two cycles, range 1-7). Efficacy (a) First course of chemotherapy with ondansetron Complete control of vomiting was achieved in 17 patients (68%) during the first 24 h and 14 patients (56%) for the full 5 days (Table II). All 25 patients had some control of vomiting during the first 24 h, but five patients failed during the subsequent 4 days (P 5 1 vs days 2-5 P