- Email: [email protected]
A Phase II study of ondansetron as antiemetic prophylaxis in patients receiving carboplatin for advanced ovarian cancer
Annals of Oncology 2: 607-608, 1991. O 1991 Kluwer Academic Publishers. Printed in the Netherlands.
Short report A Phase II study of ondansetron as antiemetic prophylaxis in patients receiving carboplatin for advanced ovarian cancer D. B. Smith,1 G. J. S. Rustin,12 N. Howells,2 H. E. Lambert3 & B. McQuade4; for the North Thames Ovary Group 1
Cancer Research Campaign Laboratories, Department of Medical Oncology, Charing Cross Hospital, London; 2 Mount Vemon Cancer Centre, Northwood, Middlesex; 3Dept. of Clinical Oncology, Hammersmith Hospital, London; AGlaxo Group Research Ltd. Greenford Rd, Middlesex; U.K.
Summary. Thirty four patients who were receiving carboplatin 400 mg/m2 for advanced epithelial ovarian cancer were treated with ondansetron antiemetic prophylaxis. Ondansetron was given as 4 mg oral + 4 mg iv 30 minutes prior to carboplatin followed by 8 mg oral tds for 5 days. Of the evaluable patients complete or major control of emesis on day one was achieved in 94% of previously untreated patients and 81% of patients refractory to conventional antiemetic therapy. For the 5 day period as a whole 88% of untreated patients and 69% of those with refractory emesis reported complete or major control of nausea and vomiting. Fifteen patients noted no side effects with mild headache (30%) and constipation (21%) the most frequent problems in the remainder. Ondansetron is effective antiemetic prophylaxis for carboplatin chemotherapy and should allow the majority of these patients to be managed on an out-patient basis. Key words: ondansetron, antiemetic, carboplatin, ovarian cancer Introduction
Ondansetron is a novel highly selective 5HT3 antagonist [1] which has been shown to be effective in preventing the emesis associated with cytotoxic chemotherapy [2] and in particular that following high dose cisplatin [2, 3]. In addition ondansetron is largely free from side effects with some 10% of patients experiencing headache or constipation but sedation and extrapyrammidal symptoms have not been reported [2, 3]. Although cisplatin therapy normally required hospital admission the lack of nephrotoxicity associated with the analogue carboplatin [4] allows this drug to be administered on an outpatient basis. However a proportion of patients treated with carboplatin suffer nausea and vomiting unresponsive to conventional antiemetics and these patients may have to be admitted for iv fluids and parenteral antiemetic therapy |5). The current study was designed to assess whether the use of ondansetron in a group of patients receiving carboplatin for advanced ovarian cancer would provide more effective antiemetic prophylaxis and thus allow more patients to be treated as out-patients. Patients and methods
The patients included in this study were part of the North Thames Ovary Group trial of single agent carboplatin in advanced epithelial ovarian cancer. Pa-
tients had FIGO stage lib, lie or IE disease and initially received 5 cycles of carboplatin 400 mg/m2 as a 30 minute infusion in 500 ml 5% dextrose. Those patients achieving a pathological complete response or minimal residual disease were then randomised to a further 5 cycles of carboplatin or whole abdominal radiotherapy. Standard antiemetic prophylaxis consisted of dexamethasone 8 mg and metoclopramide 20 mg both oral prior to the chemotherapy and dexamethasone 8 mg tds with metoclopramide 20 mg qds for 2 days following the chemotherapy. For the current study 15 consecutive patients who were refractory to the standard antiemetic regimen (>2 emetic episodes in the 24 hours following carboplatin) and 15 patients who had received no prior chemotherapy were selected. None of these patients had nausea or vomiting for other reasons eg bowel obstruction. Ondansetron was given 4 mg iv + 4 mg oral 30 minutes prior to the carboplatin and 8 mg tds for 5 days following the therapy. The initial intravenous dose was to ensure adequate 5HT3 receptor blockade before the carboplatin was given. Patients recorded details of nausea, vomiting, appetite and any adverse effects on daily diary cards for the 5 days of ondansetron treatment. Response was defined as follows: Complete response (CR): no emetic episodes Major response (MR) : 1-2 emetic episodes Minor response (mR) : 3-5 emetic episodes Fail (F) : >5 emetic episodes
608
Discussion
Table 1. Emetic episodes. Response
Untreated
Refractory
15 (88%) 1 (6%) 0 1 (6%)
11 (69%) 2(12%) 2 (12%) 1 (6%)
11 (65%) 4 (23%) 1 (6%) 1 (6%)
6 (46%) 3 (23%) 3 (23%) 1 (8%)
Day 1 CR MR mR F
Days 1-5 CR MR mR F
Definitions: CR: complete response; MR: 1-2 emetic episodes; mR: 3-5 emetic episodes; F: >5 emetic episodes.
where an emetic episode was defined as one vomit productive of liquid or 1 dry retch.
Results A total of 34 patients were entered into the study. There were 18 previously untreated patients, median age 56 (range 28-70) and 16 refractory patients, median age 58 (range 23-73). Of the 18 untreated patients one was not evaluabe and of the 16 refractory patients all were evaluable on day one of the study but two were not evaluable for days 2-5. Reasons for not being evaluable included withdrawal from the study due to the occurrence of headache and abdominal pain (2 patients) and carboplatin dose more than 10% lower than 400 mg/m2 (one patient). The results for emesis are summarised in Table 1. During day 1 complete or major control of emesis was achieved in 94% of previously untreated patients and in 81% of refractory patients. Similar results were obtained for control nausea during this period. For days 1-5, 88% of untreated patients and 69% of those with refractory emesis reported complete or major control of vomiting and 65% of untreated patients recorded their worst grade of nausea as none or mild compared with 54% for the refractory group. Treatment with ondansetron was generally well tolerated. Fifteen patients reported no side effects while the majority of the remainder noted only mild headache (30%) or constipation (21%). There were two patients who discontinued ondansetron prematurely due in one case to drowsiness, dyspepsia and abdominal pain and in the other to headache + abdominal pain.
This study demonstrates that ondansetron is highly effective in controlling the nausea and vomiting associated with carboplatin chemotherapy. 94% of chemotherapy naive patients and 81% of those refractory to previous antiemetic therapy experienced either complete or major control of their nausea and vomiting in the first 24 hours following carboplatin therapy and in the majority of patients control was maintained over the next five days. In common with other studies ondansetron was well tolerated with mild headache the most frequent side effect and with no evidence of extrapyrammidal toxicity. However constipation occurred more often than has been previously reported possibly representing an interaction with carboplatin which could be prevented by prophylactic laxative therapy. In this study ondansetron was administered orally for 5 days after the chemotherapy but with carboplatin it is unusual for vomiting to continue for more than 2-3 days and in most patients does not last more than 24 hours [4] thus a maximum of 3 days therapy should be sufficient. In conclusion the use of ondansetron as antiemetic prophylaxis in conjunction with carboplatin chemotherapy should allow in excess of 80% of patients with advanced ovarian carcinoma to receive effective outpatient treatment with minimal subjective toxicity. References 1. Brittain RT, Butler A, Coates IH et al. GR38032F: A novel selective 5HT3 receptor antagonist. Br J Pharmacol 1987; 90: 87. 2. Kris MG, Gralla RJ, Clark RA et al. Dose ranging evaluation of the serotonin antagonist CR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anti-cancer chemotherapy. J Clin Oncol 1986; 6:659-62. 3. Smith DB, Newlands ES, Rustin et al. A phase I/II study of the 5HT3 antagonist GR38032F in the antimetic prophylaxis of patients receiving high dose cisplatin chemotherapy. Cancer Chemother Pharmacol 1990; 25: 291-4. 4. Foster BJ, Clagett-Carr K, Leyland-Jones B et al. Results of NCI-sponsored phase I trials with carboplatin. Cancer Treat Rev 1985; 12:43-9. 5. Calvert AH, Baker JW, Dalley VM et al. Phase II trial of cisdiammine-1, 1 cyclobutane diacarboxylate platinum II (CBDCA, JM8), in patients with carcinoma of the ovary not previously treated with cisplatin. Dev Oncol 1984; 17: 353. Received 21 March 1991; accepted 13 May 1991. Correspondence to: Dr. D. B. Smith Dept. of Medical Oncology Charing Cross Hospital Fulham Palace Road London W6 8RF, U.K.
Short report A Phase II study of ondansetron as antiemetic prophylaxis in patients receiving carboplatin for advanced ovarian cancer D. B. Smith,1 G. J. S. Rustin,12 N. Howells,2 H. E. Lambert3 & B. McQuade4; for the North Thames Ovary Group 1
Cancer Research Campaign Laboratories, Department of Medical Oncology, Charing Cross Hospital, London; 2 Mount Vemon Cancer Centre, Northwood, Middlesex; 3Dept. of Clinical Oncology, Hammersmith Hospital, London; AGlaxo Group Research Ltd. Greenford Rd, Middlesex; U.K.
Summary. Thirty four patients who were receiving carboplatin 400 mg/m2 for advanced epithelial ovarian cancer were treated with ondansetron antiemetic prophylaxis. Ondansetron was given as 4 mg oral + 4 mg iv 30 minutes prior to carboplatin followed by 8 mg oral tds for 5 days. Of the evaluable patients complete or major control of emesis on day one was achieved in 94% of previously untreated patients and 81% of patients refractory to conventional antiemetic therapy. For the 5 day period as a whole 88% of untreated patients and 69% of those with refractory emesis reported complete or major control of nausea and vomiting. Fifteen patients noted no side effects with mild headache (30%) and constipation (21%) the most frequent problems in the remainder. Ondansetron is effective antiemetic prophylaxis for carboplatin chemotherapy and should allow the majority of these patients to be managed on an out-patient basis. Key words: ondansetron, antiemetic, carboplatin, ovarian cancer Introduction
Ondansetron is a novel highly selective 5HT3 antagonist [1] which has been shown to be effective in preventing the emesis associated with cytotoxic chemotherapy [2] and in particular that following high dose cisplatin [2, 3]. In addition ondansetron is largely free from side effects with some 10% of patients experiencing headache or constipation but sedation and extrapyrammidal symptoms have not been reported [2, 3]. Although cisplatin therapy normally required hospital admission the lack of nephrotoxicity associated with the analogue carboplatin [4] allows this drug to be administered on an outpatient basis. However a proportion of patients treated with carboplatin suffer nausea and vomiting unresponsive to conventional antiemetics and these patients may have to be admitted for iv fluids and parenteral antiemetic therapy |5). The current study was designed to assess whether the use of ondansetron in a group of patients receiving carboplatin for advanced ovarian cancer would provide more effective antiemetic prophylaxis and thus allow more patients to be treated as out-patients. Patients and methods
The patients included in this study were part of the North Thames Ovary Group trial of single agent carboplatin in advanced epithelial ovarian cancer. Pa-
tients had FIGO stage lib, lie or IE disease and initially received 5 cycles of carboplatin 400 mg/m2 as a 30 minute infusion in 500 ml 5% dextrose. Those patients achieving a pathological complete response or minimal residual disease were then randomised to a further 5 cycles of carboplatin or whole abdominal radiotherapy. Standard antiemetic prophylaxis consisted of dexamethasone 8 mg and metoclopramide 20 mg both oral prior to the chemotherapy and dexamethasone 8 mg tds with metoclopramide 20 mg qds for 2 days following the chemotherapy. For the current study 15 consecutive patients who were refractory to the standard antiemetic regimen (>2 emetic episodes in the 24 hours following carboplatin) and 15 patients who had received no prior chemotherapy were selected. None of these patients had nausea or vomiting for other reasons eg bowel obstruction. Ondansetron was given 4 mg iv + 4 mg oral 30 minutes prior to the carboplatin and 8 mg tds for 5 days following the therapy. The initial intravenous dose was to ensure adequate 5HT3 receptor blockade before the carboplatin was given. Patients recorded details of nausea, vomiting, appetite and any adverse effects on daily diary cards for the 5 days of ondansetron treatment. Response was defined as follows: Complete response (CR): no emetic episodes Major response (MR) : 1-2 emetic episodes Minor response (mR) : 3-5 emetic episodes Fail (F) : >5 emetic episodes
608
Discussion
Table 1. Emetic episodes. Response
Untreated
Refractory
15 (88%) 1 (6%) 0 1 (6%)
11 (69%) 2(12%) 2 (12%) 1 (6%)
11 (65%) 4 (23%) 1 (6%) 1 (6%)
6 (46%) 3 (23%) 3 (23%) 1 (8%)
Day 1 CR MR mR F
Days 1-5 CR MR mR F
Definitions: CR: complete response; MR: 1-2 emetic episodes; mR: 3-5 emetic episodes; F: >5 emetic episodes.
where an emetic episode was defined as one vomit productive of liquid or 1 dry retch.
Results A total of 34 patients were entered into the study. There were 18 previously untreated patients, median age 56 (range 28-70) and 16 refractory patients, median age 58 (range 23-73). Of the 18 untreated patients one was not evaluabe and of the 16 refractory patients all were evaluable on day one of the study but two were not evaluable for days 2-5. Reasons for not being evaluable included withdrawal from the study due to the occurrence of headache and abdominal pain (2 patients) and carboplatin dose more than 10% lower than 400 mg/m2 (one patient). The results for emesis are summarised in Table 1. During day 1 complete or major control of emesis was achieved in 94% of previously untreated patients and in 81% of refractory patients. Similar results were obtained for control nausea during this period. For days 1-5, 88% of untreated patients and 69% of those with refractory emesis reported complete or major control of vomiting and 65% of untreated patients recorded their worst grade of nausea as none or mild compared with 54% for the refractory group. Treatment with ondansetron was generally well tolerated. Fifteen patients reported no side effects while the majority of the remainder noted only mild headache (30%) or constipation (21%). There were two patients who discontinued ondansetron prematurely due in one case to drowsiness, dyspepsia and abdominal pain and in the other to headache + abdominal pain.
This study demonstrates that ondansetron is highly effective in controlling the nausea and vomiting associated with carboplatin chemotherapy. 94% of chemotherapy naive patients and 81% of those refractory to previous antiemetic therapy experienced either complete or major control of their nausea and vomiting in the first 24 hours following carboplatin therapy and in the majority of patients control was maintained over the next five days. In common with other studies ondansetron was well tolerated with mild headache the most frequent side effect and with no evidence of extrapyrammidal toxicity. However constipation occurred more often than has been previously reported possibly representing an interaction with carboplatin which could be prevented by prophylactic laxative therapy. In this study ondansetron was administered orally for 5 days after the chemotherapy but with carboplatin it is unusual for vomiting to continue for more than 2-3 days and in most patients does not last more than 24 hours [4] thus a maximum of 3 days therapy should be sufficient. In conclusion the use of ondansetron as antiemetic prophylaxis in conjunction with carboplatin chemotherapy should allow in excess of 80% of patients with advanced ovarian carcinoma to receive effective outpatient treatment with minimal subjective toxicity. References 1. Brittain RT, Butler A, Coates IH et al. GR38032F: A novel selective 5HT3 receptor antagonist. Br J Pharmacol 1987; 90: 87. 2. Kris MG, Gralla RJ, Clark RA et al. Dose ranging evaluation of the serotonin antagonist CR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anti-cancer chemotherapy. J Clin Oncol 1986; 6:659-62. 3. Smith DB, Newlands ES, Rustin et al. A phase I/II study of the 5HT3 antagonist GR38032F in the antimetic prophylaxis of patients receiving high dose cisplatin chemotherapy. Cancer Chemother Pharmacol 1990; 25: 291-4. 4. Foster BJ, Clagett-Carr K, Leyland-Jones B et al. Results of NCI-sponsored phase I trials with carboplatin. Cancer Treat Rev 1985; 12:43-9. 5. Calvert AH, Baker JW, Dalley VM et al. Phase II trial of cisdiammine-1, 1 cyclobutane diacarboxylate platinum II (CBDCA, JM8), in patients with carcinoma of the ovary not previously treated with cisplatin. Dev Oncol 1984; 17: 353. Received 21 March 1991; accepted 13 May 1991. Correspondence to: Dr. D. B. Smith Dept. of Medical Oncology Charing Cross Hospital Fulham Palace Road London W6 8RF, U.K.