Investigational New Drugs 8: 407-409, 1990. 9 1990KluwerAcademic Publishers. Printed in the Netherlands. Brief report
High versus low dose granisetron, a selective 5HT 3 antagonist, for the prevention of chemotherapy-induced nausea and vomiting H.C. Falkson, C.I. Falkson and G. Falkson Department o f Medical Oncology, University o f Pretoria, Pretoria, South Africa
Key words: antiemetic, chemotherapy-induced vomiting, granisetron, 5HT3-receptor antagonist Summary
Fifty six patients, with histologically confirmed cancer, who received highly emetogenic chemotherapy, were entered on a randomized double blind, low versus high dose, study of granisetron, a 5HT 3 receptor antagonist. A single dose of intravenous granisetron protected the majority of patients from nausea and vomiting, 160 ~g/kg was more effective than 40/~g/kg with no more side effects. Additional doses of granisetron conferred added benefit to patients who experienced breakthrough symptoms. Granisetron at a dose range of 40-240/zg/kg over a 24 hour period was well tolerated with the only side effect being mild headache.
Introduction
Compounds that selectively antagonize effects of 5-hydroxytryptamine at 5HT3-receptors inhibit cytotoxic-induced vomiting in experimental animals [1]. Granisetron (endo - N- (9- methyl-9- azabicyclo [3.3.1 ]non- 3 - yl)- 1 - methyl- 1H-indazole-3-carboxamide hydrochloride) is a selective, potent 5HT3-receptor antagonist developed by Beecham Pharmaceuticals. We investigated tolerance to 40 /zg/kg granisetron, and demonstrated efficacy with minor side-effects [2]. We undertook a randomized double-blind study to compare two doses, to determine if additional granisetron control breakthrough symptoms, and to assess toxicity.
Fifteen received cisplatin > 50 mg/m 2 _+ other cytotoxics; 14 received cisplatin (20-50 mg/m 2) + other cytotoxics and 27 received other emetogenic cytotoxic regimens, 12 received prednisone, but not enough to protect against emetogenesis (Table 1). Patients were randomized to a double-blinded treatment: granisetron 40 tzg/kg or 160 ~g/kg, (30 minute saline-infusion immediately prior to cytotoxic administration). If breakthrough symptoms (Grade 2 nausea, an episode of retching or vomiting) occurred during the first 24 hours, additional open label granisetron (40/zg/kg) was given, 2 additional doses, at least 10 minutes apart, were allowed. Patients were hospitalized for at least 24 hours for objective assessment. Follow-up hemogram and biochemistries were done.
Material and methods Results
Fifty six chemotherapy-naive patients (30 men, 26 women, median age 58), with histologically confirmed cancer, were studied. Hemograms, electrolytes, and serum biochemistries were normal. Informed consent was obtained.
Thirty-eight patients received one dose only, of those needing breakthrough treatment 11/18 received low dose. Median total dose was 140 #g/kg (range 40-240/zg/kg).
408 Table 1. Chemotherapy and protection from vomiting by granisetron
Cytostatic combinations*
No. of patients who did not vomit all pts
DDP >50mg/m 2 FIVB COPA BEP or EP DDP+IFX CBDCA + CTX C A F or CAV BCVPP MVAC MOPP PROMACE + CYTABOM
pts on 160/~g/m 2
8/15 8/9 5/7 4/4 6/9 1/1 4/5 2/2 1/1 1/1 2/2
6/8 4/4 2/4 1/1 3/4 0/0 3/4 2/2 0/0 1/1 0/0
42/56
22/28
* FIVB: 5-fluorouracil 500 m g / m 2 iv dl-4 + dacarbazine 500 m g / m 2 iv dl + vincristine 1.0 m g / m z iv dl & 4 + BCNU 90 m g / m 2 iv dl C O P A : cyclophosphamide 600 m g / m 2 iv dl + vincristine 1.2 m g / m 2 iv dl + prednisone 100 m g / m 2 po d l - 5 + doxorubicin 50 m g / m 2 iv dl BEP: bleomycin 30 units iv wkly + etoposide 100 m g / m 2 iv d l - 5 + cisplatin 20 m g / m 2 iv d l - 5 D D P + IFX: cisplatin 20 m g / m 2 iv + ifosfamide 1.5 g / m 2 iv d l - 5 C B D C A + CTX: carboplatin 150 m g / m 2 + cyclophosphamide 600 m g / m 2 iv C A F or CAV: cyclophosphamide 1.0 g / m 2 + doxorubicin 50 m g / m 2 + 5-fluorouraci1500 m g / m 2 or vincristine 1.4 m g / m 2 iv BCVPP: BCNU 100 m g / m 2 iv + cyclophosphamide 600 rag/ m 2 iv + vinblastine 5 m g / m 2 iv + procarbazine 100 m g / m 2 po d l - 1 0 + prednisone 60 m g / m 2 po dl-10 MVAC: cisplatin 40 m g / m 2 iv d2 + methotrexate 30 m g / m 2 iv d1,15,22 + vinblastine 3.0 m g / m 2 iv d2,15,22 + doxorubicin 30 m g / m 2. Granisetron given on d 2. M O P P : mustine 6 m g / m 2 iv + vincristine 1,4 m g / m 2 iv dl,8 + procarbazine 100 m g / m 2 po + prednisone 40 m g / m 2 po d l - 1 4 P R O M A C E C Y T A B O M : prednisone 60 m g / m 2 po d l - 1 4 + doxorubicin 25 m g / m 2 iv dl + cyclophosphamide 650 m g / m 2 iv dl + etoposide 120 m g / m 2 iv + cytosine arabinoside 300 m g / m 2 d8 + bleomycin 5 m g / m 2 iv d8
Toxicity Granisetron side-effects were mild headaches (7 patients on low and 3 on high dose) 8 of these 10 patients received additional granisetron for breakthrough symptoms (median total dose 120 tzg/kg); 2 developed constipation. No neurological symptoms or changes in pulse rate, blood pressure, ECG, serum transaminase occurred.
Therapeutic effect Thirty three (59%) of patients were completely protected, 9 experienced some nausea but no vomiting. (75~ of the patients did not vomit at all, Table 1). High dose protected 64% and low dose protected 54% from nausea. Of the 14 patients who vomited, 11 had mild (ECOG grade 1) vomiting and only 3 had moderate (ECOG grade 2) vomiting. No grade 3 nausea/vomiting occurred. Of 15 patients on cisplatin > 50 mg/m 2, 8 were completely protected (6 of these were on high dose granisetron), however, the number of patients is not large enough to state that high dose is statistically significantly different.
Discussion
Vomiting induced by cisplatin > 50 mg/m 2 is notoriously difficult to prevent and effective antiemetic treatment is constantly being sought. Metoclopramide at high doses acts as a weak, nonspecific 5-HT receptor antagonist [3]. Selective serotonin type 3 receptor antagonists appear to be effective in controlling chemotherapy-induced emesis, with minor side-effects like headache, sedation, transient hepatic transaminase elevations, dizziness, dry mouth and diarrhea [4,5]. Granisetron has not caused neurological, cardiovascular or hepatic enzyme changes [2,6]. We found a single dose of intravenous granisetron an effective antiemetic, additional doses controlled breakthrough symptoms, and a dose of 40-240/xg/kg over 24 hours was well tolerated.
409
Acknowledgements Supported by a grant from the National Cancer Association of South Africa. We wish to acknowledge the help of A.J. van Zyl who did the data management for this study.
References 1. Miner WD, Sanger GD: Inhibition of cisplatin-induced vomiting by selective 5-hydroxy-tryptamine M-receptor antagonism. Br J Pharmacol 88:497-499, 1986 2. Falkson G, Van Zyl AJ: A Phase I study of a new 5HT3-receptor antagonist, BRL43694A, an agent for the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol 193-196, 1989 3. Fozard JR, Mobarok Ali ATM: Blockade of neuronal trypta-
mine receptors by metoclopramide. Eur J Pharmacol 49:109-112, 1978 4. Hesketh PJ, Murphy WK, Lester EP, Gandara DR, Khojasteh A, Tapazoglou E, Sartiano GP, White DR, Werner K, Chubb JM: GR38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatininduced emesis. J Clin Oncol 7:700-705, 1989 5. Green JA, Watkin SW, Hammond P, Griggs J, Challoner T: The efficacy and safety of GR38032F in the prophylaxis of ifosfamide-induced nausea and vomiting. Cancer Chemother Pharmacol 24:137-139, 1989 6. Carmichael J, Cantwell BMJ, Edwards CM, Zussman BD, Thompson S, Rapeport WG, Harris AL: A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT 3 receptor antagonist: correlation with antiemetic response. Cancer Chemother Pharmacol 24:45-49, 1989
Address for offprints: G. Falkson, Department of Medical Oncology, University of Pretoria, Private Bag X 169, Pretoria 0001, Republic of South Africa
High versus low dose granisetron, a selective 5HT 3 antagonist, for the prevention of chemotherapy-induced nausea and vomiting H.C. Falkson, C.I. Falkson and G. Falkson Department o f Medical Oncology, University o f Pretoria, Pretoria, South Africa
Key words: antiemetic, chemotherapy-induced vomiting, granisetron, 5HT3-receptor antagonist Summary
Fifty six patients, with histologically confirmed cancer, who received highly emetogenic chemotherapy, were entered on a randomized double blind, low versus high dose, study of granisetron, a 5HT 3 receptor antagonist. A single dose of intravenous granisetron protected the majority of patients from nausea and vomiting, 160 ~g/kg was more effective than 40/~g/kg with no more side effects. Additional doses of granisetron conferred added benefit to patients who experienced breakthrough symptoms. Granisetron at a dose range of 40-240/zg/kg over a 24 hour period was well tolerated with the only side effect being mild headache.
Introduction
Compounds that selectively antagonize effects of 5-hydroxytryptamine at 5HT3-receptors inhibit cytotoxic-induced vomiting in experimental animals [1]. Granisetron (endo - N- (9- methyl-9- azabicyclo [3.3.1 ]non- 3 - yl)- 1 - methyl- 1H-indazole-3-carboxamide hydrochloride) is a selective, potent 5HT3-receptor antagonist developed by Beecham Pharmaceuticals. We investigated tolerance to 40 /zg/kg granisetron, and demonstrated efficacy with minor side-effects [2]. We undertook a randomized double-blind study to compare two doses, to determine if additional granisetron control breakthrough symptoms, and to assess toxicity.
Fifteen received cisplatin > 50 mg/m 2 _+ other cytotoxics; 14 received cisplatin (20-50 mg/m 2) + other cytotoxics and 27 received other emetogenic cytotoxic regimens, 12 received prednisone, but not enough to protect against emetogenesis (Table 1). Patients were randomized to a double-blinded treatment: granisetron 40 tzg/kg or 160 ~g/kg, (30 minute saline-infusion immediately prior to cytotoxic administration). If breakthrough symptoms (Grade 2 nausea, an episode of retching or vomiting) occurred during the first 24 hours, additional open label granisetron (40/zg/kg) was given, 2 additional doses, at least 10 minutes apart, were allowed. Patients were hospitalized for at least 24 hours for objective assessment. Follow-up hemogram and biochemistries were done.
Material and methods Results
Fifty six chemotherapy-naive patients (30 men, 26 women, median age 58), with histologically confirmed cancer, were studied. Hemograms, electrolytes, and serum biochemistries were normal. Informed consent was obtained.
Thirty-eight patients received one dose only, of those needing breakthrough treatment 11/18 received low dose. Median total dose was 140 #g/kg (range 40-240/zg/kg).
408 Table 1. Chemotherapy and protection from vomiting by granisetron
Cytostatic combinations*
No. of patients who did not vomit all pts
DDP >50mg/m 2 FIVB COPA BEP or EP DDP+IFX CBDCA + CTX C A F or CAV BCVPP MVAC MOPP PROMACE + CYTABOM
pts on 160/~g/m 2
8/15 8/9 5/7 4/4 6/9 1/1 4/5 2/2 1/1 1/1 2/2
6/8 4/4 2/4 1/1 3/4 0/0 3/4 2/2 0/0 1/1 0/0
42/56
22/28
* FIVB: 5-fluorouracil 500 m g / m 2 iv dl-4 + dacarbazine 500 m g / m 2 iv dl + vincristine 1.0 m g / m z iv dl & 4 + BCNU 90 m g / m 2 iv dl C O P A : cyclophosphamide 600 m g / m 2 iv dl + vincristine 1.2 m g / m 2 iv dl + prednisone 100 m g / m 2 po d l - 5 + doxorubicin 50 m g / m 2 iv dl BEP: bleomycin 30 units iv wkly + etoposide 100 m g / m 2 iv d l - 5 + cisplatin 20 m g / m 2 iv d l - 5 D D P + IFX: cisplatin 20 m g / m 2 iv + ifosfamide 1.5 g / m 2 iv d l - 5 C B D C A + CTX: carboplatin 150 m g / m 2 + cyclophosphamide 600 m g / m 2 iv C A F or CAV: cyclophosphamide 1.0 g / m 2 + doxorubicin 50 m g / m 2 + 5-fluorouraci1500 m g / m 2 or vincristine 1.4 m g / m 2 iv BCVPP: BCNU 100 m g / m 2 iv + cyclophosphamide 600 rag/ m 2 iv + vinblastine 5 m g / m 2 iv + procarbazine 100 m g / m 2 po d l - 1 0 + prednisone 60 m g / m 2 po dl-10 MVAC: cisplatin 40 m g / m 2 iv d2 + methotrexate 30 m g / m 2 iv d1,15,22 + vinblastine 3.0 m g / m 2 iv d2,15,22 + doxorubicin 30 m g / m 2. Granisetron given on d 2. M O P P : mustine 6 m g / m 2 iv + vincristine 1,4 m g / m 2 iv dl,8 + procarbazine 100 m g / m 2 po + prednisone 40 m g / m 2 po d l - 1 4 P R O M A C E C Y T A B O M : prednisone 60 m g / m 2 po d l - 1 4 + doxorubicin 25 m g / m 2 iv dl + cyclophosphamide 650 m g / m 2 iv dl + etoposide 120 m g / m 2 iv + cytosine arabinoside 300 m g / m 2 d8 + bleomycin 5 m g / m 2 iv d8
Toxicity Granisetron side-effects were mild headaches (7 patients on low and 3 on high dose) 8 of these 10 patients received additional granisetron for breakthrough symptoms (median total dose 120 tzg/kg); 2 developed constipation. No neurological symptoms or changes in pulse rate, blood pressure, ECG, serum transaminase occurred.
Therapeutic effect Thirty three (59%) of patients were completely protected, 9 experienced some nausea but no vomiting. (75~ of the patients did not vomit at all, Table 1). High dose protected 64% and low dose protected 54% from nausea. Of the 14 patients who vomited, 11 had mild (ECOG grade 1) vomiting and only 3 had moderate (ECOG grade 2) vomiting. No grade 3 nausea/vomiting occurred. Of 15 patients on cisplatin > 50 mg/m 2, 8 were completely protected (6 of these were on high dose granisetron), however, the number of patients is not large enough to state that high dose is statistically significantly different.
Discussion
Vomiting induced by cisplatin > 50 mg/m 2 is notoriously difficult to prevent and effective antiemetic treatment is constantly being sought. Metoclopramide at high doses acts as a weak, nonspecific 5-HT receptor antagonist [3]. Selective serotonin type 3 receptor antagonists appear to be effective in controlling chemotherapy-induced emesis, with minor side-effects like headache, sedation, transient hepatic transaminase elevations, dizziness, dry mouth and diarrhea [4,5]. Granisetron has not caused neurological, cardiovascular or hepatic enzyme changes [2,6]. We found a single dose of intravenous granisetron an effective antiemetic, additional doses controlled breakthrough symptoms, and a dose of 40-240/xg/kg over 24 hours was well tolerated.
409
Acknowledgements Supported by a grant from the National Cancer Association of South Africa. We wish to acknowledge the help of A.J. van Zyl who did the data management for this study.
References 1. Miner WD, Sanger GD: Inhibition of cisplatin-induced vomiting by selective 5-hydroxy-tryptamine M-receptor antagonism. Br J Pharmacol 88:497-499, 1986 2. Falkson G, Van Zyl AJ: A Phase I study of a new 5HT3-receptor antagonist, BRL43694A, an agent for the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol 193-196, 1989 3. Fozard JR, Mobarok Ali ATM: Blockade of neuronal trypta-
mine receptors by metoclopramide. Eur J Pharmacol 49:109-112, 1978 4. Hesketh PJ, Murphy WK, Lester EP, Gandara DR, Khojasteh A, Tapazoglou E, Sartiano GP, White DR, Werner K, Chubb JM: GR38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatininduced emesis. J Clin Oncol 7:700-705, 1989 5. Green JA, Watkin SW, Hammond P, Griggs J, Challoner T: The efficacy and safety of GR38032F in the prophylaxis of ifosfamide-induced nausea and vomiting. Cancer Chemother Pharmacol 24:137-139, 1989 6. Carmichael J, Cantwell BMJ, Edwards CM, Zussman BD, Thompson S, Rapeport WG, Harris AL: A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT 3 receptor antagonist: correlation with antiemetic response. Cancer Chemother Pharmacol 24:45-49, 1989
Address for offprints: G. Falkson, Department of Medical Oncology, University of Pretoria, Private Bag X 169, Pretoria 0001, Republic of South Africa
