Annals of Oncology 3: 677-678, 1992.
Editorial Serotonin antagonist antiemetics: Progress and concerns New agents and techniques in supportive care are now ular attention [11]. In addition, these authors have been part of the daily practice of oncology. Long acting anal- cautious contributors in prior supportive care trials. gesics, hematopoietic growth factors, and new drugs to When unexpected and alarming adverse effects are treat hypercalcemia have joined third generation anti- noted at an institution, it becomes difficult to deterbiotics as novel pharmaceuticals for the relief of prob- mine whether a representative sampling has been oblems associated with cancer and its treatment. With served or just one end of the spectrum of possibilities. widespread experience comes the opportunity to eval- This is the concern in the report submitted by Coates. uate new agents in an accurate perspective concerning Appropriately, they have attempted to place the obefficacy and safety. served events in the context of the whole practice in Marked progress in the control of chemotherapy in- their institution, and remained concerned. Of all the duced emesis occurred over the past decade. Anti- side effects they reported, the vascular events appear to emetic therapy grew during this period from anecdotal- be more likely to be associated with the antiemetic ly reported nostrums to carefully developed regimens rather than the chemotherapy. of high efficacy. Attention to proper antiemetic usage is Similar thrombotic or embolic events were also notnow a major priority in medical oncology. As agents ed and reported in our own early clinical trials with and knowledge have evolved, questions and concerns ondansetron [5, 6]. The incidence of these serious have been raised. events was higher than our prior experience in patients Current antiemetic therapy grew from a dissatisfac- with the same malignancies receiving the same chemotion with older agents such as phenothiazines and anti- therapy with other antiemetics. We were aware of prior histamines. Trials exploring higher doses of metoclo- reports of vascular events with a variety of chemotnerapramide stimulated interest from both clinical and peutic agents, including cisplatin, but the incidence of neuropharmacological points of view. Clinically, meto- arterial emboli observed in the population given onclopramide demonstrated a new level of efficacy when dansetron was disconcerting. In addition to the filing of given in the proper schedule and dose, and was surpris- the usual adverse reaction reports, this concern was ingly safe in most patient groups [1]. Metoclopramide specifically communicated to the manufacturer (Glaxo proved to be easy to use in combinationregimensand was Pharmaceuticals) who clearly shared this concern and associated with further improvements in activity [2]. A acted upon it to try to place these events in context. dilemma remained. In that metoclopramide is a potent The experiences of the several thousand patients redopamine antagonist at low doses, why was its antiemetic ceiving ondansetron in early clinical trials, and most efficacy enhanced at doses ten to twenty times higher? The importantly all patients in random assignment studies answer came with the hypothesis that metoclopramide comparing ondansetron with metoclopramide, were also binds to other neurotransmitter receptors; specifi- carefully analyzed for vascular events. The results of cally the type 3 serotonin (5-hydroxytryptamine) recep- this analysis were made public and were presented to tor, or 5-HT3 receptor [3, 4]. It therefore became desir- the U.S. Food and Drug Administration. In this analable to synthesize agents which bind selectively to the ysis, the incidences of both venous and arterial events 5-HT3 receptor. Such agents could preserve or im- were found to be uncommon and occurred with equal prove upon the efficacy of metoclopramide and be free frequency in those randomly assigned to either onof its dopamine related side-effects. dansetron or metoclopramide. With the infrequent ocOf the effective agents that bind selectively to currence in the whole population of thousands of 5-HT3 receptors (including granisetron, tropisetron, patients including those in prospective random assigndolasetron, and RG 12915), the best studied is on- ment trials, and without a clearly drug-related pathodansetron. Initial trials indicated safety and encourag- physiologic mechanism leading to those events, it being efficacy [5, 6], and later random assignment blinded came difficult for us to conclude that either antiemetic studies confirmed these findings [7-9]. Recently, care- induced vascular phenomena. We share the concern of ful trials with ondansetron plus a corticosteroid found Coates and colleagues, and support reporting of such observed experiences, but based on the above analysis improved antiemetic activity for the combination [10]. still cannot conclude that 5-HT3 antagonists induce Perhaps the greatest benefit from ondansetron is not vascular thrombosis. its efficacy (which is only modestly better than that of metoclopramide), but is its marked ease of use and As experience with these agents increases to include excellent safety profile. This fact is why the serious tox- millions of patient courses, other adverse and rare icity reported by Coates and colleagues requires partic- events will come to attention. Recently, dose-related
678
(and likely clinically insignificant) effects of electrocardiographic prolongation of QTc, QRS, and PR intervals have been reported with 5-HT3 antagonists [12]. As agent doses are increased and newer schedules are explored, careful analyses may note a variety of findings. Several other concerns have arisen as effective serotonin antagonist antiemetics have become accepted into clinical practice. These include the following: 1) a curious absence of well conducted antiemetic studies by pediatric oncologists to explore fully the encouraging potential of these agents in the younger population; 2) the growing trend of many recent antiemetic trials to appeal to marketing questions rather than emphasizing investigator initiated directions; 3) the failure of regulating agencies to appreciate that newer trial designs emphasizing early use of antiemetic combinations are necessary while the use of placebo or near placebo (doses that are too low) in patients receiving highly emetogenic chemotherapy are unethical; and 4) an acceptance of studies with high rates of inevaluable patients (studies completed in 24 hours should exceed a 95% evaluable rate). Oncologists must continue to understand the bases for antiemetic therapy rather than be tempted to employ regimen recipes. Only through these efforts can optimal safety and efficacy results be achieved while maintaining a responsible attitude toward costs. With continued new agent and regimen research, with attention to appropriate details, the potential for improved antiemetic control remains high.
2.
3. 4.
5.
6. 7.
8.
9.
10.
Richard J. Gralla, MX). Ochsner Cancer Institute New Orleans, Louisiana USA References 1. Gralla RJ, Itri LM, Pisko SE et al. Antiemetic efficacy of highdose metoclopramide: Randomized trials with placebo and
11.
12.
prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med 1981; 305:905-9. Kris MG, Gralla RJ, Tyson LB et al. Improved control of cisplatin-induced emesis with high-dose methoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 255 patients. Cancer 1985; 55: 527-34. Fozard JR, Mobarok A. Blockade of neuronal tryptamine receptors by metoclopramide. Eur J Pharmacol 1978; 49: 109-12. Ireland SJ, Straughan OW, Tyers MB. Influence of 5-HT uptake on the apparent 5-HT antagonist potency of metoclopramide on the rat isolated superior cervical ganglion. Br J Pharmacol 1987; 90: 151-60. Kris MG, Gralla RJ, Clark RA et al. Dose ranging evaluation of the serotonin antagonist GR-507/75 (GR38032F) when used as an antiemetic in patients receiving cancer chemotherapy. J Clin Oncol 1988; 6:659-62. Kris MG, Gralla RJ, Clark RA et al. Phase II trials of the serotonin antagonist GR38032 F for the control of vomiting caused by cisplatin. J Natl Cancer Inst 1989; 81: 42-6. Marty M, Pouillart P, Scholl S et al. Comparison of the 5-hydroxytryptamine 3 (serotonin) receptor antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990; 322: 816-21. De Mulder PH, Seynaeue C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized double-blind crossover study. Ann Intern Med 1990; 113: 834-40. Hainsworth J, Harvey W, Pendergrass K et al. A single-blind comparison of intravenous ondansetron with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy. J Clin Oncol 1991; 9: 721-8. Roila F, Tonato M, Cognetti F et al. Prevention of cisplatininduced emesis: A double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 1991; 9:674-8. Coates AS, Childs A, Cox K et al. Severe vascular adverse effects with thrombocytopenia and renal failure following emetogenic chemotherapy and ondansetron. Ann Oncol 1992; 3 (9>. 719-22. Clark RA, Gralla RJ, Grunberg SM et al. Effective single dose treatment in patients receiving high cisplatin doses: Establishment of the optimal IV dose of the 5-HT3 antagonist MDL 73, 147EF. Proc Am Soc Oncol 1992; 11:382.
Editorial Serotonin antagonist antiemetics: Progress and concerns New agents and techniques in supportive care are now ular attention [11]. In addition, these authors have been part of the daily practice of oncology. Long acting anal- cautious contributors in prior supportive care trials. gesics, hematopoietic growth factors, and new drugs to When unexpected and alarming adverse effects are treat hypercalcemia have joined third generation anti- noted at an institution, it becomes difficult to deterbiotics as novel pharmaceuticals for the relief of prob- mine whether a representative sampling has been oblems associated with cancer and its treatment. With served or just one end of the spectrum of possibilities. widespread experience comes the opportunity to eval- This is the concern in the report submitted by Coates. uate new agents in an accurate perspective concerning Appropriately, they have attempted to place the obefficacy and safety. served events in the context of the whole practice in Marked progress in the control of chemotherapy in- their institution, and remained concerned. Of all the duced emesis occurred over the past decade. Anti- side effects they reported, the vascular events appear to emetic therapy grew during this period from anecdotal- be more likely to be associated with the antiemetic ly reported nostrums to carefully developed regimens rather than the chemotherapy. of high efficacy. Attention to proper antiemetic usage is Similar thrombotic or embolic events were also notnow a major priority in medical oncology. As agents ed and reported in our own early clinical trials with and knowledge have evolved, questions and concerns ondansetron [5, 6]. The incidence of these serious have been raised. events was higher than our prior experience in patients Current antiemetic therapy grew from a dissatisfac- with the same malignancies receiving the same chemotion with older agents such as phenothiazines and anti- therapy with other antiemetics. We were aware of prior histamines. Trials exploring higher doses of metoclo- reports of vascular events with a variety of chemotnerapramide stimulated interest from both clinical and peutic agents, including cisplatin, but the incidence of neuropharmacological points of view. Clinically, meto- arterial emboli observed in the population given onclopramide demonstrated a new level of efficacy when dansetron was disconcerting. In addition to the filing of given in the proper schedule and dose, and was surpris- the usual adverse reaction reports, this concern was ingly safe in most patient groups [1]. Metoclopramide specifically communicated to the manufacturer (Glaxo proved to be easy to use in combinationregimensand was Pharmaceuticals) who clearly shared this concern and associated with further improvements in activity [2]. A acted upon it to try to place these events in context. dilemma remained. In that metoclopramide is a potent The experiences of the several thousand patients redopamine antagonist at low doses, why was its antiemetic ceiving ondansetron in early clinical trials, and most efficacy enhanced at doses ten to twenty times higher? The importantly all patients in random assignment studies answer came with the hypothesis that metoclopramide comparing ondansetron with metoclopramide, were also binds to other neurotransmitter receptors; specifi- carefully analyzed for vascular events. The results of cally the type 3 serotonin (5-hydroxytryptamine) recep- this analysis were made public and were presented to tor, or 5-HT3 receptor [3, 4]. It therefore became desir- the U.S. Food and Drug Administration. In this analable to synthesize agents which bind selectively to the ysis, the incidences of both venous and arterial events 5-HT3 receptor. Such agents could preserve or im- were found to be uncommon and occurred with equal prove upon the efficacy of metoclopramide and be free frequency in those randomly assigned to either onof its dopamine related side-effects. dansetron or metoclopramide. With the infrequent ocOf the effective agents that bind selectively to currence in the whole population of thousands of 5-HT3 receptors (including granisetron, tropisetron, patients including those in prospective random assigndolasetron, and RG 12915), the best studied is on- ment trials, and without a clearly drug-related pathodansetron. Initial trials indicated safety and encourag- physiologic mechanism leading to those events, it being efficacy [5, 6], and later random assignment blinded came difficult for us to conclude that either antiemetic studies confirmed these findings [7-9]. Recently, care- induced vascular phenomena. We share the concern of ful trials with ondansetron plus a corticosteroid found Coates and colleagues, and support reporting of such observed experiences, but based on the above analysis improved antiemetic activity for the combination [10]. still cannot conclude that 5-HT3 antagonists induce Perhaps the greatest benefit from ondansetron is not vascular thrombosis. its efficacy (which is only modestly better than that of metoclopramide), but is its marked ease of use and As experience with these agents increases to include excellent safety profile. This fact is why the serious tox- millions of patient courses, other adverse and rare icity reported by Coates and colleagues requires partic- events will come to attention. Recently, dose-related
678
(and likely clinically insignificant) effects of electrocardiographic prolongation of QTc, QRS, and PR intervals have been reported with 5-HT3 antagonists [12]. As agent doses are increased and newer schedules are explored, careful analyses may note a variety of findings. Several other concerns have arisen as effective serotonin antagonist antiemetics have become accepted into clinical practice. These include the following: 1) a curious absence of well conducted antiemetic studies by pediatric oncologists to explore fully the encouraging potential of these agents in the younger population; 2) the growing trend of many recent antiemetic trials to appeal to marketing questions rather than emphasizing investigator initiated directions; 3) the failure of regulating agencies to appreciate that newer trial designs emphasizing early use of antiemetic combinations are necessary while the use of placebo or near placebo (doses that are too low) in patients receiving highly emetogenic chemotherapy are unethical; and 4) an acceptance of studies with high rates of inevaluable patients (studies completed in 24 hours should exceed a 95% evaluable rate). Oncologists must continue to understand the bases for antiemetic therapy rather than be tempted to employ regimen recipes. Only through these efforts can optimal safety and efficacy results be achieved while maintaining a responsible attitude toward costs. With continued new agent and regimen research, with attention to appropriate details, the potential for improved antiemetic control remains high.
2.
3. 4.
5.
6. 7.
8.
9.
10.
Richard J. Gralla, MX). Ochsner Cancer Institute New Orleans, Louisiana USA References 1. Gralla RJ, Itri LM, Pisko SE et al. Antiemetic efficacy of highdose metoclopramide: Randomized trials with placebo and
11.
12.
prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med 1981; 305:905-9. Kris MG, Gralla RJ, Tyson LB et al. Improved control of cisplatin-induced emesis with high-dose methoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 255 patients. Cancer 1985; 55: 527-34. Fozard JR, Mobarok A. Blockade of neuronal tryptamine receptors by metoclopramide. Eur J Pharmacol 1978; 49: 109-12. Ireland SJ, Straughan OW, Tyers MB. Influence of 5-HT uptake on the apparent 5-HT antagonist potency of metoclopramide on the rat isolated superior cervical ganglion. Br J Pharmacol 1987; 90: 151-60. Kris MG, Gralla RJ, Clark RA et al. Dose ranging evaluation of the serotonin antagonist GR-507/75 (GR38032F) when used as an antiemetic in patients receiving cancer chemotherapy. J Clin Oncol 1988; 6:659-62. Kris MG, Gralla RJ, Clark RA et al. Phase II trials of the serotonin antagonist GR38032 F for the control of vomiting caused by cisplatin. J Natl Cancer Inst 1989; 81: 42-6. Marty M, Pouillart P, Scholl S et al. Comparison of the 5-hydroxytryptamine 3 (serotonin) receptor antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990; 322: 816-21. De Mulder PH, Seynaeue C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized double-blind crossover study. Ann Intern Med 1990; 113: 834-40. Hainsworth J, Harvey W, Pendergrass K et al. A single-blind comparison of intravenous ondansetron with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy. J Clin Oncol 1991; 9: 721-8. Roila F, Tonato M, Cognetti F et al. Prevention of cisplatininduced emesis: A double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 1991; 9:674-8. Coates AS, Childs A, Cox K et al. Severe vascular adverse effects with thrombocytopenia and renal failure following emetogenic chemotherapy and ondansetron. Ann Oncol 1992; 3 (9>. 719-22. Clark RA, Gralla RJ, Grunberg SM et al. Effective single dose treatment in patients receiving high cisplatin doses: Establishment of the optimal IV dose of the 5-HT3 antagonist MDL 73, 147EF. Proc Am Soc Oncol 1992; 11:382.
