Aapro, Matti

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Support Care Cancer (1997) 5:1-2 © Springer-Verlag 1997 Matti S. Aapro A]ways more "setrons": how many do we need? The possible abuse of "setrons" in radiation oncology [1] has been re- cently discussed, not to mention the confusing issues about the use of these excellent agents in the prevention of delayed emesis and in the area of post-anesthesia n u- sea and vomiting. This journal is- sue contains several important con- tributions to the area of cytotoxic drug induced nausea and vomiting. It actually opens with a glimpse at the future by S. M. Grunberg, which addresses everal issues, both methodological nd new agents, such as the NK-1 receptor antagonists [3]. Several such new agents are presently under devel- opment, and in view of the promis- ing results of the initial clinical studies he cites, äcute and delayed emesis might be better controlled than with present-day combina- tions. If such agents could decrease the use of steroids in potentially curative settings, they could be of benefit to the patient, as reasona- M. S. Aapro, M.D.1 Divisione di Oncologia Medica, Istituto Europeo di Oncologia, Milan, Italy and Division d'Onco-Hématologie, Hôpital Cantonal Universitaire, Genève, Switzerland Mailing address: 1 Clinique de Genolier, CH-1272 Genolier, Switzerland Tel.: (+41) 22-366 9134 Fax: (+41) 22-366 9131 ble doubt about the chronic use of of prednisone (admittedly a differ- ent approach from short-term an- tiemetic usage) has recently been expressed in the setting of adjuvant therapy for breast cancer [6]. Oth- er mechanisms of antiemetic action could also be developed, using our knowledge of peptide YY, a good candidate as a mediator of emesis [9]. One might also want to look at mixed 5-HT3 receptor antagonists/ 5-HT4 receptor agonists, such as R- zacopride, which is under develop- ment at present, and not forget the potential of drugs like metopima- zine, as discussed by Herrstedt et al. [4]. It is true, as D. Warr says in his contribution in this issue of Supportive Care in Cancer, that a combination of a 5-HT3 receptor antagonist and a corticosteroid should be considered a standard in the prevention of chemotherapy-in- duced acute nausea and vomiting, while the role of the "setrons" in delayed emesis seems modest [10]. As resources allocated for health- related issues are becoming more and more scarce, it is mandatory to discuss the cost-benefit ratio of the use of many drugs, and certainly one can advocate the use of mod- ern combinations in preventing emesis when a high proportion of patients (what is "high"?) can be expected to vomit if left untreated. Guidelines are needed in the same spirit of those that have already been developed for the use of he- mopoietic growth factors; the Mul- tidisciplinary Association for Sup- portive Care in Cancer (MASCC) will soon issue internationally valid recommendations, a  it seems diffi- cult to follow the already existing Canadian ones [7] or the soon to be published American ones. How- ever, one should not forget that the world also uses curative, but highly emetogenic chemotherapies in countries with extremely limited resources. What can be done there? In my eyes, companies should offer the "setrons" at cost in these settings, and in these countries one should not forget that metoclopramide and corticos- teroids are an acceptable and effec- tive combination, when properly used, and could still be offered as a first-line preventative combination for most cancer patients. But maybe the cost of "setrons" will be pushed even lower, as the competi- tion in the market becomes even fiercer. In most areas of the world we already have granisetron, on- dansetron and tropisetron, with variable commercial names. (When will we have a single commercial name all over the world? When will authorities accept hat many travel today?) These agents are uniformly efficacious for the pre- vention of acute chemotherapy-in- duced nausea and vomiting. There are no data from properly con- trolled randomized studies to sug- gest a major clinically significant difference in efficacy between these agents, at least when they are used at an adequate dose, as dis- cussed by Perez et al. for granise- tron [8] and by Warr for ondanse- tron [10]. So now we have in this issue a paper about a new "se- tron," which is being introduced in many countries: dolasetron. The development of this agent from phase I [5] until now makes orte wonder, as with ramosetron, azase- tron and others, if we really had to devolop another "setron." From the data reported in the paper first authored by the late B. Chevallier, it is evident that dolasetron is an efficacious and well-tolerated agent [2]. There are many other papers about the phase I I I  studies with dolasetron, and a couple are al- luded to in D. Warr's review. What do these papers tell us about this agent? Nothing of substance, noth- ing that might make one decide to change his or her prescribing ha- bits. Where is the advantage of this agent? We cannot find evidence of an advantage in efficacy, in sched- ule, in formulation, or in side ef- fects. The preclinical studies also did not indicate a major advantage for this agent compared to the oth- er available antiemetics. The realo ity is that the development of this cousin of MDL 72'222, the first 5- HT3 receptor antagonist to be tested as an antiemetic, has been slower than that of its analogues. Do we then need new "setrons"? Yes, because when highly reputa- ble companies bring new agents of the same class into the market, it tends to stabilize and usually de- crease the prices of the com- pounds. This is at least what hap- pened in many of those markets where granisetron or tropisetron were introduced to compete with one or two other "setrons." We can thus hope that at least this as- pect will be favorable for the pa- tient and strongly recommend that "setrons" that are still being devel- oped should be brought to the phase I I I  level only if they have, on top of their 5-HT3 receptor an- tagonist activity, at least some oth- er advantage, i.e., if they actually inhibit other mechanisms. Let us remember how long one thought that high-dose metoclopramide was a dopamine receptor antagonist until its 5-HT3 receptor antagonist activity was actually understood. References 1. Aapro MS (1996) Radiotherapy and drugs: setrons once again. Ann Oncol 7: 553-554 2. Chevallier B, Cappelaere P, Splinter T, Fabbro M, Wendling JL, Cals L, Catimmel G, Giovannini M, Khayat D, Bastit P, Claverie N (1997) A dou- ble-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea nd vomiting in cancer pa- tients receiving high-dose cisplatin chemotherapy. Support Care Cancer 5 : 22-30 3. Grunberg SM (1997) Innovative ap- proaches in the treatment of emesis. Support Care Cancer 5:9-11 4. Herrstedt J, Sigsgaard T, Angelo HR, Kampmann JP, Hansen M (1997) Dose-finding study of oral metopi- zamine. Support Care Cancer 5:38-43 5. Kirchner V, Aapro M, Alberto P, et al (1993) Phase I trial of MDL 73.147EF: a new 5-HT3 antagonist for the prevention of chemotherapy-in- duced nausea nd vomiting. Ann On- col 4: 481-485 6. Marini G, Murray S, Goldhirsch A, et al (1996) The effect of adjuvant pred- nisone combined with CMF on pat- terns of relapse and occurrence of second malignancies in patients with breast cancer. Ann Oncol 7:245-250 7. Osoba D, Warr DG, Fitch MI, et al (1995) Guidelines for the optimal management of chemotherapy-in- duced nausea nd vomiting: a consen- sus. Can J Oncol 5:381-400 8. Perez EA, Navari RM, Kaplan HG, Gralla R J, Grunberg SM, Palmer RH, Fitts D (1997) Efficacy and safety of different doses of granisetron for the prophylaxis of cisplatin-induced me- sis. Support Care Cancer 5:31-37 9. Perry MR, Rhee J, Smith WJ (1994) Plasma levels of peptide YY correlate with cisplatin-induced mesis in dogs. J Pharm Pharmacol 46:553-557 10. Warr D (1997) Standard treatment of chemotherapy-induced emesis. Sup- port Care Cancer 5:12-16 

Always more "setrons”: How many do we need?

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Always more "setrons”: How many do we need?

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