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

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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?

T h e possible abuse of "setrons" in radiation oncology [1] has been recently discussed, not to mention the confusing issues about the use of these excellent agents in the p r e v e n t i o n of delayed emesis and in the area of post-anesthesia nausea and vomiting. This journal issue 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 several issues, b o t h methodological and new agents, such as the NK-1 receptor antagonists [3]. Several such new agents are presently u n d e r devel- opment, and in view of the promis- ing results of the initial clinical studies he cites, äcute and delayed emesis might be b e t t e r controlled than with present-day combinations. 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 d o u b t about the chronic use of of prednisone (admittedly a different approach from short-term antiemetic usage) has recently b e e n expressed in the setting of adjuvant t h e r a p y 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]. O n e might also want to look at mixed 5-HT3 r e c e p t o r antagonists/ 5-HT4 r e c e p t o r agonists, such as R- zacopride, which is u n d e r develop- ment at present, and not forget the potential of drugs like metopima- zine, as discussed by H e r r s t e d t 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 r e c e p t o r antagonist and a corticosteroid should be considered a standard in the p r e v e n t i o n of chemotherapy-induced 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 m o r e and m o r e scarce, it is m a n d a t o r y 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 p r o p o r t i o n of patients (what is "high"?) can be expected to vomit if left untreated. Guidelines are n e e d e d in the same spirit of those that have already

b e e n developed for the use of he- mopoietic growth factors; the Mul- tidisciplinary Association for Sup- portive Care in Cancer ( M A S C C ) will soon issue internationally valid recommendations, as it seems diffi- cult to follow the already existing Canadian ones [7] or the soon to be published A m e r i c a n ones. How- ever, one should not forget that the world also uses curative, but highly emetogenic chemotherapies in countries with extremely limited resources. W h a t 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 m e t o c l o p r a m i d e 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 m a y b e the cost of "setrons" will be pushed even lower, as the competi- tion in the m a r k e t b e c o m e s even fiercer. In most areas of the world we already have granisetron, on- dansetron and tropisetron, with variable commercial names. ( W h e n will we have a single commercial n a m e all over the world? W h e n will authorities accept that many travel today?) These agents are uniformly efficacious for the prevention of acute chemotherapy-induced nausea and vomiting. T h e r e are no data from properly con-

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trolled r a n d o m i z e d studies to sug- gest a m a j o r clinically significant difference in efficacy b e t w e e n these agents, at least w h e n they are used at an a d e q u a t e dose, as discussed by Perez et al. for granisetron [8] and by W a r r for ondanse- tron [10]. So now we have in this issue a p a p e r a b o u t a new "setron," which is being introduced in m a n y countries: dolasetron. T h e d e v e l o p m e n t of this agent f r o m phase I [5] until n o w m a k e s orte wonder, as with r a m o s e t r o n , azase- tron and others, if we really had to d e v o l o p a n o t h e r "setron." F r o m the data r e p o r t e d in the p a p e r first a u t h o r e d by the late B. Chevallier, it is evident that dolasetron is an efficacious and well-tolerated agent [2]. T h e r e are m a n y other papers a b o u t the phase I I I studies with dolasetron, and a couple are al-

luded to in D. W a r r ' s review. W h a t do these p a p e r s tell us a b o u t this agent? Nothing of substance, nothing that might m a k e one decide to change his or her prescribing ha- bits. W h e r e is the a d v a n t a g e of this agent? W e cannot find evidence of an a d v a n t a g e in efficacy, in sched- ule, in formulation, or in side ef- fects. T h e preclinical studies also did not indicate a m a j o r a d v a n t a g e for this agent c o m p a r e d to the other available antiemetics. T h e realo ity is that the d e v e l o p m e n t of this cousin of M D L 72'222, the first 5- H T 3 r e c e p t o r antagonist to b e tested as an antiemetic, has b e e n slower than that of its analogues. D o we then n e e d new " s e t r o n s " ? Yes, b e c a u s e when highly reputa- ble c o m p a n i e s bring new agents of the same class into the m a r k e t , it tends to stabilize and usually de-

crease the prices of the com- pounds. This is at least what hap- p e n e d in m a n y of those m a r k e t s w h e r e granisetron or t r o p i s e t r o n w e r e introduced to c o m p e t e with o n e or two o t h e r "setrons." W e can thus h o p e that at least this as- pect will be f a v o r a b l e for the patient and strongly r e c o m m e n d that " s e t r o n s " that are still being devel- o p e d should be b r o u g h t to the phase I I I level only if they have, on top of their 5-HT3 r e c e p t o r antagonist activity, at least some other advantage, i.e., if they actually inhibit other mechanisms. L e t us r e m e m b e r how long one thought that high-dose m e t o c l o p r a m i d e was a d o p a m i n e r e c e p t o r antagonist until its 5-HT3 r e c e p t o r 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 and vomiting in cancer patients 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-induced nausea and vomiting. Ann On- col 4: 481-485

6. Marini G, Murray S, Goldhirsch A, et al (1996) The effect of adjuvant prednisone 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-induced nausea and 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 emesis. Support Care Cancer 5:31-37 9. Perry MR, Rhee J, Smith WJ (1994)

Plasma levels of peptide YY correlate with cisplatin-induced emesis 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