2007 - Comparative Activity of Antiemetic Drugs

Critical Reviews in Oncology/Hematology 61 (2007) 162175

Comparative activity of antiemetic drugs

Content

1. Intro2. Anti

2.1.

2.2.

2.3.

2.4.

2.5.

2.6.

CorrespE-mail

1040-8428doi:10.101Karin Jordan a,, Hans J. Schmoll a, Matti S. Aapro ba Department of Internal Medicine IV, Haematology/Oncology, Martin-Luther-University Halle/Wittenberg,

Ernst-Grube-Str. 40, 06120 Halle/Saale, Germanyb Institut Multidisciplinaire dOncologie, Clinique de Genolier S.A., CH-1272 Genolier, Switzerland

Accepted 25 August 2006

s

duction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163emetic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

5-HT3-receptor-antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642.1.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642.1.2. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642.1.3. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1652.1.4. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662.1.5. Genetic polymorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662.1.6. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662.2.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662.2.2. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662.2.3. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1672.2.4. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1672.2.5. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Neurokinin-1-receptor-antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1672.3.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1672.3.2. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1682.3.3. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1682.3.4. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1682.3.5. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168Substituted benzamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1702.4.1. Metoclopramide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1702.4.2. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1702.4.3. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1702.4.4. Dose recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1702.4.5. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1702.4.6. Metopimazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1702.4.7. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170Neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712.5.1. Phenothiazines/butyrophenones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712.5.2. Atypical neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712.5.3. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712.6.1. Lorazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

onding author. Tel.: +49 345 557 2924; fax: +49 345 557 2950.address: [email protected] (K. Jordan).

/$ see front matter 2006 Elsevier Ireland Ltd. All rights reserved.6/j.critrevonc.2006.08.003

K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175 163

2.6.2. Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1712.6.3. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

2.7. Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

2.8. A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

2.9. H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

3. Conclu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Referen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Biograp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Abstract

Nausea an s receivvomiting (C d, occuare available ptor-adopamine-re s. Within 7080% o evelopThe pathoph hanismrecent develo d the la 2006 Else

Keywords: A lines; 5antagonists; C

1. Introdu

The goasea and vowere com

apy and fpotentiallover thethe contr(CINV).(5-HT3-Rin chemoacute CINdelayed Cbeen intronew agen

Corticshow whantiemetiCINV. Anantagonisin this clshown thbinationand delaychemothe

CINVoccurring

delayeent; a

nts whose emetic episodes are triggered by taste, odour, thoughts, or anxiety secondary to a history of poormon adverse events of certain types of chemother-orced up to 20% of patients to postpone or refusey curative treatment [1]. Clinical and basic researchpast 25 years has lead to steady improvements inol of chemotherapy-induced nausea and vomitingThe development of the 5-HT3-receptor-antagonistsAs) has been one of the most significant advancestherapy of cancer patients. While being effective in

V, 5-HT3-RAs fail to completely protect againstINV. Palonosetron, a new 5-HT3-RA, has recentlyduced into clinical practice. The actual role of thist has to be established in the daily practice.osteroids are often underestimated although theyen combined with other antiemetic agents goodc efficacy in the prevention of acute and delayedother group of antiemetics, the neurokinin receptor-ts, has recently been developed, and the first drugass, aprepitant, has been approved. Studies haveat patients benefit from the use of this drug in com-with standard antiemetic therapy, both in the acuteed setting of highly and moderately emetogenicrapy.may be classified into three categories: acute onset,within 24 h of initial administration of chemother-

response to antiemetic agents or by inadequate antiemeticprophylaxis in the previous cycle of chemotherapy [2,3](Table 1).

The emetogenic potential of the chemotherapeutic agentsused is the main risk factor for the degree of CINV. In regardto its emetogenic potential, the chemotherapeutic agents areclassified into four emetic risk groups: high, moderate, lowand minimal [46]. Other patient risk factors including youngage, female gender, a history of low alcohol intake, experi-ence of emesis during pregnancy, impaired quality of life and

Table 1Three categories of chemotherapy-induced nausea and vomiting (CINV)Acute nausea and vomiting

- within the first 24 h after chemotherapy- mainly by serotonin (5 HT) release from the enterochromaffin cells

Delayed nausea and vomiting- after 24 h to 5 days after chemotherapy- various mechanisms: mainly substance P mediated, disruption of

the blood brain barrier, disruption of the gastrointestinal motility,adrenal hormones [3]

Anticipatory nausea and vomiting- Occurrence is possible after 1 cycle of chemotherapy [2]- Involves the element of classic conditioning2.7.1. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ntihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.8.1. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .erbs as antiemetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.9.1. Ginger (Zingiber ofcinale Roscoe) . . . . . . . . . . . . . . . . . . . .2.9.2. Peppermint (Mentha x piperita Lamiaceae) . . . . . . . . . . . . .2.9.3. Comparative assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .sion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .hy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

d vomiting continues to be an important problem for cancer patientINV) are classified as acute, occurring within the first 24 h, or delayefor the management of nausea and vomiting, including 5-HT3-receceptor antagonists, benzodiazepines, neuroleptics and cannabinoidf patients, whereas the control of nausea remains suboptimal. The dysiology of delayed emesis is less well understood, and multiple mecpments in the antiemetic therapy, including new antiemetic drugs an

vier Ireland Ltd. All rights reserved.

ntiemetic drugs; Antiemetic therapy; MASCC guidelines; ASCO guidehemotherapy-induced nausea and vomiting (CINV)

ction

l of each antiemetic therapy is to abolish nau-miting. Twenty years ago, nausea and vomiting

apy;treatmpatiesighting chemotherapy. Chemotherapy-induced nausea andrring after the first 24 h. A number of antiemetic agents

ntagonists, corticosteroids, NK-1-receptor-antagonists,modern antiemetic therapy, vomiting can be preventedment of acute emesis is known to depend on serotonin.s may contribute, including substance P. Here, the most

test guidelines for antiemetic prophylaxis, are reviewed.

-HT3-receptor-antagonists; Steroids; Neurokinin-1-receptor-

d onset, occurring 24 h to several days after initialnd anticipatory nausea and vomiting, observed in

164 K. Jordan et al. / Critical Reviews in Oncology/Hematology 61 (2007) 162175

previous experience of chemotherapy are known to increasethe risk of nausea and vomiting after chemotherapy [4,7].

This article will review the most recent developmentsin antiemeantagonistolanzapine

2. Antiem

With mpreventedantiemeticthe control

2.1. 5-HT3

The intrved the minduced emdrugs inhas confirmRAs, ondapalonosetroStates.

2.1.1. MecSeroton

emesis aftein three sizone locateius of the vis a circumfourth ventbarrier, andcirculationis located imajor inpuand sympa

Followitonin (5-HTsmall intestent neuronereleased se5-HT3 receresponse mthe area po

2.1.2. Clin2.1.2.1. 5-setron, thethe Unitedin 1994. Sithe field toof acute CIadvantageoclopramide

of acute CINV in both highly and moderately emetogenicchemotherapies [7,1214].

.2. 5-ly emelly aclayedotheraeffica

hasonpporteer-SmIAA) e

(80 mafter

s thereomitiOf coitanth rate3-RAshed aoll eten ofAprepegime

in tultin

MASC3-RAogenicoderaRAs ioversiemonsficantldexamthe c

nsetro59.6%ism wbalancthe u

nsetrobothombinwere

addresion trer thann fromDelayinatio

nother3-RApermtic therapy, including the neurokinin-1-receptor-aprepitant, the new 5-HT3-RA, palonosetron andan atypical antipsychotic drug.

etic agents

odern antiemetics, vomiting can completely bein up to 7080% of patients [8,9]. Combinationregimens have become the standard of care forof CINV.

-receptor-antagonists

oduction of 5-HT3-RAs has dramatically impro-anagement of chemotherapy- and radiotherapy-esis. The wide experience acquired with these

daily clinical practice since the early 1990sed the remarkable safety profile. Five 5-HT3-

nsetron, granisetron, tropisetron, dolasetron andn, are currently available in Europe and the United

hanism of actionin is the main neurotransmitter responsible forr chemotherapy. The 5-HT3 receptors are locatedtes: gastrointestinal tract, chemoreceptor triggerd in the area postrema and nucleus tractus solitar-omiting centre. The chemoreceptor trigger zoneventricular organ located at the caudal end of thericle. This structure lacks an effective bloodbrain

will detect emetic agents in both the systemicand the cerebrospinal fluid. The vomiting centren the brainstem medullary structures. It receivests from the chemoreceptor trigger zone, and a vagalthetic input from the gut.ng exposure to radiation or cytotoxic drugs, sero-

) is released from enterochromaffine cells in theinal mucosa, which are adjacent to the vagal affer-s on which 5-HT3 receptors are located [10]. Therotonin activates vagal afferent neurones via theptors which lead ultimately to a severe emeticediated via the chemoreceptor trigger zone withinstrema [11].

ical studiesHT3-receptor-antagonists in acute CINV. Ondan-first 5-HT3-RAs developed, became available inStates in 1991 and was followed by granisetronnce then, numerous trials have been published inevaluate the role of 5-HT3-RAs in the preventionNV. All studies demonstrated that 5-HT3-RAs areus in comparison to other antiemetics (e.g., meto-, dexamethasone and aprepitant) in the prevention

2.1.2Highversa

of dechembe asametis suWild(5-Hplatinpeakpeakand v[20].aprepa hig5-HTpubliSchmregim[21].trol rCINVthe Mcer (5-HTemet

MHT3-contrbe dsigniwithet al.ondaarm (criticwelluatedondafromthe carm

trialbinatbettetectio[25].comb

A5-HTwereHT3-receptor-antagonists in delayed emesis.togenic chemotherapy: 5-HT3-RAs are not uni-

cepted as standard therapy in preventive treatmentCINV in patients receiving highly emetogenicpy [1517]. Metoclopramide has been shown tocious as 5-HT3-RAs when combined with dex-

e in the prevention of delayed CINV [18,19]. Thisd by a study looking into serotonin metabolism.ith measured urinary 5-hydoxyindoleacetic acidxcretion during the 48 h following high dose cis-g/m2). They found a significant urinary 5-HIAA

6 h after the induction of chemotherapy, with noafter, suggesting that the delayed period nausea

ng is not associated with the release of serotoninurse, also due to the fact that the combination ofand dexamethasone in the delayed phase showedof protection is important for the assessment of

s in the delayed phase [8,9]. Although not fullyt the accrual of the new guidelines the study ofal. compared an aprepitant regimen with a controlondansetron + dexamethasone given for 4 days

itant and dexamethasone were superior to the con-n (ondansetron and dexamethasone) in preventinghe delayed phase. Based on all these findings,ational Association for Supportive Care in Can-C) and ASCO guidelines no longer recommend

s for the prevention of delayed CINV in highlychemotherapy [12].

tely emetogenic chemotherapy: The role of 5-n moderately emetogenic chemotherapy remainsal. In a recently published meta-analysis, it couldtrated that the addition of a 5-HT3-RA did noty improve control of delayed emesis as comparedethasone monotherapy [22]. In a study by Kaizer

omplete response rate for delayed emesis in then arm was significantly higher than in the placebo

versus 41.1%, p = 0.012) [23,24]. However, oneas that the patient baseline characteristics were noted in both groups. Another multicenter study eval-se of dexamethasone alone or in combination withn [24]. In terms of providing complete protectiondelayed vomiting and moderate to severe nausea,ation therapy arm and the dexamethasone alone

statistically equivalent. Another big randomisedsed the same issue. The results showed that com-atment (dexamethasone plus 5-HT3-RA) was notdexamethasone alone in achieving complete pro-

delayed emesis (41% versus 47%, respectively)ed nausea, however, was significantly less in then arm.recently published study compared two different

s palonosetron and ondansetron [26]. No steroidsitted during the study period. A single i.v. dose


Table 2Pharmacokinetic parameters of 5-HT3-receptor-antagonists

Ondansetron Granisetron Tropisetron Dolasetron Palonosetron

Half-life (h) 8.0 7.5 40Receptor bind 8.8 7.6 10.5

of palonoswere admiemesis, nonificantly bondansetrothat the effiemesis is dlong plasmdoses of ppared to aarm [27]. D5% of patieshowed a mdelayed peto evaluatecombinatio

Due tolines recomof choice ain the preverate emetin patientsbased chem

2.1.2.3. Coreceptor-anare efficaciof the syspalonosetroagent overgranisetronall studies[31], andgranisetronwith ondanof more thshowed annificant adclear advana subanalysstrated thati.v., appearthis observthat were uthe commoa lack ofDespite th5-HT3-RAclinically rmeta-analy

d so far at that time [26,27]. In the three availablemised studies, palonosetron has proven to be at leastective as the presently available 5-HT3-RAs in the pre-on of acute emesis after both highly and moderatelyogenic chemotherapy. In the setting of highly emeto-chemotherapy, palonosetron was as effective as a singleof ondansetron for the prevention of delayed eme-

s lately published by Aapro et al. [36]. In the settingoderately emetogenic chemotherapy, a single dose ofosetron 0.25 mg provided significant better control than

r ondansetron 32 mg (Pal. versus Ond.: 81.0% versus) or

2.9%)have

ondann thag thesary wd at lelighteen s, ondosetrointerc

. Doshen adinto c

e lowed (Tativity bal andsched

emoth

3es of 5-

setron

etron

etron

etron4.0 9.0ing constant, pKi 8.1 8.4

etron (0.25 or 0.75 mg) or ondansetron (32 mg)nistered on day 1. Complete response rates (norescue medication) in the delayed phase were sig-etter in the 0.25 mg palonosetron arm than in then arm (74% versus 51%). The authors suggestedcacy of palonosetron in the prevention of delayedue to its high 5-HT3 receptor binding affinity anda elimination half-life. In another study singlealonosetron (0.25 and 0.75 mg i.v.) were com-single dose of dolasetron 100 mg i.v. as the thirdue to a late amendment allowing corticosteroids,nts received these additional agents. Palonosetronarkedly improved complete response rate in the

riod (54.0% versus 38.7%). Further studies havethe role of this new 5-HT3-RA palonosetron inn with steroids.these findings, the MASCC and ASCO guide-mend that dexamethasone should be the agent

nd 5-HT3-RAs can be used as an alternative agentention of delayed nausea and vomiting in mod-ogenic chemotherapy [6,28]. Recommendationsreceiving an anthracycline + cyclophosphamide-otherapy are different and discussed below.

mparative efcacy of the available 5-HT3-tagonists. All currently marketed 5-HT3-RAs

ous in preventing acute CINV [7,12,29,30]. Nonetematic reviews done so far (no inclusion ofn) have clearly demonstrated superiority of oneanother. These studies included a comparison of, ondansetron, tropisetron and dolasetron, usingas references rather than head-to-head trials

meta-analyses of randomised trials comparingwith ondansetron [32], granisetron or tropisetronsetron [33]. A recently performed meta-analysisan 40 cisplatin and non-cisplatin based studiesequivalence of ondansetron and granisetron, a sig-vantage for granisetron over tropisetron, and notage of ondansetron over tropisetron [34,35]. Inis of granisetron and ondansetron, it was demon-in non-cisplatin-based studies, ondansetron, 8 mgs to be inferior to granisetron, 3 mg i.v., althoughation comes from an analysis of small studiesnderpowered. No comparisons were made withnly used dose of 1 mg i.v. granisetron due to

studies comparing this dose with ondansetron.e statistically significant differences among the

lisherandoas effventiemetgenicdosesis aof mpaloneithe68.8%sus 5phaseandknowamon

neces

istereIn

has bdosespalonto be

2.1.3W

taken

Thus

ac

Or No

ch

TableDosag

Drug

Ondan

Granis

Tropis

Dolass, it is difficult to know if these differences areelevant. Palonosetron was not included in thissis because only two studies were fully pub-

Palonosetron

Adapted fromdolasetron 100 mg. (Pal. versus Dol.: 63.0% ver-[26,27]. However, results referring to the delayedto be interpreted with caution because dolasetron

setron only were given on day 1 although it ist the half-life and receptor binding is differentthree 5-HT3-RAs (Table 2). Further studies arehen the comparator 5-HT3-RA has to be admin-ast for 3 days.of the new MASCC and ASCO guidelines, ituggested that, given at biologically equivalent

ansetron, granisetron, dolasetron, tropisetron andn are equally efficacious, equally safe, and appearhangeable [6,12].

e recommendationministering 5-HT3-RAs, several points should beonsideration [7,12,37]:

est fully effective dose for each agent should beble 3); higher doses do not enhance any aspect ofecause of the receptor saturation.intravenous route are equally effective.ule is better than a single dose daily given before

erapy.

HT3-RAsRoute Recommended dose per day

p.o. 1224 mgi.v. 8 mg (0.15 mg/kg)p.o. 2 mgi.v. 1 mg (0.01 mg/kg)p.o. 5 mgi.v.

p.o. 100 mg

i.v. 100 mg (1.8 mg/kg)i.v. 0.25 mg

refs. [7,12,30,37].


Table 4Cytochrome P450 (CYP) enzymes involved in the metabolism of 5-HT3-RAs

5-HT3-receptantagonists

GranisetronOndansetronDolasetronTropisetronPalonosetron

2.1.4. SideThe adv

with headadescribed [trocardiograll availablof commerhave not be

2.1.5. GenThe cyt

the metaboicant roleshown in Twidest specmainly byCYP1A2. Hers of CYAUC of padolasetronTropisetron2D6 isoenzof poor andof tropisetrin poor meers (1 out ohealthy volclinical restropisetron[40,44]. Gfound to hpared with

2.1.6. ComWithout

in the prevactivity inactivity inpatient migthe delayedstrated antifurther invesary to exp

In accoappear to b

analysis suggests some differences between the 5-HT3-RAs,but it is not clear yet if these findings translate into clinicalpractice.

Steroi

eroidsmeticothert in rarioritycy [7]

. Mece me

ity araglandl fluide [46]act asonin i3 rece

. Clin

.1. Stonistsnstratpy inf 75%

observotheraer evametic

hasonoved tbo or

51].

.2. Stonistsxame

atedmethaotherachieveotheraes witelayedor- Enzyme system

CYP3A4/5CYP1A1, CYP1A2, CYP2D6, CYP3A/4/5CYP2D6, CYP3A/4/5CYP2D6, CYP3A/4/5CYP2D6, CYP1A2, CYP3A

effectserse effects of 5-HT3-RAs are generally mild,che, constipation, diarrhea and asthenia mainly38]. Small, transient, reversible changes in elec-aphic parameters have been shown to occur withe 5-HT3-RAs. However, after more than 13 yearscial use, clinically relevant cardiovascular effectsen reported [39].

etic polymorphismochrome P450 enzyme system participates inlism of all five 5-HT3-RAs, but plays a signif-only in the metabolism of tropisetron [40]. Asable 4, ondansetron and palonosetron utilizes thetrum of isoenzymes. Palonosetron is metabolisedCYP2D6 and to a lesser extent by CYP3A andowever, a study on poor and extensive metabolis-

P2D6 has not shown any modification of thelonosetron in these subjects [41]. Tropisetron andare predominately metabolised by CYP2D6 [42].undergoes metabolism by the cytochrome P450

yme system, which shows phenotypic populationextensive metabolisers. This means that the T 1/2

on is 7.3 h in most patients, but is prolonged to 30 htabolisers and shortened in ultrafast metabolis-f 12 caucasians) [43,44]. Studies in patients and

unteers have demonstrated these differences in theponses and pharmacokinetics of ondansetron andare due to genetic polymorphisms of CYP2D6

enetically defined ultra-rapid metabolisers wereave higher scores of nausea and vomiting, com-poor metabolisers who had the lowest scores.

parative assessmentdoubt 5-HT3-RAs are the most important agentsention of CINV. Whereas they have excellentthe prevention of acute CINV, they show little

2.2.

Stantiewitheffecsupeeffica

2.2.1Th

activprostspinacentrmayserot5-HT

2.2.22.2.2antagdemotheration owas

chemfurthAntieametimprplace[49

2.2.2antagof deevaludexachemare a

chemstudi

D

the prevention of delayed CINV. However, someht benefit from the additional usage of setrons insetting. Palonosetron, a new 5-HT3-RA, demon-

emetic activity in the delayed period. However,stigation with different study designs are neces-

lore the actual role of palonosetron.rdance to the new guidelines, the 5-HT3-RAse interchangeable. A recently performed meta-

preventionan antiemesuperiorityagainst delits antiemeneurolepticnausea andchemotherads

are an integral component of almost eachtherapy [12,30,45]. When used in combinationantiemetics, steroids appear to exert a booster

ising the emetic threshold. No study supports theof one corticosteroid over another in terms of.

hanism of actionchanism by which steroids exert their antiemetice not fully understood, but they may affectin activity in the brain, modify the bloodcerebro-barrier and inhibit cortical input to the vomiting

. Further, the anti-inflammatory effect of steroidsan antiemetic by either preventing the release ofn the gut or by interfering with the activation ofptors in the gastrointestinal tract [47].

ical studieseroids before the introduction of 5-HT3-receptor-. First results about the efficacy of steroids wereed in patients refractory to standard antiemetic1980. In a study by Silvey et al. in 1988, a reduc-

in the incidence of nausea and 82% in vomitinged of 55 patients treated with different kinds ofpies [48]. These initial observations led to theluation of corticosteroids in randomised trials.benefit was evident when a single dose of dex-

e administered before chemotherapy significantlyhe control of nausea and vomiting compared withcompared with traditional antiemetics at this time

eroids after the introduction of 5-HT3-receptor-. Acute CINV: The efficacy of the combination

thasone and 5-HT3-receptor-antagonist has beenin numerous randomised clinical trials. Whensone is administered in the first 24 h afterpy, complete response rates between 80 and 90%d in patients receiving moderately emetogenicpy [52,53], and between 60 and 70% in most

h cisplatin [54,55].CINV: Dexamethasone plays a major role in theof delayed CINV although it is not approved astic. Available data from a meta-analysis showedof dexamethasone over a 5-HT3-RA in protectionayed CINV [56]. Dexamethasone has also showntic efficacy over other agents (metoclopramide,s and benzodiazepines) for preventing delayedvomiting in both non-cisplatin and cisplatin basedpy [16,18,24].


2.2.2.3. Steroids after the introduction of NK-1-receptor-antagonists. In the two approval studies of aprepitant,dexamethasone was used in combination for both acute anddelayed CINV [8,9]. Due to inhibition of CYP3A4 throughaprepitant, dexamethasone was given in a reduced dose. Inthe study by Warr et al., in patients receiving moderate/highlyanthracycline-cyclophosphamide-based chemotherapy, dex-amethasone was used for the prevention of acute but not fordelayed CINV in both study arms [57]. Use of aprepitant asa mono therapy in the prevention of delayed emesis achieveda complete response rate of 55%. In the ondansetron, single-agent arm complete response was 49%. It is assumable thatthe combindelayed phrate. Furthe

2.2.2.4. Imcosteroids.highly emeethasone, ggave the beThe 20 mgwith 4, 8 aseen at 20doses [58].

The latesone in moby the Italiaferent dose4 mg dexamtogether wito 5 oral deemetic episthe acute (A80%; B: 81ethasone 8be the prefmoderate e

2.2.3. DosFor pre

coadministchemotheramoderatelychoice (TabMASCC an

Table 5Steroids

Drug

Dexamethaso

Methylpredni

2.2.4. Side effectsSteroids are considered to be safe antiemetics. Side effects

are usually dependent on dose and duration of therapy. In arecently pusone in themoderate-stion/epigasappetite (1week follomay interfthrough imfirmed in c

dditioarteryoved t[61].

. Comorticosmeticgent. Tntiemed CIhasonest proas shostudieg.e newrate ad. Pro

chemFor tostero

ogenicemetonted.

Neuro

e potreatmeniseded emNK-1meticand dotheraodera

. Mecbstan

ates ite NK-er-zonointesation of both dexamethasone and aprepitant in thease would have enhanced the antiemetic efficacyr studies are warranted.

portant studies to nd the optimal dose of corti-A large randomised study in patients receiving

togenic chemotherapy demonstrated that dexam-iven as a single 20 mg dose with a 5-HT3-RA,st results in preventing both nausea and vomiting.dose was the highest tested and was compared

nd 12 mg doses. No increase of side effects wasmg of dexamethasone compared with the lower

st publication finding the best dose of dexametha-derate emetogenic chemotherapy was publishedn Group for Antiemetic Research [45]. Three dif-

s of (A) 8 mg, (B) 24 mg or (C) 8 mg followed byethasone every 6 h for 24 h were administered

th a 5-HT3-RA. All patients received from days 2xamethasone 4 mg bid. Complete protection (noodes) was similar in all three treatment groups in: 89%; B: 84%; C: 85%) and delayed period (A:

%; C: 81%). The authors concluded that dexam-mg as a single dose prior to chemotherapy shoulderred dose to prevent acute emesis induced bymetogenic chemotherapy.

e recommendationvention of acute CINV, 20 mg (12 mg whenered with aprepitant) in highly emetogenicpy and a single dose of 8 mg dexamethasone inemetogenic chemotherapy should be the dose ofle 5) [45,58] and has been recommended by thed ASCO guidelines [6,12,13].

Route Recommended dose perday (mg), moderate/high

ne p.o. 8/12i.v.

solone p.o. 40125/40125i.v

the aaticimprvival

2.2.5C

antiegle afor adelayametthe bas w

thersettin

Thmodeperiogenicdrug.corticemetimalwarra

2.3.

Ththe trecogdelayfirstantieacutechemand m

2.3.1Su

mediThestrigggastrblished study, in patients receiving dexametha-prophylaxis of delayed CINV patients reported

evere problems with insomnia (45%), indiges-tric discomfort (27%), agitation (27%), increased9%), weight gain (16%) and acne (15%) in thewing chemotherapy [59]. Concerns that steroidsere with the antitumor effects of chemotherapymunosuppressive mechanisms have not been con-linical trials [60]. In one study by Kemeny et al.,n of dexamethasone to floxuridine into the hep-in patients with colorectal cancer significantly

olerance and showed a trend toward improved sur-

parative assessmentteroids improve the effect of almost any otheragent and have also considerable efficacy as sin-herefore, corticosteroids are an important agent

etic prophylaxis and therapy in both acute andNV. It is possible that the combination of dex-e and aprepitant in the delayed setting will givetection in moderately emetogenic chemotherapywn for highly emetogenic chemotherapy. Fur-

s should aim to evaluate this combination in this

guidelines recommend corticosteroids in high,nd low emetogenic chemotherapy for the acutephylaxis in patients receiving minimal emeto-otherapy is not warranted by any antiemetic

he prevention of delayed nausea and vomiting,ids are recommended for high and moderatechemotherapy. No prophylaxis of low and min-

genic chemotherapy by any antiemetic drug is

kinin-1-receptor-antagonists

ential value of the NK-1-receptor-antagonists innt of chemotherapy-induced vomiting was firstin ferret studies, showing that both acute andesis were completely absent. Aprepitant, the

-receptor-antagonist represents a new class ofagents. Aprepitant has been approved to be used inelayed emesis resulting from highly emetogenicpy (FDA) or cisplatin based chemotherapy (EU)tely emetogenic chemotherapy.

hanism of actionce P, a neuropeptide (mammalian tachykinin),s action through neurokinin-1-receptors (NK-1).1-receptors are abundant in the chemoreceptor-e (CTZ), nucleus tractus solitarius (NTS) andtinal tract (GI tract) [62].


2.3.2. Clinical studies2.3.2.1. Highly emetogenic chemotherapy. It has beenshown in several studies that aprepitant augments theantiemeticamethasonemesis infirst studyNK-1-recereceiving cCP-122,72platin impremarkablya small nuantagonistsacute and d

Navari ethree-arm tplatin, 67%dexamethathis improvthe NK-1-rfrom 33% ireceived thwas notedNK-1-recethere was nilar results[65].

The studand Campoa 5-HT3-Rreplaced bystudies conemesis wit

The stud[9] formedantagonist,two large rplatin navwere rando(standard thamethasonprior chemsone on dawas complecation). Thstudies wadelayed pestandard tand 78% indelayed pe

The stucomparedimen in whon day 1, aA common

of a 5-HT3-RA and a corticosteroid for multiple days. In arecently published trial the aprepitant regimen was comparedwith a multiple-day ondansetron regimen similar to that used

nicalhighe

p in th% ver

.2. Memetor [57]ting aion ofe firstproveperio

o sign5%, pps ovefor thothera

. Dosrando

le of ag per o

. Sidedverseitantanor

9,70].n patiemethamethaprepit3A4 a3A4itant atudy,sensiticomb

hasonapre

en et ar the ptaxel iitanta lowus che

. Come pub

of NKpy (5ficantactivity of the 5-HT3-receptor-antagonist and dex-e to inhibit both, acute and, particularly, delayedcisplatin based chemotherapy (Table 6). Thewas done by Kris et al. [63] evaluating the

ptor-antagonist CP-122,721 in 17 cancer patientsisplatin greater than 80 mg/m2. The addition of1 to a 5-HT3-RA and dexamethasone prior to cis-roved the control of acute and delayed emesis

as shown in Table 6.These promising results inmber of patients suggested that NK-1-receptor-may be useful in controlling cisplatin-induced

elayed vomiting.t al. [64] evaluated NK-1-receptor-antagonist in arial with 159 patients. In the first 24 h after cis-

of the patients who received granisetron andsone alone had a complete control of emesis, anded to 9394% in those patients who also receivedeceptor-antagonist. Delayed emesis was improvedn the placebo group to 7882% in the patients whoe NK-1-receptor-antagonist. Only little differencein the groups who received either 1 or 5 days theptor-antagonist. In terms of serious adverse events,o difference in the three treatment groups. Sim-were achieved in the study from Hesketh et al.

ies from Van Belle et al. [66], Cocquyt et al. [67]s et al. [68] demonstrated again the importance ofA in the prevention of acute emesis which cannot

an NK-1-receptor-antagonist. Furthermore thesefirmed the findings of the improvement of delayedh the use of an NK-1-receptor-antagonist.ies from Hesketh et al. [8] and Poli-Bigelli et al.the basis for the approval of the NK-1-receptor-aprepitant by the FDA in March 2003. In theseandomised, double-blind controlled studies cis-e patients received cisplatin (70 mg/m2) andmised to receive ondansetron and dexamethasoneerapy) plus placebo prior chemotherapy and dex-

e on days 24 or standard therapy plus aprepitantotherapy followed by aprepitant and dexametha-ys 2 and 3. The primary endpoint in both studieste response (no emesis and no use of rescue medi-

e complete response of the aprepitant group in boths significantly higher in the acute (8389%) andriod (6875%). In comparison, patients receivingherapy achieved complete response between 68the acute period and between 47 and 56% in the

riod.dies from Hesketh et al. and Poli-Bigelli et al.the aprepitant regimen with an ondansetron reg-ich ondansetron and dexamethasone were givennd dexamethasone alone was given on days 24.clinical used antiemetic regimen is a combination

in cliwere

grou(74.1

2.3.2erateso favomibinatin thdaysstudywas n

sus 5groubasischem

2.3.3A

profi80 m

2.3.4A

aprepness,

[66,6ilar idexadexa

ACYPCYPaprepIn a sas a

whenametwhenNygreithedoceaprephaveveno

2.3.5Th

tiontherasignipractice (Table 6) [21]. Complete response ratesr in the aprepitant group than in the ondansetrone acute (87.7% versus 79.3%), and delayed phasessus 63.1%) and reached statistical significance.

oderately emetogenic chemotherapy. In the mod-genic setting, one randomised study is published. Primary endpoint was complete response (nond no use of rescue medication). The triple com-ondansetron, dexamethasone and aprepitant used24 h followed by aprepitant mono for another 2d to be superior over the 5 days of the wholed (51% versus 42%, p = 0.015). However, thereificant difference in the delayed period (49% ver-

= 0.064). The control of nausea was similar in bothr the entire study period. This study formed thee approval of aprepitant for moderate emetogenicpy.

e recommendationmised study established the most favorable riskprepitant at doses of 125 mg per os on day 1 ands on days 2 and 3 [69].

effectseffects observed during clinical trials with

have included headache, abdominal pain, dizzi-exia, hiccups and mild transaminase elevationIn general, the incidence of adverse events is sim-nts treated with aprepitant plus a 5-HT3-RA and

sone and those treated with just the 5-HT3-RA andsone [8,9].ant is eliminated primarily by metabolism ofnd is a substrate and a moderate inhibitor of

[71]. Therefore, possible interactions betweennd other drugs have been investigated intensively.

a two-fold increase in the AUC of dexamethasoneve substrate of CYP3A4 could be demonstratedined with aprepitant [72]. In conclusion, the dex-

e dose should be reduced by approximately 50%pitant is administered. However, in a study byl, aprepitant had no clinically significant effect onharmacokinetics or toxicity of standard doses of

n cancer patients [73]. The authors concluded thatgiven at clinically recommended doses may onlypotential to affect the pharmacokinetics of intra-motherapeutic agents metabolised by CYP3A4.

parative assessmentlished studies have demonstrated that the addi--1-receptor-antagonist to the standard antiemetic-HT3-RA plus dexamethasone) appear to haveeffect in controlling cisplatin-induced acute as

K.Jo

rdanet

al./CriticalReviewsin

Oncology/H

ematology

61(2007)162175169

Table 6Studies with neurokinin-1-receptor-antagonists, mostly with aprepitant in highly emetogenic chemotherapies

n pts. Antiemetics day 1 CR in %day 1acute phase

p-Value(day 1)

Antiemetics days 23 (4) CR in %days 25delayed phase

p-Value(days 25)

p-Value overallphase (days 15)

Reference

NK-1-RA Setron Steroid NK-1-RA Setron Steroid

17 NK 15a NA 86a NA NA [63]NK 5-HT3-RA DEX 100 80

159 GRAN DEX 67 0.001 33 0.001 0.001 [64]APR GRAN DEX 94 78APR GRAN DEX 93 APR 82

61 GRAN DEX 67 0.09 37 0.0425 0.009 [65]NK GRAN DEX 86 NK 68

351 GRAN DEX 51 0.01 22 0.01 [68]APR GRAN DEX 75 APR 41APR* DEX 44 APR 39APR DEX 41 APR 39

53 OND 48 NS 17 0.04 NA [67]APR 37 48

177 OND DEX 83 0.001 38 0.05 NA [66]APR DEX 36 46APR DEX 44 APR 59

523 OND DEX 68 0.001 DEX 47 0.001 0.001 [9]APR OND DEX 83 APR DEX 68

521 OND DEX 78 0.001 DEX 56 0.001 0.001 [8]APR OND DEX 89 APR DEX 75

484 OND DEX 79 0.005 OND DEX 63 0.004 0.003 [21]APR OND DEX 88 APR DEX 74

CR, complete response (no vomiting and no use of rescue medication); APR, aprepitant; NA, not available; NS, not significant; NK, neurokinin-1-receptor-antagonist; DEX, dexamethasone; OND, ondansetron;GRAN, granisetron; 5-HT3-RA, 5-HT3-receptor-antagonist.

* An extra dose of aprepitant 400 mg per os given the evening before day 1 of cisplatin administration.a Response: no emesis.


well as delayed emesis. In all studies, the comparativebenefit of the aprepitant regimen was more pronounced inthe delayed phase [21]. In accordance to these findings,the triple cand aprepihighly emeConferenceguidelinesal. [21], thcomparisonsimilar todelayed ph

In the mtion was imafter chemthis study aguidelinesmen that inwith an antrecommendsetting is re

Comparperiod in tare surprisithe importanot adminiemetogenicessary to exin the delatogenic chto explorechemothera

2.4. Substi

2.4.1. MetBefore t

usually atplayed a pr

2.4.2. MecMetoclo

peripheralltrigger-zondose metocantagonism

2.4.3. ClinGralla e

metoclopraintroductioby 5-HT3-metoclopraproven effiIn these twter than th

antiemetic research study, the combination therapy of steroidplus metoclopramide versus steroid plus 5-HT3-RAs in thedelayed phase were equally effective (complete response:

versu

mendlines8], mntionendeded CIrole ois res3-RA

. Dosetoclo

s as a donist.h (co

d by G

. Sidee sid

ide ind) esstaticBiper

. Metetopimminere che

ne torally s

in prighlynts exondan

ndanswith

setrondversede sedts. Exery un

. Comnce thide isclopra

com

, it iASCOthrouul if oIt waombination of a 5-HT3-RA plus dexamethasonetant is now recommended in patients receivingtogenic chemotherapy by the Perugia Consensus

(MASCC guidelines) and the updated ASCO[6,12]. Also, in the latest study by Schmoll ete addition of aprepitant to dexamethasone into ondansetron and dexamethasone, a regimen

one frequently used in clinical practice in thease proved to be superior.

oderate emetogenic setting, vomiting preven-proved by 9% (p = 0.015) for the 5-day period

otherapy with the aprepitant regimen. Based onprepitant is recommended by the updated ASCOin patients receiving any chemotherapeutic regi-cludes cyclophosphamide alone or in combinationhracycline. In the updated MASCC guidelines, theed use of aprepitant in the moderate emetogenicstricted to the AC protocol.ing the complete response rates of the delayedhe moderate and high emetogenic setting, therengly no major differences. This finding indicatesnce of a steroid in the delayed period, which was

stered in the study to patients receiving moderatechemotherapy. Therefore, further studies are nec-plore the role of aprepitant together with steroidsyed period in patients receiving moderate eme-emotherapy. Furthermore, studies are warrantedspecific clinical situations such as multiple daypy and high dose chemotherapy.

tuted benzamides

oclopramidehe introduction of 5-HT3-RAs, metoclopramide,high doses and in combination with a steroid,imary role in the management of acute CINV.

hanism of actionpramide is a D2-antagonist and is activey in the gut and centrally in the chemoreceptor-e. Today, it is recognised that the effect of highlopramide in patients receiving cisplatin is due toat 5-HT3 receptors [74,75].

ical studiest al. reported in 1981 the efficacy of high-dosemide in patients receiving cisplatin [74]. After then of 5-HT3-RAs, metoclopramide was replacedRAs in the prevention of acute CINV. However,mide in combination with corticosteroids still hascacy in the prevention of delayed CINV [76,77].

o studies, the combination therapy was bet-e steroid mono therapy. In the Italian group for

60%recom

guide[12,2preveomm

delayThelines5-HT

2.4.4M

doseantagq 46geste

2.4.5Th

pramrelateorthowith

2.4.6M

dopavia thmazigenemens

or hpatieplusfor obinedgrani

Ainclueffecare v

2.4.7Si

prammetowhenCINVandbreakcessf[84].s 62%) [19]. Consequently, metoclopramide wased by the former MASCC and former ASCO

[7,78]. In the new MASCC and ASCO guidelinesetoclopramide is no longer recommended in theof delayed CINV. Indeed, 5-HT3-RAs are rec-as an alternative to steroids in the prevention of

NV due to moderately emetogenic chemotherapy.f metoclopramide in the updated ASCO guide-erved for patients intolerant of or refractory tos, dexamethasone and aprepitant.

e recommendationpramide has antiemetic properties both in lowopamine antagonist and in high doses a serotoninThe usual recommended doses are 2040 mg po

nventional dose) or 23 mg/kg (high dose) as sug-ralla et al. [74].

effectse effects commonly associated with metoclo-clude mild sedation, dystonic reactions (age

pecially in higher doses, akathisia, diarrhea andhypotension [74]. Dystonic reactions can be dealtiden.

opimazineazine is a phenothiazine derivate with anti-

gic activity [79]. It exerts its antiemetic effectsmoreceptor trigger zone. The addition of metopi-ondansetron or ondansetron plus prednisoloneignificantly increased the efficacy of the regi-eventing CINV in patients receiving moderatelyemetogenic chemotherapy. The percentage ofperiencing no acute emesis with metopimazinesetron was 6378% compared with 4750%

etron monotherapy [8082]. Metopimazine com-prednisolone was significantly less effective thanin the acute setting [83].effects occasionally reported with metopimazine

ation, orthostatic hypotension and anticholinergictrapyramidal symptoms, including dyskinesias,common [79].

parative assessmente introduction of the modern antiemetics, metoclo-no longer the antiemetic drug of choice. Althoughmide has to be proven as effective as 5-HT3-RAs

bined with steroids in the prevention of delayeds not recommended again in the new MASCC

guidelines in this setting. In the treatment ofgh CINV the use of metoclopramide might be suc-ptimal treatment has been given as prophylaxis

s stated that metoclopramide should be reserved


for special circumstances, including known intolerance to 5-HT3-RAs or steroids. In conclusion, while metoclopramideis still included in the NCCN guidelines as an option, metopi-mazine andby ASCO a

2.5. Neuro

Dopamiantiemeticthey have lointo phenobutyrophenneurolepticpramide, m

2.5.1. PheThe role

ally limitedplay a roleeffects inclare commo

2.5.2. AtypOlanzap

antiemetictor sites im[85]. It hasthe treatmein advancesmall phasof delayedately emetoacceptableprior chemapy until 7effect wasIn a followwith granischemotheration therapacute anding highlyIn 10 patiecomplete r100% in thfor the mod

Future svide additidue to chetion on thestudy wasing also a hperiod (daywere combor moderat

2.5.3. Comparative assessmentPhenothiazines and butyrophenones have limited

antiemetic properties and are not recommended as first-antiem

eatmes promdrug

Benzo

enzodens in

. Loraials wtancesk ofe of o

ed andt recoed thain theective

. Mididazoxamplsistanl phasexam

eviouszolamg theon ofone grevioueffects

. Comenzodtance

ticipatnal adful opal sta

ld inclas no

Canna

ials wportsmarijudrona

ity atstemmetoclopramide are currently not recommendednd MASCC.

leptics

ne receptor antagonists were the basis oftherapy from the 1950s to the early 1980s, butw efficacy as single agent. They can be subdivided

thiazines (e.g., promethazine and metopimazine),ones (e.g., haloperidol and droperidol), atypicals and substituted benzamides (e.g., metoclo-etopimazine and alizapride).

nothiazines/butyrophenonesof phenothiazines and butyrophenones is usu-in the prevention of CINV. However, they still

in the treatment of breakthrough CINV [84]. Sideude sedation and extrapyramidal syndromes thatn among all dopamine-blocking drugs.

ical neurolepticsine, an atypical antipsychotic drug has potentialproperties because of its action at multiple recep-plicated in the control of nausea and vomitingbeen found to be efficacious and well tolerated innt of chronic nausea related to opioids for paind cancer patients [86]. In a recently publishede I study, olanzapine was used in the preventionemesis in patients receiving highly or moder-genic chemotherapy [87]. Olanzapine showed antoxicity profile in a dose of 5 mg daily 2 days

otherapy and 10 mg daily from start of chemother-days after finishing chemotherapy. Mean side

a depressed level of consciousness and fatigue.ing phase II trial of olanzapine in combinationetron and dexamethasone for the prevention ofpy-induced nausea and vomiting, the combina-y proved to be highly effective in controllingdelayed nausea and vomiting in patients receiv-and moderately emetogenic chemotherapy [88].nts receiving highly emetogenic chemotherapy,esponse (no emesis, no rescue) was achieved ine first 24 h and in 80% in the days 25. The resultserately emetogenic chemotherapy were similar.tudies on the use of olanzapine may not only pro-onal options for the control of nausea and emesismotherapy but may also provide new informa-

pathophysiology of CINV. The latest phase IIpresented on ASCO 2006 by Navari et al. show-igh complete response rate over the whole studys 15) when palonosetron and dexamethasone

ined with olanzapine in patients receiving highlyely emetogenic chemotherapy [89].

linethe trseem

other

2.6.

Bregim

2.6.1Tr

accepthe ridegrelimitis noshownentto eff

2.6.2M

for esis resmaland din prMidadurinductileastthe pside

2.6.3B

accepof anoptioa use

optimshouthis w

2.7.

Trtal reused(e.g.,activbrainetics although they may prove to be helpful innt of breakthrough emesis. In contrast, olanzapineising as an enhancer of the antiemetic effect of

when used in combination therapy.

diazepines

iazepines can be a useful addition to antiemeticcertain circumstances.

zepamith lorazepam have shown a high degree of patient. As such, they serve to reduce anxiety and reduceanticipatory nausea. Lorazepam may add a smallbjective antiemetic efficacy, although the effect isthe use of lorazepam as a single-agent antiemetic

mmended [6]. A double-blind randomised studyt its known antianxiety effects can be quite promi-chemotherapy administration setting when addedantiemetic combination [2,10].

azolamlam is a short acting benzodiazepine which is usede in patients with prolonged postoperative eme-t to usual treatment [90]. In a recently publishede II study, midazolam was added to granisetronethasone in patients with refractory acute CINVcycles of highly emetogenic chemotherapy [91].was given as a continuous infusion of 0.04 mg/kgadministration of chemotherapy. With the intro-midazolam, 73% of patients had a reduction of atrade of nausea and vomiting in comparison withs cycle of chemotherapy. No details of potential, such as sedation, were described.

parative assessmentiazepines have shown a high degree of patient. They serve to reduce anxiety and reduce the riskory nausea and are therefore recommended as anjunct to antiemetic regimens. Midazolam may betion in patients with refractory emesis in spite ofndard antiemetic prophylaxis and treatment. Thisude aprepitant as standard prophylaxis, althought part of the study discussed above.

binoids

ith cannabinoids were encouraged by anecdo-of decreased emesis in younger patients whoana while receiving chemotherapy. Cannabinoidsbinol, nabilone) are thought to exert antiemeticthe cannabinoid receptor, likely located in the[75]. In a study done by Sallan et al. in 1975,


oral tetrahydrocannabinol showed antiemetic properties andwas significantly better than a placebo in reducing vomit-ing caused by chemotherapeutic agents [92]. In a systematicreview of tof nausea aslightly betpramide, pusefulnesstoxic effectOn the othepotentiallyommendedor refractor34 h, oralUsually 1 o[97].

2.7.1. ComThe com

tially benecannabinoiapy in selecof dizzines

2.8. Antihi

Antihistics and adjdopamine ahydroxyzinvomiting hactivity [7]

In palliatreatment osystem. Sidry mouth,

2.8.1. ComDue to a

tamines shpreventionthe treatmeare not ind

2.9. Herbs

Herbs aand are inctial benefitand vomitivomiting in

2.9.1. GinThe det

ginger is k

not at the central nervous system level [99]. Ginger is con-sumed via oral ingestion of powdered extract capsules indoses of 500 mg taken up to three times daily. The results of

es donontrov[100,1t be bea.

. Pepppperm

t, prodint haepsia,

olytinow,

juncterminperati

. Comerbs a

treatmadjun

onclu

ith thonist

ausea

inatioonist80%e updinatio

ogenicogenic

or ininatio

. For pogenicrecepl.e ner halfotherother

oved cfullyosetrointereesignnsetrouidelinntionhe efficacy of oral cannabinoids in the preventionnd vomiting, it was found that cannabinoids wereter than conventional antiemetics (e.g., metoclo-henothiazines, haloperidol) [93]. However, theirwas generally limited by the high incidence ofs such as dizziness, dysphoria and hallucinations.r hand, side effects like euphoria and sedation maybe beneficial [94]. Accordingly, dronabinol is rec-for consideration in the treatment of breakthroughy emesis. Doses in the range of 510 mg/m2, everyly appear to be among the most useful [95,96].r 2 mg of nabilone twice a day is recommended

parative assessmentbination of weak antiemetic efficacy with poten-ficial side effects (sedation, euphoria) makeds to a useful adjunct to modern antiemetic ther-ted patients. However, the associated side effects

s and dysphoria should not be underestimated.

stamines

amines have been administered both as antiemet-unctive agents to prevent dystonic reactions withntagonists [98]. Studies with diphenhydramine ore in the prevention of chemotherapy nausea andave not shown that these drugs have antiemetic.

tive care, the antihistamines have a role in thef nausea thought to be mediated by the vestibular

de effects of antihistamines include drowsiness,and blurred vision.

parative assessmentlack of efficacy proven in several studies, antihis-

ould not be utilized as an antiemetic agent in theof CINV. Antihistamines may be a useful drug innt of nausea and vomiting when these symptomsuced by the chemotherapy itself.

as antiemetics

re used by at least 80% of the worlds populationreasingly popular. Some studies showed a poten-of ginger and peppermint in postoperative nauseang as well as in the management of nausea andpregnancy.

ger (Zingiber ofcinale Roscoe)ailed mechanism of action is unknown, althoughnown to exert its antiemetic effect at the gut and

studiare c

cacymighnaus

2.9.2Pe

agenpermdyspspasmUp toan adPeppposto

2.9.3H

in theas an

3. C

Wantagof ncombantagin 70In thcombemetemetalonecomblinesemetHT3-pane

Thlongeto theover

imprThepalonwiththe donda

Gprevee with ginger in patients receiving chemotherapyersial and do not demonstrate convincing effi-01]. There is some evidence, however, that gingereneficial as an adjunctive therapy for intractable

ermint (Mentha x piperita Lamiaceae)int acts as an internal calcium channel-blockingucing intestinal smooth muscle relaxation. Pep-s supportive evidence for use in patients withirritable bowel syndrome and as an intraluminalc agent during barium enemas endoscopy [102].there is no published study using peppermint as

ive therapy for patients receiving chemotherapy.t seems to lessen this symptom in the treatment ofve nausea [103].

parative assessments antiemetics do not show any convincing efficacy

ent of CINV. There is some evidence that gingerctive therapy may lessen nausea.

sion

e introduction of the neurokinin-1-receptor-aprepitant, a further step forward the preventionand vomiting has been made. With the triplen therapy of a 5-HT3-RA, neurokinin-1-receptor-and dexamethasone, vomiting can be preventedof patients receiving highly emetogenic therapy.ated MASCC and ASCO guidelines, the triplen is recommended in patients receiving highlychemotherapy. In patients receiving moderatelychemotherapy that includes cyclophosphamidecombination with an anthracycline the triple

n is also recommended by the ASCO guide-atients receiving other chemotherapy of moderate

risk, the two drug combination of a 5-tor-antagonist and a steroid is advised by the

w 5-HT3-RA palonosetron has a significantly-life and a higher binding activity in comparison5-HT3-RAs. Palonosetron may offer advantages5-HT3-RAs with respect to convenience and

ontrol of CINV in the acute and delayed period.published papers of the combined treatment ofn, aprepitant and dexamethasone are awaitedst. Study results to date are promising, butof one study is controversial in regard to the

n control arm.es no longer recommend metoclopramide in theof acute or delayed CINV despite the fact that


they show similar activity in the prevention of delayed CINVwhen compared to the 5-HT3-RAs.

Olanzapine, an atypical antipsychotic drug, showedpromisingRA and ainvestigatio

RegardlCINV afterantiemeticare requireinduced na

Reviewers

StevenPharmacolmont, UHCUSA.

Gaia Pirportive CarHelsinn Hezallo, Swit

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in Jordan received her doctorate in the fieldsis from the University of Halle, Germany. Shestdoctoral training in the Department of Hema-ology, Director Prof. Schmoll. Dr. Jordan is aseveral scientific societies and she is activelythe supportive care group within the German

ciety. Current areas of research interest includecare with a special focus on antiemesis.

Comparative activity of antiemetic drugsIntroductionAntiemetic agents5-HT3-receptor-antagonistsMechanism of actionClinical studies5-HT3-receptor-antagonists in acute CINV5-HT3-receptor-antagonists in delayed emesisComparative efficacy of the available 5-HT3-receptor-antagonists

Dose recommendationSide effectsGenetic polymorphismComparative assessment

SteroidsMechanism of actionClinical studiesSteroids before the introduction of 5-HT3-receptor-antagonistsSteroids after the introduction of 5-HT3-receptor-antagonistsSteroids after the introduction of NK-1-receptor-antagonistsImportant studies to find the optimal dose of corticosteroids

Dose recommendationSide effectsComparative assessment

Neurokinin-1-receptor-antagonistsMechanism of actionClinical studiesHighly emetogenic chemotherapyModerately emetogenic chemotherapy

Dose recommendationSide effectsComparative assessment

Substituted benzamidesMetoclopramideMechanism of actionClinical studiesDose recommendationSide effectsMetopimazineComparative assessment

NeurolepticsPhenothiazines/butyrophenonesAtypical neurolepticsComparative assessment

BenzodiazepinesLorazepamMidazolamComparative assessment

CannabinoidsComparative assessment

AntihistaminesComparative assessment

Herbs as antiemeticsGinger (Zingiber officinale Roscoe)Peppermint (Mentha x piperita Lamiaceae)Comparative assessment

ConclusionReviewersReferences

Documents

2007 - Comparative Activity of Antiemetic Drugs