review

www.nature.com/clinicalpractice/onc : an update and the MASCC guidelines applied in clinical practice Jørn Herrstedt

SUMMARY INTRODUCTION Cancer chemotherapy has been used for more Nausea and vomiting are two of the most severe problems for patients than 50 years,1 but clinical research treated with chemotherapy. Until the late 1970s, nausea and vomiting has, in general, only been actively pursued for induced by chemotherapy was an almost neglected research area. With the the past 25 years. With the introduction in the introduction of , the cytotoxin with the highest emetic potential, research was stimulated and has now resulted in the development of two late 1970s of cisplatin, the cytostatic with new classes of antiemetics, the and neurokinin antagonists. the highest emetic potential, nausea and vomiting soon became two of the most severe prob- A large number of trials have fine-tuned antiemetic therapy and made 2 evidence-based recommendations possible for the majority of patients lems for patients treated with chemotherapy. receiving chemotherapy. This Review discusses the pathophysiology of Chemotherapy-induced nausea and vomiting is nausea and vomiting, the development of antiemetics, highlights some categorized into the acute and the delayed phases, of the newest antiemetics, and finally summarizes recommendations from which occur 0–24 h and 24–120 h after initiation the evidence-based guidelines developed by the Multinational Association of chemotherapy, respectively. Antiemetics should of Supportive Care in Cancer. be given prophylactically and treatment depends on the chemotherapy regimens used. A number Keywords antiemetics, chemotherapy, neurokinin antagonists, serotonin antagonists of patient-related risk factors have been defined, including female sex and young age. It is also well- Review criteria known that patients who experience acute emesis The information for this Review was obtained by searching the PubMed have a higher risk of developing delayed emesis and MEDLINE databases for original articles and reviews published until than those who are completely protected during 1 April 2007. Electronic early-release publications were also included. Only articles published in English and German were considered. The search terms the acute phase. This carry-over effect from the included “serotonin antagonist”, “”, “”, “”, acute to the delayed phase should be recognized “”, “”, “neurokinin antagonist”, “”, “”, when results from antiemetic trials are inter- “”, “corticosteroid”, “methylprednisolone”, “ antagonist”, preted. This Review discusses the pathophysiology “”, “”, “”, “”, “”, of nausea and vomiting, the development of “ghrelin”, guidelines” and “nausea or vomiting”. Papers from the search were reviewed, and when possible primary sources have been quoted. antiemetics, highlights some of the newest anti- emetics, and finally summarizes recommendations from clinical evidence-based guidelines.

HISTORY OF PATHOPHYSIOLOGY Although the history of the pathophysiology of chemotherapy-induced nausea and vomiting goes back more than a hundred years, it is still only partly elucidated. The most likely mechanism of chemotherapy-induced nausea involves the release of emetic transmitters () such as dopamine, serotonin and substance P, which bind J Herrstedt is Chief Physician at the Department of Oncology, Copenhagen to different receptors located in areas of the gut University Hospital, Herlev, Denmark. and the central nervous system. Most antiemetics

Correspondence are thought to exert their effect by binding to the Department of Oncology, Odense University Hospital, DK–5000 Odense C, Denmark same receptors (antagonists), thereby preventing [email protected] the emetic stimuli. The existence of a vomiting center, which Received 7 May 2007 Accepted 22 August 2007 www.nature.com/clinicalpractice is located in the medulla oblongata, was first doi:10.1038/ncponc1021 proposed by Thumas in 1892,3 and further

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Table 1 History of serotonin and 5-HT receptors. Year of Identification and development of 5-HT and its receptors References publication 1948 Isolation of serotonin Rapport et al. (1948)16 1957 Two different receptors for 5-HT described Gaddum and Picarelli (1957)17

1978 Metoclopramide; a weak 5-HT3-RA discovered Fozard and Mobarok ALI (1978)24 1979 Identification of two different binding sites for 5-HT in brain tissue Peroutka and Snyder (1979)18 26 1984 First demonstration of a selective 5-HT3-RA—MDL 72222 Fozard (1984) 27 1984–1987 5-HT3 receptors demonstrated in abdominal visceral afferent Miner and Sanger (1986) neurons and in the CNS 1986 MDL 72222/ICS 205-930 effective against cisplatin-induced Costall et al. (1986)28 emesis 1986 Classification of three serotonin receptor groups Bradley et al. (1986)19

1987 First clinical trial of a 5-HT3-RA with antiemetic effect Leibundgut and Lancranjan (1987)29 22 1987–1990 Discovery that the highest number of 5-HT3 receptors Kilpatrick et al. (1987) is in the NTS Pratt et al. (1990)23 1994 Reclassification of serotonin receptors into seven groups Hoyer et al. (1994)20 21 2005 5-HT3-receptor subunits cloned Barrera et al. (2005)

Abbreviations: CNS, central nervous system; 5-HT, 5-hydroxytryptamine (serotonin); 5-HT3-RA, 5-hydroxytryptamine3-; NTS, nucleus of the solitary tract.

explored in 1923 by Hatcher and Weiss,4 who also dose-dependent manner in dogs13 and ferrets.14 found that the sensory nuclei of the vagi nerves Studies of D2-receptor antagonists comprised are important. Wang and Borison5,6 identified the first antiemetic research and began in the the chemoreceptor trigger zone, which is located 1960s.15 Owing to the limited antiemetic activity, in the area postrema outside the blood–brain the adverse effects of some of these compounds barrier, and as such is sensitive to both blood- (e.g. metoclopramide, haloperidol) or the limited borne and cerebrospinal fluid-borne emetic distribution of these drugs worldwide (e.g. stimuli. During the next 40 years the existence of metopimazine), these agents are primarily used the chemoreceptor trigger zone was supported as rescue antiemetics. by some groups,7–9 but questioned by others.10 Today we don’t consider the vomiting center to Serotonin and 5-HT receptors be a well-defined anatomical area, but to exist Serotonin was isolated in 1948,16 and 9 years later as interconnecting neural networks penetrating Gaddum and Picarelli identified two pharmaco­ into the nucleus of the tractus solitarius.11,12 The logically different receptors for serotonin, today 17 most important antiemetics are the serotonin known as the 5-HT2 and 5-HT3 receptors. In (5-hydroxytryptamine; 5-HT) 5-HT3-receptor 1979, Peroutka and Snyder provided evidence for antagonists, neurokinin (NK)1-receptor antago- two binding sites in brain tissue, namely 5-HT1 18 nists and corticosteroids. An overview of serotonin and 5-HT2 receptors (Table 1). In 1986, a classifi­ and serotonin receptors and of tachykinins and cation system categorized serotonin receptors neurokinin receptors is shown in Tables 1 and 2. into three main groups, 5-HT1-like, 5-HT2 and 19 5-HT3 receptors. Today we know of seven main Dopamine and dopamine receptors groups20 and several subgroups, the most recently 21 Dopamine receptors are divided into five groups discovered being 5-HT3A and 5-HT3B. The (D1–D5), but until recently only the D2 recep- 5-HT3 receptor is a transmitter-gated ion channel tors were associated with the genesis of emesis. of the cysteine-loop family, that occurs with Studies now indicate that central D3 receptors are highest frequency in the gut and in the nucleus 22,23 involved because the selective D3-receptor , of the tractus solitarius. The hypothesis that 7-hydroxy-2-(N,N-di-n-propyl-amino) tetraline 5-HT3-receptor antagonists might be useful as (7-OH-DPAT), was able to induce emesis in a antiemetics was based on the results of several

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Table 2 History of tachykinins and neurokinin receptors. Year of Identification of peptides and compounds References publication 1931 Isolation of substance P Von Euler and Gaddum (1931)30 1970 Substance P purified and structure revealed Chang and Leeman (1970)31 32 1981 First NK1-receptor antagonist demonstrated Leander et al. (1981) 1983 NKA and NKB isolated Kangawa et al. (1983)92 Kimura et al. (1983)93 1985 NPK isolated Tatemoto et al. (1985)94 1988 NPγ isolated Kage et al. (1988)95 33 1991 First non-peptide NK1-receptor antagonist (CP 96,345) Snider et al. (1991) 1993 Substance P, NKA and NKB shown to be present in CNS and PNS Maggi et al. (1993)96 1993 Study suggests that emesis might have a tachykinin component Tattersall et al. (1993)34 35 1997 First clinical trial of a NK1-RA with antiemetic effect Kris et al. (1997)

Abbreviations: CNS, central nervous system; NK1-RA, neurokinin 1-receptor antagonist; NKA, neurokinin A; NKB; neurokinin B; NPγ, neuropeptide γ; PNS, peripheral nervous system.

studies, including the findings that metoclo- antiemetic profile including effect against emesis 24 pramide is a weak 5-HT3-receptor antagonist, induced by chemotherapy, , lopera­ and that high-dose metoclopramide is effec- mide, motion, copper sulfate, ipecacuanha and tive against cisplatin-induced emesis.25 These nicotine. The first clinical study with one of these discoveries led to the development of selective components was published in 1997.35 26 5-HT3-receptor antagonists, the demonstra- tion of antiemetic effect in animal models,27,28 Other transmitters and receptors and the publication of the first clinical study of an Other transmitters that are involved in the emetic 29 5-HT3-receptor antagonist in 1987. reflex arch include histamine, acetylcholine, endorphins, gamma-aminobutyric acid and Tachykinins and neurokinin receptors . Histamine and acetylcholine are Substance P was isolated in 193130 but not puri- important in the induction of motion sickness. fied and sequenced until 1970.31 Tachykinins Consequently, studies investigating are a family of peptides of small and medium and showed little36 or no effect37 size. The receptors for the tachykinins, the NK- against chemotherapy-induced nausea and receptors, have been cloned and identified as vomiting. The only other transmitter known to G-protein-coupled receptors; substance P is the be involved in chemotherapy-induced emesis preferred tachykinin at NK1-receptors. The first is the (CB)1-receptor. In contrast selective NK1-receptor antagonist was developed to other antiemetics, the cannabinoids exert 32 in 1981, but the potential of NK1-receptor antiemetic effects by agonism at CB1 receptors. antagonists as antiemetics was not realized until Studies from the 1970s and early 1980s showed the development of a non-peptide NK1-receptor that agents like and have antagonist 10 years later.33 In order to exert their antiemetic effects in patients receiving moder- antiemetic effects the NK1-receptor antagonists ately emetogenic chemotherapy, but their use is need to cross the blood–brain barrier, and it was restricted because of associated adverse events, this requirement that led to the delay in their use particular in elderly patients.38 as antiemetics. The first indication that emesis might have a tachykinin component came from HISTORY OF ANTIEMETIC THERAPY a study demonstrating that a non-peptide NK1- Low-dose dopamine (D2)-receptor receptor antagonist attenuated cisplatin-induced antagonists emesis in the ferret.34 A number of studies using The development of antiemetic therapy is different animal models have shown that NK1- summarized in Table 3. A few trials investigating receptor antagonists have a broad-spectrum low doses of dopamine D2-receptor antagonists

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Table 3 History of antiemetic therapy. Year of Identification of antiemetic therapies References publication 1979 Corticosteroids demonstrated as superior to placebo Baker et al. (1979)39 1981 Hd-MCP demonstrated as effective Gralla et al. (1981)25 1984 A corticosteroid demonstrated to improve effect of hd-MCP Allan et al. (1984)41

1987 First clinical trial with a 5-HT3-RA Leibundgut and Lancranjan (1987)29 1991 A corticosteroid demonstrated to improve the effect Roila et al. (1991)42 of 5-HT3-RAs (HEC) 1993 A demonstrated to improve the effect Herrstedt et al. (1993)59 of a 5-HT3-RA 1995 A corticosteroid demonstrated to improve the effect Italian Group for Antiemetic 43 of 5-HT3-RAs (MEC) Research (1995) 35 1997 First clinical trial with a NK1-RA Kris et al. (1997) 71 2003 NK1-RA demonstrated to improve effect of 5-HT3-RA Poli-Bigelli et al. (2003) plus corticosteroid (HEC) Hesketh et al. (2003)72 73 2005 NK1-RA demonstrated to improve effect of 5-HT3-RA Warr et al. (2005) plus corticosteroid (MEC)

Abbreviations: hd-MCP, high-dose metoclopramide; HEC, highly emetogenic chemotherapy; 5-HT3-RA, 5-hydroxytryptamine3- receptor antagonist; MEC, moderately emetogenic chemotherapy; NK1-RA; neurokinin 1-receptor antagonist.

showed modest or no effect against different High-dose metoclopramide kinds of chemotherapy.15,25 Some of the pheno- One of the most frequently quoted articles in thiazines, (e.g. metopimazine and the substituted the antiemetic literature is by Gralla et al., which , metoclopramide) showed an indica- demonstrates that the antiemetic effects of high- tion of a dose-dependent effect, and higher doses dose metoclopramide are superior to those of of these drugs were investigated.38 placebo and .25 The median number of emetic episodes per patient receiving Corticosteroids cisplatin-based chemotherapy was reduced from Baker and co-workers published the first 10.5 in the placebo arm and 12 in the prochlor- randomized trial comparing dexamethasone arm to 1–1.5 with high-dose meto­ with placebo.39 They found that the antiemetic clopramide. These findings showed that patients effects of 10 mg of intramuscular dexamethasone receiving cisplatin-based chemotherapy could were significantly superior to placebo in patients be offered an effective antiemetic therapy. Other receiving various kinds of non-cisplatin chemo- studies tried to fine-tune the metoclopramide therapy. This study led to the initiation of a large regimen, and revealed that although high-dose number of clinical trials investigating different metoclopramide is effective, it causes extra­ corticosteroids, which concluded that, when pyramidal reactions in a number of patients and given as single agents, corticosteroids have an only 40% of patients are completely protected antiemetic effect in patients receiving moderately from emesis in the first 24 h after cisplatin adminis­ emetogenic chemotherapy, but are less effective tration. Agents such as the antihistamine diphen- against cisplatin-induced emesis.38,40 Subsequent hydramine, the benzodiazepine or the studies showed that corticosteroids increase the biperidene, were all able to prevent effect of other antiemetics such as low-dose and the extrapyramidal reactions associated with 41 high-dose metoclopramide, 5-HT3-receptor metoclopramide, but did not significantly improve 42,43 46 antagonists and the NK1-receptor antagonist, antiemetic effect. As mentioned earlier, cortico- aprepitant (Table 4). Studies have now verified steroids significantly improve the antiemetic effect that dexamethasone is one of the most potent of high-dose metoclopramide in cisplatin-induced antiemetics for the prevention of delayed nausea emesis,41 and a three-drug combination of high- and vomiting.44,45 dose metoclopramide, a corticosteroid and either

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Table 4 Phase III trials with the neurokinin 1-receptor antagonist aprepitant. Reference Design Number Chemotherapy Antiemetic regimens Day 1 Days 2–5 Days 1–5 of patients (mg/m2) acutea delayeda totala (%) (%) (%) Poli-Bigelli R, DB, 569 CIS ≥70 + others OND day 1 + DEX days 1–4 68.4 46.8 43.3 et al. (2003)71 2P OND day 1 + DEX days1–4 + APR days 1–3 82.8 67.7 62.7 Hesketh R, DB, 530 CIS ≥70 + others OND day 1 + DEX day 1–4 78.1 55.8 52.3 et al. (2003)72 2P OND day 1 + DEX days 1–4 + APR days 1–3 89.2 75.4 72.7 Schmoll et al. R, DB, 489 CIS ≥70 + others OND days 1–4 + DEX days 1–4 79.3 63.1 60.6 (2006)74 2P OND day 1 + DEX days 1–4 + APR days 1–3 87.7 74.1 72 Warr et al. R, DB, 857 C alone 750–1,500 OND day 1 + DEX day 1 all patients – – – (2005)73 2P or A ≤60 + C 500–1,500 + OND day 2–3 69 49 42 or E ≤100 + C 500–1,500 + APR day 1–3 76 55 51 aPercentage of patients with no emesis and with no use of rescue antiemetics. Abbreviations: 2P, parallel, 2-arm trial; A, doxorubicin; APR, aprepitant; CIS, cisplatin; C, cyclophosphamide; DB, double-blind; DEX, dexamethasone; E, epirubicin; OND, ondansetron; R, randomized.

lorazepam or was considered both agents offered equal protection against the standard antiemetic regimen for patients nausea and vomiting during the first 24 h after receiving cisplatin-based chemotherapy until the the initiation of chemotherapy.54 development of the serotonin antagonists.46 Warr et al. investigated granisetron in two studies and found that granisetron was as effective 5-HT3-receptor antagonists as the combination of high-dose metoclopramide After the publication of the first studies with a and dexamethasone in patients treated with 29,47 55 5-HT3-receptor antagonist, the develop- cisplatin, and superior to dexamethasone plus ment of these agents was accelerated. The first prochlorperazine in patients receiving moder- two agents that were marketed, at the beginning ately emetogenic chemotherapy.56 Although of the 1990s, were ondansetron and granisetron, many of the aforementioned studies followed followed by tropisetron, and dolasetron, and patients for 3–5 days, all studies were designed most recently palonosetron in 2003. Two other to evaluate acute nausea and vomiting. The agents and are marketed in efficacy of the serotonin antagonists against Japan only. The clinical development of ondan- delayed emesis is much less pronounced,57 and setron and granisetron followed two different dexamethasone and/or the NK1-receptor antago- strategies. Ondansetron was compared with the nist, aprepitant, are recommended as first choice single agents most effective in patients receiving antiemetics against delayed emesis.44,45 cisplatin-based and non-cisplatin chemotherapy. A large number of trials have compared two or Studies showed that ondansetron was signifi- three of the serotonin antagonists. There seem to cantly superior to high-dose metoclopramide in be no major differences in effect or safety between the prevention of cisplatin-induced emesis,48–50 these agents, with mild headache and constipa- but no major differences in the protection against tion being the two most frequently reported side nausea were observed. Other studies compared effects. In the setting of highly emetogenic42,58 or metoclopramide51–53 or dexamethasone54 with moderately emetogenic43 chemotherapy, protec- ondansetron in patients receiving different tion from acute emesis with serotonin antagonists types of non-cisplatin chemotherapy, primarily is improved by the addition of dexamethasone. cyclophosphamide plus an anthracycline. In two A few studies have shown that the dopamine studies, ondansetron was significantly superior antagonist, metopimazine, can improve the effect to metoclopramide in the protection from both of ondansetron,59,60 but this agent is not avail- nausea and vomiting,51,52 whereas in the third able in the US, Canada or Japan. For more than study no significant differences in the degree 10 years, the combination of a serotonin antago- of protection were observed.53 In the study nist plus a corticosteroid was the recommended comparing dexamethasone and ondansetron, standard antiemetic regimen in patients receiving

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moderately or highly emetogenic chemotherapy,61 even though cisplatin is considered highly emeto- but the advent of new antiemetics have changed genic at any dose. Despite these limitations, the this picture. data strongly indicate that palonosetron is supe- rior to ondansetron and dolasetron. As a conse- NEW ANTIEMETICS quence of the difficult interpretation, the US FDA Palonosetron has approved palonosetron for the prevention of Two new antiemetics were marketed in 2003, the both acute and delayed nausea and vomiting in serotonin antagonist palonosetron, and aprepi- patients treated with moderately emetogenic tant, the first of a new class of antiemetics—the chemotherapy and for the prevention of acute NK1-receptor antagonists. Palonosetron has emesis in patients treated with highly emeto- been studied in five phase I, one phase II and genic chemotherapy. By contrast the European three phase III trials. In addition, a number of Agency for the Evaluation of Medicinal Products small post-marketing trials have recently been has approved palonosetron for the prevention of published. Palonosetron has a strong and selec- acute symptoms only. tive binding affinity for 5-HT3-receptors, and a half-life of around 40 h, compared with less Aprepitant than 10 h for the other 5-HT3-receptor antago- There are no published phase I trials of aprepitant, nists.62 Phase I and II trials confirmed the safety but five phase II trials66–70 and three phase III of palonosetron, noting the same adverse effects trials have been published.71–73 A large post- observed with the other agents of this class. marketing randomized study74 and a few small Two randomized, double-blind trials compared studies have also been published recently. The palonosetron with ondansetron and dolasetron in phase II trials were randomized and double- patients treated with chemotherapy of a moderate blind, enrolling between 53 and 376 patients emetogenic potential.63,64 Gralla and coauthors receiving cisplatin-based chemotherapy. The compared single intravenous doses of palono- studies examined the efficacy of aprepitant in setron (0.25 mg and 0.75 mg) with ondansetron the prevention of acute nausea and vomiting from (32 mg),63 and found that palonosetron was supe- cisplatin-based chemotherapy. The trials clearly rior to ondansetron in the prophylaxis of both demonstrated that aprepitant as a single agent66 acute and delayed nausea and vomiting. Eisenberg or in combination with dexamethasone68,69 is et al. compared palonosetron with a single intra- inferior to ondansetron66,68 and granisetron69 venous dose of 100 mg dolasetron using the same but increases the efficacy of granisetron plus design and doses of palonosetron.64 They found dexamethasone67,69 and ondansetron plus dexa- equal efficacy against acute nausea and vomiting, methasone regimens.70 In all five studies, aprepi­ but palonosetron was superior against delayed tant was active in the prophylaxis of delayed symptoms. Aapro et al. found that 0.25 mg (day 2–5) nausea and vomiting. We know from palonosetron was as effective as ondansetron in several previous studies, that patients who vomit the prevention of nausea and vomiting induced on the day of chemotherapy have a higher risk by highly emetogenic, primarily cisplatin- of delayed emesis. It is, therefore, noteworthy ­based, chemotherapy.65 The interpretation of the that in the three studies in which the aprepitant- results of these studies has, however, been inten- based regimen was inferior to the serotonin sively debated because of the trial design. All antagonist-based regimen on day 1, the aprepitant- trials used a non-inferiority design and included ­based regimen was superior in the delayed chemotherapy-naive patients as well as patients phase.66,68,69 Four of the phase II trials used an who had previously received chemotherapy. intravenous prodrug66,68 or higher dose of oral Furthermore, the recommended prophylaxis aprepitant67,70 than was used in phase III trials. included dexamethasone, but in each of the three The reduction of the aprepitant dose in phase trials only 0%,63 5%64 and 67%65 of the patients III was because of results from a fifth phase II received dexamethasone. The studies did not use trial, which showed that aprepitant increased the the optimum design for investigation of delayed of dexamethasone via interactions symptoms because patients received different with the CYP3A4 enzymes.70 Furthermore, the antiemetics against acute symptoms, and anti- number of patients with infection was higher emetics were given only on day 1. Finally, patients in the aprepitant arm than in the comparative receiving low-dose cisplatin were included in the arm. In conclusion, phase II studies revealed moderately emetogenic chemotherapy studies, that aprepitant is not a substitute for a serotonin

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antagonist in the prevention of acute nausea and from nausea (no nausea days 1–5) obtained vomiting, but has utility as an additive to the with the aprepitant-based regimen (49% versus antiemetic combination of serotonin antagonist 39%, P <0.05).71 plus dexamethasone. Furthermore, they demon- In the study including patients receiving cyclo- strated that aprepitant is effective against delayed phosphamide plus an anthracycline,73 99% were symptoms as a single agent and recommended women with breast cancer treated in the adjuvant that the schedule for phase III studies should be setting or for metastatic disease. Patients were 125 mg on day 1, followed by 80 mg on days 2 and randomized to an oral control regimen consisting 3 given as single oral doses. They also concluded of 2 × 8 mg ondansetron plus 20 mg dexa- that in phase III studies, the dose of dexametha- methasone on day 1, followed by ondansetron sone used in the aprepitant-based regimen should 2 × 8 mg on days 2–3 or to an oral aprepitant- be reduced to 50–60% of that used in the control ­based regimen of 2 × 8 mg ondansetron with arm. Special attention to the number of patients 12 mg dexamethasone plus 125 mg aprepitant with infection in phase III studies was also recom- on day 1, followed by 80 mg aprepitant on days mended. The optimum treatment duration was 2–3. The aprepitant-based regimen resulted in not addressed in phase II studies. Two studies a 9% improvement in the number of patients showed that there was no significant difference achieving a complete response during days 1–5 between 1-day and 5-day regimens for aprepitant (51% versus 42%, P = 0.015), and in a 17% incre- administration, in terms of efficacy of antiemetic ment in the number of patients with no emesis effect.67,75 The 3-day regimen for phase III was, on days 1–5 (76% versus 59%, P <0.001). No therefore, arbitrarily chosen. significant differences in the protection from Phase III trials were published between 2003 nausea were seen. The phase III studies demon- and 2005, and a large post-marketing study was strated that in patients receiving cisplatin-based published in 2006 (Table 4).74 In three studies, or cyclophosphamide/anthracycline chemo- patients received cisplatin-based chemo- therapy, aprepitant increases the proportion therapy, and in one study patients received a who receive complete response by 9–21%. The combination of cyclophosphamide plus an benefit is primarily attributable to an approxi- anthracycline. All studies used a randomized, mately 20% reduction in the number of emetic double-blind, placebo-controlled design.71–74 episodes; the reduction in nausea seems to be Two of the studies71,72 used an identical limited. The advantage of the aprepitant-based design and compared the effect of single intra­ regimen was maintained during 4–6 cycles venous doses of 32 mg ondansetron plus 20 mg of chemotherapy.76,77 p.o. dexamethasone on day 1 followed by 2 × 8 mg Aprepitant is a CYP3A4 substrate and the dexamethasone on days 2–4, with single doses effects of aprepitant on drugs that inhibit (i.e. of intravenous 32 mg ondansetron plus 12 mg ketoconazole, diltiazem) or induce (i.e. rifampin) p.o. dexamethasone plus 125 mg p.o. aprepitant CYP3A4 have, therefore, been investigated. on day 1. This latter regimen was followed by a Caution is advised when administering aprepi­ single oral dose of 8 mg dexamethasone on days tant with strong inhibitors of CYP3A4. The 2–4 plus a single oral dose of aprepitant 80 mg bioavailability of oral CYP3A4 substrates (e.g. on days 2–3. The primary efficacy parameter was and other benzodiazepines) may complete response (i.e. defined as “no emesis and increase when coadministered with aprepitant. no need for rescue antiemetics”) during the first Rifampin is a strong inducer of CYP3A4 and 5 days after cisplatin treatment. The third study lowers the area under the receiver operating used the same design and dose schedule; however, characteristic curve of aprepitant significantly patients in the control arm also received ondan- compared with administration of aprepi- setron 2 × 8 mg p.o. for delayed emesis protec- tant alone; coadministration might, therefore, tion (days 2–4).74 The number of patients with decrease the antiemetic effect of aprepitant. a complete response in the control regimens of Aprepitant is also an inducer of CYP2C9 and these three trials were 43%,71 52%72 and 61%,74 could result in lower plasma concentrations respectively, compared with 63%,71 73%72 and of drugs metabolized by this enzyme. This 72%74 in the aprepitant-based regimens. The effect of aprepitant administration could be of difference in complete response of 11–21% clinical significance for drugs metabolized by was statistically significant. In only one study was CYP2C9 that have a narrow therapeutic index a statistically significant difference in protection (e.g. warfarin, phenytoin). A study showed that

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aprepitant has no effect on docetaxel pharmaco­ of Supportive Care in Cancer (MASCC),84 kinetics.78 This finding is important because ASCO85and the European Society for Medical docetaxel is primarily metabolized by CYP3A4. Oncology. The National Comprehensive Cancer Apart from the interaction between aprepitant Network (NCCN) has developed guidelines and oral dexamethasone, no clinically relevant on the basis of the knowledge of US opinion interactions between aprepitant and other anti- leaders. The recommendations by MASCC, ASCO emetics have been described. Despite these poten- and the European Society for Medical Oncology tial interaction risks, the safety of aprepitant was are generally in agreement. MASCC developed confirmed in phase III studies: no association their first set of evidence-based guidelines for was found between aprepitant administration chemotherapy induced nausea and vomiting in and incidence of febrile neutropenia. 1997.61 The topics to be included in the MASCC guidelines were selected on the basis of a question­ POTENTIAL NEW ANTIEMETICS naire distributed to 118 experts in 31 countries.86 Casopitant and other NK1-receptor From this process, eight main topics were identi­ antagonists fied for discussion at a subsequent consensus Casopitant has demonstrated antiemetic activity conference. Presentations reviewing specific in patients receiving moderately79 and highly80 antiemetic therapies were given by experts and emetogenic chemotherapy, and is now in phase discussed among the 300 participants at the III clinical testing. SCH-619734 is being investi- consensus conference. The expert panel primarily gated in phase II trials, and other agents such as comprised physicians, but two statisticians and , are in earlier clinical development. a physiologist were also included. The MASCC guidelines state the level of scientific confidence Olanzapine and the extent of consensus among the experts. Olanzapine is an that blocks several The second MASCC consensus conference was in receptors such as dopamine, serotonin, muscarine 2004, during which 23 experts representing nine cholinergic, adrenergic and histamine receptors. It different organizations updated the 1997 recom- has been investigated in phase I and II trials. The mendations and developed the setup for future most recent trial demonstrated exceptionally high updates. The latest version of these recommen- complete protection rates from both acute and dations was published in 2006,84 but the most delayed nausea and vomiting using a regimen that recent update is available on the MASCC website comprised palonosetron (day 1), dexamethasone (www.mascc.org). MASCC has divided cyto- (day 1) and olanzapine (days 1–4).81 toxic agents into four emetic risk groups and has provided recommendations for the prophylaxis Other agents of acute and delayed nausea and vomiting for The benzodiazepine midazolam is effective in each group, as shown in Box 1. prevention of postoperative vomiting. A phase II The recommendations given in the MASCC trial reported that midazolam given in combina- and ASCO guidelines are almost identical. tion with granisetron and dexamethasone was One exception is the recommendation for effective in the treatment of acute nausea and the prophylaxis of delayed emesis in patients vomiting after treatment with highly emeto- receiving a combination of cyclophosphamide genic chemotherapy in patients with vomiting plus an anthracycline. The MASCC guidelines84 refractory to antiemetic prophylaxis with grani­ recommend using dexamethasone or aprepi­ setron and dexamethasone.82 Another potential tant, whereas the ASCO guidelines85 recom- antiemetic, ghrelin, is a peptide secreted by the mend aprepitant alone. Both recommendations gastric mucosa, which stimulates gastrointestinal can be justified. No trial has compared these motility, protects the gastric mucosa and is able to two antiemetics in this setting, so the MASCC stimulate appetite in humans. In a recent trial in recommendation is reasonable, on the basis of ferrets, ghrelin was able to reduce the number of available evidence. Nonetheless, it seems rational vomiting events induced by cisplatin.83 to continue with aprepitant on days 2 and 3 in patients who received aprepitant on day 1. EVIDENCE-BASED GUIDELINES Several international societies and groups have GUIDELINES APPLIED IN PRACTICE developed evidence-based antiemetic guide- Clinical practice guidelines can be of consider- lines, including the Multinational Association able use and can enable physicians to prescribe

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Box 1 Four emetic risk groups as categorized by Nonetheless, the effort involved in their the Multinational Association of Supportive Care implementation is worthwhile because patients in Cancer. who receive evidence-based antiemetic therapy, do better87 and effective antiemetic therapy can High emetic risk group (more than 90% risk) 88 Includes cisplatin, dacarbazine and high-dose be cost-effective. Barriers to execution of anti- cyclophosphamide (≥1,500 mg/m2) emetic guidelines include reimbursement policy, ■ Acute: serotonin antagonist plus dexamethasone linguistic problems, the fact that new drugs are plus aprepitant expensive and not available in all countries, and underestimation of the magnitude of the ■ Delayed: aprepitant days 2–3 plus dexamethasone days 2–3 (or 2–4) problem of preventing chemotherapy-induced nausea and vomiting.89 Moderate emetic risk group (30–90% risk) Includes cyclophosphamide (<1,500 mg/m2), CONCLUSIONS anthracyclines, oxaliplatin and carboplatin The combination of ondansetron, dexametha- ■ Acute: serotonin antagonist plus dexamethasone sone and aprepitant is able to protect 66–78% ■ Delayed: dexamethasone days 2–3, if there of patients from emesis and 48–49% from is a risk of delayed nausea and vomiting; nausea during the first cycle of cisplatin-based this is rarely the case for oral cytotoxins, chemotherapy.72,73,75 In women receiving cyclo­ such as temozolomide. If a corticosteroid is contraindicated, a serotonin antagonist can be phosphamide/anthracycline-based chemotherapy used instead for breast cancer, the corresponding figures are 76% and 33%.74 In a recent phase II study ■ Patients receiving a combination of comprising 58 patients who received moder- cyclophosphamide plus an anthracycline ately emetogenic chemotherapy, palonosetron in should receive acute emesis protection as recommended for the high-emetic-risk group, combination with aprepitant and dexamethasone and delayed emesis protection with aprepitant completely protected 91% of patients from emesis 90 or dexamethasone days 2–3 and 52% from nausea. Grunberg et al. published preliminary results Low emetic risk group (10–30% risk) Includes topotecan, gemcitabine, taxanes, from a phase II study investigating antiemetic capecitabine and trastuzumab therapy in patients with solid tumors who ■ Acute: low dose of dexamethasone received cyclophosphamide and/or anthracycline for the first time. Patients received a 1-day three- Delayed: no routine prophylaxis ■ drug antiemetic regimen of single doses of intra- Minimal emetic risk group (less than 10% risk) venous palonosetron and p.o. dexamethasone Includes bleomycin, vinca-alkaloids and bevacizumab and aprepitant. None of the 15 patients vomited ■ Acute and delayed: no routine prophylaxis during the first 5 days after chemotherapy, none reported significant acute nausea, and only 47% reported significant delayed nausea.91 Although the results from these phase II studies the optimum prophylaxis and therapy. There are very promising, the use of palonosetron, aprepi­ are, however, a number of potential barriers and tant and dexamethasone should be validated limitations to their use. Some antiemetic topics in large randomized studies. are very well investigated whereas others have New antiemetics have been highly successful been addressed in only a limited number of trials in the prophylaxis of emesis, but are less effec- that often include only a small number of tive in the prevention of nausea. There is, there- patients. Consequently, antiemetic guidelines fore, a particular interest in initiating trials to are highly evidence-based for the prophylaxis investigate agents with potential anti-nausea of acute cisplatin-induced (i.e. highly emeto- effect, such as olanzapine. Guidelines such as the genic) nausea and vomiting, whereas the recom- MASCC antiemetic guidelines are only useful if mendations for prophylaxis of delayed nausea they are continuously updated and implemented and vomiting induced by highly or moderately in the daily clinic. To encourage implementation, emetogenic chemotherapy are made on the basis the MASCC guidelines have been translated into of a lower level of scientific evidence. several languages, are updated every 6 months (as Several studies have shown that the implemen­ new data arise), and are always accessible on the tation of antiemetic guidelines is difficult. MASCC website.

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