Review
`Chemotherapy-induced nausea and vomiting: current
`and
`new standards in the antiemetic prophylaxis and treatment
`Karin Jordan, Christoph Kasper z, Hans-Joachim Schmoll *
`Department of Internal Medicine IV, Haematology/Oncology, Martin-Luther-University Halle/Wittenberg, Ernst-Grube-Str. 40, 06120
`Halle/Saale, Germany
`Received 23 September 2004; accepted 24 September 2004
`Available online 6 November 2004
`Abstract
`Nausea and vomiting are considered as two of the most distressing side-effects of chemotherapy. Chemotherapy-induced nausea
`and vomiting have been classified into acute, delayed and anticipatory based on the time of onset. The frequency of nausea and
`vomiting depends primarily on the emetogenic potential of the chemotherapeutic agents used. With the introduction of the 5-
`HT3 receptor-antagonists in combination with dexamethasone in the early 1990s approximately 70% of patients receiving highly
`emetogenic chemotherapy were protected from acute emesis. However, 40% of patients have symptoms in the delayed phase.
`Another group of antiemetics, the neurokinin-1-receptor-antagonists, have recently been introduced. The addition of neurokinin
`receptor (NK1 receptor)-antagonists to standard therapy significantly improves emesis protection in the acute and in particular
`in the delayed phase by approximately 20%. Due to these new developments, revised antiemetic guidelines have been set. Here,
`the most recent developments in antiemetic therapy, including these guidelines, are reviewed.
`/C2112004 Elsevier Ltd. All rights reserved.
`Keywords: Anti-emetic therapy; MASCC-guidelines; NCCN-guidelines; Chemotherapy; 5-HT
`3 receptor-antagonists; Steroids; Neurokinin-1-rece-
`ptor-antagonists
`1. Introduction
`The goal of antiemetic therapy is to abolish nausea
`and vomiting. Twenty years ago, nausea and vomiting
`were inevitable adverse events of chemotherapy and
`forced up to 20% of patients to postpone or refuse
`potentially curative treatment. The introduction of the
`5-HT
`3 receptor-antagonists in the 1990s dramatically re-
`duced chemotherapy-induced emesis, particularly when
`used in combination with corticosteroids. Another
`group of antiemetics, the neurokinin receptor-antago-
`nists, have recently been developed, and the first drug
`in this class, aprepitant, has been approved by the
`authoritative bodies of the Food Drug Administration
`(FDA) and European Union (EU). Studies have shown
`that patients benefit from the use of this drug in combi-
`nation with standard antiemetic therapy, both in the
`acute and delayed setting of cisplatin-induced nausea
`and vomiting.
`This article will review the most recent developments
`in antiemetic therapy including the results from the 2004
`Perugia Consensus Conference on antiemetic therapy,
`the Multinational Association of Supportive Care in
`Cancer (MASCC guidelines) and the National Compre-
`hensive Cancer Network (NCCN) guidelines from 2004
`[1,2] and will present a practical treatment approach for
`antiemetic prophylaxis.
`0959-8049/$
`- see front matter /C2112004 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.ejca.2004.09.026
`* Corresponding author. Tel.: +49 345 557 2924; fax: +49 345 557
`2950.
`E-mail address: hans-joachim.schmoll@medizin.uni-halle.de (H.-J.
`Schmoll).
`www.ejconline.com
`European Journal of Cancer
`41 (2005) 199–205
`European
`Journal of
`Cancer
`HELSINN EXHIBIT 2081
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 7
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`2. Acute/delayed/anticipatory nausea and vomiting
`Chem
`otherapy-induced nausea and vomiting usually
`are classified into 3 categories: acute onset, occuring
`within 24 h of the initial administration of chemother-
`apy; delayed onset, occuring 24 h to several days after
`initial treatment; and anticipatory nausea and vomiting,
`observed in patients whose emetic episodes are triggered
`by taste, odour sight, thoughts, or anxiety secondary
`to a history of poor response to antiemetic agents
`(Table 1 ).
`3.
`Classification of the emetic-risk
`The emetogenic potential of chemotherapeutic agents
`is the main risk factor for the degree of chemotherapy-
`induced nausea and vomiting. With regard to their eme-
`togenic potential, chemotherapeutic agents are classified
`into 4 emetic risk groups: high, moderate, low and min-
`imal ( Table 2 ) [1]. Other risk factors, including young
`age,
`female gender, low alcohol intake, experience of
`emesis during pregnancy, impaired quality of life and
`previous experience of chemotherapy, are known to in-
`crease the risk of nausea and vomiting after chemother-
`apy [3,4].
`4.
`Antiemetic agents
`With modern antiemetic therapy, nausea and vomit-
`ing can completely be prevented in almost 70–80% of
`patients [5,6]. Combination antiemetic regimens have
`beco
`me the standard of care for the control of chemo-
`therapy-induced nausea and vomiting.
`4.1. 5-HT3 receptor-antagonists
`The 5-HT 3 receptor-antagonists are without doubt
`the most effective antiemetics in the prophylaxis of acute
`nausea and vomiting. The following five 5-HT 3 receptor-
`antagonists are currently available: ondansetron, gran-
`isetron, tropisetron, dolasetron and palonosetron ( Table
`3). More than 50 randomised trials have compared the
`c
`linical effect of two or more of these agents and have
`Table 1
`Categories
`of chemotherapy-induced nausea and vomiting
`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
`24 h to 5 days after start of chemotherapy
`Various mechanisms: mainly substance P-mediated, disruption of the blood–brain barrier, disruption of gastrointestinal motility, adrenal
`hormones [28]
`Anticipatory nausea and vomiting
`Occurrence
`is possible after 1 cycle of chemotherapy
`Involves the element of classic-conditioning
`In approximately 30% of patients by the fourth treatment cycle after experience of emetic episode(s)
`Table 2
`Emetogenic
`risk of chemotherapeutic agents
`High (emesis risk> 90% without antiemetics)
`Carmustine Lomustine (>60 mg/m 2)
`Cisplatin Mechlorethamine
`Cyclophosphamide (>1500 mg/m 2) Pentostatin
`Dacarbazine, DTIC Streptozotocin
`Dactinomycin, Actinomycin D
`Moderate (emesis risk 30–90% without antiemetics)
`Altretamin Irinotecan
`Carboplatin Lomustine (<60 mg/m
`2)
`Cyclophosphamide (<1500 mg/m 2) Melphalan i.v.
`Cyclophosphamide, per os Mitoxantrone (>12 mg/m 2)
`Cytarabine (>1 g/m 2) Oxaliplatin
`Daunorubicin Procarbazine, per os
`Doxorubicin Temozolamide
`Epirubicin Treosulfan
`Idarubicin Trabectedin
`Ifosfamide
`Low (emesis risk 10–30% without antiemetics)
`Aldesleukin (IL-2) Mitomycin
`Asparaginase Mitoxantrone (<12 mg/m 2)
`Bortezomib Paclitaxel
`Cetuximab Pegasparaginase
`Cytarabine (<1 g/m
`2) Pemetrexed
`Docetaxel Teniposide
`Etoposide i.v., per os Thiopeta
`5-Fluorouracil Topotecan
`Gemcitabine Trastuzumab
`Methotrexate
`Minimal (emesis risk<10% without antiemetics)
`Bleomycin: Bevacizumab Gifitinib
`Busulfan a-, b-, c-Interferon
`Capecitabine Melphalan per os
`Chlorambucil Mercaptopurine
`Cladribine Methotrexate (<100 mg/m 2)
`Cytarabine (<100 mg/m 2) Rituximab
`Erlotinib Thioguanin
`Fludarabine Vinblastine
`Hydroxyurea Vincristine
`Imatinib mesylate Vinorelbine
`Adapted from [1,9,29], i.v., intravenous; p.o., orally.
`200 K.
`Jordan et al. / European Journal of Cancer 41 (2005) 199–205
`Page 2 of 7
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`been unable to find clinically meaningful differences [7].
`How
`ever, a meta-analysis conducted recently and pre-
`sented at the American Society of Clinical Oncology
`(ASCO) 2004 meeting including more than 40 studies
`and comparing all of the available 5-HT
`3 receptor-an-
`tagonists suggested a possible advantage for granisetron
`compared with tropisetron [8]. In consideration of the
`MASC
`C guidelines, it was stated that given at biologi-
`cally equivalent doses, ondansetron, granisetron, dolase-
`tron, tropisetron and palonosetron are equally
`efficacious, equally safe, and appear to be interchangea-
`ble [1,9,10]. The adverse effects of 5-HT
`3 receptor-antag-
`onists are generally mild, with headache and
`constipation being most commonly described.
`When administering 5-HT
`3 receptor-antagonists, the
`following statements should be taken into account:
`/C15The lowest fully effective dose for each agent should
`be used; higher doses do not enhance any aspect of
`activity because of receptor saturation.
`/C15The oral and intravenous routes are similarly
`effective.
`/C15Single dose regimens are as effective as multiple dose
`regimens.
`/C15Adverse effects of these agents are comparable.
`4.2. Steroids
`The mechanisms by which steroids exert their anti-
`emetic activity are not fully understood. Steroids are
`considered to be effective and safe antiemetics. When
`used in combination with other anti-emetics, they ap-
`pear to exert a booster effect in raising the emetic thresh-
`old. Theoretical concerns that steroids may interfere
`with the antitumour effects of chemotherapy through
`immunsuppressive mechanisms have not been confirmed
`in clinical trials [11]. In one study by Kemeny and col-
`leagues [12] the addition of dexamethasone to floxuri-
`dine
`into the hepatic artery in patients with colorectal
`cancer significantly improved tolerance and showed a
`trend towards improved survival. It is not evident that
`there is any difference between the different steroids,
`but dexamethasone appears to be the most intensively
`investigated ( Table 4 ). For prevention of acute emesis
`an
`8 mg single dose of dexamethasone for moderately
`emetogenic chemotherapy and 20 mg for highly emeto-
`genic chemotherapy should be the doses of choice
`[1,13,14].
`Side-e
`ffects are usually dependent on the dose and
`duration of therapy and include insomnia and
`hyperglycemia.
`4.3. Neurokinin-1-(NK1)receptor-antagonists
`Aprepitant represents a new class of anti-emetic. It is
`a potent selective, central nervous system (CNS)-pene-
`trant, oral non-peptide antagonist of the NK1 receptor.
`Aprepitant has recently been approved by the United
`States (US) FDA and by the EU authorities to be used
`in acute and delayed emesis resulting from highly emeto-
`genic chemotherapy, including cisplatin (FDA) or cisp-
`latin-based therapy (EU). It has been shown in several
`studies to augment the antiemetic activity of the combi-
`nation of the 5-HT
`3 receptor-antagonist and dexameth-
`asone to inhibit both, acute and, particularly, delayed
`emesis in cisplatin-based chemotherapy. Furthermore a
`randomised study of patients receiving moderately eme-
`togenic chemotherapy showing superiority of the triple
`combination of a 5-HT
`3 receptor-antagonist, dexameth-
`asone and aprepitant used in the first 24 h followed by
`aprepitant alone for another 2 days. Whereas, the
`recently released MASCC-guidelines (April 2004) rec-
`ommend aprepitant only for cisplatin-based chemother-
`apy a revision including aprepitant as well in the
`moderate emetogenic setting is expected soon. However,
`the NCCN guidelines already recommend aprepitant for
`moderate emetogenic chemotherapy in selected patients
`in combination with a 5-HT
`3 receptor-antagonist plus
`dexamethasone [2].
`Concer
`ning the dose, a randomised study established
`the most favourable risk profile of aprepitant at doses of
`125 mg orally (p.o.) on day 1 and 80 mg p.o. on days 2
`and 3 ( Table 5 ) [15].
`Table 3
`Dose
`of 5-HT 3 receptor-antagonists
`Drug Route Recommended dose per day
`Ondansetron p.o. 12–24 mg
`i.v. 8 mg (0.15 mg/kg)
`Granisetron p.o. 2 mg
`i.v. 1 mg (0.01 mg/kg)
`Tropisetron p.o. 5 mg
`i.v. 5 mg
`Dolasetron p.o. 100 mg
`i.v. 100 mg (1.8 mg/kg)
`Palonosetron i.v. 0.25 mg
`Adapted from [1,2,9]. p.o., orally.
`Table 4
`Dose
`of steroids
`Drug Route Recommended dose per day (mg)
`Moderate/High
`Dexamethasone p.o. 8/20
`i.v.
`Methylprednisolone p.o. 40–125/40–125
`i.v.
`Table 5
`Dose
`of neurokinin-1-receptor-antagonist
`Drug name Route of administration Recommended dose
`Aprepitant p.o. 125 mg day 1,
`80 mg days 2 + 3
`K. Jordan et al. / European Journal of Cancer 41 (2005) 199–205 201
`Page 3 of 7
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`Aprepitant is eliminated primarily by metabolism of
`CYP
`3A4 and is a substrate and moderate inhibitor of
`CYP3A4 [16]. Therefore, possible interactions between
`aprep
`itant and other drugs have been investigated inten-
`sively. A 2-fold increase in the area under concentration
`curve (AUC) of dexamethasone, as a sensitive substrate
`of CYP3A4, could be demonstrated when it was com-
`bined with aprepitant. Therefore, the dose of dexameth-
`asone should be reduced by approximately 50% when
`aprepitant is coadministered. As such, a potential risk
`of interaction with cytotoxic drugs metabolised by
`CYP3A4 may occur. So far, preliminary data from an
`ongoing trial have shown no interaction between docet-
`axel (metabolised by CYP3A4) and aprepitant [16].I n
`clini
`cal trials in general, patients treated with aprepitant
`do not have a statistically different incidence of adverse
`events from those receiving placebo.
`4.4. Dopamine receptor antagonists
`Dopamine receptor antagonists were the basis of
`antiemetic therapy from the 1950s to the early 1980s,
`but their efficacy as single agents is relatively low. They
`can be divided into phenothiazines (e.g., promethazine
`and metopimazine), butyrophenones (e.g., haloperidol
`and droperidol) and substituted benzamides (e.g., meto-
`clopramide and alizapride).
`Metoclopramide has been most intensively investi-
`gated and possesses antiemetic activity when given in
`conventional doses to patients receiving mildly or mod-
`erately emetogenic chemotherapy [17]. However, in pa-
`tient
`s receiving cisplatin-based chemotherapy,
`conventional doses of metoclopramide are not signifi-
`cantly different from placebo. Today, it is recognised
`that the effect of high-dose metoclopramide in patients
`receiving cisplatin is due to antagonism at the 5-HT
`3
`receptors [18]. Adverse effects are mainly extrapyramidal
`sympt
`oms, especially in higher doses, sedation and
`orthostatic hypotension.
`4.5. Benzodiazepines
`Benzodiazepines can be a useful addition to anti-
`emetic regimens in certain circumstances. Trials with
`lorazepam have shown a high degree of patient accept-
`ance. As such, they serve to reduce anxiety and reduce
`the risk of anticipatory nausea. Lorazepam may add a
`small degree of objective anti-emetic efficacy. However,
`this property is so limited that the use of lorazepam as
`a single-agent antiemetic is not recommended. A dou-
`ble-blind randomised study showed that its known
`anti-anxiety effects can be quite prominent in the chem-
`otherapy administration setting when added to effective
`antiemetic combinations [19]. Lorazepam is the pre-
`ferr
`ed agent for anticipatory nausea and vomiting.
`4.6. Cannabinoids
`Cannabinoids (e.g. dronabinol) are thought to exert
`antiemetic activity at the cannabinoid receptor, likely lo-
`cated in the brain stem [20]. In a systematic review of the
`e
`fficacy of oral cannabinoids in the prevention of nausea
`and vomiting, it was found that cannabinoids were
`slightly better than conventional antiemetics (e.g., meto-
`clopramide, phenothiazines, haloperidol). However,
`their usefulness was generally limited by the high inci-
`dence of toxic effects such as dizziness, dysphoria and
`hallucinations. Accordingly, dronabinol is recom-
`mended for consideration in the treatment of break-
`through or refractory emesis. Doses in the range of 5–
`10 mg/m
`2, every 3–4 h, orally, appear to be among the
`most useful [21].
`4
`.7. Antihistamines
`Antihistamines have been administered both as anti-
`emetics and adjunctive agents to prevent dystonic reac-
`tions with dopamine antagonists. Studies with diph-
`enhydramine or hydroxyzine in the prevention of
`chemotherapy induced nausea and vomiting have not
`shown any antiemetic activity for these drugs [9].
`In
`palliative care, the antihistamines have a role in the
`treatment of nausea thought to be mediated by the ves-
`tibular system. Side-effects of antihistamines include
`drowsiness, dry mouth, and blurred vision.
`5. Recommendations
`Focused on the new MASCC guidelines from 2004
`and NCCN Guidelines from 2004, the following treat-
`ment options are recommended ( Table 6 ) [1,2]. The
`a
`ppropriate antiemetic regimen is based on the emesis
`risk categories ( Table 2 ).
`5
`.1. Prevention of acute nausea and vomiting
`High risk of emesis: For agents in the high-risk cate-
`gory, the MASCC and NCCN guidelines suggest unan-
`imously a combination of 5-HT 3 receptor-antagonist,
`dexamethasone and aprepitant within the first 24 h.
`Moderate risk of emesis: Due to a lack of published
`randomised studies in the moderate emetogenic setting
`when creating the guidelines, conflicting recommenda-
`tions are present. The NCCN guidelines recommended
`aprepitant already in selected patients for the moderate
`emetogenic chemotherapy in combination with a 5-HT
`3
`receptor-antagonist plus dexamethasone. However, the
`actual MASCC guidelines recommend a 5-HT
`3 recep-
`tor-antagonist plus dexamethasone without aprepitant
`because of a lack of published studies at the time of
`the Perugia Consensus Conference. Considering the pos-
`202 K. Jordan et al. / European Journal of Cancer 41 (2005) 199–205
`Page 4 of 7
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`itive results from the most recent study in the moderate
`emet
`ogenic setting showing a significantly better emesis
`control with aprepitant presented at the annual ASCO
`meeting in 2004, a revision of the MASCC guidelines
`including aprepitant is expected soon [22].
`Low
`risk of emesis: Both guidelines recommend unan-
`imously the use of a steroid alone.
`Minimal risk of emesis: It is suggested that, for pa-
`tients treated with agents of low emetic risk, no anti-
`emetic drug should be routinely administered before
`chemotherapy.
`5.2. Prevention of delayed nausea and vomiting
`Trials have indicated that between 60 to nearly 90%
`of patients receiving cisplatin will experience delayed
`emesis if not given preventive antiemetics. Despite the
`efficacy of 5-HT
`3 receptor-antagonists in the initial 24
`h period after the start of chemotherapy, the therapeuti-
`cal role in the delayed phase is rather limited [23]. The
`recomm
`ended treatment options for the delayed phase
`according to the MASCC and NCCN guidelines are
`shown in Table 6 .
`High
`risk of emesis: In two Phase III studies an aver-
`age increase of 20% complete response rates was
`achieved in patients receiving apreptiant plus standard
`antiemetic therapy in comparison to standard antiemetic
`therapy plus placebo only [5,6]. On that basis, both pan-
`els
`suggested the combination of dexamethasone and
`aprepitant to prevent delayed emesis in cisplatin-based
`chemotherapy (MASCC) and highly emetogenic chemo-
`therapy (NCCN).
`Moderate risk of emesis: As stated for the acute eme-
`sis, there are different recommendations in the delayed
`setting as well. In the NCCN guidelines, aprepitant is
`already recommended in selected patients for moder-
`ate emetogenic chemotherapy in combination with
`dexamethasone. The MASCC guidelines suggest dexa-
`methasone alone or a 5-HT
`3 receptor-antagonist
`alone. In contrast to the NCCN guidelines metoclopr-
`amide is no longer recommended by the MASCC
`guide-lines.
`Low and minimal risk of emesis: No regular preventive
`use of antiemetics for delayed emesis is suggested for pa-
`tients receiving these chemotherapeutic agents.
`5.3. Treatment of anticipatory nausea and vomiting
`Prevention of chemotherapy-induced vomiting is seen
`as the best strategy for preventing anticipatory nausea
`and vomiting [24]. If it occurs, anticipatory nausea and
`vo
`miting should be managed by psychological tech-
`niques (e.g., behavioural therapy with systematic desen-
`sitisation). An alternative to or addition to
`psychological techniques is the use of benzodiazepines,
`in particular lorazepam. [1,9].
`5.4.
`Management of breakthrough nausea and vomiting
`Breakthrough nausea and vomiting is defined as an
`event that happens in spite of optimal preventative treat-
`ment. Treatment of breakthrough symptoms is referred
`to as rescue therapy. If optimal treatment has been given
`as prophylaxis, repeated dosing of the same agents is un-
`likely to be successful [25]; an addition of a dopamine
`recept
`or antagonist might be useful. Anecdotal reports
`indicate that various interventions that sedate patients
`may be of value in cases of breakthrough emesis. These
`comprise the use of benzodiazepines and neuroleptic
`agents, as suggested by the ASCO guidelines [9].
`5.5.
`Refractory nausea and vomiting
`Refractory nausea and vomiting refers to nausea or
`vomiting, or both, that recurs in subsequent cycles of
`therapy when all previous preventive and rescue treat-
`ments have failed. In one trial of granisetron failing with
`metoclopramide, dexamethasone and ondansetron indi-
`cated a response to alternative 5-HT
`3 receptor-antago-
`nists in 53–60% of cases [26]. These findings suggest a
`pos
`sible patient variability in response to the setrons.
`The reason may be an interindividually different hepatic
`metabolisation of the 5-HT 3 receptor-antagonists. Thus,
`tropisetron, dolasetron and palonosetron are mainly
`metabolised by the genetically polymorphic cytochrome
`P450 enzyme, 2D6. Ondansetron is metabolised par-
`tially through CYP2D6, as well as through cytochrome
`P450 enzymes, 3A4, 2E1, and 1A2. Ultrafast metabolis-
`ers for 2D6 show a lower maximal blood concentration
`and shorter half-life for tropisetron than poor metabo-
`lisers do [27].
`Table 6
`Antiemetic
`prevention based on the emesis risk category according to the MASCC and NCCN-guidelines
`Emesis risk Acute (day 1) Followed by Delayed (days 2–5)
`High 5-HT3 + Dex + NK1 ! Dex + NK1
`Moderate 5-HT 3 + Dex + NK1 in selected
`patients or 5-HT 3 + Dex
`! Dex alone or 5-HT 3 alone or metoclopramide alone or
`DEX + NK1 in selected patients
`Low Dex ! None
`Minimal None ! None
`Adapted from [1,2]. 5-HT 3: 5-HT 3 receptor-antagonist, Dex: dexamethasone, NK1: neurokinin-1- receptor antagonist.
`K. Jordan et al. / European Journal of Cancer 41 (2005) 199–205 203
`Page 5 of 7
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`5.6. Multiple-day chemotherapy
`A
`considerable number of chemotherapeutic proto-
`cols are given over more than one day, of which the 5-
`day cisplatin represents the classical example. If after
`24 h the same drug, i.e., cisplatin is given both an acute
`and eventually a delayed stimulus is generated. The ex-
`pert panel creating the MASCC guidelines recom-
`mended for multiple–day cisplatin the use of a 5-HT
`3
`receptor-antagonist in combination with dexamethasone
`for acute nausea and vomiting and dexamethasone
`alone for delayed nausea and vomiting [1].
`The
`use of a NK-1-receptor antagonist will probably
`add to the observed efficacy when the single day obser-
`vations are extrapolated to the multiple day setting.
`However, no study is available to formally prove this
`proposal.
`6. Conclusions
`With the introduction of the neurokinin-1-receptor
`antogonist, a further step forwards in the prevention
`of nausea and vomiting has been made. With the triple
`combination therapy of a 5-HT
`3 receptor-antagonist,
`neurokinin-1-receptor antogonist and dexamethasone,
`vomiting can be prevented in approximately 70–80%
`of patients receiving highly emetogenic therapy. Pre-
`venting emesis is a high priority for patients and to ob-
`tain optimal control, the results from antiemetic
`research must be transferred to clinical practice. Unfor-
`tunately, guidelines designed to define optimal care in
`this setting are often not followed in daily practice lead-
`ing to suboptimal control of nausea and vomiting. One
`barrier to the implementation of guidelines is the under-
`estimation of delayed nausea and vomiting by nurses
`and physicians. In spite of major improvements in con-
`trolling emesis after chemotherapy the effectiveness of
`the available antiemetic prophylaxis for nausea is still
`limited.
`Conflict of interest statement
`None declared.
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