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Symptom Management and Supportive Care

Symptom Management and Supportive Care

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Guidelines for Antiemetic Treatment of Chemotherapy-InducedNausea and Vomiting: Past, Present, and Future Recommendations
K
ARIN
J
ORDAN
, C
HRISTOPH
S
IPPEL
, H
ANS
-J
OACHIM
S
CHMOLL
Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle/Wittenberg,Halle/Saale, Germany
Key Words.
Antiemetic therapy ASCO antiemetic guidelines MASCC antiemetic guidelinesNCCN practice antiemesis guidelines 5-HT
3
serotonin-receptor antagonists Neurokinin
1
-receptor antagonist
Disclosure:
Nopotentialconflictsofinterestwerereportedbytheauthors,planners,reviewers,orstaffmanagersofthisarticle.
L
EARNING
O
BJECTIVES
After completing this course, the reader will be able to:1. Explain the optimal antiemetic prophylaxis for patients receiving chemotherapy in regard to the emetogenicpotential of the therapy.2. Describe the difference between acute and delayed emesis.3. Discuss the properties and optimal use of the different antiemetic drugs.
Access and take the CME test online and receive 1
AMA PRA Category 1 Credit 
at CME.TheOncologist.com
CMECME
A
BSTRACT
Clinicians should be aware that chemotherapy-inducednausea and vomiting (CINV) is still one of the mostfeared side effects of chemotherapy. With the correctuse of antiemetics, CINV can be prevented in almost70% to up to 80% of patients. Treatment guidelines areuseful tools that enable physicians to integrate the latestclinical research into their practices. The large volumeof rapidly evolving clinical data has been summarizedand incorporated into treatment recommendations bywell-knownandreliableinstitutions,includingtheMul-tinationalAssociationofSupportiveCareinCancer,theAmerican Society of Clinical Oncology, and the Na-tional Comprehensive Cancer Network. Despite theavailability of such guidelines, however, there is evi-dence that adherence to and implementation of treat-ment recommendations are less than optimal. Thisreview focuses, in particular, on the conformity and dif-ferences of these three guidelines. Furthermore, openquestions and trends in the field of antiemesis are dis-cussed as well.
TheOncologist
2007;12:1143–1150
Correspondence: Karin Jordan, M.D., Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle/ Wittenberg, Ernst-Grube-Str. 40, 06120 Halle/Saale, Germany. Telephone: 49-345-557-2924; Fax: 49-345-557-2950; e-mail:Karin.jordan@medizin.uni-halle.de Received March 19, 2007; accepted for publication July 9, 2007. ©AlphaMed Press 1083-7159/ 2007/$30.00/0 doi: 10.1634/theoncologist.12-9-1143
T
he
O
ncologist
®
S
ymptom
M
anagement and
S
upportive
C
are
TheOncologist
2007;12:1143–1150 www.TheOncologist.com
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I
NTRODUCTION
The goal of each antiemetic therapy is to abolish nauseaand vomiting. Twenty years ago, nausea and vomitingwere common adverse events of certain types of chemo-therapy and forced up to 20% of patients to postpone orrefuse potentially curative treatment [1]. Clinical and ba-sic research over the past 25 years has led to steady im-provements in the control of chemotherapy-inducednausea and vomiting (CINV). The development of the5-HT
3
-receptor antagonists (5-HT
3
RAs) in the early1990s was one of the most significant advances in thechemotherapy of cancer patients. Another group of anti-emetics, the neurokinin
1
-receptor antagonists (NK
1
RA),has recently been developed, and the first drug in thisclass, aprepitant, was incorporated into the updated anti-emetic guidelines.In 1998, the first Multinational Association of Support-ive Care in Cancer (MASCC) antiemetic guidelines basedon the results of the Perugia consensus conference werepublished, followed by the American Society of ClinicalOncology (ASCO) guidelines in 1999 [2, 3]. Last year,these two guidelines, as well as the National Comprehen-sive Cancer Network (NCCN) guidelines, were updated[4–6].Thisreviewcomparesthesethreeguidelineswithre-spect to the use of antiemetics.
C
LASSIFICATION OF
CINV
AgreementexistsonhowtoclassifyCINV.CINVisdiffer-entiatedintothreecategories:acuteonset(mostlyserotoninrelated), occurring within 24 hours of initial administrationof chemotherapy; delayed onset (in part substance P re-lated), occurring 24 hours to several days after initial treat-ment; and anticipatory, observed in patients whose emeticepisodesaretriggeredbytaste,odorsight,thoughts,oranx-iety secondary to a history of poor response to antiemeticagentsorinadequateantiemeticprophylaxisinthepreviouscycle of chemotherapy [7, 8].
E
METOGENICITY OF
C
HEMOTHERAPEUTIC
A
GENTS
The emetogenic potential of the chemotherapeutic agentsused is the main risk factor for the degree of CINV. In re-gard to their emetogenic potential, the chemotherapeuticagents are classified into four emetic risk groups: high(90%), moderate (30%–90%), low (10%–30%), and mini-mal (
10%), as suggested by all three guidelines (the fig-ures in parentheses represent the percentage of patientshaving emetic episode(s) when no prophylactic antiemeticprotection provided) [4–6]. Hence, antiemetic prophylaxisis directed toward the emetogenic potential of the chemo-therapy(Table1andTable2).IntheMASCCguidelines,inparticular,theemetogenicpotentialoforalchemotherapeu-tic agents is recognized separately (Table 2). In the revisedclassifications (MASCC and NCCN), i.v. etoposide is la-beled as having low emetogenic potential. However, oraletoposide is classified as having moderate emetogenic po-tential,implyingthatthereisa30%–90%incidenceofeme-
Table 1.
Emetogenic risk of i.v. chemotherapeuticagents [4–6]
High (emesis risk,
>
90% without antiemetics)
Carmustine, BCNU LomustineCisplatin MechlorethamineCyclophosphamide (
1,500 mg/m
²
) PentostatinDacarbazine, DTIC StreptozotocinDactinomycin, actinomycin D
Moderate (emesis risk, 30%–90% withoutantiemetics)
Altretamine IfosfamideCarboplatin IrinotecanCyclophosphamide (
1,500 mg/m
²
) MelphalanCytarabine (
1 g/m
²
) Mitoxantrone(
12 mg/m
²
)Daunorubicin OxaliplatinDoxorubicin TemozolomideEpirubicin TrabectedinIdarubicin Treosulfan
Low (emesis risk, 10%–30% without antiemetics)
Asparaginase Mitoxantrone(
12 mg/m
²
)Bortezomib PaclitaxelCetuximab PegasparaginaseCytarabine (
1g/m
²
) PemetrexedDocetaxel TeniposideEtoposide Thiopeta5-Fluorouracil TopotecanGemcitabine TrastuzumabMethotrexate (
100 mg/m
²
)
Minimal (emesis risk,
<
10% without antiemetics)
Bleomycin
-,
-,
 
-interferonBevacizumab MelphalanBusulfan MercaptopurineChlorambucil Methotrexate(
100 mg/m
²
)Cladribine ThioguanineCytarabine (
100 mg/m
²
) VinblastineFludarabine VincristineHormone VinorelbineHydroxyurea
1144
Antiemetic Treatment of CINV
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sis[5,6].InarecentlypublishedstudybyEinhornetal.[9],oral etoposide seemed indeed to have only low emetogenicpotential.AlsoofinterestisthatimatinibisclassifiedbytheMASCCandNCCNguidelinesasamoderatelyemetogenicagent, whereas the daily use of antiemetics is not recom-mended in the special case of imatinib by the NCCN. TheASCO guidelines do not implicate any of the oral chemo-therapeutic agents in their classification system [4].
P
ATIENT
-R
ELATED
R
ISK
F
ACTORS
Patient-related risk factors, including young age, femalegender, a history of low alcohol intake, experience of eme-sis during pregnancy, impaired quality of life, and previousexperience with chemotherapy, are known to increase therisk for CINV [4–6, 10, 11]. In the choice of the optimalantiemetic prophylaxis, patient-related risk factors have noinfluence on the primary decision. Further research is nec-essary to verify the usefulness of integrating a patient-related risk factor profile into the primary decision-makingprocess. This would make sense, considering the widerange of emetogenic potential (30%–90%) in the moder-ately emetogenic setting. However, whether or not such amodel would translate into daily routine practice is ques-tionable.
A
NTIEMETICS
5-HT
3
RAs
The5-HT
3
RAsarewithoutdoubtthemosteffectiveantiemet-icsintheprophylaxisofacuteCINV.Thedifferent5-HT
3
RAsappeartobeinterchangeable.Thelowestfullyeffectiveonce-dailydoseforeachagentshouldbeusedasindicatedinTable3. The oral and i.v. routes are similarly effective. These state-ments are supported by all three guidelines.
 Dolasetron
All three guidelines recommend the same doses of dola-setron of 100 mg or 1.8 mg/kg i.v. and 100 mg orally.
Granisetron
All three guidelines recommend granisetron at a dose of 1mg or 0.01 mg/kg i.v., and 2 mg orally (MASCC andASCO) or 1–2 mg orally (NCCN).
Ondansetron
In regard to the dosing of ondansetron, different statementsaregivenbytheNCCNthanbytheMASCCandASCO.Assuch, the NCCN guidelines recommend ondansetron at adose of 16–24 mg orally and 8–12 mg (maximum, 32 mg)i.v., whereas the MASCC and ASCO guidelines recom-mend ondansetron at a dose of 24 mg orally (MASCC, 16mg orally for moderately emetogenic chemotherapy) and 8mg or 0.15 mg/kg i.v. In a recently published meta-analysiscomparing low-dose ondansetron (8 mg) with high-doseondansetron (24 or 32 mg), in a subanalysis in cisplatin-basedchemotherapy,high-doseondansetronappearedtobemore effective (
 p
.012) [12].
 Palonosetron
All three guidelines recommend palonosetron at a dose of 0.25 mg i.v. Oral palonosetron is not yet available. Palono-setron has a significantly longer half-life and a higher bind-ing activity than the other 5-HT
3
RAs. The actual role of palonosetron in comparison with the other available5-HT
3
RAs is discussed controversially in the guidelines.However, none of the three guidelines designates a pre-ferred 5-HT
3
RA, although palonosetron outperformed on-dansetronanddolasetroninsomesecondaryendpointsinonestudy [13]. For a better understanding, the results of thethreeavailablerandomizedstudieswithpalonosetronintheacute phase are outlined in Table 4. In a recently publishedmeta-analysis, palonosetron was not included because onlytwo studies were fully published at that time [12–14].
Tropisetron
Adoseof5mgorallyori.v.isrecommendedfortropisetronby the ASCO and MASCC guidelines, whereas tropisetronis not part of the NCCN guidelines because it is not avail-able in the U.S.
Table 2.
Emetogenic risk of oral chemotherapeuticagents [5, 6]
High (emesis risk,
>
90% without antiemetics)
Hexamethylmelamine Procarbazine
Moderate (emesis risk, 30%–90% withoutantiemetics)
Cyclophosphamide TemozolomideEtoposide VinorelbineImatinib
Low (emesis risk, 10%–30% without antiemetics)
Capecitabine Fludarabine
Minimal (emesis risk,
<
10% without antiemetics)
Chlorambucil MelphalanErlotinib MethotrexateGefitinib SorafenibHydroxyurea SunitinibL-Phenylalanine mustard 6-Thioguanine
1145
Jordan, Sippel, Schmoll
www.TheOncologist.com
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