Chemotherapy-Induced Nausea and Vomitingdownloads.hindawi.com/journals/specialissues/417182.pdf · dard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting:

BioMed Research International

Chemotherapy-Induced Nausea and Vomiting

Guest Editors: Bernardo Leon Rapoport, Alexander Molasiotis, Haralambos Raftopoulos, and Fausto Roila

BioMed Research International


Guest Editors: Bernardo Leon Rapoport,Alexander Molasiotis, Haralambos Raftopoulos,and Fausto Roila

Copyright © 2015 Hindawi Publishing Corporation. All rights reserved.

This is a special issue published in “BioMed Research International.” All articles are open access articles distributed under the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the originalwork is properly cited.

Contents

Chemotherapy-Induced Nausea and Vomiting, Bernardo Leon Rapoport, Alexander Molasiotis,Haralambos Raftopoulos, and Fausto RoilaVolume 2015, Article ID 457326, 2 pages

Prevention of Nausea and Vomiting in Patients Undergoing Oral AnticancerTherapies for SolidTumors, Ana Lúcia Costa, Catarina Abreu, Teresa Raquel Pacheco, Daniela Macedo, Ana Rita Sousa,Catarina Pulido, António Quintela, and Luı́s CostaVolume 2015, Article ID 309601, 7 pages

A Randomized, Double-Blind Pilot Study of Dose Comparison of Ramosetron to PreventChemotherapy-Induced Nausea and Vomiting, Ka-Rham Kim, Gaeun Kang, Myung-Seo Ki,Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung, Jong-Keun Kim, Seongwook Jeong,and Sang-Hee ChoVolume 2015, Article ID 523601, 7 pages

Management of Chemotherapy Induced Nausea and Vomiting in Patients on Multiday Cisplatin BasedCombination Chemotherapy, Praveen Ranganath, Lawrence Einhorn, and Costantine AlbanyVolume 2015, Article ID 943618, 8 pages

A Review of NEPA, a Novel Fixed Antiemetic Combination with the Potential for Enhancing GuidelineAdherence and Improving Control of Chemotherapy-Induced Nausea and Vomiting, Paul J. Hesketh,Matti Aapro, Karin Jordan, Lee Schwartzberg, Snezana Bosnjak, and Hope RugoVolume 2015, Article ID 651879, 12 pages

Efficacy of Olanzapine CombinedTherapy for Patients Receiving Highly Emetogenic ChemotherapyResistant to Standard AntiemeticTherapy, Masakazu Abe, Yuka Kasamatsu, Nobuhiro Kado, Shiho Kuji,Aki Tanaka, Nobutaka Takahashi, Munetaka Takekuma, and Yasuyuki HirashimaVolume 2015, Article ID 956785, 6 pages

Prophylactic Management of Radiation-Induced Nausea and Vomiting, Petra Feyer, Franziska Jahn,and Karin JordanVolume 2015, Article ID 893013, 8 pages

Treatment of Breakthrough and Refractory Chemotherapy-Induced Nausea and Vomiting,Rudolph M. NavariVolume 2015, Article ID 595894, 6 pages

Biological and Pharmacological Aspects of the NK1-Receptor, Susana Garcia-Recio and Pedro GascónVolume 2015, Article ID 495704, 14 pages

EditorialChemotherapy-Induced Nausea and Vomiting

Bernardo Leon Rapoport,1 Alexander Molasiotis,2

Haralambos Raftopoulos,3 and Fausto Roila4

1The Medical Oncology Center of Rosebank, Saxonwold, Johannesburg 2196, South Africa2School of Nursing, The Hong Kong Polytechnic University, Hong Kong3Merck & Co., Rahway, NJ 07065, USA4Medical Oncology, Santa Maria Hospital, Terni, Italy

Correspondence should be addressed to Bernardo Leon Rapoport; [email protected]

Received 15 June 2015; Accepted 15 June 2015

Copyright © 2015 Bernardo Leon Rapoport et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

In the past two decades, significant advances have beenmadein the management of chemotherapy-induced nausea andvomiting (CINV). These advances are primarily due to agreater understanding of the physiological and molecularpathways underlying CINV, which resulted inmajor progressin the management of patients with CINV.

In the early 1990s, CINV treatment consisted of dex-amethasone [1]. Improvements in the management ofCINV control were achieved with the discovery of 5-hydroxytryptamine (5HT

3) receptor and the development of

5HT3receptor antagonists (RA). This pathway is primarily

involved in the acute phase of CINV. Subsequent studiesdemonstrated that the usage of the combination of 5HT

3RA

and dexamethasone resulted in additional improvements inCINV control [2, 3].

Over the last decade, the discovery of the neurokinin-1receptor antagonists (NK

1-RA) and its role in the pathogen-

esis of delayed phase of CINV has led to significant develop-ments in the management of this complication of anticancertreatment. More importantly, these milestone achievementsare significant and resulted in an improvement in anticancertreatment compliance, as well as an improvement in thequality of life of patients diagnosed with cancer.

Despite these achievements, nausea, in particular, andvomiting remain a clinically significant problem for patientsreceiving both highly emetogenic chemotherapy (HEC) andmoderately emetogenic chemotherapy (MEC). Seventy per-cent of patients treated with cisplatin-basedHECwill achievean overall antiemetic complete response when managed witha triple therapy consisting of a NK

1RA aprepitant in combi-

nationwith a 5HT3RA and corticosteroids prophylaxis [4, 5].

The current antiemetic guidelines (MASCC/ESMO, ASCO,and NCCN) endorse triple therapy treatment for patientsreceiving cisplatin- andAC-based chemotherapy regimes [6–8].

The current special issue includes several reviews includ-ing the biology and pharmacology of the NK

1receptor and

substance P, the antiemetic management of germ cell tumorpatients undergoing multiple days’ chemotherapy treatment,radiotherapy induced nausea and vomiting (RINV), CINVinduced by oral cytotoxic agents and targeted therapies inpatients undergoing treatment for solid tumors, adherence toCINV guidelines and the benefits of NEPA (a new agent con-sisting of a combination of netupitant and palonosetron), andthe treatment of breakthrough and refractory chemotherapy-induced nausea and vomiting. Additionally, 2 original clinicalpapers are presented investigating the ramosetron and olan-zapine in the management of CINV.

The review article by S. Garcia and P. Gascon provides anextensive overview of the basic knowledge of the NK

1recep-

tor and substance P biology and the pharmacological basis ofthe usage of NK

1receptor antagonists in the management of

delayed phase of CINV.The 5-HT

3receptor antagonists play an important role

in the pathogenesis of the acute phase of CINV. K.-R.Kim et al. presented a pilot study with the potential usageof ramosetron, a tetrahydrobenzimidazole derivative struc-turally independent of the previously developed 5-HT

3

receptor antagonists, such as ondansetron, granisetron, andtropisetron.

Patients with germ cell tumor undergoing 5 days ofcisplatin-based chemotherapy have a different mechanism

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 457326, 2 pageshttp://dx.doi.org/10.1155/2015/457326

http://dx.doi.org/10.1155/2015/457326

2 BioMed Research International

and pattern of CINV compared to those receiving single daychemotherapy. The efficacy of antiemetic drugs, as observedin single day chemotherapy, is therefore not applicable. Inthis issue, P. Ranganath et al. from Indiana University discusscurrent recommendations and future directions for patientsundergoing multiple day treatment.

Depending on the site of irradiation, dosing, fraction-ation, irradiated volume, and radiotherapy techniques, theincidence of nausea and vomiting after radiotherapy isapproximately 50–80%. RINV is a very important and notwell researched area often underestimated by physicians.K. Jordan et al. include an overview of RINV and currentguidelines recommendations as well as future directions.

The treatment of nausea and vomiting caused by oralantineoplastic agents is primarily empirical, consisting of theadministration of daily oral antiemetic therapy. The level ofevidence of prophylactic antiemetics recommended for theseagents is low. A. L. Costa et al. discuss the managementof CINV induced by oral cytotoxic agents and targetedtherapies in patients undergoing treatment for solid tumors.This article highlights the differences in the classification ofemetogenic potential of oral antineoplastic agents betweenthe different international guidelines, as well as differentrecommendations for prophylactic antiemetic treatments.

NEPA is a new oral single fixed combination agent,containing a highly selective NK

1RA, netupitant with

palonosetron.This agent is a pharmacologically and clinicallydistinct 5-HT

3RA. Palonosetron has a longer half-life com-

pared with older 5-HT3RAs. Palonosetron works synergis-

tically with netupitant and has the potential to improve theefficacy in the prevention of the delayed phase of CINVwhenused in combination. P. J. Hesketh et al. discuss the use ofNEPA in the context of howNEPAmay overcome some of thebarriers interfering with adherence to the various antiemeticguidelines.

Several studies have shown that the antipsychotic agentolanzapine is effective in the management of CINV. Thepharmacological mechanism of action consists of the block-ing of neurotransmitter receptors including dopaminergic atD1, D2, D3, and D

4brain receptors, serotonergic at 5-HT2a,

5-HT2c, 5-HT3, and 5-HT6 receptors, catecholamines atalpha1adrenergic receptors, acetylcholine at muscarinic

receptors, and histamine at H1receptors. In this special issue,

R. M. Navari discusses the treatment of breakthrough andrefractory chemotherapy-induced nausea and vomiting withspecial reference to olanzapine in this setting. In anotherpaper, M. Abe et al. retrospectively analyze the role of olan-zapine in 50 gynecologic cancer patients receiving cisplatin-based chemotherapy who had nausea despite the use ofstandard therapy.

The treatment of CINV is evolving and this special issuehighlights some of the recent developments as well as someof the controversies in this important field of oncology.

Bernardo Leon RapoportAlexander Molasiotis

Haralambos RaftopoulosFausto Roila

References

[1] M. S. Aapro andD. S. Alberts, “Dexamethasone as an antiemeticin patients treated with cisplatin,” The New England Journal ofMedicine, vol. 305, no. 9, article 520, 1981.

[2] G. Falkson and A. J. van Zyl, “A phase I study of a new 5HT3-receptor antagonist, BRL43694A, an agent for the preven-tion of chemotherapy-induced nausea and vomiting,” CancerChemotherapy and Pharmacology, vol. 24, no. 3, pp. 193–196,1989.

[3] D. B. Smith, E. S. Newlands, O. W. Spruyt et al., “Ondansetron(GR38032F) plus dexamethasone: effective anti-emetic prophy-laxis for patients receiving cytotoxic chemotherapy,” BritishJournal of Cancer, vol. 61, no. 2, pp. 323–324, 1990.

[4] P. J. Hesketh, S. M. Grunberg, R. J. Gralla et al., “Theoral neurokinin-1 antagonist aprepitant for the prevention ofchemotherapy-induced nausea and vomiting: a multinational,randomized, double-blind, placebo-controlled trial in patientsreceiving high-dose cisplatin—the aprepitant protocol 052study group,” Journal of Clinical Oncology, vol. 21, no. 22, pp.4112–4119, 2003.

[5] S. Poli-Bigelli, J. Rodrigues-Pereira, A. D. Carides et al., “Addi-tion of the neurokinin 1 receptor antagonist aprepitant to stan-dard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: results from a randomized,double-blind, placebo-controlled trial in Latin America,” Can-cer, vol. 97, no. 12, pp. 3090–3098, 2003.

[6] National Comprehensive Cancer Network, “NCNN Guidelines1.2012: antiemesis 1.2015,” Tech. Rep. 1.2015, 2015.

[7] F. Roila, J. Herrstedt, M. Aapro et al., “Guideline updatefor MASCC and ESMO in the prevention of chemotherapy-and radiotherapy-induced nausea and vomiting: results of thePerugia consensus conference,” Annals of Oncology, vol. 21,supplement 5, pp. v232–v243, 2010.

[8] E. Basch, A. A. Prestrud, P. J. Hesketh et al., “Antiemetics: Amer-ican Society of Clinical Oncology clinical practice guidelineupdate,” Journal of Clinical Oncology, vol. 29, no. 31, pp. 4189–4198, 2011.

Review ArticlePrevention of Nausea and Vomiting in Patients Undergoing OralAnticancer Therapies for Solid Tumors

Ana Lúcia Costa,1 Catarina Abreu,1 Teresa Raquel Pacheco,1,2 Daniela Macedo,1

Ana Rita Sousa,1 Catarina Pulido,1 António Quintela,1 and Luís Costa1,2

1Oncology Division, Hospital de Santa Maria, Centro Hospitalar de Lisboa Norte, EPE, Avenida Professor Egas Moniz,1649-035 Lisbon, Portugal2Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz,1649-028 Lisbon, Portugal

Correspondence should be addressed to Luı́s Costa; [email protected]

Received 21 November 2014; Accepted 11 May 2015

Academic Editor: Bernardo L. Rapoport

Copyright © 2015 Ana Lúcia Costa et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances inits prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high,moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one dayregimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targetedtherapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oralantineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agentsis low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the internationalguidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemeticregimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate riskand low to minimal risk of emetogenicity.

1. Introduction

Chemotherapy-induced nausea and vomiting (CINV) is stilla common and debilitating side effect despite recent advancesin its prevention and treatment.

At the 2004 Perugia Antiemetic Consensus Guidelinemeeting, an expert panel used best available data to estab-lish rankings of emetogenicity. The anticancer therapy wasdivided into four emetic risk groups: high (>90%), moderate(30–90%), low (10–30%), andminimal (


Table 1: Emetogenic potential of oral antineoplastic agents mostused in solid tumors (based onMASCC andESMOguidelines 2010).

MASCC and ESMO guidelines 2010Degree of emetogenicity (incidence) Agent

High (>90%) HexamethylmelamineProcarbazine

Moderate (30–90%)

CyclophosphamideTemozolomideVinorelbineImatinib

Low (10–30%)

CapecitabineEtoposideSunitinibEverolimusLapatinib

Minimal (75mg/m2/day)Vismodegib

Minimal to low

AxitinibCabozantinibCapecitabineCyclophosphamide (

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guidelines are more recent and more frequently updatedbut the bibliographic references are identical to MASCCand ESMO guidelines [4]. Considerations about the dose ofchemotherapeutic agents are onlymade onNCCN guidelinesfor cyclophosphamide and temozolomide, suggesting that,for lower doses of these drugs, the recommended antiemeticprophylaxis for moderate risk of emetogenicity may beexcessive.

Usually CINV is classified as acute, delayed, or anticipa-tory, and these distinctions have important implications forpatient management [7]. Although with extended regimensof daily oral use the distinction between acute and delayedemesis is less clear, cumulative emesis must be considered, assome of the newer agents may only become emetogenic aftera week or more of continuous administration [4, 5].

3. Antiemetics

There are three categories of drugs most efficient for themanagement of CINV: type three 5-hydroxytryptamine (5-HT3) receptor antagonists, neurokinin-1 receptor (NK1R)antagonists, and glucocorticoids (especially dexamethasone)[7]. These agents are used alone (glucocorticoids) or in com-binations depending on the specific chemotherapy regimenbeing administered, as recommended in the MASCC andESMO guidelines and in the ASCO guidelines [1, 8].

The prevention of acute and delayed CINV for intra-venous agents and one day regimens is well studied [1, 8],although there is little data about management of CINVcaused by oral cytotoxic agents and targeted therapies, usuallyadministered in extended regimens of daily oral use.

NCCNguidelines recommend antiemetic prophylaxis forthe following oral agents, classified as having high or moder-ate emetic risk: hexamethylmelamine, crizotinib, cyclophos-phamide (≥100mg/m2/day), estramustine, etoposide, lomus-tine (single day), mitotane, procarbazine, temozolomide(>75mg/m2/day or ≤75mg/m2/day with concurrent radio-therapy), and vismodegib.The antiemetics recommended areoral 5-HT3 antagonists (such as dolasetron 100mg po daily,granisetron 2mg po daily, or 1mg po bid or ondansetron 16–24mg po daily) with or without lorazepam (0.5–2mg po orsublingual every 4 or every 6 h on as needed basis) and withor without either an H2 blocker or a proton pump inhibitor.These antiemetics should be started before chemotherapy andcontinue daily during chemotherapy. For oral agents of lowor minimal emetic risk no routine premedication is requiredand recommended antiemetics include oral 5-HT3 antago-nists,metoclopramide, prochlorperazine, or haloperidol withor without lorazepam and with or without either an H2blocker or a proton pump inhibitor on as needed basis only[6].

There is no data incorporating NK1 receptor antagonistswith oral regimens [6].

These antiemetic recommendations apply to oralchemotherapy only. When combined with intravenousagents in a combination chemotherapy regimen, the anti-emetic recommendations for the agent with the highest levelof emetogenicity should be followed.

4. Antineoplastic Agents with HighEmetogenic Potential

There are two oral chemotherapy agents with high emeto-genic potential, being rarely used in clinical practice [1, 6].

Hexamethylmelamine (also known as altretamine) is analkylating agent that may be used in persistent or recur-rent epithelial ovarian cancer. The recommended dosage is260mg/m2/day in 4 divided doses for 14 or 21 days of a 28-day cycle.

Procarbazine is also an alkylating agent used in cen-tral nervous system tumors. The PCV regimen includesprocarbazine 60mg/m2 on days 8 to 21 every 6 weeks (incombination with lomustine and vincristine) for 6 cycles or75mg/m2 on days 8 to 21 every 6 weeks (also in combinationwith lomustine and vincristine) for up to 4 cycles.

NCCN recommendations for antiemetic prophylaxis formoderate to high emetogenic risk may be followed for theseagents.

5. Antineoplastic Agents with ModerateEmetogenic Potential

Themoderate risk category covers awide range of frequenciesof emesis from 30% to 90%.The period of risk lasts for at least2 days after the last dose of chemotherapy [6].

The agents included in this category are cyclophos-phamide, temozolomide, vinorelbine, and imatinib accordingto MASCC and ESMO guidelines.

According to NCCN guidelines other agents are alsoincluded such as crizotinib, estramustine, etoposide, lomus-tine (single day), mitotane, and vismodegib.

Cyclophosphamide is an alkylating agent. The oralcyclophosphamide is used in adjuvant breast cancer reg-imens just like cyclophosphamide, methotrexate, and flu-orouracil (100mg/m2/day on days 1 to 14 every 28 daysfor 6 cycles). In this regimen an antiemetic protocol forhigh/moderate emetogenic chemotherapy is recommended[9]. The British Columbian Cancer Agency (BCCA) recom-mends ondansetron 8mg po and dexamethasone 8–20mg poon D1 of chemotherapy and dexamethasone 4mg po in theevening of D1 and then 4mg po bid on D2-D3/4. Prochlor-perazine 10mg po or metoclopramide 10–40mg po could beused on as needed basis [10]. In 1993, Buser et al. showed thatondansetron given orally, 8mg three times a day for 15 days,was safe and effective in the control of emesis induced by oralmultiple-day cyclophosphamide treatment in breast cancerpatients receiving chemotherapy with CMF [11].

Temozolomide is an alkylating agent used in malignantbrain tumors and in malignant melanoma (with brain metas-tasis). Patients with newly diagnosed malignant gliomastreated with concomitant temozolomide (75mg/m2 po dailyfor 6 weeks) and RT should be medicated with ondansetron8mg given 30 minutes prior to first dose of temozolomideand then prochlorperazine 10mg po 30minutes prior to eachsubsequent dose of temozolomide [10]. For adjuvant and pal-liative temozolomide (150mg/m2 once daily for 5 days every28 days) the recommended premedication is ondansetron


8mg po 30 minutes prior to each dose of temozolomide[12, 13]. Palonosetron has been tested in a phase II study inthe adjuvant treatment of glioblastoma patients. A single doseof palonosetron 0.25mg iv before the initiation of multipleoral doses of temozolomide, in patients on treatment withsteady doses of dexamethasone, provides a good protectionagainst CINV throughout the overall phase (0–168 h) [14].In malignant melanoma (temozolomide 200mg/m2/day for5 days every 28 days) the premedication is also ondansetron8mg po 30 minutes prior to each dose of temozolomide [15].

Vinorelbine is a mitotic inhibitor. Oral vinorelbine isused in non-small-cell lung cancer and in breast cancer inmono- or polychemotherapy. In monotherapy the startingdose is 60mg/m2 given on days 1 and 8 of a 3-week cycleand thereafter 80mg/m2 on D1 and D8. It may induce nauseaor vomiting because of local gastrointestinal irritation, so aprimary prophylaxis with 5-HT3 receptor antagonist 30minbefore each intake is recommended [16]. In the associationswith cisplatin or taxanes the antiemetic regimens are chosenbased on these drugs because of their highest emetic risk. Inassociationwith capecitabine or trastuzumab, the prophylaxiscould be donewith 5-HT3 receptor antagonist before vinorel-bine intake.

Imatinib is a tyrosine kinase inhibitor. In GIST (adjuvantand metastatic) it is used as 400mg once daily but may beincreased up to 800mg daily (400mg twice daily) in diseaseprogression [17, 18]. In MASCC and ESMO guidelines itis considered as having moderate emetogenic potential andBCCA recommends antiemetic protocol for low/moderateemetogenic chemotherapy. InNCCNguidelines it is classifiedasminimal to low risk of emetogenicity and so no prophylaxisof emesis is recommended.

Crizotinib is an anaplastic lymphoma kinase (ALK)tyrosine kinase inhibitor used in treatment of metastaticALK-positive non-small-cell lung cancer. It is administeredas 250mg twice daily. BCCAdoes not recommend antiemeticpremedication [19]. In the product monograph it is men-tioned that median time to the onset for nausea and vomitingis 2 to 3 days andmost events aremild tomoderate in severityand declined in frequency after 3 to 4 weeks of treatment. Inclinical trials, the most commonly used antiemetic medica-tions were ondansetron and prochlorperazine [20].

Estramustine is an alkylating agent used in hormonerefractory and metastatic prostate cancer. The recommendeddosage is 14mg/kg/day (range: 10–16mg/kg/day) in 3 or 4divided doses [21]. Transient nausea and vomiting may occurduring the first two weeks of therapy [22].

Etoposide is a topoisomerase II inhibitor. It is classified ashaving low emetogenic risk byMASCC andESMOguidelinesand asmoderate to high risk byNCCNguidelines. It is used insmall cell lung cancer (first-line in combination, second-linealone or in combination), non-small-cell lung cancer (aloneor in combination), and testicular cancer (in combination,oral therapy for refractory disease). The usual dosage is 100to 200mg/m2/day for 5 days. If daily doses are >200mg theyshould be administered in 2 divided doses. Dosage must bemodified to take into account the myelosuppressive effectsof other drugs in the combination. The product monograph

mentioned that the severity of nausea and vomiting due tooral etoposide is generally mild to moderate with treatmentdiscontinuation required in 1% of patients. Symptoms canusually be controlled with standard antiemetic therapy [23,24]. The emetic potential of oral etoposide was studied byEinhorn and Brames in 16 patients with refractory germ cellcancer who received daily oral etoposide 50mg/m2 for 21consecutive days every 4 weeks [25]. None of the patientsreceived prophylactic antiemetics, 11 of 16 had no nausea orvomiting, and only two patients required antiemetic support,being treated with lorazepam and lorazepam with prochlor-perazine.The authors suggested that daily oral etoposide doesnot require prophylactic antiemetics.

Lomustine is an alkylating agent (nitrosourea). It is usedin the treatment of recurrent malignant brain tumors. Theusual dosage is 130mg/m2 (single dose at fasting or at bed-time) once every 6 weeks. Nausea and vomiting may occur 3to 6 hours after administration and the duration is generally


the prophylactic antiemetic regimens recommended bythe international guidelines, we propose the followingrecommendations.

General Recommendations

(i) The anticancer agent must be taken with food, unlessit is specified differently in summary of productcharacteristics.

(ii) Choose the antiemetic regimens according to theemetogenic potential of the antineoplastic agent.

(iii) If the antiemetic regimen chosen is insufficient, asso-ciate an antiemetic from a different category.

(iv) Check for possible interactions between each antineo-plastic agent and the proposed antiemetic regimens.

Antiemetic Regimens. For oral antineoplastic agents with highor moderate emetic risk we suggest antiemetic prophylaxiswith oral 5-HT3 antagonists, such as ondansetron 8–16mg30minutes before the antineoplastic agent or 8mg bid duringthe days in which the oral antineoplastic is administeredplus one or two days after it is ended. It may be associatedwith a glucocorticoid as dexamethasone 4–8mg 30 minutesbefore the antineoplastic agent or 2–4mg bid during oralchemotherapy. The glucocorticoid is especially useful withantineoplastic agents administered one time each week (e.g.,vinorelbine). Olanzapine 10mg once daily may be associatedwith continuous oral regimens (see the following list).

High to Moderate Emetic Risk: Emesis Prevention

Start before chemotherapy and continue daily:(i) 5-HT3 antagonist: ondansetron 8mg po bid,(ii) ±glucocorticoid: dexamethasone 2–4mg po bid,(iii) ±olanzapine 10mg po id.

For oral agents of low or minimal emetic risk no routineantiemetic premedication is required and if necessary dom-peridone 10mg 3-4 times daily or metoclopramide 10mg 3-4 times daily with or without lorazepam 0.5–2mg every 4–6hours as needed is recommended (see the following list).

Low to Minimal Emetic Risk: Emesis Prevention

No antiemetic prophylaxisOr(i) domperidone 10mg po 3-4 times daily, or(ii) metoclopramide 10mg po 3-4 times daily,(iii) ±lorazepam 0.5–2mg every 4–6 hours as needed.

8. Differential Diagnosis for Emesis in Patientsunder Oral Antineoplastic Treatment

The oral antineoplastic agents can be responsible for nauseaand vomiting in patients under treatment, but with theexception of some drugs previously mentioned, most of thesedrugs are relatively well tolerated.

So, other causes should be sought in these patients.A meticulous history and physical examination should beperformed. Symptom duration (acute versus chronic), fre-quency, temporal relationship with the oral antineoplasticagents or other drugs, severity, and the characteristics ofvomiting episodes and associated symptoms must be char-acterized. In some circumstances the etiology can be multi-factorial. Most frequent disorders associated with nausea andvomiting are listed in the following list.

Differential Diagnosis for Emesis in Patients underOral Antineoplastic Treatment

(i) Tumor related causes are as follows:

(a) malignant mechanical obstruction (bowelobstruction, gastric obstruction, and extrinsiccompression by hepatomegaly or ascites);(b) increased intracranial pressure: primary orsecondary brain tumors;(c) metabolic abnormalities: hypercalcemia,hyponatremia, and adrenal insufficiency.

(ii) Treatment related causes are as follows:

(a) chemotherapy induced;(b) anticipatory nausea and vomiting;(c) radiotherapy induced;(d) postoperative nausea and vomiting.

(iii) Organic causes (generally not tumor related) areas follows:

(a) acute gastritis/gastroenteritis;(b) gastroesophageal reflux disease;(c) functional gastrointestinal disorders;(d) acute cholecystitis and acute pancreatitis;(e) constipation;(f) chronic intestinal pseudo-obstruction;(g) vestibular dysfunction;(h) myocardial ischemia;(i) uremia;(j) diabetic ketoacidosis;(k) hyperparathyroidism, hypoparathyroidism,and hyperthyroidism;(l) sepsis;(m) hemorrhage intracranial and abscessintracranial;(n) migraine;(o) pregnancy;(p) psychiatric disease.

(iv) Drug-induced causes (may not be tumor related)are as follows:

(a) analgesics: opioids, tramadol, nonsteroidalanti-inflammatory drugs, aspirin;


(b) antidepressants: selective serotonin reuptakeinhibitors and bupropion;(c) anticonvulsants;(d) iron supplements;(e) antibiotics/antivirals: erythromycin, tetracy-cline, sulfonamides, and acyclovir;(f) cardiovascular medications: digoxin, antiar-rhythmics, antihypertensives, and oral antidia-betics.

9. Conclusions

In clinical practice, for patients on treatment with oral anti-neoplastic agents, each emetic event represents a distressingsymptom that could alter the absorption of chemotherapywith potentially negative effects in terms of efficacy.Until nowalmost no prospective data is available to guide the use ofantiemetic agents in such cases.

We reviewed the evidence for antiemetic regimens usedfor the most commonly used oral antineoplastic agents forsolid tumors and propose antiemetic regimens for agents ofhigh tomoderate risk and low tominimal risk of emetogenic-ity.

Treatment of nausea and vomiting caused by oral antineo-plastic agents still remains largely empirical and we hope foradvances in management of emetogenicity of oral regimensfor solid tumors.

Conflict of Interests

The authors have no disclosures to report.

References

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[6] D. Ettinger, M. Berger, D. Armstron et al., NCCN ClinicalPractice Guidelines in Oncology—Antiemesis, version 2.2014,2014.

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[8] E. Basch, A. A. Prestrud, P. J. Hesketh et al., “Antiemetics: amer-ican Society of Clinical Oncology clinical practice guidelineupdate,” Journal of Clinical Oncology, vol. 29, no. 31, pp. 4189–2117, 2011.

[9] S. Ellard, BCCA Protocol Summary for Adjuvant Therapyfor High-Risk Breast Cancer using Cyclophosphamide (oral),Methotrexate and Fluorouracil, 2014.

[10] P. Hoskins, BBCA Guidelines for Prevention and Treatmentof Chemotherapy-Induced Nausea and Vomiting in Adults, BCCancer Agency, 2014.

[11] K. S. Buser, R. A. Joss, D. Piquet et al., “Oral ondansetron inthe prophylaxis of nausea and vomiting induced by cyclophos-phamide, methotrexate and 5-fluorouracil (CMF) in womenwith breast cancer. Results of a prospective, randomized,double-blind, placebo-controlled study,” Annals of Oncology,vol. 4, no. 6, pp. 475–479, 1993.

[12] B. Thiessen, “BCCA protocol summary for concomitant (dualmodality) and adjuvant temozolomide for newly diagnosedmalignant gliomas with radiation,” BC Cancer Agency ProtocolSummary CNAJTZRT, 2014, http://www.bccancer.bc.ca/chem-otherapy-protocols-site/Documents/CNAJTZRT Protocol1Sep2014.pdf.

[13] B. Thiessen, BCCA Protocol Summary for Therapy for Malig-nant Brain Tumours Using Temozolomide, 2014.

[14] A. Rozzi, C. Nardoni, M. Corona et al., “Palonosetron for theprevention of chemotherapy-induced nausea and vomiting inglioblastoma patients treated with temozolomide: a phase IIstudy,” Supportive Care inCancer, vol. 19, no. 5, pp. 697–701, 2011.

[15] R. Klassa, BCCA Protocol Summary for Palliative Therapy forMalignant Melanoma with Brain Metastases Using Temozolo-mide, 2014.

[16] M. Aapro and J. Finek, “Oral vinorelbine in metastatic breastcancer: a review of current clinical trial results,” Cancer Treat-ment Reviews, vol. 38, no. 2, pp. 120–126, 2012.

[17] M. Knowling, BCCA Protocol Summary for Adjuvant Treat-ment of C-Kit Positive High Risk Gastrointestinal Stromal CellTumours Using Imatinib, 2014.

[18] M. Knowling, “BCCA Protocol Summary for Treatment ofAdvanced C-Kit Positive and C-Kit Negative GastrointestinalStromal Cell Tumours (GISTs) Using Imatinib (GLEEVEC),”2014.

[19] C. Lee, BCCAProtocol Summary for Second-Line Treatment ofALK-PositiveAdvancedNon-Small Cell LungCancer (NSCLC)with Crizotinib, 2014.

[20] Pfizer Canada Inc, Crizotinib (XALKORI) Product Monograph,Pfizer Canada Inc., Québec, Canada, 2014.

[21] K. Chi, “BCCA Protocol Summary for Androgen-IndependentProstate Cancer Using Estramustine Phosphate (Interim Ver-sion),” November 2014.

[22] Pfizer Canada Inc, MCYT Product Monograph, Pfizer CanadaInc, Québec, Canada, 2008.

[23] N. Murray, BCCA Protocol Summary for Palliative Therapyof Extensive Stage Small Cell Lung Cancer (SCLC) with OralEtoposide, 2014.

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[28] K. Savage, “BCCA Protocol Summary for the Treatment ofMetastatic or Locally Advanced Basal Cell Carcinoma UsingVismodegib,” November 2014.

Clinical StudyA Randomized, Double-Blind Pilot Study ofDose Comparison of Ramosetron to PreventChemotherapy-Induced Nausea and Vomiting

Ka-Rham Kim,1 Gaeun Kang,2 Myung-Seo Ki,1 Hyun-Jeong Shim,1

Jun-Eul Hwang,1 Woo-Kyun Bae,1 Ik-Joo Chung,1 Jong-Keun Kim,2,3

Seongwook Jeong,4 and Sang-Hee Cho1

1Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju 519-763, Republic of Korea2Division of Clinical Pharmacology, Chonnam National University Hospital, Gwangju 519-763, Republic of Korea3Department of Pharmacology, Chonnam National University Medical School, Gwangju 519-763, Republic of Korea4Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School,Gwangju 519-763, Republic of Korea

Correspondence should be addressed to Sang-Hee Cho; [email protected]

Received 19 December 2014; Revised 21 January 2015; Accepted 3 February 2015

Academic Editor: Bernardo L. Rapoport

Copyright © 2015 Ka-Rham Kim et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. This study was conducted to determine the optimal dose titration of ramosetron to prevent the Rhodes Index of Nausea,Vomiting, and Retching (RINVR). Methods. Patients treated with folic acid, 5-fluorouracil, and oxaliplatin were randomized intothree groups (0.3mg, 0.45mg, and 0.6mg ramosetron before chemotherapy). The pharmacokinetics and pharmacodynamicsusing RINVR were evaluated. Results. Seventeen, 15, and 18 patients received ramosetron at doses of 0.3mg, 0.45mg, and 0.6mg,respectively. 𝑇max (h), 𝐶max (ng/mL), and AUClast (ng⋅h/mL) were associated with dose escalation significantly, showing a reversecorrelation with the RINVR during chemotherapy. Acute CINV was observed in four patients (22.2%), two patients (14.3%), andone (5.6%) patient and a delayed CINV on day 7 was found in eight (47%), three (21.4%), and five (27.8%) patients in each group.The complete response rate was increased with dose escalation (35.3%, 50.0%, and 72.2% in each group) and also showed thetendency for decreasing moderate-to-severe CINV. Conclusions. This study shows a trend regarding the dose-response relationshipfor ramosetron to prevent CINV, including delayed emesis. It suggested that dose escalation should be considered in patients withCINV in a subsequent cycle of chemotherapy, and an individual approach using RINVR could be useful to monitor CINV.

1. Introduction

Chemotherapy-induced nausea and vomiting (CINV) re-mains one of themost feared adverse events of chemotherapyamong cancer patients [1]. Not only early onset CINV (acute,within 24 h after chemotherapy) but also delayed CINV(≥2 days after chemotherapy) can interfere with compli-ance of treatment and cause patients to receive delayedchemotherapy, contemplate refusing further treatment, anddevelop anticipatory CINV [2]. CINV is an autonomic reflexcontrolled by multiple neurotransmitter systems. Amongthem, the serotonin/5-hydroxytrptamine 3 receptor (5-HT

3)

and substance P/neurokinin-1 receptor (NK-1) systems haveplayed important roles in controlling CINV, and block-ing both systems has been demonstrated to reduce CINVin patients receiving chemotherapy [3–5]. Based on theguidelines of the National Comprehensive Cancer Network,patients receiving a moderately emetogenic chemotherapy(MEC) regimen are recommended a 5-HT

3receptor antag-

onist and dexamethasone, while those receiving a highlyemetogenic chemotherapy (HEC) regimen are given a 5-HT3receptor antagonist, a corticosteroid, and an NK-1

receptor antagonist [6]. As shown above, the 5-HT3receptor

antagonist is the most crucial drug to control CINV in a


http://dx.doi.org/10.1155/2015/523601


MEC or HEC regimen. However, even if the standard doseof the 5-HT

3receptor antagonist has been used, 20–30% of

patients complain of nausea or vomiting in practice [7, 8],and studies concerning the optimal concentration of 5-HT

3

receptor antagonists are lacking.Ramosetron, a new member in the class of selective

5-HT3receptor antagonists and is a tetrahydrobenzimida-

zole derivative structurally independent of the previouslydeveloped 5-HT

3receptor antagonists, such as ondansetron,

granisetron, and tropisetron. Ramosetron is more potentand has longer-lasting effects than older agents because of aslower rate of dissociation from the target receptor and higherbinding affinity [9]. 5-HT

3antagonists such as granisetron

or palonosetron have been investigated extensively regardingthe optimal dose to treat postoperative nausea and vomiting(PONV) or CINV. Generally, the dose required to preventCINV is two- to threefold higher than that needed for PONV[10–12]. However, a similar dose of ramosetron has been usedfor both PONV and CINV, and no study has evaluated theoptimal dose titration for ramosetron to prevent CINV.

To evaluate the efficacy of antiemetics, complete response(CR: no emesis and no rescue medication) and completeprotection (CP: no emesis, no use of rescue medication,and no significant nausea) have been commonly used asmeaningful indices [7, 13, 14]; nevertheless, they do notquantify mild-to-severe CINV. The Rhodes Index of Nausea,Vomiting, and Retching (RINVR) was developed by Rhodesand McDaniel to assess nausea or vomiting after surgery orthe administration of chemotherapy [15]. In this scale, eightitems to evaluate the experience of nausea/vomiting, occur-rence of nausea/vomiting, and issues with nausea/vomitingare listed. A higher point indicates more intense CINV;therefore, the RINVR is used to assess the severity of CINVmore precisely. In addition, antiemetics have been widelyused; the incidence of vomiting has been decreased. In thecontrary, nausea and retching have been major concerns anda new parameter for monitoring CINV is needed.

We hypothesized that if dose escalation of a 5-HT3

antagonist could be effective against CINV, the frequencyor severity of CINV could also be reduced by subsequentdose increases in the next cycle of chemotherapy in patientswho experienced moderate-to-severe CINV in the previouscycle. Based on this concept, the purpose of the present studywas to evaluate the optimal concentration of ramosetron toprevent CINV using the RINVR clinical parameter based onpharmacokinetic (PK) and pharmacodynamic (PD) studiesas a pilot trial.

2. Materials and Methods

2.1. Patients. To evaluate the efficacy of ramosetron for eachdose, we limited the enrolled patients only to those receivingFOLFOX (folic acid, 5-fluorouracil, and oxaliplatin), whichdoes not require inclusion of an NK-1 receptor antagonistduring the first cycle. Patients were eligible if they werediagnosed with colon cancer and treated with FOLFOX asadjuvant chemotherapy after curative resection or palliation.Additionally, patients who were at least 19 years old and hadan Eastern Cooperative Oncology Group performance score

of 0–2 with adequate bone marrow and organ function wereincluded in the present study (i.e., absolute neutrophil count≥1,500/𝜇L, platelet count ≥100,000/𝜇L, serum bilirubin level


blood samples were collected into EDTA tubes. Each samplewas then centrifuged at 1500 g for 10min at 4∘C. At least0.4mL plasma was harvested and stored at −70∘C until anal-ysis.The plasma concentrations of ramosetron were analyzedusing validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Briefly, 200 𝜇Lplasma sample was mixed with 20 𝜇L of an internal standard(5 ng/mL risperidone). Next, 1.5mL methyl tert-butyl etherwas added, and the mixture was vortexed for 2min andcentrifuged at 12,000 rpm for 2min. The supernatants weretransferred and evaporated under nitrogen. The residue wasreconstituted in 100 𝜇L 40% acetonitrile, and 10 𝜇L of thelatter mixture was injected into the HPLC-MS/MS system(HPLC system, Shimadzu LC-20A HPLC system (ShimadzuCo., Kyoto, Japan); MS/MS system, API 4000Q-TRAP massspectrometer (AB SCIEX, Framingham, MA, USA)). Thecolumn was a Gemini C18 2.0 × 100mm (Phenomenex,Torrance, CA, USA), and the mobile phase consisted ofammonium acetate (10mM) and acetonitrile (40 : 60, v/v).The flow rate was maintained at 0.25mL/minute. Linearcalibration curves were validated in the ranges of 0.1–100 ng/mL for ramosetron (𝑟2 = 0.98). The intra- andinterday precision and accuracy were verified within 15% and85–115%, respectively.

2.5. Pharmacokinetic Analysis. The pharmacokinetic param-eters of ramosetron were analyzed by noncompartmentalmethods usingWinNonlin version 6.3 (Pharsight Co.,Moun-tain View, CA, USA). The maximum concentration (𝐶max)and time to 𝐶max (𝑇max) were obtained directly from theconcentration-time data. The area under the concentration-time curve of ramosetron from zero to the last measurableconcentration (AUClast) was calculated using the linear trape-zoidal rule. From the terminal slope of the concentrationtime curve, the elimination rate constant was estimated usinglinear regression, and the terminal half-life (T

1/2), clearance

(CL), and volume of distribution at the steady state (𝑉ss) werecalculated.

2.6. Evaluation of Nausea/Vomiting and Safety. The RINVR,used to assess the degree of CINV, comprises eight ques-tions, each with a total of five choices rating the frequencyand intensity of symptoms. Among the survey questions,numbers 1, 4, 6, 7, and 8 address the subclass of symptomoccurrence, and numbers 2, 3, and 5 address the subclassof symptom distress by assessing the degree of discomfortcaused by the symptoms. The scores from all eight questionsare then summed to obtain the subclass of symptom experi-ence points.Therefore, the total sum of the nausea, vomiting,and retching experience points is defined as RINVR point.RINVR was recorded during an interview at 1 h, 6 h, 24 h,and 48 h after starting chemotherapy. Seven days after start-ing chemotherapy, the RINVR was reassessed by telephoneinterview to evaluate the presence of delayed emesis. TheRINVR scorewas divided into four groups for comprehensiveanalysis as follows: none (0), mild (1–8), moderate (9–16),and severe (17–32). A CR was defined as no emetic episode

and no use of rescue medication during the first cycle ofchemotherapy.

Safety was evaluated based on the results of laboratorytests and electrocardiography. The signs and symptoms weregraded according to the Common Terminology Criteria forAdverse Events (CTCAE), version 4.0.

2.7. Statistics. This study was planned as a pilot study toevaluate the efficacy of dose escalation of ramosetron. Sincethere is no data on target population to use for sample sizecalculation for pilot study, we adopt sample size that wasused in a previous similar granisetron study [16]. Data arepresented as mean ± SD for continuous data and absolutefrequencies (n) and percentages for frequency data. To assessthe pharmacokinetic linearity, statistical comparisons ofthe dose-normalized 𝐶max (𝐶max/D), dose-normalized AUC(AUClast/D), T1/2, CL, and 𝑉ss among the ramosetron dosegroups were performed using the Kruskal-Wallis test. One-way analysis of variance (with Bonferroni post hoc test) wasutilized to assess the differences in patient characteristicsand to compare the RINVR score and concentration oframosetron. 𝜒2 test or Fisher’s exact probability test wasused to compare the proportions of categorical variables.Thenumber of emetic episodes, severity of nausea, and RINVRwere compared among the ramosetron dose groups usingtheKruskal-Wallis test. Statistical significancewas recognizedwhen the 𝑃 value was less than 0.05. SPSS version 21.0 (IBM,Inc., Chicago, IL, USA) was utilized for statistical analyses.

3. Results

3.1. Patient Characteristics. From October 2012 to October2013, fifty-one patients were enrolled, and one patient refusedto participate in the present study; therefore, the data from50 patients were analyzed. Seventeen, 15, and 18 patientsreceived ramosetron at a dose of 0.3mg, 0.45mg, and0.6mg, respectively.Their baseline clinical characteristics aresummarized in Table 1. There was no difference betweenthe groups in terms of sex, age, weight, height, or bodysurface area (BSA). Although female is well known risk factorfor CINV, thirty-three patients (66%) were male in presentstudy. This result is associated with colon cancer prevalencewhich is more common in male than female. Thirty-eightpatients (74%) were diagnosed with stage III colon cancerafter curative resection, and 12 patients (26%) with stage IVdisease. Patients with nausea, vomiting, or retching despiteusing ramosetron received metoclopramide, domperidonemaleate, or lorazepam as rescue medication. There was nosignificant difference in the frequency of the rescue doseamong the ramosetron dose groups.

3.2. Pharmacokinetic Analysis. The mean plasma concen-tration-time profiles of ramosetron at doses of 0.3mg,0.45mg, and 0.6mg are shown in Figure 1. Table 2 showsthe arithmetic mean ± standard deviations (SDs) of thepharmacokinetic parameters determined using noncompart-mental analysis. A dose-dependent increase in the mean𝐶max and AUClast of ramosetron is shown in all three dose


Table 1: Clinical characteristics.

0.3mg 0.45mg 0.6mg𝑃 value

(𝑁 = 17) (𝑁 = 15) (𝑁 = 18)Male 8 (53.3%) 12 (80.0%) 13 (72.2%) 0.157Age (year) 58.94 ± 9.74 61.64 ± 7.76 57.72 ± 10.13 0.547Weight (kg) 63.82 ± 11.83 62.94 ± 10.34 61.82 ± 9.07 0.385Height (cm) 162.72 ± 4.92 164.31 ± 7.67 163.62 ± 7.55 0.885BSA (m2) 1.69 ± 0.18 1.70 ± 0.16 1.67 ± 0.18 0.923Colon cancer

Stage III 12 (71%) 12 (80%) 14 (78%) 0.895Stage IV 5 (29%) 3 (20%) 4 (22%)

Use of rescue antiemetic 3 (17.6%) 5 (33.3%) 3 (16.7%) 0.810Data are presented as mean ± standard deviation.BSA, body surface area

10

8

6

4

2

0

0 5 10 15 20 25

Time (h)

Ram

oset

ron

conc

entr

atio

n (n

g/m

L)

0.3mg (N = 17)0.45mg (N = 15)0.6mg (N = 18)

Figure 1: Mean plasma concentration-time profiles of ramosetronafter a single intravenous injection of 0.3, 0.45, and 0.6mg oframosetron. Bars represent standard errors.

groups.Themean𝐶max ranged from 3.2 to 7.3 ng/mL, and themean AUClast ranged from 17.9 to 35.2 ng⋅h/mL. The meanclearance (CL) and volume of distribution at the steady state(𝑉ss) were in the ranges of 17.1–22.5 L/h and 110.6–142.3 L/h,respectively, for the three ramosetron dose groups. Therewere no significant differences in the 𝐶max/D (𝑃 = 0.450),AUClast/D (𝑃 = 0.301), T1/2 (𝑃 = 0.845), CL (𝑃 = 0.235), or𝑉ss (𝑃 = 0.361) among the ramosetron dose groups, indicatingthat ramosetron exhibited linear pharmacokinetic properties.

3.3. Efficacy of Ramosetron in Dose Escalation. Nausea isthe most common symptom of CINV (40%), followed byretching (18%) and vomiting (8%). None of the patientshad CINV during the first 6 h after starting chemotherapy.CINV showed an increasing tendency for 7 days. The totalRINVR scores at 1 h, 6 h, 24 h, 48 h, and 7 days after startingchemotherapy are shown in Table 3. There was no statistical

Table 2: Pharmacokinetic parameters of ramosetron after a singleintravenous injection of 0.3, 0.45, and 0.6mg of ramosetron.

0.3mg 0.45mg 0.6mg(𝑁 = 17) (𝑁 = 15) (𝑁 = 18)

𝐶max (ng/mL) 3.2 ± 1.3 4.9 ± 3.3 7.3 ± 9.3𝑇max (h) 0.67 0.67 0.67AUClast (ng⋅h/mL) 17.9 ± 6.9 25.9 ± 16.0 35.2 ± 34.8𝑇1/2

(h) 6.4 ± 2.2 6.5 ± 3.2 6.4 ± 1.8CL (L/h) 17.1 ± 6.6 21.3 ± 13.6 22.5 ± 11.8𝑉ss (L) 110.6 ± 38.7 128.5 ± 60.6 142.3 ± 86.6Data are presented as mean ± standard deviation.𝐶max, maximum concentration; 𝐶max/𝐷, maximum concentration/dose;𝑇max, time to 𝐶max; AUClast, area under the concentration-time curve oframosetron from zero to the last measurable concentration; AUClast/𝐷, areaunder the concentration-time curve of ramosetron from zero to the lastmeasurable concentration/dose; 𝑇1/2, terminal half-life; CL, clearance; 𝑉ss,volume of distribution at steady state.

Table 3: Rhodes Index ofNausea, Vomiting, andRetching (RINVR)scores among 0.3mg, 0.45mg, and 0.6mg dosing groups at 1 hour,6 hours, 1 day, 2 days, and 7 days after starting chemotherapy.

0.3mg 0.45mg 0.6mg(𝑁 = 17) (𝑁 = 15) (𝑁 = 18)

1 hr 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.006 hr 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.001 day 0.78 ± 1.56 0.36 ± 0.93 0.11 ± 0.472 days 1.11 ± 2.52 0.79 ± 1.12 0.44 ± 1.347 days 3.61 ± 4.80 0.71 ± 1.44 2.39 ± 4.07Data are presented as mean ± standard deviation.

significance between the RINVR and dose escalation, but areverse correlation with RINVR was found at 1 day (𝑃 =0.237) and 7 days (𝑃 = 0.377) after starting chemotherapyaccording to dose escalation. Twenty-five patients (80%) hadCINV of at least one point on the RINVR, among whomnine patients (18%) showed moderate or severe RINVR. Oneday after starting chemotherapy, four patients (22.2%), twopatients (14.3%), and one (5.6%) patient who received 0.3mg,0.45mg, and 0.6mg of ramosetron, respectively, showed


Table 4: Treatment related adverse events (𝑛 = 50).

Dose of ramosetron0.3mg, 𝑛 (%) 0.45mg, 𝑛 (%) 0.6mg, 𝑛 (%)

Grade 1 Grade 2 Grade 1 Grade 2 Grade 1 Grade 2AST 1 (6) 1 (6) 0 0 1 (6) 0ALT 2 (12) 1 (6) 1 (7) 0 2 (11) 0r-GTP 1 (6) 1 (6) 0 0 1 (6) 0Constipation 3 (18) 1 (6) 0 0 3 (17) 0Rash 0 0 1 (7) 0 0 0ECG QT prolongation 0 0 0 0 1 (6) 0

0

10

20

30

40

50

60

70

80

90

100

RIN

VR

(% o

f pat

ient

s)

Moderate-severeMild

None

0.3 0.45 0.6

(mg)

Figure 2: Total Rhodes Index of Nausea, Vomiting, and Retching(RINVR) score during 7 days according to ramosetron dose group(𝑛 = 50).

CINV. Delayed CINV 7 days after chemotherapy occurredin eight (47%), three (21.4%), and five (27.8%) patients in therespective ramosetron groups. Patients who received a higherdose of ramosetron showed a greater trend for a CR than didpatients who received a lower dose of ramosetron (Figure 2).Regarding the severity, all symptoms for 2 days were gradedasmild RINVR. However, five (29%) and three patients (17%)in the 0.3 and 0.6mg ramosetron-treated groups, respectively,showed moderate RINVR on day 7. Severe RINVR was seenin only one patient who was treated with 0.3mg ramosetron.

3.4. Safety. Of the 50 patients, there were no grade 3 or 4adverse events. Constipation and elevated liver enzymes werecommon symptoms, but most of these were considered tobe unrelated to ramosetron and instead were associated withunderlying disease or chemotherapy. One patient showedQT prolongation on electrocardiography; however, he had

no subjective symptoms, and the condition disappeared onthe next cycle of chemotherapy. The incidence and grade ofevents were similar among the three dose groups (Table 4).

4. Discussion

When the role of chemotherapy is expanded as an adjuvantor for palliation, the willingness to preserve the quality oflife and the completion of planned chemotherapy are alsoincreased. Although 5-HT

3antagonists and neurokinin-1

inhibitors can provide better supportive care than they didpreviously [7, 17], limitations of these drugs persist. CINV isassociated not only with the chemotherapeutic regimen butalso with patient characteristics, such as previous morningsickness, age, gender, performance status score, and smokingor alcohol habits [18].The standard dose of antiemetics wouldnot be sufficient for high-risk patients, and the precisionmarker to predict these high-risk patients has not beenidentified.Therefore, themeticulous and individual approachused for patients with CINV in the previous cycle would beimportant to prevent further CINV on subsequent cycles.

Several studies concerning the dose escalation of anti-emetics to prevent CINV have been performed [19, 20]. Thefirst generation of 5-HT

3antagonists, such as ondansetron,

dolasetron, granisetron, and tropisetron, has been very effec-tive in the control of acute emesis but has not been as effectiveagainst delayed emesis [21, 22]. Among 5-HT

3antagonists,

ramosetron and palonosetron are recently developed agents.Ramosetron has been shown to have higher selectivity forserotonin than other first generation 5-HT

3antagonists

showing superior efficacy in the acute and delayed CINVthan other first generation 5-HT

3antagonists. Palonosetron,

which is second generation of 5-HT3antagonists, has been

investigated extensively in the setting of PONV and CINV asa recommended dose of 0.075mg IV and 0.25mg IV, respec-tively. Compared with palonosetron, the study of ramosetronhas been limited, and the recommended dose of ramosetronis 0.3mg IV in both PONV and CINV. In a previous studyevaluating the efficacy of different doses of palonosetron(0.075mg, 0.25mg, and 0.75mg IV in each group), CR wasachieved in 44.4% of the 0.25mg group and 59.3% of the0.75mg group in patients receiving Adriamycin/carboplatinor epirubicin/carboplatin.Thiswas very similar to the currentresults showing a CR of 35.3% in the 0.3mg group and 61.1%in the 0.6mg group. Not only dose escalation but also the


repeated administration of palonosetron improved CINVusing 0.75mg IV on days 1 and 3 [23]. As a result, CRoccurred in 76.9% of patients who received MEC or HEC.The studies that used high doses of palonosetron up to sixfoldthe standard dose suggest that dose escalation of a 5-HT

3

antagonist could improve CINV. In the present study, twicethe standard dose (0.6mg) of ramosetron resulted in betterclinical outcomes compared with the standard dose (0.3mg)in chemotherapy-näıve patients. This suggests that the doseof ramosetron needed to be escalated to control CINV orescalated individually in patients that experienced CINV,despite the prevention using a standard dose of ramosetron.Although the stratification was not performed according togender, age, height, weight, or BSA, there was no significantdifference in each dose group. In pharmacokinetic analyses,the current study showed the highest AUClast of ramosetronin the 0.6mg group among the three dosing groups; therefore,the 0.6mg group had a higher exposure to ramosetron thandid the low-dose group when the other conditions wereconsistent.

In addition to clinical effectiveness for CINV, the currentstudy revealed that RINVR is a useful tool to monitor CINV.In addition to CR or CP, the National Cancer Institute-Common Terminology Criteria (NCI-CTC) have been usedto monitor nausea or vomiting related to chemotherapytoxicities. However, it is not completely sufficient to reflectthe CINV based only on its frequency and degree of nauseaand vomiting or retching.The current study showed improve-ment in the RINVR according to the dose of ramosetron withmoderate-to-severe RINVR in six (35%) and three patients(17%) treated with 0.3mg and 0.6mg of ramosetron on day7, respectively. These results suggest that even though thecomplete inhibition of CINV was not achieved, a high doseof ramosetron could attenuate the degree of CINV; therefore,RINVR could be another valuable tool to assess CINV.

Based on the pattern of CINV, nausea is the mostcommon symptomand vomiting the least prevalent symptomaccording to the RINVR scores. The cause might be relatedto the MEC regimen used in this study, and the routine useof antiemetics can prevent vomiting, but the prevalence ofnausea and retching was increased relatively. In addition, theRINVR score showed an increasing tendency over 7 days,and 47% of the patients who received 0.3mg ramosetron hadCINV at least of one score of RINVR; in contrast, 28% ofthe patients who received 0.6mg ramosetron experiencedCINV on day 7. Although the concentration of ramosetronwas cleared within the first 2 days according to the phar-macokinetic data, this result suggested that the control ofacute emesis could affect the delayed emesis, and a high doseof ramosetron could help to reduce the delayed emesis. Inconsideration of the prevalence of delayed emesis, the studyabout the usefulness of dose escalation of ramosetron orintroduction of NK-1 receptor antagonist would be helpfulto prevent delayed emesis. As a limitation of this study,there was no statistically significant difference in CINV basedon RINVR among the three dose groups. The reason forthis might be related to the small number of patients ineach group, MEC regimen which could be related to fewerCINV events compared with an HEC regimen, and small

number of female patients who are more prone to CINV, thusdiluting the efficacy of the antiemetics. Further large-scalestudies are needed to confirm the efficacy of dose escalationin the subsequent chemotherapy for patients who showedmoderate-to-severe CINV in previous chemotherapy.

5. Conclusion

This pilot study showed dose-dependent pharmacokineticsof ramosetron with a better RINVR trend according to thedose escalationwith a good safety profile. In addition, RINVRwould be a useful tool to assess the quantification of CINV.Based on this pilot trial, further large-scale study is neededfor more robust clinical outcomes.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

This study was supported by Health & Medical TechnologyR&D Project from Korea National Enterprise for ClinicalTrials (A07000112311450100).

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Review ArticleManagement of Chemotherapy InducedNausea and Vomiting in Patients on MultidayCisplatin Based Combination Chemotherapy

Praveen Ranganath, Lawrence Einhorn, and Costantine Albany

Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence should be addressed to Praveen Ranganath; [email protected]

Received 25 November 2014; Revised 10 May 2015; Accepted 30 May 2015

Academic Editor: Alexander Molassiotis

Copyright © 2015 Praveen Ranganath et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Introduction of cisplatin based chemotherapy has revolutionized the treatment of germ cell tumors. A common side effect ofmultiday cisplatin chemotherapy is severe nausea and vomiting. Considerable progress has been made in the control of theseside effects since the introduction of cisplatin based chemotherapy in the 1970s. Germ cell tumor which is a model for a curableneoplasm has also turned into an excellent testing ground to develop effective strategies to prevent chemotherapy induced nauseaand vomiting (CINV) in multiday cisplatin based regimens. The use of combination of a 5-hydroxytryptamine (HT)

3receptor

antagonist, a neurokinin-1 (NK1) antagonist, and dexamethasone has greatly improved our ability to prevent and control acute and

delayedCINV.Mechanism and pattern of CINVwithmultiday chemotherapymay differ from those in single day chemotherapy andtherefore efficacy of antiemetic drugs as observed in single day chemotherapymay not be applicable.There are only few randomizedclinical trials with special emphasis onmultiday chemotherapy. Further studies are essential to determine the efficacy, optimal dose,and duration of the newer agents and combinations in multiday cisplatin based chemotherapy.

1. Introduction

Germ cell tumors are rare cancers accounting for only 1%of all malignancies in American males. The introductionof cisplatin based combination chemotherapy revolution-ized the treatment of germ cell tumors. The majority ofpatients with testicular cancer are cured with standard dosecisplatin based combination chemotherapy [1]. A commonside effect of cisplatin based regimens is severe nausea andvomiting. Cisplatin in germ cell tumors is administered forfive consecutive days and is appropriately categorized ashighly emetogenic chemotherapy (HEC) with patients beingvulnerable to nausea and vomiting on all five days. Mediannumber of emetic episodes with cisplatin based regimens inthe 1970s and the 1980s for germ cell tumors on day 1 was tenand decreasing on subsequent days [2].These symptomsweresignificantly debilitating for patients. Considerable progresshas been made in the control of nausea and vomiting fromthose early days but there is still paucity of data on antiemetic

regimens for patients undergoing multiday cisplatin com-bination chemotherapy regimen. Germ cell tumor, whichis a model for a curable neoplasm, has also turned intoan excellent testing ground to develop effective strategiesto prevent chemotherapy induced nausea and vomiting(CINV) in these regimens. Phases II and III randomizedclinical trials focusing on multiday chemotherapy regimensare summarized in Table 1. The purpose of this paper isto review our current understanding of CINV in multidaycisplatin regimens and to evaluate clinical agents available forprevention and treatment of CINV as well as areas of futureresearch.

2. Pathophysiology

It has been established that different pathways exist in thebody that induce emesis, each relying on a set of different neu-rotransmitters, including serotonin, dopamine, histamine,and substance P. Receptors for these neurotransmitters are


http://dx.doi.org/10.1155/2015/943618


Table 1: Selected phases II and III trials of various agents for treatment of chemotherapy induced nausea and vomiting in patients undergoingmultiday cisplatin based chemotherapy.

Study Phase 𝑁 CINV prophylaxis Emesis NauseaDay 1 CR Days 1–5 CR

Einhorn et al.,1990 [14] II 36 Ondansetron 77% 30% NA

Sledge et al.,1992 [15] III 45

Ondansetron versusmetoclopramide

78% versus 14%(𝑝 < 0.001) 30% versus 9% (𝑝 = 0.002)

VAS scores 8 versus58.5 (𝑝 < 0.001)

Bremer, 1992[17] III 200

Granisetron versusalizapride (substitutedbenzamide) +dexamethasone

90% versus 66%(𝑝 < 0.001) 49% versus 35%. NA

Fox et al., 1993[21] III 45

Ondansetron +dexamethasone +chlorpromazine versusondansetron

95% versus 82% 55% versus 32% (𝑝 = 0.22) VAS scores 5.5 versus15 (p = 0.046)

Noble et al.,1994 [18] III 200

Ondansetron versusgranisetron NA

40% versus 44% Patientpreference, 34% versus 26%(𝑝 = 0.048)

NA

Fauser et al.,2000 [22] III 210

Dolasetron +dexamethasone versusdolasetron

NA

73% versus 41% (𝑝 < 0.0001).CR rates on each study daywere also significantly higher(𝑝 = 0.029)

VAS score of 0 (nonausea) day 1: 88%versus 60%(𝑝 < 0.001); day 5:63% versus 37%(𝑝 = 0.017)

Einhorn et al.,2007 [23] II 41

Palonosetron +dexamethasone 88% 51%

No or mild nausea,self-reported 59%

Albany et al.,2012 [24] III 69

Aprepitant + 5-HT3 RA(other thanpalonosetron) +dexamethasone versusaprepitant +dexamethasone

NA 47% versus 15% (𝑝 = 0.01)VAS: aprepitant betterthan placebo on all 6days

Hamada et al.,2014 [25] II 30

Aprepitant +palonosetron +dexamethasone

NA 90% Mild to no nausea70%

CR: complete response (no emesis and no need for rescue medication); VAS: visual analog scale for nausea; 5-HT3 RA: 5-hydroxytryptamine receptorantagonists; NA: not available.

found in high numbers in the dorsal vagal complex, areapostrema, and gastrointestinal tract [3]. Cisplatin damagesthe GI tract and causes calcium dependent exocytic releaseof 5-hydroxytryptamine (HT)

3from enterochromaffin cells

in the GI mucosa. Released 5-HT3binds to its receptors

on the vagal afferent neurons and this binding activatesthe chemoreceptor trigger zone (CTZ) and vomiting center(VC). When CTZ is activated, it also releases various neuro-transmitters which in turn stimulate the VC. Once activated,the VC modulates efferent transmission to respiratory, vaso-motor, and salivary centers as well as to abdominal muscles,diaphragm, and esophagus, resulting in emesis [3, 4].

Substance P is a neurotransmitter of the tachykinin familyand is widely located in the central and peripheral nervoussystem, including gut, the nucleus tractus solitarius (NTS),and the area postrema. It acts through the neurokinin-1(NK1) pathway and has been implicated in the pathogenesis

of emesis [5]. Preclinical studies have shown that NK1-

receptor antagonists prevent emesis by acting centrally withinthe NTS [6]. Evaluation of NK

1receptor antagonists in

animal emesis models also indicated that they were highlyeffective against the delayed phase of emesis caused by cis-platin [5, 6]. Dopamine receptors are also present in CTZ anddopamine antagonists like phenothiazines, butyrophenones,and metoclopramide have been effective in treating CINV,although restricted by their side effects.

3. Historical Perspective

Phenothiazines, introduced as antipsychotic medications,were the first group of drugs to demonstrate activity inchemotherapy induced vomiting and remained the main-stay of antiemetic therapy for almost 3 decades from their


introduction in the 1950s. Standard agents included chlorpro-mazine hydrochloride and prochlorperazine which mainlyacted as dopamine antagonists. Low doses were not effectivewhile higher doses carried risk of extrapyramidal reactions,liver dysfunction, marrow aplasia, and excessive sedation.They were also ineffective if patient failed to respond to it inthe first course of treatment [7].

Metoclopramide, a substituted benzamide, was used inEurope for decades for prevention ofmotion sickness but wasconsidered ineffective against chemotherapy induced nausea.But in the 1980s, it was discovered that massive doses of thedrug (2mg/kg given before and after chemotherapy) helpedto minimize nausea and vomiting in most patients treatedwith cisplatin. However, high doses of metoclopramide wereassociated with troublesome Parkinsonian symptoms whichwere somewhat dissipated with addition of diphenhydramine[8].

Steroids, particularly dexamethasone, were tried aloneand in various combinations with older agents with goodcontrol of nausea and vomiting. In combination with meto-clopramide and other agents like lorazepam, it was notedthat 50–60% of patients experienced no emesis comparedto around 20% with either of the agents alone [9]. CINVprophylaxis with combination of dexamethasone and meto-clopramide was the mainstay of treatment in the 1980s tillintroduction of ondansetron. At IndianaUniversity, metoclo-pramide or lorazepam in combination with dexamethasonebefore and after cisplatin for the first 2 days, followedby chlorpromazine on the other 3 days, was utilized withadequate antiemetic efficacy in patients undergoing multidaycisplatin based chemotherapy.

Based on observations that smoking marijuana helpsto alleviate CINV, tetrahydrocannabinol as an antiemeticagent was evaluated by Sallan et al. Antiemetic effect wasobserved in 14 of 20 tetrahydrocannabinol courses and in0 of 22 placebo courses. No patient had vomiting episodeswhile experiencing a subjective “high” [10]. Subsequently, ina double-blind prospective study, Einhorn et al. demon-strated superiority of nabilone, a synthetic cannabinoid, com-pared to prochlorperazine in patients undergoing multidaycisplatin chemotherapy. In patients treated with prochlor-perazine, the mean number of emetic episodes on the firstday of multiple-day cisplatin therapy was 10.3 compared with7.05 on nabilone. It was however associated with significantdry mouth and dysphoria [11]. This has not been replicatedin the era of 5-HT

3receptor antagonists. A study by Meiri

et al. evaluating dronabinol, ondansetron, or combinationdemonstrated equivalent efficacy between all groups and didnot show any benefit from addition of cannabinoids to a 5-HT3receptor antagonist [12].

4. 5-HT3 Receptor Antagonist

Just as cisplatin revolutionized the cure rate for germ celltumors, ondansetron, the first 5-HT

3receptor antagonist,

greatly mitigated the severe cisplatin-associated nausea andvomiting [13]. In 1990, Einhorn et al. piloted ondansetron0.15mg/kg intravenously for 3 doses in a phase II study with

35 patients receiving 4- to 5-day cisplatin based regimens.Ten patients (29%) had no vomiting or retching throughoutthe entire study period and 18 patients (51%) experiencedtwo or fewer emetic episodes during the entire study period.Ondansetron was very well tolerated in all 35 patients [14]. Asubsequent phase III study by Sledge Jr. et al. [15] evaluated 3intravenous doses of ondansetron 0.15mg/kg intravenouslyor metoclopramide 1mg/kg in patients undergoing multi-day cisplatin chemotherapy. Proportion of patients with noemetic episodes throughout the entire study period washigher in the ondansetron arm (30% versus 9%, 𝑝 = 0.077).Significantly fewer antiemetic treatment failures (more thanfive emetic episodes or withdrawal from the study) occurredwith patients given ondansetron (9%) than with thosegiven metoclopramide (50%) during the entire study period(𝑝 = 0.002). Although ondansetron clearly demonstratedsuperiority over metoclopramide as a single agent, 70% ofpatients treated with ondansetron in this study experiencedat least one emetic episode during the 5-day treatmentperiod. Ondansetron was very efficacious on the first dayof chemotherapy and its effect diminished over subsequentdays.

Other 5-HT3receptor antagonists, such as granisetron

and dolasetron, were subsequently approved by the FDA andhave demonstrated equivalent efficacy and toxicity relativeto ondansetron [16]. A single blind prospective study bythe granisetron study group evaluated efficacy of prophylac-tic intravenous granisetron versus alizapride (a substitutedbenzamide) with dexamethasone in patients receiving frac-tionated chemotherapy (cisplatin or ifosfamide) for 5 days.Granisetron was superior to the combination in preventingnausea and vomiting, 54% versus 43% complete responders,respectively, in the cisplatin group. Adverse events werealso lower in the granisetron group [17]. A subsequent,double-blind, randomized, and crossover comparison ofsingle daily intravenous doses of granisetron compared withthree daily intravenous doses of ondansetron in 5-day frac-tionated chemotherapy demonstrated equal efficacy, safety,and patient preference, with both agents achieving goodcontrol of emetic symptoms with 5-day complete responserates of 44.0% with granisetron compared to 39.8% in theondansetron arm [18].

Single agent 5-HT3receptor antagonists were ineffective

in prevention of delayed CINV, which is a major issue withmultiday cisplatin based chemotherapy. A meta-analysis of 5studies comparing a 5-HT

3receptor antagonist as monother-

apy compared to placebo showed no clinical evidence ofimprovement of control of delayed emesis with additionof 5-HT

3receptor antagonists [19]. In early clinical trials,

addition of dexamethasone consistently improved efficacycompared to 5-HT

3receptor antagonist alone, making it

the standard for patients receiving cisplatin based therapy.In a multicenter trial looking at ondansetron plus dexam-ethasone compared to ondansetron alone in cisplatin basedchemotherapy, patients who received the combination hadhigher complete antiemetic response rate (61% versus 46%)and less nausea as per visual analog scale (18% versus 33%)


Table 2: Antiemetic prophylaxis regimen for multiday cisplatin chemotherapy for germ cell tumors, Indiana University protocol.

Day 1 Day 2 Day 3 Day 4 Day 5 Days 6–8Dexamethasone20mg IV

Dexamethasone20mg IV

Palonosetron0.25mg IV

Palonosetron0.25mg IV

Dexamethasone4mg BID PO

Palonosetron∗0.25mg IV

Fosaprepitant150mg IV

Fosaprepitant150mg IV

∗Alternatively, ondansetron 16mg orally daily can be utilized from days 1–5 if palonosetron is not available.

[20]. Fox et al. conducted a phase III trial in 44 patientscomparing ondansetron with combination of ondansetron,dexamethasone, and chlorpromazine in multiday cisplatinchemotherapy. There was a reduction in total number ofemetic episodes in favor of the combination arm but this didnot reach statistical significance (55 versus 32%, 𝑝 value =0.22).Mean change of nausea controlmeasured by visual ana-log scale (VAS) was superior with the combination regimen.It is unsure what role chlorpromazine played in this study andit is questionable that it addedmuch value to the ondansetronand dexamethasone combination [21]. A bigger phase IIItrial demonstrated that adding dexamethasone to dolasetronsignificantly increased effectiveness in preventing nauseaand vomiting related to fractionated cisplatin chemotherapy.Complete response rates were significantly better in all 5 daysin the combination arm compared to dolasetron alone [22].These studies clearly established the superiority of 5-HT

3

receptor antagonist-dexamethasone combination inmultidaycisplatin based chemotherapy and soon became the standardof care.

However optimal duration of dexamethasone has neverbeen clearly established. Side effects of 5 consecutive daysof dexamethasone during cisplatin administration and threeadditional days for delayed nausea and vomiting and repeatedcourses every 3 weeks are going to be substantial [26]. Ina retrospective study evaluating dexamethasone toxicity inpatients receiving moderately emetogenic chemotherapy, allpatients received dexamethasone (10 or 20mg intravenously)and oral dexamethasone for delayed prophylaxis (4mg twicedaily for 2-3 days). In this study, 45% of patients reportedmoderate to severe problems with insomnia, 27% had indi-gestion or epigastric discomfort, and 27% had agitation [27].Late toxicity from dexamethasone is of particular concern,particularly with avascular necrosis of the hip on long termdexamethasone [26, 28]. Our antiemetic prophylaxis regimenfor cisplatin chemotherapy in germ cell tumors restrictsdexamethasone to days 1 and 2 of cisplatin administration(Table 2).

Palonosetron is a unique 5-HT3receptor antagonist with

activity at both central and GI sites and also has a longplasma terminal phase elimination half-life of approximately40 hours [29]. A phase II trial by Einhorn et al. [23] evaluatedpalonosetron 0.25mg IV on chemotherapy days 1, 3, and 5plus dexamethasone in patients receiving multiday cisplatinchemotherapy for germ cell tumor. Majority of patients hadno emesis at any time throughout days 1–5 (51%) or days6–9 (83%), had no moderate or severe nausea, and didnot require rescue medication. Most patients reported that

the nausea they experienced had no significant effect on dailyfunctioning. Recently, two studies have demonstrated thatsingle dose (0.25mg IV) of palonosetron maintains responserates for acute and delayed CINV over repeated coursesof chemotherapy in patients on HEC [30, 31]. An open-label, single-arm, and multicenter study was performed inpatients with testicular germ cell tumor who were scheduledto receive 5-day cisplatin based combination chemotherapy.The antiemetic therapy consisted of palonosetron 0.75mg onday 1, aprepitant 125mg on day 1, 80mg on days 2 to 5, dexam-ethasone 9.9mg on day 1, and 6.6mg on days 2 to 8. Completeresponse (CR) rate, which was defined as no vomiting and norescue medication use, was achieved in 90% of the patients inthe first chemotherapy course, and high CR rates were alsoobserved in the second and third courses (82.1 and 78.3%,resp.) [25]. This trial was conducted in Japan, where 0.75mgintravenous dose of palonosetron is the commonly useddose. Trials evaluating single dose (0.25mg intravenously) ofpalonosetron or head to head comparison of palonosetroncompared to ondansetron in multiday cisplatin chemother-apy have not been performed. Our antiemetic prophylaxisrecommends palonosetron 0.25mg IV on days 1, 3, and 5,based on the phase II trial results. Ondansetron 16mg orallydaily on days 1–5 can be alternatively used in patients who areunable to get palonosetron due to insurance reasons or otherissues (Table 2).

5. NK1 Receptor Antagonists

Introduction of NK1receptor antagonists substantially inc-

reased our ability to control nausea and vomiting and isnow an important component of antiemetic managementstrategies in multiday cisplatin based chemotherapy. Inthe first multicenter, double-blind, and placebo-controlledtrial conducted by Navari et al., addition of NK

1receptor

antagonists (aprepitant) to granisetron and dexamethasoneresulted in significant decrease in acute CINV and delayedemesis for single day HEC [32]. In 3 studies comparing theaddition of aprepitant (125mg on day 1, 80mg on days 2and 3) to intravenous ondansetron 32mg (on day 1) and oraldexamethasone (12 or 20mg on days 1 and 8 or 16mg on days2 and 3), addition of aprepitant resulted in absolute increase incomplete response rate from 11% to 20%, favoring aprepitant.Also there was a significant benefit observed in prevention ofdelayed emesis [33–35].

Albany et al. (see Table 1) conducted the first randomized,double-blind, placebo-controlled, and phase III crossoverstudy evaluating the oral NK

1antagonist aprepitant in com-

bination with several 5-HT3receptor antagonists (except


palonosetron) and dexamethasone in patients with germ celltumors receiving 5-day cisplatin combination chemotherapy[24]. Patients were randomly assigned to aprepitant 125mgon day 3 and 80mg per day on days 4 through 7 or to placebowith initial course and crossover to opposite treatment withthe second course. Among 69 patients in the study, 42%achieved complete response for days 1–8, defined as no emeticepisodes with no use of rescue medicat