Support Care Cancer

DOI 10.1007/s00520-016-3332-x

SPECIAL ARTICLE

2016 Updated MASCC/ESMO consensus recommendations:

Emetic risk classification and evaluation of the emetogenicity
of antineoplastic agents
Karin Jordan 1 & Alexandre Chan 2 & Richard J. Gralla 3 & Franziska Jahn 1 &
Bernardo Rapoport 4 & David Warr 5 & Paul J. Hesketh 6

Received: 21 April 2016 / Accepted: 6 July 2016

# Springer-Verlag Berlin Heidelberg 2016

Abstract identified. Seven moderately emetogenic agents, 26 low

Purpose Employing the same framework as in previous
guideline updates, antineoplastic agents were classified into
four emetic risk categories. The classification of the
emetogenic level of new antineoplastic agents, especially for
the oral drugs, represents an increasing challenge. Accurate
reporting of emetogenicity of new antineoplastic agents in the
absence of preventive antiemetic treatment is rarely available.
Methods A systematic search was conducted for drugs ap-
proved after 2009 until June 2015 using EMBASE and
PubMed. The search term was Bdrug name.^ The restrictions
were language (English records only), date (2009 to 2015),
and level of evidence (Bclinical trial^).
Results From January 2009 to June 2015, 42 new antineoplas-
tic agents were identified and a systematic search was con-
ducted to identify relevant studies to help define emetic risk
levels. The reported incidence of vomiting varied across stud-
ies for many agents, but there was adequate evidence to allow
41 of the 42 new antineoplastic agents to be classified accord-
ing to emetogenic risk. No highly emetogenic agents were
* Karin Jordan
karin.jordan@uk-halle.de
1
Department for Hematology/Oncology, Martin-Luther-University
Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany
2
Department of Pharmacy, National University of Singapore, 21
Lower Kent Ridge Rd, Singapore, Singapore
3
Albert Einstein College of Medicine, Bronx, New York, USA
4
Medical Oncology Centre of Rosebank, Johannesburg, South Africa
5
Princess Margaret Cancer Centre, University of Toronto,
Toronto, Canada
6
Lahey Hospital & Medical Center, Burlington, MA, USA
emetogenic, agents and eight minimal emetogenic agents
were identified and classified accordingly. The MASCC/
ESMO update committee also recommended reclassification
of the combination of an anthracycline and cyclophosphamide
(AC) as highly emetogenic.
Conclusion Despite several limitations, we have attempted to
provide a reasonable approximation of the emetic risk associ-
ated with new antineoplastic agents through a comprehensive
search of the available literature. Hopefully by the next up-
date, more precise information on emetic risk will have been
collected during new agent development process.
Keywords Emetogenicity . Nausea . Vomiting . Risk
classification . Antineoplastic agents
Introduction
The emetogenic classification of antineoplastic agents has
provided a framework for defining antiemetic treatment rec-
ommendations. Prior to the 2004 Perugia Antiemetic
Consensus Conference, the most widely employed classifica-
tion schema defined five emetic risk levels (expected frequen-
cy of emesis in the absence of antiemetic prophylaxis): <10,
10–30, 30–60, 60–90, and >90, with the 30–60 % range con-
sidered moderately emetogenic [3]. After the 2004 Perugia
conference, this classification schema was modified to four
levels by MASCC [6] and ASCO [5] by combining the prior
level 3 (30–60 %) and level 4 (60–90 %) into a single (30–
90 %) moderately emetogenic group. The change was made
because clinical differentiation between the groups had be-
come difficult with the introduction of new antiemetic agents
[1]. However, the broad range of expected emesis in the mod-
erate level has posed an increasing challenge to efforts to
 Support Care Cancer

Table 1 Emetic risk groupsa

High Moderate Low Minimal

Risk in nearly all patients Risk in 30 to 90 % of Risk in 10 to 30 % of Fewer than 10 % at

(>90 %) patients patients risk
a
Proportion of patients experiencing emesis in the absence of effective antiemetic prophylaxis

provide a single recommendation for antiemetic treatment ap-
propriate for the entire moderate category [4].
As numerous new antineoplastic agents, especially oral
agents, have been introduced since the last MASCC/ESMO
antiemetic guideline update, there is a need to incorporate
these new agents into the emetogenic classification schema.
Such efforts continue to be hampered by the limited record-
ing of Bcommon^ toxicities such as emesis during antineo-
plastic drug development and the unregulated use of pro-
phylactic antiemetics during antineoplastic drug develop-
ment even before emetogenicity of the agents were
established. Furthermore, information might be incomplete
or uninterpretable when only severe vomiting or nausea or
combing nausea and vomiting are listed. Patients in trials
with new agents are often heavily pretreated with other
antitumor agents and therefore may be more prone to de-
velop emesis. In this respect, another problem is that all
vomiting while on antineoplastic therapy might not be
due to antineoplastic therapy. As an example, the placebo-
controlled erlotinib pivotal trial showed a 25 % incidence
of vomiting with erlotinib and 23 % incidence with placebo
[7]. The increasing use of oral agents has created an addi-
tional challenge; many agents tend to be used in extended
regimens of daily oral use rather than the single bolus
administration schedule commonly employed with intrave-
nous agents.
Committee I sought to address the following questions re-
lating to antineoplastic agent emetogenicity as part of the cur-
rent update of the MASCC/ESMO antiemetic guideline:
search term was Bdrug name.^ The restrictions were language
(English records only), date (2009 to 2015), and level of evi-
dence (Bclinical trial^). The screening step was conducted by
two independent reviewers. Studies in which the drug of in-
terest was used as monotherapy were preferred. If monother-
apy data were not available, then studies in which the effect of
the single-agent could be isolated (even when used as combi-
nation therapy) were also considered. Studies were excluded if
the drug of interest was being used to treat nonneoplastic
diseases or were phase I, PK/PD or preclinical or pediatric
studies.
Data verification: for each product, the Summary of
Product Characteristics and/or Product Information was
also found and reviewed for information regarding nau-
sea and vomiting rates. Any relevant information was
added to the evidence table. Utilizing the Summary of
Product Characteristics and/or Product Information
helped to ensure that all the key phase II/III studies
had been captured in our search and also served as an
additional source of information.
Data on the various variables (e.g., study phase, control
group, number of patients enrolled, type of tumor, chemothera-
py naïve, route of administration, dose, grade of nausea and

1) identify new antineoplastic agents approved by FDA and/

or EMA from January 2009 to June 2015;
2) conduct a systematic literature search to characterize the
emetic potential of the new agents and place them in an
appropriate level in the four-level classification schema
and;
3) determine whether the combination of an anthracycline
and cyclophosphamide (AC) should be allocated to the
high emetic risk group.

Methods

A systematic search was conducted for drugs approved after

2009 until June 2015 using EMBASE and PubMed. The Fig. 1 Search algorithm
Support Care Cancer

vomiting, and prophylactic antiemetics) were extracted from the
publications and collated into an evidence table.
Vomiting rates were summarized and the antineoplastic
agents were classified as being at minimal, low, moderate, or
high emetic risk according to the MASCC/ESMO risk cate-
gories. If several studies of an agent had different classifica-
tions, results of the Bworst outcome^ were taken.
Results
The antineoplastic agents were classified into four risk cate-
gories (Table 1). For oral agents, the emetic potential was
based upon a full course of therapy and not a single dose.
Within the defined time frame, 42 new antineoplastic
agents were identified and 168 studies could be extracted in
order to classify the antineoplastic agents (Fig. 1). The report-
ed incidence of vomiting varied across studies for many
agents, but there was adequate evidence to allow 41 of 42
new agents identified to be classified according to emetogenic
risk (Tables 2 and 3). All agents in Tables 2 and 3 were listed
in alphabetical order. This represents a change from prior
MASCC/ESMO antiemetic guideline updates. The committee
members felt that attempting to classify the relative
emetogenicity of agents within a given emetic level was no
longer possible. This was mainly due to the largely different
incidence rates of vomiting, which was found in the available
studies for the corresponding searched drug.

Table 2 Emetogenic potential of single intravenous antineoplastic agents

HIGH Anthracycline/cyclophosphamide combinationa

Carmustine
Cisplatin
Cyclophosphamide > 1500 mg/m2
Dacarbazine
Mechlorethamine
Streptozocin
MODERATE Alemtuzumab Epirubicin
Azacitidine Idarubicin
Bendamustine Ifosfamide
Carboplatin Irinotecan
Clofarabine Oxaliplatin
Cyclophosphamide < 1500 mg/m2 Romidepsin
Cytarabine > 1000 mg/m2 Temozolomideb
Daunorubicin Thiotepac
Doxorubicin Trabectedin
LOW Aflibercept Ipilimumab
Belinostat Ixabepilone
Blinatumomab Methotrexate
Bortezomib Mitomycin
Brentuximab Mitoxantrone
Cabazitaxel Nab- paclitaxel
Carfilzomib Paclitaxel
Catumaxumab Panitumumab
Cetuximab Pemetrexed
Cytarabine < 1000 mg/m2 Pegylated liposomal doxorubicin
Docetaxel Pertuzumab
Eribulin Temsirolimus
Etoposide Topotecan
5-Fluorouracil Trastuzumab-emtansine
Gemcitabine Vinflunine
MINIMAL Bevacizumab Pembrolizumab
Bleomycin Pixantrone
Busulfan Pralatrexate
2-Chlorodeoxyadenosine Rituximab
Cladribine Trastuzumab
Fludarabine Vinblastine
Nivolumab Vincristine
Ofatumumab Vinorelbine
a
The combination of an anthracycline and cyclophosphamide in patients with breast cancer should be considered highly emetogenic.
b
No direct evidence found for temozolomide IV; as all sources indicate a similar safety profile to the oral formulation, the classification was based on
oral temozolomide.
C
classification refers to individual evidence from pediatric trials
 Support Care Cancer

Table 3 Emetogenic potential of single oral antineoplastic agents

HIGH Hexamethylmelamine Procarbazine

MODERATE Bosutinib Imatinib
Ceritinib Temozolomide
Crizotinib Vinorelbine
Cyclophosphamide
LOW Afatinib Olaparib
Axatinib Nilotinib
Capecitabine Pazopanib
Dabrafenib Ponatinib
Dasatinib Regorafenib
Everolimus Sunitinib
Etoposide Tegafur Uracil
Fludarabine Thalidomide
Ibrutinib Vandetanib
Idelalisib Vorinostat
Lapatinib
Lenalidomide
MINIMAL Chlorambucil Pomalidomide
Erlotinib Ruxolitinib
Gefitinib Sorafenib
Hydroxyurea 6-Thioguanine
Melphalan Vemurafenib
Methotrexate Vismodegib
L-Phenylalanine mustard

*Classified emetic potential of oral agents based upon a full course of therapy and not a single dose

No highly emetogenic agents were identified. Seven moder-
ately emetogenic agents were identified (intravenous:
Temozolomide, Trabectedin, Romidepsin, and Thiotepa; oral:
Bosutinib, Crizotinib, and Ceritinib). Twenty-six agents were
classified as low emetogenic (intravenous: Aflibercept,
Belinostat, Blinatumomab, Brentuximab, Cabazitaxel,
Carfilzomib, Eribulin, Ipilimumab, Nab-Paclitaxel, Pegylated li-
posomal doxorubicin, Pertuzumab, Trastuzumab-emtansine, and
Vinflunine; oral: Afatinib, Axatinib, Dabrafenib, Dasatenib,
Ibrutinib, Idelalisib, Nilotinib, Olaparib, Pazopanib, Ponatinib,
Regorafinib, Vandetanib, and Vorinostat). Finally, eight agents
were classified as minimally emetogenic (intravenous:
Nivolumab, Ofatumumab, Pembrolizumab, and Pixantrone; oral:
Pomalidomid, Ruxolitinib, Vemurafenib, and Vismodegib). The
emetic risk classification only refers to adult patients.
The update committee also recommended reclassification
of the combined AC regimen as highly emetogenic. This clas-
sification has historically been a difference between the
ASCO 2011 and MASCC/ESMO 2010 guidelines. Within
this update, data from placebo-controlled trials indicating a
risk of vomiting in 85 % of patients not receiving antiemetic
prophylaxis were acknowledged in accordance with the
ASCO guidelines.
Discussion
Accurately defining the emetic risk associated with new anti-
neoplastic agents remains a challenging process. Ultimately,
this process will only improve if appropriate information on
nausea and vomiting is collected during the initial clinical
trials with a new antineoplastic agent. There is a unique op-
portunity during the initial evaluation process of a new anti-
neoplastic agent to obtain definitive information on the
emetogenic potential and pattern of emesis in the absence of
routine antiemetic treatment [2]. Such information should be
routinely recorded during the initial in-human studies of new
antineoplastic agents. Limitations of available studies with
new antineoplastic agents include the following: a lack of
specific information on nausea/vomiting, listing only grade
3/4 nausea/vomiting or the combination, and not specifying
the observation period or antiemetic use. All grades of nausea
and vomiting recorded as separate entities should be reported
in these initial studies. Other additional factors include limited
data for single antineoplastic agents and as well as the inclu-
sion of heavily pretreated patient populations. Another signif-
icant issue is the failure to report the time frame of emetic
outcomes, thus providing little basis to determine the potential
of a new antineoplastic agent to induce acute or delayed nau-
sea and vomiting. Oral antineoplastic agents provide addition-
al challenges. These agents are typically administered chron-
ically over protracted periods. Traditional concepts of acute
and delayed nausea and vomiting lose their relevance in these
settings. A more appropriate way to report emetic risk would
be the likelihood of nausea and vomiting over an entire course
of therapy. In addition, it should be acknowledged that the
MASCC antiemetic guideline recommendations at present
can only be applied to intravenously administered
Support Care Cancer
antineoplastic agents given the virtual absence of antiemetic
trials with orally administered antineoplastics. Despite these
limitations, we have attempted to provide a reasonable ap-
proximation of the emetic risk associated with new antineo-
plastic agents through a comprehensive search of the available
literature. Hopefully by the next update, more precise infor-
mation on emetic risk will have been collected during a new
agent development process.
Acknowledgments The authors express our sincere appreciation
to the late Steven Grunberg, our esteemed colleague whose con-
tributions to the previous guideline recommendations were of
great significance.
Compliance with ethical standards
Funding The systematic search was supported by an unrestricted grand
form Helsinn Healthcare, SA.
Conflict of interest Karin Jordan is a consultant and advisor for
Helsinn Healthcare, Merck, MSD, and Tesaro. Alexandre Chan is a
consultant and advisor for MSD and Mundipharma. Richard J. Gralla
is a consultant and advisor for Helsinn Healthcare, Merck, MSD, and
Tesaro. Franziska Jahn is a consultant Helsinn Healthcare, MSD, and
Tesaro. Bernardo Rapoport is a consultant and advisor for MSD,
Tesaro, and Roche. David Warr works for Merck as an advisor and
speaker bureau and for Helsinn as an advisor. Paul J. Hesketh is an
uncompensated consultant for Helsinn Healthcare and Tesaro.
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