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 emetogenic, agents and eight minimal emetogenic agents
guideline updates, antineoplastic agents were classified into were identified and classified accordingly. The MASCC/
four emetic risk categories. The classification of the ESMO update committee also recommended reclassification
emetogenic level of new antineoplastic agents, especially for of the combination of an anthracycline and cyclophosphamide
the oral drugs, represents an increasing challenge. Accurate (AC) as highly emetogenic.
reporting of emetogenicity of new antineoplastic agents in the Conclusion Despite several limitations, we have attempted to
absence of preventive antiemetic treatment is rarely available. provide a reasonable approximation of the emetic risk associ-
Methods A systematic search was conducted for drugs ap- ated with new antineoplastic agents through a comprehensive
proved after 2009 until June 2015 using EMBASE and search of the available literature. Hopefully by the next up-
PubMed. The search term was Bdrug name.^ The restrictions date, more precise information on emetic risk will have been
were language (English records only), date (2009 to 2015), collected during new agent development process.
and level of evidence (Bclinical trial^).
Results From January 2009 to June 2015, 42 new antineoplas- Keywords Emetogenicity . Nausea . Vomiting . Risk
tic agents were identified and a systematic search was con- classification . Antineoplastic agents
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 Introduction
41 of the 42 new antineoplastic agents to be classified accord-
ing to emetogenic risk. No highly emetogenic agents were The emetogenic classification of antineoplastic agents has
provided a framework for defining antiemetic treatment rec-
ommendations. Prior to the 2004 Perugia Antiemetic
* Karin Jordan Consensus Conference, the most widely employed classifica-
[email protected] tion schema defined five emetic risk levels (expected frequen-
cy of emesis in the absence of antiemetic prophylaxis): <10,
1
10–30, 30–60, 60–90, and >90, with the 30–60 % range con-
Department for Hematology/Oncology, Martin-Luther-University
Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany
sidered moderately emetogenic [3]. After the 2004 Perugia
2
conference, this classification schema was modified to four
Department of Pharmacy, National University of Singapore, 21
Lower Kent Ridge Rd, Singapore, Singapore
levels by MASCC [6] and ASCO [5] by combining the prior
3
level 3 (30–60 %) and level 4 (60–90 %) into a single (30–
Albert Einstein College of Medicine, Bronx, New York, USA
90 %) moderately emetogenic group. The change was made
4
Medical Oncology Centre of Rosebank, Johannesburg, South Africa because clinical differentiation between the groups had be-
5
Princess Margaret Cancer Centre, University of Toronto, come difficult with the introduction of new antiemetic agents
Toronto, Canada [1]. However, the broad range of expected emesis in the mod-
6
Lahey Hospital & Medical Center, Burlington, MA, USA 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- search term was Bdrug name.^ The restrictions were language
propriate for the entire moderate category [4]. (English records only), date (2009 to 2015), and level of evi-
As numerous new antineoplastic agents, especially oral dence (Bclinical trial^). The screening step was conducted by
agents, have been introduced since the last MASCC/ESMO two independent reviewers. Studies in which the drug of in-
antiemetic guideline update, there is a need to incorporate terest was used as monotherapy were preferred. If monother-
these new agents into the emetogenic classification schema. apy data were not available, then studies in which the effect of
Such efforts continue to be hampered by the limited record- the single-agent could be isolated (even when used as combi-
ing of Bcommon^ toxicities such as emesis during antineo- nation therapy) were also considered. Studies were excluded if
plastic drug development and the unregulated use of pro- the drug of interest was being used to treat nonneoplastic
phylactic antiemetics during antineoplastic drug develop- diseases or were phase I, PK/PD or preclinical or pediatric
ment even before emetogenicity of the agents were studies.
established. Furthermore, information might be incomplete Data verification: for each product, the Summary of
or uninterpretable when only severe vomiting or nausea or Product Characteristics and/or Product Information was
combing nausea and vomiting are listed. Patients in trials also found and reviewed for information regarding nau-
with new agents are often heavily pretreated with other sea and vomiting rates. Any relevant information was
antitumor agents and therefore may be more prone to de- added to the evidence table. Utilizing the Summary of
velop emesis. In this respect, another problem is that all Product Characteristics and/or Product Information
vomiting while on antineoplastic therapy might not be helped to ensure that all the key phase II/III studies
due to antineoplastic therapy. As an example, the placebo- had been captured in our search and also served as an
controlled erlotinib pivotal trial showed a 25 % incidence additional source of information.
of vomiting with erlotinib and 23 % incidence with placebo Data on the various variables (e.g., study phase, control
[7]. The increasing use of oral agents has created an addi- group, number of patients enrolled, type of tumor, chemothera-
tional challenge; many agents tend to be used in extended py naïve, route of administration, dose, grade of nausea and
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:

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 Within the defined time frame, 42 new antineoplastic
publications and collated into an evidence table. agents were identified and 168 studies could be extracted in
Vomiting rates were summarized and the antineoplastic order to classify the antineoplastic agents (Fig. 1). The report-
agents were classified as being at minimal, low, moderate, or ed incidence of vomiting varied across studies for many
high emetic risk according to the MASCC/ESMO risk cate- agents, but there was adequate evidence to allow 41 of 42
gories. If several studies of an agent had different classifica- new agents identified to be classified according to emetogenic
tions, results of the Bworst outcome^ were taken. 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
Results members felt that attempting to classify the relative
emetogenicity of agents within a given emetic level was no
The antineoplastic agents were classified into four risk cate- longer possible. This was mainly due to the largely different
gories (Table 1). For oral agents, the emetic potential was incidence rates of vomiting, which was found in the available
based upon a full course of therapy and not a single dose. 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- this process will only improve if appropriate information on
ately emetogenic agents were identified (intravenous: nausea and vomiting is collected during the initial clinical
Temozolomide, Trabectedin, Romidepsin, and Thiotepa; oral: trials with a new antineoplastic agent. There is a unique op-
Bosutinib, Crizotinib, and Ceritinib). Twenty-six agents were portunity during the initial evaluation process of a new anti-
classified as low emetogenic (intravenous: Aflibercept, neoplastic agent to obtain definitive information on the
Belinostat, Blinatumomab, Brentuximab, Cabazitaxel, emetogenic potential and pattern of emesis in the absence of
Carfilzomib, Eribulin, Ipilimumab, Nab-Paclitaxel, Pegylated li- routine antiemetic treatment [2]. Such information should be
posomal doxorubicin, Pertuzumab, Trastuzumab-emtansine, and routinely recorded during the initial in-human studies of new
Vinflunine; oral: Afatinib, Axatinib, Dabrafenib, Dasatenib, antineoplastic agents. Limitations of available studies with
Ibrutinib, Idelalisib, Nilotinib, Olaparib, Pazopanib, Ponatinib, new antineoplastic agents include the following: a lack of
Regorafinib, Vandetanib, and Vorinostat). Finally, eight agents specific information on nausea/vomiting, listing only grade
were classified as minimally emetogenic (intravenous: 3/4 nausea/vomiting or the combination, and not specifying
Nivolumab, Ofatumumab, Pembrolizumab, and Pixantrone; oral: the observation period or antiemetic use. All grades of nausea
Pomalidomid, Ruxolitinib, Vemurafenib, and Vismodegib). The and vomiting recorded as separate entities should be reported
emetic risk classification only refers to adult patients. in these initial studies. Other additional factors include limited
The update committee also recommended reclassification data for single antineoplastic agents and as well as the inclu-
of the combined AC regimen as highly emetogenic. This clas- sion of heavily pretreated patient populations. Another signif-
sification has historically been a difference between the icant issue is the failure to report the time frame of emetic
ASCO 2011 and MASCC/ESMO 2010 guidelines. Within outcomes, thus providing little basis to determine the potential
this update, data from placebo-controlled trials indicating a of a new antineoplastic agent to induce acute or delayed nau-
risk of vomiting in 85 % of patients not receiving antiemetic sea and vomiting. Oral antineoplastic agents provide addition-
prophylaxis were acknowledged in accordance with the al challenges. These agents are typically administered chron-
ASCO guidelines. 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
Discussion be the likelihood of nausea and vomiting over an entire course
of therapy. In addition, it should be acknowledged that the
Accurately defining the emetic risk associated with new anti- MASCC antiemetic guideline recommendations at present
neoplastic agents remains a challenging process. Ultimately, can only be applied to intravenously administered
Support Care Cancer

antineoplastic agents given the virtual absence of antiemetic References

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Conflict of interest Karin Jordan is a consultant and advisor for Multinational Association of Supportive Care in Cancer (2006)
Helsinn Healthcare, Merck, MSD, and Tesaro. Alexandre Chan is a Prevention of chemotherapy- and radiotherapy-induced emesis: results
consultant and advisor for MSD and Mundipharma. Richard J. Gralla of the 2004 Perugia international antiemetic consensus conference.
is a consultant and advisor for Helsinn Healthcare, Merck, MSD, and Ann Oncol 17:20–28
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speaker bureau and for Helsinn as an advisor. Paul J. Hesketh is an Bezjak A, Clark G, Santabarbara P, Seymour L, National Cancer
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