Download Evaluation of new antiemetic agents and definition of

Support Care Cancer (2005) 13: 80–84
DOI 10.1007/s00520-004-0718-y
Steven M. Grunberg
David Osoba
Paul J. Hesketh
Richard J. Gralla
Sussanne Borjeson
Bernardo L. Rapoport
Andreas du Bois
Maurizio Tonato
Received: 17 August 2004
Accepted: 26 August 2004
Published online: 14 December 2004
# Springer-Verlag 2004
S. M. Grunberg
University of Vermont,
Burlington, VT, USA
REVIEW ARTICLE
Evaluation of new antiemetic agents
and definition of antineoplastic agent
emetogenicity—an update
S. M. Grunberg (*)
Division of Hematology/Oncology,
Fletcher Allen Health Care,
UHC Campus/St. Joseph 3400, 1 South
Prospect Street,
Burlington, Vermont, 05401, USA
e-mail: [email protected]
Tel.: +1-802-8470770
Fax: +1-802-8475946
D. Osoba
QOL Consulting,
West Vancouver, BC, Canada
P. J. Hesketh
St. Elizabeth’s Medical Center,
Boston, MA, USA
R. J. Gralla
New York Lung Cancer Alliance,
New York, NY, USA
S. Borjeson
Division of Nursing Science,
Linkoping University,
Linkoping, Sweden
B. L. Rapoport
The Medical Oncology Centre of
Rosebank,
Johannesburg, South Africa
A. du Bois
Dr Horst-Schmidt-Kliniken,
Wiesbaden, Germany
M. Tonato
Policlinico Monteluce,
Perugia, Italy
Abstract Development of effective
antiemetic therapy depends upon an
understanding of both the antiemetic
agents and the emetogenic challenges
these agents are designed to address.
New potential antiemetic agents
should be studied in an orderly
manner, proceeding from phase I to
phase II open-label trials and then to
randomized double-blind phase III
trials comparing new agents and
regimens to best standard therapy.
Use of placebos in place of antiemetic
therapy against highly or moderately
emetogenic chemotherapy is
unacceptable. Nausea and vomiting
should be evaluated separately and for
both the acute and delayed periods.
Defining the emetogenicity of new
antineoplastic agents is a challenge,
since such data are often not reliably
Evaluating new antiemetic agents
New antiemetic drug development should follow an orderly and logical progression beginning with open-label
phase I/II tolerance and dose-finding trials and progressing
recorded during early drug development. A four-level classification
system is proposed for emetogenicity
of intravenous antineoplastic agents.
A separate four-level classification
system for emetogenicity of oral
antineoplastic agents, which are often
given over an extended period of
time, is also proposed.
Keywords Antiemetic .
Emetogenicity . Emesis . Nausea .
Classification
through phase III comparative trials (Table 1). Appropriate
candidates for phase I trials are normal volunteers or cancer patients for whom prior conventional antiemetic treatments have failed. In this type of trial efficacy parameters
are important, but clearly secondary to toxicity assess-
81
Table 1 Recommendations on evaluation of new agents
1. Phase I/II trials should always precede phase III trials
Level of consensus—High
Confidence level—High
2. Phase I/II trials should define minimal fully effective dose
Level of consensus—High
Confidence level—High
3. Phase III trials should employ a double-blind, randomized parallel
design
Level of consensus—High
Confidence level—High
4. Phase III trials should use best available treatment as comparator
Level of consensus—High
Confidence level—High
5. Placebo comparators are not appropriate for trials against acute or
delayed emesis with chemotherapeutic agents for which there is a
significant emetic risk
Level of consensus—High
Confidence level—High
ments. After successful completion of phase I trials, phase
II trials should be completed to confirm antiemetic efficacy and define minimal fully effective doses. If substantial efficacy has been noted in initial studies, then
appropriate populations for study may include chemotherapy-naive patients receiving moderately to highly
emetogenic chemotherapy.
Phase III trials should be initiated only after completion
of phase I/II trials. A prerandomization stratification for
important prognostic variables such as gender and ethanol
consumption should be considered unless a large sample
population of patients is enrolled in the study and the
impact of prognostic factors can be analyzed by a multifactorial analysis at the end of the study. Other patient
characteristics such as increased fatigue, low social functioning, and pre-existing nausea may also be of importance [13]. A randomized, parallel double-blind study is
the preferred design for comparative trials. The comparator arm should contain the current best available treatment. If efficacy results of phase II trials are sufficiently
compelling, then the new agent can be compared as a
single agent against the best available therapy. An acceptable alternative design is to combine the new agent
with the current best standard and compare it with the
current best standard combined with placebo.
Treatment with antiemetic placebos alone is no longer
acceptable with chemotherapies known to induce emesis
in most patients. This includes the evaluation of acute or
delayed emesis in patients receiving moderately or highly
emetogenic chemotherapy. If a placebo treatment is employed for other antiemetic trials, there should be zero
tolerance for the development of breakthrough emesis or
nausea, with immediate rescue of patients developing
symptoms.
A key element in new agent and new regimen evaluation is a careful assessment of the side effect profile.
This includes objectively measurable side effects, such as
changes in vital signs, blood chemistries, electrocardiograms or physical examination. In addition, subjectively
measurable side effects, such as headache, akathisia, sedation, and diarrhea, should also be assessed. Typically
these effects are measured by their presence or absence
and then with a categorical rating by the patient (mild,
moderate or severe effects). An ongoing challenge in the
evaluation of the side effects of new agents is separating
the adverse effects of the antiemetics from those of the
chemotherapy, symptoms of malignancy, intercurrent illnesses or concomitant medications.
Defining chemotherapy emetogenicity
Defining the emetogenicity of chemotherapy agents is of
value for at least two important reasons. First, such a
classification can be used as a framework for defining
antiemetic treatment guidelines. Second, it can provide a
means for clinical investigators to attain a more precise
definition of the emetogenic challenge that is being
employed in an antiemetic trial. A useful schema would
provide enough information to be utilized for both of these
purposes. At present there is no commonly accepted
schema for classifying the emetogenicity of cancer chemotherapy agents or combinations. A number of schemas
have been proposed in which chemotherapy agents have
been divided among three to five emetogenic levels [1, 4,
9, 10, 15]. The literature has been a very limited source of
useful information in the development of these schemas,
given the imprecise, inconsistent and extremely limited
ways in which information on emesis and nausea has been
recorded in most therapeutic trials. Most schemas have not
differentiated between the various types of emesis, such as
acute, delayed and anticipatory, and few have accounted
for important treatment- and patient-related variables, such
as chemotherapy dose, rate and route of administration,
gender, age, and history of ethanol consumption [5, 7].
A new problem in emetic assessment is the growing use
of extended oral administration of cytotoxic agents [11,
12, 14, 16] and targeted biologic agents [2, 3]. The distinction between acute and delayed emesis loses significance when an agent is given orally over a period of
several days or weeks. The tendency of even experienced
physicians and nurses to underestimate the incidence of
emesis that occurs in the days after the patient has left the
clinic and is no longer under direct observation [6] may
also contribute to the erroneous assumption that such
agents are only minimally emetogenic. Careful follow-up
and careful observation of overall emetogenicity may
therefore become the only valid method of assessment for
such agents.
82
Hesketh et al. have proposed a classification system for
acute emesis that accounts for chemotherapy dose and
standardizes the rate and route of chemotherapy administration [8]. Chemotherapy agents were divided into five
levels according to the expected frequency of emesis in the
absence of effective antiemetic prophylaxis. Given the
paucity of objective data in the literature, however, this
schema, like others proposed earlier, reflects primarily the
opinions of the authors and is thus potentially open to
some of the criticisms that have been directed at prior
schemas.
At present, no single schema addresses all of the important issues that must be taken into account in creating
a definitive emetogenic classification system, and further work should be carried out on this important issue
(Table 2). Overall a system that emphasizes classification
according to intrinsic emetogenicity (emetogenicity without concomitant antiemetic therapy) is favored, with the
recognition of certain limitations. Some chemotherapeutic
agents, such as the taxanes and pemetrexed, require concomitant use of corticosteroids for safe administration, and
evaluation of baseline emetogenicity must take use of
this necessary combination into account. It is also recognized that combination chemotherapy regimens may have
a greater emetogenic potential than any single included
agent. Cyclophosphamide and doxorubicin, for example,
are each moderately emetogenic, but the combination of
these agents is considered to be highly emetogenic. However, no prospectively validated or generally accepted algorithm has been devised for calculating the expected
emetogenicity of combination regimens.
One potential area in which new information can be
obtained relates to the emetogenic potential of new antineoplastic agents. During the initial phase I and phase II
evaluation process of a new antineoplastic agent, there is a
Table 2
therapy
unique opportunity to obtain definitive information on the
emetogenic potential and pattern of emesis in the absence
of routine antiemetic treatment. However, early clinical
trials often do not restrict antiemetic use and reports of
such trials of new cytotoxic and biologic agents seldom
describe whether concomitant antiemetic agents were
given. It is suggested that prophylactic antiemetic agents
not be routinely used in initial trials of new agents unless
Table 3 Emetogenic potential of single intravenous antineoplasticagents
Degree of emetogenicity (incidence)
Agent
High (>90%)
Cisplatin
Mechlorethamine
Streptozotocin
Cyclophosphamide ≥1500
mg/m2
Carmustine
Dacarbazine
Oxaliplatin
Cytarabine >1 g/m2
Carboplatin
Ifosfamide
Cyclophosphamide <1500
mg/m2
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Irinotecan
Paclitaxel
Docetaxel
Mitoxantrone
Topotecan
Etoposide
Pemetrexed
Methotrexate
Mitomycin
Gemcitabine
Cytarabine ≤100 mg/m2
5-Fluorouracil
Bortezomib
Cetuximab
Trastuzumab
Bleomycin
Busulfan
2-Chlorodeoxyadenosine
Fludarabine
Vinblastine
Vincristine
Vinorelbine
Bevacizumab
Moderate (30–90%)
Low (10–30%)
Recommendations on defining emetogenicity of chemo-
1. Emetic potential and pattern of emesis should be rigorously
assessed during clinical development of new antineoplastic agents
Level of consensus—High
Confidence level—High
2. A comprehensive schema for classifying antineoplastic agent
emetogenicity incorporating all important treatment and patient
related prognostic variables should be developed
Level of consensus—High
Confidence level—High
3. Descriptive classifications based upon clinical databases of
homogeneously treated patients should be developed and enhanced
Level of consensus—High
Confidence level—Moderate
4. Working schema for use in defining emetogenicity of intravenous
and oral antineoplastic agents are proposed
Level of consensus—Moderate
Confidence level—Low
Minimal (<10%)
83
Table 4 Emetogenic potential of single oral antineoplasticagents
Degree of emetogenicity (incidence)
Agent
High (>90%)
Hexamethylmelamine
Procarbazine
Cyclophosphamide
Etoposide
Temozolomide
Vinorelbine
Imatinib
Capecitabine
Fludarabine
Chlorambucil
Hydroxyurea
L -Phenylalanine mustard
6-Thioguanine
Methotrexate
Gefitinib
Moderate (30–90%)
Low (10–30%)
Minimal (<10%)
the existence of significant emetic risk has been established through clinical experience with the investigational
agent or through prior experience with similar standard
agents. It is also suggested that the existence and intensity
of nausea and vomiting be recorded using standard antiemetic methodology rather than the less informative Common Toxicity Criteria.
Several other methods of defining chemotherapy emetogenicity have been proposed. Analysis of large databases
in which information on emesis has been prospectively
recorded and antiemetic prophylaxis was uniform could
provide information on residual emetogenicity and potentially permit gender and other important prognostic
variables to be taken into account. However, it is controversial whether emetogenicity of specific antineoplastic
agents should be solely classified with, rather than without, the use of state-of-the-art antiemetic agents as a practical clinical guide. Such a classification schema would
markedly change with the introduction of each new anti-
emetic agent or antiemetic strategy and would not provide
valuable information on intrinsic emetogenicity. The validity of such a schema for combination chemotherapy
would be further compromised by the numerous doses and
schedules under which the “same” combination regimen
can be given and by the confounding effects on emetogenicity of the demographic characteristics of the specific
patient populations for which different combination regimens are designed or used. Recognition of the common
phase III clinical trial design in which established antineoplastic agents or combinations are administered with or
without a new antineoplastic agent has also led to the
concept of differential emetogenicity, by which the intrinsic emetogenicity of the new agent would be estimated
as the difference between the observed emetogenicity of
the two study arms. However, there is significant concern
that such an estimate would be heavily dependent on the
emetogenicity of the baseline standard regimen itself. For
example, addition of a moderately emetogenic investigational agent to a regimen that is already highly emetogenic
would add little to the overall emetogenicity of the
combination and could lead to marked underestimation of
the intrinsic emetogenicity of the new agent.
Despite the limitations of the emetogenic classification
schemas proposed to date, there is still a need to agree
upon a working schema that can be employed for treatment recommendations and for defining the emetogenic
challenge in clinical trials. For this purpose, a modification
of the schema of Hesketh et al. [8] based on intrinsic
emetogenicity of single agents is proposed. Intravenous
chemotherapy agents are listed with division across four
broad emetogenic groups: high, moderate, low, and minimal (Table 3). A separate listing of oral agents is also
proposed (Table 4). Since oral agents tend to be given
daily for several days to several weeks, emetogenicity can
only be judged for the entire period without a distinction
between acute and delayed emesis, and antiemetic regimens will tend to differ from those recommended for
single-dose intravenous chemotherapeutic agents.
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