Defining the Emetogenicity of Cancer Chemotherapy

Regimens: Relevance to Clinical Practice

PAUL J. HESKETH
St. Elizabeth’s Medical Center, Boston, Massachusetts, USA

Key Words. Chemotherapy · Emesis · Emetogenicity

A BSTRACT
Significant progress has been made in recent years in population (age, gender, history of ethanol consumption,
developing more effective and better tolerated means to and prior experience with chemotherapy), and some relate
prevent nausea and vomiting induced by cancer to the treatments administered. Clearly, the most impor-

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chemotherapy. The most significant development has been
the introduction of a new class of antiemetic agents, the
selective antagonists of the type 3 serotonin receptor. With
the new antiemetic therapeutic options and their attendant
higher costs has come a need to define evidence-based
guidelines to assist in their judicious and cost-effective use.
A number of predictive factors for antiemetic risk have
been defined. Some of these factors relate to the patient
tant of all these factors in predicting risk of emesis is the
intrinsic emetogenicity of the chemotherapy. Although an
“ideal” emetogenic classification schema for chemother-
apy has yet to be realized, recent developments in this area
have allowed a more precise estimation of emetogenic
risks and have provided antiemetic guideline groups
with a useful foundation on which to base their treatment
recommendations. The Oncologist 1999;4:191-196

INTRODUCTION guidelines to help ensure their rational and cost-effective use.

Nausea and vomiting have consistently ranked high on
the list of factors most feared by patients receiving
chemotherapy [1, 2]. Inadequately controlled emesis signif-
icantly impairs quality of life and increases the risk of
patient non-compliance with therapy. Substantial progress
has been made over the last decade in developing more
effective and better tolerated means to prevent chemother-
apy-induced emesis [3]. Several factors have contributed to
the therapeutic advances in this area, including new insights
into the pathophysiology of emesis, recognition of the value
of combination antiemetic therapy, tailoring therapy for both
acute emesis (≤ 24 h after chemotherapy), and delayed eme-
sis (>24 h after chemotherapy) and the development of new
antiemetic agents, particularly the selective antagonists of the
type 3 serotonin (5-hydroxytyptamine [5-HT3]) receptor.
There are currently three 5-HT3 receptor antagonists
(dolasetron, granisetron, and ondansetron) approved for use
in the United States. As with other new supportive care
agents, however, the availability of new antiemetic agents
with their attendant higher acquisition costs compared with
older antiemetics has created a need to develop practice
A reliable method of predicting the risk of emesis following
cancer chemotherapy would provide a solid foundation for the
development of treatment guidelines for the appropriate use
of the 5-HT3 receptor antagonists and other antiemetics in
patients receiving chemotherapy.
Over the last 15 years, there has been growing recogni-
tion of a number of factors that are important in predicting
the risk of emesis following antineoplastic chemotherapy
[4-6]. Some of these factors are related to the treatment,
including the specific agent(s), chemotherapy dose, route
and rate of administration, and antiemetic regimen
employed. With many chemotherapy agents, emetic risk is
directly proportional to chemotherapy dose. In addition, in
general, short i.v. infusions induce more emesis than pro-
tracted i.v. infusions or administration by the oral route.
Other factors relate to the patient population, including
patient age, gender, history of ethanol consumption, and
history of prior chemotherapy. Factors associated with
decreased risk of emesis include older age, male gender,
history of heavy ethanol consumption, and no emesis with
prior chemotherapy. Of all these predictive factors, the

Correspondence: Paul J. Hesketh, M.D., Division of Hematology/Oncology, St. Elizabeth’s Medical Center, 736 Cambridge
Street, Boston, Massachusetts 02135, USA. Telephone: 617-789-2317; Fax: 617-789-2959; e-mail phesketh@aol.com
Accepted for publication March 31, 1999. ©AlphaMed Press 1083-7159/99/$5.00/0

The Oncologist 1999;4:191-196

Hesketh 192

intrinsic emetogenicity of the chemotherapy has consistently

Table 1. Emetogenic potential of chemotherapy agents
emerged as the most important.
Frequency of
Level emesis (%)* Agent
EMETOGENICITY CLASSIFICATION SCHEMAS
5 >90 Carmustine > 250 mg/m2
An “ideal” emetogenic classification schema would take Cisplatin ≥ 50 mg/m2
into account a number of key factors, including: A) derivation Cyclophosphamide > 1,500 mg/m2
from objective data rather than opinion; B) ability to account Dacarbazine
for the different types of emesis with an ability to predict the Mechlorethamine
Streptozocin
likelihood of acute and delayed emesis; C) ability to account
for important patient- and treatment-related predictive factors; 4 60-90 Carboplatin
Carmustine ≤ 250 mg/m2
D) ability to account for the emetogenic potential of com-
Cisplatin < 50 mg/m2
binations, and E) simplicity of use. Several efforts have Cyclophosphamide > 750 mg/m2 ≤ 1,500 mg/m2
been made in the past to devise classification schemas for Cytarabine > 1 g/m2
chemotherapy emetogenicity [7-11]. None of these sys- Doxorubicin > 60 mg/m2
Methotrexate > 1,000 mg/m2
tems have achieved widespread acceptance as a “standard”

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Procarbazine (oral)
schema. Most have significant limitations, including: failure
3 30-60 Cyclophosphamide ≤ 750 mg/m2
to account for important treatment-related factors, such as Cyclophosphamide (oral)
chemotherapy dose and rate and route of administration; fail- Doxorubicin 20-60 mg/m2
ure to account for combinations or different patterns of eme- Epirubicin ≤ 90 mg/m2
sis, and reliance on opinion rather than objective data in Hexamethylmelamine (oral)
Idarubicin
stratifying chemotherapy agents. In addition, none attempted Ifosfamide
to account for important patient-related variables. Irinotecan
Methotrexate 250-1,000 mg/m2
Mitoxantrone < 15 mg/m2
A NEW PROPOSAL FOR DEFINING ACUTE
EMETOGENICITY OF CANCER CHEMOTHERAPY 2 10-30 Capecitabine
Docetaxel
Recently, a number of individuals with a longstanding Etoposide
interest in the antiemetic field have proposed a new classifi- 5-Fluorouracil < 1,000 mg/m2
cation schema for acute emesis [12]. This schema builds Gemcitabine
upon the system proposed by Lindley et al. [10]. It standard- Methotrexate > 50 mg/m2 < 250 mg/m2
Mitomycin
izes chemotherapy rate and route of administration (short i.v. Paclitaxel
infusion) and patient age (adults), attempts to account for the Topotecan
importance of chemotherapy dose where clinically relevant, 1 <10 Bleomycin
includes newer chemotherapy agents, and also proposes an Busulfan
algorithm to predict the emetogenicity of combination Chlorambucil (oral)
2-Chlorodeoxyadenosine
regimens. A few oral agents were also classified using Fludarabine
customary administration schedules. On the basis of a com- Hydroxyurea
prehensive literature search and the consensus of the Methotrexate ≤ 50 mg/m2
authors, individual chemotherapy agents were assigned to L-phenylalanine mustard (oral)
Thioguanine (oral)
one of five emetogenic levels. The five levels define the Vinblastine
risk of acute emesis in the absence of effective antiemetic Vincristine
prophylaxis. Table 1 lists individual chemotherapy agents Vinorelbine
by emetogenic level.
*Proportion of patients who experience emesis in the absence of effective
Since the publication of this schema, a number of addi- antiemetic prophylaxis.
tional chemotherapeutic agents have received regulatory Adapted with permission from [12].
approval in the United States and are now incorporated into
clinical practice. These include the camptothecin analogs
irinotecan and topotecan, and the oral fluoropyrimidine car- EMETOGENICITY OF CHEMOTHERAPY COMBINATIONS
bamate capecitabine. Review of the clinical experience None of the older emetogenic classification schemas
with these agents to date in phase I and II trials would sug- adequately accounted for the impact on emetogenicity of
gest that capecitabine [13] and topotecan [14, 15] are level administering chemotherapy agents in combination.
2 agents and that irinotecan is a level 3 agent [16-18]. Recognizing that most chemotherapy agents are administered
 193
Table 2. Algorithm for defining the emetogenicity of combination regimens
1. Identify the most emetogenic agent in the combination.
2. Determine the relative contribution of other agents to the emetogenicity of the
combination. When considering other agents, the following rules apply:
(A) Level 1 agents do not contribute to the emetogenicity of a given regimen.
(B) Adding one or more level 2 agents increases the emetogenicity of the
combination by one level greater than the most emetogenic agent in the
combination.
(C) Adding level 3 or 4 agents increases the emetogenicity of the combination
by one level per agent.
Adapted with permission from [12].
as part of various combinations and not as single agents, it
would be useful in predicting antiemetic risk to have an
appropriate means of predicting the effect of combination reg-
imens. Table 2 illustrates an algorithm to help predict the
emetogenicity of chemotherapy combinations. The algorithm
begins with the identification of the most emetogenic agent in
the combination. The relative contribution of other
chemotherapy agents to the overall emetogenicity of the com-
bination is then assessed. When considering other agents, the
following rules were suggested: A) Level 1 agents do not con-
tribute to the emetogenicity of a given regimen; B) adding one
or more level 2 agents increases the emetogenicity of the
combination by one level greater than the most emetogenic
agent in the combination, and C) adding level 3 or 4 agents
increases the emetogenicity of the combination by one level
per agent.
The algorithm was validated in part using a database of
197 patients assigned to receive a placebo antiemetic as
part of four clinical trials comparing the 5-HT 3 receptor
antagonist ondansetron with placebo [19-22]. The pre-
dicted incidence of emesis with a variety of chemotherapy
regimens based upon the algorithm was compared with the
actual observed frequency of emesis. For example, 44
patients received a combination of cyclophosphamide
(<750 mg/m2) and doxorubicin (20-60 mg/m2) ± vin-
cristine. The predicted emetogenic potential of this combi-
nation by the algorithm is level 4 (60%-90% frequency of
emesis). Eighty-two percent (36/44) of patients receiving
these regimens developed acute emesis when they received
a placebo as antiemetic prophylaxis. Similar close correla-
tions were noted between the predicted and observed fre-
quency of emesis with a number of other chemotherapy
regimens.
A number of potential limitations of this algorithm
should be kept in mind, however, The majority of patients
from the latter database were women (88%) with breast
cancer (79%) receiving primarily cyclophosphamide- and/or
Chemotherapy Emetogenicity
anthracycline-based chemotherapy. Few had a history of
significant ethanol consumption. Therefore, based upon our
knowledge of important patient-related factors, this group
has to be considered somewhat high risk for the develop-
ment of emesis. In addition, the algorithm attempts to pre-
dict only acute emesis risk. There is no accounting for the
potential for delayed emesis. Clinicians are therefore
advised to be cautious in attempting to generalize this algo-
rithm to more diverse populations receiving other
chemotherapy regimens. Further studies will be needed to
determine the relevance of this algorithm to other patient
populations.
DEFINING RISK OF DELAYED EMESIS
All efforts to date to define emetogenic schemas for
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chemotherapy agents have concentrated on the potential
for emesis within the first 24 h (acute emesis). This is
appropriate given the potential severity of uncontrolled
acute emesis and the observation that emesis induced by
many chemotherapy agents will resolve within 24 h. For a
classification schema to be most relevant and serve as a
basis for treatment recommendations, however, it must
also account for the ability of certain chemotherapy agents
to produce emesis beyond the 24-h period following
chemotherapy, so-called “delayed emesis.” Cisplatin is the
classic agent by which delayed emesis has been defined. In
the absence of appropriate antiemetic prophylaxis, there is
an approximate 65%-90% likelihood of delayed emesis
following administration of cisplatin [23-25]. A number of
other agents, including cyclophosphamide, carboplatin,
and doxorubicin, also have the potential to induce delayed
emesis. Although the risk of delayed emesis is less than
with cisplatin, up to one-third of patients receiving these
agents will experience delayed emesis in the absence of
delayed antiemetic prophylaxis [26].
RELEVANCE OF CHEMOTHERAPY EMETOGENICITY
TO CURRENT ANTIEMETIC USE AND CLINICAL
RESEARCH
At present, no comprehensive emetogenic classifica-
tion schema that fulfills all the criteria of the “ideal”
schema has been devised. However, given the pressing
need to define rational evidence-based guidelines to help
guide antiemetic use, the recently proposed schema [12]
has been used as a framework for such recommendations.
The National Comprehensive Cancer Network (NCCN)
has used this classification schema as the basis for their
recently released antiemetic guidelines [27]. For acute
antiemetic prophylaxis in patients receiving chemother-
apy with level 3-5 emetogenic potential, they recom-
mended the use of an oral 5-HT3 receptor antagonist
 Hesketh
National Comprehensive Cancer Network (NCCN)
Antiemesis Practice Guidelines
Acute Primary treatment (Day 1)
emetogenic
potential PO tolerated:*
Granisetron, 2 mg PO qd or 1 mg bid
or Ondansetron, 8 mg PO bid (for high: category 2)
or Dolasetron, 100 mg PO qd (for high: category 2)
High to + Dexamethasone, 10-20 mg PO
moderate ➝ ± Lorazepam, 0.5-2.0 mg PO
(levels 5 + 4 + 3) • Start before chemotherapy
• Repeat daily for fractionated doses of chemotherapy
PO not tolerated:*
Ondansetron, 8 mg (maximum, 32 mg) i.v.
or Granisetron, 10 µg/kg (maximum, 1 mg ) i.v.
or Dolasetron, 1.8 mg/kg i.v. or 100 mg i.v.
+ Dexamethasone, 10-20 mg i.v.
± Lorazepam, 0.5-2.0 mg i.v.
Categories of acceptability for guideline recommendations
Category 1: Recommendations that are uncontested and generally accepted by
all authorities in that particular cancer.
Category 2: Recommendations that are somewhat controversial.
Category 3: Recommendations that caused real disagreements among members
of the NCCN panel.
Figure 1. Recommended antiemetic prophylaxis for patients receiving
chemotherapy with level 3-5 acute emetogenic potential.
*Order of listed antiemetics does not reflect preference. Reproduced with
permission from [27].
The NCCN guidelines are a statement of consensus of its authors regard-
ing their views of currently accepted approaches to treatment. Any clinician
seeking to apply or consult any NCCN guideline is expected to use independent
medical judgment in the context of individual clinical circumstances to deter-
mine any patient’s care or treatment. The National Comprehensive Cancer
Network makes no warranties of any kind whatsoever regarding their content,
use, or application and disclaims any responsibility for their application or use
in any way.
combined with oral dexamethasone prior to chemotherapy
(Fig. 1). For patients receiving level 2 chemotherapy, they
recommended an oral dose of a dopaminergic antagonist
or oral dexamethasone alone. For level 1 chemotherapy,
no routine antiemetic prophylaxis was recommended (Fig.
2). Recognizing the potential of certain agents to induce
delayed emesis, they also offered specific recommendations
in this setting as well (Fig. 3).
A simple-to-use, comprehensive emetogenic classifica-
tion schema would also have potential relevance to antiemetic
research. Efforts to develop additional useful antiemetic
agents to address unmet needs (delayed emesis, high-dose
chemotherapy, and multi-day chemotherapy) are continuing.
Cisplatin has traditionally served as the gold standard emeto-
genic challenge in new agent development. As cisplatin use
declines, however, the ability to evaluate new agents in a
194
National Comprehensive Cancer Network (NCCN)
Antiemesis Practice Guidelines
Acute Primary treatment (Day 1)
emetogenic
potential PO tolerated:*
Dexamethasone, 10-20 mg PO
or Prochlorperazine, 10 mg PO q4-6h
or 15mg spansule PO q8-12h
Low or Thiethylperazine, 10 mg PO q4-6h
(level 2) ➝ or Metoclopramide, 20 mg PO q4-6h
+ diphenhydramine, 25 mg PO q4-6h PRN
± Lorazepam, 0.5-1.0 mg PO q4-6h
• Start 30 min before chemotherapy
• Repeat daily for fractionated doses of chemotherapy
PO not tolerated:*
Dexamethasone, 20 mg i.v.
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or Prochlorperazine, 10 mg i.v. q4-6h
or Metoclopramide, 0.5 mg/kg i.v. q3-4h
+ diphenhydramine, 25-50 mg i.v. PRN
± Lorazepam, 0.5-1.0 mg i.v., q4-6h
Unlikely
(level 1) ➝ No prophylactic treatment
Figure 2. Recommended antiemetic prophylaxis for patients receiving
chemotherapy with level 1-2 acute emetogenic potential.
*Order of listed antiemetics does not reflect preference. Reproduced with
permission from [27].
The NCCN guidelines are a statement of consensus of its authors regard-
ing their views of currently accepted approaches to treatment. Any clinician
seeking to apply or consult any NCCN guideline is expected to use independent
medical judgment in the context of individual clinical circumstances to deter-
mine any patient’s care or treatment. The National Comprehensive Cancer
Network makes no warranties of any kind whatsoever regarding their content,
use, or application and disclaims any responsibility for their application or use
in any way.
timely manner has become an increasing challenge. An
emetogenic classification schema that allows more precision
in defining emetic risk, particularly in “high-risk” patient
categories, could potentially facilitate new antiemetic agent
development.
SUMMARY
Substantial progress has been realized over the last 15
years in predicting the risk of emesis following cancer
chemotherapy. Of the known predictive factors, the intrinsic
emetogenicity and pattern of emesis have emerged as the
most clinically relevant. A better understanding of the latter
factors has allowed the development of rational guidelines
to help assist the clinician in using antiemetic agents in the
most rational and cost effective manner possible. Efforts
should continue to develop more comprehensive emeto-
genic schemas that attempt to take into account all of the
known patient- and treatment-related factors.
195 Chemotherapy Emetogenicity

Figure 3. Recommended antiemetic

prophylaxis for patients receiving
chemotherapy with delayed emetogenic
potential.
*Order of listed antiemetics does
not reflect preference. Reproduced with
permission from [27].
The NCCN guidelines are a state-
ment of consensus of its authors regard-
ing their views of currently accepted
approaches to treatment. Any clinician
seeking to apply or consult any NCCN
guideline is expected to use independent
medical judgment in the context of indi-
vidual clinical circumstances to deter-
mine any patient’s care or treatment.
The National Comprehensive Cancer
Network makes no warranties of any
National Comprehensive Cancer Network (NCCN)
Delayed
emetogenic
potential
Cisplatin, ≥ 50 mg/m2
Carboplatin, ≥ 300 mg/m2
Cyclophosphamide,
≥ 600-1,000 mg/m2
Doxorubicin, ≥ 50 mg/m2
Antiemesis Practice Guidelines
Prevention (Days 2-5)
*Metoclopramide, 0.5 mg/kg PO qid × 4 days
➝ + Dexamethasone, 8 mg PO bid × 2 days,
then ≤ 4 mg bid × 2 days
(category 2 for cyclophosphamide or doxorubicin)
or Ondansetron, 8 mg PO bid × 3 days
± Dexamethasone, 8 mg PO bid × 3 days
(category 2 for cyclophosphamide or doxorubicin)
or Dexamethasone, 8 mg PO bid × 2 days,
then ≤ 4 mg bid × 2 days
± Lorazepam, 0.5-2 mg PO q6h
± Diphenhydramine, 25-50 mg PO q6h

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kind whatsoever regarding their con-
tent, use, or application and disclaims any responsibility for their application or use in any way.

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