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Best Practice Management of CINV
in Oncology Patients: I. Physiology
and Treatment of CINV
Multiple Neurotransmitters and Receptors and the
Need for Combination Therapeutic Approaches
David G. Frame, PharmD
T he etiology of nausea and vomiting is multifactorial, and the relevant pathways often involve multiple neurotransmitters and receptors. Thus, optimal pharmacologic therapy
that modulates several neurotransmitter and receptor systems will likely be necessary to prevent chemotherapy-induced nausea and vomiting (CINV).
It is believed that CINV occurs largely via (1)
a peripheral pathway involving activation of neurotransmitters as a result of local gastrointestinal
(GI) irritation or damage and (2) a central pathway
involving activation of neurotransmitters in the chemoreceptor trigger zone (CTZ) directly through the
blood or cerebrospinal fluid. The currently accepted
model includes these two pathways and the neurotransmitters that are critical in the development of
CINV.1 The peripheral pathway is activated by serotonin (5-hydroxytryptamine, 5-HT) that is released
by damaged or otherwise activated enterochromaffin
cells (which contain approximately 80% of the body’s
supply of serotonin) and induce emesis by binding to
serotonin type 3 (5-HT3) receptors along the vagus
nerve in the GI tract. Afferent vagal nerve impulses
are thought to be transmitted to the CTZ and vomiting center of the brain. The central pathway is actiFrom a satellite symposium, Best Practice Management of
CINV in Oncology Patients, held in conjunction with the Fifth
Annual Chicago Supportive Oncology Conference on October 1, 2009, in Chicago, Illinois.
Manuscript submitted February 1, 2010;
accepted February 19, 2010.
Correspondence to: David G. Frame, PharmD, Clinical Hematology/Oncology/BMT Specialist, Assistant Professor of Pharmacy, Department of Pharmacy B2D321, University of Michigan
Health System, Ann Arbor, MI 48109; telephone: 934-936-8209;
fax: 734-426-7790; e-mail: [email protected]
J Support Oncol 2010;8(suppl 1):5–9
© 2010 Elsevier Inc. All rights reserved.
Volume 8, Supplement 1 ■ March/April 2010
Abstract Chemotherapy-induced nausea and vomiting (CINV) involves
multiple neurotransmitter and receptor systems; thus, its optimal treatment
is likely to require a combination of therapies targeting multiple systems.
Antiemetic regimens have evolved from use of dopamine antagonists alone
to combination regimens such as a corticosteroid plus an antagonist of the
serotonin (5-hydroxytryptamine) type 3 receptor or this combination with a
neurokinin-1 receptor antagonist. The net result is that antiemetic efficacy
has markedly increased with the addition of each new class of agent to treatment regimens. Further research is needed to determine optimal uses of
available classes and agents for managing CINV, to elucidate the roles of additional neurotransmitters and receptors in both nausea and vomiting, and
to develop new antiemetic agents.
vated by substance P, which is abundant in the CTZ
of the area postrema and is present in small amounts
about GI vagal efferent nerve fibers. Substance P induces vomiting by binding to neurokinin-1 (NK1) receptors, which are highly concentrated in the brain.
However, in addition to serotonin and 5-HT3 receptors, and substance P and NK1 receptors, other
neurotransmitter and receptor systems may play
important roles in the vomiting response. These
include serotonin and 5-HT4 receptors; dopamine
(D) and D2 and D3 receptors; cannabinoids (CBs)
and CB1 receptors; histamine (H) and H1 receptors;
acetylcholine and the muscarninic (M) acetylcholine M3 and M5 receptors; and γ-aminobutyric acid
(GABA) and GABAβ receptors. In fact, more than
two dozen neurotransmitter and receptor systems
have roles in the vomiting reflex; however, the relationships among them have not been completely
elucidated, and pharmacologic agents for modulating their activity may as yet be unavailable. The
known sites of action of available classes of antiemetic agents in the brain are shown in Figure 1.2
www.SupportiveOncology.net
Dr. Frame is
Assistant Professor
of Pharmacy and
Clinical Hematology/
Oncology/BMT
Specialist, Department
of Pharmacy, University
of Michigan, Ann
Arbor, Michigan.
5
Physiology and Treatment of CINV
Cortex, limbic region
CB1 agonists
Benzodiazepines
Chemoreceptor trigger zone
D2 antagonists
NK1 antagonists
CB1 antagonists
5-HT3 antagonists
Vomiting center
Antihistamines
Anticholinergics
Visceral afferents
5-HT3 antagonists
5-HT4 agonist (metoclopramide)
Figure 1 Sites of Action of Different Classes
of Antiemetic Agents
CB = cannabinoid; D = dopamine; NK = neurokinin; 5-HT = 5-hydroxytryptamine (serotonin)
Adapted from Hornby2
It has proven even more difficult to identify neurotransmitter and
receptor systems and interrelationships involved in nausea. Moreover, nausea is often problematic even when emesis is controlled.
This further supports the notion that numerous neurotransmitter
and receptor systems are involved in CIN and CIV, underscoring the
need for treatments that target multiple systems.
Classification of CINV
CINV commonly is classified as acute—occurring and
resolving within 24 hours of chemotherapy; delayed—occurring at > 24 hours after chemotherapy administration;
breakthrough—occurring despite antiemetic treatment; refractory—unmanageable with current antiemetics; and anticipatory—a conditioned response after prior, inadequately controlled
CINV. Anticipatory nausea is most common.
It bears noting that although both overlapping and differing
mechanisms clearly are involved in acute as well as delayed CINV,
the 24-hour criterion was established based on the emetic activity after cisplatin administration and to evaluate responses in antiemetic trials with that agent. Hence, this model does not explain
the underlying physiology of CINV from all chemotherapy agents,
and the 24-hour mark is not a magic number that neatly delineates
acute and delayed physiologic responses.
It should also be noted that anticipatory CINV may not
solely be a conditioned response to prior inadequately prevented CINV. That is, patients may have experienced nausea or
vomiting from other causes before their first chemotherapy, or
they may expect to experience these adverse effects after chemotherapy based on information they hear or read. This component of anticipatory CINV should be taken into account in
efforts to manage these adverse effects of treatment.
Characteristics and Use of Current
Antiemetic Regimens
Use of Dexamethasone with 5-HT 3
receptor Antagonists
In the author’s experience, dexamethasone is far too frequently not included as an essential agent in a combination
antiemetic regimen with a 5-HT3 antagonist. This is an important point, particularly because a large meta-analysis of studies
that compared the combination with a 5-HT3 antagonist alone
clearly showed the combination is superior for preventing
acute emesis.5 The addition of dexamethasone improves control of emesis by 15%–20% and should be given with a 5-HT3
antagonist unless contraindicated or not tolerated.
Metoclopramide in Delayed Emesis
A timeline of development of antiemetic treatments for
De Mulder and colleagues6 conducted a study to compare
the first-generation 5-HT3 receptor antagonist ondansetron
with metoclopramide, which is a strong dopamine receptor antagonist and a weak 5-HT3 receptor antagonist. In the study, 79
patients receiving cisplatin (50–100 mg/m2) were treated with
ondansetron (8 mg IV followed by 1 mg/h on day 1 and 8 mg
orally three times per day on days 2–6) or metoclopramide (3
mg/kg IV followed by continuous infusion on day 1 and 20 mg
orally three times per day on days 2–6). Patients who received
ondansetron were more likely to have no vomiting episodes on
day 1 (72% vs 41%), whereas the rates of no emesis were similar
on days 2–5 for the ondansetron and metoclopramide groups
(65% vs 62%). It is important to remember that high doses of
metoclopramide are also more likely to cause extrapyramidal
symptoms, which are associated with dopamine antagonists, so
patients in this study also received diphenhydramine.
In addition, inadequately controlled acute CINV is a primary
risk factor for delayed CINV, so the fact that metoclopramide
was much less likely to control acute vomiting but equivalent to
www.SupportiveOncology.net
The Journal of Supportive Oncology
Development of Antiemetic Therapies
6
CINV highlights several major advances after the use of phenothiazines, such as prochlorperazine, alone.3 Subsequently,
corticosteroids were shown to be superior to placebo in treating CINV in the late 1970s, and, by the early 1980s, high-dose
metoclopramide was shown to be more effective than phenothiazines. In addition, antiemetic control was superior when highdose metoclopramide and a corticosteroid such as dexamethasone were administered together.
Similarly, clinical trials in the late 1980s and early 1990s
demonstrated superior efficacy of 5-HT3 receptor antagonists
over older antiemetics to control CINV from highly emetogenic chemotherapy (HEC).4 The activity of 5-HT3 antagonists
was also enhanced by the addition of a corticosteroid.
Clinical research from then to now has also confirmed that the
addition of D2 receptor antagonist to a 5-HT3 receptor antagonist
regimen may improve antiemetic control, that a corticosteroid plus
a 5-HT3 receptor antagonist also improves control of CINV from
moderately emetogenic chemotherapy (MEC), and that NK1 receptor antagonists also add efficacy when combined with a 5-HT3
antagonist and a corticosteroid for both HEC and MEC.
Frame
Differences Among 5-HT 3 Receptor Antagonists
Although response rates in individual trials comparing firstgeneration 5-HT3 receptor antagonists sometimes differed, overall efficacy of these agents are similar in the settings of HEC and
MEC.7 Palonosetron is a second-generation 5-HT3 receptor antagonist with a half-life of approximately 40 hours (compared with
4–8 hours for first-generation agents; Table 1).8,9 Two parallel trials of 1,132 patients receiving MEC compared single IV doses of
palonosetron, 0.25 mg or 0.75 mg, with single IV doses of ondansetron, 32 mg, in a first trial10 or dolasetron, 100 mg, in the second
trial.11 Corticosteroids were administered to only approximately
5% of patients in these trials. Pooled results showed significantly
higher rates of complete control of emesis with palonosetron 0.25
mg (n = 378) versus ondansetron or dolasetron (n = 376) in
the acute time frame (72.0% vs 60.6%), the delayed time frame
(60.0% vs 46.8%), and overall (57.7% vs 42.0%; all P < 0.025).12
Results of the trial comparing palonosetron with ondansetron are
shown in Figure 2.10 There was no significant difference in treatment failure rates between palonosetron and ondansetron, but
the separation of the curves for the palonosetron groups versus
the ondansetron group after 24 hours indicates that palonosetron’s longer half-life was associated with some preventive benefit
as no further therapy was given past day 1 in the ondansetron
and dolasetron arms. This observation, in turn, indicates that serotonin does indeed play a role in delayed emesis. The results of
these studies also serve as a reminder that without combination
therapy, treatment with 5-HT3 inhibitors, whether they are longacting or not, will still fail in some 40%–50% of patients. This also
highlights that serotonin receptor antagonists should not generally be used alone for preventing delayed CINV.
CYP2D6 Ultrarapid Metabolism
Table 1
Pharmacologic Differences Among
Serotonin (5-Hydroxytryptamine) Type 3
(5-HT3) Receptor Antagonists
Agent
Palonosetron
Ondansetron
Granisetron
Dolasetron
pKi, −log(Ki)
T½, h
Metabolism
10.45 ± 0.2a
8.39 ± 0.1a
8.91 ± 0.03a
7.6b
~ 40
4−6
5−8
5−8
CYP2D6, CYP3A4
CYP2D6, CYP3A4
CYP3A4
CYP2D6, CYP3A4
CYP = cytochrome P450, Ki = dissociation constant, T1/2 = half-life
Source: a Wong et al8 and b Clark et al9
100
Palonosetron 0.25 mg (n = 223)
Palonosetron 0.75 mg (n = 223)
Ondansetron 32 mg (n = 221)
80
Patients (%)
ondansetron for controlling delayed CINV suggests that the dopamine-antagonist effect of metoclopramide is important for preventing delayed symptoms. Furthermore, it is not possible to rule
out some modest diphenhydramine-induced antiemetic effect.
60
40
20
P = NS for palonosetron 0.25 mg or 0.75 mg vs ondansetron
0
0
24
48
72
96
120
Time (h)
Figure 2 Time to Treatment Failure with
Palonosetron vs Ondansetron
Treatment failure was defined as a first emetic episode or use of rescue
medication. Patients received single IV doses of palonosetron, 0.25 or 0.75
mg, or ondansetron, 32 mg, in the setting of moderately emetogenic chemotherapy. From Gralla et al.10
Cytochrome P450 (CYP) enzymes metabolize 5-HT3 receptor
antagonists (Table 1).8,9 CYP2D6 is responsible for the majority of
metabolism of dolasetron and palonosetron and partially for metabolism of ondansetron, whereas CYP3A4 is responsible for the
majority of metabolism of granisetron and partially for metabolism
of ondansetron. It has been shown that genetic polymorphisms in
CYP2D6 can dramatically alter the antiemetic effects of agents
metabolized by that enzyme. Individuals can be categorized as poor
metabolizers (having two deficient alleles), intermediate metabolizers, extensive metabolizers (comprising the majority of the population), or ultrarapid metabolizers (having duplicated or amplified
active alleles) who clear drug so rapidly it appears to decrease the
therapeutic effect of agents having a short half-life.13,14 As shown
in Figure 3,14 patients receiving chemotherapy who have three active 2D6 genes (ie, are ultrarapid metabolizers) have a significantly
greater mean number of acute and delayed emesis episodes when
given ondansetron or tropisetron (also metabolized by 2D6). The
data also suggest that ultrarapid metabolism was associated with increased severity of nausea. Interestingly, it appears that metabolism
has a smaller effect on palonosetron, as pharmacokinetics for this
agent vary only slightly between poor and extensive metabolizers.15
Volume 8, Supplement 1 ■ March/April 2010
www.SupportiveOncology.net
Transdermal Granisetron
A transdermal formulation of granisetron has been developed in the attempt to prolong drug activity. In a recent
randomized, double-blind, phase III noninferiority trial, 582
patients receiving multiday HEC or MEC were given pills (placebo or active drug) for 3–5 days and an opposite transdermal
patch (active drug or placebo) for 6 days starting 1 day before
chemotherapy.16 The oral granisetron dosage was 2 mg per day,
and the total patch dose was 34.3 mg with an average daily
absorption of 3.1 mg. There was no significant difference in
complete response rates between patients receiving the patch
and those receiving oral granisetron (60% vs 64%). The patch
option is particularly attractive in the setting of multiday chemotherapy or radiation therapy regimens, and in facilitating
antiemetic treatment in patients in whom CINV might make
oral administration difficult.
7
Physiology and Treatment of CINV
4
Mean episodes of vomiting
0–4 hours
5–24 hours
3
2
1
0
0
1
2
Number of CYP2D6 genes
3
Mean VAS for nausea (% of scale)
50
40
0–4 hours
5–24 hours
30
20
10
0
0
1
2
Number of CYP2D6 genes
3
Figure 3 Effect of Number of Active CYP2D6 Genes
on Chemotherapy-Induced Nausea
and Vomiting in Patients Receiving
Ondansetron or Tropisetron
Shown are mean number of vomiting episodes (top) and mean visual analog scale (VAS) score for nausea (bottom). From Kaiser et al.14
Aprepitant
The success of a combination therapy approach to CINV is
again emphasized by outcomes with addition of the NK1 antagonist aprepitant to 5-HT3 receptor antagonist and corticosteroid
treatment. Hesketh and colleagues17 and Poli-Bigelli and colleagues18 completed two phase III trials of patients receiving cisplatin-based chemotherapy, which showed 20% improvements in
complete response rates (73% vs 52% and 63% vs 43%, respectively) with the addition of aprepitant to standard ondansetron plus
dexamethasone. A notable finding in these studies was the larger
benefit for women compared with men. For instance, in phase III
trials of aprepitant plus ondansetron and dexamethasone versus
ondansetron and dexamethasone alone (control group), the rate
of complete response of acute emesis was 86% in women receiving aprepitant and 66% in the control group (P < 0.001).19 The
8
www.SupportiveOncology.net
benefit of adding aprepitant conferred a significant, but smaller,
difference in control of acute emesis in men (response rates of 87%
vs 80%, P < 0.05).
Another recent phase III trial compared aprepitant (125 mg
on day 1 and 80 mg on days 2 and 3) plus ondansetron (8 mg
twice daily on day 1) and dexamethasone (12 mg on day 1) with
a regimen of ondansetron (8 mg twice daily on days 1–3) plus
dexamethasone (20 mg on day 1) in women with breast cancer
receiving MEC.20 The addition of aprepitant significantly increased the 5-day complete response rate from 43.5% to 51.0%
(P < 0.05) and the 5-day no-emesis rate from 59.0% to 76.0% (P
< 0.001). Again, the gender disparity suggests that NK1 plays an
especially important role in CINV in female patients, which may
help change the fact that women have consistently exhibited antiemetic treatment response rates 10%–20% lower than those men
in antiemetic trials of both HEC and MEC done before the advent
of NK1 antagonists.4,21
Some evidence indicates that the first 125-mg dose of aprepitant results in blockade of approximately 80% of NK1 receptors in
the brain.22 Although aprepitant is currently approved as a 3-day
regimen, ongoing studies are attempting to determine whether additional doses contribute significantly to the efficacy of this agent,
and for what period of time. A recent small study compared 1 day
versus 3 days of aprepitant, both in combination with palonosetron on day 1 and dexamethasone on days 1–4.23 Interestingly,
there were no differences in outcome for emesis, nausea, or use of
breakthrough medications between the two arms.
It should be remembered that aprepitant is a moderate
CYP3A4 inhibitor, with effects in this regard similar to those
of grapefruit juice, diltiazem, and verapamil. Thus, it is recommended that dexamethasone, which is metabolized by
CYP3A4, be used at a reduced dose when combined with
aprepitant. Additionally, there may be a potential drug interaction between aprepitant and chemotherapeutic agents such
as ifosfamide that also are metabolized by CYP3A4. A recent
retrospective review involving 45 patients who received ifosfamide with or without aprepitant found that 6 of 8 patients
experiencing ifosfamide neurotoxicity were also receiving
aprepitant.24 In the author’s experience, an option for patients
receiving ifosfamide would be to give aprepitant starting the day
after the final dose of ifosfamide, because delayed nausea and delayed vomiting are major problems with this chemotherapeutic
agent. Thus, giving aprepitant at the end of ifosfamide dosing
can avoid a potential drug interaction while providing coverage for delayed symptoms.
Olanzapine
Olanzapine is a US Food and Drug Administration–approved
antipsychotic that blocks multiple neurotransmitters, including dopamine, serotonin, catecholamines, acetylcholine, and
histamine.25 Many of these transmitters are involved in CINV,
and olanzapine has been shown to be effective in prevention of
these adverse effects. A phase II trial evaluated the efficacy of
olanzapine added to granisetron plus dexamethasone on day 1
and added to dexamethasone in the delayed period.26 Results
showed a very high rate of complete response and excellent conThe Journal of Supportive Oncology
Frame
trol of nausea. A second phase II study combined palonosetron
with dexamethasone plus olanzapine; the dexamethasone was
given on day 1 only, and the olanzapine was given on days 2–4
after chemotherapy administration.27 For the first cycle of chemotherapy, the complete response rate was 100% in the acute
period and 75% in the delayed period. Further studies are needed to define the comparative efficacy of olanzapine; however, it
does appear to be an active agent in the prevention of CINV.
Conclusion
A thorough understanding of the pathophysiology of CINV
is essential for its treatment. Realizing that there are multiple
neurotransmitters involved leads to the design of appropriate
References antiemetic combinations. Because CINV results from activation
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is required to prevent acute and delayed symptoms. All of the
current nationally recognized guidelines for prevention of CINV
recommend combination therapy approaches, and it is imperative that these principles are understood and followed to provide
the best outcome and quality of life for patients with cancer.
Acknowledgments: The author would like to acknowledge
and thank Matt Stenger for his assistance in the preparation
of the paper.
Conflicts in interest: Dr. Frame serves as a consultant or has an advisory
role with Merck.
PubMed ID in brackets
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