Supportive Care of Cancer - Understanding Chemotherapy-Induced Nausea and Vomiting
1. Supportive Care of
Cancer -- Part 2
Chirag
Dave,
Pharm.
D.
Candidate
Class
of
2012
Systems
Pharmacology
V
2. Learning
Objectives
1. Explain
the
pathophysiology
of
chemotherapy
induced
nausea
and
vomiting
(CINV).
2. Describe
the
classes
of
medications
used
to
treat
CINV;
specifically
where
they
act,
when
they
should
be
used,
and
their
major
side
effects.
3. Recognize
Oral
Cavity/GI
tract
complications
associated
with
chemotherapy
and
how
they
can
be
prevented
and
treated.
4. Explore
the
concept
of
“Cancer-‐Related
Fatigue”
Side
effects
are
what
kill
you!
5. Overview
• Estimated
that
70-‐80%
cancer
patients
experience
chemotherapy
induced
nausea
and
vomiting,
despite
being
treated
for
it.
• Prophylaxis
is
the
most
effective
method
of
managing
CINV.
• N/V
can
significantly
affect
quality
of
life
(fatigue,
treatment
adherence,
days
off
work,
etc…)
• What
else?
(Think
physical
implications)
• Dehydration,
electrolyte
imbalances,
malnutrition,
aspiration
pneumonia,
and
esophageal
tears.
6. Definitions
• Nausea:
the
subjective
feeling
of
the
need
to
vomit.
• Vomiting:
forceful
expulsion
of
the
stomach
contents.
• Retching:
rhythmic
contraction
of
the
abdominal
muscles
without
actual
emesis.
8. Pathophysiology
of
NV
Areas
involved
in
N/V
Location
Important
Receptors
Vomiting
Center
(VC)
CNS
H1
M1
NK1
5-‐HT3
Chemoreceptor
Trigger
Zone
(CTZ)
CNS
5-‐HT3
D2
NK1
Chemoreceptors
GI
System
Periphery
5-‐HT3
Mechanoreceptors
Chemoreceptors
Vestibular
System
Periphery
H1
M1
Cerebral
cortex,
Limbic
system,
Meninges,
Thalamus
&
Hypothalamus
CNS
Complex
9. Vomiting
Center
• Located
in
the
Medulla
Oblongata.
• Acts
as
the
coordinator
of
the
emetic
response.
• Receives
afferent
signals
from
CTZ,
GI
system,
Vestibular
system,
and
other
areas
of
the
brain.
• Sends
signals
to
effector
organs
(salivary
glands,
abdominal
muscles,
&
cranial
nerves)
10. CTZ
• Chemoreceptors
sense
toxins
and
noxious
substances
(in
blood
&
CSF).
• This
is
where
D2
receptors
are
located
and
where
D2
antagonists
act.
• Also
has
mu-‐opioid
receptors
present.
11. GI
System
• GI
mucosa
contains
enterochromaffin
cells.
• Contain
large
amount
of
body’s
serotonin
stores.
• When
chemically
or
physically
stimulated/irritated,
they
release
5-‐HT.
• This
stimulates
Cranial
nerves
IX,
X
(afferent
nerves).
• As
well
as
VC
&
CTZ
via
5-‐HT3
receptor
activation.
12. Vestibular
System
• Implicated
in
motion
sickness
&
vertigo.
• Patients
who
are
predisposed
to
motion
sickness
will
have
a
harder
time
with
chemotherapy.
• Stimulate
the
VC
through
ACh
and
Histamine.
13. Cerebral
Cortex
&
Limbic
System
• Implicated
in
anticipatory
nausea/vomiting
due
to
anxiety.
• Which
class
of
medications
is
often
used
to
treat
anxiety?
• “Place
&
Taste”
association
is
important
to
consider
in
treatment,
especially
with
children
• Can’t
change
the
place.
• Taste
management.
14. CINV
Classification
• Acute
Onset:
• Occurs
minutes-‐hours
after
drug
administration.
• Peaks
after
5-‐6h
• Commonly
resolves
within
24h.
• Delayed-‐Onset:
• Occurs
>24h
after
CTX.
• Commonly
implicated
agents:
cisplatin,
carboplatin,
cyclophosphamide,
doxorubicin.
• Anticipatory:
Incidence
is
18-‐57%,
and
is
more
common
in
younger
patients.
• Breakthrough:
vomiting
that
occurs
despite
Px
that
requires
rescue
antiemetic
use.
• Refractory:
emesis
that
occurs
despite
Px
and
rescue
antiemetic
use.
15. Relevant
Causes
of
NV
• CNS
disorders:
brain
metastases,
anxiety.
• Metabolic
disorders:
hyponatremia,
uremia.
• GI
disorders:
bowel
obstructions,
gastroparesis,
distention
• Medications:
chemotherapy
agents,
antibiotics,
antifungals,
opiates,
and
irradiation.
• Radiation
can
cause
N/V,
particularly
when
patients
receive
whole
body
or
upper
abdominal
radiation.
16. Incidence
&
Severity
of
CINV
1. Agents
used
(refer
to
“Emetogenic
Potential”).
2. Dosage
of
agents/duration
of
infusion
3. Schedule
and
Route
of
Administration
4. Concurrent
radiation
therapy
5. Patient
factors:
1. Age:
Younger
(<50y/o)
=
More
NV
2. Sex:
Female
3. Prior
CTX
4. Alcoholism:
IMPROVES
ability
to
tolerate
NV
5. Previous
history:
motion
sickness,
other
N/V
17. Emetogenic
Potential
Category
Frequency
in
patients
High
emetic
risk
>90%
frequency
of
emesis
Moderate
emetic
risk
30-‐90%
frequency
of
emesis
Low
emetic
risk
10-‐30%
frequency
of
emesis
Minimal
emetic
risk
<10%
frequency
of
emesis
• Antineoplastic
agents’
emetogenic
potential
is
established
by
the
%
of
patients
that
experience
emesis
on
the
agent
WITHOUT
any
anti-‐emetic
therapy.
• The
risk
of
CINV
is
present
for
at
least
3
days
for
“HIGH”
risk
CTX
and
2
days
for
“MEDIUM”
Risk
CTX.
21. Treatment
of
CINV
• Various
combinations
of
the
following
classes
of
medications
are
used,
according
to
NCCN
guidelines.
1. Serotonin
Receptor
Antagonists
(5-‐HT3)
2. Dopamine
Antagonists
(D2)
3. NK-‐1
Receptor
Antagonists
4. Systemic
Corticosteroids
(SCS)
5. Benzodiazepines
(Bzd)
6. H2
blockers/PPIs
22. Recommended
Prophylactic
Combinations
(IV
Agents)
Category
Combination
High
(>90%)
Day
1:
5-‐HT3
+
SCS+
NK-‐1
Day
2-‐3:
5-‐HT3
(per
institution)
(+/-‐)
H2/PPI
(+/-‐)
Bzd
Moderate
(30-‐90%)
Day
1:
5-‐HT3
+
SCS
(+/-‐)
NK-‐1
Day
2-‐3:
5-‐HT3
or
SCS
or
NK-‐1
(+/-‐)
H2/PPI
(+/-‐)
Bzd
Low
(10-‐30%)
SCS
or
D2
(Metoclopramide
or
Prochlorperazine)
(+/-‐)
H2/PPI
(+/-‐)
Bzd
Minimal
(<10%)
No
routine
prophylaxis
All
agents
on
Day
1
are
started
before
chemotherapy
(morning)
23. Breakthrough
Emesis
Management
• The
principle
is
to
add
an
agent
from
a
different
drug
class
than
the
routine
anti-‐
emetics.
Recommended
Classes:
Used
often
Not
used
often
Benzodiazepines
Cannabinoids
Dopamine
Antagonists
Scopolamine
5-‐HT3
SCS
24. 1.
Serotonin
Receptor
Antagonists
• Mechanism
of
Action:
• Blocks
5-‐HT3
receptors,
preventing
Serotonin
binding,
thereby
inhibiting
afferent
nerve
transmission
to
VC.
• PK/PD:
• All
agents
are
equally
effective
at
equal
doses.
• Dose
response
curve
is
flat
• Not
more
effective
than
other
classes
for
delayed
CINV
(other
than
palonosetron).
• Give
30
minutes
prior
to
CTX.
• Side
effects:
• *CONSTIPATION*…Treat
with
what?
• QT
Prolongation
• Headache
• Transient
elevation
of
LFTs
25. 1.
Serotonin
Receptor
Antagonists
4Half-‐life
Metabolism
Dose
Cost
Ondansetron
3-‐6h
3A4
substrate
16-‐24mg
PO
8-‐24mg
IV
(MDD
=
32mg)
30
tab
x
4mg
=
$70.99
Granisetron
(Patch
too!)
6h
PO
9h
IV
-‐
2mg
PO
0.01mg/kg
IV
(MDD
=
1mg)
2
tab
x
1mg
=
$45.99
1
patch
=
$359.98
Dolasetron
(PO
for
CTX)
6-‐8h
-‐
100mg
PO
5
tab
x
100mg
=
$355.96
Palonosetron
~40h
-‐
0.25mg
IV
1
vial
=
$406.98
26. 2.
NK-‐1
Receptor
Antagonists
• Mechanism
of
Action:
• Blocks
NK-‐1
receptors,
preventing
Substance
P
from
binding
in
the
CNS.
• PK/PD:
• Watch
for
drug
interactions:
with
CTX
and
other
medications
(e.g.
Warfarin
,
OC)
• 3A4
substrate,
Inhibits
3A4,
Induces
3A4
&
2C9
• Can
be
used
for
acute
and
delayed
CINV,
in
combination
with
a
5-‐HT3
&
SCS.
• Give
PO
1
hour
prior
to
CTX,
give
IV
30
min
prior
TO
CTX.
• Side
Effects:
mild
• Fatigue
• Headache
• Diarrhea
27. 2.
NK-‐1
Receptor
Antagonists
Half-‐
life
Metabolism
Dose
Cost
Aprepitant
(PO)
9-‐13h
3A4
substrate
Inhibits
3A4
Induces
3A4
&
2C9
-‐125mg
Day
1
-‐80mg
on
Day
2
&
Day
3
3
day
regimen
=
$383.99
Fosaprepitant
(IV)
2min
Rapidly
converted
to
Aprepitant
115mg
over
30
minutes,
then
80mg
on
Day
2
&
Day
3
1
vial
(115mg)
=
$223.79
• +Warfarin
(2c9):
Monitor
INR
during
the
7-‐10d
period
after
administration.
• +Oral
Contraceptives:
Decreases
AUC
for
OCs,
therefore
use
alternative
method
of
contraceptive
1
month
after
administration.
28. 3.
Dopamine
Antagonists
• Mechanism
of
Action:
• Block
D2
receptors,
preventing
Dopamine
from
binding
in
the
CNS.
• PK/PD:
• Agent
specific
• Best
used
for
breakthrough
CINV,
as
PRN.
• Side
Effects:
• *Somnolence*
• Monitor
for
EPS
symptoms
(i.e.
dystonia).
• Pay
attention
to
BBWs
(i.e.
with
Olanzapine).
29. 3.
Dopamine
Antagonists
Dose
Cost
Haloperidol
0.5-‐2mg
PO/IV
q4-‐6h
PRN
90
tab
x
1mg
=
$19.99
Metoclopramide
10-‐40mg
PO/IV
q4h
or
q6h
PRN
30
tab
x
5mg
=
$12.99
Olanzapine
2.5mg-‐5mg
PO
BID
30
tab
x
10mg
=
~$500
Prochlorperazine
25mg
suppository
q12h
OR
10mg
PO/IV
q4h
or
q6h
12
Supp
x
25mg
=
$33.99
30
tab
x
5mg
=
$13.99
Promethazine
12.5-‐25mg
PO
or
IV
(via
central
line)
q4h
30
tab
x
12.5mg
=
$15.99
30. Misc.
Agents
4.
Systemic
Corticosteroids:
Main
agent
used
is
Dexamethasone
• Exact
MoA
in
CINV
is
unknown,
but
enhances
efficacy
of
5-‐HT3s
(~20%)
• Have
anti-‐tumor
properties
(used
in
some
regimens,
i.e.
CHOP)
• Useful
for
acute
and
delayed
CINV.
5.
Benzodiazepines:
Main
agent
used
is
Lorazepam
• Used
for
anticipatory
CINV
due
to
anxiety.
• Take
night
before/morning
of.
6.
H2s
&
PPIs:
Used
for
dyspepsia.
31. Misc.
Agents
7.
Cannabinoids:
Dronabinol,
Nabilone
• Used
in
refractory
cases.
• Exact
mechanism
is
not
known,
but
there
are
cannabinoid
receptors
in
the
CTZ
and
VC.
8.
Scopolamine:
• Antagonizes
serotonin
and
histamine.
• Used
in
motion
sickness.
• Patch
is
applied
behind
the
ear.
33. Overview
• Approximately
40%
of
CTX
patients
have
oral
cavity
complications,
and
almost
100%
with
head/neck
radiation.
• GI
tract
complications
are
also
an
issue
as
chemotherapy
and
radiation
affects
gut
flora
and
may
cause
structural
alterations.
• Some
of
the
issues
that
result
are
mucositis,
xerostomia,
infection,
bowel
movement
changes,
and
intestinal
malabsorption.
34. Mucositis
• It
is
the
inflammation
and
ulceration
of
affected
mucosal
membranes.
• Most
often,
non-‐keratinized
mucosa
is
affected
@
basal
layers.
• VERY
PAINFUL…It
feels
like
you’re
swallowing
razors.
• Occur
about
5-‐7d
after
CTX
(cell
turnover
is
7-‐14d),
and
resolves
completely
in
1-‐3
weeks.
• Happens
most
often
with
antimetabolites
(i.e.
methotrexate,
cytarabine)
and
antitumor
antibiotics
35. Mucositis
Presentation:
• Severe
pain,
often
requiring
systemic
opioids.
• Decreased
ability
to
eat,
speak,
swallow.
• Infection
(viral,
bacterial,
or
fungal),
most
often
local.
Treatment:
Palliative
and
Preventative
• Prevention:
• Time
between
CTX
and
Radiation.
• Chlorhexidine
rinses…AVOID
ALCOHOL
rinses
(i.e.
Listerine).
• Cryotherapy:
Ice
chips
in
the
mouth
during
treatment.
• Palifermin:
• A
keratinocyte
growth
factor,
resulting
in
proliferation
of
epithelial
tissue.
• Give
IV
3
consecutive
days
before
myelotoxic
therapy.
• Side
effect:
rash,
edema.
37. Xerostomia
• Damage
to
salivary
glands
leads
to
“dry
mouth”
• Other
effects:
• Lower
salivary
pH
• Decrease
salivary
IgA
• *Altered
sense
of
taste
38. Xerostomia
Treatment:
• Amifostine:
• Preventative
therapy
• Not
for
everyone
due
to
Cost
&
SEs
(N/V,
hypotension).
• Pilocarpine:
• Stimulates
salivary
flow.
• Cholinergic
side
effects.
• Any
other
agents
that
stimulate
salivation
(sugar
free
candy/
gum).
• Why
sugar
free?
• Salivary
substitutes
(MANY…but
Biotene
may
be
familiar).
39. Oral
Complications
• Because
of
all
this,
we
see
increased
infection
(aided
by
neutropenia),
dental
caries
(tooth
decay),
and
decalcification.
• Prevention
of
caries
is
done
through
fluoride
rinses
and
good
dental
hygiene.
• What
about…Osteonecrosis
of
the
jaw?
40. Lower
GI
Complications
• Microvilli
on
intestinal
cells
atrophy
and
function
is
affected.
• Decreased
medication
absorption.
Constipation:
• Vinca
alkaloids
are
known
offenders
(cause
autonomic
nerve
dysfunction)
• Also
a
troubling
side
effect
of
5-‐HT3
antagonists.
41. Lower
GI
Complications
Diarrhea:
• Sometimes
due
to
the
cancer
itself,
often
due
to
medications
(i.e.
5-‐FU,
cytarabine)
• Irinotecan:
SEVERE
diarrhea
&
other
cholinergic
symptoms
• Early
(within
24h,
linked
to
PSNS
stimulation)
and
DELAYED
diarrhea
• Issues:
dehydration,
F&E
imbalances,
other
cholinergic
symptoms
• Treatment:
• F&E
Management
• Early:
Atropine
@
time
of
treatment.
• Delayed:
Loperamide
@
promptly
after
first
episode.
• Octreotide:
somatostatin
analog
which
has
many
effects
but
reduction
in
GI
motility
+
F&E
retention
is
what
we’re
interested
in.
43. Overview
• Cancer-‐
related
fatigue
(CRF)
is
rarely
an
isolated
symptom
and
occurs
with
pain,
distress,
anemia,
and
sleep
disturbances.
• CRF
can
severely
affect
QoL,
which
is
most
of
the
battle,
and
activities
of
daily
living
(ADLs)
44. Causes
• Anemia
• Decreased
RBC
production
&
increased
RBC
destruction
à
net
negative
blood
volume.
• Managed
acutely
with
blood
transfusions
and
chronically
with
epoetin/darbopoetin
alpha.
• Pain
• Nutritional
deficits
• Emotional
distress
45. Management
• Screening
should
be
systematic
and
at
the
start
of
every
visit
(using
a
standardized
assessment
scale).
• Nutritional
consults
• Exercise!
• Limit
naps
to
<1h
to
not
interfere
with
night-‐time
sleep.
• Cognitive
behavioral
therapy.
46. Pharmacologic
Treatment?
• Psychostimulants
can
be
considered,
but
use
remains
investigational.
• Methylphenidate
has
more
evidence
of
benefit
than
modafinil.
• Caffeine?
48. Additional
Resources
Lohr
L.
Nausea
and
Vomiting.
In:
Koda-‐Kimble
MA,
Young
LY,
Alldredge
BK
et
al.,
eds.
Applied
Therapeutics:
The
Clinical
Use
of
Drugs.
9th
ed.
Baltimore:
Lippincott
Williams
&
Wilkins;
2009:
1-‐12.
Falla,
L.
Implications
of
recent
guideline
updates
on
the
management
of
chemotherapy
induced
nausea
and
vomiting.
The
Oncology
Pharmacist.
2o1o;
3(6):
4-‐10.
Ettinger
DS,
Armstrong
DK,
Barbour
S
et
al.
Antiemesis
(Version
1.2012).
NCCN
Guidelines.
2011.
Berger
AM,
Abernethy
PA,
Atkinson
A
et
al.
Cancer-‐Related
Fatigue
(Version
1.2011).
NCCN
Guidelines.
2010.
Worthington
HV,
Clarkson
JE,
Bryan
G
et
al.
Interventions
for
preventing
oral
mucositis
for
patients
with
cancer
receiving
treatment.
Cochrane
database
of
systematic
reviews.
2011;
4:
1-‐275
