Transcript + Dex - Medical Oncology at University of Toronto

All you need to know about
antiemetics for chemotherapy
David Warr
University of Toronto
[email protected]
CINV: 30 Years of Progress
Cisplatin (Highly Emetic)
5-day No emesis:
“AC” Chemotherapy
100%
75%
70%
75%
50% 55%
50%
25%
0%
10%
1980
2000
2005
No Useful Rx
5-HT3 + Dex
Dex 5-HT3 + NK1
Pathophysiology of
Chemotherapy-Induced Emesis
Dexamethasone??
Peripheral – 5-HT3
Central – NK1
MASCC/ESMO Antiemetic
Guidelines 2010
Cisplatin
Mechlorethamine
HIGH
Streptozocin
Cyclophosphamide > 1500 mg/m2
Carmustine
Dacarbazine
MODERATE
Oxaliplatin
Cytarabine > 1000 mg/m2
Carboplatin
Ifosfamide
Cyclophosphamide < 1500 mg/m2
Azacitidine
Alemtuzumab
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Irinotecan
Bendamustine
Clofarabine
MASCC/ESMO Antiemetic
Guidelines 2010
LOW
Paclitaxel
Mitomycin
Docetaxel
Gemcitabine
Mitoxantrone
Cytarabine < 1000 mg/m2
Topotecan
5-Fluorouracil
Etoposide
Bortezomib
Pemetrexed
Cetuximab
Methotrexate
Trastuzumab
Doxorubicin HCL liposome injection
Catumaxomab
Temsirolimus
Panitumumab
Ixabepilone
SUMMARY ACUTE NAUSEA
AND VOMITING
EMETIC RISK GROUP
High
5HT3
5HT3 +
Anthracycline +
Cyclophosphamide (AC)
Moderate (other than AC)
Low
Minimal
5HT3 = serotonin receptor antagonist
ANTIEMETICS
5HT3
5HT3 +
+
DEX
+
+
DEX
+
DEX
+
DEX
+
APR
APR
APR
APR
PALO + DEX
PALO + DEX
DEX
DEX
No routine prophylaxis
DEX = DEXAMETHASONE
APR= APREPITANT
The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer.
Ann Oncol 2010; www.mascc.org.
PALO = PALONOSETRON
SUMMARY DELAYED NAUSEA
AND VOMITING
EMETIC RISK GROUP
High
ANTIEMETICS
5HT3
Anthracycline +
Cyclophosphamide (AC)
Moderate (other than AC)
Low
DEX + APR
+ DEX + APR
APR
5HT3 + DEX +
APR
(IF risk of delayed emesis)
DEX
PALO + DEX
No routine prophylaxis
DEX
No routine prophylaxis
Minimal
DEX = DEXAMETHASONE
APR= APREPITANT
The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer.
Ann Oncol 2010; www.mascc.org.
Problems with the guidelines
• Reflect the risk of vomiting if NO antiemetics
were given. What you want to know is often the
residual risk of vomiting after dex or after dex +
a ‘setron
• E.g. Oxaliplatin and carboplatin are both
“moderately emetogenic” yet the risk of emesis
after dex plus ondansetron is <10% for oxali but
30% for carboplatin.
• For oxali, the use of aprepitant front line makes
no sense but reasonable for carboplatin
Problems with the guidelines
• The anticancer drugs listed include MoAbs.
• #1 Most of the “emesis” was probably not
drug related
• #2 There is no info to suggest that the
mechanism of emesis is the same as for
chemo
Problems with the guidelines
• For AC chemotherapy, dexamethasone is no
longer recommended beyond 24 hours simply
because the design of the study with aprepitant
did not include corticosteroids
• The suggestions for PRN antiemetics are
based upon tradition, not data from randomized
trials
Dexamethasone for > 24
hours?
• High dose cisplatin
• “AC” type chemotherapy
• The rest
Corticosteroids for delayed emesis
Kris J Clin Oncol 1989
• A double blind randomized trial in 91 lung cancer
patients who received cisplatin 120 mg/m2
• All received dexamethasone 20 mg IV plus
metoclopramide (MCP) 3 mg/kg x 2 doses plus
• Placebo OR
• Dexamethasone for 4 days OR
• Dexamethasone + MCP 0.5 mg/kg qid x 4 days
Incidence of delayed emesis
(day 2-5)
X2 Test for trend P=0.006
Kris J Clin Oncol 1989
Olver Annals of Oncology 1996
No Emesis day 1-6
(N = 604 with cisplatin > 70 mg/m2)
P< 0.05 for both comparisons
Note: Ondansetron was NOT better than placebo
IGAR Anticancer Drugs 1999
No Emesis day 1-3
(N = 532 with cisplatin )
100
P< 0.01
78.9
80
60
58
40
20
0
Gran
Dex + Gran
Is Dexamethasone necessary with
palonosetron?
Celio et al Support Care Cancer (in press)
• Randomized trial in 332 patients receiving
moderately emetogenic chemotherapy
• Not blinded
• Palonosetron 0.25 mg + Dex 8 mg on day 1
• Dex 8 mg PO on day 2-3 or nothing
• Concluded that a single dose of
dexamethasone was “non-inferior” to 3 days
of dexamethasone (67.5% vs 71.1%)
What didn’t appear in the abstract
• Only 1/3 of the chemotherapy administered
was “AC” based (the only MEC chemotherapy
for which dexamethasone in the delayed
phase has been unequivocally
recommended)
• In the AC group, the difference was 12.8%!
(P=0.02)
• Correct conclusion: dexamethasone in the
delayed phase may be unnecessary with
oxaliplatin or carboplatin
What didn’t appear in the abstract
• Another similarly designed study came to the
same “no difference” conclusion but did not
describe the kind of chemotherapy that was
given except to say that it was for breast
cancer! Aapro Ann Oncol 2010
• There is no evidence with cisplatin which has
the biggest problem with delayed emesis
• At this time the evidence does not support
limiting the dexamethasone to day 1 only
Optimizing 5-HT3 RA use
• Originally ondansetron was prescribed for 5
days
• 10 clinical trials examined the value of
‘setrons beyond the first 24 hours
• A meta-analysis of those trials has changed
our belief about the importance of serotonin
beyond day 1
Trials to evaluate the use of a
5-HT3 RA beyond 24 hours
• All were double blind, randomized
• All patients received a 5-HT3 RA +
dexamethasone in the first 24 hours
Type # 1:
• 5HT3 RA versus placebo beyond 24 hours
Type #2
• 5-HT3 RA + Dex versus placebo + Dex beyond 24
hrs
Absolute Reduction in Emesis Using
a 5-HT3 RA Beyond Day1
•
•
•
•
5-HT3/placebo only
5-HT3/placebo + steroid
5 Trials
N = 1716
Abs decrease = 8.2%
95% CI = 3 to13%
•
•
•
•
5 trials
N = 1754
Abs decrease = 2.6%
95% CI = - 0.6 to 6%
Conclusion: not cost effective beyond 24 hours
($12,877 US/patient protected from delayed emesis)
Adapted from Geling J Clin Oncol 2005: 23:1289-94
Aprepitant (Emend®)
• An NK1 receptor antagonist (the only one)
• Binds very tightly to the NK1 receptor in the brain
(where substance P binds)
• Its only known application is as an antiemetic
although there are recent case series of its
efficacy for pruritus (itching)
• Available as a 3 day package (125/80/80 mg) but
a single injection of 150 mg is equivalent Grunberg
ASCO 2010
When is aprepitant standard?
• Guidelines consistent for cisplatin – it should be
part of standard therapy
• 4 phase III studies with high dose cisplatin show
~ 20% absolute improvement in rate of emesis
Warr Eur J Ca 2005; Schmoll Ann Oncol 2006. Takahashi Cancer
Sci 2010
• Adverse events similar to placebo
• The best evidence for many physicians has been
personal experience but the following trials
illustrate why personal experience has been
positive
Antiemetic regimens: Cisplatin
Aprepitant
125 mg PO
Regimen with
aprepitant
Aprepitant
80 mg PO qd
Ondansetron
32 mg IV
Dexamethasone
12 mg PO
Active control
Dexamethasone
8 mg PO qd
Ondansetron
32 mg IV
Dexamethasone
20 mg PO
Day 1
Dexamethasone
8 mg PO bid
Day 2
Day 3
Day 4
Hesketh J Clin Oncol 2003;21:4112-9; Poli-Bigelli Cancer 2003;97:3090-8
Pivotal Phase III Cisplatin Studies
n= 1043
P < .001
P < .001
Std
Aprep
N. America, Europe, Australia,Taiwan
Hesketh J Clin Oncol 2003
S. America
Polli-Bigelli Cancer 2003
Is there a low risk group?
• Many physicians say “MY patients do better.
They must be at lower risk”
• Being older, male, drinking alcohol regularly,
lower cisplatin dose are all associated with a
lower risk of emesis
• Is there a group that does so well with
ondansetron and dexamethasone alone that
aprepitant is unnecessary?
% With Complete Response
Complete response rate: gender
100
∆=25.6%
(P<0.0001)
∆=16.0%
(P<0.0001)
80
68.9%
66.2%
60
52.9%
40.6%
40
20
n=216
n=219
n=306
n=306
0
Female
Male
Regimen with aprepitant
Active control
Hesketh Support Care Cancer 2010
Complete response: alcohol
% With Complete Response
100
∆=18.4%
(P=0.016)
∆=19.9%
(P=0.017)
79.5%
80
65.6%
61.1%
60
45.7%
40
20
0
n=442
n=451
Light/Nondrinker
n=78
n=72
Drinker
a
Regimen with aprepitant
Active control
Light/nondrinker < 5 drinks/week.
Hesketh Support Care Cancer 2010
Complete response: age
% With Complete Response
100
∆=18.6%
(P<0.0001)
∆=22.0%
(P<0.0001)
76.1%
80
63.9%
60
54.1%
45.3%
40
20
0
n=357
n=375
n=163
<65 years
n=148
≥65 years
Regimen with aprepitant
Active control
Hesketh Support Care Cancer 2010
Complete response: cisplatin dose
∆=22.8%
(P<0.0001)
n=180
n=175
∆=18.6%
(P<0.0001)
n=340
n=348
Hesketh Support Care Cancer 2010
When is aprepitant standard?
• Guidelines consistent for “AC” in women- it
should be part of standard therapy
• 2 phase III trials show 15-17% improvement
in rate of emesis Warr J Clin Oncol 2005, Rapoport
Support Care Cancer 2009
• Unable to identify low risk group in women
who received ondansetron plus
dexamethasone Warr Support Care Cancer 2010_
Prognostic factors for no emesis
in multivariate analysis (n=866)
• Aprepitant use
p<0.0001
• Age (≥55 years)
p=0.006
• Alcohol use (≥5 drinks week)
p=0.005
• No vomiting during pregnancy
p=0.0007
• No motion sickness tendency
p= ns
Adapted from Warr Support Care Ca 2010
% No emesis (0-120 hrs)
Prognostic Factors in AC (n=866)
Dex, OND, Aprepitant
Dex, OND
100
??
87.5
80
63.4
66.4
60
40
38.6
20
0
3
2
1
0
Number of high risk factors
% of Total
22
48
27
Adapted from Warr Support Care Ca 2010
3
Does all “AC” require aprepitant?
• NOT necessarily
• Palonosetron prevented emesis in 86% of 86
patients receiving CHOP Di Renzo Support Care
Cancer 2010
• Lower anthracycline dose, 50% male, older,
better 5-HT3 RA, ? alcohol (Italian)
• CHOP may constitute an “AC” that does not
warrant use of aprepitant
Summary
• Major advances in the control of emesis
sometimes are not realized in clinics because
optimal therapy is not used
• Corticosteroids play an important role in the first
24 hours and beyond
• Administering ‘setrons beyond the first 24 hours
is not usually beneficial
• The evidence suggests that palonosetron is a
superior 5-HT3 RA for high dose cisplatin as well
as other chemotherapy
Summary
• Aprepitant is from a completely different drug
class with no side effect that is clearly different
from placebo
• Prognostic factors have not been helpful in
selecting “low risk” patients receiving cisplatin
• There is a 20% improvement in control of emesis
with the addition of aprepitant
• MASCC-ESMO, ASCO and NCCN guidelines
recommend aprepitant as part of standard
antiemetic therapy for cisplatin
A final thought
• When it comes to supportive care, please
treat your patients as you would wish to be
treated in the same situation
What are the results for the
“toughest” chemo?
• The most widely studied chemotherapy is
high dose cisplatin and “AC” chemotherapy in
women
• Several large double blind results evaluating
a triple combination (aprepitant, corticosteroid
and 5-HT3 RA) vs a doublet (corticosteroid, 5HT3 RA)
Is there still a problem?
• “Best practice” not always followed (article in
press). Can’t predict the 25% who won’t do well
• Nausea is more challenging to prevent than
vomiting but as distressing
• There are few randomized trials that tell us
what to do with those who have problems
despite best practice
CINV: 30 Years of Progress
Cisplatin (Highly Emetic)
5-day No emesis:
“AC” Chemotherapy
100%
75%
70%
75%
50% 55%
50%
25%
0%
50% 30%
No nausea
10%
1980
2000
2005
No Useful Rx
5-HT3 + Dex
Dex 5-HT3 + NK1
Can you predict the problem based
upon patient characteristics?
• Several studies established that young age,
female gender, low alcohol intake and higher
cisplatin dose are associated with greater risk
of emesis
• Can we select a low risk group for which a
‘setron and corticosteroid are adequate?
Unfortunately not
• Re-analyzing the pivotal aprepitant trials with
high dose cisplain, there was no group that
had a >60% control of emesis with
ondansetron and dexamethasone alone Hesketh
Support Care Cancer 2010
Unfortunately not
• In breast cancer patients receiving “AC” for
chemotherapy, a “low risk” group was
identified in the 866 patients randomized to
ondansetron and dexamethasone +
aprepitant/placebo Warr Support Care Cancer 2010
• The low risk group constituted only 3% of the
entire patient population so was not useful
What other options exist?
• One small RCT suggested benefit from
switching from ondansetron to granisetron if
problems with cycle 1 De Wit Br J Cancer 2001
• Two phase II studies and one phase III study
suggest that olanzapine has pronounced
antiemetic activity Navari Support Care Cancer 2005 &
2007, Tan J Exp Clin Cancer Res 2009
• Ginger reported to have an antiemetic activity
Ryan ASCO 2009 but effect size VERY small
What other options exist?
• Acupressure NS effective for CINV Roscoe J Pain
Symptom Manage 2003 and acupuncture not well
tested in the modern era
• Cannabinoids not properly tested, toxicity
issues for some and stigma
Summary
• For emetogenic chemotherapy, enormous
progress has been made IF one uses the
most effective agents
• There are still patients who have poorly
controlled emesis. Patient characteristics
have not been helpful in defining who is at
risk.
• There is no consensus on how to treat these
patients
Summary
• Thus far non traditional approaches (ginger,
acupuncture/acupressure) have not been
established as effective
• Be aware of other causes. Anecdotally, the
heartburn/nausea combination does respond
to proton pump inhibitors