Transcript Chemotherapy-Induced Nausea and Vomiting (CINV)

Innovation ● Investigation ● Application
Chemotherapy Induced Nausea
and Vomiting (CINV)
Causes, Challenges, Evaluation and
Optimizing Clinical Management
Program Co-Chairman
Lee S. Schwartzberg, MD, FACP
Medical Director, The West Clinic
Supportive Oncology Services
President, Accelerated Community
Oncology Research Network
Memphis, TN
Chemotherapy Experienced Patients
Rank Severe CINV Near Death
1.00
0.90
Moderate Delayed Nausea
Poorly Controlled
Acute & Delayed CINV
0.80
Median VAS Scores
0.70
0.60
0.50
0.40
Complete
Control
0.30
0.20
0.10
0.00
Sun C et al. Support Care Cancer. 2005
Death
Mucositis
Emetogenic Potential of Single
Antineoplastic Agents
HIGH
Risk in nearly all patients (> 90%)
MODERATE
Risk in 30% to 90% of patients
LOW
Risk in 10% to 30% of patients
MINIMAL
Fewer than 10% at risk
Patient-Specific Risk Factors for CINV
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Age <50 years
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Women > men
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History of light alcohol use
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History of vomiting with prior exposure
to chemotherapeutic agents
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Other risks
● History of motion sickness
● History of nausea or vomiting during pregnancy
● History of anxiety
ASHP. Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. Drugs. 1997:54:273-298.
Types of CINV: Definitions
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Acute (post-treatment)
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Delayed
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●
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Learned or conditioned response from poorly controlled
nausea and vomiting associated with previous chemotherapy
Breakthrough
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CINV that begins after first 24 hours
May last for 120 hours
Anticipatory
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Occurs within first 24 hours after administration of cancer
chemotherapy
CINV that occurs despite prophylaxis and requires rescue
Refractory
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Occurs during subsequent treatment cycles when prophylaxis
and/or rescue has failed in previous cycles
Pathophysiology of
Chemotherapy-Induced Emesis
Chemotherapy-Induced Emesis:
Key Treatment Milestones
Aprepitant, March 2003
Palonosetron July, 2003
Pharmacologic Agents
► Corticosteroids
► Dopamine
► Serotonin
► NK-1
antagonists
(5-HT3) antagonists
receptor antagonists
► Cannabinoids
1st Generation 5HT3 RAs
Are Therapeutically Equivalent
• Highest Level Evidence &
Not Debated
• 1st Generation Agents are
Therapeutically Equivalent
• Dolasetron
• Ondansetron
• Granisetron
•
1st
Generation oral and IV
doses equally effective
Perez et al. J Clin Oncol 1998;16:754
Complete Control (%)
• MASCC 2004
• NCCN 2009
• ASCO 2006
Pts receiving MEC* (N=1,085)
Oral granisetron 2 mg
IV ondansetron 32 mg
59.0 58.0
60.0 58.0
Total
Nausea
71.0 72.0
Emesis
80% of pts received prophylactic steroids
*Cyclophosphamide 500 - 1200 mg/m2, carboplatin
≥300 mg/m2
Palonosetron
►
►
►
►
Second generation 5-HT3 antagonist
Pharmacologic differences from older 5-HT3 antagonists
● prolonged half-life (~40 hours)
● enhanced receptor binding affinity (30-fold)
FDA approved
● IV formulation
July 25, 2003
● Oral formulation August 22, 2008
Regimens
● IV 0.25 mg pre chemotherapy
acute/delayed HEC/MEC
● PO 0.50 mg pre chemotherapy
acute MEC
Palonosetron vs. 1st gen HT-3RA:
Complete Response on Day of Chemo & Beyond
Palonosetron 0.25 mg (n=378)
Ondansetron/Dolasetron 32/100 mg (n=376)
Complete Response (CR)
(% of Patients)
100
80
*
72.0
60.6
*
64.0
*
57.7
60
46.8
42.0
40
20
0
Acute: 0-24
(Day 1)
Delayed: 24-120
(Days 2-5)
Overall: 0-120
(Days 1-5)
Time (hr)
CR = no emetic episodes or use of rescue medications
*p<0.025 for pairwise difference (2-sided Fisher’s exact test) between palonosetron and ondansetron/dolasetron.
Gralla R et al. Ann Oncol. 2003; Eisenberg P et al. Cancer. 2003.
Rubenstein EB et al. Proc Am Soc Clin Oncol. 2003. Abstract 2932.
Palonosetron vs Ondansetron
High Emetic Risk Chemotherapy
Patients Also Receiving Dexamethasone
N=447
(67%)
*
p < 0.05
Aapro M Support Care Cancer 2003:11:391
*
Phase III Trial of IV Palonosetron vs. IV Granisetron
with Cisplatin or AC-Based Chemotherapy
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1114 patients
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Cisplatin (57%) or anthracycline/cyclophosphamide (43%)
Single 0.75 mg dose of palo vs. single 40 μg/kg dose of
granisetron
Dexamethasone 16 mg d1; 4mg/d d 2-3 (AC/EC);
►
►
►
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8mg/d d 2-3 CDDP
Objective: demonstrate non-inferiority d1
and superiority d 2-5 of palo
Primary endpoint complete response (no emesis/no rescue)
Saito M et al. Lancet Oncol. 2009;10(2):115-24
Phase III Trial Palonosetron vs. Granisetron
both with Dexamethasone in HEC
Palo+ Dex
(n=555)
%
Grani+ Dex
(n=558)
%
P
Complete Response,
Acute (0-24h)
CR, Delayed (24-120h)
73.7
72.1
ND
53.0
42.4
0.0003
CR, Overall (0-120h)
No Nausea:
0-120 hours
No Emesis:
0-120 hours
47.9
32
38.1
25
0.0007
0.01
58
49
0.006
Saito M et al. Lancet Oncol. 2009;10(2):115-24
Palonosetron: 5-HT3 Antagonist of Choice?
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Palonosetron is a 5-HT3 antagonist with strong receptor binding affinity
and an extended half-life
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In 2 MEC trials, IV palonosetron (single dose) was superior to dolasetron
and ondansetron (single dose) in the prevention of acute and delayed
emesis in a post-hoc analysis
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In 1 HEC trial, emetic control was comparable between IV palonosetron
and ondansetron; better control with palonosetron in the subset receiving
dexamethasone
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In large phase III trial with cisplatin or AC, palonosetron was equivalent to
granisetron in acute control and superior during the delayed phase
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Comparable tolerability
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Ease of use and trends towards superiority favor palonosetron as the
preferred 5-HT3 antagonist
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Definitive proof of superiority to first generation 5-HT3 antagonists would
require trials with control arms utilizing corticosteroids, NK1 antagonists
and repetitive dosing of the first generation agents
Aprepitant
►
Selective antagonist of the binding of Substance P to the
neurokinin 1 (NK1) receptor
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FDA approved
● Oral formulation: March 26, 2003
● IV formulation (fosaprepitant): January 31, 2008
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Regimen
● 125 mg PO day 1, 80 mg PO days 2-3
acute/delayed HEC/MEC
● 115 mg IV day 1, 80 mg PO days 2-3
acute/delayed HEC/MEC
Aprepitant Randomized Trial:
Patients Receiving AC
Group
Day 1
O
D
Days 2-3
A
Aprepitant
(n = 438)
8 mg
BID
12 mg 125 mg
Standard
(n = 428)
8 mg
BID
20 mg
P
0
A
P
80 mg
8 mg
BID
O = ondansetron PO
A = aprepitant PO
D = dexamethasone PO
P = placebo PO
Warr DG et al. J Clin Oncol 2005; 23:2822-2830
P
Complete Response (CR)
(% of Patients)
Aprepitant in Anthracycline/Cyclophosphamide
Chemotherapy: Complete Response (N=857)
Aprepitant (n=433)
Standard (n=424)
100
80
*
76
69
55
60
49
*
51
42
40
20
0
Acute: 0-24
(Day 1)
Delayed: 24-120
(Days 2-5)
*p<0.05
Time (hr)
Complete response (CR): no emesis and no rescue medication.
Warr DG et al. J Clin Oncol 2005; 23:2822-2830
Overall: 0-120
(Days 1-5)
Aprepitant in Moderately Emetogenic
Chemotherapy: Percent of Patients with No Emesis
100
Emesis-Free
(% of Patients)
80
*
Aprepitant (n=433)
Standard (n=424)
*
88
*
81
77
76
69
59
60
40
20
0
Acute: 0-24
(Day 1)
*p<0.001
Delayed: 24-120
(Days 2-5)
Time (hr)
Warr DG et al. J Clin Oncol 2005; 23:2822-2830
Overall: 0-120
(Days 1-5)
Aprepitant in Moderately Emetogenic Chemotherapy:
Percent of Patients with No Nausea
Aprepitant (n=430)
Standard (n=424)
100
Nausea-Free
(% of Patients)
80
61
60
59
37
40
36
33
33
20
0
Acute: 0-24
(Day 1)
Delayed: 24-120
(Days 2-5)
Overall: 0-120
(Days 1-5)
Time (hr)
No nausea: score <5 mm on 0-100 mm VAS.
Warr DG et al. J Clin Oncol 2005; 23:2822-2830; Warr DG et al. Support Care Cancer. 2004. Abstract A027.
Phase III Aprepitant Study (801):
Multiple-day Ondansetron
•Initial cycle cisplatin > 70 mg/m2
•445 patients
Group
Day 1
Days 2-3
O D
A
Aprepitant
32
12
125
Control
32
20
P
O
Day 4
D
A
O
P
8
80
P
8
16
16
P
16
16
O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo
Schmoll et al: Ann Oncol 17:1000-6, 2006
D
Phase III Aprepitant Study (801):
Multiple-day Ondansetron
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Identical design to Protocols 052 and 054 except
ondansetron dosed days 1-4
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Primary endpoint: complete response on days 1 - 5
after cisplatin
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Aprepitant regimen superior to control regimen of
protracted ondansetron and dexamethasone dosing,
CR 72% vs. 61% respectively
Schmoll et al: Ann Oncol 17:1000-6, 2006
Palonosetron + Aprepitant + Dexamethasone
Phase II Study Design
• Multicenter, phase II, open-label study
• Naïve and non-naïve patients receiving moderately to moderatelyhighly emetogenic chemotherapy
• Treatment:
Day 1
PALO
D
Days 2-3
A
D
0.25 mg 12 mg 125 mg
PALO = palonosetron IV
8 mg
A
80 mg
A = aprepitant PO
D = dexamethasone PO
Grote T et al. Proc Am Soc Clin Oncol. 2004. Abstract 8262.
Palonosetron + Aprepitant + Dexamethasone
Complete Response (ITT, N=58)
Complete Response (CR)
(% of Patients)
100
87.9
80
77.6
77.6
Delayed: 24-120
(Days 2-5)
Overall: 0-120
(Days 1-5)
60
40
20
0
Acute: 0-24
(Day 1)
Time (hr)
Grote T et al. Proc ASCO 2004. Abstract 8262
Perception vs Reality:
Emetogenic Chemotherapy
Highly Emetogenic Chemotherapy
Grunberg S. Cancer. 2004;100:2261-2268.
Moderately Emetogenic Chemotherapy
% of Pts w/ Delayed CINV
Despite Compliance w/ Guidelines Problems
Remain: Better Antiemetics Needed
100
90
80
After Adjustment For Prognostic
Factors For Delayed CINV
•Age
•Gender
•Emetogenic Potential
•Presence of Acute CINV
70
60
50
40
30
20
10
0
Noncompliance w/ Guidelines
Compliance w/ Guidelines
Even when physicians follow guidelines (using 1st generation 5HT3
RAs), 50% of pts experience delayed CINV
DeMoor C et al. Proc Am Soc Clin Oncol. 2003. Abstract 2924.
Relationship Between Acute CINV and
Delayed CINV: Questions
►
Is acute CINV a strong predictive factor for delayed
CINV in patients receiving moderately emetogenic
chemotherapy?
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Is prevention of delayed CINV a carryover effect
from prevention of acute CINV or a true
pharmacologic effect during the delayed phase?
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What is the difference in the treatment effect of the
first-generation 5-HT3 receptor antagonists vs
palonosetron in preventing delayed CINV after
accounting for known prognostic factors, including
the carryover effect?
Grunberg SM et al. Proc Am Soc Clin Oncol. 2004. Abstract 8051.
Protection From Delayed CINV:
All Patients
75
80
No Delayed CINV
(% of Patients)
70
60
50
40
30
20
17
10
0
With Acute CINV
(n=254)
Grunberg SM et al. Proc Am Soc Clin Oncol. 2004. Abstract 8051.
Without Acute CINV
(n=500)
Protection From Acute and Delayed CINV:
Palonosetron vs Ondansetron/Dolasetron
Protection From Delayed CINV
(n/n with No Acute CINV)
Protection From
Acute CINV
PALO 0.25 mg
OND 32 mg/
DOL 100 mg
Yes
(218/272)
80% *
(158/228)
69%
No
(24/106)
23% †
(18/148)
12%
*p=0.005 for palonosetron vs ondansetron/dolasetron.
†p=0.027 for palonosetron vs ondansetron/dolasetron.
Grunberg SM et al. Proc Am Soc Clin Oncol. 2004. Abstract 8051.
Are Oral Followup 5-HT3 RAs
Really Effective for Delayed CINV?
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671 pts receiving doxorubicin-based chemotherapy
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all treated w/ 1st generation 5HT3 + Dex on Day 1 of CT
Pts then randomized for days 2 and 3:
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Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h)
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Arm 2: Any oral 5-HT3 antiemetic, using standard dosing
regimens
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Arm 3: Prochlorperazine 10 mg p.o. as needed for nausea
Rescue medications for control of symptoms were
allowed
Hickock et al ASCO 2005 Final Results URCC-CCOP
1st Generation Oral 5HT3 RAs:
Majority of Patients Experience Nausea
100
90
80
70
60
50
40
30
20
10
83
75
87
Prochlorperazine q 8h*
5HT3*
Prochlorperazine PRN*
* p = 0.002 (overall comparison); p = 0.06 (Prochlorperazine q 8 h vs 5-HT3 );
p = NS (Prochlorperazine prn vs 5-HT3 )
• Patients randomized for days 2 and 3; rescue medications allowed
•
Hickock et al ASCO 2005 Final Results URCC-CCOP
1st Generation Oral 5HT3 RAs
Not Effective for Delayed CINV
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Vomiting
●
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Significantly more patients vomited at least once during
the delayed period (34%) than on the day of treatment
(19%) p <0.01
Nausea
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Nausea severity was significantly greater during the
delayed period than on the day of treatment p < 0.01
●
More patients getting oral 5HT3 RAs required rescue
medications (45%) than patients getting Compazine®
(27-30%) p=0.002
Hickock et al ASCO 2005 Final Results URCC-CCOP
Meta-Analysis of Efficacy of 5-HT3RA in Prevention
of Delayed Emesis from Chemotherapy
Reviewed 5 studies, 1,716 pts comparing 5-HT3 RA to placebo,
5 studies, 2,240 pts comparing 5-HT3 RA + dexamethasone to
dexamethasone alone
5-HT3 RA as monotherapy
Absolute RR (95% CI)
NNT 12.2
8.2% (3.0-13.4)
Number of doses per protected pt: 74.4
5-HT3 RA as adjunct to dexamethasone
Absolute RR (95% CI)
NNT 38.8
2.6% (-0.6-5.8)
Number of doses per protected pt: 423
Geling and Eichler, JCO 23:1289-1294
ASCO 2006/NCCN 2009 Recommendations
by Risk Category
High (>90% emetic risk)
Including AC containing regimens
Three-drug combination of a HT3
serotonin receptor antagonist,
(palonosetron preferred-NCCN)
dexamethasone, and aprepitant
Moderate (>30% to 90% emetic
risk)
Two-drug combination of a HT3
serotonin receptor antagonist and
dexamethasone (+/-aprepitant for
selected patients)
Low (10% to 30% emetic risk)
Dexamethasone 8-12 mg
Minimal (<10% emetic risk
No antiemetic routinely
How Can We Improve the Value of
Care in CINV?
Value = Quality Cost
• Direct
• Indirect
 CR
 Nausea or Emesis  Functioning
 Side Effects
 Compliance or  Patient
Inconvenience
 Access to Care
Summary
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1st generation 5HT3 RA’s therapeutically equivalent & major
advance in supportive care for control of acute emesis
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No major progress in CINV for ~ 10+ yrs until aprepitant &
palonosetron
►
Treatment guidelines have changed
●
●
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Degree of nausea incurred has been refined for many agents
Delayed CINV recommendations are updated
Prevention of CINV has improved, but challenges remain
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●
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Improving detection of CINV, especially after 24 hours
Educating patients and oncology healthcare givers
The development and evaluation of clinically useful
assessment tools
Further development of regimens to treat delayed CINV