prevention of chemotherapy induced nausea and vomiting … · emetogenic chemotherapy gralla rj et...
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PREVENTION OF CHEMOTHERAPY INDUCED NAUSEA AND VOMITING IN ELDERLY CANCER PATIENTS
JØRN HERRSTEDT, M.D.COPENHAGEN UNIVERSITY HOSPITAL
HERLEV, DENMARK
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HISTORY OF ANTIEMETICS1979 A corticosteroid is superior to placebo.1981 High-dose metoclopramide (hd-MCP) is effective.
1984 A corticosteroid improves effect of hd-MCP.
1987 First clinical trial with a serotonin receptor antagonist (5-HT3-RA).
1991 A corticosteroid improves the effect of 5-HT3-RAs (HEC).
1993 A dopamine antagonist improves the effect of a 5-HT3-RA.
1995 A corticosteroid improves the effect of 5-HT3-RAs (MEC).
1997 First clinical trial with a neurokinin1-receptor antagonist (NK1-RA).
2003 NK1-RA improves effect of 5-HT3-RA plus corticosteroid (HEC).
2005 NK1-RA improves effect of 5-HT3-RA plus corticosteroid (MEC).
THE OLD ERA
THE SEROTONIN ERA
THE NEW ERA
Baker et al., NEJM 1979. Gralla et al., NEJM 1981. Allan et al., BMJ 1984. Leibundgut & Lancranjan, The Lancet 1987. Roila et al., JCO 1991. Herrstedt et al., NEJM 1993. IGAR, NEJM 1995. Kris et al., JNCI 1997. Hesketh et al., JCO 2003. Poli-Bigelli et al., Cancer 2003. Warr et al., JCO 2005.
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5-HT3-receptor antagonists5-HT3-receptor antagonists• Azasetron Y-25130• Batanopride BMY-25801• Bemesetron MDL 72222• Dazopride AHR-5531• Dolasetron MDL 73,147EF AnzemetR
• Eusetron RG 12915• Granisetron BRL 43694 KytrilR• Itasetron DAU 6215• Lerisetron F-0930• Ondansetron GR 38032 ZofranR
• Palonosetron RS 25259-197 AloxiR• Pancopride LAS 30451• Ramosetron YM060• Renzapride BRL 24924• Tropisetron ICS 205-930 NavobanR
• Zacopride AHR-111906• Zatosetron LY 277359
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Palonosetron vs Ondansetron in Patients Receiving Moderately
Emetogenic Chemotherapy
Gralla RJ et al. Palonosetron Improves Prevention of Chemotherapy-induced Nausea and Vomiting Following Moderately Emetogenic Chemotherapy: Results of a Double-blind Randomized Phase III Trial Comparing Single Doses of Palonosetron with Ondansetron. Ann Oncol 2003;14:1570-1577.
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Complete Response Acute and Delayed Emesis
50.3%69.3%*Overall (0-120 h)
55.1%74.1%*Delayed (24-120 h)
68.6%81.0%*Acute (0-24 h)
Ondansetron32 mg
(n=185)
Palonosetron0.25 mg(n=189)
*97.5% CIs and two-sided Fisher’s exact test (significance level = 0.025) indicate a difference between palonosetron and ondansetron.
Complete Response (CR) = no emesis, no rescue medication.
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NK1-receptor antagonists• CI-1021*• CJ 11,974 Ezlopitant• CP 99,994• CP 122,721• FK 888• GR 203040• GR 205171 Vofopitant• GW 597599• GW 679769 Casopitant• HSP-117• L-741671• L-743310• L-754,030 Aprepitant EmendR
• L-758,298***• LY306740**• NKP-608**• RP-67580• RPR-100893** Dapitant• SR-140333** Nolpitantium
* Previously PD-154075; ** Not investigated as an antiemetic; *** Prodrug to L-754030
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HIGH EMETIC RISK CHEMOTHERAPY (HEC)
Hesketh PJ et al. J Clin Oncol 2003;21:4112-19.Poli-Bigelli S et al. Cancer 2003;97:3090-98. Schmoll HJ et al. Ann Oncol 2006;17:1000-1006.
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HEC - Aprepitant Phase III TrialsTreatment Groups (n = 1099)
Day 4Day 1 Days 2-3
APR
CONT
DO D A D A 8 + P8012 125 8 + P32
8 x 2 8 x 2P32 20 P
O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo
1. Hesketh PJ et al. JCO 2003;21:4112-19. 2. Poli-Bigelli S et al. Cancer 2003;97:3090-98.
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HEC - Aprepitant Phase III TrialTreatment Groups (n = 489)
Day 4Day 1 Days 2-3DO D A D AO O
12 125 P x 2 80 P x 232APR 8 + P 8 + P
CONT P32 20 8 x 2 8 x 2 8 x 2 8 x 2P
O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo
Schmoll HJ et al. Ann Oncol 2006;17:1000-1006.
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HEC Studies: Cycle 1Primary Endpoint: Complete Response (0-120 h)
73% 72%
63% 61%
43%
52%
0102030405060708090
100
Hesketh Poli-Bigelli Schmoll
p<0.001 p<0.001 p=0.003
Perc
enta
ge o
f Pat
ient
s
Aprepitant Regimen Standard Regimen
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MODERATE EMETIC RISKCHEMOTHERAPY (MEC)
Warr DG et al. J Clin Oncol 2005;23:2822-2830.
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Treatment Groups (n = 866)
Day 1 Days 2-3
MEC - Aprepitant Phase III Trial
OND DEX APR OND APR
APR Placebo8 mg x 2 12 mg 125 mg 80 mg
CONT 8 mg x 28 mg x 2 20 mg Placebo Placebo
OND = ondansetron p.o. Anthracycline plusDEX = dexamethasone p.o. CyclophosphamideAPR = aprepitant p.o.
CONT = placebo-controlled arm
Warr DG et al. J Clin Oncol 2005;23:2822-2830.
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MEC Study: Cycle 1Primary Endpoint: Complete Response (0-120 h)
Aprepitant Regimen (N=433)Standard Regimen (N=424)
0
10
20
30
40
50
60
70
80
90
100
51%
Perc
enta
ge o
f Pat
ient
s
p=0.015
Complete Response (CR)
p<0.001
76% p=ns
59% 59% 56%
42%
No Vomiting No Rescue Therapy
Components of CR
Warr DG et al. J Clin Oncol 2005;23:2822-2830.
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MULTIPLE CYCLES OF MODERATE EMETIC RISK CHEMOTHERAPY (MEC)
Herrstedt J et al. Cancer 2005;104:1548-1555.
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Sustained No Vomiting Rate
76%70%
67%63%
59%
Aprepitant RegimenStandard Regimen
Number at Risk:
Aprepitant Regimen 432 296 258 234
Standard Regimen 424 224 168 139
1 2 3 4Time (Cycle) since First Chemotherapy
0
Perc
enta
ge o
f Pat
ient
s
20
40
80
60
Log-rank test, p<0.001
48%42%
39%
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GUIDELINES ON ANTIEMETICS
MASCCASCOESMOASHPNCCNCCO
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No routine prophylaxisMinimal
Dexamethasone Low
Serotonin antagonist + dexamethasone
Moderate (other than AC)
Serotonin antagonist + dexamethasone + aprepitant
Anthracycline + Cyclophosphamide (AC)
Serotonin antagonist + dexamethasone + aprepitant
High AntiemeticsEmetic risk group
Prophylaxis of acute nausea and vomiting
The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer. Ann Oncol 2006;17:20-28. WWW.MASCC.ORG
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No routine prophylaxisMinimal
No routine prophylaxisLow
DexamethasoneA serotonin antagonist may be used as an alternative
Moderate (other than AC)
Aprepitant or dexamethasoneAnthracycline + Cyclophosphamide (AC)
Dexamethasone + aprepitant High AntiemeticsEmetic risk group
Prophylaxis of delayed nausea and vomiting
The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer.
Ann Oncol 2006;17:20-28. WWW.MASCC.ORG
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WHAT ABOUT ANTIEMETIC THERAPY IN ELDERLY?
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RISK FACTORS - CINV
• Emetic potential of chemotherapy
• Patients
• Antiemetic prophylaxis
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RISK FACTORS - CINV
• Emetic potential of chemotherapy
– Elderly often receive less toxic
(less emetogenic) chemotherapy.
• Patients
• Antiemetic prophylaxis
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PATIENTSEfficacy Risk Factors
• Age• Gender• Previous chemotherapy• Alcohol consumption• Motion sickness• Nausea and vomiting in pregnancy
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PATIENTSToxicity Risk Factors
• Age?• Variations in pharmacokinetics
– Absorption– Renal function– Hepatic function
• Polypharmacy– Side effects from other medication– Risk of interactions
• Compliance• Comorbidity
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PHARMACOKINETICS AND PHARMACODYNAMICS
PALONOSETRON• Age
Population PK analysis and clinical safety and efficacy data did not reveal any differences between cancer patients > 65 years of age and younger patients (18-64 years). No dose adjustment is required for these patients.
• Renal and hepatic functionDosage adjustment is not necessary in patients withany degree of renal or hepatic impairment.
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PHARMACOKINETICS AND PHARMACODYNAMICS
APREPITANT• Age
The pharmacokinetics of aprepitant are not significantly affected by race, gender, body weight, or age.
• Renal and hepatic functionDose adjustment of aprepitant is not necessaryin patients with renal insufficiency or mild to moderate hepatic insufficiency.
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DRUG INTERACTIONS PALONOSETRON
• Palonosetron is not an inhibitor or an activator of CYP enzymes. Therefore the potential for clinically significant drug interactions withpalonosetron appears to be low.
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DRUG INTERACTIONSAPREPITANT
• The aprepitant regimen for CINV produces slightinduction of CYP2C9 activity.
• Drugs with narrow therapeutic indices that are known to be metabolized by CYP2C9 may have transiently lower plasma concentrations whencoadministered with aprepitant. – e.g. warfarin, phenytoin.
• For patients on warfarin INR should be appropiatelymonitored.
• Increases the bioavailability of oral steroids.
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DRUG INTERACTIONSOTHER
• Risk of interaction with SSRIs have been described.– Increased toxicity of paroxetine given concomitantly
with ondansetron.– Decreased effect of ondansetron given concomitantly
with fluoxetine.
• Metoclopramide decreases the effect of levodopa.• Phenothiazines increase the sedative effect of
hypnotics, antihistamines, alcohol and analgesics and enhance the effect of antihypertensives.
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COMORBIDITY
• Cardiovascular– Prolongation of QTC with serotonin antagonists
and droperidol.
• Epilepsy– Increased risk of convulsions with metoclopramide
and prochlorperazine.
• Diabetes – Increased risk of constipation with serotonin
antagonists due to autonomic neuropathy.– Increased risk of hyperglycemia with steroids.
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CONCLUSIONS• The risk of CINV is lower in elderly.• Guidelines include no specific recommendations for the prophylaxis of CINV in elderly.
• No dose adjustment of aprepitant or serotonin antagonists is necessary due to decrease in
– renal or– hepatic function (NB: ondansetron/apreptant).
• Due to polypharmacy the risk of interactions is higher in elderly.
• Comorbidity/Compliance should be evaluted.