Chemotherapy Induced Nausea Chemotherapy Induced Nausea and Vomiting (CINV)and Vomiting (CINV)

Causes, Challenges, Evaluation and Causes, Challenges, Evaluation and Optimizing Clinical Management Optimizing Clinical Management

Innovation ● Investigation ● ApplicationInnovation ● Investigation ● Application

Program Co-ChairmanProgram Co-ChairmanLee S. Schwartzberg, MD, FACPLee S. Schwartzberg, MD, FACP

Medical Director, The West ClinicMedical Director, The West ClinicSupportive Oncology ServicesSupportive Oncology Services

President, Accelerated Community President, Accelerated Community Oncology Research NetworkOncology Research Network

Memphis, TNMemphis, TN

Taste

Cha

nge

Taste

Cha

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Chemotherapy Experienced Patients Chemotherapy Experienced Patients Rank Severe CINV Near DeathRank Severe CINV Near Death

Sun C et al. Support Care Cancer. 2005Sun C et al. Support Care Cancer. 2005

Throm

bocy

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nia

Throm

bocy

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nia0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Me

dia

n V

AS

Sco

res

Remiss

ion

Remiss

ion

CINV 1

CINV 1

Curre

nt H

ealth

Curre

nt H

ealth

Alopec

ia

Alopec

ia

Depre

ssion

Depre

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Ototo

xicity

Ototo

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Weig

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ain

Weig

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ain

Sexua

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Sexua

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func

tion

Mem

ory l

oss

Mem

ory l

oss

Consti

patio

n

Consti

patio

n

Leg

pain

Leg

pain

Fatigu

e

Fatigu

eFluFlu

Periph

eral

Neuro

path

y

Periph

eral

Neuro

path

y

Diarrh

ea

Diarrh

ea

Dysur

ia

Dysur

ia

CINV 4

CINV 4

CINV 6

CINV 6

CINV 5

CINV 5

Death

Death

Perfe

ct Hea

lth

CINV 2

CINV 2

Muc

ositis

Muc

ositis

CINV 3

CINV 3

Febrile

Neu

trope

nia

Febrile

Neu

trope

nia

Complete Complete ControlControl

Mucositis

Death

Moderate Delayed NauseaModerate Delayed Nausea

Poorly Controlled Poorly Controlled Acute & Delayed CINVAcute & Delayed CINV

Emetogenic Potential of Single Emetogenic Potential of Single Antineoplastic Agents Antineoplastic Agents

HIGHHIGH Risk in nearly all patients (> 90%)Risk in nearly all patients (> 90%)

MODERATEMODERATE Risk in 30% to 90% of patientsRisk in 30% to 90% of patients

LOWLOW Risk in 10% to 30% of patientsRisk in 10% to 30% of patients

MINIMALMINIMAL Fewer than 10% at riskFewer than 10% at risk

Patient-Specific Risk Factors for CINVPatient-Specific Risk Factors for CINV

► Age <50 yearsAge <50 years

► Women > menWomen > men

► History of light alcohol use History of light alcohol use

► History of vomiting with prior exposure History of vomiting with prior exposure to chemotherapeutic agents to chemotherapeutic agents

► Other risksOther risks● History of motion sickness History of motion sickness ● History of nausea or vomiting during pregnancyHistory of nausea or vomiting during pregnancy● History of anxietyHistory of anxiety

ASHP. ASHP. Am J Health Syst Pharm.Am J Health Syst Pharm. 1999:56:729-764; Balfour and Goa. 1999:56:729-764; Balfour and Goa. DrugsDrugs. 1997:54:273-298.. 1997:54:273-298.

Types of CINV: DefinitionsTypes of CINV: Definitions

► Acute (post-treatment)Acute (post-treatment)● Occurs within first 24 hours after administration of cancer Occurs within first 24 hours after administration of cancer

chemotherapychemotherapy

► DelayedDelayed● CINV that begins after first 24 hoursCINV that begins after first 24 hours● May last for 120 hoursMay last for 120 hours

► AnticipatoryAnticipatory● Learned or conditioned response from poorly controlled nausea Learned or conditioned response from poorly controlled nausea

and vomiting associated with previous chemotherapyand vomiting associated with previous chemotherapy

► BreakthroughBreakthrough● CINV that occurs despite prophylaxis and requires rescueCINV that occurs despite prophylaxis and requires rescue

► RefractoryRefractory● Occurs during subsequent treatment cycles when prophylaxis Occurs during subsequent treatment cycles when prophylaxis

and/or rescue has failed in previous cyclesand/or rescue has failed in previous cycles

Pathophysiology of Pathophysiology of Chemotherapy-Induced EmesisChemotherapy-Induced Emesis

Chemotherapy-Induced Emesis: Chemotherapy-Induced Emesis: Key Treatment MilestonesKey Treatment Milestones

Palonosetron July, 2003Aprepitant, March 2003

Pharmacologic AgentsPharmacologic Agents

► CorticosteroidsCorticosteroids

► Dopamine antagonistsDopamine antagonists

► Serotonin (5-HT3) antagonistsSerotonin (5-HT3) antagonists

► NK-1 receptor antagonistsNK-1 receptor antagonists

► CannabinoidsCannabinoids

11stst Generation 5HT Generation 5HT3 3 RAs RAs Are Therapeutically EquivalentAre Therapeutically Equivalent

Pts receiving MEC* (N=1,085)Pts receiving MEC* (N=1,085)

80% of pts received prophylactic steroids80% of pts received prophylactic steroids*Cyclophosphamide 500 - 1200 mg/m*Cyclophosphamide 500 - 1200 mg/m22, carboplatin , carboplatin ≥300 mg/m≥300 mg/m22

59.0 60.0

71.0

58.0 58.0

72.0

TotalTotal NauseaNausea EmesisEmesis

Oral granisetron 2 mgIV ondansetron 32 mg

Co

mp

lete

Con

trol

(%

)C

om

ple

te C

ontr

ol (

%)

•Highest Level Evidence & Highest Level Evidence & Not DebatedNot Debated

•MASCC 2004MASCC 2004

•NCCN 2009NCCN 2009

•ASCO 2006ASCO 2006

•11stst Generation Agents are Generation Agents are Therapeutically EquivalentTherapeutically Equivalent

•DolasetronDolasetron

•OndansetronOndansetron

•GranisetronGranisetron

•11stst Generation oral and IV Generation oral and IV doses equally effectivedoses equally effective

Perez et al. J Clin Oncol 1998;16:754Perez et al. J Clin Oncol 1998;16:754

Palonosetron Palonosetron

► Second generation 5-HTSecond generation 5-HT33 antagonist antagonist► Pharmacologic differences from older 5-HTPharmacologic differences from older 5-HT33 antagonists antagonists

● prolonged half-life (~40 hours)prolonged half-life (~40 hours)● enhanced receptor binding affinity (30-fold)enhanced receptor binding affinity (30-fold)

► FDA approved FDA approved ● IV formulation IV formulation July 25, 2003July 25, 2003● Oral formulation August 22, 2008Oral formulation August 22, 2008

► RegimensRegimens● IV 0.25 mg pre chemotherapyIV 0.25 mg pre chemotherapy acute/delayed HEC/MEC acute/delayed HEC/MEC● PO 0.50 mg pre chemotherapyPO 0.50 mg pre chemotherapy acute MECacute MEC

Palonosetron vs. 1Palonosetron vs. 1stst gen HT-3RA: gen HT-3RA:Complete Response on Day of Chemo & BeyondComplete Response on Day of Chemo & Beyond

Palonosetron 0.25 mg (n=378)Palonosetron 0.25 mg (n=378)Ondansetron/Dolasetron 32/100 mg (n=376)Ondansetron/Dolasetron 32/100 mg (n=376)

46.846.842.042.0

**57.757.7

**64.064.0

**72.072.0

60.660.6

00

2020

4040

6060

8080

100100

Time (hr)Time (hr)

Acute: 0-24Acute: 0-24(Day 1)(Day 1)

Delayed: 24-120Delayed: 24-120(Days 2-5)(Days 2-5)

Overall: 0-120Overall: 0-120(Days 1-5)(Days 1-5)

Com

plet

e R

espo

nse

(CR

)C

ompl

ete

Res

pons

e (C

R)

(% o

f Pat

ient

s)

(% o

f Pat

ient

s)

**pp<0.025 for pairwise difference (2-sided Fisher’s exact test) between palonosetron and ondansetron/dolasetron.<0.025 for pairwise difference (2-sided Fisher’s exact test) between palonosetron and ondansetron/dolasetron.

Gralla R et al. Gralla R et al. Ann OncolAnn Oncol. 2003; Eisenberg P et al. . 2003; Eisenberg P et al. CancerCancer. 2003.. 2003.Rubenstein EB et al. Rubenstein EB et al. Proc Am Soc Clin Oncol.Proc Am Soc Clin Oncol. 2003. Abstract 2932. 2003. Abstract 2932.

CR = no emetic episodes or use of rescue medicationsCR = no emetic episodes or use of rescue medications

pp < 0.05 Aapro M Support Care Cancer 2003:11:391 < 0.05 Aapro M Support Care Cancer 2003:11:391

Palonosetron vs Ondansetron Palonosetron vs Ondansetron

High Emetic Risk Chemotherapy High Emetic Risk Chemotherapy Patients Also Receiving Dexamethasone Patients Also Receiving Dexamethasone

* *

N=447(67%)

Phase III Trial of IV Palonosetron vs. IV Granisetron Phase III Trial of IV Palonosetron vs. IV Granisetron with Cisplatin or AC-Based Chemotherapywith Cisplatin or AC-Based Chemotherapy

► 1114 patients1114 patients► Cisplatin (57%) or anthracycline/cyclophosphamide (43%) Cisplatin (57%) or anthracycline/cyclophosphamide (43%) ► Single 0.75 mg dose of palo vs. single 40 Single 0.75 mg dose of palo vs. single 40 μμg/kg dose of g/kg dose of

granisetrongranisetron► Dexamethasone 16 mg d1; 4mg/d d 2-3 (AC/EC); Dexamethasone 16 mg d1; 4mg/d d 2-3 (AC/EC);

8mg/d d 2-3 CDDP8mg/d d 2-3 CDDP► Objective: demonstrate non-inferiority d1 Objective: demonstrate non-inferiority d1

and superiority d 2-5 of paloand superiority d 2-5 of palo► Primary endpoint complete response (no emesis/no rescue)Primary endpoint complete response (no emesis/no rescue)

Saito M et al. Lancet Oncol. 2009;10(2):115-24 Saito M et al. Lancet Oncol. 2009;10(2):115-24

Phase III Trial Palonosetron vs. Granisetron Phase III Trial Palonosetron vs. Granisetron both with Dexamethasone in HECboth with Dexamethasone in HEC

Palo+ Dex(n=555)

%

Grani+ Dex(n=558)

%

P

Complete Response, Acute (0-24h)

73.7 72.1 ND

CR, Delayed (24-120h) 53.0 42.4 0.0003

CR, Overall (0-120h) 47.9 38.1 0.0007

No Nausea:0-120 hours

32 25 0.01

No Emesis:0-120 hours

58 49 0.006

Saito M et al. Lancet Oncol. 2009;10(2):115-24 Saito M et al. Lancet Oncol. 2009;10(2):115-24

Palonosetron: 5-HTPalonosetron: 5-HT33 Antagonist of Choice? Antagonist of Choice?

► Palonosetron is a 5-HTPalonosetron is a 5-HT33 antagonist with strong receptor binding affinity antagonist with strong receptor binding affinity and an extended half-life and an extended half-life

► In 2 MEC trials, IV palonosetron (single dose) was superior to dolasetron In 2 MEC trials, IV palonosetron (single dose) was superior to dolasetron and ondansetron (single dose) in the prevention of acute and delayed and ondansetron (single dose) in the prevention of acute and delayed emesis in a post-hoc analysisemesis in a post-hoc analysis

► In 1 HEC trial, emetic control was comparable between IV palonosetron In 1 HEC trial, emetic control was comparable between IV palonosetron and ondansetron; better control with palonosetron in the subset receiving and ondansetron; better control with palonosetron in the subset receiving dexamethasonedexamethasone

► In large phase III trial with cisplatin or AC, palonosetron was equivalent to In large phase III trial with cisplatin or AC, palonosetron was equivalent to granisetron in acute control and superior during the delayed phasegranisetron in acute control and superior during the delayed phase

► Comparable tolerability Comparable tolerability

► Ease of use and trends towards superiority favor palonosetron as the Ease of use and trends towards superiority favor palonosetron as the preferred 5-HTpreferred 5-HT33 antagonist antagonist

► Definitive proof of superiority to first generation 5-HTDefinitive proof of superiority to first generation 5-HT33 antagonists would antagonists would require trials with control arms utilizing corticosteroids, NKrequire trials with control arms utilizing corticosteroids, NK11 antagonists antagonists andand repetitive dosing of the first generation agents repetitive dosing of the first generation agents

AprepitantAprepitant

► Selective antagonist of the binding of Substance P to the Selective antagonist of the binding of Substance P to the neurokinin 1 (NK1) receptorneurokinin 1 (NK1) receptor

► FDA approved FDA approved ● Oral formulation: March 26, 2003Oral formulation: March 26, 2003● IV formulation (fosaprepitant): January 31, 2008IV formulation (fosaprepitant): January 31, 2008

► RegimenRegimen● 125 mg PO day 1, 80 mg PO days 2-3125 mg PO day 1, 80 mg PO days 2-3 acute/delayed acute/delayed

HEC/MECHEC/MEC● 115 mg IV day 1, 80 mg PO days 2-3115 mg IV day 1, 80 mg PO days 2-3 acute/delayed acute/delayed

HEC/MECHEC/MEC

Aprepitant Randomized Trial: Aprepitant Randomized Trial: Patients Receiving ACPatients Receiving AC

GroupGroup Day 1Day 1 Days 2-3Days 2-3

AprepitantAprepitant

(n = 438)(n = 438)

StandardStandard

(n = 428)(n = 428)

OO DD AA 00 AA8 mg 8 mg BIDBID

12 mg12 mg 125 mg

8 mg 8 mg BIDBID

20 mg20 mg PP

80 mg

8 mg 8 mg BIDBID

PP

Warr DG et al. Warr DG et al. J Clin Oncol J Clin Oncol 2005; 23:2822-2830 2005; 23:2822-2830

O = ondansetron PO A = aprepitant POO = ondansetron PO A = aprepitant PO

D = dexamethasone PO P = placebo POD = dexamethasone PO P = placebo PO

PP

Aprepitant in Anthracycline/Cyclophosphamide Aprepitant in Anthracycline/Cyclophosphamide Chemotherapy: Complete Response (N=857)Chemotherapy: Complete Response (N=857)

**pp<0.05 <0.05 Complete response (CR): no emesis and no rescue medication.Complete response (CR): no emesis and no rescue medication.

Warr DG et al. Warr DG et al. J Clin Oncol J Clin Oncol 2005; 23:2822-2830 2005; 23:2822-2830

*

*

76

55 51

69

4942

0

20

40

60

80

100

Acute: 0-24(Day 1)

Delayed: 24-120(Days 2-5)

Overall: 0-120(Days 1-5)

Com

plet

e R

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(CR

)C

ompl

ete

Res

pons

e (C

R)

(% o

f P

atie

nts)

(% o

f P

atie

nts)

Aprepitant (n=433) Standard (n=424)

Time (hr)Time (hr)

Aprepitant in Moderately Emetogenic Aprepitant in Moderately Emetogenic Chemotherapy: Percent of Patients with No EmesisChemotherapy: Percent of Patients with No Emesis

Warr DG et al. Warr DG et al. J Clin OncolJ Clin Oncol 2005; 23:2822-2830 2005; 23:2822-2830

**pp<0.001<0.001

**

*88

817677

6959

0

20

40

60

80

100

Acute: 0-24(Day 1)

Delayed: 24-120(Days 2-5)

Overall: 0-120(Days 1-5)

Em

esis

-Fre

eE

mes

is-F

ree

(% o

f Pa

tient

s)(%

of P

atie

nts)

Aprepitant (n=433) Standard (n=424)

Time (hr)

Aprepitant in Moderately Emetogenic Chemotherapy:Aprepitant in Moderately Emetogenic Chemotherapy: Percent of Patients with No Nausea Percent of Patients with No Nausea

No nausea: score <5 mm on 0-100 mm VAS.No nausea: score <5 mm on 0-100 mm VAS.

Warr DG et al. Warr DG et al. J Clin OncolJ Clin Oncol 2005; 23:2822-2830; Warr DG et al. 2005; 23:2822-2830; Warr DG et al. Support Care CancerSupport Care Cancer. 2004. Abstract A027.. 2004. Abstract A027.

61

3733

59

36 33

0

20

40

60

80

100

Acute: 0-24Acute: 0-24(Day 1)(Day 1)

Delayed: 24-120Delayed: 24-120(Days 2-5)(Days 2-5)

Overall: 0-120Overall: 0-120(Days 1-5)(Days 1-5)

Nau

sea-

Fre

eN

ause

a-F

ree

(% o

f Pa

tient

s)(%

of P

atie

nts)

Aprepitant (n=430) Standard (n=424)

Time (hr)Time (hr)

Phase III Aprepitant Study (801):Phase III Aprepitant Study (801):Multiple-day OndansetronMultiple-day Ondansetron

Aprepitant Aprepitant

ControlControl

GroupGroup Day 4Day 4

16

8

Day 1Day 1

32 12 125

3232 20

Days 2-3Days 2-3

808

16

OO DD AA DDDD AA

O=ondansetron; D=dexamethasone; A=aprepitant; P=placeboO=ondansetron; D=dexamethasone; A=aprepitant; P=placebo

PPPP

PP

1616

PP

16

OO OO

Schmoll et al: Ann Oncol 17:1000-6, 2006Schmoll et al: Ann Oncol 17:1000-6, 2006

•Initial cycle cisplatin Initial cycle cisplatin >> 70 mg/m2 70 mg/m2•445 patients445 patients

Phase III Aprepitant Study (801):Phase III Aprepitant Study (801):Multiple-day OndansetronMultiple-day Ondansetron

► Identical design to Protocols 052 and 054 except Identical design to Protocols 052 and 054 except ondansetron dosed days 1-4 ondansetron dosed days 1-4

► Primary endpoint: complete response on days 1 - 5 after Primary endpoint: complete response on days 1 - 5 after cisplatincisplatin

► Aprepitant regimen superior to control regimen of Aprepitant regimen superior to control regimen of protracted ondansetron and dexamethasone dosing, CR protracted ondansetron and dexamethasone dosing, CR 72% vs. 61% respectively 72% vs. 61% respectively

Schmoll et al: Ann Oncol 17:1000-6, 2006Schmoll et al: Ann Oncol 17:1000-6, 2006

Palonosetron + Aprepitant + Dexamethasone Palonosetron + Aprepitant + Dexamethasone Phase II Study DesignPhase II Study Design

Day 1Day 1 Days 2-3Days 2-3

PALOPALO DD AA DD AA0.25 mg 12 mg 125 mg 80 mg

Grote T et al. Grote T et al. Proc Am Soc Clin OncolProc Am Soc Clin Oncol. 2004. Abstract 8262.. 2004. Abstract 8262.

PALO = palonosetron IV A = aprepitant POPALO = palonosetron IV A = aprepitant PO

D = dexamethasone PO D = dexamethasone PO

8 mg

• Multicenter, phase II, open-label studyMulticenter, phase II, open-label study• Naïve and non-naïve patients receiving moderately to moderately-Naïve and non-naïve patients receiving moderately to moderately-

highly emetogenic chemotherapyhighly emetogenic chemotherapy• Treatment:Treatment:

Grote T et al. Proc ASCO 2004. Abstract 8262

Palonosetron + Aprepitant + Dexamethasone Palonosetron + Aprepitant + Dexamethasone Complete Response (ITT, N=58)Complete Response (ITT, N=58)

87.9

77.6 77.6

0

20

40

60

80

100

Acute: 0-24(Day 1)

Delayed: 24-120(Days 2-5)

Overall: 0-120(Days 1-5)

Com

plet

e R

espo

nse

(CR

)C

ompl

ete

Res

pons

e (C

R)

(% o

f Pa

tient

s)(%

of P

atie

nts)

Time (hr)Time (hr)

Perception vs Reality: Perception vs Reality: Emetogenic ChemotherapyEmetogenic Chemotherapy

Grunberg S. Grunberg S. CancerCancer. 2004;100:2261-2268.. 2004;100:2261-2268.

Highly Emetogenic ChemotherapyHighly Emetogenic Chemotherapy Moderately Emetogenic ChemotherapyModerately Emetogenic Chemotherapy

Despite Compliance w/ Guidelines Problems Despite Compliance w/ Guidelines Problems Remain: Better Antiemetics NeededRemain: Better Antiemetics Needed

DeMoor C et al. Proc Am Soc Clin Oncol. 2003. Abstract 2924. DeMoor C et al. Proc Am Soc Clin Oncol. 2003. Abstract 2924.

2020

3030

4040

5050

6060

7070

8080

% o

f Pts

w/

% o

f Pts

w/ D

ela

yed

De

laye

d C

INV

CIN

V

Noncompliance w/ GuidelinesNoncompliance w/ Guidelines00

1010

1001009090

Compliance w/ GuidelinesCompliance w/ Guidelines

Even when physicians follow guidelines (using 1Even when physicians follow guidelines (using 1stst generation 5HT generation 5HT33

RAs), 50% of pts experience delayed CINVRAs), 50% of pts experience delayed CINV

•AgeAge•GenderGender•Emetogenic PotentialEmetogenic Potential•Presence of Acute CINVPresence of Acute CINV

After Adjustment For Prognostic After Adjustment For Prognostic Factors For Delayed CINVFactors For Delayed CINV

Relationship Between Acute CINV and Relationship Between Acute CINV and Delayed CINV: QuestionsDelayed CINV: Questions

► Is acute CINV a strong predictive factor for delayed Is acute CINV a strong predictive factor for delayed CINV in patients receiving moderately emetogenic CINV in patients receiving moderately emetogenic chemotherapy?chemotherapy?

► Is prevention of delayed CINV a carryover effect Is prevention of delayed CINV a carryover effect from prevention of acute CINV or a true from prevention of acute CINV or a true pharmacologic effect during the delayed phase?pharmacologic effect during the delayed phase?

► What is the difference in the treatment effect of the What is the difference in the treatment effect of the first-generation 5-HTfirst-generation 5-HT33 receptor antagonists vs receptor antagonists vs palonosetron in preventing delayed CINV after palonosetron in preventing delayed CINV after accounting for known prognostic factors, including accounting for known prognostic factors, including the carryover effect?the carryover effect?

Grunberg SM et al. Grunberg SM et al. Proc Am Soc Clin Oncol.Proc Am Soc Clin Oncol. 2004. Abstract 8051. 2004. Abstract 8051.

Protection From Delayed CINV:Protection From Delayed CINV:All PatientsAll Patients

17

75

0

10

20

30

40

50

60

70

80

With Acute CINVWith Acute CINV(n=254)(n=254)

Without Acute CINVWithout Acute CINV(n=500)(n=500)

No

Del

ayed

CIN

VN

o D

elay

ed C

INV

(% o

f Pa

tient

s)(%

of P

atie

nts)

Grunberg SM et al. Proc Am Soc Clin Oncol. 2004. Abstract 8051.

Protection From Acute and Delayed CINV:Protection From Acute and Delayed CINV:Palonosetron vs Ondansetron/DolasetronPalonosetron vs Ondansetron/Dolasetron

Protection From Delayed CINV Protection From Delayed CINV

(n/n with No Acute CINV) (n/n with No Acute CINV)

Protection From Protection From

Acute CINVAcute CINVPALO 0.25 mgPALO 0.25 mg OND 32 mg/OND 32 mg/

DOL 100 mgDOL 100 mg

YesYes(218/272) (218/272)

80% *80% *(158/228) (158/228)

69%69%

NoNo(24/106) (24/106)

23% 23% ††

(18/148) (18/148) 12%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.

► 671 pts receiving doxorubicin-based chemotherapy671 pts receiving doxorubicin-based chemotherapy● all treated w/ all treated w/ 11stst generation generation 5HT5HT3 3 + Dex+ Dex on Day 1 of CT on Day 1 of CT

► Pts then randomized Pts then randomized for days 2 and 3for days 2 and 3::● Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h)Arm 1: Prochlorperazine 10 mg p.o. three times daily (q 8 h)

● Arm 2: Arm 2: Any oral 5-HTAny oral 5-HT3 3 antiemetic, using standard dosing antiemetic, using standard dosing regimens regimens

● Arm 3: Arm 3: ProchlorperazineProchlorperazine 10 mg p.o. as needed for nausea 10 mg p.o. as needed for nausea

► Rescue medications for control of symptoms were Rescue medications for control of symptoms were allowedallowed

Are Oral Followup 5-HTAre Oral Followup 5-HT33 RAs RAs Really Effective for Delayed CINV? Really Effective for Delayed CINV?

Hickock et al ASCO 2005 Final Results URCC-CCOPHickock et al ASCO 2005 Final Results URCC-CCOP

11stst Generation Oral 5HT Generation Oral 5HT33 RAs: RAs:Majority of Patients Experience NauseaMajority of Patients Experience Nausea

• Patients randomized for days 2 and 3; rescue medications allowedPatients randomized for days 2 and 3; rescue medications allowed

• Hickock et al ASCO 2005 Final Results URCC-CCOPHickock et al ASCO 2005 Final Results URCC-CCOP

* p = 0.002 (overall comparison); p = 0.06 (* p = 0.002 (overall comparison); p = 0.06 (Prochlorperazine q 8 h vs 5-HTq 8 h vs 5-HT3 3 ); );

p = NS (p = NS (Prochlorperazine prn vs 5-HTprn vs 5-HT3 3 ))

102030405060708090

100 Prochlorperazine q 8h*

5HT33**Prochlorperazine PRN*

% P

atie

nts

with

Del

ayed

Nau

sea

7583 87

11stst Generation Oral 5HT Generation Oral 5HT33 RAs RAs Not Effective for Delayed CINV Not Effective for Delayed CINV

► Vomiting Vomiting

● Significantly Significantly more patients vomitedmore patients vomited at least once during the at least once during the delayed period delayed period (34%)(34%) than on the day of treatment than on the day of treatment (19%) p (19%) p <0.01<0.01

► NauseaNausea

● Nausea severity was significantly greater during the Nausea severity was significantly greater during the delayed period than on the day of treatment delayed period than on the day of treatment p < 0.01p < 0.01

● More patients getting oral 5HTMore patients getting oral 5HT33 RAs required rescue RAs required rescue medications medications (45%)(45%) than patients getting Compazine than patients getting Compazine®® (27-(27-30%)30%) p=0.002p=0.002

Hickock et al ASCO 2005 Final Results URCC-CCOPHickock et al ASCO 2005 Final Results URCC-CCOP

Meta-Analysis of Efficacy of 5-HTMeta-Analysis of Efficacy of 5-HT33RA in Prevention RA in Prevention of Delayed Emesis from Chemotherapyof Delayed Emesis from Chemotherapy

Reviewed 5 studies, 1,716 pts comparing 5-HTReviewed 5 studies, 1,716 pts comparing 5-HT3 3 RA to placebo, RA to placebo,

5 studies, 2,240 pts comparing 5-HT5 studies, 2,240 pts comparing 5-HT33 RA + dexamethasone to RA + dexamethasone to dexamethasone alonedexamethasone alone

5-HT5-HT33 RA as monotherapy RA as monotherapy

Absolute RR (95% CI) 8.2% (3.0-13.4)Absolute RR (95% CI) 8.2% (3.0-13.4)

NNT 12.2 Number of doses per protected pt: 74.4NNT 12.2 Number of doses per protected pt: 74.4

5-HT5-HT33 RA as adjunct to dexamethasone RA as adjunct to dexamethasone

Absolute RR (95% CI) Absolute RR (95% CI) 2.6% (-0.6-5.8)2.6% (-0.6-5.8)

NNT 38.8 NNT 38.8 Number of doses per protected pt: 423Number of doses per protected pt: 423

Geling and Eichler, JCO 23:1289-1294Geling and Eichler, JCO 23:1289-1294

ASCO 2006/NCCN 2009 Recommendations ASCO 2006/NCCN 2009 Recommendations by Risk Categoryby Risk Category

High (>90% emetic risk)High (>90% emetic risk)

Including AC containing regimensIncluding AC containing regimens

Three-drug combination of a HTThree-drug combination of a HT33

serotonin receptor antagonist, serotonin receptor antagonist, (palonosetron preferred-NCCN) (palonosetron preferred-NCCN) dexamethasone, and aprepitantdexamethasone, and aprepitant

Moderate (>30% to 90% emetic Moderate (>30% to 90% emetic risk)risk)

Two-drug combination of a HTTwo-drug combination of a HT33

serotonin receptor antagonist and serotonin receptor antagonist and dexamethasone (+/-aprepitant for dexamethasone (+/-aprepitant for selected patients)selected patients)

Low (10% to 30% emetic risk)Low (10% to 30% emetic risk) Dexamethasone 8-12 mgDexamethasone 8-12 mg

Minimal (<10% emetic riskMinimal (<10% emetic risk No antiemetic routinelyNo antiemetic routinely

How Can We Improve the Value of How Can We Improve the Value of Care in CINV?Care in CINV?

Value = Value = QualityQuality CostCost

CR CR

Nausea or EmesisNausea or Emesis Functioning Functioning

Side EffectsSide Effects

Compliance or Compliance or Patient Patient

InconvenienceInconvenience

Access to CareAccess to Care

•DirectDirect•IndirectIndirect

Summary Summary

► 11stst generation 5HT generation 5HT3 3 RA’s therapeutically equivalent & major RA’s therapeutically equivalent & major advance in supportive care for control of acute emesisadvance in supportive care for control of acute emesis

► No major progress in CINV for ~ 10+ yrs until aprepitant & No major progress in CINV for ~ 10+ yrs until aprepitant & palonosetronpalonosetron

► Treatment guidelines have changed Treatment guidelines have changed ● Degree of nausea incurred has been refined for many agentsDegree of nausea incurred has been refined for many agents● Delayed CINV recommendations are updatedDelayed CINV recommendations are updated

► Prevention of CINV has improved, but challenges remainPrevention of CINV has improved, but challenges remain● Improving detection of CINV, especially after 24 hoursImproving detection of CINV, especially after 24 hours● Educating patients and oncology healthcare giversEducating patients and oncology healthcare givers● The development and evaluation of clinically useful The development and evaluation of clinically useful

assessment tools assessment tools ● Further development of regimens to treat delayed CINVFurther development of regimens to treat delayed CINV