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New Treatment Strategies for Chemotherapy-Induced

Nausea and Vomiting

Rowena N. Schwartz, Pharm.D., BCOPDirector of Oncology Pharmacy

The Johns Hopkins HospitalAdjunct Associate Professor of Pharmacy Therapeutics

University of Pittsburgh School of Pharmacy

Chemotherapy-Induced Nausea Vomiting: The Challenge of Management

Patient Case: LT is 46 y/o women diagnosed with sarcoma admitted to the hospital for treatment with 3rd cycle of

doxorubicin and ifosfamide 1st cycle: complicated with severe acute and delayed CINV 2nd cycle: complicated with severe acute and delayed CINV During admission evaluation today, LT told her nurse that

if she experiences CINV she will not receive any more chemotherapy.


Patient Case: LT is 46 y/o women diagnosed with sarcoma admitted

to the hospital for treatment with her 3rd cycle of doxorubicin and ifosfamide

1st cycle of chemotherapy:• Prevention: 5HT 3 antagonist +

dexamethasone• Treatment: dopamine antagonist

2nd cycle of chemotherapy:• Prevention: 5HT 3 antagonist +

dexamethasone + lorazepam• Treatment: dopamine antagonist


CINV is a broad term for a range of symptoms associated with chemotherapy:• pathophysiology• manifestation

- nausea and/or vomiting- timing (e.g. onset, duration)- intensity

• impact of symptom


CINV is a broad term for a range of symptoms associated with chemotherapy

Chemotherapy is a broad category of medications:

• classical chemotherapy• biotherapy• oral versus parenteral chemotherapy• combination of medications• impact of dose of chemotherapy

Patterns of Acute Emesis

0

10

20

30

40

50

60

70

80

90

100

2 4 6 8 10 12 14 16 18 20 22 24

Cisplatin

Carboplatin

% o

f pt

s w

/ vo

miti

ng

Time (hours)

Martin M. Oncology 1996;53(suppl 1):26-31

New Treatment Strategies for Chemotherapy-Induced Nausea and Vomiting

discuss new treatment strategies based on current understanding of pathophysiology of CINV

list published guidelines for management of CINV

discuss strategies for individualization of treatment strategies for CINV

Pathophysiology of Chemotherapy-Induced Emesis

Rubenstein ED, et al Cancer J 2006

NeuroanatomicalCenters:Emetic centerChemoreceptor trigger zoneVagal afferents of GI tract

Neurotransmitters:Dopamine (DA)Serotonin (5HT)Substance P

Emetic Center

CTZ

Chemotherapy Induced Nausea and Vomiting

Emetic Center

CorticalGI

vestibular

Nausea / Vomiting

CTZ

Neurokinins:Substance P DA

5HT

Chemotherapy Induced Nausea / Vomiting

Emetic Center

CorticalGI

vestibular

Nausea / Vomiting

CTZ

NeurokininsDA

5HT3

Neurotransmitter Crosstalk in CINV

Animal data demonstrate: modulation of the 5HT3 receptor can directly effect

NK receptors signaling modulation of NK receptors can influence 5HT3

receptor substance P has shown to potentiate 5HT3 receptor

mediated inward current in rat trigeminal ganglion neuronHu WP, et al. Neuroscie Letter 2004:365:147

serotonin unmasks substance P inducible depolarization of NK receptors in nodose ganglion neuronsMoore KA, et al. J Appl Physiol 2002:92:2529Minami M, et al. Eur J Pharmacol 2001:428:215

Rubenstein ED, et al Cancer J 2006

NeuroanatomicalCenters:Emetic centerChemoreceptor trigger zoneVagal afferents of GI

Neurotransmitters: Dopamine (DA) Serotonin (5HT) Substance P GABA Cannabinoid I Acetylcholine Endorphins

Emetic Center

CTZ

CINV: Classification

Anticipatory Acute Delayed

Chemo 16 - 24 hours

Serotonin and Chemotherapy

0

2

4

6

8

10

12

14

16

0 5 10 15 20 25 30

Cisplatin

Uri

nar

y 5H

IAA

Hours after chemotherapy administration

Cubeddu, L.X. Oncology 1996;53(suppl 1):18-25

Serotonin and Chemotherapy

0

2

4

6

8

10

12

14

16

0 5 10 15 20 25 30

Cyclophosphamide

Cisplatin

Uri

nar

y 5H

IAA

Hours after chemotherapy administration

Cubeddu, L.X. Oncology 1996;53(suppl 1):18-25

Perception vs Reality: Emetogenic Chemotherapy

Percent of patients

34

17

39

22

33

13

6253

010203040506070

Acute Nausea Acute Vomiting Delayed Nausea DelayedVomiting

MD/RN Prediction Patient Experience

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

Percent of patients

24

13

2415

37

13

53

28

010203040506070

Acute Nausea Acute Vomiting Delayed Nausea DelayedVomiting

MD/RN Prediction Patient Experience

Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy

Chemotherapy-Induced Nausea / Vomiting

N = 322

76% Nausea

43% Acute

39% Acute & Delayed

73% Delayed

30% Vomiting

11% Acute

7% Acute & Delayed

25% Delayed

Hickok, JT, et al. Cancer 2003;97:2880-6

Acute CINV ⇒ Delayed CINV

No Acute CINV

No Delayed76%

Delayed24%

Yes Acute CINV

No Delayed20%

Delayed80%

CINV: A Broad Definition

Anticipatory acute delayed ….

chemotherapyadministration

CINV: Current Problem

CINV is still a clinical problem do not fully understand the pathophysiology

of CINV (e.g. acute, delayed) “traditional” definition of acute and delayed

CINV does not match the physiology Appears that:

• acute CINV impacts delayed CINV• prevention of acute CINV may help

management of delayed CINV

New Treatment Strategies for Chemotherapy-Induced Nausea and Vomiting

discuss new treatment strategies based on current understanding of pathophysiology of CINV

• aprepitant• palonosetron

CINV

Emetic Center

CorticalGI

vestibular

Nausea / Vomiting

CTZ

Neurokinins:Substance P

Substance P

prototypic neuropeptide of the 50 known neuroactive molecules• now recognized as a member of the tachykinin family

of neurotransmitters• neurokinins are tachykinins found in mammals

(substance P, NKA, NKB)• 3 categories of NK receptors

NK1 - affinity for substance PNK2 - affinity for NKANK3 - affinity for NKB

currently considered a modulator of nociception, stress, anxiety, nausea / vomiting

DeVane CL. Pharmacotherapy 2001:21:1061-9

CINV: Aprepitant (Emend)

aprepitant (Emend , Merck & Co., Inc.) approved in the US in 2003

Mechanism of action:• selective, high affinity antagonist of human

substance P at neurokinin 1 (NK 1) receptors ⇒ interferes with the substance P pathway that produces N/V

• no affinity for serotonin (5HT 3), dopamine and corticosteroid receptors

Indication:

• combination with other antiemetics

• indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy

Neurokinin-1 Antagonist: Role in CINVPurpose: neurokinin-1 antagonist (NK-1a) vs. ondansetronStudy design: dbl-blind randomized, parallel study in cisplatin naive pts

group I (n = 61)acute: NK-1a x 1 dose + dexamethasone 20 mg IV x 1 delayed: NK-1a po q d x 4 days

group II (n = 58)acute: NK-1a IV x 1 dose + dexamethasone 20 mg IV x 1delayed: placebo x 4 days

group III (n = 57)acute: ondansetron 32 mg IV x 1 delayed: placebo x 4 days

Van Belle S, et al. ASCO 1999. Abstract 2281

Neurokinin-1 Antagonist: Role in CINV

group I : NK-1a + dexamethasone⇒ NK-1a

group II: NK-1a + dexamethasone ⇒ placebo

group III: ondansetron ⇒ placebo

Results (% patients without emesis):

Acute Emesis

group I - 50% group II - 47% group III - 84%

Delayed Emesis

group I - 68% group II - 63% group III - 41%

Van Belle S, et al. ASCO 1999. Abstract 2281


Multicenter, dbl blind, parallel-group trial in CDDP naive patients (n=351)

Groups:

acute delayed

I gran + dex placebo

II gran + NK-1a + dex NK-1a

III NK-1a + dex NK-1a

IV NK-1a + dex NK-1a

Campos-D, et al. JCO 2001


Group I: granisetron + dexamethasone⇒ placebo

Group II: granisetron + NK-1a + dexamethasone ⇒ NK-1a

Group III: NK-1a + dexamethasone ⇒ NK-1a

Group IV: NK-1a + dexamethasone ⇒ NK-1a

Percentage of patients without emesis: acute delayed I 57 % 29 %II 80 % 63 %III 46 % 51 %IV 43 % 57 %

Campos-D, et al. JCO 2001


Purpose: evaluation of time course of emesis for antiemetic strategies

Patients: CDDP naïve ⇒ CDDP ≥ 70 mg/m2acute (day 1) delayed (day 2-5)

group I: gran + dex placebogroup II: gran + NK-1a + dex NK-1agroup III: NK-1a * + dex NK-1a group IV: NK-1a + dex NK-1a

* higher dosegranisetron = grandexamethasone = dex

Hesketh PJ, et al. ASCO 2002 (abst 1476)

Neurokinin-1 Antagonist: Role in CINVgroup I: gran + dex ⇒ placebo

group II: gran + NK1a + dex ⇒ NK1a

group III: NK1a* + dex ⇒ NK1a

group IV: NK1a + dex ⇒ NK1a

Results: % of patients without emesis

group 0 - 8 hrs 0 - 16 hrs 0 - 24 hrs 0 - 120 hrs

I 92 % 81 % 57 % 23 %

II 88 % 86 % 80 % 57 %

III49 % 47 % 46 % 35 %

IV45 % 44 % 43 % 37 %

Hesketh PJ, et al. ASCO 2002 (abst 1476)

CINV: A Broad Definition

Anticipatory Early acute

Chemo

Late acute Delayed

16 hours 24 hours

CINV: Aprepitant (Emend)

aprepitant (Emend , Merck & Co., Inc.) approved in the US in 2003

Mechanism of action:• selective, high affinity antagonist of human

substance P at neurokinin 1 (NK 1) receptors ⇒ interferes with the substance P pathway that produces N/V

• no affinity for serotonin (5HT 3), dopamine and corticosteroid receptors

Indication:

• combination with other antiemetics

• indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy

Aprepitant Administration

Given for three days as part of a regimen that includes a 5-HT3 antagonist and a corticosteroid

Recommended dose 125 mg po 1 hour prior to chemotherapy 80 mg daily in the morning on days 2 and 3

Supplied in 125- and 80-mg capsules

Aprepitant Metabolism

metabolized in the liver through the P450 enzyme system

primarily metabolized by the CYP3A4 isozyme Some drug-drug interactions may be more

significant for oral medications (first pass effect)

Aprepitant: Drug Interactions

CYP3A4 Inducers: • Rifampin• Carbamazepine• Phenytoin

⇓ aprepitant level

CYP3A4 Inhibitors:• Ketoconazole• Itraconazole• Nefazodone• Troleandomycin• Clarithromycin• Ritonavir• Nelfinavir

⇑ aprepitant level

Effect of Other Drugs on Aprepitant

0.09

1

4.8

2

1.3

0

0.51

1.5

22.5

33.5

44.5

5

AUC ratio

Rifampin

Control

Ketoconazole

Diltiazem

Dexamethasone

Aprepitant: Impact on CYP450

Aprepitant is primarily metabolized by the CYP3A4 isoenzyme

Aprepitant inhibits CYP3A4 (as early as 1 hr after first dose)

Induces its own metabolism upon dosing for 2 weeks (autoinduction) via CYP 3A4

Aprepitant induces CYP2C9 Shadle CR, et al. J Clin Pharmacol 2004

Aprepitant: Drug Interactions

• paclitaxel

• etoposide

• vinorelbine

• docetaxel

• irinotecan

• ifosfamide

• imatinib

• vinblastine

• vincristine

Antineoplastic agents commonly metabolized

through CYP3A4:

Aprepitant’s effect on Plasma Concentrations of Dexamethasone

N=12 per treatment

Dexamethasone: 20 mg P.O. Day 1, 8 mg/d P.O. Days 2-5Aprepitant: 125 mg Day 1, 80 mg/d Days 2-5

0 6 12 18 24

Time (hr)

0

50

100

150

200

250

Dex

amet

haso

ne

Day 1

Con

cent

ratio

n (

ng/m

L)

0 6 12 18 240

50

100

150

200

250

869-41 Dexa D1&D5 Feb. 19, 2003

Day 5

with Aprepitantwithout Aprepitant

De

xam

eth

ason

e P

lasm

a C

onc

ent

ratio

n (n

g/m

L)

Aprepitant Does Not Affect Docetaxel Pharmacokinetics

Plasma ConcentrationProfiles of Docetaxel

Docetaxel AUC of individual patients

Without WithAprepitant Aprepitant

0

1

2

3

4

5

869-51 Doce 2 Feb. 25, 2003

Do

ceta

xel A

UC

0-∞

0 4 8 12Time (hr)

0.01

0.1

1

10

Doc

eta

xel C

onc.

(m

cg/m

L)

with Aprepitantwithout Aprepitant

Do

ceta

xel P

lasm

a C

once

ntra

tion

(mcg

/mL)

Aprepitant: Challenges for Care

Potential drug interactions with anticancer medication

Evaluation of drug interactions should look at impact beyond 24 hours

Potential drug interactions with other medications (e.g. chronic)

The Complexity of Pharmacotherapy inthe Patient with Cancer

Drug A - chronic

Drug B - chronic

Drug C - chronic


Jan Feb March AprilDrug A - chronic

Drug B - chronic

Drug C - chronic



Drug B - chronic

Drug B - chronic

Chemotherapy



Drug B - chronic

Drug B - chronic

Chemotherapy

Antiemetic(s)

AntibioticPain Medication

And so the complexity continues…..



Drug B - chronic

Drug C - chronic

Chemotherapy

Antiemetic(s)




Drug B - chronic

Drug C- chronic

Chemotherapy

Antiemetic(s)


CINV: Triple Upfront Therapy5HT3 Antagonist + NK1 Antagonist + Dexamethasone

Clinical Trials: Phase III for highly emetogenic chemotherapy: Cisplatin Pooled analysis:

⇑ Overall vomiting prevention with triple drug approach by 20%

⇑ Improvement in acute nausea and vomiting by 13%

⇑ Improvement in delayed nausea and vomiting by 21%

No differences in treatment-related adverse effect comparison

Warr et al. Eur J Cancer 2005

CINV: Triple Upfront TherapyRationale: Clinical Guidelines

Guidelines include triple upfront therapy for highly emetogenic regimens: MASCC NCCN 2007 ASCO 2006

Kris MG, et al. JCO 2006:24:2932

CINV: Triple Upfront TherapyAprepitant for Moderately Emetogenic Chemotherapy

(Breast Cancer Regimens)

Aprepitant

Control

Group Day 1

12 125

20

Days 2-3

80

16

O D A O A

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

P P

P16

16

Warr, D.G., et al. J Clin Oncol 2005;23:2822-30 N = 866

CINV: Triple Upfront TherapyMEC Breast Cancer Regimens

Overall CR favored triple drug therapy51% vs 42%

Acute CR favored triple drug therapy76% vs 69%

Delayed CR favored triple drug therapy55% vs 49%

Patients experiencing no vomiting higher in the triple drug therapy group

76 % vs 59% Increased QOL (measured by FLIE) in patients

receiving triple drug therapy85% vs 71%

Warr, D.G., et al. J Clin Oncol 2005;23:2822-30

CINV: Triple Upfront TherapyModerately Emetogenic Therapy

0

10

20

30

40

50

60

70

80

CR (0-120) CR (0-24) CR (24-120)

AprepitantControl

Co

mp

lete

Res

pon

se (

%)

Warr, DG, et al. J Clin Oncol 2005;23:2822-30

CINV

Emetic Center

CorticalGI

vestibular

Nausea / Vomiting

CTZ

Neurokinins:Substance P DA

5HT

5HT3 Receptor Antagonists

Prototypes: • Ondansetron• Granisetron• Dolasetron• Palonosetron

MOA: Inhibition of 5-HT3 receptors on vagal afferent neurons in GI and in CTZ

Efficacy improved when used with a steroid Well tolerated, minimal side effects

• headache• constipation• bradycardia

*Log-scale.†In vitro data; clinical significance has not been established.

5-HT3 Antagonist Half-Life (h) Binding Affinity (pKi)*†

Palonosetron (Aloxi®) 40.0 10.45

Ondansetron (Zofran®) 4.0 8.39

Dolasetron (Anzemet®) 7.3 7.60

Granisetron (Kytril®) 9.0 8.91

Half-Life and Binding Affinities of 5-HT3

Receptor Antagonists

Palonosetron: Metabolism and Excretion

Approximately equal contribution of renal and hepatic routesof elimination

~40% renally cleared unchanged

~50% of administered dose metabolized Total body clearance is not significantly affected by

gender, age, hepatic impairment, renal impairment Plasma protein binding of ~60% Does not inhibit or induce cytochrome P450 isozymes

at clinically relevant concentrations.

Palonosetron vs Ondansetron: CINV

Study Design:• Phase III randomized, multicenter, double-blind, active-

controlled, stratified, parallel-arm trial• Moderately emetogenic chemotherapy (single dose)• Active comparator trial (n = 563)

Day 1:Palonosetron 0.25 mg IVPalonosetron 0.75 mg IVOndansetron 32 mg IV

• No corticosteroid administered prophylactically• Patients were followed for 14 days for evaluation

Gralla R et al. Ann Oncol. 2003;14:1570-1577.

Palonosetron vs Ondansetron: CINV Demographics (ITT population)

Palonosetron0.25 mg(n=189)

Palonosetron0.75 mg(n=189)

Ondansetron32 mg

(n=185)

Age, mean yrs 56.1 54.8 55.3

Gender, %

Male 28.6 27.0 28.1

Female 71.4 73.0 71.9

Ethnic group, %

White 98.4 99.5 98.9

Other 1.6 0.5 1.1

Chemotherapeutic history, %

Naïve 40.2 42.3 42.2

Non-naïve 59.8 57.7 57.8


Palonosetron vs Ondansetron: CINV Chemotherapy Agents and Tumor Types

Chemotherapy, %†‡

Palonosetron 0.25 mg (n=189)


Ondansetron32 mg

(n=185)Cyclophosphamide (<1500 mg/m2) 63.0 63.5 63.3

Doxorubicin (>25 mg/m2) 51.3 46.0 47.0

Cisplatin (≤50 mg/m2) 19.0 17.5 16.8

Methotrexate (>250 mg/m2) 12.2 16.9 19.5

Carboplatin 7.9 13.2 13.5

Tumor Type, %†

Breast 60.3 54.5 56.8

Lung 11.1 10.6 11.3

Bladder 2.6 6.3 6.5

Colon 5.8 5.8 1.6

Gastric 3.2 3.2 3.2†Reported for the most common categories.‡Multiple agents were possible.


Palonosetron vs Ondansetron: CINV Complete Response: Acute and Delayed Emesis

Palonosetron 0.25 mg (n=189)Palonosetron 0.75 mg (n=189)Ondansetron 32 mg (n=185)

Time (hr)

0

20

40

60

80

100

Acute: 0-24(Day 1)

Delayed: 24-120(Days 2-5)

Overall: 0-120(Days 1-5)

Complete Response (% of Patients)

*81.0

73.568.6

*74.1

64.655.1

*69.3

58.750.3

*97.5% CIs and 2-sided Fisher’s exact test (significance level = 0.025) indicate a difference between palonosetron and ondansetron.

Complete response (CR): no emesis, no rescue medication.


Palonosetron vs Ondansetron: CINV Complete Control: Acute and Delayed Emesis

Time (hr)

76.2 *66.7

*63.0

70.9

58.753.4

65.4

50.344.9

0

20

40

60

80

100

Acute: 0-24(Day 1)



Co

mp

lete

Co

ntr

ol

(% o

f P

atie

nts

)



Ondansetron 32 mg (n=185)

*p≤0.05 for palonosetron vs ondansetron (Chi-Square test).Complete control (CC): no emesis, no rescue medication, no more than mild nausea.


Palonosetron vs Ondansetron: CINV Patients With No Emetic Episodes: Acute and Delayed

*p≤0.05 for palonosetron vs ondansetron (Chi-Square test).

Palonosetron 0.25 mg (n=189)Palonosetron 0.75 mg (n=189)Ondansetron 32 mg (n=185)

Time (hr)

*85.2

*80.4

75.177.8 *72.0 *

65.171.4

61.655.1

0

20

40

60

80

100

Acute: 0-24(Day 1)



Em

esis

-Fre

e

(% o

f P

atie

nts

)

*


Phase III: Palonasetron vs Ondansetron Highly Emetogenic Chemotherapy

Time (h)

10

20

0

30

40

50

60

70

80

90

100

0 24 48 72 96 120

Per

cen

t o

f P

atie

nts



Ondansetron 32 mg (n=221)

P=NS for palonosetron 0.25 mg or 0.75 mg vs ondansetron.

Time to Treatment Failure = time to 1st emetic episode or use of rescue medication.

PALO-99-05 HEC

Palonosetron: What is the role?

5HT3 antagonist with a long half life (40 hr)

Appears to have activity in both acute and delayed CINV

Initial studies done with single day chemotherapy ⇒ how does this apply to multiple day therapy?

How does this agent impact decision for use of aprepitant?

Neurotransmitter Crosstalk in CINV

Animal data demonstrate: modulation of the 5HT3 receptor can directly effect

NK receptors signaling modulation of NK receptors can influence 5HT3

receptor substance P has shown to potentiate 5HT3 receptor

mediated inward current in rat trigeminal ganglion neuronHu WP, et al. Neuroscie Letter 2004:365:147

serotonin unmasks substance P inducible depolarization of NK receptors in nodose ganglion neuronsMoore KA, et al. J Appl Physiol 2002:92:2529Minami M, et al. Eur J Pharmacol 2001:428:215

CINV: Upfront Therapy

Selection of the patient / patient groups Current:

• emetogenicity potential of regimen• prior history of CINV

Future:• identify and utilize patient specific factor

(e.g. pharmacogenomics)



doxorubicin and ifosfamide 1st cycle: complicated with severe acute and delayed CINV 2nd cycle: complicated with severe acute and delayed CINV During admission evaluation today, LT told her nurse that




doxorubicin and ifosfamide 1st cycle: complicated with severe acute and delayed CINV

5HT 3 antagonist corticosteroid ? Aprepitant prn dopamine antagonist

2nd cycle: complicated with severe acute and delayed CINV During admission evaluation today, LT told her nurse that




doxorubicin and ifosfamide 1st cycle: complicated with severe acute and delayed CINV

5HT 3 antagonist corticosteroid ? Aprepitant prn dopamine antagonist

2nd cycle: complicated with severe acute and delayed CINV evaluation of acute and delayed CINV from

first cycle evaluation of contibutory factors for CINV

Etiology of Nausea and Vomiting in Patients with Cancer

Direct Treatment Related:

• chemotherapy

- acute

- delayed

- anticipatory

- breakthrough N/V

- refractory N/V

• radiation therapy• prophylactic antibiotics

Indirect Treatment Related:• mucositis• opiates• anti-infectives• gastroparesis• infection• hyperacidity• anorexia• diarrhea• pain• anxiety



doxorubicin and ifosfamide 1st cycle: complicated with severe acute and delayed CINV 2nd cycle: complicated with severe acute and delayed CINV

evaluation of acute and delayed CINV from first cycle

evaluation of contibutory factors for CINV scheduled:

• 5HT3 antagonist• Corticosteroid• Dopamine antagonist• Benzodiazepine• antihistamine

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