Chemotherapy-Induced Nausea and Vomiting (CINV ... CINV.pdf1 Chemotherapy-Induced Nausea and...

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Chemotherapy-Induced Nausea and Vomiting (CINV):

Perceptions, Mechanisms, and Treatment Guidelines

Charles Loprinzi, M.D.Regis Professor of Breast Cancer Research

Mayo Clinic College of Medicine

Chemotherapy-Induced Emesis Classification

–Acute (0-24 hr after chemotherapy)

–Delayed (24-120 hr after chemotherapy)• May last up to 6 days

• Incidence without treatment 20%-90%

–Anticipatory (prior to chemotherapy)

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1. Gregory RE, et al. Drugs. 1998;55:173-189.2. Hesketh PJ, et al. J Clin Oncol. 1997;15:103-109.

Chemotherapy-Induced Emesis: Risk Factors

• Patient-related risk factors1:– Younger age (<50 years)– Female gender– No/minimal prior history of alcohol use– Prior CINV– Anxiety – Hx of morning sickness or motion sickness– Other medical conditions (e.g. intest. obstr., brain mets)

• Treatment-related risk factors1,2:– High emetogenicity of chemotherapy agents/regimens– High drug dose, rapid infusion rate

The Four Emetic Risk Groups of Chemotherapeutic Drugs (ASCO/MASCC/NCCN)

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

Perugia Guidelines 2004, NCCN Guideline Update 2006

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Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy

Rank 19831 19932 19953 19994

1. Vomiting Nausea Nausea Nausea

2. Nausea Constantly tired Loss of hair Loss of hair

3. Loss of hair Loss of hair Vomiting Constantly tired

4. Thought of coming for treatment

Effect on family Constantly tired Vomiting

5. Length of time treatment takes

Vomiting Having to havean injection

Changes in the way things taste

1. Coates A, et al. Eur J Cancer Clin Oncol. 1983;19:203-208.2. Griffin AM, et al. Ann Oncol. 1996;7:189-195.3. De Boer-Dennert M, et al. Br J Cancer. 1997;76:1055-1061.4. Lindley C, et al. Cancer Pract. 1999;7:59-65.

Perception vs Reality: Nausea and Vomiting Incidence Rates in 2001–2002

Moderately Emetogenic Chemotherapy

24

13

24

15

37

13

52

28

0

10

20

30

40

50

60

70

AcuteNausea

AcuteVomiting

DelayedNausea

DelayedVomiting

Perc

ent o

f Pat

ient

s

MD/RN PredictionPatient Experience

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

International observational study 298 pts, 14 practices.

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Perception vs Reality: Nausea and Vomiting Incidence Rates in 2001–2002

Highly Emetogenic Chemotherapy

Perc

ent o

f Pat

ient

s

MD/RN PredictionPatient Experience

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

34

17

39

22

33

12

60

50

0

10

20

30

40

50

60

70

AcuteNausea

AcuteVomiting

DelayedNausea

DelayedVomiting

International observational study 298 pts, 14 practices.

Evolution of Anti-emetic Agents ReflectsAdvances in Neuropharmacology of Emesis

1960s 1970s 1980s 1990s 2000s

Phenothiazines (Dopamine,D2)

High-dose metoclopramide (serotonin) Combination regimens

Predictive variables identified

First NK1 receptor antagonist (Substance P)

Dex=dexamethasone.Hesketh PJ. Support Care Cancer. 1994;2:286-292.

First 5-HT3 receptor antagonist (serotonin) Further understanding of delayed emesis

Combination of Dex and 5-HT3 receptor antagonist

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Olanzapine 2010s

Proposed Pathophysiology of CINV

• Central mechanism– Chemotherapeutic agent activates the CTZ.

• Peripheral mechanism– Chemotherapeutic agent causes irritation and damage

to GI mucosa, resulting in the release of neurotransmitters.

• Combined mechanism– Some chemotherapeutic agents activate both the central

and peripheral mechanisms.

Berger AM, Clark-Snow RA. In: Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins: 2001.

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Emesis and Cancer TreatmentApproach to the Problem

In controlling emesis, the strategy ispreventionrather thantreatment

Emetic reflex

GABA

Histamine

Endorphins

Acetylcholine

Dopamine/DA RAs

Serotonin/5-HT3 RAs

Cannabinoids

Neurotransmitters/TreatmentsAssociated With Emesis

Substance P/NK-1 RAs

DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin; RAs = receptor antagonists.

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Antiemetic Arsenal

• 5-HT3-RA Ondansetron Granisetron (oral and transdermal)DolasetronPalonosetron

• Corticosteroids Dexamethasone

• NK1-RA Aprepitant

Fosaprepitant

Netupitant (NEPA)

Rolapitant

• Dopamin-RA ProchlorperazineMetoclopramide

Benzodiazepines Lorazepam

• Cannabinoid Dronabinol

• Multi-receptor Olanzapine

Serotonin and 5-HT3 Receptors

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Serotonin and 5-HT3 Receptor Pathway

• First recognized with high-dose metoclopramide.1

• Introduction of 5-HT3 antagonists offered an improved treatment option.– Effective in acute vomiting, variable efficacy

for delayed events.2

– Usually used with dexamethasone.2

• Primary mechanism of action appears to be peripheral.3,4

1. Berger AM, Clark-Snow RA. In: Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins; 2001.2. Gralla RJ et al. J Clin Oncol. 1999;17:2971-2994. 3. Endo T et al. Toxicology. 2000;153:189-201.4. Hesketh PJ et al. Eur J Cancer. 2003;39:1074-1080.

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

Palonosetron has a binding affinity at least 30-fold higher than other 5-HT3 RA.

Half-Life and Binding Affinities of 5-HT3 Receptor Antagonists

1. Aloxi® package insert, 2004. 2. Zofran® package insert, 2001. 3. Anzemet® package insert, 2000. 4. Kytril® package insert, 2000. 5. Wong EHF et al. Br J Pharmacol. 1995;114:851-859. 6. Miller RC et al. Drug Dev Res. 1993;28:87-93.

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

Palonosetron (Aloxi®) 40.01 10.455

Ondansetron (Zofran®) 4.02 8.395

Dolasetron (Anzemet®) 7.33 7.606

Granisetron (Kytril®) 9.04 8.915

Tropisetron (Navoban®) 8.05 8.75

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Protection from cisplatin-induced emesis by various 5-HT3

antagonists. Reprinted, with permission, from Grunberg.

Palonosetron vs Ondansetron in MEC – Complete Response: Acute and Delayed Emesis

Palonosetron 0.25 mg IV (n=189)Ondansetron 32 mg IV (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)

Com

plet

e R

espo

nse

(No

Emes

is, N

o R

escu

e)(%

of P

atie

nts)

*81.0

68.6

*74.1

55.1

*69.3

50.3

*p<0.025 (Fisher’s exact test)

• 72% female; mean age 56 years

• 41% chemotherapy-naïve

• Majority receiving cyclophosphamide and/or doxorubicin combination MEC for breast cancer

• No concomitant dexamethasone pretreatment

Gralla R, et al. Ann Oncol. 2003;14:1570-1577. PALO-99-03

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Palonosetron vs Ondansetron in MEC – Complete Response: Acute and Delayed Emesis

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

Time (hr)

0

20

40

60

80

100

Acute: 0-24(Day 1)



Com

plet

e R

espo

nse

(No

Emes

is, N

o R

escu

e)(%

of P

atie

nts)

*

81.0

68.6

*74.1

55.1

*69.3

50.3

*p<0.025 (Fisher’s exact test)


Gralla R, et al. Ann Oncol. 2003;14:1570-1577. PALO-99-03

Palonosetron vs Ondansetron in MEC – No Nausea: Daily

• 72% female; mean age 56 years

• 41% chemotherapy-naïve

• Majority receiving cyclophosphamide and/or doxorubicin combination MEC for breast cancer


Palonosetron 0.25 mg IV (n=189)

Ondansetron 32 mg IV (n=185)

0

20

40

60

80

100

1 2 3 4 5

Day

Nau

sea-

Free

(%

of P

atie

nts)

60.3 56.8

47.6

59.850.3

64.660.0

72.568.6

78.3*

**

*p < 0.05 (Chi-Square test)

PALO-99-03Gralla R, et al. Ann Oncol. 2003;14:4570-1577.

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Palonosetron vs Ondansetron in MEC – No Nausea: Daily




0

20

40

60

80

100

1 2 3 4 5

Day

Nau

sea-

Free

(%

of P

atie

nts)

60.3 56.8

47.6

59.850.3

64.660.0

72.568.6

78.3*

**

*p < 0.05 (Chi-Square test)


Palonosetron vs Ondansetron in MEC – Time to Treatment Failure

Time (hr)

100

90

80

70

60

50

40

30

20

10

0

Perc

ent o

f Pat

ient

s

0 24 48 72 96 120



*

*p=0.0003

Time to Treatment Failure: time to first emetic episode or use of rescue medication.



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What about transdermal granisetron?

Dexamethasone

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Ioannidis JPA, et al. J Clin Oncol. 2000:3409-3422.

Dexamethasone Meta-analysis

• Objective: Review efficacy of dexamethasone for acute and delayed CINV

• 1,200 literature citations screened

• 32 studies with 42 pertinent comparisons analyzed

• 5,613 patients total

• Conclusion: Dexamethasone is effective for acute and delayed emesis

• It improves things by about 10%

Jantunen IT, et al. Eur J Cancer. 1997;33:66-74

Acute Emesis:Dexamethasone + 5-HT3 Antagonist

Percentage of patients with emesis

Study author 5-HT3 + Dex 5-HT3

Adams 11% 25%

Carmichael 15% 24%

Heron 34% 44%

Hesketh 39% 54%

IGAR 7% 28%

Joss 24% 44%

Latreille 36% 61%

Roila 9% 36%

Smith 4% 4%

Smyth 42% 58%

Sorbe 25% 60%

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Optimal Dosing of Dexamethasone in Highly to Moderately Emetogenic Chemotherapy

85 8184 8189

80

0

20

40

60

80

100

Acute Emesis Delayed Emesis

Com

plet

e C

ontr

ol(%

of P

atie

nts)

Dexamethasone 8 mg IV + 4 mg po Days 2–5Dexamethasone 24 mg IVDexamethasone 8 mg IV

Roila F, et al. Proc Am Soc Clin Oncol. 2003;22:729. Abstract 2930.

All patients received ondansetron 8 mg IV in combination with dexamethasone.

Continue Dex if no N/V on Day 1?

• Consider stopping if no symptoms on day 1, for MEC and A/C, when palonosetron and NK1RA are given…..

Celio…Aapro; SCC (2016); 24: 1025-1034Kosaka et al; SCC (2016); 24: 1405-1411

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Substance P and NK1 Receptors

Antiemetic Arsenal

NK1-RAs

• Aprepitant• Oral days 1-3

• Fosaprepitant• IV, day 1 only, venous toxicity

• Netupitant• PO, with palonosetron, day 1 only

• Rolapitant• Oral, day 1

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Substance P and NK1 Receptor Pathway

• Relays noxious sensory information to the brain (ie, modulates nociception).1

• High density of substance P/NK1 receptors located in brain regions implicated in the emetic reflex.2,3

• Primary mechanism of NK1 receptor blockade action appears to be central.4

– Effective for both acute and delayed events.

– Augments antiemetic activity of a 5-HT3 receptor antagonist and corticosteroid.

1. DeVane CL. Pharmacotherapy. 2001;21:1061–1069. 2. Hargreaves R. J Clin Psychiatry. 2002;63(suppl 11):18-24. 3. Saria A. Eur J Pharmacol. 1999;375:51-60.4. Hesketh PJ. Support Care Cancer. 2001;9:350-354.

Saria A. Eur J Pharmacol. 1999;375:51-60.

Substance P and NK Receptors

• Substance P is one of three tachykinins identified to date– Substance P, NKA, NKB

• Binds to neurokinin (NK) receptors– Three subtypes isolated: NK1, NK2 and NK3/3B

• Substance P has affinity for NK1 receptors– Possibly implicated in emesis, depression, asthma, bladder

irritability, inflammatory bowel disease, functional GI diseases

• Substance P induces emesis in ferrets and dogs

• Blocking NK1-receptor decreases acute + delayed emesis

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Aprepitant in Patients Receiving Cisplatin 70 mg/m2: Phase III Trials 052 and 054

Group Day 1 Days 2-3 Day 4

Aprepitant

Standard

O D A D A D

32 mg 12 mg 125 mg

20 mg P

8 mg 80 mg

8 mg BID

P

8 mg

8 mg BID

O = ondansetron IV A = aprepitant po

D = dexamethasone po P = placebo po

32 mg

Warr D, et al. Proc Am Soc Clin Oncol. 2003;22:726. Abstract 2919.

Aprepitant in Patients Receiving Cisplatin: Trial 052 + 054 Complete Response Rates

Complete response (CR): no emesis and no rescue medication.*p<0.001.

Warr D, et al. Proc Am Soc Clin Oncol. 2003;22:726. Abstract 2919.

*

**

Acute: 0-24 (Day 1)



Time (hr)

86

7268

73

5247

0

20

40

60

80

100

% o

f Pat

ient

s

Aprepitant (n=520) Standard (n=523)

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Time Course of Emesis Following Cisplatin With a 5-HT3 Antagonist or Aprepitant

Time Since Cisplatin (hr)

0 8 24 40 60 80 100 1200

20

40

60

80

100 Granisetron + dexamethasone d1/placebo d2–5Granisetron + dexamethasone + aprepitant d1/aprepitant d2–5Aprepitant d0/aprepitant + dexamethasone d1/aprepitant d2–5Aprepitant + dexamethasone d1/aprepitant d2–5

Hesketh PJ, et al. Eur J Cancer. 2003;39:1074-1080.

Do you need 3 days of aprepitant?

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Phase III randomized double-blind study of single-dose fosaprepitant for prevention of cisplatin-

induced nausea and vomiting.

Grunberg S et al. JCO 2011;29:1495-1501

Study Drug Schedule

Day 1 Day 2 Day 3 Day 4

Fosaprepitant regimen

Fosaprepitant150 mg IV

Dexamethasone12 mg PO




Ondansetron32 mg IV

Aprepitantregimen

Aprepitant125 mg PO

Aprepitant80 mg PO

Aprepitant80 mg PO





Ondansetron32 mg IV

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Complete response (CR) and no vomiting (NV) by phase.


©2011 by American Society of Clinical Oncology

Phase III randomized double-blind study of single-dose fosaprepitant for prevention of cisplatin-induced

nausea and vomiting.

Steven M. Grunberg, MD, et al


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Venous toxicity

Infusion site adverse events such as pain, erythema, induration, and thrombophlebitis

•Noted to be infrequent

•More frequently with fosaprepitant, compared to aprepitant (2.7% vs. 0.3%, respectively)


Fosaprepitant-induced PhlebitisMayo Experience with AC

•148 patients analyzed

•98 patients initially received fosaprepitant

•44 received aprepitant

•Venous toxicity

• 34% with fosaprepitant

• 2% with aprepitant

•All with peripheral IV access

Leal, Loprinzi et al; Support Care Cancer. 2014; 22:1313-17.

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Fosaprepitant-induced Venous Toxicity Less Problematic with Cisplatin Regimens

• 100 non-AC HEC patients analyzed

• All initially received fosaprepitant

• All with peripheral IV access

• Venous toxicity

• 7% with cisplatin regimens

• 16% with other non-AC HEC regimens

Hegerova , Loprinzi et al; Support Care Cancer. 2015 Jan;23(1):55-9

NEPA

• Netupitant plus palonosetron

• Hesketh-Annals of Oncology 2014

• HEC

• DB, 5 arm study• (Palo vs 100, 200, 300 of Netupitant/palo vs apr/ond)

• NEPA 300 was the best dose• Better than lower doses (not unexpected, as more is often

better)• Better than palo alone (expected, as adding an NK1RA)• Better than the ond/apr regimen (expected, as using palo)

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NEPA

• Gralla et at -Annals of Oncology 2014

• HEC plus MEC

• DB, 2 arm study• (300 of Netupitant/palo vs

apr/palo)• Dex also used• Multiple dose study

• Comparable efficacy (not surprising)

NEPA

• Aapro-Annals of Oncology 2014

• DB

• MEC

• NEPA vs Palo

• CR better 74% vs 67% (p=0.001); as expected….

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Rolapitant

• Hesketh et al ASCO 2015

• Non-AC MEC

• DB

• CR better• 80% vs 75% (p=0.001) for carbo

regimens• 67% vs 54% (p=0.001) for non-

carbo regimens

Thoughts on NK1 RA Choices

• There are no data that one is superior to another

• They appear to be quite similar to each other

• Pick one based on cost

• The end

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Olanzapine

Olanzapine

• Thienobenzodiazapine

• Anti-psychotic

• Dirty agent: many receptors

• Increases appetite (like megestrol acetate)

• Both of these drugs also decrease nausea/vomiting

• Rudy Navari, and others-independently

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• Impact on multiple receptors

• Anxiolytic effects as well as anti-emetic

Why olanzapine might perform well against nausea

Olanzapine vs Aprepitant Trials

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Olanzapine versus aprepitant for the prevention of chemotherapy-

induced nausea and vomiting (CINV): A randomized phase III

trial. Rudy Navari, et al

South Bend, IN

ASCO 2010, Abstract # 9020

Study design basics

• Sixty-one chemotherapy naïve patients randomized to an OLN or APR regimen

• Out-patient clinic

Antiemetic Regimens

OLN APR

Cisplatin (>70 mg/m2): 12 10

Doxorubicin (>50 mg/m2), Cyclophosphamide: 19 20

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Treatments

OLANZAPINE:

Day 1:Olanzapine, 10 mg oralPalonosetron, 0.25 mg, IVDexamethasone 20 mg, IV

Days 2-4:Olanzapine, 10 mg/day, oral

APREPITANTDay 1:

Aprepitant, 125 mg oralPalonosetron, 0.25 mg, IVDexamethasone 12 mg, IV

Days 2-4:Aprepitant, 80 mg/day, oral, days 2,3

Dexamethasone, 4mg BID, oral, days 2-4

No Nausea (%)

Time Period (hours)

Acute (0 – 24):

Delayed (24 – 120):

Overall (0 – 120):

OLN (n=31) APR (n=30)

90% 87% p –Not Sig

68% 37% p < 0.01

68% 37% p < 0.01

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Olanzapine + Palonosetron + Dexamethasone versus Aprepitant + Palonosetron +

Dexamethasone: Study Design

Day 1 Day 2 Day 3 Day 4

Olanzapine Oln + Palo + Dex Oln Oln Oln

Aprepitant Apr + Palo + Dex Apr + Dex Apr + Dex Dex

• Multi‐center, phase III, open‐label study

• 257 Chemotherapy‐naïve patients receiving highly emetogenic chemotherapy (HEC)

• Schema

Navari RM et al. J Supp Oncol 9:188‐195, 2011.

97

77 77

87

73 73

Acute (0‐24 h) Delayed (24‐120 h) Overall (0‐120 h)

Percent of Patients w

ith Complete Resp

onse

OLN+PAL+DEX vs. APR+PAL+DEXComplete Response

Complete Response OPD (n=121)

Complete Response APD (n=120)

Navari RM, et al, J Support Oncol. 9 (2011) 188-195.

OlanzapineAprepitant

30

87

69 69

87

38 38

Acute (0‐24 h) Delayed (24‐120 h) Overall (0‐120 h)

Percent of Patients w

ith N

o N

ause

a

OLN+PAL+DEX vs. APR+PAL+DEXNo Nausea

No Nausea OPD (n=121)

No Nausea APD (n=120)

Navari RM, et al, J Support Oncol. 9 (2011) 188-195.

OlanzapineAprepitant

Olanzapine (OLN) versus Fosaprepitant (FOS) for the

prevention of chemotherapy-induced nausea and vomiting (CINV) in

patients receiving concurrent chemo-radiation treatment: a randomized,

double blind, phase III trial

R M Navari, C K NagyIndiana University School of Medicine South Bend

University of Notre Dame

2015 ASCO Abstract 9502

Manuscript in press, 2016

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Complete Response (%)

Time Period (hrs) OLN FOS

(n=51) (n=49)

Acute (0-24): 88 84*

Delayed (24-120): 76 73*

Overall (0-120): 76 73*

*p- not significant

No Nausea (%)

Time Period (hrs) OLN FOS

(n=51) (n=49)

Acute (0-24): 86 77*

Delayed (24-120): 71 41#

Overall (0-120): 71 41#

*p>0.05, #p<0.01

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The data from these 3 trials support that olanzapine is:

• As good as aprepitant for preventing vomiting, if not a little better

• Better than aprepitant for preventing nausea

Also, note the price differential…..

Olanzapine (OLN) versus placebo in combination with standard antiemetics for the prevention of

chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy

(HEC): Alliance A221301, a randomized, double blind, phase III trial

Rudolph M. Navari, Rui Qin, Kathryn J. Ruddy, Heshan Liu,

Steven F. Powell, Madhuri Bajaj, Leah Dietrich, Jacqueline M. Lafky, Charles L. Loprinzi

Alliance Clinical Trials in Oncology

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Olanzapine for the preventionof CINV: Alliance A221301

Patients Receiving HEC R

Olanzapine + 5-HT3 RA + Aprepitant + Dexamethasone

SPlacebo + 5-HT3 RA +Aprepitant +Dexamethasone

End Points:

Primary: No Nausea

Secondary: Complete Response (No emesis, No rescue)

No Nausea (%)

Time Period (hrs) OLN PLA p value

(n=192) (n=188)

Acute (0-24): 73.8 45.3 <0.0001

Delayed (24-120) 42.4 25.4 0.0008

Overall (0-120): 37.3 21.9 0.0015

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Presented by:

Complete Response (%)

Time Period (hrs) OLN PLA p value

(n=192) (n=188)

Acute (0-24): 85.7 64.6 <0.0001

Delayed (24-120): 66.9 52.4 0.0073

Overall (0-120): 63.6 40.6 <0.0001

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Sedation Scores on Day 2

SedationScores

Olanzapine (n=192)

Placebo (N=188)

0 58% 65%1 6% 10%

2 2% 7%3 8% 4%

4 2% 4%5 4% 4%

6 4% 2%7 3% 1%

8 8% 2%9 2% 1%

10 3% 1%Missing 11 7

20% 7%

16% 19%

36

The data from this 3 trial supports that olanzapine :

• Provides additional benefit over aprepitant for preventing nausea and vomiting

• Causes some sedation

Guidelines

37

Guidelines

• ASCO

• MASCC/ESMO

• NCCN

Adapted from Basch et al, JCO Nov 1 2011: 4189-4198..

ASCO 2011 Antiemetic Consensus Guidelines –HEC

•NK1RA (aprepitant or fosaprepitant); the only ones out then

•5HT3RAs (ond, gran, dolosetron, palo)

•Dex 12 mg PO/IV, plus oral days 1-3 or 1-4

•Hesketh et al JCO; 2016 381-386

•Can use netupitant/palonosetron oral agent

38


ASCO 2011 Antiemetic Consensus Guidelines –MEC

•Palo

•Dex

•If NK1RA used, then can use any 5HT3RA


ASCO 2011 Antiemetic Consensus Guidelines –Low Emetogenic

•Single 8-mg dose of dexamethasone before chemotherapy

39


ASCO 2011 Antiemetic Consensus Guidelines –Minimally Emetogenic

•No routine antiemetic before or after chemotherapy

MASCC/ESMO-2013

• Very similar to ASCO

• AC still not upgraded to HEC, but treated as such

40

NCCN 2015

• HEC-3 options1. As per previous 2 guidelines

2. Netupitant/Palo oral and dex 12 mg D-1, plus dex on D-2-4

3. Olanzapine Regimen

Olanzapine 10 mg PO D1-4

Palo 0.25 mg IV and Dex 20 mg

• MEC-3 options-Similar to HEC, except1. with/without NK1RA

2. Netupitant regimen: +/- Dex on days 2,3

3. Olanzapine Regimen: Olanzapine 10 mg PO only 3 days, not 4

• This guideline suggests that pt factors can influence anti-emetic choice for MEC

Institutional Guideline Processes

• Kadakia KC, Leal AD, Seisler DK, Qin R, Fee-Schroeder KC, Grendahl DC, Sorgatz KM, Loprinzi CL. Antiemetic prescribing practices using a computerized physician order system. Support Care Cancer 2014 Jan;22(1):217-23.

41

How Well Do Anti-emetics Work for Treatment of CINV?

0

1

2

3

4

5

6

0 30 60 90 120 150 180 210 240

Time (minutes)

Mea

n N

ause

a S

cale

(0-

10)

prochlorperazine

5HT3 antagonist

J Palliat Med 2011; 14(7):810-4.

42

• The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

Rudy Navari, MD

Supp Care Cancer; 2013: 1653-66

• DB, phase III trial Treatment of breakthrough CINV in chemotherapy-naive patients receiving HEC

• 112 pts with breakthrough N/V

• Randomized to – Olanzapine, 10 mg orally daily for 3 days

– Metoclopramide, 10 mg orally TID for 3 days.

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Results

• 3 day observation period

• No vomiting– Olanzapine, 70% (39 out of 56)

– Metoclopramide, 31% (16 out of 52)

– p < 0.01

• No nausea (0, scale 0-10, M.D. Anderson Symptom Inventory) – Olanzapine, 68% (38 of 56)

– Metoclopramide, 23% (12 of 52)

– p < 0.01

Megestrol Acetate

44

Antiemetic activity of megestrol acetate in patients receiving chemotherapy

Zang, et alSichuan Province, 610041, China.

Support Care Cancer. 2011 May;19(5):667-73. Epub 2010 Apr 26.

PATIENTS AND METHODS

• Patients receiving chemotherapy

• Randomized to receive, days -1 to 4 – Megestrol acetate 320 mg PO

– Placebo

• All also received, on day 1 – Granisetron 3 mg IV

– Metoclopramide 20 mg IM

• Crossover design during two consecutive cycles

45

RESULTS

Endpoint Megestrol Placebo P value

Complete Protection 45% 17% < 0.001

CP, acute phase 85% 72% 0.011

CP, delayed emesis 49% 18% < 0.001

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