Chemotherapy – Induced Nausea and Vomiting.

Case Presentation & Wrap Up

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo University

JW Marriott, CairoMundiPharma Stand Alone MeetingFriday, 11/03/2016

Disclosures:

Speaker, Consultant and Advisory Board Member for:• Amgen• Merck Serono• Janssen Cilag• Astra Zeneca• Pfizer• Astellas.• Hoffman La Roche• Novartis• Mundipharma

CINV:Overview:

Rank* 19831 19932 19953 19994 20045

1 Vomiting Nausea Nausea Nausea Fatigue

2 Nausea Constantly tired Loss of hair Loss of hair Nausea

3 Loss of hair Loss of hair Vomiting Constantly tired Sleep Disturbances

4Thought of coming for treatment

Effect on family Constantly tired Vomiting Weight loss

5 Length of time treatment takes Vomiting Having to have

an injectionChanges in the

way things taste Loss of hair

* In order of patients’relevance1. Coates A, et al. Eur J Cancer Clin Oncol. 1983;19:203-2082. Griffin AM, et al. Ann Oncol. 1996;7:189-1953. De Boer-Dennert M, et al. Br J Cancer. 1997;76:1055-10614. Lindley C, et al. Cancer Pract. 1999;7:59-655. Medscape CME

CINVThe Problem:

Ineffective Control or Persistent CINV

Quality of LifeActivities of Daily Livings

Treatment Outcome

Adherence to Treatment

Schedule

Economic BurdenHospital Stay & Medical Care

1. Curran MP et al. Drugs. 2009;69(13):1853-78 2. Aapro M et al. Ann Oncol. 2012 Aug;23(8):1986-92. Epub 2012 Mar 6.3. Janelsins MC et al. Expert Opin Pharmacother. 2013 April ; 14(6): 757–766.4. Burke TA et al. Support Care Cancer. 2011 Jan;19(1):131-40.

FLIE, Functional Living Index-EmesisLindley CM, et al. Qual Life Res. 1992;1(5):331-340; used with permission from Kluwer Academic Publishers ©1992.

80

70Patients experiencing CINV Patients without CINV

Mea

n FL

IE S

core

s

90

110

100

120 115

* 85

121

Before chemotherapy (day 1) After chemotherapy (day 3)

130 122(N = 122)

*P = .001

CINVImpact on Quality of Life:

CINVQoL & Physician’ Perception:

Does Not Fit with Health Care Providers’ Perception

Does Not Fit with Health Care Providers’ Perception

CINVQoL & Physician’ Perception:Total = 947

Physicians = 375

Nurses = 186

Patients =386

Vidall et al. Support Care Cancer (2015) 23:3297–3305

CINVImpact on Treatment Adherence & Survival:

EORTC RCT HEC Testis Ovary Lung

CINVImpact on Treatment Adherence & Survival:

P = .004

Neymark & Crott. Support Care Cancer (2005) 13: 812–818

Controlling Chemotherapy-Induced Emesis Progress Over the Past 30 Years:

Efficacy

1980 1990Cisplatin (highly emetic)

5-day complete control:

100% -

75% -

50% -

25% -

AC chemotherapy

0% 10%

50% 50%60% 50%

2000

85% 75%

2010

5-HT3 +steroids

Added NK1

AC, anthracycline–cyclophosphamide

Chemotherapy

Basch E, et al. J Clin Oncol. 2011;29(31):4198-4198, Roila F, et al. Ann Oncol. 2010;21(Suppl 5):v232-v243.

Risk Examples

High >90% Cisplatin, streptozotocin, carmustine, dacarbazine

Carboplatin, cyclophosphamide, doxorubicin, ifosfamide, oxaliplatin,

irinotecan, alemtuzumab, azacitidine, bendamustine

Etoposide, gemcitabine, 5FU, docetaxel, paclitaxel,

cetuximab, panitumumabVinca alkaloids,

bleomycin, bevacizumab

Moderate 30% to

90%

Low 10% to

30%Minimal <10%

Emetogenic Potential: IV Agents

Chemotherapy Risk Examples

High >90% Hexamethylmelamine, procarbazine

Roila F, et al. Ann Oncol. 2010;21(Suppl 5):v232-v243.

Moderate 30% to

90%

Cyclophosphamide, temozolomide, vinorelbine,

imatinib

Capecitabine, fludarabine, etoposide, everolimus, lapatinib,

lenalidomide, sunitinib, thalidomideChlorambucil,

hydroxyurea, L-phenylalanine mustard,

6-thioguanine, methotrexate, gefitinib, erlotinib, sorafenib

Low 10% to

30%

Minimal <10%

Emetogenic Potential: Oral Agents

“The antiemetic therapy for oral agents has to be individualized”

Patterns of emesisDifferences among antineoplastic agents

Cyclophosphamide/Carboplatin

CisplatinIn

tens

ity o

f Em

esis

Acute phase

Days

Delayed phase

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

Different patterns of emesis induced by different antineoplastic drugs: to be considered for CINV management in clinical practice

Antiemetic Efficacy of Treatments Acute EmesisDelayed Emesis

Jordan K, et al. Crit Rev Oncol Hematol. 2007;61(2):162-175.

Mode of Action Class

5-HT3 receptor 5-HT3

antagonists (ondansetron, palonosetron)

NK1 antagonists (aprepitant, fosaprepitant)

Steroids Benzamides (metoclopramide)

Benzodiazepines

+++++++

+/-+/-+

++NK1 receptor

MultipleDopamine D2 receptor

GABA-chloride channelcomplexDopamine D2 receptor Multiple receptorsCB1-Receptor Muscarinic/ cholinergic rec.

+(+)(+)(+)

+(+)(+)(+)

Classical neuroleptics Olanzapine

Cannabinoids Antihistamine

s

(+)+

(+)−

(+)+

(+)−

Antiemetic Drugs

Binding Affinity of 5-HT3 Receptor Antagonists

1. Wong EH, et al. Br J Pharmacol. 1995;114(4):851-859. 2. van Wijngaarden I, et al. Eur J Pharmacol. 1990;188(6):301-312. 3. Miller RC, et al. Drug Dev Res. 1993;28(1):87-93.

5-HT3 Antagonist: pKi (nM):

Palonosetron1 10.4

Granisetron2 8.4

Ondansetron2 8.1

Dolasetron3 7.6

The Effect of Adding Dexamethasone to 5-HT3 Antagonists on Acute Emesis

P. 00001

antunen IT, et al. Eur J Cancer. 1997;33(1):66-74.

Neurotransmitters, Antiemetics, and

Receptors- Acute Emesis: Moderate and High

Risk -

Setron >

Aprep>NK1

MCP >(In highDoses)

Serotonin

Substance P

Dopamine

5-HT3

D2

Aprep, aprepitant, MCP, metoclopramide

NEURON

NEPA + Dex*

80% 75% 90% 84%

Palonosetron + Dex* 72% 69% 72% 66%

Effectiveness of Netupitant + Palonosetron (“NEPA”) + DEX versus Palonosetron (“NEPA”) + DEX:

A Randomized Trial In 1450 Patients Receiving “AC” Chemo

* All regimen comparisons P≤.020

Aapro M, et al. Ann Oncol. 2014;25(7):1328-1333.

Observer Results Patient Reported Outcomes

No Emesis

No Nausea

No Impact on Daily Living: VOMITING

No Impact on Daily Living:

NAUSEA

• Female gender

• Young age

• Anxious personality• Minimal alcohol use (Caveat ≥5 drinks week

is protective)

• History of emesis during pregnancy

• History of motion sickness

• History of chemotherapy

Roila F, et al. J Clin Oncol. 1991;9(4):675-678. Morrow GR, et al. Support Care Cancer. 2002;10(2):96-105.

Individual Risk Factors

Not Taken into Considerations in Guidelines

More Than Chemicals Tricks Of The Trade

• What to eat or avoid: Flavors, odors, spicy foods

• Less quantity and more meal times• Hydration• Coca-Cola• Digipressure• Relaxation

Roles of Nurses

• Can help in guideline utilization if aware and understand the guidelines

• Lack of access to evidence-based medicine/nursing

• Position in institutions• Recognition of

education/competencies• Nurses-led clinics

Clinical Scenario :Anthracycline Chemotherapy

• 47-year-old woman with right sided 3 cm breast cancer– Grade 3 ER, 80%; Ki, 67%-30%– HER2 negative– 3/16 positive lymph nodes

• Recommended FE100C x 3 + docetaxel x 3 adjuvant chemotherapy– Hyperemesis in pregnancy– Normal LFTs and renal function

• Very fearful that vomiting will be severe

Please assume all agents are available and reimbursed…

1. Granisetron / ondansetron + dexamethasone2. Palonosetron + dexamethasone3. Aprepitant / fosaprepitant + 5-HT3 inhibitor + dexamethasone

4. NEPA (netupitant + palonosetron) + dexamethasone

*Plus rescue medication with PRN domperidone / metoclopramide / prochlorperazine

Which antiemetic regimen would you like to recommend for cycle 1*?

Take Home Message:

• Effective control of CINV is a pre-requisite in any cancer management.

• 5-H3 Receptor blockers are the cornerstone in management particularly Palonosetron.

• NK-1 Receptor Block: Mainly in HEC.• Role of Dexamethasone.• Combined Receptor Blockade.

Thank You