management of chemotherapy induced nausea and vomiting as an integral part of cancer management and not palliative talking

1. Chemotherapy – Induced
Nausea and Vomiting.
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Mundipharma Symposium
Asyut Annual Conference
Tuesday 20/02/2018

2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, Bayer, Sanofi-
Genzyme.
Speaker Disclosures:

3. Antineoplastic Therapy Induced
Adverse Events:
CTH - AE
Alopecia
Weakness
Fatigue
Hematological
Psychological
NauseaVomiting
Sexual
Dermatologic
Lower GIT
GUT
Uptodate. Accessed 26/08/2016

4. What Do Patients Receiving AC Based Cth Rate As the
Worst Side Effects?
*Other: eg, constipation, hypotension
Hernandez TC, et al. Support Care Cancer.
2015;23(11):3341-3359.

5. What Is the Real World Incidence of CINV With
"Optimal" Antiemetic Prescribing?
1. Dranitsaris G, et al. Ann Oncol. 2017;28(6):1260-1267. 2. Dranitsaris G, et al. Support Care
Cancer. 2016;24(4):1563-1569.
Grade 2
• Nausea: Reduced oral
intake, but no significant
weight loss, dehydration
or malnutrition
• Vomiting: 2-5 episodes in
24 hours

7. CINV
The Problem:
Ineffective Control
or Persistent CINV
Quality of Life
Activities of
Daily Livings
Treatment
Outcome
Adherence
to Treatment
Schedule
Economic Burden
Hospital 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.

8. FLIE, Functional Living Index-Emesis
Lindley CM, et al. Qual Life Res. 1992;1(5):331-340; used with permission from Kluwer Academic Publishers ©1992.
80
70
Patients experiencing CINV Patients without CINV
MeanFLIEScores
90
110
100
120
115
*
85
121
Acute Emesis (day 1) Delayed Emesis (day 3)
130
122(N = 122)
*P = .001
CINV
Impact on Quality of Life:

9. CINV
Impact on Treatment Adherence & Survival:
EORTC RCT
HEC
Testis Ovary Lung

10. CINV
Impact on Treatment Adherence & Survival:
P = .004
Neymark & Crott. Support Care Cancer
(2005) 13: 812–818

11. Chemotherapy-Induced Nausea and
Vomiting: Risk Factors
Patient-related risk factors1,2: Treatment-related risk factors:1,3
• Younger age (<50 years)
• History of Excessive alcohol and
tobacco use
• Susceptibility to motion sickness
• PriorCINV
• Anxiety
• Emesis during pregnancy
• Impaired performance status
• Previous exposure to chemotherapy
• Emetogenic potential of chemotherapy
agents or regimens (Hesketh classification)3
• Chemotherapy dose and schedule1
• Use of multiple chemotherapy agents3
1. Gregory RE, et al. Drugs. 1998;55(2):173-189. 2. Jordan K, et al. Oncologist. 2007;12(9):1143-1150. 3. Hesketh PJ,
et al. J Clin Oncol. 1997;15(1):103-109. 4. Janelsins MC, et al. Expert Opin Pharmacother. 2013; 14(6): 757-766.

12. CINV – Perception versus Reality:
Cumulative incidence of adverse symptom events over time as
reported by patients versus clinicians at
successive office visits
Basch E. N Engl J Med.
2010;362(10):865-869.
Months Months
*Patient-reported symptoms were collected directly from 467 persons with different malignant conditions at a total of 4034 clinic visits at
Memorial Sloan-Kettering Cancer Center, New York
**Clinician-reported symptoms were recorded by physicians and nurses treating those patients at the same visits

13. CINV: Perception vs Reality:
Healthcare providers’ predictions of incidence rates of
nausea and emesis
Grunberg SM, et al. Cancer. 2004;100(10):2261-2268.
HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; RN, registered nurse; MD, physician
HEC MEC
10
0
20
30
40
50
60
70
34 33
17
12
39
60
22
50
24
37
13 13
24
52
15
28
Patients(%)
MD/RN Prediction
Patient Experience
Acute
Nausea
Acute Delayed Delayed
Vomiting Nausea Vomiting
Acute Acute Delayed Delayed
Nausea Vomiting Nausea Vomiting
HEC MEC

14. CINV
QoL & Physician’ Perception:
Total =
947
Physicians =
375
Nurses =
186
Patients =
386
Vidall et al. Support Care Cancer (2015) 23:3297–3305

15. Controlling Chemotherapy-Induced
Emesis Progress Over the Past 30 Years:
Efficacy
1980 1990
Cisplatin (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

16. Cancer
Management
Surgery
Medical Control of CINV
Radiation

18. Is There an Optimal Regimen for Breast
Cancer Patients Receiving Anthracycline +
Cyclophosphamide?
• 47 antiemetic
regimens
• 15 CINV endpoints
• Heterogeneous
patient
populations,
chemotherapy, and
interventions
• All endpoint data not
available
• Cross trial
comparisons
difficult
Network diagram of
antiemetic regimens
Notes: Node size proportional to number of patients studied; line thickness
reflects number of trials
a, acute; d, delayed; OLANZ, olanzapine; STER,
steroids
Hutton B, et al. Cancer Treat Rev.
2015;41(10):951-959.

19. Effective Management of CINV:
1. Real perception of the problem & its
consequences.
2. Well orientation of risk factors.
3. Understanding the pathophysiology.
4. Anticipating the type of emesis.
5. Proper medical coverage.
6. Others to be considered.

20. Pathophysiology of CINV:
CPG
= VC
AP NTS CTZ
Enterochromaffin
Cells
D2
5-
HT3
NK1
Chemotherapy
5-
HT
5-
HT3
VagalAfferent
Gut Wall
Sub
P
Upper GIT
 Emesis
Vagal Efferent
Higher Cortical Centers
Anticipatory
Vomiting

21. Receptors Implicated in Emetic Reflex:
Emetic
Reflex
Endorphins
Cannabinoids
Histamine
Acetylcholine
Serotonin
Substance P
Dopamine
GABA

22. Types of CINV:
Anticipatory Acute Delayed Breakthrough
Before and may be
after
0 – 12 Hour 24 – 96 Hr Any time and
persistent
Cognitive - Cortical H3 Receptors NK1 Psychological
Needs
Psychological
Support
Anti – H3 Anti-NK1 Problem
Tavorath R, Hesketh PJ. Drug treatment of chemotherapy-induced delayed emesis. Drugs 1996; 52:639.
Hesketh PJ, Sanz-Altamira P, Bushey J, Hesketh AM. Prospective evaluation of the incidence of delayed nausea and vomiting in
patients with colorectal cancer receiving oxaliplatin-based chemotherapy. Support Care Cancer 2012; 20:1043.
Morrow GR, Roscoe JA, Kirshner JJ, et al. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care
Cancer 1998; 6:244.

23. 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, panitumumab
Vinca alkaloids,
bleomycin, bevacizumab
Moderate
30%
to
90%
Low
10%
to
30%
Minimal <10%
Emetogenic Potential: IV Agents

24. 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, thalidomide
Chlorambucil,
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”

25. Patterns of emesis
Differences among antineoplastic agents
Cyclophosphamide/Carboplatin
Cisplatin
IntensityofEmesis
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

26. Antiemetic Efficacy
Acute Delayed
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
Multiple
Dopamine D2 receptor
GABA-chloride channel
complex
Dopamine D2 receptor
Multiple receptors
CB1-Receptor Muscarinic/
cholinergic rec.
+(+)
(+)
(+)
+(+)
(+)
(+)
Classical neuroleptics
Olanzapine
Cannabinoids
Antihistamines
(+)
+
(+)
−
(+)
+
(+)
−
Antiemetic Drugs

27. • 1198 patients enrolled in five non-interventional CINV
prospective studies
• 4197chemotherapy cycles
• http://www.riskcinv.org
Dranitsaris G, et al. Ann Oncol.
2017;28(6):1260-1267.

28. Chemotherapy Induced Nausea
and Vomiting
CINV can be prevented and should not
occur.
Use this tool to estimate your patient's risk (for
both acute and delayed CINV).

29. Prevalence of
any CINV with
no antiemetic
use

30. Questionnaire (Step
2 of 2)
1. Whatis the patient’s
gender?
2. What is the
patient’s age?
5.Doesthepatient expect
to devebp INV?
4. Did the patient have
morningsickness
e
More
Information
Referen
ces
Fem
ale
CIllV Risk
Assessment
5. Did the patient sleep 7 or
more hours
6.Afier the pevous cycH
ofcMmotherapy
(JapplrabH) dkJthpatient
take non- ant
7. Has the patient had any
nausea or a vomiting
episode in the priorcycle?
B.Is the chemotherapy
Anthracycline or
Pbtinum based?
Ye
s
Ye
s

31. Nausea: Reduced oral
intake, but no significant
weight loss, dehydration,
or malnutrition
Vomiting: 2-5 episodes in
24 hours

32. 49.8
°/‹
CINVRisk
EMETIC RISKGROUP ANTIEMETI
CS
SpecificRiskFactors: High NDn-AC 5-HT, + DEX N 1
• Age
• Anthracyclire-Dasedor Platinurfr
»•
5-HT,
Carboplatin 5-HT, + DEX + NK1
MDderate (other than
carboplatin)
5-HT, + DEX
LDW 5-HT, o
r
DEx or EN3P
Minimal No
routine prophylaxis

33. MASCC/ESMO Guidelines

34. Steroids as Anti-emetics:
Mechanism of Action:
1. Anti-inflammatory effect.
2. Central interaction with NTS.
3. Interaction with Serotonin.
4. Interaction with NK1 Receptor.
5. Maintain organ physiology.
6. Regulate hypothalamic-Pituitary-Adrenal axis
7. Reducing pain and use of opiates.
Chu et al. Eur J Pharmacol. 2014 Jan 5;722:48-54

35. 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.
antunen IT, et al. Eur J Cancer. 1997;33(1):66-74.

36. Pharmacology
Chemical structure and main features of commonly used 5-HT3 RAs
1. Constenla, M. Ann Pharmacother. 2004;38(10):1683-1691. 2. Granisetron [prescribing information]. Heron Therapeutics, Inc. Redwood City,
CA; 2016. 3. Wong EH, et al. Br J Pharmacol. 1995;114(4):851-859. 4. Rojas C, et al. Anesth Analg. 2008;107(2):469-478. 5. Rojas C, et al. Eur J
Pharmacol. 2010;626(2-3):193-199. 6. Rojas C, et al. J Pharmacol Exp Ther. 2010. 335(2):362-368. 7. Saito M, et al. Lancet Oncol.
2009;10(2):115-124. 8. Janelsins MC, et al. Expert Opin Pharmacother. 2013;14(6):757-766.
PALO Ondansetron Granisetron
Half life (h)1 >40 5-6 Oral: 11.6, Subcu:
242
Binding affinity (pKi)3 10.45 8.39 8.91
Positive cooperativity4 YES NO NO
Inhibition of
receptor function5
Long
lasting
Short lasting Short lasting
Receptor
Internalization
YES NO NO
Inhibition of 5-HT3/NK1
receptor cross-talk6
YES NO NO

37. • Potent and selective NK1 RAs
• Competitively bind to and block activity of human SP receptors
• High binding affinity, differences in half-life (see also
fosaprepitant)
• High and long-lasting (for up to 96 hours) brain receptor
occupancy after single oral dose
• Influencing CYP3A4 (netupitant and (fos)aprepitant) or CYP2D6
(rolapitant)
1. Lorusso V, et al. Future Oncol. 2015;11(4):565-577. 2. Aprepitant [prescribing information]. Merck & Co., Inc.
Whitehouse Station, NJ; 2003. 3. Rizzi A, et al. Peptides. 2012;37(1):86-97. 4. Spinelli T, et al. J Clin Pharmacol.
2014;54(1):97-108. 5. Rolapitant [prescribing information]. TESARO, Inc. Waltham, MA; 2015. 6. Bernareggi A, et
al. Support Care Cancer. 2015;23(Suppl 1): Abstract 11-30-P. 7. Van Laere K, et al. Clin Pharmacol Ther.
2012;92(2):243-250.
PHARMACOLOGY
Main features of oral NK1RAs
Netupitant Aprepitant Rolapitant
Half-life (h) 961 9-132 169-1835
Binding Affinity
(pKi)
9.03 high2 high5
Striatum RO
reached at
120 hours
75%6 37-76%7 73%5

38. TheOncologist 2011;16:207–216

39. TheOncologist 2011;16:207–216

40. TheOncologist 2011;16:207–216

41. TheOncologist 2011;16:207–216

42. The Art of Today:
• Effective control of CINV is integral part of cancer
management nowadays.
• Effective control of CINV improves OAS.
• Risk model guiding the management is advisable and
coinciding with guidelines.
• 2nd Generation 5H3 blockers is much preferred than 1st
generation agents in terms of bioavailability,
pharmacodynamics and kinetics.
• Palonosetron is effective in controlling acute & delayed
CINV and is considered the backbone of any antiemetic
regimens.
• NK1 Receptor antagonist is more effective in delayed than
acute CINV and can be considered in addition to 5H3-RA in
certain patients and regimens
• Still Dexamethasone is added to most regimens.

43. To effectively control CINV;
Follow guidelines and Risk Stratification Models
Better than Expert judgment