Pathophysiology of ChemotherapyInduced Nausea and Vomiting (CINV)

Slide 1

Mechanisms of Chemotherapy-Induced Nausea and Vomiting (CINV)

Central mechanism
Chemotherapeutic agent activates the chemoreceptor trigger zone (CTZ) Activated CTZ invokes release of various neurotransmitters, which stimulate vomiting center

Peripheral mechanism
Chemotherapeutic agent causes irritation and damage to gastrointestinal (GI) mucosa, resulting in the release of neurotransmitters Activated receptors send signals to vomiting center via vagal afferents
Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:28692880.
Slide 2

Proposed Pathways for ChemotherapyInduced Nausea and Vomiting (CINV)

Higher CNS centers

Chemoreceptor trigger zone Vomiting center Medulla

Chemotherapy

oblongata

Increased afferent input to the chemoreceptor trigger zone and vomiting center Cell damage

Small intestine
Release of neuroactive Activation of vagus agents and splanchnic nerves
Adapted from Grunberg SM et al N Engl J Med 1993;329:17901796.

Slide 3

Serotonin and 5-HT3 Receptor Pathway

First recognized with high-dose metoclopramide Development of 5-HT3 antagonists has had dramatic
impact
Highly effective in acute vomiting, less effective for delayed events Optimal use is with dexamethasone

Primary mechanism of action appears to be peripheral

Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:28692880. Gralla RJ et al J Clin Oncol 1999;17:29712994. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819. Endo T et al Toxicology 2000;153:189201. Hesketh PJ et al Eur J Cancer Slide 4 2003;39:10741080.

Neurotransmitters Involved in CINV

Substance P
Histamine

Serotonin

Emetic Reflex

Endorphins

GABA*

Acetylcholine

Dopamine
*Gamma-aminobutyric acid. Diemunsch P, Grlot L Drugs 2000;60:533546. Grunberg SM, Hesketh PJ N Engl J Med 1993;329:17901796. Hornby PJ Am J Physiol Gastrointest Liver Physiol 2001;280:G1055G1060.

Slide 5

Substance P and Neurokinin1 (NK1) Receptor Pathway

High density of substance P/NK1 receptors located in
brain regions implicated in the emetic reflex Primary mechanism of NK1 receptor blockade action appears to be central
Effective for both acute and delayed events Augments antiemetic activity of a 5-HT3 receptor antagonist and corticosteroid

Hargreaves R J Clin Psychiatry 2002;63(suppl 11):1824. Saria A Eur J Pharmacol 1999;375:5160. Hesketh PJ Support Care Cancer 2001;9:350354.

Slide 6

Localization of Neurokinin1 (NK1) Receptors in Humans

Binding of positron emission tomography (PET) tracer to NK1 receptors

Striatum: High NK1 receptor expression
Low
Adapted from Hargreaves R J Clin Psychiatry 2002;63(suppl 11):1824.

Tracer Binding High

Slide 7

Acute Chemotherapy-Induced Nausea and Vomiting (CINV)

Starts within the first 24 hours after chemotherapy
administration
Majority of chemotherapeutic agents induce emesis approximately 13 hours following administration

Most researched type of CINV

Remains common despite dramatically improved protection

Pisters KMW, Kris MG. In: Principles and Practice of Supportive Oncology. Lippincott-Raven; 1998. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819.

Slide 8

Delayed Chemotherapy-Induced Nausea and Vomiting (CINV)

Starts 24 hours or more after chemotherapy administration First defined with high doses of cisplatin but known to
occur with other chemotherapy agents
Carboplatin Cyclophosphamide Doxorubicin Epirubicin Anthracyclines

Mechanism not known; appears to differ from

acute emesis
Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins, 2001:28692880. Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Ann Oncol 1998;9:811819.
Slide 9

Cisplatin Biphasic Pattern of ChemotherapyInduced Nausea and Vomiting (CINV)

Acute Delayed

Time (Days)

Maximal emetic intensity seen within 24 hours postdose Distinct second phase seen, occurring on Days 25 postdose
Adapted from Tavorath R, Hesketh PJ Drugs 1996;52:639648. 1996. Used with permission from Adis International Limited.
Slide 10

Postcisplatin: Differential Involvement of Neurotransmitters Over Time

ACUTE (Day 1) DELAYED (Days 25)

Serotonindependent mechanisms (peripheral)

Substance Pdependent mechanisms (central)

12

24

120

Hours after cisplatin

Hesketh PJ et al Eur J Cancer 2003;39:10741080.
Slide 11

Pathophysiology of Chemotherapy-Induced Nausea and Vomiting (CINV): Summary

Different neurophysiologic mechanisms contribute to
different CINV phases
Unlike acute events, delayed CINV appears to be mediated by nonserotonin mechanisms

Role of multiple neurotransmitters continues to support

rationale for combination regimens
Neurokinin-1 (NK1) receptor antagonists target substance P, a key neurotransmitter involved in the emetic pathway, for additional protection
Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams & Wilkins; 2001:28692880. Hesketh PJ et al Eur J Cancer 2003;39:10741080. Grunberg SM, Hesketh PJ N Engl J Med 1993;329:17901796.

Slide 12

Pathophysiology of Chemotherapy-Induced Nausea and Vomiting (CINV)

Before prescribing any of the products mentioned in this slide presentation, please consult the manufacturers prescribing information.

Copyright 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 4-05 EMD 2004-W-6150-EM VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
Slide 13