Antiemetic prophylaxis for Chemotherapy

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Antiemetic prophylaxis for Chemotherapy

• 2004.4.1.

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Progress in Antiemetics

• 1960-1980s
• dopamine receptor antagonist (benzamide,
  metoclopramide), butyrophenones (haloperidol,
  droperidol), corticosteroid
• 1990s serotonin receptor antagonist
• 1999 ASCO guideline
• 2000-2004 substance P, NK-1 receptor antagonist

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• Neurophysiology of Emesis
• 1999 ASCO guidelines Recommendations for the use
  of antiemetics
• Problems poor compliance with guideline and
  delayed emesis
• A New Agent NK-1 receptor antagonist

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• Neurophysiology of Emesis
• 1999 ASCO guidelines Recommendations for the use
  of antiemetics
• Problems poor compliance with guideline and
  delayed emesis
• A New Agent NK-1 receptor antagonist

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Neurophysiology of Emesis

• Neurotransmitter
• dopamine, acetylcholine, histamine,
  serotonin, opiates and substance P
• Emetic Afferent signal
• 1) CTZ (chemoreceptor trigger zone) area
  postrema
• 2) Enterochromaffin cell
• 3) Limbic system
• 4) labyrinth

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Emetic Signal Neurotransmitter

• Area Postrema highly vascularized with
  fenestrated vessels, which lack tight junctions
  between capillary endothelial cells, so
  anatomically specialized to readily sample
  elements present in the circulating blood and
  cerebrospinal fluid
• Enterochromaffin Cell release 5-HT(serotonin)
  and activate 5-HT receptors on vagal nerve

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5-hydroxytryptamine(5-HT)

• Cisplatin generate free radical and cause
  calcium-dependent exocytic release of serotonin
  from enterochromaffin cells in GI tract
• Increase in urinary output of 5-HIAA (metabolite
  of 5-HT) within 24hrs after cisplatin
  administration
• 5-HIAA response profile correlated with time
  course of clinical efficacy of profile of 5-HT3
  RA
• 5-HT3 RA respond poorly since 24hrs after
  chemotherapy, so 5-HT is NOT believed to be a
  significant mediator of delayed emesis.

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Substance P

• High level in area postrema of dogs(Amin, 1954)
• Co-localized with serotonin in enterochromaffin
  cells
• Elevation of substance P level in peripheral
  circulation since 24hrs after cisplatin
  administration (Matsumoto, 1999)
• May have major role in delayed emesis!

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Serotonin vs substance P

• Ondansetron
• antagonist 5-HT Rc
• acts mainly acute phase of vomiting
• L-758298
• antagonist of substance P
• acts mainly delayed phase of vomiting
• (Hesketh, 2003)

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• Neurophysiology of Emesis
• 1999 ASCO guidelines Recommendations for the use
  of antiemetics
• Problems poor compliance with guideline and
  delayed emesis
• A New Agent NK-1 receptor antagonist

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1999 ASCO Guidelines for Antiemetics Acute
Emesis
Antiemetics prescription according to the emetic
risk of patient characterstics and
chemotherapeutic agents!
high risk prior chemotherapy, female sex, a low
chronic alcohol intake or history, and younger age
High Risk(gt30) cisplatin, carboplatin,
cytoxan... Intermediate Risk(10-30) irinotecan,
taxol,docetaxel Low risk(lt10) vinorelbine,
fluorouracil, tamoxifen
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5-HT RA Corticosteroid

• Complete control rate of acute emesis
  75(58-96)
• 5-HT RA corticosteroid combination yield
  greater antiemetic protection than single 5-HT RA
  
• Better emetic control than metoclopramidecorticos
  teroid
• Regimens of choice for patients receiving
  cisplatin or noncisplatin chemotherapy of high
  emetic risk

(The Italian Group for Antiemetic Research,
1995)
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5-HT RA All Equivalent Efficacy

• granisetron, dolasetron, ramosetron pure 5-HT3
  antagonist
• Ondansetron, tropisetron weak antagonists at the
  5-HT4 receptor
• All 5-HT RA have equivalent safety and efficacy
• Single dose before chemotherapy, with oral form

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1999 ASCO Guidelines for Antiemetics Delayed
Emesis
The Most Important patient characteristics
predicting for greater risk for delayed
emesis Poor control of acute emesis

• 5-HT RA corticosteroid vs Metoclopramide
  corticosteroid
• Equivalent for delayed emesis
• Favor metoclopramide d/t cost

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Problems Poor Compliance with Guideline

• Adherence to Acute emesis prophylaxis guideline
  more than 90
• But for delayed emesis, prescription of
  corticosteroid is too often omitted
• Mertens et al(2003) postchemotherapy DN
  prophylaxis
• steroid25
• 5-HT RA 52
• metoclopramide50
• 5-HT RA with steroid after cisplatin none

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• Neurophysiology of Emesis
• 1999 ASCO guidelines Recommendations for the use
  of antiemetics
• Problems poor compliance with guideline and
  delayed emesis
• A New Agent NK-1 receptor antagonist

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Problems Delayed Emesis

• Without acute emesis, delayed emsis can be
  protected with dexa 5HT RA more effectively
  than dexamethasone alone
• Once acute emesis occurs, delayed emesis cannot
  be protected effectively with any regimen

The Italian Group for Antiemetic Research, 2000
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• Neurophysiology of Emesis
• 1999 ASCO guidelines Recommendations for the use
  of antiemetics
• Problems poor compliance with guideline and
  delayed emesis
• A New Agent NK-1 receptor antagonist

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Neurokinin-1 receptor antagonist
Standard Regimen Granisetron Dexamethasone

• Neurokinin-1 receptor antagonist antagonism of
  substance P
• L-754,030 significant reduction of acute and
  delayed emesis (Navari,
  1999)

L754,030 only before chemotherapy
L754,030 before and after chemotherapy
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Aprepitant (EMEND)

• Selective NK-1 receptor antagonist
• Dose 120mg before chemotherapy, 80mg D2-3 or
  D2-5
• Approved by FDA on Mar 2003
• Interaction with corticosteroid increase serum
  concentration of corticosteroid because
  aprepitant is a inhibitor of cytochrome P 450 3A4

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Aprepitant on phase III trial

• Add aprepitant to standard 5-HT RA
  corticosteroid sinificant reduction of acute and
  delayed emesis

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Aprepitant on phase III trial

• With aprepitant, consistently better antiemetic
  protection can be maintained over multiple cycle
  compared with standard regimen

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Epilogue

• Antiemetics allows to be treated comfortably on
  an outpatient basis and eliminates nutritional
  problem
• Newer Agent NK-1 Receptor Antagonist
• Review of current antiemetic regimen risk
  stratification, dose, schedule..