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CHEMOTHERAPY-INDUCED NAUSE and VOMITING. Doç. Dr. AHMET SELİM YURDAKUL Gazi University Faculty of Medicine Department of Pulmonary Medicine. CHEMOTHERAPY-INDUCED NAUSE and VOMITING. Importance of control of nause and vomiting Pathophysiology of nause and vomiting

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Chemotherapy induced nause and vomiting

CHEMOTHERAPY-INDUCED NAUSE and VOMITING

Doç. Dr. AHMET SELİM

YURDAKUL

Gazi University Faculty of Medicine

Department of Pulmonary Medicine


Chemotherapy induced nause and vomiting1
CHEMOTHERAPY-INDUCED NAUSE and VOMITING

  • Importance of control of nause and vomiting

  • Pathophysiology of nause and vomiting

  • Clinical features of nause and vomiting

  • Treatment approach of nause and vomiting

  • Future treatments of nause and vomiting


  • Nause and vomiting are common side effects for patients treated systemic chemotherapy (70-80 %).

  • Approximately, half of patients refuse of systemic chemotherapy because of side effects.

  • 10-44% of these patients are “Anticipatory emesis”.

  • Patients treated systemic chemotherapy are risked for 5 days.

Morrow GR. Chemotherapy-related nausea and vomiting:etiology and management. Cancer J Clin 1989;39:89-104.

Morran C, Smith DC, Anderson DA, et al. Incidence of nausea and vomiting with cytotoxic chemotherapy:

A prospective random­ized trial of antiemetics. Br Med J 1979;1:1323-4.

Jenns K. Importance of nause. Cancer Nurs 1994;17:488-93.


Acute treated systemic chemotherapy (70-80 %).

vomiting

Delayed

vomiting


Importance of control of nause and vomiting
Importance of control of nause and vomiting treated systemic chemotherapy (70-80 %).

  • It effects patients’ quality of life.

  • The compliance of treatment was decreased.

  • It causes metabolic changes.

  • It effects functional and intelligence capacity of patients.

  • It causes anorexia and nutritional deficiency.

  • Aspiration pneumonia and oesophagus damage might be seen.

  • Effective chemotherapy treatments were discontinued because of this side effect.


Pathophysiology of nause and vomiting
Pathophysiology of nause and vomiting treated systemic chemotherapy (70-80 %).


Higher central nervous system centers treated systemic chemotherapy (70-80 %).

5-HT

Amygdala

5-HT3 receptor

Medulla

Third

route

Vagus nerve

Second

route

AP NTS

CTZ

Chemotherapy

VC

First

route

Enterochromaffin

cells

Small Intestine

Vagal afferents


Receptors stimulat ed by chemotherepy drugs and their metabolities
Receptors treated systemic chemotherapy (70-80 %).stimulated by chemotherepy drugs and their metabolities

Dopamine

Serotonin

Histamine

Emetic Reflex

Substance P

acetylcholine

GABA

Cannabinoids

Norepinephrine,

Apomorphine

Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43.

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.


Higher central nervous system centers treated systemic chemotherapy (70-80 %).

5-HT

Amygdala

5-HT3 receptor

Medulla

Third

route

Vagus nerve

Second

route

  • CTZ

  • 5-HT3 receptors

  • NK1 receptors

  • Dopamine receptors

AP NTS

CTZ

  • VC

  • 5-HT3 receptors

  • NK1 receptors

  • Dopamin ereceptors

Chemotherapy

VC

First

route

Enterochromaffin

cells

Small Intestine

Vagal afferents


Carpenter DO. Neural mechanisms of emesis. Can J Physiol Pharmacol 1990;68:230-6.

Miller AD, Nonaka S, Jakus J.Brain areas essential or non-essential for emesis. Brain Res1994;647:255-64.

Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43.

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.


Etiologies of nause and vomiting
Etiologies of nause and vomiting Pharmacol 1990;68:230-6.

  • Chemotherapy

  • Radiotherapy

  • Cranial metastasis

  • Drugs (Opiates etc.)

  • Metabolic disorders (hypercalcemia, hyperglycemia, hyponatremia)

  • Uremia

  • Psychogenic causes (Anxiete, anticipatory emesis)

  • Intestinal obstruction

  • Vestibular function disorders

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.


Chemotherapy induced emesis
CHEMOTHERAPY-INDUCED EMESIS Pharmacol 1990;68:230-6.

  • Acute emesis

  • Delayed emesis

  • Anticipatory emesis

  • Breakthrough emesis

  • Refractory emesis

Herrstedt J. Antiemetics:an update andthe MASCC guidelines applied in clinical practice.

Nat Clin Pract Oncol 2008;5:32-43.


Type of Emesis Pharmacol 1990;68:230-6.

Acute emesis

Acute emesis occurs within 0-24 hours after chemotherapy administration

Delayed emesis

Delayed emesis occurs 24 or more hours after chemotherapy administration

Anticipatory emesis

Anticipatory emesis (conditioned emesis) occurs before chemotherapy administration

Breakthrough emesis

Breakthrough emesis occurs despite of prophylactic treatment and we must provide additional therapy.

Refractory emesis

Refractory emesis occurs among patients who have experienced unsuccessful control of emesis during previous courses of chemotherapy


Chemotherapy induced nause and vomiting prognostic factors
CHEMOTHERAPY-INDUCED NAUSE and VOMITING Pharmacol 1990;68:230-6. Prognostic Factors

  • Chemotherapy related

  • Route/rate/frequency of administration

  • Dose

  • Drug combination emetogenicity

Patient related

  • Effects of prior exposure to chemotherapy

  • Pretreatment anxiety

  • Depression

  • Female gender

  • Motion sickness

  • Low alcohol intake

  • Age (<30years old)

  • Various tastes and odors

HainsworthJD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.


Emetic risk of chemotherapeutic agents
Emetic Risk of Chemotherapeutic Agents Pharmacol 1990;68:230-6.

  • High risk > 90%

  • Moderate risk 30-90%

  • Low risk 10-30%

  • Minimal risk < 10%

incidence of emesis

Hesketh PJ, Kris MG, Grunberg SM. Proposal for classifying the acute emetogenicity of cancer chemotherapy.

J Clin Oncol 1997;15:103-9.

NCCN antiemesis guidline-2008


High emetic risk 90 of chemotherapeutic agents

Cisplatin Pharmacol 1990;68:230-6. ≥ 50 mg/m2

Carmustine >250 mg/m2

Cyclophosphamide >1500 mg/m2

Dacarbazine

Mechlorethamine

Procarbazine (oral)

Streptozotocin

Altretamine

High Emetic Risk (>90%) of Chemotherapeutic Agents

NCCN antiemesis guidline-2008


Severity of emesis

1

2

3

4

5

DAYS


Moderate emetic risk 30 90 of chemotherapeutic agents

Carboplatin Pharmacol 1990;68:230-6.

Cisplatin< 50mg/m2

Cyclophosphamide ≤ 1500 mg/m2

Cyclophosphamide (oral)

Doxorubicine

Etoposide (oral)

İfosfamide

İrinotecan

Methotrexate 250-1000 mg/m2

Oxaliplatin > 75 mg/m2

Vinorelbine (oral)

Moderate Emetic Risk (30-90%) of Chemotherapeutic Agents

NCCN antiemesis guidline-2008


Low emetic risk 10 30 of chemotherapeutic agents

Docetaxel Pharmacol 1990;68:230-6.

Doxorubicine (lipozomal)

Etoposide

5-Fluorouracil

Gemcitabine

Mitomycin

Paclitaxel

Pemetrexed

Topotecan

Methotrexate 50-250

Low Emetic Risk (10-30%) of Chemotherapeutic Agents

NCCN antiemesis guidline-2008


Minimal emetic risk 10 of chemotherapeutic agents

Bevacizumab Pharmacol 1990;68:230-6.

Bleomycin

Cetuximab

Vinblastine

Vincristine

Vinorelbine

Erlotinib

Gefitinib

Fludarabine

Talidomid

Rituximab

Minimal Emetic Risk (<10%) of Chemotherapeutic Agents

NCCN antiemesis guidline-2008


Treatment of chemotherapy induced nause and vomitting
Treatment of chemotherapy-induced nause and vomitting Pharmacol 1990;68:230-6.

  • Antiemetic drugs prevent nause and vomiting by blocking different neural networks and preventing emetic stimuli on different points.

  • There is no single agent preventing all stages of chemotherapy-induced nause and vomiting.

  • Antiemetic drugs block the different receptors when they are used properly doses.

  • Combination of antiemetic drugs is more effective than single agent.


Treatment of chemotherapy induced nause and vomitting1
Treatment of chemotherapy-induced nause and vomitting Pharmacol 1990;68:230-6.

Highest therapeutic index

5-HT3 receptor antagonists

NK-1 (neurokinin-1) receptor antagonists

Corticosteroids

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

Kris MG, Hesketh PJ, Herrstedt J, et al. Consensus proposals for the prevention of acute and delayed vomiting

and nausea following high-emetic risk chemotherapy. Support Care Cancer 2005;13:85-96.


Treatment of chemotherapy induced nause and vomitting2
Treatment of chemotherapy-induced nause and vomitting Pharmacol 1990;68:230-6.

Lower therapeutic index

  • Metoclopramide

  • Phenothiazines (Proclorperazine, promethazine)

  • Butyrophenones (Haloperidol, droperidol)

  • Cannabinoids (Dronabinol, Nabilone)

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

Kris MG, Hesketh PJ, Herrstedt J, et al. Consensus proposals for the prevention of acute and delayed vomiting

and nausea following high-emetic risk chemotherapy. Support Care Cancer 2005;13:85-96.


Treatment of chemotherapy induced nause and vomitting3
Treatment of chemotherapy-induced nause and vomitting Pharmacol 1990;68:230-6.

Adjunctive Drugs

  • Benzodiazepines (Lorazepam)

  • Antihistamines

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.

Kris MG, Hesketh PJ, Herrstedt J, et al. Consensus proposals for the prevention of acute and delayed vomiting

and nausea following high-emetic risk chemotherapy. Support Care Cancer 2005;13:85-96.


5 ht 3 serotonin receptor antagonists
(5-HT Pharmacol 1990;68:230-6. 3) Serotonin receptor antagonists

Single dose before chemotherapy

  • Ondansetron → oral 16-24 mg

    İV 8 mg or 0.15 mg/kg

  • Granisetron → oral 2 mg

    İV 1 mg or 0.01 mg/kg

  • Dolasetron → oral 100 mg

    İV 100 mg or 1.8 mg/kg

  • Tropisetron → oral or İV: 5 mg

  • Palonosetron → İV: 0.25 mg

Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43.

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.


5 ht 3 serotonin receptor antagonists1
(5-HT Pharmacol 1990;68:230-6. 3) Serotonin receptor antagonists

  • (5-HT3) serotonin receptor antagonists have equivalent efficacy and safety.

  • Oral or IV form of (5-HT3) serotonin receptor antagonists have equivalent efficacy.

  • Side effects

    -Mild headache

    -Transient elevation serum aminotreansferases

    -Constipation

  • Combination with corticosteroids increased their efficacy.

  • (5-HT3) serotonin receptor antagonists are not effective for preventing delayed emesis (except palonosetron)

Herrstedt J. Antiemetics:an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008;5:32-43.

Hainsworth JD. Nausea and vomiting. In:Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds.

Clinical oncology. 3rd ed. USA:Elsevier Churchill Livingstone;2004:759-73.


5 ht 3 serotonin receptor antagonists2
(5-HT Pharmacol 1990;68:230-6. 3) Serotonin receptor antagonists

Palonosetron

  • Second generation (5-HT3) serotonin receptor antagonist

  • It is longer serum half-life (40 hour) and higher binding affinity to the (5-HT3) serotonin receptor.

  • It is effective for the prevention delayed emesis

Gralla RJ et alAnn Oncol 14:1570-77, 2003

Eisenberg P et al.Ann Oncol 15: 330-337, 2004

Aapro MS et al.Ann Oncol 17:1441-449, 2006


Pathophysiology of nause and vomiting1
Pathophysiology of nause and vomiting Pharmacol 1990;68:230-6.

  • PET studies in humans demonstrated that substance P (SP) and neurokinin-1 (NK1) receptor were located in the central of brainstem and substance P (SP) is a neurotransmitter and neuromodulator that mediates vomitting reflex in the brain predominantly via the neurokinin-1 receptors (NK1Rs).

Hargreaves R. Imaging substance Preceptors (NK1) in the living human brain

using positron emission tomography. J Clin Psyc 2002;63:18-24.


Nk 1 neurokinin 1 receptor antagonist aprepitant
NK Pharmacol 1990;68:230-6. 1 (neurokinin-1) receptor antagonist Aprepitant

  • The effect of aprepitant is blockade of NK1 receptors.

  • Aprepitant is effective for the prevention acute and delayed emesis.

  • Aprepitant increased the antiemetic effect of seratonin receptor antagonist and steroids.

Jardon K, et al. The Oncologist 12:1143–50, 2007


Nk 1 neurokinin 1 receptor antagonist
NK Pharmacol 1990;68:230-6. 1 (neurokinin-1) receptor antagonist

Aprepitant

  • Drugs interaction! (cytochrome p450 enzyme CYP3A4)

  • Terfenadine, astemizole and cisapride are not used with aprepitant.

  • Aprepitant inhibits the effect of coumadin and oral contraceptive and induces the effect of steroids.

NCCN Clinical Practice Guidelines in Oncology: Antiemesis, 2008


Nk 1 neurokinin 1 receptor antagonists
NK Pharmacol 1990;68:230-6. 1 (neurokinin-1) receptor antagonists

  • Aprepitant (Emend): 125 mg PO before chemotherapy, 80 mg PO second and third days.

  • Fosaprepitant (Emend):İV dose: 115 mg before chemotherapy.


Corticosteroids

Before Chemotherapy Pharmacol 1990;68:230-6.

With Aprepitant

İV dose: 12 mg,

PO dose: 12 mg

b) WithoutAprepitant

İV dose: 20 mg,

PO dose: 20 mg

After Chemotherapy

With Aprepitant

PO dose: 8 mg 2th-4th days

b) WithoutAprepitant

PO dose: 8 mg 2x1 2th-4th days

Corticosteroids


Recommendation for antineoplastic therapy of high emetic risk 90
Recommendation for antineoplastic therapy of high emetic risk (> 90%)

MASCC: Multinational Association of Supportive Care in Cancer

ASCO: American Society of Clinical Oncology

NCCN: National Comprehensive Cancer Network


Recommendation for antineoplastic therapy of moderate emetic risk 30 90
Recommendation for antineoplastic therapy of moderate emetic risk (30%-90%)

MASCC: Multinational Association of Supportive Care in Cancer

ASCO: American Society of Clinical Oncology

NCCN: National Comprehensive Cancer Network


Recommendation for antineoplastic therapy of low emetic risk 10 30
Recommendation for antineoplastic therapy of low emetic risk (10%-30%)

MASCC: Multinational Association of Supportive Care in Cancer

ASCO: American Society of Clinical Oncology

NCCN: National Comprehensive Cancer Network


Recommendation for antineoplastic therapy of minimal emetic risk 10
Recommendation for antineoplastic therapy of minimal emetic risk (<10%)

MASCC: Multinational Association of Supportive Care in Cancer

ASCO: American Society of Clinical Oncology

NCCN: National Comprehensive Cancer Network


Anticipatory emesis
Anticipatory Emesis risk (<10%)

  • Anticipatory emesis occurs in patients who have had poor control of vomitting with prior chemotherapy and a history of motion sickness predisposes patients to anticipatory emesis.

  • The most effective method for preventing anticipatory emesis was to apply optimal effective antiemetic therapy during the chemotherapy treatment

  • Behavioral therapy

    • Relaxation, Hypnoz

    • Music therapy, Acupuncture

  • Alprazolam 0.5-2 mg before treatment

  • Lorazepam 0.5-2 mg before treatment

Laszlo J, ClarkRA, Hanson DC, Tyson L, Crumpler L, Gralla R. Lorazepam in cancer patients treated with cisplatin:

A drug with antiemetic amnesic, and anxiolytic effects . J Clin Oncol 1985;3:864-9.

Morrow GR. Prevalence and correlates of anticipatory nausea and vomiting in chemotherapy patients. J Natl Cancer Inst 1982;68:585-8.


Refractory emesis
Refractory Emesis risk (<10%)

  • Evaluate antiemetic agents, chemotherapy drugs, tumour status, risk factors, concurrent disease, other drugs.

  • Check the antiemetic therapy whether the best regimen is being administered for the emetic setting, or not.

  • Consider adding lorazepam to the regimen.

  • Consider treating the patients with dopamine antagonist (Metoclopramide) instead of 5-HT3 receptor antagonist therapy.

  • Evaluate the antiemetic therapy carefully for the patients treated with chemotherapy and radiotherapy, because the risk of emesis is increased in these patients.


New ant i eme tic drugs
risk (<10%)New” Antiemetic drugs

  • CASOPITANT

  • OLANZAPINE

  • GABAPENTIN

Arpornwirat W, et al. ASCO 24:471s (ab.8512) 2006

Navari RM, et al. Support Care Cancer 13:529-34,2005

Guttuso T, et al. Lancet 361:1703-05, 2003

Rudd JA et al. Neuroscience Letters 92:79-85, 2006


Non pharmacologic treatment
Non-Pharmacologic Treatment risk (<10%)

  • Eat the foods smaller and more frequent.

  • Eat the foods served at room temperature or cold.

  • Eat the fruits, ice-cream, sandwich, white cheese and oderless foods.

  • Drink the liquids one hour before or after meals.

  • Eat the cracker, toast, salty biscuit, haricot foods if the emesis occur in the morning.


Non pharmacologic treatment1
Non-Pharmacologic Treatment risk (<10%)

  • Walking short distance outdoors and inhale air deeply and slowly.

  • Keep away from odors of foods, perfüme and fume.

  • Put on comfortable clothes.

  • Do not sleep immediately after dinner.

  • Begin eating light foods (soup, yoghurt, puree) after control nause and vomitting.


In the first systemic chemotherapy treatment risk (<10%)

True and effective antiemetic treatment

Control the symptoms of nause and vomitting

Success of continuation of chemotherapy treatment and complet the chemotherapy treatment of patients

It is very important point.


Çalışmadan, öğrenmeden, yorulmadan risk (<10%)

rahat yaşamanın yollarını aramayı

alışkanlık haline getirmiş milletler,

evvele haysiyetlerini,

sonra hürriyetlerini

ve daha sonra da

istikballerini kaybetmeye mahkumdurlar.

M. Kemal ATATÜRK


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