1 Chemotherapy-Induced Nausea and Vomiting (CINV): Perceptions, Mechanisms, and Treatment Guidelines Charles Loprinzi, M.D. Regis Professor of Breast Cancer Research Mayo Clinic College of Medicine Chemotherapy-Induced Emesis Classification – Acute (0-24 hr after chemotherapy) – Delayed (24-120 hr after chemotherapy) • May last up to 6 days • Incidence without treatment 20%-90% – Anticipatory (prior to chemotherapy)
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Chemotherapy-Induced Nausea and Vomiting (CINV):
Perceptions, Mechanisms, and Treatment Guidelines
Charles Loprinzi, M.D.Regis Professor of Breast Cancer Research
Mayo Clinic College of Medicine
Chemotherapy-Induced Emesis Classification
–Acute (0-24 hr after chemotherapy)
–Delayed (24-120 hr after chemotherapy)• May last up to 6 days
• Incidence without treatment 20%-90%
–Anticipatory (prior to chemotherapy)
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1. Gregory RE, et al. Drugs. 1998;55:173-189.2. Hesketh PJ, et al. J Clin Oncol. 1997;15:103-109.
Chemotherapy-Induced Emesis: Risk Factors
• Patient-related risk factors1:– Younger age (<50 years)– Female gender– No/minimal prior history of alcohol use– Prior CINV– Anxiety – Hx of morning sickness or motion sickness– Other medical conditions (e.g. intest. obstr., brain mets)
• Treatment-related risk factors1,2:– High emetogenicity of chemotherapy agents/regimens– High drug dose, rapid infusion rate
The Four Emetic Risk Groups of Chemotherapeutic Drugs (ASCO/MASCC/NCCN)
Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy
Rank 19831 19932 19953 19994
1. Vomiting Nausea Nausea Nausea
2. Nausea Constantly tired Loss of hair Loss of hair
3. Loss of hair Loss of hair Vomiting Constantly tired
4. Thought of coming for treatment
Effect on family Constantly tired Vomiting
5. Length of time treatment takes
Vomiting Having to havean injection
Changes in the way things taste
1. Coates A, et al. Eur J Cancer Clin Oncol. 1983;19:203-208.2. Griffin AM, et al. Ann Oncol. 1996;7:189-195.3. De Boer-Dennert M, et al. Br J Cancer. 1997;76:1055-1061.4. Lindley C, et al. Cancer Pract. 1999;7:59-65.
Perception vs Reality: Nausea and Vomiting Incidence Rates in 2001–2002
Moderately Emetogenic Chemotherapy
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13
24
15
37
13
52
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0
10
20
30
40
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60
70
AcuteNausea
AcuteVomiting
DelayedNausea
DelayedVomiting
Perc
ent o
f Pat
ient
s
MD/RN PredictionPatient Experience
Grunberg S. Cancer. 2004;100:2261-2268.
International observational study 298 pts, 14 practices.
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Perception vs Reality: Nausea and Vomiting Incidence Rates in 2001–2002
Highly Emetogenic Chemotherapy
Perc
ent o
f Pat
ient
s
MD/RN PredictionPatient Experience
Grunberg S. Cancer. 2004;100:2261-2268.
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17
39
22
33
12
60
50
0
10
20
30
40
50
60
70
AcuteNausea
AcuteVomiting
DelayedNausea
DelayedVomiting
International observational study 298 pts, 14 practices.
Evolution of Anti-emetic Agents ReflectsAdvances in Neuropharmacology of Emesis
Dex=dexamethasone.Hesketh PJ. Support Care Cancer. 1994;2:286-292.
First 5-HT3 receptor antagonist (serotonin) Further understanding of delayed emesis
Combination of Dex and 5-HT3 receptor antagonist
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Olanzapine 2010s
Proposed Pathophysiology of CINV
• Central mechanism– Chemotherapeutic agent activates the CTZ.
• Peripheral mechanism– Chemotherapeutic agent causes irritation and damage
to GI mucosa, resulting in the release of neurotransmitters.
• Combined mechanism– Some chemotherapeutic agents activate both the central
and peripheral mechanisms.
Berger AM, Clark-Snow RA. In: Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins: 2001.
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Emesis and Cancer TreatmentApproach to the Problem
In controlling emesis, the strategy ispreventionrather thantreatment
Emetic reflex
GABA
Histamine
Endorphins
Acetylcholine
Dopamine/DA RAs
Serotonin/5-HT3 RAs
Cannabinoids
Neurotransmitters/TreatmentsAssociated With Emesis
Substance P/NK-1 RAs
DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin; RAs = receptor antagonists.
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Antiemetic Arsenal
• 5-HT3-RA Ondansetron Granisetron (oral and transdermal)DolasetronPalonosetron
• Corticosteroids Dexamethasone
• NK1-RA Aprepitant
Fosaprepitant
Netupitant (NEPA)
Rolapitant
• Dopamin-RA ProchlorperazineMetoclopramide
Benzodiazepines Lorazepam
• Cannabinoid Dronabinol
• Multi-receptor Olanzapine
Serotonin and 5-HT3 Receptors
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Serotonin and 5-HT3 Receptor Pathway
• First recognized with high-dose metoclopramide.1
• Introduction of 5-HT3 antagonists offered an improved treatment option.– Effective in acute vomiting, variable efficacy
for delayed events.2
– Usually used with dexamethasone.2
• Primary mechanism of action appears to be peripheral.3,4
1. Berger AM, Clark-Snow RA. In: Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins; 2001.2. Gralla RJ et al. J Clin Oncol. 1999;17:2971-2994. 3. Endo T et al. Toxicology. 2000;153:189-201.4. Hesketh PJ et al. Eur J Cancer. 2003;39:1074-1080.
*Log-scale.†In vitro data; clinical significance has not been established.
Palonosetron has a binding affinity at least 30-fold higher than other 5-HT3 RA.
Half-Life and Binding Affinities of 5-HT3 Receptor Antagonists
1. Aloxi® package insert, 2004. 2. Zofran® package insert, 2001. 3. Anzemet® package insert, 2000. 4. Kytril® package insert, 2000. 5. Wong EHF et al. Br J Pharmacol. 1995;114:851-859. 6. Miller RC et al. Drug Dev Res. 1993;28:87-93.
•No routine antiemetic before or after chemotherapy
MASCC/ESMO-2013
• Very similar to ASCO
• AC still not upgraded to HEC, but treated as such
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NCCN 2015
• HEC-3 options1. As per previous 2 guidelines
2. Netupitant/Palo oral and dex 12 mg D-1, plus dex on D-2-4
3. Olanzapine Regimen
Olanzapine 10 mg PO D1-4
Palo 0.25 mg IV and Dex 20 mg
• MEC-3 options-Similar to HEC, except1. with/without NK1RA
2. Netupitant regimen: +/- Dex on days 2,3
3. Olanzapine Regimen: Olanzapine 10 mg PO only 3 days, not 4
• This guideline suggests that pt factors can influence anti-emetic choice for MEC
Institutional Guideline Processes
• Kadakia KC, Leal AD, Seisler DK, Qin R, Fee-Schroeder KC, Grendahl DC, Sorgatz KM, Loprinzi CL. Antiemetic prescribing practices using a computerized physician order system. Support Care Cancer 2014 Jan;22(1):217-23.
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How Well Do Anti-emetics Work for Treatment of CINV?
0
1
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5
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0 30 60 90 120 150 180 210 240
Time (minutes)
Mea
n N
ause
a S
cale
(0-
10)
prochlorperazine
5HT3 antagonist
J Palliat Med 2011; 14(7):810-4.
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• The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.
Rudy Navari, MD
Supp Care Cancer; 2013: 1653-66
• DB, phase III trial Treatment of breakthrough CINV in chemotherapy-naive patients receiving HEC
• 112 pts with breakthrough N/V
• Randomized to – Olanzapine, 10 mg orally daily for 3 days
– Metoclopramide, 10 mg orally TID for 3 days.
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Results
• 3 day observation period
• No vomiting– Olanzapine, 70% (39 out of 56)
– Metoclopramide, 31% (16 out of 52)
– p < 0.01
• No nausea (0, scale 0-10, M.D. Anderson Symptom Inventory) – Olanzapine, 68% (38 of 56)
– Metoclopramide, 23% (12 of 52)
– p < 0.01
Megestrol Acetate
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Antiemetic activity of megestrol acetate in patients receiving chemotherapy
Zang, et alSichuan Province, 610041, China.
Support Care Cancer. 2011 May;19(5):667-73. Epub 2010 Apr 26.
PATIENTS AND METHODS
• Patients receiving chemotherapy
• Randomized to receive, days -1 to 4 – Megestrol acetate 320 mg PO
– Placebo
• All also received, on day 1 – Granisetron 3 mg IV