Nausea and Vomiting - most common side effects seen in patients receiving chemotherapy.

1. CHEMOTHERAPY-INDUCED
NAUSEAAND VOMITING (CINV)
Presenter: DR. MONICA P
Radiation Oncologist

2. Table of Contents :
• Introduction of nausea & vomiting
• Causes of nausea & vomiting
• Types of nausea & vomiting
• CINV
• Pathophysiology of CINV
• Types of CINV
• Classification of anticancer agents
• Anti-emetic agents
• Anti-emetic treatment by clinical setting
• RINV

3. Nausea and Vomiting
• Nausea is usually defined as an inclination to vomit or as a feeling in the throat or epigastric
region alerting an individual that vomiting is imminent. (Subjective)
• Vomiting is defined as the ejection or expulsion of gastric contents through the mouth, often
requiring a forceful event. (Reflexive)
• Nausea and vomiting caused by anticancer agents(chemotherapy, targeted therapy and
immunotherapy) and/or radiation therapy will significantly affect the patients QOL , which
leads to poor compliance with further anticancer agents and/or RT.

4. • Nausea and vomiting can result in:
i. dehydration
ii. metabolic imbalances
iii. degeneration of self-care and functional ability
iv. nutrient depletion
v. anorexia
vi. decline of the patients performance status and mental status
vii. wound dehiscence
viii. oesophageal tears
ix. withdrawal from potentially useful or curative anticancer treatment.

5. INCIDENCE AND SEVERITY OF NAUSEA & VOMITING INDUCED BY ANTICANCER THERAPY
AGENTS AND RADIATION DEPENDS ON:
• Specific therapeutic agents used
• Dosage of the agents
• Schedule and route of administration of the agents
• Target of the radiation therapy (eg., whole body, upper abdomen)
• Individual patient variability (eg., younger age, female gender, prior anticancer agents, history of little or no
alcohol use, morning sickness, motion sickness, anxiety)
• More than 90% of the patients receiving Highly Emetogenic Chemotherapy (HEC) will have CINV.
• However, if these patients receive prophylactic antiemetic regimens before treatment with HEC, then only 30%
of the patients will have CINV.

6. CAUSES OF NV
• Differential diagnosis of nausea & vomiting in cancer patients are:
1. CINV or RINV
2. Partial or complete bowel obstruction
3. Vestibular dysfunction
4. Brain metastases
5. Electrolyte imbalances (hypercalcemia, hyperglycaemia, hyponatremia)
6. Uremia
7. Gastroparesis
8. Excess secretions (as seen in head and neck cancer patients)
9. Malignant ascites
10. Cannabinoid hyperemesis syndrome
11. Rapid opioid withdrawal
12. Pancreatitis
13. Psychophysiologic causes.

7. TYPES OF NAUSEAAND/OR VOMITING:
1. CHEMOTHERAPY-INDUCED NAUSEAAND/OR VOMITING (CINV)
2. RADIATION-INDUCED NAUSEAAND/OR VOMITING (RINV)

8. CINV
o Chemotherapy has played an important role in
improving patient outcomes in oncology and is a
cornerstone of therapy for most patients with cancer.
o But it is also important to know the side-effects from
chemotherapy and how to manage them.
o The most common and most dreaded side-effects from
a patient perspective remains – nausea and vomiting.

9. What happens if the CINV is not treated?

10. PATHOPHYSIOLOGY OF NAUSEA & VOMITING
• CNS is thought to play a critical role in the
physiology of nausea & vomiting , serving as the
primary site where a variety of emetic stimuli are
received and processed.
• CNS is also believed to have primary role in
generating the efferent signals to a number of
structures in the body that eventually result in the
development of nausea & vomiting .

11. • Borison and Wang proposed that two sites within the brainstem were critical in the control of
emesis.
1. Area postrema – circumferential structure located at the caudal end of the fourth ventricle;
positioned outside BBB and therefore is accessible to emetic substance borne in either blood or
CSF. It is also termed as chemoreceptor trigger zone (CTZ)
2. Vomiting center – parvocellular reticular formation, the Botzinger complex, and the nucleus
tractus solitarius collectively referred as vomiting center.

12. PATHOPHYSIOLOGY OF EMESIS
• Chemotherapy agents either directly or
indirectly access the gut mucosa, causing
release of local mediators from
enterochromaffin cells and stimulating vagal
and splanchnic afferent fibres within the
bowel wall.
• These afferent fibres will initiate emetic
reflex.
• Input from the vestibular system may also
induce emesis.

13. • KEY POINTS IN PATHOPHYSIOLOGY:
• Activation of neurotransmitter receptors (in chemoreceptor trigger zone CTZ, vomiting centre, and GI tract) by
chemotherapeutic agents are responsible for CINV.
• Principle neuroreceptors involved in the emetic response are:
1. Serotonin (5-hydroxytryptamine3) receptors
2. Dopamine receptors
• 5-HT3 receptors are associated with acute emesis via peripheral pathway.
• Dopamine D2 receptors are found in the area postrema.
• Other neuroreceptors involved in emesis are: acetylcholine, corticosteroid, histamine, cannabinoid, opioid,
neurokinin-1(NK-1) receptors – which are located in vomiting and vestibular centres of the brain..

14. • NK-1 receptors : found in GI tract, area postrema, nucleus tractus solitarius.
• NK-1 receptors are associated with delayed emesis via a central pathway
• The most relevant site of action of serotonin occurs at the peripheral level by increasing afferent stimuli from
the gut to the vomiting center and area postrema.
• Another neurotransmitter, Substance P belongs to tachykinins, which bind to neurokinin (NK-1) receptors
preferentially.
• Endogenous cannabinoids
• Enkephalins exert an agonist antiemetic effect.
• γ- aminobutyric acid (GABA)

15. • Antiemetics can block different neuronal pathways, exert their effects at different points during the course
of emesis, or behave synergistically with other antiemetics to potentiate an antiemetic effect.
• When these antiemetics are used at certain concentration, they predominantly block one receptor type,
except, olanzapine which blocks multiple receptors involved in the emetic pathway.
• Hence, no single agent can be expected to provide complete protection from various emetic phases of
anticancer agents.
• So, prophylactic antiemetic regimens for HEC and moderately emetogenic chemotherapy (MEC) include
two to four antiemetics that block different receptors.

16. TYPES OF NAUSEAAND/OR VOMITING:
1. CHEMOTHERAPY-INDUCED NAUSEAAND/OR VOMITING
2. RADIATION-INDUCED NAUSEAAND/OR VOMITING
NAUSEA
AND/OR
VOMITING
CHEMOTHERAPY-INDUCED
NAUSEA &/OR VOMITING
ACUTE-
ONSET
DELAYED-
ONSET
ANTICIPATORY
CINV
BREAKTHROU
GH CINV
REFRACTORY
CINV
RADIATION-
INDUCED
NAUSA &/OR
VOMITING

17. CINV
ACUTE-ONSET NV DELAYED-ONSET NV ANTICIPATORY CINV BREAKTHROUGH CINV REFRACTORY CINV
Occurs within few minutes to
several hours after
administration of certain
anticancer agent
it develops in patients >24hrs
after anticancer agent
administration
Occurs before patients receive
their next treatment with
anticancer agents
It refers to nausea &/or
vomiting that occurs despite
prophylactic antiemesis
treatment and/or requires
rescue with antiemetics.
It refers to nausea and/or
vomiting that occurs during
subsequent treatment cycles
when antiemetic prophylaxis
and /or rescue has not been
effective in earlier cycles.
Completely resolves within
first 24hrs.
Intensity is at peaks after 5-
6hrs
Examples:
Cisplatin (in >90% patients)
Carboplatin
Cyclophosphamide
Anthracyclines
Cause: due to conditioned
response, anticipatory emesis
occurs after a previous
negative experience with
anticancer agents.
Factors affecting: type and
dosage of the drug, h/o nausea
& vomiting , environment in
which the drug is
administered, efficacy of the
antiemetic regimen.
It appears to be less severe
than acute emesis but can last
for a longer period of time.
Incidence : 18% - 57%
Nausea is more common than
vomiting
It is seen more in
younger(<50yrs) women with
h/o motion sickness, morning
sickness, no or low ethanol
use
For Cisplatin: emesis reaches
its maximal intensity 48-
72hrs after administration,
lasts for 6-7days.
Younger patients are more
susceptible because they
generally receive more
aggressive anticancer agents

18. ANTICIPATORY CINV
• Prevention is important in this type of CINV
• Prevention is gained by:
 Use of optimal antiemetic therapy during every cycle of treatment
 Avoid strong smells that may precipitate symptoms
Treatment is by
1. Behavioural therapy:
 Relaxation/systematic desensitization, hypnosis, relaxation exercises: guided imagery, progressive muscle
relaxation, biofeedback, music therapy, Cognitive distraction, yoga
2. Acupuncture / acupressure
3. Consider anxiolytic therapy : Lorazepam 0.5-2mg PO given on night before treatment, and repeated the next
day 1-2hrs before anticancer therapy begins.

19. CLASSIFICATION OF ANTICANCER AGENTS
 NCCN(National Comprehensive Cancer Network) guidelines uses Hesketh/Grunberg classification of
emetogenic potential for parenteral agents in antiemetic treatment
 It divides chemotherapeutic agents into 4 levels according to the % of patients who developed acute
emesis when they do not take any antiemetic prophylaxis.
TYPE OF EMETIC RISK % OF PATIENTS EXPFERIENCE
ACUTE EMESIS
HIGH EMETIC RISK >90
MODERATE EMETIC RISK >30 TO 90
LOW EMETIC RISK 10 TO 30
MINIMAL EMETIC RISK <10%

20. TYPE OF EMETIC
RISK
HIGH (>90%) MODERATE (30 –
90%)
LOW (10 – 30%) MINIMAL (<10%)
ANTINEOPLASTIC
AGENT
• Anthracycline /
cyclophosphamide
combination
• Carboplatin AUC ≥ 4
• Cisplatin
• Cyclophosphamide (≥
1500mg/m2)
• Dacarbazine
• Doxorubicin
≥60mg/m2
• Carmustine
• Azacitidine
• Carboplatin
AUC < 4
• Cyclophosphamid
e (<1500mg/m2)
• Doxorubicin
• Ifosfamide
• Oxaliplatin
• Temozolamide
(oral)
• Thiotepa
• Aflibercept
• Bortezomib
• Cabazitaxel
• Cetuximab
• Docetaxel
• Etoposide
• 5-fluorouracil
• Gemcitabine
• Methotrexate
• Mitomycin
• Paclitaxel
• Pegylated liposomal
doxorubicin
• Temsirolimus
• Transtuzumab
emtansine
• Bleomycin
• Busulfan
• 2-chlorodeoxydenosine
• Rituximab
• Vinblastine
• Vincristine
NOTE: CHEMOTHERAPY AGENT WHICH DOES NOT CAUSE ALOPECIA? EG: CAPECITABINE, 5-FU

21. ANTIEMETIC AGENTS
1. HIGHEST THERAPEUTIC
INDEX
DRUG PRE CHEMOTHERAPY
DOSE (DAY 1)
POST
CHEMOTHERAPY
DOSE
NK1 RECEPTOR
ANTAGONISTS
NK1 RECEPTOR
ANTAGONIST/5-HT3 R
ANTAGONIST
COMBINATION
CORTICOSTEROIDS
5-HT3 RECEPTOR
ANTAGONISTS
Others
• Aprepitant
• Fosaprepitant
• Rolapitant
• Netupitant-
Palonosetron
• with NK1
antagonist
• Ondansetron
• Granisetron
• Palonosetron
• Olanzapine
125mg orally
150mg IV
180mg orally, 166.5mg IV
300mg/0.5mg (NEPA) orally
12mg orally or IV
8mg orally BD
2mg orally; 1mg or
0.01mg/kg IV
0.25mg IV ; 0.5mg orally
10mg day 1
80mg orally day 2 & 3
8mg days 2-4
8mg BD days 2 & 3
10mg days 2-4

22. • Among 5-HT3 antagonists, a metaanalysis of RCTs comparing palonosetron with 1st generation serotonin
antagonists shows that: palonosetron was significantly more effective in preventing acute and delayed nausea &
vomiting for both HEC and MEC.
• Subcutaneous Granisetron extended-release injection is preferred serotonin antagonist option when used with
dexamethasone in antiemetic regimens that do not contain an NK1 RA.
• 1st generation drugs are effective in preventing acute emesis but are less effective for delayed emesis.
• A single dose of IV palonosetron appears to be effective for preventing both delayed and acute emesis.
• Corticosteroids are a mainstay in the prevention of both acute and delayed CINV.
• In acute phase, Dexamethasone is found to increase the chance of complete prevention of CINV by 25-30% versus
placebo.

23. • With MEC and HEC regimens, Dexamethasone is used in combination with other antiemetics.
• Appropriate doses of dexamethasone in HEC and MEC are 20mg and 8mg respectively.
• Aprepitant is an inhibitor of cytochrome P450 enzyme CYP3A4, which is involved in mechanisms of drugs like
dexamethasone and certain chemotherapeutic agents.
• Olanzapine is an antagonist of multiple neurotransmitters, Including dopamine and serotonin, and has shown to be
effective in preventing both acute and delayed CINV.
• Navari et al reported a phase III trail in which patients receiving HEC comparing a 4-drug regimen(5-HT3 receptor
antagonist on D1, dexamethasone on D1 to D4, NK1 antagonist- fosaprepitant on D1/ aprepitant on D1 to D3,
olanzapine on D1 to D4) to the 3-drug regimen(regimen(5-HT3 receptor antagonist on D1, dexamethasone on D1 to
D4, NK1 antagonist- fosaprepitant on D1/ aprepitant on D1 to D3) with a matching olanzapine placebo on D1 to
D4.
• Result : complete response was better with 4-drug regimen(86%) compared with 3-drug regimen (65%)

24. 2. LOWER THERAPEUTIC
INDEX (DRUGS)
PRECHEMOTHERAPY
DOSE
POSTCHEMOTHERAPY
DOSE
Prochlorperazine 10mg orally or IV
Nabilone 1-2mg orally 1-2mg BD / TID as needed
• Drugs of lower therapeutic index are: metoclopramide, butyrophenones, phenothiazines, cannabinoids.
• These drugs are mostly used in patients who are unable to tolerate/do not respond to highest therapeutic
index drugs.
• A number of complementary therapies such as Ginger, Acupuncture and Acupressure have been used for
CINV with varying results. But at present guideline panels have not recommeneded for or against these
approaches.

25. ANTIEMETIC TREATMENT BY CLINICAL SETTING
• Basic principles to be considered are:
1. Primary goal – complete prevention of nausea & vomiting
2. To minimize the risk of anticipatory emesis, antiemetic therapy should be appropriately maximized from
the initial cycle of chemotherapy
3. Antiemetic therapies should be chosen to match the intrinsic emetogenicity of the chemotherapy
4. Consider prescribing antiemetics for use in the event breakthrough emesis develops.

26. Emetic risk category Day 1 prechemotherapy After chemotherapy
HIGHLY EMETOGENIC
CHEMOTHERAPY(HEC)
CISPLATIN
Combination of Anthracycline and
cyclophosphamide
5-HT3 receptor antagonist +
Dexamethasone + NK1 antagonist +
Olanzapine
5-HT3 receptor antagonist +
Dexamethasone + NK1 antagonist +
Olanzapine
Dexamethasone + Olanzapine
on days 2 to 4
Olanzapine on days 2 to 4
MODERATELY EMETOGENIC
CHEMOTHERAPY(MEC)
CARBOPLATIN AUC ≥ 4
All others
5-HT3 receptor antagonist +
Dexamethasone + NK1 antagonist
5-HT3 receptor antagonist +
Dexamethasone
Dexamethasone on days 2 and 3
LOW AND MINIMALLY
EMETOGENIC CHEMOTHERAPY
Dexamethasone or prochlorperazine or
5-HT3 receptor antagonist as needed
No preventive measures
RECOMMENDED ANTIEMETIC THERAPY FOR SINGLE-DAY IV CHEMOTHERAPY

27. RADIATION-INDUCED NV
• Patients receiving total body RT have greatest likelihood of developing nausea & vomiting (>90% emesis).
• Patients receiving upper abdominal RT are at moderate risk of emesis (30-90%)
• GI tract (small intestine) contains rapidly dividing cells that are particularly sensitive to RT.
• The potential for nausea & vomiting increases with larger daily fractional doses of RT, larger total doses and
larger amounts of irradiated tissue.
• Total body irradiation when given before bone marrow transplantation, commonly induces nausea & vomiting .

28. • RECOMMENDED ANTIEMETIC THERAPY FOR RINV:
RISK LEVEL IRRADIATED AREA ANTIEMESIS
GUIDELINES
HIGH Total body irradiation, total
nodal irradiation
Prophylaxis with 5-HT3
receptor antagonist +
Dexamethasone
MODERATE Upper abdomen, half-body
irradiation, upper-body
irradiation
Prophylaxis with 5-HT3
receptor antagonist + optional
Dexamethasone
LOW Cranium, craniospinal, head &
neck, lower thorax region,
pelvis
Prophylaxis or rescue with a
5-HT3 receptor antagonist (or
Dexamethasone in brain
radiation)
MINIMAL Extremities, breast Rescue with a dopamine
receptor antagonist or a 5-HT3
receptor antagonist