This document discusses chemotherapy-induced nausea and vomiting (CINV) management. It begins by outlining the magnitude of CINV as a problem for patients and its impact on quality of life. It then defines the different types of CINV and classifies chemotherapeutic agents based on their emetic risk. The pathophysiology of CINV is described as involving several areas of the brain and neurotransmitters like serotonin, dopamine, acetylcholine, and histamine. Guidelines for assessing, classifying severity of, and treating CINV are provided, focusing on the main classes of antiemetics - 5HT3 antagonists, dopamine antagonists, and NK1 receptor antagonists.

1. CINV (chemo therapy induced
nusea and vomiting )
management
presented by : Heba bakri
Ass. Lecturer clin.onc.dep. AUH

2. Agenda :
• magnitude of the problem
• Definition , Types of CINV and AE
• Classification of ematogenic agents
• Pathophysiology and Risk factors
• Classification of anti emetics
• management ( assessment - treatment – general guidelines )
• Asco and NCCN guidelines

3. Magnitude of the problem
- N& V are two of the greatest fears of patients with cancer.
- May be a result of the disease status of the patient but are more frequently
associated with anti-cancer treatment.
- They are distressing symptoms have a considerable impact on all aspects of
the patients’ quality of life , their family and caregivers which lead to escalate
over time, and potentially lead to changes in or delay of the chemotherapy
regimen, or even patient’s refusal to continue

4. If Inadequately controlled can precipitate a number of medical
complications that may prove life-threatening, including dehydration,
electrolyte imbalance and malnutrition, or cause physical damage,
including Mallory–Weiss rupture of the oesophagus.

5. Nausea should be clearly distinguished from
vomiting !!!!!
•Nausea refers to the gastric and/or medullary distress
with distaste for food and an urge to vomit, but without necessarily
encompassing vomiting.
It should be emphasised that a patient who is not vomiting may still
experience severe nausea that needs to be comprehensively
diagnosed and managed .

6. 4Types of nausea and vomiting :
AssociationPersistanceTime
Early : 12 h after CTH
Late : > 12 to 24h after CTH
Acute
following the
administration of platinum
analogues, alkylating
agents or anthracyclines.
persist for 6–7 days .more than 24–48 hoursChronic
linked to visual, gustatory,
olfactory and
environmental
factors associated with
previously administered
chemotherapy (the “white
uniform” syndrome
before, during or after the
administration of a
subsequent course of
treatment if previous emetic
control has been inadequate
Anticipatory

7. 4- Breakthrough nausea and vomiting :
• Occur despite prophylactic treatment and are usually abrupt, sudden
and acute.
• The specific reasons for it inadequately understood
• often in young patients, and/or women, and/or with history of
motion illness)
• but they represent a medical emergency that needs to be timely
diagnosed and treated.

8. Aetiology:
• a) Treatment-induced
• b) metabolic Causes
• c) Gastrointestinal Causes
• d) Neurological Disorders
• e) others

9. *** metabolic Causes
- Hypercalcaemia - Renal failure (uraemia)
- Adrenocortical failure - Hypo-or hyperglycaemia
*** Gastrointestinal Causes
- Liver metastases or hepatitis - Biliary duct obstruction
- Pancreatic disorders - Acute abdomen/peritonitis
- Functional bowel disease (reduced bowel motility, paralytic ileus)
- Obstructive bowel disease (peritoneal carcinomatosis, colorectal cancer)
- Gastric or oesophageal cancer
-Gastritis, gastro-oesophageal reflux disease, ulcus, pyloric stenosis

10. *** Neurological Disorders
- Brain metastases with high intracranial pressure
- Medullary or cerebellar dysfunction
- Carcinomatous or infectious meningitis
- Cerebral hemorrhage
*** Others
Myocardial infarction, viral infections, hypertension crisis

11. Treatment-induced nausea and vomiting is the
most important cause
• Chemotherapy: usually within 5 days following treatment
• Analgesics (e.g. opioids)
• Radiotherapy (especially when upper gastrointestinal [GI] tract or
mediastinum is involved in the radiation field)
- Selective serotonin reuptake inhibitors (many cancer patients develop
depression )
- Postoperative nausea and vomiting (after general anaesthesia)

12. Classification of CTH agents acc.to
ematogenic risk :
• Highly emetic
• Moderately emetic
• Low emetic
• Minimal risk of emesis

15. Pathophysiology
Vomiting center (VC ) receives input from GI mucosa, Chemoreceptor trigger
zone(CTZ), and vestibular apparatus , Efferents fibers from this center when
stimulated , cause stimulation of phrenic nerve supplying to diaphragm and of
somatic nerve supplying the abdominal muscles to promote emesis

16. • Irritation of GI mucosa by drugs or irritants leads to release of serotonin
that stimulates VC via 5HT3 receptors
• CTZ is rich in D2 receptor (release of dopamine ) and 5HT3 (release of
serotonin ) and neurokinin (NK1) receptor
• stimulation of vestibular apparatus and cerebellum, these structures
result in stimulation of VC by activating M1 (release of acetylcholamine )
& H1 receptors( realease histamine )

18. • Neurotransmitters Involved :
- Histamine via H1 receptors
- Serotonin via 5HT3 receptor
- Acetylcholine via M receptors
- Dopamine via D2 receptors

21. Risk factors
• Younger age
• Female gender
• Tumour burden
• Rate, route and dosage of chemotherapy administration
• Emetogenic potential of chemotherapy agent
• Anxiety or depression

22. D.D ????
• Obstructive Bowel Disease :
- In cancer patients, bowel obstruction is often a reason for nausea and
vomiting , the obstruction can occur at any level distal to the duodenum.
Usually, treatment starts conservatively over a period of 2–5 days by
(nasogastric tube, adequate intravenous fluid supplementation, diuresis
monitoring).
• If no improvement occurs within 72 hours, surgery should be considered.
In malignant large bowel obstruction, endoscopically placed, self expanding
metal stents may be used as palliation.

23. Assessment
• 1- questions
• 2- grading
• 3- investigations

24. a) Questions :
• what is Primary cancer diagnosis?
• what is cancer treatment ?
• When was the last treatment / tablet taken?
• History of onset, duration, frequency, volume.
• Review use of anti-emetics and other medications.
• Any abdominal pain? Review dietary intake over last few days
• N.B : If the patient is on oral anticancer therapy that is associated with
nausea and vomiting and the patient has moderate or severe symptoms,
the anticancer therapy must not be continued until it has been discussed
with the treating oncology medical team or the on-call oncologist

25. Grading of N&v :
1-2 episode / dayGrade 1Mild
3-5 episodes / dayGrade 2Moderate
> 6 episode /day
>10 episode /day
*** requires urgent intervention
can be life thretening
Grade 3
Gadre 4
Severe

26. c) Investigation
1- Clinical examination
• Abdomen, neurological examination, blood pressure, diuresis.
2- Blood examination
• Liver tests, renal function , electrolytes , blood gas.
3- Imaging modalities
• Ultrasonography, abdominal X-ray.
• If clinical examination suggests neurological disorder: CT or MRI , lumbar
puncture if carcinomatous or infectious meningitis is suspected
• If clinical examination suggests abdominal cause: Gastrografin meal, abdominal
CT scan
• Endoscopic examination (gastro-oesophagoscopy, colonoscopy) whenever
clinically indicated

28. 1- Serotonin 5HT3 Antagonist :
• Drugs Available and dose per day :
1st generation of 5HT3antagonists :
1- Ondansetron (ZOFRAN ) (ONDALENZ ) 32 mg / day
(Ondansetron 8 mg iv slow over 15 mins , ½ hr before chemotherapy , 2 doses 4 hr apart ) .
2- Granisetron (GRANISET) (GRANYTRIL) (EMEX) 10 mg / kg / day
(1-3 mg diluted in 20-50 ml saline infused iv over 5 mins before chemotherapy, repeat after
12 hrs )
3- Dolasetron 1.8 mg / kg / day

29. • 2nd generation of 5HT3antagonists :
Palonosetron (ALOXI) 250µg
• by slow iv inj 30 min before chemo
• longest acting 5HT3 receptor blocker with highest affinity for 5HT3
receptor (t1/2=40 hrs)
APF530 250-mg (sub cut. Granisetrone )
subcutaneous dose is equivalent to granisetron at 5 mg IV, and the 500-
mg dose is equivalent to granisetron at 10 mg IV.
APF530 is non inferior to IV palonosetron in preventing acute CINV
after MEC or HEC.

30. • Mechanism of Action :

31. • Pharmacological criteria :
- Potent anti emetics
- Excellent safety profile
- Ondansetron- prototype
- the antiemetic action is restricted to emesis caused by vagal stimulation.
- High first pass metabolism
- Excreted by liver & kidney
- No dose reduction in renal insufficiency but needed in hepatic insufficiency
- orally or intravenously.

32. • Indications
1- Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy.
2- Postoperative & post radiation nausea & vomiting
• Adverse Effects
1- Headache & constipation
2- All three drugs cause prolongation of QT interval, but more pronounced
with dolasetron
3- Palonosetron ( ALOXI ) :-
- Rapid i.v. injection causes blurring of vision

34. 2-Dopamine D2 Antagonists
• Drugs available
- Metoclopramide(PRIMBERAN ) :
2.5 mg b.d , ORAL OR iv , cross BBB
- Domperidone (motilium )
10 mg b.d ORAL ONLY , don’t cross BBB

35. Mechanism of action :
1- act on CTZ which is outside BBB both have antiemetic effects.
But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side
effects but Domperidone is well tolerated
2- Both drugs are also prokinetic agents due to their 5 HT4 agonist activity.
Indication :
- Antiemetic- ( Postoperative, drug induced, radiation , disease associated ( migraine)
- Gastro kinetic- to accelerate gastric emptying, GERD

36. Adverse effects of Metoclopramide
Sedation, Dizziness, loose stools, muscle dystonias, Long term parkinsonism,
galactorrhoea, gynaecomastia
Adverse effects of domperidone :
- Low ceiling antiemetic and prokinetic , Less Efficacious gastrokinetic, not
useful in highly emetogenic chemotherapy
- Side effects- Less as compared to Metoclopramide ( Dry mouth, loose
stools, headache, rashes, galactorrhoea are mild )

37. 3-NK1 receptor antagonist

38. 1- Aprepitant :- ( emend oral)
Dose- 125 mg+ 80 mg+ 80mg for 3 days Aprepitant- Cisplatin induced vomiting
Combined with IV Ondansetron and Dexamethason
- Metabolism Well absorbed orally and penetrates BBB ,Metabolised in liver by
CYP3A4
2- Fosaprepitant ( emend IV) :
-Well tolerated
- Avoid combination with cisapride-QT prolongation

39. Mechanism of action

40. • Indication :
aprepitant : For patient undergoing multiple cycles of chemotherapy
Fosapritant : PONV (preoperative nusea and vomiting ), adjuvant in
CINV
adverse events :
Weakness, fatigue, flatulence, rise in liver enzymes

42. 4- anti psycotics

43. • Lorazepam is an adjunctive drug but not recommended as a single
agent
• diphenhydramine is no longer accepted as an adjunctive drug for
emesis prophylaxis.
• Trials with cannabinoids are old and no comparison with
contemporary antiemetics is found.
• medical marijuana use or complementary/alternative therapies (such
as ginger, acupuncture, acupressure etc.) remains insufficient for a
recommendation regarding for the prevention of treatment related
N&V in patients with cancer.

44. Evidence based medicine

46. • The systematic review of literature which focused only on
randomised controlled trials (RCTs) and systematic reviews between
November 1, 2009 and June 1, 2016.
• The review process yielded 41 publications (35 RCTs and 6 meta-
analyses), majority about prevention of chemotherapy-related N&V,
and less publications about radiation-induced N&V and for paediatric
patients found.

48. - addition of olanzapine (10 mg/day, po, D1-4), which is an antipsychotic drug that
blocks multiple neurotransmitters in central nervous system, to standard of care (SOC;
NK1 antagonist + dexamethasone 12 mg on D1 and 8 mg D2-4 + 5HT3 antagonist) was
tested in patients treated with high-emetogenic risk chemotherapy. showed the
superiority no nausea during the overall assessment period (0–120 h) and complete
response (no emetic episodes and no rescue medication), respectively.
-ASCO panel revealed the new SOC antiemetic regimen that should be used for
high-emetogenic risk drugs as a 4-drug combination (NK1 antagonist + 5HT3
antagonist + dexamethasone + olanzapine). To note, for antracycline and
cyclophosphamide regimen dexa is recommended only for the first day, if a 4-drug
antiemetic combo will be used as aprepiant affect metabolism of dexa
High-emetic risk,
single-day chemo:
-another NK1 antagonist, rolapitant which was formerly approved by FDA in 2015, listed among the options
that could be used in the treatment of CINV. Also, non-inferiority of subcutaneous extended release
granisetron to i.v. palonosetron and superiority to ondansetron were shown in different trials.

49. 1- receiving carboplatin with a dose AUC ≥4 are
accepted at the higher end in terms of emesis risk in this
category. Studies of both rolapitant and aprepitant
showed superior emesis prophylaxis in these patients
with regard to 5HT3 + dexa combination.
Moderate-emetic risk, single-day chemo:
Recommendations regarding moderate-emetogenic
regimens could be reviewed in 3 parts.
2- the majority of moderate-emetogenic regimens a
combination of 5HT3 + dexa on D1 only would be
enough.
However, if the patient will receive an agent that is
known to cause delayed emesis (like cyclophosphamide,
oxaliplatin or doxorubicin) dexa may be offered for D2-
3,
3- palonosetron is no longer the agent of choice for
moderate-emetogenic risk drugs owing to lack of
convincing data, thus any 5HT3 antagonist is acceptable
for this risk group.

50. • Low-emetic risk, single-day chemo: Since the quality of evidence about
antiemetic prophylaxis is low for this stratum, the guideline proposed
single 5HT3 antagonist or single dose 8 mg dexamethasone with an
informal consensus and moderate strength of evidence.
• Minimal-emetic risk, single-day chemo: As previous, these patients
should not be offered routine antiemetic prophylaxis, unless foreseen
such a need by the treating physician.

51. • recommendations about the antiemetic approach for radiation therapy (RT)
in this update.
1- For high (risk > 90%, total body irradiation) and moderate risk (30–90%,
craniopsinal, upper abdomen RT) radiation therapies:
prophylactic approach with 5HT3 plus dexamethasone is recommended.
2- Whereas for low (risk 10–30%, brain, head&neck, thorax, pelvis) or minimal
risk (<10%, extremity, breast) RT :
a rescue strategy is recommended primarily with 5HT3, dexamethasone or
dopamine antagonist.
The emetic risk of anti-neoplastic agent should guide the antiemetic
prophylaxis in patients receiving chemoradiotherapy unless the risk related
with RT is higher.

52. Treatment of CINV :
• If moderate vomiting, without complications
Outpatient management
1- treatment with serotonin antagonist orally (or intrarectally) and/or
metoclopramide and/or corticosteroids
2- Avoid drugs that reduce bowel motility (e.g. loperamide, hyoscyamine,
anticholinergic agents)
3- Check the evolution after 24 hours

53. • If severe or in case of complications
Consider hospitalisation
1- Serotonin antagonists: e.g.
a) granisetron: (granytril ) 3 mg × 1–3/day intravenously (i.v.)
or
b) ondansetron: (Zofran ) 8 mg × 1–3/day i.v. over at least 10 minutes, and at
regular intervals thereafter (“round the clock” administration).
• In case of resistance: continuous i.v. perfusion of chlorpromazine 25 mg/day,
or olanzapine 5–20 mg/day

54. General principles in management of multiday
ematogenic chemotherapy regimen

63. • N& V are two of the greatest fears of patients with cancer.
• If Inadequately controlled can precipitate a number of medical complications
that may prove life-threatening,
• 4 types ( acute (<12 h) – chronic (12-24 h) – anticipatory – break through )
• AE (Treatment-induced , metabolic , Gastrointestinal , Neurological ,
others )
• Classification of eamtogenicity of CTH agents (Highly emetic , Moderately
emetic , low emetic , Minimal risk of emesis )
• Grading of N&v : mild (grade 1 ) (1-2 episode /day ) , moderate (grade 2) ( 3-
5 episode ) , severe (grade 3) (>6 ) (garde 4 ) ( > 10 ) episode .
• Classification of antiemetics ( 5HT3 antagonists , serotonin antagonists , NK1
RA )