Chemotherapy induced N/V (CINV)

step-wise approach

ID source - pathophysiology

ID pathway/receptors - neurotransmitters

utilize med with complimentary action

dietary counseling - small, frequent meals
*nutrition = important!
eating challenges - mucositis, pain, depletion of nutrients, lots of N/V

CINV: 3 potential causes

intestinal distension → 5HT₃ in GI vagal/gut
*from large tumor - colon cancer, intestinal, ovarian or inflammation/GI flu bug in bowel, suspended by gas

cytotoxic chemotherapy → 5HT₃ in both GI vagal/gut & chemoreceptor trigger zone
*NOT only impact gut, but also crosses BBB into brain

radiotherapy → 5HT₃

*traditional chemotherapy is very good at attacking rapidly dividing cells (cancer), so are cells lining in gut, mouth (mucositis), hair follicles (lose hair due to chemotherapy)

vomiting center (brain stem): 4 receptors

ACh_m, H₁, mu-opioid, 5HT₃/NK-1
→ salivation center, abdominal muscles, respiratory centers & cranial nerves
*goal = target/stop the receptors upstream prior to vomiting center

gastrointestinal vagal/gut: 3 causes

nonspecific (?) - mechano- & chemoreceptors

radiotherapy (inflammatory receptors) & intestinal distention (from large tumor - colon cancer, intestinal, ovarian or inflammation/GI flu bug in bowel, suspended by gas), obstruction (partial; either from constipation or benign/malignant tumors) → 5HT₃ → need 5HT₃ antagonists (Zofran)

cytotoxic chemotherapy (*traditional chemotherapy is very good at attacking rapidly dividing cells (cancer), so are cells lining in gut, mouth (mucositis), hair follicles (lose hair due to chemotherapy) → 5HT₃ → need 5HT₃ antagonists (Zofran)

chemoreceptor trigger zone (CTZ; brain): 3 causes

cytotoxic chemotherapy (NOT only impact gut, but also crosses BBB into brain) → 5HT₃ → need 5HT₃ antagonists (Zofran)

opioids & digoxin (= nauseating drugs; med-induced that’s not chemo does NOT work on gut; Sinemet, Mirapex) and hypercalcemia & uremia (metabolic & electrolyte imbalances, common cause in end-stage renal failure or advanced CKD) → D₂ → need DA antagonist (Compazine, Haldol, Phenergan, olanzapine = NOT good line therapy for Parkinson’s)

α₂ → pain management

cerebral cortex (outside area of brain): 2 causes

fear & anxiety (can happen both in oncology & outside; if every time I eat I vomit → anxious when eating; anxiety can induce N/V independent of even having food in mouth; conditional response) → GABA → BZDP (lorazepam OR diazepam) or hydroxyzine?

5HT₃

raised intracranial pressure (anytime have sth in brain that should NOT be there = malignant/benign/pituitary tumor or 2ndary metastatic tumor in brain; pressure highest in AM, very nauseous, slowly starts to feel better as pressure decreases as day goes on) → dexamethasone
*emotional, anticipatory-driven N/V

vestibular nuclei (center balances in ear; motion sickness): 2 causes

movement & vertigo → ACh_m & H₁ (what makes room spin) → anticholinergic or antihistamine (meclizine, Benadryl)

CINV: 5 additional potential causes

electrolyte imbalance: hypercalcemia, hyperglycemia, hyponatremia

gastroparesis: tumor/chemotherapy, comorbid conditions (diabetes)

excessive secretions: head & neck cancer diagnoses → gastric distention, stimulate saliva release

malignant ascites, pancreatitis

abrupt medication withdrawal (opioids)

CINV: 3 types

acute-onset & delayed-onset

anticipatory

breakthrough & refractory

CINV: acute-onset

timing: mins - several hrs after chemo administered
peaks 5-6 hrs
resolves within 24 hrs

goal: admin before & after chemo

factors that increase risk
• <50yo
• female
• environment
• h/o EtOH: ↓ emesis (NOT contributing but negating factor)
• motion sickness
• previous episodes - 1st chemo infusion has to go well b/c it sets up anxiety for subsequent infusions
• emetogenic agent
• efficacy of antiemetic
• abnormal taste

CINV: delayed-onset

timing: >24 hrs after chemo

chemo regimens at big risk of delayed N/V should have anti emetics ordered for 2-4 days post-infusion

goal: admin 24 hrs after chemo (2-4 days)

CINV: anticipatory

prevention - easier than treatment
• optimize antiemetic therapy during every cycle
conditioned response
18-57% N > V
younger pts at risk due to
• use of aggressive chemo → goal = survival
• poor emesis control

strategies
• behavioral therapy
➢ relaxation/desensitization
➢ hypnosis/guided imagery
➢ music therapy
• acupuncture/acupressure

before chemo infusion: night before & then 1-2 hrs before chemo
*2 doses, will need someone to drive
look at PMH - nervous for chemo regimen?

pharmacotherapy
• alprazolam (Xanax) 0.5-2 mg TID qHS before treatment
• lorazepam (Ativan) 0.5-2 mg qHS before & qAM of treatment

CINV: breakthrough

occurs despite prophylactic treatment

“rescue”

*hopefully does NOT become refractory

CINV: refractory

despite prophylactic, breakthrough have failed during earlier cycles
*gastric suction

emetogenic chemotherapy classification

% of pts NOT receiving antiemetics who experience acute emesis

experience acute emesis
• high: ≥90% - if don’t give antiemetics, 90% are going to have N/V
*combination, individual drug, dose dependent
• moderate: 30-90%
• low: 10-30%
• minimal: <10%

emetogenic chemotherapy

antiemetic regimen should be selected based on highest emetic risk in chemo regimen

high emetogenic potential IV chemotherapy
• delayed onset of N/V = 3 days, most profound

moderate emetogenic potential IV chemotherapy
• delayed onset of N/V = 2 days

*NO low → NO Aloxi!

drug therapy options

5HT₃ receptor antagonists - cornerstone

neurokinin-1 receptor antagonists - equally important

adjuvant options
• steroids
• phenothiazines/antipsychotics → target DA
• prokinetics → metoclopramide
• BZDP → anticipatory N/V
• other: dronabinol, nabilone, scopolamine patches

serotonin 5HT₃ receptor antagonists

significant advance in antiemetic therapy
demonstrated equal efficacy

3 options: ondansetron (Zofran), granisetron (Kytril), palonosetron (Aloxi) - unique

serotonin 5HT₃ receptor antagonists: ondansetron (Zofran)

SE: headache, malaise, fatigue, constipation, drowsiness, dizziness
*is that SE or drug? NOT significant

severe liver disease (Child-Pugh C) = 8 mg/d

many interactions
• substrate: CYP1A2, 2D6, 3A4 (major)
• inhibits: CYP1A2, 2C9, 2D6

formulations: tabs, ODT, solution, IV, PR (cmpd)

serotonin 5HT₃ receptor antagonists: granisetron (Kytril)

SE: headache (< w/ patch), constipation, weakness, dizziness, drowsiness

decreased clearance w/ liver impairment

fewer interactions
• substrate: CYP3A4 (minor)

formulations: tabs, solution, TD, IV
• TD apply 24-48 hrs prior to 1st chemotherapy → nice option
• cover patch while applied & 10 days after removal

serotonin 5HT₃ receptor antagonists: palonosetron (Aloxi)

SE: headache, constipation, dizziness

100x higher binding affinity for 5HT₃ receptor → unique
• t_½ = ~40hrs → incredible

superior to other 5HT₃ for delayed-onset = preferred
• NO role in breakthrough N/V due to long t_½ → Zofran or Kytril

neurokinin-1 receptor antagonist: aprepitant (PO)/fosaprepitant (IV) (Emend)

MOA: blocks binding of substance P in CNS (another pathway that influences N/V)
• minimal affinity: 5HT₃, DA, corticosteroid

dose
• 130 mg IV x day 1 (just for day 1)
• 125 mg PO x day 1, 80 mg days 2-3 (higher dose day 1, lower dose days 2-3)

CYP3A4 substrate & moderate inhibitor/inducer

benefits for acute & delayed N/V

minimal SE: fatigue, nausea (~10%), constipation, weakness, hiccups, dizziness

neurokinin-1 receptor antagonist: rolapitant (Varubi)

MOA: blocks binding of substance P in CNS

dose: 180 mg PO daily 1-2 hrs before

NO renal/hepatic dose adjustments

benefits for delayed N/V, not acute

SE: dizziness, anorexia, dyspepsia, neutropenia

neurokinin-1 receptor antagonist-combo: netupitant/palonosetron (Akynzeo)

indicated for acute & delayed N/V
*Aloxi - NO role for acute alone

dose: 300-0.5 mg cap 1 hr prior to chemo

MOA: synergistic (1+1=3)
• NK-1 antagonist/substance P inhibitor
• 5HT₃ antagonist: blocks 5HT on peripheral vagal & central CTZ (blocks cross talk between 5HT₃ & NK-1)

SE: headache, fatigue (both ~10%)

antiemetic adjuvants: phenothiazines & antipsychotics

promethazine (Phenergan), prochlorperazine (Compazine)
haloperidol (Haldol), olanzapine (Zyprexa), chlorpromazine (Thorazine)

MOA: DA receptors in CTZ

SE: EPS, sedation (dose-related; 5-10 mg olanzapine → ↓2.5 mg), QT prolongation* (monitor ECG in high risk pts)
*most pts use olanzapine as part of antiemetics are NOT at high risk but some populations are: prior arrhythmia, cardiac abnormalities that impact conduction

antiemetic adjuvants: prokinetic

metoclopramide (Reglan) - solution, tabs, IV

MOA: blocks serotonin receptors in CTZ, DA antagonism (>40 mg/day), peripheral action
• ↑ LES pressure
• ↑ gastric emptying - gastric, pancreatic, liver, ovarian, small intestine cancer - delay in gastric emptying, blockage of small intestine
*↑ movement in small intestine
• does NOT increase gastric, biliary, pancreatic secretions - can be very painful if does
• does NOT stimulate large intestine (colon) - NOT a laxative

SE: EPS, anxiety, restlessness, diarrhea, sedation (higher dose related), Parkinson-like symptoms, EPS/TD

antiemetic adjuvants: droperidol (Marinol) or (Inapsine)

MOA: cannabinoid receptors (CB1) in CNS

liquid > bioavailability vs. cap (2.1 mg = 2.5 mg)

caution
• other CNS depressants
• abuse hx
• withdrawal syndrome
• geriatric - hypotension

SE: euphoria, N/V, confusion, palpitations - tachycardia, xerostomia, very sedating

high-antiemetic regimen backbones

1) NK-1 (IV or PO) + 5HT + steroid x day 1; NK-1 (PO, aprepitant) + steroid days 2-4

2) 5HT + steroid + DA antagonist x day 1; DA (olanzapine) days 2-4

3) NK-1/5HT + steroid x day 1; steroid days 2-4

4) NK-1 + 5HT + steroid + DA x day 1; NK-1 (PO) + steroid + DA

high emetogenic potential #1 IV
NK-1 (IV or PO) + 5HT + steroid x day 1; NK-1 (PO, aprepitant) + steroid days 2-4

NK-1 inhibitor
• aprepitant (Emend) 125 mg PO, 30 min prior day 1 (before chemo administered); 80 mg qD x2-3 days, 30 min prior
• fosaprepitant 115 mg IV only
• rolapitant 180 mg PO once

AND steroid
• dexamethasone 12 mg PO/IV day 1; 8 mg PO/IV qD-BID

AND 5HT3 antagonist
• ondansetron (Zofran) 16-24 mg PO; 8-16 mg IV day 1
• granisetron (Kytril) 2 mg PO qD OR 1 mg BID; 0.01 mg/kg IV; 3.1 mg TD apply 24-48 hrs prior 1st dose chemo day 1
• palonosetron (Aloxi) 0.25 mg IV day 1 (preferred-high); most efficacious agent

+/- lorazepam (Ativan) 0.5-2 mg PO/IV/SL day 1; 0.5-2 mg PO/IV/SL
*anticipatory history, anxiety

+/- H2 blocker → GI history, reflux, tummy trouble

high emetogenic potential #2 IV
5HT + steroid + DA antagonist x day 1; DA (olanzapine) days 2-4

day 1
• olanzapine 10 mg PO once → if sedated or sensitive, ↓5 or 2.5 mg
• palonosetron 0.25 mg IV once
• dexamethasone 20 mg IV
• +/- lorazepam (Ativan) q4-6hr days 1-4
• +/- H2 blocker

days 2-4
• olanzapine 10 mg PO daily
• +/- lorazepam (Ativan) q4-6hr days 1-4
• +/- H2 blocker

moderate emetogenic potential IV
*delayed onset = 2 days

day 1, before chemo administered
• dexamethasone 12 mg PO/IV
• 5HT3 antagonist - palonosetron (Aloxi) = preferred
• +/- lorazepam (Ativan) 0.5-2 mg PO/IV/SL q4-6hr PRN
• +/- H2 blocker

days 2-3 (just steroid)
• dexamethasone 12 mg PO/IV qD
• +/- lorazepam (Ativan) 0.5-2 mg PO/IV/SL q4-6hr PRN
• +/- H2 blocker

low emetogenic potential IV

start before chemotherapy administered, repeat daily for multiday doses of chemo

• dexamethasone 12 mg PO/IV qD OR
• prochlorperazine (Compazine) 10 mg PO q4-6h OR
• metoclopramide (Reglan) 10-40 mg PO/IV q4-6h PRN OR
• 5HT3 antagonist, no Aloxi (only used for delayed onset) → Zofran or Kytril
• +/- lorazepam (Ativan) 0.5-2 mg PO/IV q4-6hr PRN
• +/- H2 blocker/PPI

minimal emetogenic potential IV

NO routine prophylaxis

nausea & emesis 0-24 hr after infusion

could consider using drug therapy

PRN
• better to be safe than sorry

breakthrough N/V treatment

easier to prevent than treat
• breakthrough creates difficulties - set back in treatment: electrolyte abnormalities, dehydration, metabolic complications, distress

3 strategies
• give agent from another drug class
• consider pt history
• maintain hydration & electrolyte balance

*when pt comes back for next chemo infusion, upgrade antiemetic regimen to stronger/higher even though chemotherapy stays the same, ex: moderate → high

breakthrough (IV or PO chemo)

give additional agent from different drug class PRN

• metoclopramide (Reglan) 10-40 mg PO/IV q4-6h PRN
*based on history & pathology, used for pancreatic cancer where NOT great gastric emptying or tumor pressing on stomach
• lorazepam (Ativan) 0.5-2 mg PO q4-6h PRN
• 5HT3 options, NO Aloxi
• dexamethasone 12 mg PO/IV qD PRN
• dronabinol (Marinol) 5-10 mg PO q3-6h PRN
• prochlorperazine (Compazine) 10 mg PO q4-6h PRN or 25 mg supp q12h PRN
• promethazine (Phenergan) 12.5-25 mg PO/IV q4h PRN
• haloperidol (Haldol) 0.5-2 mg PO q4-6h PRN
• olanzapine (Zyprexa) 10 mg PO daily x3 days
• scopolamine (Transderm) 1 patch q72h

breakthrough: management

emesis controlled → continue as scheduled NOT PRN

emesis uncontrolled → change to higher-level primary treatment