L4: Chemotherapy induced n/v - Siver

What are the ADE of CINV?

Qol, dehydration, impaired absorption, malnutrition, electrolyte disturbances, treatment delays

SEQ acute n/v pathophys

1. chemo induce dmg and free radical generation and release 5-HT3 from enterochromaffin cell

2. 5HT3 binds to 5HT3 receptors → stim afferent vagal nerve signaling to the area postrema (vomiting center) in the medulla, inducing emesis

SEQ delayed n/v pathophys

1. chemo activates receptors in chemoreceptor trigger zone (CTZ) which stim nucleus tractus solitarious (NTS/vomiting center) in the postrema in the medulla → induce substance P release from neurons

2. substance P binds to the NK1 receptors in the area postrema to induce vomiting

What type of CINV occurs within 24h after chemotherapy admin and is mediated through activation of serotonin receptors?

acute

What type of CINV occurs any time after 24h post chemotherapy administration; seen w mod to high emetogenic regimens; mediated through substance P/NK1 receptors

delayed

What type of CINV occurs before admin of chemotherapy; psychologically induced due to memory assoc w previous cycles; common in pediatrics and adolescence

anticipatory

What type of CINV occurs within 5 days of chemotherapy admin, despite use of guideline recommended anti-emetic therapy

breakthrough

What type of CINV has persistent n/v not relieved by guideline antiemetic agents in subsequent chemotherapy cycles after guideline directed therapy fails

refractory

What are the patient related risk factors of CINV?

1. <50 yrs

2. female

3. ho morning sickness during preg, motion sickness

4. anxiety/high pretreatment of anticipatory n

5. no ho alcohol consumption

6. location of malignancy (brain, GI tumors)

7. < 7 hrs of sleep the night b4 treatment

what are the treatment related risk factors of CINV?

1. prior CINV w previous cycle

2. high emetogenic potential of chemotherapy regimen

3. electrolyte imbalance

4. gastroparesis

5. concomitant drug therapy (opioids)

Which agents are high (>90% risk of emetogenicity)?

1. AC combo as any chemotherapy w anthracycline and cyclophosphamide

2. cisplatin

3. fam-trastuzumab deruxtecan

T/F cyclophosphamide + anthracycline (AC combo) is always considered high emetogenic risk

true

if patient is on multi day chemotherapy, how should you monitor emetogenicity?

follow emetogenic risk of agents received that day and follow antiemetic recommendations for 3 days post therapy for highly emetogenic regimens and 2 days post therapy for moderately emetogenic regiments

5HT3 receptor antagonists block serotonin, both peripherally on vagal nerve terminals, and centrally in the CTZ. What is the indication?

prevention of acute CINV, treatment breakthrough and refractory CINV

What are the ADE of 5HT3RA?

HA, c, fatigue, dizzy, QTc prolongation (except palonstron and vincristine), serotonin syndrome

Ondansetron, Granisetron, and Palonosetron are indicated for prevention of acute CINV, which ones are also breakthrough?

Ondansetron and Granisetron (longer T1/2)

What are the toxicities of 5TH3RAs?

1. ondansetron: Qtc prolong w single IV doses > 16 mg, and >24mg/d

2. granisetron: subq dose superior to IV dose

3. palonsetron: bradycardia, lowest risk of QTC prolong

neurokinin 1 (NK1) receptor antagonists inhibit substancec P/ NK1 receptor which augments antiemetic activity of5 HT3 receptor antagonists and corticosteroids. When is it indicated?

prevention of acute and delayed phases of CINV in combo w 5HT3 agonist and/or steroids

What are the ADE of NK1 receptor antags?

fatigue, hiccups, d

What are the clinical pearls of fosaprepitant?

IV, give 30 min prior to chemo; major CYP3A4 inhibition (ifophosphamide), minor CYP2D6, CYP1A2

• contains polysorbate 80 → hypersens rxn

What are the clinical pearls of aprepitant?

• IV given 30 min prior to chemo on day 1: contains egg lecithin and soybean allergens

• oral capsules/solution given 1 hour b4 chemo then 80mg po QD on day 2 and 3 of cycle (3 day therapy)

• same CYP as fosprepitant

What are the clinical peals of rolapitant?

• IV or oral given 2 hrs b4 chemo day 1

• CYP2D6 inhibition (persist for 7d after dose)

• longer half life, should NOT be admin <2 wks intervals

what are the clinical peals of netupitant/palonosetron

• oral capsule combo product given 30 min b4 chemo on day 1

• major CYP3A4 inhib

• 5HT3 antag with NK1RA

Corticosteroid moa is unknown, but antiemetic effect may be due to interactions w various CNS receptors located centrally in medulla. What are the indications?

prevention of acute and delayed CINV in combo with other agents, treatment of breakthrough and refractory CINV

What are the ADE of corticosteroids

insomnia, inc appetite, hyperglycemia, fluid retention, emotional lability, dyspepsia (H2RA/PPI)

What is the regimen for dexamethasone?

1. day 1 of chemo in combo w fos/arep/netu/fosnetu/rolapit and 5-HT3 RA: 12mg IV/PO

2. day 2-4: 8mg IV/PO

avoid as antiemetic for 3-5 days before and 90 days after CAR T cell therapy; may be left out of preventative antiemetics for certain leukemia/lymphoma regimens where steroids used for chemo

Dopamine receptor antagonists blcok multiple receptors assoc w CINV (serotonin, dopa 1 and 2, histamine, alpha 1 adrenergic). What are the indications?

1. prevention and treatment of breakthrough/refractory CINV

2. olanzapine: prevent acute and delayed CINV

What are the ADE of dopamine receptor antagonists?

sedation, HA, dizziness, extrapyramidal symptoms (EPS)

What are the clinical pearls of metoclopramide? (d2ra)

oral and IV before chemo or q6-8 hrs

short terms use <12wks due to inc risk of tardive dyskinesia (dose limiting)

What are the clinical pearls of olaznapine? (d2ra)

acute/delayed/breakthrough/anticipatory

oral 2.5-10mg day 1, them 2.5-10mg QD days 2-4

wt gain, lethargy, QTc prolongation, anticholinergic

What are the clinical pearls of haloperidol (d2ra)

oral, iv every 4-6 hours

sedation, lethargy, QTc prolongation, anticholinergic fx

What are the clinical pearls of prochlorperazine (phenothiazine D1RA, D2RA)

breakthrough, refractory

oral 3-4x daily, or rectal q12hrs

lethargy

What are the clinical pearls of promethazine (phenothiazine D1RA, D2RA)

breakthrough, refractory

oral q4-6h, rectal q6h; IV not recommended (severe tissue injury)

sedation >> than prochlorphenazine

Extrapyramidal Syndrome; which combos inc risk?

intermittent involuntary spasmodic contractions of muscles (dystonia); do not use agents in combination due to additive risks

• metoclopramide + promethazine or olanzipine or prochlorperazine

• olanzapine + prochloraperazine

How do you treat dystonic reactions?

diphenhydramine 25-50mg PO/IV q 4-6hrs or benztropine 1-2mg IV x 1 dose if allergic to diphenhydramine

Benzodiazepine enhances the inhibitory effect of GABA-A receptors and has anxiolytic and amnestic properties of CINV. What are the indications?

treatment of breakthrough, refractory or anticipatory CINV

What are the ADE of benzodiazepines?

sedation, amnesia, lethargy, drowsiness

What are the clinical pearls about lorazepam (benzodiazepine)?

oral tabs/solution; IV/PO q6h prn

caution w CNS depressants; BBW risks (respiratory depression) assoc w concomitant opioids

caution w pts at risk for falls (elder, debilitated, frail)

antihistamines are competitive inhibition of H1 receptors on cells in the GI tract and vomiting center (NTS). What are the indications?

breakthrough CINV, prevention of EPS with D2RA

What are the ADE of antihistamines?

anticholinergic fx: blurry vision, urinary retention, mydriasis

sedation/drowsiness

What are the clinical peals of scopolamine?

breakthrough, refractory CINV

transdermal patch to hairless area behind ear once every 3 days

CNS depression, anticholinergic fx

useful when mvt/excessive secretions trigger n

Cannabinoids activate cannabinoid CB1 and CB2 receptors in both the brainstem and vomiting center (NTS). When is it indicated?

breakthrough and refractory CINV

What are the ADE of cannabinoids?

1. drowsiness, dizzy, euphoric, paranoia, amnesia, HoT, tachycardic, tachyphylaxis/tolerance

2. excessive cannabinoid use can lead to cannabinoid hyperemesis

How do you administer dronabinol (cannabinoid)

breakthrough CINV

capsules/oral soln 1-3hrs b4 chemo then 2-4hrs after chemo (q4-6hrs per day)

What are the clinical pearls of dronabinol?

CYP3A4, CYP2C9 systemic clearance reduced in pts with CYP2C9 genetic polymorphism

• monitor: CNS effects, BP, HR, appetite stimulation substance abuse profile (controlled substance)

How do you take nabilone? (cannabinoid)

breakthrough CINV

capsiles BID, titrate up slowly

What are the clinical pearls of nabilone (cannabinoid)

CYP3A4, CYP2C9 metabolism

• monitor: CNS effects, BP, HR, appetite stimulation substance abuse profile (controlled substance) same as dronabinol

what is a dosing pearl abt cannabinoids dronabinol and nabilone?

start dose low in marijuana/THC naive pts and titrate to effect

How do you prevent CINV for HEC parenteral agents on Day 1?

Olanzapine 2.5-10mg once + NK1RA + 5HT3RA + dexamethasone 12mg IV/PO once

How do you prevent CINV for HEC parenteral agents on Day 2?

Olanzapine 2.5-10mg QD QHS + Aprepitant 80mg PO QD days 2-3 (if aprepitant PO used on day 1) + dexamethasone 8mg IV/PO daily o days 2,3,4

what is contraindicated for cellular based therapies or steroid containing regimens?

corticosteroids

if prevention of CINV for MEC day 1 is 5HT3RA + dexamethasone 12mg IV/PO once, what should be given on day 2-3?

Dexamethasone 8mg IV/PO daily or 5HT3RA monotherapy

if prevention of CINV for MEC day 1 is olanzapine 2.5-10mg PO once + Palonsetron 0.25mg IV once + Dexamethasone 12mg IV/PO once, what should be given on day 2-3?

Olanzapine 2.5-10mg PO daily at bedtime

if prevention of CINV for MEC day 1 is NK1RA + 5HT3RA + Dexamethasone 12 mg IV/PO once, what should be given on day 2-3?

Aprepitant 80 mg PO daily on days 2,3 (if aprepitant PO used day 1) ± dexamethasone 8mg IV/PO daily

If patient is at low emetic risk, what should be done to prevent CINV?

repeat daily for multiday doses of chemo (choose one):

• dexamethasone 8-12mg IV/PO once

• prochloraperazine 10mg IV/PO once

• ORal 5HT3RA (choose one)

If patient is at minimal emetic risk, what should be done to prevent CINV?

no routine prophylaxis required

what is the general rule for management of breakthrough CINV parenteral agents?

add one agent from a different drug class that current schedule preventative regimen

What are the approaches to refractory CINV?

1. add agents from diff drug classes until controlled

2. consider dose optimization and schedule meds instead of prn

3. change antiemetic prevention to a higher level of primary treatment

4. change chemo orders for subsequent cycles to reflect therapeutic changes

How do you prevent anticipatory CINV?

lorazepam night before schedule chemo or and repeat dose following day 1-2 hours before start of chemo OR olanzapine 5mg as a single dose the night b4 scheduled chemo

What are the nonpharm approaches of anticipatory CINV?

breathing/visualization exercises to calm anxiety, music therapy, hypnosis (preferred over pharm)

what are the non pharm preventative measures to CINV?

avoid food/smells that contribute to n, prior to cycle and during cycle eat bland, non fatty foods if tolerated

what are the behavoriral preventative measures to CINV?

relaxation exercises, yoga, acupuncture, hypnosis