chemo toxicities

breakthrough nausea/vomiting

occurs despite prophylactic Tx and/or requires rescue

Refractory nausea/vomiting

nausea and emesis during subsequent cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles

2 ways chemo causes nausea and vomiting (pathobiology)

1. direct stimulation of chemo trigger zone which then stimulates N/V

2. chemo stimulates release of serotonin from enterochromaffin cells of GI tract which then binds to 5HT3 receptors and sends afferent response to chemo trigger zone which sends an efferent response back of N/V

what pathway is involved in the acute (24hr) phase of chemo induced N/V

peripheral pathway involving 5HT release from enterochromaffin cells of the GI tract and binding to 5HT3 receptors

which meds are only used in acute phase of N/V

5HT3 antagonists (ex: ondansetron)

which pathway is involved in delayed (>24hr) phase of chemo induced N/V

direct stimulation of chemo trigger zone BUT mechanism not fully understood?

is acute or delayed N/V easier to treat

acute

anticipatory N/V

nausea and or vomiting before a patient receives chemo, after having a negative experience with chemo

nausea more than vomiting

Treatment specific risk factors for N/V

emetogenecity of chemo agent

tumor burdon

combo regimens

combined modality therapy (ex: chemo + radiation)

rapid infusion rate

repetitive daily doses

Patient specific risk factors for chemo induced N/V

children> adults

women>men

alcohol Hx (decreases risk)

Hx of motion sickness

Hx of morning sickness

prior chemo induced vomiting

depression, anxiety

clinical consequences of chemo induced N/V

serious metabolic derangements

nutritional depletion and anorexia

deterioration of patients physical and mental status

degeneration of self care and fxnal ability

discontinuation of therapy

emetogenicity

% of pts who experience emesis if not treated

how to dose 5HT3 antagonists

use lowest tested fully effective dose

no schedule is better than a single dose given before chemo

which 5ht3 antagonists are most efficacious

all comparable- palonosatron may be better than ondansetron, grimesatron which have the same efficacy

is IV or oral 5HT3 antagonists better

same effectiveness and safety

caution with 5HT3 antagonists

QT prolongation

what must be given with 5ht3 antagonist

dexamethasone

Compare Palonoseteron vs other agents

stronger binding affinity to 5HT3

longer t1/2 (40hr)

effective in acute and delayed phase NV

dexamethasone sparing (can cut back dex dose)

Ex of NK1 antagonists

aprepitant, fosaprepitant, netupitant

NK1 receptor antagonist substance involved

Substance P

DIs with NK1 receptor antagonist

fosaprepitant/aprepitant/netupitant- moderate 3A4 inhibitor, weak 2C19 inducer

Dex is a major substrate of 3A4 therefore need to reduce dex dose by 50%

when is olanzapine used for chemo induced N/V

preferred agent for breakthrough CINV?

dr edwards loves it

explain highly emetogenitic chemo N/V regimens

Pre Chemo: Dex 8-12mg + NK1 (ex: fosiprepitant) and 5HT3 antagonist (ex: ondansetron)

Post Chemo: Dex 4mg evening of chemo then bid x 2-4 days

Plus one as needed anti emetic: Prochlorperazine q 6hr prn x 3-4 days, or metoclopramide q 4-6hr x 3-4 days

explain moderately emetogenic chemo induced N/V regimen

Pre chemo: Dex + one 5HT3 antagonist

Post chemo: Dex x 2-3 days

with or without one anti emetic prn: Prochlorperazine or metoclopramide x 3-4 days

Low emetogenicity N/V regimen

Pre chemo: Dex OR prochlorperazine OR metoclopramide OR ondansetron OR granisetron OR nothing

Post chemo PRN: Dex x 2-3 days, OR prochlorperazine x 3-4 days, OR metoclopramide x 3-4 days OR no prophylaxis

List the 3 steps to approaching treatment failure of N/V agents

1. rule out/treat other causes of N/V

2. control this episode of N/V

3. plan prophylactic regimen for next cycle

what are other causes of N/V to rule out/treat if patient experiences N/V despite optimal prophylaxis

intestinal obstruction

gastritis

meds (pain meds)

brain metastases

vestibular dysfxn

lyte imbalance

infection

How to control the current episode of N/V after prophylaxtic Tx failure

give additional anti emetic from diff class

use rectal or IV if patient is vomiting

consider around the clock dosing rather than prn

monitor hydration and lytes

may need multiple agents in alternating schedules

How to plan prophylactic regimen for next cycle after treatment failure of prophylactic N/V meds

anticipatory N/V- give lorazepam 0.5mg-1mg orally or SL night before chemo

ensure further anti emetic cover full period of delayed nausea- dex may be extended to 5-7 days as indicated (ex: add dex for how long they are sick + 24hr)

consider adding NK1 antagonist if not already on

Metoclopramide main receptor + SE

D2

EPS (akathisia, dystonia, dyskinesia)

prochlorperazine main receptor + SE

D2

sedation, hypotension (also EPS)

haloperidol main receptor + SE

D2

rarely EPS

ondansetron receptor + SE

5HT3

headache, constipation

dimenhydrinate receptor + SE

H1, Ach

sedation, dry mouth, blurred vision

steroids (dex) SE

insomnia, hyperglycemia, heart burn, mood changes

olanzapine SE

sedation

pathobiology of chemo induced diarrhea

1. secretory diarrhea- increased secreted of electrolytes caused by luminal secretagogues or reduced absorptive capacity (due to surgery or epithelial damage)

2. osmotic diarrhea- increased intraluminal osmotic substances

3. altered GI motility

Risk factors for chemo induced diarrhea

Therapy related:

• chemo, radiation, multi modal therapy

Neurologic:

• anxiety

GI factors

• previous GI surgery, IBD, lactose intolerance, nutritional supplements, dietary fiber

Drugs

• antibiotics, laxatives and antacids, misoprostol, metoclopramide

clinical consequences of diarrhea

loose or watery stools (BM)

abdominal cramps, pain, bloating

sore skin in the anal area from frequent bowel movements

dehydration and fatigue from excess water loss, can lead to renal failure and death

can lead to treatment delays, increased cost of care, reduced QoL, diminished compliance with treatment regimens

prevention of chemo induced diarrhea

prophylactic anti-diarrheals is not a standard approach

some exceptions now exist

initial management of uncomplicated diarrhea

administer standard doses of oral loperamide (initial dose 4mg followed by 2mg after each loose BM q 4hrs) up to 16mg/day

stop chemo, prevent dehydration thru bland foods and clear liquids

How to treat persistent grade 1-2 diarrhea with no risk factors after standard dose loperamide

increase loperamide to 2mg q 2hr (24mg/day)

if max dose loperamide (24mg/day) doesnt work how to treat persistent grade 1-2 diarrhea with no risk factors

Add second line agent (octreotide subq, diphenoxylate-atropine, deodarized tincture of opium)

if patient fails max dose loperamide and second line options what to do for persistent diarrhea with or without risk factors

admit to hospital

IV fluids (and abx if needed)

loperamide 4mg then 2mg q 2hrs or 4mg q 4hrs until diarrhea free for 12hrs

ocretide subq tid with dose increase if needed

Caution with loperamide

>24mg/day can result in serious cardiac AE including QT prolongation, TdP or other ventricular arrythmias, syncope, cardiac arrest

most effective agent for diarrhea (rank them)

Octreotide>Loperamide > lomotil

AE loperamide

constipation, abdominal pain, QT prolonging high doses

AE lomotil

drowsiness, flushing, dry mouth, tachycardia, dilated pupils, rash, nausea

(sx of excess cholinergic + narcotic effects)

AE octreotide

abd cramps, mild nausea, hypoglycemia w/ high doses

what causes constipation in pts with cancer

poor oral intake

drugs such as opioids, anti emetics (ondansetron) which slow intestinal transit time

risk factors for constipation with cancer patients

taking opioids

lack of physical activity

low fiber diet + decreased food intake

decreased fluid intake, dehydration

bed rest

depression

certain chemo drugs (vinca alkaloids)

certain supportive care drugs (5HT3 antagonistd)

signs and symptoms of constipation

anorexia, early satiety, N/V, abd pain, bloating, tenesmus (Straining)

Preventing constipation

drink 8-10 glasses of fluid a day

add fibre to diet

stay active and exercise

if starting narcs initiate bowel regimen

Constipation meds not used in cancer patients

do not use enemas, suppositories or disimpaction if patient is neutropenic

dietary modifications and bulk laxatives- not effective for vinca alkaloids or opioids + should be avoided in pts with low fluid intake due to increased risk of obstruction

Treatment of constipation in cancer patients

encourage increased fluid intake

start laxatives at first sign of constipation

first line laxatives: osmotic agents (PEG, lactulose), and stimulants (senna, bisacodyl)

frequently reassess patient for response to treatment with changes or additions made to Tx regimen

onset of mucositis

5-7 days after drug admin, heals in 2-4 wks

parallels neutropenia

risk factors for mucositis

pre existing oral disease

poor oral hygiene or poorly fitting dentures

younger patients (perhaps bc of higher epithelial mitotic rate)

combined Tx with chemo + radiation

Clinical consequences of mucositis

oral mucositis manifests as erythema, inflammation, ulceration, and hemorrhage in mouth and throat

ranges from mild inflammation to frank bleeding

painful condition that interferes significantly with patient functioning and tolerance for cancer treatment

dehydration, malnutrition, poor QoL, non compliance

secondary systemic infections

preventing mucositis

Good oral hygiene, soft brush

salt and soda rinse 5-10cc bid-qid (table salt and baking soda)

keep lips moist with moistrizers

avoid flossing if low platelets

avoid hot, spicy, acidic foods, alcohol, hard or coarse foods

cryotherapy with 5FU (hold ice chips in mouth x 30min)

Treatment of mucositis

efficacy of promoting healing uncertain- more for palliation and comfort care

continue preventative measures

magic mouthwash- diphenhydramine, maalox, viscous lidocaine (no standard recipe)

if pts unable to eat due to pain- IV opioids, IV fluids, TPN

systemic antibacterials for infections

topical antifungals (nystatin swish) for mild fungal infection

mod-severe oral candidiasis aggresive systemic Tx usually with azoles

most common mucositis infections

G+ (normal mouth flora)

chlorhexidine in mucositis

may decrease gram + colonization, may increase gram negative rods by eliminating normal mouth flora

not shown to be effective vs basic mouth care

therefore not recommended

Stomatitis vs mucositis

stomatitis is from targetted therapy and causes distinct lesions which typically occur in areas of friction- lateral side and front of tongue

Treatment of stomatitis

triamcinolone in orabase

Dex prevention

Fever definition

single oral temp 38.3+C (101F) OR a temp 38+C (100.4F) which lasts >1hr

Neutropenia definition

abnormally low number of neutrophils in the blood (ANC <1.0 × 10^9/L)

most life threatening potential SE of chemo

febrile neutropenia and complications of neutropenia

primary dose limiting chemo toxicity

neutropenia

2 types / causes of neutropenia

disease induced, treatment induced

When is the risk of infection highest

Nadir period (usually 7-10days post chemo, lowest ANC)

risk factors for neutropenia

Tx factors- chemo regimen, radiotherapy regimen, multimodal regimen

patient factors- age 65+, female sex, poor performance status

highest risk in first cycle of chemo

what toxicity is an oncological emergency

febrile neutropenia

clinical consequences of neutropenia

febrile neutropenia is an emergency, if untreated can lead to sepsis quickly, ARDs, and/or septic shock

severe/prolonged neutropenia increases pt risk of infection (mod risk 7-10days, high risk >10 days)

chemo dose delays, reductions or d/c Tx

primary vs secondary neutropenia prophylaxis

primary- using granulocyte CSFs in first cycle of myelosuppresive chemo with the goal of preventing neutropenic complications

secondary- using granulocyte CSF in subsequent chemo cycles after neutropenic fever occured in a prior cycle

when to use primary prophlyxis for neutropenia

when anticipated incidence of neutropenic fever is 20% or higher or sometimes when risk is 10-20 (consider)

when to use secondary prophylaxis for neutropenia

in patients who experience a neutropenic complication such as fever or Tx delay from a prior cycle of chemo (if they didnt get primary prophylaxis) if reduce dose may comprimise Tx outcome

Examples of meds used for neutropenia prophylaxis

Pegylated G-CSF SQ x 1 dose

filgrastim single daily SQ injection x 7-14 days

what chemo regimens cannot get pegfilgrastim and must get filgrastim (if need neutropenia prophylaxis)

chemo regimens <q 2wks

timing of neutropenia prophylaxis

24-72hrs post chemo

AE of GCSF

Bone pain

• dose dependant mild-mod medullary bone pain

• most common in sternum, pelvis, lower back

how to prevent/Tx GCSF bone pain

non opioid oral analgesics like tylenol

sever cases- opioids

when does bone pain occur with GCSF

transient, lasts 24-48hrs

occurs 1-2 days prior to increase in neutrophils