IC5 GI Sx (CINV, C&D, mucositis) Flashcards
What are the two phases of CINV and what systems are involved in these phases?
Acute - peripheral pathway (gut)
Delayed - central pathway (CNS)
Briefly describe the pathophysiology of the acute CINV
chemotherapy interacts with enterochromaffin cells of the GI tract causing the release of 5-HT3
stimulates n&v via vagal afferent nerves
Briefly describe the pathophysiology of the delayed CINV
chemotherapy directly affects the vomiting center
causes vagus nerves to release substance P to NK1 receptors
What are the 5 main types of CINV?
acute
delayed
breakthrough
anticipatory
refractory
What is the timeframe for acute CINV?
usually starts within 1-2 hours of administration, peak intensity within 5-6 hours, resolution at 12-24 hours
What is the timeframe for delayed CINV?
peak onset 48-72h after chemotherapy, diminishing after 1-3 days
Define refractory CINV
n&v occurring during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in previous cycles
What are the 3 main steps in treating CINV
1) assess emetic risk group
2) assess patient risk factors for CINV
3) select antiemetic combinations
Whats the one important drug combination for high emetogenic risk to remember?
AC combination:
anthracycline (doxorubicin) + cyclophosphamide
What are the 7 patient-specific risk factors for CINV?
- Younger age (<50 years old)
- Female gender
- History of low chronic prior alcohol intake ( <1 glass of alcohol a day)
- History of previous chemotherapy induced emesis
- History of motion sickness
- History of emesis during past pregnancy
- Anxiety
What are the rough combinations for high emetogenic risk for
- day 1
- day 2-4
- Day 1 → NK1 antagonist + 5HT3 antagonist + Dexamethasone +/- Olanzapine
(i.e. Aprepitant + Ondansetron + Dexamethasone +/- Olanzapine) - Day 2 onwards → Dexamethasone D2-4 + Olanzapine D2-4 (if used on day 1)
What are the rough combinations for moderate emetogenic risk for
- day 1
- day 2-3
- Day 1 → 5HT3 antagonist + Dexamethasone
(i.e. Ondansetron + Dexamethasone) - Day 2 onwards → Dexamethasone D2-3
What are the rough combinations for low emetogenic risk
5HT3 antagonist / Dexamethasone / Dopamine angatonist
(Ondansetron / Dexamethasone / Metoclopramide)
What are the neurokinin 1 antagonist drugs and which phase of CINV are they helpful for?
Aprepitant, Netupitant
useful for acute and delayed CINV
What are NK1 antagonist (aprepitant, netupitant) MOA?
binds to NK-1 receptors, preventing substance P (nociceptive neurotransmitter) from binding and attenuates vagal afferent signals to exert antiemetic effect
How should aprepitant (emend) be dosed?
day 1 - 125mg PO
days 2-3 - 80mg PO
How should netupitant (akynzeo) be dosed?
0.5mg on day 1 (single dose)
given w palonosetron
What are the side effects associated with NK1 antagonists (aprepitant, netupitant)?
low frequency of fatigue, weakness, nausea, hiccups
What are the DDIs associated with NK1 antagonists (aprepitant, netupitant)? (4)
steroids
warfarin
benzodiazepines (increases bzd conc due to reduced metabolism)
certain chemotherapy drugs (like ifosfamide (decreases ifosfamide metabolism))
What are the 5HT3 antagonist drugs and which phase of CINV are they helpful for?
Ondansetron, Granisetron, Palonosetron
useful for acute CINV
What are 5HT3 antagonist (ondansetron, granisetron, palonosetron) MOA?
blocks 5HT-3 receptors peripherally in the GI tract and centrally in the medulla (2 pathways)
What is the difference between granisetron and ondansetron
Granisetron is longer acting but more costly
How should ondansetron be dosed?
day 1 - PO/IV 8-16mg OD
day 2-4 - PO/IV 8mg BD (max 16mg)
How should granisetron be dosed?
day 1 - PO/IV 1mg OD
day 2-4 - PO/IV 1mg OM
What are the side effects associated with 5HT3 antagonists (ondansetron, granisetron, palonosetron)? (2+1)
headache and constipation (in 15% of patients)
may cause QTc prolongation (black box warning)
What is the concern when 5HT3 antagonists are given with SSRIs?
5HT3 antagonists may have interactions with SSRIs (serotonin syndrome), but since ondansetron is usually given as a once off dose, evaluate the risk vs benefit (usually not significant)
What is dexamethasone’s place in therapy for CINV?
useful for acute and delayed CINV
How should dexamethasone be dosed?
day 1 - PO/IV 12mg OD
day 2-4 - PO/IV 8mg OD
What are side effects associated with dexamethasone? (4+2)
transient elevations in glucose
insomnia
anxiety
gastric upset
less common ones include psychosis (young pts) and reactication of ulcers
What are two potential counselling points for dexamethasone based on side effects?
If insomnia then counsel to take at night, if GI concerns then take with or after food
What is olanzapine place in therapy for CINV?
useful for acute and delayed CINV
What is olanzapine’s MOA?
Antagonist of multiple receptors involved in CINV (i.e. dopamine, serotonin, histamine, cholinergic)
How should olanzapine be dosed
PO Olanzapine 5-10mg OD (consider 2.5mg for elderly) for 4 days
What are the side effects associated with olanzapine?
fatigue
sedation
postural hypotension
anticholinergic side effects
What DDI is important to take note of for olanzapine?
Olanzapine has a DDI with metoclopramide, category X (both are dopamine antagonists and will result in EPSE and NMS), hence if patient is on high emetogenic risk regimen, they will likely be on olanzapine already and should avoid metoclopramide until day 5
Which dopamine antagonist can be used in CINV and what is its place in therapy?
Metoclopramide
useful for acute CINV in low emetogenic regimens and breakthrough CINV
How should metoclopramide be dosed?
IV/PO Metoclopramide 10mg TDS PRN
What are the side effects associated with metoclopramide?
mild sedation
diarrhea
EPSE (eg. dystonia, akathisia)
When are benzodiazepines indicated for CINV?
useful for anticipatory CINV
What are benzodiazepine’s MOA?
binds to bzd receptors on postsynaptic GABA neurons to enhance inhibitory effects of GABA, also leads to sedation, reduction of anxiety, and possibly depression of the vomiting centre
How should alprazolam and lorazepam be dosed?
- PO Alprazolam 0.5-1mg on the night before treatment and then 1-2h before chemotherapy begins (total two doses before chemo)
- PO Lorazepam 0.25-2mg (same as alprazolam)
What are the two other main adjunctive agents that can be used in CINV? What are their mechanisms of action?
Haloperidol
Phenothiazines (Prochlorperazine, chlorpromazine, promethazine)
Blocks dopamine receptors in CTZ
How should haloperidol and prochlorperazine be dosed?
PO/IV haloperidol 0.5-2mg q4-6h PRN
PO prochlorperazine 10mg TDS-QDS PRN
When are adjunctive agents like haloperidol and prochlorperazine indicated for CINV?
can be considered for refractory CINV
(not efficacious upfront for acute or delayed CINV)
What is the main principle for breakthrough CINV
give an additional agent from a different drug class to target a possible different MOA
What are the 6 non-pharmacological management strategies for CINV?
- Take small frequent meals and avoid heavy meals
- Avoid greasy, spicy, very sweet or salty foods and foods with strong flavours or smells
- Sip small amounts of fluid often instead of trying to drink a full glass at one time
- Avoid caffeinated beverages
- Avoid lying flat for 2 hours after eating
- Consider hydration (fluid and electrolytes)
How should antiemetics be given for multi-day chemotherapy regimens for CINV?
Guidelines suggest giving appropriate prophylactic therapy for the expected emetogenecity on each day of the chemotherapy administration
Continue delayed prophylaxis alone for 2-3 days after the completion of chemotherapy if indicated
What are some of the agents that can commonly cause CID? (no need to memorise, just be familiar)
Cisplatin/oxaplatin
cyclophosphamide
cytarabine
5-FU/capecitabine
gemcitabine
MTX
doxorubicin/daunorubicin
taxanes
irinotecan/topotecan
oral targeted therapy (like TKIs)
How do EGFR inhibitors cause CID?
They cause CID by increasing EGFR in the inflamed mucosa within 2-3 days of therapy
Which chemotherapy agent requires antidiarrheal prophylaxis and how should it be given
Neratinib requires antidiarrheal prophylaxis with loperamide for the first 2 cycles
What are the 6 risk factors for CID?
- age greater than 65
- female
- ECOG performance status of at least 2 (related for fitness)
- bowel inflammation or malabsorption
- bowel malignancy
- biliary obstruction
What does grade 1-5 mean in CID grading?
- Grade 1: increase of < 4 stools per day above baseline
- Grade 2: increase of 4-6 stools per day above baseline, limiting activities of daily living
- Grade 3: increase of ≥ 7 stools per day above baseline, hospitalisation needed, limiting self-care
- Grade 4: life threatening with urgent intervention needed
- Grade 5: death
Based on CID grading (1-5), what constitutes uncomplicated and complicated CID?
-
Uncomplicated:
- Grade 1 or 2 with no complicating signs or symptoms
-
Complicated:
- Grade 3 or 4
- Grade 1 or 2 with one of the following: cramping, grade 2 nausea or vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, dehydration
What are 3 steps to take for uncomplicated CID?
- Withhold PO chemotherapy momentarily if grade 2 (consider if cancer will progress) and consider dosage reduction
- Dietary modification with oral hydration with 8-10 large glasses of clear liquids
- PO Loperamide 4mg then 2mg every 2-4 hours or after every episode of diarrhea, continue until 12h free of diarrhea then stop (max 16mg in a day)
What should be done if diarrhea improves after 12-24h and if it persists after 12-24h
improve: continue with diet modifications and begin to add solid food
persist: schedule Loperamide 2mg every 2h, start oral Abx
What are 4 steps to take for uncomplicated CID that progresses beyond 24-48h?
- Withhold chemotherapy and resume when all symptoms resolve, while restarting at a decreased dosage
- Administer PO Octreotide
- Start IV fluid hydration
- Start IV antibiotics (e.g. ciprofloxacin x 7d) due to infection risk
How should Octreotide be dosed for complicated CID?
Octreotide 100-150 mcg SC TDS
or
IV Octreotide with dose escalation up to 500mcg TDS
What are high doses of loperamide associated with
High doses associated with paralytic ileus
Where is octreotide particularly useful in
beneficial for patients with 5-FU and irinotecan-induced CID
What are the 4 main non-pharm points for CID
- Probiotics with Lactobacillus are suggested to prevent diarrhea
- Dietary modification (avoid caffeine, alcohol, fruit juice, foods that contain lactose, foods that are spicy or high in fat or fibre, or dietary supplements with high osmolarity)
- Eat small and frequent meals and encourage BRAT diet (bananas, rice, applesauce and toast)
- More than 3L of clear fluids containing salt and sugar (electrolyte-containing fluids are ideal)
What should be avoided if patient is on 5-FU treatment?
Lactose for at least a week after CID has resolved
Due to 5-FU-induced lactose intolerance because lactase activity can be lost temporarily
Describe the pathophysiology of irinotecan-associated diarrhea (3 steps)
- irinotecan is converted to SN38 (causes a lot of diarrhea)
- SN38 is deactivated by glucuronidation to SN38-G
- Some patients homoxygous for UGT1A1*28 which have decreased expression of the glucuronidation enzyme hence decreased deactivation
- gut bacteria reactivates SN38-G to SN38
- irinotecan alters commensal bacteria
- SN38 further damages gut mucosa
- cancer cells + irinotecan further kills gut and intestinal cells resulting in acute and delayed diarrhea
What are the time frames for acute and delayed irinotecan-associated diarrhea?
acute: within 24h of administration
delayed: can take a week
How should acute-phase irinotecan-associated diarrhea be treated?
SC/IV Atropine 0.25-1mg (maximum 1.2mg) (usually SC)
Where is atropine contraindicated?
glaucoma
How should late-phase irinotecan-assocaited diarrhea be treated?
Loperamide 4mg after first loose bowel movement, then 2mg every 2h (or 4mg every 4 hours at night so patient can sleep) until 12 hours have passed without bowel movement (exceeds max of 16mg a day)
What are risk factors for constipation? (9)
- Lowered fluid intake and dehydration
- Loss of appetite (anorexia)
- Lack of fibre or bulk-forming foods in the diet
- Vitamin or mineral supplements such as iron or calcium pills
- Overuse of laxative
- Low level of physical activity or a lot of bed rest
- Thyroid problems
- Depression
- High levels of calcium or potassium in the blood
- Cancer growing into the large intestine (bowel) or pressing on the spinal cord
What are some drugs that treat cancer or drugs are used to treat side effects of therapy that can cause constipation? (3)
- Pain relievers (esp opioid narcotic medicines like morphine or codeine)
- Chemotherapy drugs like vinca alkaloids (including vincristine, vinblastine or vinorelbine)
- Antinausea drugs such ondansetron, granisetron, or anticonvulsant drugs
What are the 4 non-pharm management points for constipation?
Eat more fibre
Eat natural laxatives (veggies, coffee, prunes)
Increase physical activity
Eat enough
In which populations should certain non-pharm points be counselled with caution?
CRC patients - may be on fibre restriction
Diabetic patients - prunes very sweet
Name bulk forming, stimulant and osmotic laxatives
bulk forming - fybogel (psyllium husk)
stimulant - senna (sennoside), lactulose, bisacodyl
osmotic - PEG, glycerin
When are suppositories or enemas not recommended?
When white blood cell or platelet counts are low due to the risk of infection or bleeding
What are the 5 main stages of mucositis?
initiation
upregulation
signalling and amplification
ulceration
healing
Outline mucositis stage 1: initiation
chemo causes direct toxicity by generating oxidative stress and reactive oxygen species
there is an increase in vascular permeability by inflammatory mediators
this allows local accumulation of toxic drugs
Outline mucositis stage 2: upregulation
4-5 days after treatment, ROS damage DNA leading to epithelial cell death
concurrently, nuclear factor-κB is activated by chemotherapy or radiation, causing gene upregulation,
Outline mucositis stage 3: signalling and amp
this leads to the production of pro-inflammatory cytokines and expression of adhesion molecules
ultimately resulting in tissue damage, activation of COX-2 pathway, angiogenesis and apoptosis
Outline mucositis stage 4: ulceration
most symptomatic phase when blood counts are lowest about 7 days after treatment
prior injury to basal epithelial cells causes atrophy and mucosal breakdown
oxidative stress leads to inflammatory infiltrates, and bacterial cell-wall materials (gram pos, gram neg and anaerobes) activate macrophages, further increasing the production of pro-inflammatory cytokines
Outline mucositis stage 5: healing
begins with white blood cell count recovery at day 12-16
epithelial cells begin to proliferate and differentiate and local flora return
because of continued angiogenesis, patients are an an increased risk of mucositis in the future.
What are patient-related risk factors for mucositis? (6)
autoimmune disorder
diabetes
female (5-FU induced)
caucasians > african american
genetic predisposition to tissue damage (deficiency in genes producing enzymes for metabolising chemo)
folic acid or vit B12 deficiency
What are the 4 broad treatment related risk factors for mucositis?
chemo-related
radio-related
smoking and alcohol consumption
presence of xerostomia and infection
What are the chemo-related treatment risk factors for mucositis? (7)
S-phase specific agents have the highest risk
duration dose intensity and schedule
prolonged or repetitive lower doses result in higher risk than bolus doses
risk increases with number of cycles
risk increases when chemo clearance is delayed by renal/hepatic impairment
previous therapies toxic to mucosa
risk increases with previous mucositis episodes
What are the radio-related treatment risk factors for mucositis? (5)
risk of mucositis increases when radiation is added to chemotherapy
dependent on radiation source
dosage
dose intensity
volume of mucosa irradiated
What are the 4 main treatment options for mucositis?
Palifermin IV
Benzydamine HCl mouthwash
LLLT (lazer beams)
Oral cryotherapy for prevention
How should palifermin be dosed for mucositis?
Palifermin 60mcg/kg/day
First 3 doses prior to myelotoxic therapy with the third dose given 24-48h before therapy begins
Last 3 doses administered after myelotoxic therapy with the first of these doses after but on the same day as hematopoietic stem cell infusion and at least 4 days after the most recent dose of palifermin
What is palifermin’s MOA
keratinocyte growth factor drug
What does Oracare suspension contain and when should it be taken
nystatin (antifungal)
tetracycline (antibiotic)
diphenhydramine (antihistamine and antiinflammatory)
take after food
What does Mylocaine suspension contain and when should it be taken
diphenhydramine (antihistamine and antiinflammatory)
lignocaine (anesthetic)
take before food
when should morphine sulfate solution be taken
take before food
Why should alcohol-based mouthwashes be avoided?
alcohol has a drying effect and might cause more xerostomia, resulting in mucositis
