Supportive and Palliative Care (GI) Flashcards
Why does CINV, CID and mucositis occur?
Chemo not only kills cancer cells but also fast reproducing cells –> damage to mucosa of oral cavity, pharynx, larynx, esophagus and GIT
Explain the emesis pathway in CINV
Central pathway via CNS: Vomiting center in medulla send signals to vagus nerve to release substance P that is taken up by NK 1 receptors causing CINV.
Peripheral pathway via gut: Enterochromaffin cells of the GIT releases serotonin that is taken up by the 5HT3 receptors in vagal afferent, causing CINV
Central pathway mainly causes which phase of CINV?
Delayed phase
Peripheral pathway mainly causes which phase of CINV?
Acute phase
Describe acute CINV
- Usually starts within 1-2hrs after administration
- Peak intensity within 5-6hrs, resolution at 12-24hrs
Describe delayed CINV
- Peak onset 48-72hrs after chemo, diminishing after 1-3days
- Occurs in 50-90% (highly emetogenic regimens), 35-80% (moderately emetogenic therapy) of pts
What is breakthrough CINV?
N/V occurring despite preventive therapy
What is anticipatory CINV?
- Conditioned response
- Assoc with uncontrolled emesis prior chemotherapy
What is refractory CINV?
- N/V occurring during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in previous cycles
Examples of high emetic risk of IV drugs (>90% freq of emesis)
- AC combination defined as any chemotherapy regimen that contains an anthracycline (eg. doxorubicin) and cyclophosphamide.
- Carboplatin AUC >=4
- Cisplatin
One example of low emetic risk of IV drugs (10-30% freq)
Etoposide
Risk factors for CINV
- Younger age (<50 years old)
- Female gender
- History of low prior chronic alcohol intake (<1 glass of alcohol/day)
- History of previous chemotherapy induced emesis
- History of motion sickness
- History of emesis during past pregnancy
- Anxiety
What classes of antiemetics are given for high emetogenic risk?
Acute (given on day 1):
- NK1
- 5HT3
- DEXA
- +/- OLA
Delayed (day 2 onwards):
- DEXA D2-4
- +/- OLA D2-4
What classes of antiemetics are given for moderate emetogenic risk?
Acute:
- 5HT3
- DEX
Delayed:
- DEX D2-3
What classes of antiemetics are given for low emetogenic risk?
Acute only: 5HT3 or DEX or DOPA
MOA of Neurokinin-1 (NK1) antagonist
Binds to NK-1 receptors, which prevents substance P (nociceptive neurotransmitter) from binding. Attenuates vagal afferent signals and exert antiemetic effect
Examples of NK1 antagonist and their doses
- Aprepitant (Emend) 125 mg PO day 1, 80 mg PO days 2-3
- Netupitant 300mg (+ 5HT3 Palonosetron 0.5mg) (Akynzeo) PO day 1
What is the advantage of using Akynzeo over Emend?
Akynzeo is only 1 day course vs Emend which is a 3 day course
Adverse effects of NK1 antagonist
Low frequency of fatigue, weakness, nausea, hiccups
DDI with NK1 antagonist
- Steroids
- Warfarin
- Benzodiazepines (increase benzodiazepine concentrations due to reduced metabolism)
- Certain chemotherapy eg Ifosfamide (decreases metabolism of ifosfamide) → chemotoxicity
MOA of Serotonin (5HT3) antagonist
Block 5HT-3 receptors peripherally in the gastrointestinal tract and centrally in the medulla
Examples of 5HT3 antagonist
- IV/PO Ondansetron
- IV/PO Granisetron (longer acting that ondansetron, but cost $$$ more)
- IV/PO Palonosetron (PO form available in combination with NK-1 antagonist Netupitant given on Day 1 of chemotherapy)
Dosing of ondansetron and granisetron
- IV/PO Ondansetron 8-16mg OD Day 1, IV/PO Ondansetron 8mg BD Day 2 onwards (max 16mg/dose)
- IV/PO Granisetron 1mg OD Day 1, IV/PO Granisetron 1mg OM Day 2 onwards
Adverse effects of 5HT3 antagonist
Headache and constipation - occurring in 15% of patients.
May cause QTc prolongation (black box warning)
Dosing of dexamethasone
IV/PO 12mg OD D1, IV/PO 8mgOD D2 onwards for highly emetogenic regimens
Adverse effects of dexamethasone
- Most common: transient elevations in glucose, insomnia (counsel to take night dose early, 5pm), anxiety, and gastric upset
- Less common: psychosis (esp paediatrics, they become hyperactive causing problems for parents), or reactivation of ulcers (take after or with food or take PPI before food)
MOA of olanzapine
Antagonist of Dopamine, Serotonin, Histamine, Cholinergic receptors involved in CINV
Dosing of olanzapine
5mg–10mg OD, consider lower doses (2.5mg OD) for elderly
Adverse effects of olanzapine
Fatigue, sedation, postural hypotension, anticholinergic side effects
Note: as olanzapine prevents CINV at low doses, the risk of AE is also lower
Example of dopamine antagonist and its dose
PO/IV Metoclopramide 10mg TDS PRN
Note: as it is given PRN, check with pt if they are still using before prescribing more.
MOA of dopamine antagonist
Blockade of dopamine receptors in the chemoreceptor trigger zone; stimulation of cholinergic activity in the gut, increasing (forward) gut motility; and antagonism of peripheral serotonin receptors in the intestines
Which class of antiemetic agent is used for breakthrough CINV?
Dopamine antagonist (metoclopramide)
Adverse effects of dopamine antagonist
Mild sedation and diarrhea, extrapyramidal reactions (e.g.,dystonia,akathisia)
What should be avoided when giving metoclopramide?
Avoid prescribing Metoclopramide with Olanzapine– increase risk of extrapyramidal reactions (tardive dyskinesias, neuroleptic malignant syndrome)
Which class of antiemetic is used for anticipatory CINV?
Benzodiazepines
MOA of benzodiazepine
- Binds to benzodiazepine receptors on the postsynaptic GABA neuron to enhance inhibitory effect of GABA
- Leads to sedation, reduction in anxiety, and possibly depression of the vomiting centre
Dosing of benzodiazepine
PO alprazolam 0.5-1mg/PO lorazepam 0.5-2mg on the night before treatment and then 1-2 hours before chemotherapy begins
Note: do not give long acting benzo
Adverse effects of benzodiazepine
- Drowsiness, dizziness, hypotension, anterograde amnesia, paradoxical reactions (hyperactive, aggressive behaviour)
Note: Caution in elderly (risk of falls, prescribe lowest effective dose)
What classes of antiemetics are used in refractory CINV? Give some examples and their doses
Butyrophenones (haloperidol): PO/IV 0.5-2mg q4-q6hr
Phenothiazines (prochlorperazine, chlorpromazine, promethazine): Prochlorperazine PO 10mg TDS/QDS PRN
Adverse effects of butyrophenones
Sedation and extrapyramidal symptoms
Adverse effects of phenothiazines
Drowsiness, hypotension, akathisia, and dystonia, extrapyramidal symptoms
MOA of butyrophenones and phenothiazines
Block dopamine receptors in the chemoreceptor trigger zone
What are some considerations for treating breakthrough CINV?
- General principle is to give an additional agent from a different drug class- diff MOA
- Choice of agent should be based on assessment of the current prevention strategies used
- Consider use of several agents utilizing different mechanism of actions if necessary
- If PO route not feasible due to ongoing vomiting, consider IV route
- Hydration and fluid repletion for losses (ORS, 100plus)
- Reassess next cycle’s antiemetics to ensure anti-emetic regimen is appropriate
Non pharm for CINV
- Take small, frequent meals. Avoid heavy meals.
- Avoid greasy, spicy, very sweet or salty food and food with strong flavors 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.
What is the impact of chemo induced diarrhoea (CID)?
Can result in abnormal electrolytes, inappropriate fluid balance, malnutrition, renal failure, weight loss, fatigue, and dehydration
Examples of drugs that cause CID
- Taxanes
- MTX
- 5FU
- Irinotecan
- Doxorubicin
- Cyclosphosphamide
- Cisplatin
- Oral targeted therapy
- Gemcitabine
- Cytarabine
Which class of EGFR inhibitor commonly causes grade 3 CID?
Tyrosine kinase inhibitor
Which drug for breast cancer requires antidiarrheal prophylaxis for first 2 cycles
Neratinib
Risk factors for CID
1) Age greater than 65 years
2) Female
3) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of at least 2
Shows how fit pt is: can do daily activities/walk ard/bedridden?
0: v. fit
>2: not so fit
4) Bowel inflammation or malabsorption
5) Bowel malignancy
6) Biliary obstruction
Other predictive factors may include first cycle of chemotherapy, cycle duration greater than 3 weeks, concomitant neutropenia, other symptoms such as mucositis, vomiting, anorexia, or anaemia
Severity grading for CID
Grade 1: ↑ of <4 stools/day above baseline
Grade 2: ↑ of 4-6 stools/day above baseline and limits daily activites
Grade 3: ↑ of >=7 stools/day above baseline, hospitalisation needed, limiting self care
Grade 4: life threatening, urgent intervention needed
Grade 5: death
What grade is uncomplicated CID?
Grade 1 or 2
No complicating S&S
What grade is complicated CID?
- Grade 3 or 4
- Grade 1 or 2 with >=1 of:
Cramping
>Grade 2 N/V
Decreased performance status
Fever
Sepsis
Neutropenia
Frank bleeding
Dehydration
What is goals of treatment for CID
- Decrease morbidity and mortality from CID
- Improve quality of life and activities of daily living.
- Improve recovery of intestinal mucosa.
- Decrease hospitalization
What is the treatment for uncomplicated CID?
- Withhold chemotherapy for grade 2
- Diet modifications
- Oral hydration with 8-10 large glasses of clear liquids
- Loperamide 4 mg by mouth, then 2 mg by mouth every 4 hours or after every episode of diarrhea. (max 16mg/day) Continue until 12 hours free of diarrhea, then stop.
If diarrhea is improving after 12–24 hours, continue with diet modifications and begin to add solid food.
If diarrhea persists after 12–24 hours:
1) Schedule loperamide 2 mg every 2 hours.
2) Start oral antibiotics.
3) For diarrhea that progresses to severe or complicated, treat as such.
4). For diarrhea that persists as uncomplicated 12– 24 hours after scheduled loperamide, begin octreotide or other second-line agent.
What is the treatment for complicated CID?
1) Withhold chemotherapy. Resume when all symptoms resolve.
2) Restart at decreased dosage.
3) Administer octreotide 100–150 mcg subcutaneously three times a day or IV with dose escalation up to 500 mcg three times a day.
4) Start IV fluid hydration.
5) Start IV antibiotics (e.g., ciprofloxacin × 7 days)
MOA of loperamide
Opioid that inhibits smooth-muscle contraction of intestine to decrease motility (primary neurotransmitter is acetylcholine)
Adverse effects of loperamide
Constipation, abdominal pain, dizziness, rash, bloating, nausea and vomiting, dry mouth, drowsiness
Note: high doses have been assoc w paralytic ileus
MOA of octreotide
Causes decreased hormone secretion, which increases transit time within intestine, decreases secretion of fluid, and increases absorption of fluid and electrolytes
Adverse effects of octreotide
bradycardia, arrhythmias, constipation, abdominal pain, enlarged thyroid, nausea and vomiting, headache, dizziness
Dose of octreotide
Most commonly recommended dosage is 100–150 mcg subcutaneously three times a day
Because of the dose–response relationship, may increase dosage at 50-mcg increments after 24 hours to 500 mcg three times a day or as continuous IV infusion (25–50 mcg/hour)
Octreotide is beneficial for which drugs that cause CID?
5FU and irinotecan-induced CID
Nonpharm for CID
- Probiotics with Lactobacillus are suggested to prevent Chemotherapy-or radiation- induced diarrhea.
Diet modification:
- Avoid caffeine, alcohol, fruit juice, foods that contain lactose, foods that are spicy or high in fat or fiber, or dietary supplements with high osmolarity.
- Eat small, frequent meals.
- BRAT diet (bananas- bulk forming, rice, applesauce, toast)
- More than 3L of clear fluids containing salt and sugar: Electrolyte-containing fluids are ideal. eg. ORS or 100plus
How does irinotecan cause CID?
- Irinotecan is converted primarily in the liver to active metabolite SN-38, which is 100–1,000 times more cytotoxic than the parent drug and is responsible for diarrhea.
- SN-38 is deactivated by glucuronidation via UDP-GT1A1 to SN38-G.
- Increased toxicity in those homozygous for UGT1A1*28, which causes decreased expression of UGT1A1
- Bacteria found in the gut produce β-glucuronidase that reactivate SN38-G to SN-38 via deconjugation.
Commensal bacteria in gut are altered in the presence of irinotecan.
SN-38 damages gut mucosa during excretion. - Leads to ablation of crypts, villus blunting, and atrophy of the epithelium in small and large intestine
How to treat acute irinotecan-associated diarrhoea?
Atropine 0.25–1 mg (maximum 1.2 mg) subcutaneous or IV (usually SC)
Mechanism of action: inhibits acetylcholine at muscarinic receptor as a competitive antagonist
Adverse effect of atropine
- insomnia, dizziness,
- tachycardia, blurred vision, dry mouth,
- constipation
- CI in glaucoma
How to treat delayed irinotecan-associated diarrhoea?
Loperamide 4 mg after first loose bowel movement, then 2 mg every 2 hours (4 mg every 4 hours at night might be better) until 12 hours have passed without bowel movement
Difference btw early/acute and late/delayed irinotecan-associated diarrhoea?
Early:
- within 24hrs of administration
- Dose dependent
- Avg symptom duration: 30mins
- most symptoms occur during infusion
Late:
- after 24hrs
- occur at any dose or frequency
- avg onset is 6days if given every 3wk dosing
- avg onset is 11days if given weekly dosing
Factors that increase risk of developing constipation
- 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 laxatives
- 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
- Certain drugs that are used to treat cancer or the side effects of treatment can also cause constipation
These include:
Pain relievers, especially opioid narcotic medicines, such as morphine or codeine
Chemotherapy drugs such as the vinca alkaloids, which include vincristine vinblastine or vinorelbine
Antinausea drugs such as ondansetron, granisetron or anticonvulsant drugs
Diarrhoea meds.
Symptoms of constipation
- Bloating or feeling of fullness
- Cramping or pain
- Gas, or flatulence
- Belching
- Loss of appetite
- No regular bowel movement for 2 or more days
- Straining to have a bowel movement
- Small Hard Stools That Are Difficult To Pass
- Rectal pressure
- Leakage of small amounts of stool resembling diarrhea
- Swollen, ordistended, abdomen
- Nausea or vomiting
How to prevent constipation
- Eat more fibre - add bulk to stools
- Eat natural laxatives: veg, coffee, prunes- v. sweet, caution in diabetes
- Increase physical activity
- Sufficient food
How to manage constipation?
- Stool softeners help the stool hold water to keep it soft.
- Laxatives may be used to help promote,or stimulate, bowel activity eg. senna or sennosides, mineral oil and lactulose.
- Laxatives may also be used to increase fibre or produce bulk eg. Psyllium
- Laxatives may be given as a suppository placed in the rectum. Suppositories can help promote bowel activity. eg. glycerine and bisacodyl
- Enemas maybe used to clean out the bowel or deliver laxatives eg. phosphate enema (Fleet) and tap water.
- Sometimes a stool softener and a laxative are used together.
- A suppository or enema may not be recommended when white blood cell or platelet counts are low because of the risk of infection or bleeding when these products are use.
How does mucositis occur?
Chemotherapy or radiation causes direct damage to epithelial stem cells:
- Tissue response varies by seasonal and circadian changes.
- Targeted therapies such as cetuximab, bevacizumab, rituximab, and a variety of small-molecule inhibitors have demonstrated the potential to cause a variety of GI toxicities, including mucositis.
- Epidermal growth factor plays a role in maintaining mucosal integrity.
- EGFR can be found in the esophagus, and levels are increased in inflamed mucosa
What are the 5 stages that occur in mucositis?
Stage 1 Initiation:
- Direct toxicity to cells
- Oxidative stress
- Increased vascular permeability
Stage 2 Upregulation:
- DNA damage
- Prdtn of pro-inflammatory cytokines
Stage 3 Signaling and Amplification:
- Pro-inflammatory cytokines released
- Positive feedback
Stage 4 Ulceration:
- Atrophy and mucosal breakdown
- Inflammatory infiltrates
- Macrophages activated by colonizing bacteria
Stage 5 Healing:
- Proliferation of epithelial cells
- Return of local flora
How does mucositis progress with time?
Day 0-5:
- mostly asymptomatic
- redness
- swelling
- burning
- increased sensitivity
Day 0-7:
- desquamation
- white patches
- often mistaken for candidiasis
Day 6-12:
- contiguous pseudomembranes
Day 7-16:
- painful erosions
- ulceration
Risk factors for mucositis
Risk of mucosal injury is affected by patient- and treatment- related factors.
- Patient-related factors:
Autoimmune disorders
Diabetes
Female (5-FU induced)
Caucasians > African Americans.
Genetic predisposition to tissue damage
Deficiency in genes that produce enzymes responsible for metabolizing chemotherapy
Folic acid or vitamin B12 deficiency - Treatment related factors:
Chemotherapy
Radiation
Smoking and alcohol
Depends on radiation source, dosage, dose intensity and volume of mucosa irradiated
Xerostomia and infection
Goals of treatment for mucositis
Prevent or decrease severity of mucositis
Manage pain and other associated symptoms
Prevent chemotherapy delays or dosage reductions
Treatment options for prevention of oral mucositis
- Palifermin
- Benzydamine HCI mouthwash
- Oral cryotherapy
- LLLT (laser therapy)
Pharmacological management for mucositis
- Oracare Suspension (Nystatin 125,000U, Tetracycline 62.5mg, hydrocortisone 5mg, diphenhydramine 11.5mg/10mL)
- Mylocaine suspension (diphenhydramine 11.5mg, lignocaine 16.7mg/10mL)
- Morphine sulfate solution 1mg/mL
Is oracare suspension taken after or before food?
After food to kill the germs
Is mylocaine suspension and morphine solution taken after or before food?
Before food to help with the pain during eating
Should you swallow oracare suspension, mylocaine suspension and morphine solution?
Yes so that it covers the back of the throat and gut
Can you swallow benzydamine?
No
What other adjuncts can be given for mouth ulcers
Oracort-E
Soragel
Medigel
Non pharm management for mucositis
Oral 7 mouthwash
BioXtra mouthwash
What type of mouthwash should be avoided in mucositis?
Alcohol based mouthwashes as it has drying effect and might cause more xerostomia resulting in mucositis
Which is preferred? Oral7 vs BioXtra
Oral7: uses natural enzymes at neutral pH so it acts as “fake saliva” to prevent dry mouth
