IC5 Supportive and Palliative Care (Cancer therapy side effects) Flashcards
What is the most bothersome side effects of chemotherapy?
N&V
What are the 2 types of emesis pathways?
- Central pathway – CNS – predominantly delayed phase of CINV
- Chemotherapy triggers the vomiting centre (area postrema) in the medullae (brainstem) → send signals via the vagus nerve → releases substance P at the synapse which binds to and agonises NK1 receptors → inducing N&V
- Peripheral pathway – Gut – predominantly acute phase of CINV
- Chemotherapy triggers enterochromaffin cell of the GIT → releases serotonin which binds to and agonises the 5-HT3 receptors on the vagal afferent → inducing N&V
What are the types of CINV?
- Acute
- Usually starts within 1-2 hours after administration
- Peak intensity within 5-6 hours, resolution at 12-24 hours
- Delayed
- Peak onset 48-72 hours after chemotherapy, diminishing after 1-3 days
- Occurs in 50-90% (highly emetogenic regimens), 35-08% (moderately emetogenic regimens) of patients
- Breakthrough
- N&V occurring despite preventive therapy
- Anticipatory CINV
- fear for chemotherapy, when dr say that u need to go for chemo then they will have nausea and vomiting
- Conditioned response
- Associated with uncontrolled emesis prior chemotherapy
- Refractory CINV
- N&V occurring during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in previous cycles
- time where u have to use agents that have less evidence in guidelines
What are the steps to take to manage CINV?
Step 1: Assess Emetic Risk Groups – IV drugs
Step 2: Assess Patient Risk Factors for CINV
Step 3: Select anti-emetic combination(s)
What is the percentage ranges for the different levels of emetogenic risk of the IV cancer drugs?
High emetic risk (91-100%)
Moderate emetic risk (31-90%)
Low emetic risk (10-30%)
What are some IV chemotherapy that have high emetogenic risk?
High emetic risk (91-100%)
- AC combination → chemo that contains anthracycline and cyclophosphamide
- Anthracycline e.g. doxorubicin and epirubicin
- cisplatin, carmustine
What are some IV chemotherapy that have moderate emetogenic risk?
Moderate emetic risk (31-90%)
- Daunorubicin
- carboplatin AUC<4
- Daunorubicin
What are some IV chemotherapy that have low emetogenic risk?
Low emetic risk (10-30%)
- 5-FU
- paclitaxel
What is the percentage ranges for the different levels of emeetogenic risk for Oral chemotherapy?
Minimal-low: 1-30%
Moderate-high: 31-100%
What are the risk factors for CINV?
Patient-related risk factors
- 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 are the anti-emetic combinations for the different levels of emetogenic risks?
High emetogenic risk
- Acute antiemetics (Day 1): NK1, 5HT3, DEXA +/- Olanzapine
- Delayed antiemetics (Day 2 onwards): DEXA D2-4, Olanzapine D2-4 (if it was used)
Moderate emetogenic risk
- Acute antiemetic (Day 1): 5HT3, DEXA
- Delayed antiemetics (Day 2 onwards): DEXA D2-3
Low emetogenic risk
- Acute antiemetic (Day 1): 5HT3 or DEXA or DOPA
Minimal emetogenic risk
- NIL
What arethe anti-emetic medications present?
NK1 antagonist:
Aprepitant (Emend®)
PO 125mg OD Day 1, 80mg OD Day 2, Day 3
5HT3 antagonist:
IV/PO Ondansetron 8-16mg OD Day 1
IV/PO Granisetron 1mg OD Day 1
Combination NK1 + 5HT3 antagonist
Netupitant 300mg + Palonosetron 0.5mg (Akynzeo®)
PO 1 capsule OD Day 1
Dexamethasone
IV/PO 12mg OD Day 1, IV/PO 8mg OD Day 2 onwards
Dopamine antagonist
IV/ PO Metoclopramide 10mg OD-TDS
What is the place of therapy for Neurokinin-1 (NK1) antagonists?
What is the MOA?
What is the dosing?
What are the ADRs?
What are the DDIs?
Neurokinin-1 (NK-1) antagonists
- Strongest we have in the market to prevent CINV
Place in therapy:
- Prevents acute and delayed CINV
Mechanism of action (MOA):
- Binds to NK-1 receptors, which prevents substance P (nociceptive neurotransmitter) from binding.
- Attenuates/reduces vagal afferent signals and exert antiemetic effect
Dosing:
- Aprepitant (Emend®) 125 mg PO day 1, 80 mg PO days 2-3
- Netupitant 300mg (in combination with 5HT3 antagonist Palonosetron 0.5mg) (Akynzeo® 4-5 yrs ago) PO day 1
Common adverse effects:
- Low frequency of fatigue, weakness, nausea, hiccups
Drug Interactions:
- Steroids
- Warfarin
- Benzodiazepines (increase benzodiazepine concentrations due to reduced metabolism)
- Certain chemotherapy eg Ifosfamide (decreases metabolism of ifosfamide)
- Need to consider risk and benefits
What is the place of therapy for 5-HT3 (Serotonin) antagonists?
What is the MOA?
What is the dosing?
What are the ADRs?
What are the DDIs?
Serotonin (5HT-3) Antagonists
Place in therapy:
- Prevents acute CINV
MOA:
- Block 5HT-3 receptors peripherally in the gastrointestinal tract and centrally in the medulla
Examples:
- 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
- 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 events: Headache and constipation - occurring in 15% of patients. May cause QTc prolongation (black box warning)
- Cancer patients very scared cannot pass motion, so pharmacist will selectively not counsel on constipation, because they won’t take and if they don’t take they will vomit, unless they ask or if it’s great importance
- Consider if on meds that cause high risk of QTc prolongation e.g. fluoroquinolones, haloperidol, phenothiazines, SSRIs, TCA
What is the place of therapy for dexamethasone?
What is the MOA?
What is the dosing?
What are the ADRs?
What are the DDIs?
Dexamethasone
Place in therapy:
- Prevents acute and delayed CINV
MOA:
- Unknown
- May be partially due to its activity in the central nervous system
Dosing:
- IV/PO 12mg OD D1, IV/PO 8mg OD D2 onwards for highly emetogenic regimens
Adverse Effects
- Most common – transient elevations in glucose, insomnia, anxiety, and gastric upset
- Will counsel to take the night dose earlier
- Less common – psychosis, or reactivation of ulcers
- Psychosis is common especially amongst young patients, when they take they will become hyper and cranky then give parents a lot of problems
- Cause ulcers so should take after or with food
- If see that patients have previous gastric issues, it’s not wrong to give omeprazole (take before food) as gastric protection together with the steroids
What is the place of therapy for olanzapine?
What is the MOA?
What is the dosing?
What are the ADRs?
What are the DDIs?
Olanzapine (Atypical Antipsychotic)
Place in therapy: Prevents acute and delayed CINV
MOA
- Antagonist of multiple receptors involved in CINV
- Dopamine, Serotonin (5HT3), Histamine, Cholinergic
Dose: 5mg – 10mg OD , consider lower doses (2.5mg OD) for elderly
Adverse effects
- Fatigue, sedation, postural hypotension, anticholinergic side effects
- Don’t feel much since the dose is low
- Some older consultant don’t use olanzapine much since this drug came in in 2017 guidelines
- Impt to look at risk factors and risk of chemotherapy and then balance to make the best choice
What is the place of therapy for dopamine antagonists (metoclopramide)?
What is the MOA?
What is the dosing?
What are the ADRs?
What are the DDIs?
Dopamine Antagonists (Metoclopramide)
Place in therapy:
- Prevents acute CINV in low emetogenic regimens
- Useful for breakthrough CINV
MOA:
- 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.
Dosing:
- PO/IV Metoclopramide 10mg TDS PRN
Adverse events:
- Mild sedation and diarrhea, extrapyramidal reactions (e.g., dystonia, akathisia)
- Avoid prescribing Metoclopramide with Olanzapine – increase risk of extrapyramidal reactions (tardive dyskinesias, neuroleptic malignant syndrome)
- Metoclopramide has more CNS effect so it’s not sold as P-only compared to domperidone
What types of benzodiazepines are used for CINV?
What is the place of therapy for benzodiazepines?
What is the MOA?
What is the dosing?
What are the ADRs?
What are the DDIs?
Benzodiazepines
- Choose not long acting ones e.g. lorazepam, alprazolam
Place in therapy:
- Useful for anticipatory CINV
MOA:
- 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
- Used for those who are anxious about chemo due to perception
Dosing:
- PO alprazolam 0.5-1mg/PO lorazepam 0.5-2mg on the night before treatment and then 1-2 hours before chemotherapy begins (take twice)
Adverse events
- Drowsiness, dizziness, hypotension, anterograde amnesia, paradoxical reactions (hyperactive, aggressive behaviour)
- Caution in elderly (risk of falls, prescribe lowest effective dose)
What types of adjunctive agents are used for CINV?
What is the place of therapy for adjunctive agents?
What is the MOA?
What is the dosing?
What are the ADRs?
What are the DDIs?
Adjunctive Agents
Place in therapy:
- Not efficacious to be used upfront anti-emetic for acute or delayed CINV
- May be considered in refractory CINV
- Butyrophenones (haloperidol)
MOA: Block dopamine receptors in the chemoreceptor trigger zone
Usual dose: PO/IV 0.5-2mg q4-q6hr
Adverse events: Sedation, extrapyramidal symptoms are also seen
- Phenothiazines (prochlorperazine, chlorpromazine [usually used for giddiness], promethazine [usually used for cough])
MOA: Block dopamine receptors in the chemoreceptor trigger zone
Dosing: Prochlorperazine PO 10mg TDS/QDS PRN
Adverse events: Drowsiness, hypotension, akathisia, and dystonia, extrapyramidal symptoms
How to manage breakthrough CINV?
Breakthrough CINV
- General principle is to give an additional agent from a different drug class
-Block different pathways that can affect patients wrt CINV
E.g. oral route can’t work then IV route - 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 (e.g. ORS, 100plus)
- Reassess next cycle’s antiemetics to ensure anti-emetic regimen (better than the last one) is appropriate
What are the non-pharm management for CINV?
Non-Pharmacologicals 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. (because can cause them to vomit too)
- Avoid caffeinated beverages.
- Avoid lying flat for 2 hours after eating.
How to manage multi-day chemotherapy anti-emesis regimen?
What about Multi-day Regimens?
- Guidelines suggest: Give appropriate prophylactic therapy for expected emetogenicity on each day of chemotherapy administration
- Continue delayed prophylaxis alone for 2-3 days after completion of chemotherapy if indicated
Example: 3-day regimen of Carboplatin (AUC 3, which <4) + Etoposide (EC)
will cover for moderate emetogenic risk (carboplatin) acute and delayed (D2-3) + acute low emetogenic risk (etoposide)
How to manage anticipatory CINV?
For anticipatory CINV:
- Prevention is key
- Use optimal anti-emetic therapy during every cycle of treatment
- Behavioral therapy
- Relaxation/systematic desensitization
- Hypnosis/guided imagery
- Music therapy
- Acupuncture/acupressure
- Consider use of benzodiazepines before treatment
- Most of the time drs just use this :”) just a few doses for standby
- It’s PRN
Example: Add PO Lorazepam 0.5mg 30 minutes before treatment
What is the most common chemotherapy to cause diarrhea / CID?
Tyrosine kinase inhibitors (-tinibs) and EGFRi (epithelial growth factor receptor inhibitors)
e.g. cetuximab and panitumumab –> grade 2 diarrhea
erlotinib, gefitinib, lapatinib –> any grade of diarrhea
neratinib –> need diarrhea prophylaxis and loperamide
What are the risk factors of CID?
Risk Factors for CID
- Age greater than 65 years
- Female
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of at least 2
- Just saying how fit the patient is
- 0 means very fit, can do daily activities, can walk around and stand up
- More than 2 means not so fit
- Bowel inflammation or malabsorption
- Bowel malignancy
- 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.
Caused by direct damage and inflammation to mucosa of intestine, which leads to
imbalance between absorption and secretion
What are the grades in the severity grading for CID?
Grade 1
- increase of <4 stools per day above baseline
Grade 2
- increase 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
- Urgent intervention needed
Grade 5
- Death
What is an uncomplicated vscomplicated diarrhea?
Uncomplicated (low grade, less diarrhea and no complicating thing)
- Grade 1 or 2
- No complicating signs or symptoms
Complicated (more serous need to stay in the hospital)
- Grade 3 or 4
- Grade 1 or 2 with at least one of the following
- Cramping
- > Grade 2 nausea or vomiting
- Decreased performance status
- Fever
- Sepsis
- Neutropenia
- Frank bleeding
- Dehydration
How to manage uncomplicated CID?
Withhold chemotherapy for grade 2.
- Resume when symptoms resolve
- Consider dosage reduction of drug
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. 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:
- Schedule loperamide 2 mg every 2 hours.
- Start oral antibiotics.
- For diarrhea that progresses to severe or complicated, treat as such.
- For diarrhea that persists as uncomplicated 12– 24 hours after scheduled loperamide, begin octreotide or other second-line agent.
How to manage complicated CID?
- Withhold chemotherapy. Resume when all symptoms resolve.
- Restart at decreased dosage.
- Administer octreotide 100–150 mcg subcutaneously three times a day or IV with dose escalation up to 500 mcg three times a day.
- Start IV fluid hydration.
- Start IV antibiotics (e.g., ciprofloxacin Å~ 7 days).
What is the MOA of loperamide?
What is the dosing?
What are the ADRs?
Mechanism of action: opioid that inhibits smooth-muscle contraction of intestine to decrease motility (primary neurotransmitter is acetylcholine)
Adverse effects: constipation, abdominal pain, dizziness, rash, bloating, nausea and vomiting, dry mouth, drowsiness
High dosages have been associated with paralytic ileus.
Efficacy: has been shown to reduce fecal incontinence, frequency of bowel movements, and stool weight
Demonstrated greater efficacy than diphenoxylate but limited efficacy in grade 3–4 diarrhea
Up to 30% of patients do not respond
Clinical pearls: Start with 4 mg followed by 2 mg every 2–4 hours or after every unformed stool (maximum = 16 mg per day).
Need to know dosing!!
What is the MOA of Octreotide?
What is the dosing?
What are the ADRs?
What are the DDIs?
Not commonly used in hospitals, very rare
But the long-acting one is used for other cancers
This is the injection form, SUBQ or IV
Mechanism of action: Causes decreased hormone secretion, which increases transit time within intestine, decreases secretion of fluid, and increases absorption of fluid and electrolytes
Adverse effects: bradycardia, arrhythmias, constipation, abdominal pain, enlarged thyroid, nausea and vomiting, headache, dizziness
Efficacy: found to be beneficial for patients with 5-FU (fluorouracil) and irinotecan-induced CID
- 90% of patients had resolution of diarrhea by day 3, compared with 15% receiving loperamide.
- More than 75% of patients had complete resolution of CID after 500 mcg or more of octreotide.
- Patients who had received a 5-FU–based regimen were given octreotide 500 mcg three times a day or loperamide 4 mg three times a day. By day 4 diarrhea improved in 80% of patients who received octreotide and 30% treated with loperamide (p < .001).
- 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)
What is the non-pharm management of CID?
Non-pharmacological Management
- 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.
- Up to 10% of patients experience 5-FU–induced lactose intolerance because lactase activity can be lost temporarily.
- Lactose-containing foods should be avoided for at least a week after CID has resolved.
- Eat small, frequent meals.
BRAT diet (bananas, rice, applesauce, toast) - Sometimes dont counsel banana because a lot of singaporeans think that banana is to help constipation; basically banana is bulk forming so can help reduce diarrhea
- So for exam can put banana but in practice there will be a lot of questions
- More than 3 L of clear fluids containing salt and sugar
- Electrolyte-containing fluids are ideal.
How does irinotecan cause diarrhea?
- Irinotecan Well known to cause diarrhea (most likely will ask this qns in exam :» hahah)
- Well known to be used in colorectal cancer, can cause acute and delayed 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 (active metabolite) is deactivated by glucuronidation via UDP-GT 1A1 to SN38-G.
- Increased toxicity in those homozygous for UGT1A1-28, which causes decreased expression of UGT1A1
- Bacteria found in the gut produce β-glucuronidases 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.
- Means more diarrhea later (since take times to work, have lag time)
- Leads to ablation of crypts, villus blunting, and atrophy of the epithelium in the small and large intestine
What are the types of irinotecan induced diarrhea?
- Early: develops within 24 hours of irinotecan administration
- Dose dependent
- Most symptoms occur during infusion.
- More than 80% experience mild to moderate symptoms, and 10% of patients experience grade 3–4 symptoms.
- Irinotecan is a selective, reversible inhibitor of acetylcholine esterase leading to a cholinergic response.
- Mean symptom duration is 30 minutes.
- Late: administration develops after 24 hours of irinotecan
- Can occur at any dosage or frequency
- Experienced by 60%–87% of patients receiving irinotecan
- Median onset with every-3-week dosing is 6 days.
- Median onset with weekly dosing is 11 days.
What is the treatment for early irinotecan induced diarrhea? What is the contraindication of the therapy?
Treatment: 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
**Used to reduce secretions **
Adverse effects:
insomnia, dizziness,
tachycardia, blurred vision, dry mouth,
Constipation (due to reduced secretions) [the other SE not common since the dose given is small)
Efficacy: prevention or treatment of acute-onset irinotecan-induced diarrhea
Contraindicated in glaucoma
What is the treatment for late irinotecan induced diarrhea?
Treatment: loperamide 4 mg after first loose bowel movement, then 2 mg every 2 hours (4 mg every 4 hours at night) until 12 hours have passed without bowel movement
- Can be many capsules a day (more than 8 capsules)
- 4mg every 4hrs becos waking up every 2hrs is no go and the patient will kill u:)
What are the risk factors of 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
What are the drugs that can cause constipation?
- Pain relievers, especially opioid narcotic medicines, such as morphine or codeine
- Chemotherapy drugs such as the vinca alkaloids, which include vincristine, vinblastine or vinorelbine
- Anti-diarrheal pills
- Antinausea drugs such as ondansetron, granisetron or anticonvulsant drugs
What are the 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, or distended, abdomen
- Nausea or vomiting
How to prevent constipation from occuring? / What are the non-pharm managements of constipation?
- Eat more fibre (bulk stool, but if patients have colorectal cancer can’t eat too much fibre, especially if have surgery, if eat a lot of fiber will make the colon worse) + water
- Tailor the counselling to patients depending on their hx but for other patients who don’t have gut issues, then would counsel fully on this since don’t need to use drugs
- Eat natural laxatives e.g. vegetables, coffee, prune (but it’s very sweet so will worsen diabetes)
- Increase physical activity
- Move more then things will move down more
- Eat enough
- Nothing go in, nothing come out (since no appetite)
What are the types of medications present for constipation?
How to manage constipation?
- Stool softeners (emollient, surfactant laxatives) e.g. dulcolax
- osmotive e.g. lactulose, fleet phosphate enema, glycerin (hyperosmotic), PEG
- bulk-forming e.g. psyllium, fybogel
- stimulant e.g. senna, bisacodyl supp
- lubricant e.g. mineral oil
When patients have low blood count / low platelet cound / immunocompromised, what types of laxatives should be avoided and why?
Fleet enema and suppositories, this is becos inserting anything into the anus could cause bleeding and infection
What are the common chemotherapy that can cause mucositis? Why/how?
EGFR inhibitors e.g. cetuximab, bevecizumab, rituximab
EGF helps in maintaining mucosal integrity, thus giving these EGFRi prevents EGF from exerting it’s effect and thus the mucosa is prone to damage
Chemotherapy or radiation causes direct damage to epithelial stem cells.
Tissue response varies by seasonal and circadian changes.
Targeted therapies [e.g. EGFR inhibitors) 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 (receptor) can be found in the esophagus, and levels are increased in inflamed mucosa.
What are the 5 stages of mucositis?
- Initiation:
- Chemotherapy or radiation causes direct toxicity to cells, tissues, and vasculature via generation of oxidative stress and reactive oxygen species. In addition, an (maybe cells damage so) increase in vascular permeability by inflammatory mediators allows local accumulation of toxic drugs.
- Upregulation with generation of messengers:
- 4–5 days after treatment, reactive oxygen species damage DNA, leading to epithelial cell death. (maybe cell lysing) Extent of damage to tissues is based on the rate of oral epithelium proliferation. Concurrently, nuclear factor-ĸB is activated by chemotherapy or radiation, causing gene upregulation, which leads to the production of proinflammatory cytokines and expression of adhesion molecules, ultimately resulting in tissue damage, activation of the cyclooxygenase-2 pathway, angiogenesis, and apoptosis.
- Signalling and amplification:
- Signalling mediators released after initial injury include pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) as part of positive feedback loops that indirectly increase and extend damage to the mucosa. Biology is altered, but tissue will still appear normal.
-
Ulceration:
Most symptomatic phase that peaks when blood counts reach their nadir (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 positive, gram negative, and anaerobes) activate macrophages, further increasing the production of pro- inflammatory cytokines. - 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 at an increased risk of mucositis in the future.
What is the grading for mucositis?
Grade 0: no evidence of mucositis
Grade 1: erythema and soreness
Grade 2: ulcers, eating solids
Grade 3: ulcers, requires liquid diet
Grade 4: ulcers, not able to take PO
Graed 5: N/A (death)
What are the risk factors of mucositis?
Patient-related factors
- Autoimmune disorders
- Diabetes
- Female (5-FU induced)
- Caucasians are at greater risk than African Americans
- Genetic predisposition to tissue damage
- Deficiency in genes that produce enzymes responsible for metabolising chemotherapy
- Folic acid or vitamin B12 deficiency
Treatment-related factors:
-
Chemotherapy
Varies by agent and regimen
S-phase specific agents (drugs that target S-phase) have highest risk.
Duration, dose intensity, schedule
Prolonged or repetitive lower doses result in higher risk than bolus doses.
Risk increases with the number of cycles.
Risk increases when clearance of chemotherapy is delayed by renal or hepatic impairment
Previous therapies toxic to mucosa
Risk increases with previous episodes of mucositis.
EGFR inhibitors can cause ulcers quite often -
Radiation
Risk of mucositis increases when radiation is added to chemotherapy.
Radiation therapist will manage this but they often go to the pharmacist to get meds for side effects
Risk is dependent on radiation source, dosage, dose intensity, and volume of mucosa irradiated - Smoking and alcohol consumption increase risk.
- Risk is higher in the presence of xerostomia and infection.
What are the possible managements of mucositis?
- Palifermin 60mcg/kg/day x 3 days IV after high-dose chemotherapy and TBI (total body irradiation) for autologous HSCT (hematopoietic stem cell transplantation) in hematologic malignancies
- Benzydamine HCI mouthwash after radiation <50 Gy for HNC
- Benzydamine mouthwash is difflam
- LLLT laser therapy → shoot laser beams to prevent ulcer
- Oral cryotherapy for prevention after bolus 5-FU
What is perlifermin specifically indicated for?
What is the dosing?
Not registered in Singapore
Palifermin, keratinocyte growth factor (Exemption Drug, $21,900 per box of 3 vials)
Very expensive but it works
- Reduces duration and severity of oral mucositis after intensive chemotherapy and radiotherapy for hematologic cancers
- approved by FDA to decrease incidence and severity of severe oral mucositis associated with haematological malignancies in patients receiving myelotoxic therapy requiring HSCT
Recombinant keratinocyte growth factor (KGF) produced in E. coli
-
IV 60 mcg/kg/day for 3 consecutive days before and after myelotoxic therapy (total of 6 doses)
Administer first 3 doses prior to myelotoxic therapy, with the 3rd dose given 24-48 hours before therapy begins. The last 3 doses should be 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 does oracare suspension contain?
What does mylocaine suspension contain?
What is the administration instruction for both the suspensions?
What is the administration instructions for morphine solution?
- Oracare Suspension (Nystatin 125,000U, Tetracycline 62.5mg, hydrocortisone 5mg, Diphenhydramine 11.5mg/10mL)
- Antifungal, Antibiotic, Steroids (reduce inflammation), Antihistamine (reduce the itch)
- “Magic mouthwash” since cover everything, quite a good drugs
-
Mylocaine suspension (diphenhydramine 11.5mg, lignocaine 16.7mg/10mL)
Antihistamine, and anesthesia for pain
- Before food, since it helps to stop pain, then eat, then later gurgle with the oracare suspension mouthwash since it kills germs
- Some drs would give both while some would give 1 → impt to counsel properly
- These 2 meds above don’t have commercial preparation so there’s a pharmacist lab that makes these
- Can swallow, and must swallow becos what if the throat at the back have ulcer, lies all the way to your gut so it’s good
- Have stigma that mouthwash cannot be swallowed
- Have a medicine taste
- Morphine sulfate solution 1mg/mL
- Before food since it helps to relieve pain (even though the monograph say before or after is fine since the body PK is ok for this)
- The relief is really outstanding
What are the topical medications for mucositis?
- Oracort E (lidocaine, triamcinolone acetate)
- Medijel (aminacrine (antiseptic), lidocaine
- Soragel (Choline salicylate)
- Difflam gargle/spray (Benzydamine)
- contains alcohol as a preservative thus small amt is ok
- the difflam gurgle has chlorhexidine, can’t be swallowed
What are the suitable mouthwashes to use for mucositis?
What mouthwashes to avoid for mucositis and why?
- Oral7 mouthwash (“fake saliva”, natural enzymes, alcohol free)
- BioXtra Mouthwash (“fake saliva”, manmade enzymes, alcohol free)
AVOID Listerine / alcohol based mouthwash
- can worsen mouth dryness and worsen mucositis
All these mouthwashes are meant to be spit out (Unlike the mylocaine and oracare suspensions)
Patient is scheduled to receive cisplatin 25 mg/m2 daily for 4 days plus 5-fluorouracil 1000mg/m2 daily for 4 days for treatment of nasopharyngeal carcinoma. Based on NCCN antiemetic guidelines, select the APPROPRIATE ACUTE antiemetic(s) to be prescribed for patient on Day 1 of chemotherapy? (Select all that apply)
A) PO Akynzeo® 1 capsule, IV Granisetron 1 mg, IV Dexamethasone 12 mg
B) PO Olanzapine 5 mg, PO Aprepitant 125mg, PO Dexamethasone 12 mg
C) PO Aprepitant 125mg, IV Granisetron 1 mg, IV Dexamethasone 12 mg, PO Olanzapine 5mg
D) PO Olanzapine 5 mg, PO Akynzeo® 1 capsule, PO Dexamethasone 12 mg
Answer: (c) and (d)
- Cisplatin: high emetogenic risk - so need the 4 drug regimens.
- 5FU: low emetogenic risk
- ASCI guidelines
- NK1 (Aprepitant), 5HT3 (Granisetron), Dexa (STEROID), OLA (extra drug)
- Option A is wrong because of duplicate therapy (5HT3).
- Option B is wrong due to absence of 5HT3 Antagonist
- need to know what are your classes of drugs, high/mod/low emetogenic risks need to use what then from the regimen choose the therapy
- Take note not just of day 1 but 234 as well (post chemo too)
Patient is a 45-year-old female who received AC adjuvant chemotherapy (IV Doxorubicin 60 mg/m2 &IV Cyclophosphamide 600 mg/m2) 3 weeks ago for treatment of breast cancer. She is back for review prior to cycle 2 chemotherapy. She reported to have grade 1 nausea from day 1 that lasted till day 4 and vomited once on day 2 and day 3. She claimed to be adherent to all antiemetics prescribed except the PRN metoclopramide. Which of the following would be APPROPRIATE advice to prepare her for her next chemotherapy? (Select all that apply)
A) Suck candies such as lemon drops
B) Distract herself by eating out in noisy environment
C) Eat smaller 6 to 8 regular meals
D) Take metoclopramide as prescribed
Ans: A and C
- Nonpharm of CINV
- Metoclopramide and olanzapine DDI –> increase risk of extrapyramidal reactions (tardive dyskinesias, neuroleptic malignant syndrome)
- must know that patients take Olanzapine (since they say all antiemetic :«)
- Cat X - same drug class (dopamine antagonist together)
- If on olanzapine and give metoclopramide, only give metoclopramide after d5
- Should have assumed that on the 4 meds for N&V where olanzapine is inside
- Not take them together at the same time point
- Option D is wrong because, assuming patient is taking olanzapine, Olanzapine and Metoclopramide have DDI. Same drug class.
- NOT: prepare her own food, consume warm liquid food
- Preparing own food is only to help prevent infections from eating out.
- Suck candies is good
SA 65-year-old woman with metastatic breast cancer presented with Bristol scale type 2 stool. In addition to fluid intake, what is the MOST APPROPRIATE dietary advice for patient at this moment?
A) Eat foods high in insoluble fibre
B) Eat simple carbohydrates
C) Eat small frequent meals
D) Avoid lactose-rich food
Ans: A
- Simple carbo is only if patient has diarrhoea and wants the patient to absorb as much as possible
- Small frequent meals is CINV counseling point
- Lactose: advice for those lactose intolerant which can cause diarrhea, so should be the opposite but usually don’t ask them to eat lactose rich food for constipation
- Rare counselling point to ask people to eat lactulose to poop
