IC5 cancer adjunct Flashcards
CINV pathophysiology
- Central pathway
- CNS - delayed phase
- Vomiting center –> vagus nerve –> release sub P –> bind to NK1 receptors on vagal efferent
- Peripheral pathway
- Gut– acute phase CINV
- Enterochromaffin cell of GIT –> 5HT3 release –> vagal afferent 5HT3 receptor
types of CINV (based on onset)
Acute
* 1-2hrs after admin
* Peak within 5-6hr, resolve in 12-24hr
Delayed
* Peak onset 48-72hrs after chemo
* resolve after 1-3d
* 50-90% of highly emetogenic regimen
Breakthrough
* NV despite preventive therapy
Anticipatory
* Conditioned response
* a/w uncontrolled emesis prior chemo
Refractory
* N/V occurring during subsequent cycles of chemo when antiemetic prophylaxis or rescue therapy has failed in previous cycles
3 step method for antiemetic regimen
1) assess chemotherapy emetogenicity
2) assess pt risk factors
3) select antiemetic regimen
nk1, 5ht, dex, olan, DA
assess emetic risk of tx drugs (IV)
Highly emetic risk (>90% risk)
- Combination chemo regimen (ANTHRACYCLINE+ CYCLOPHOSPHAMIDE)
- Carboplatin AUC ≥4
- Carmustine >250mg/mm3
- cisplatin
- cyclophosphamide > 1500 mg/m2
- decarbazine
- doxorubicin ≥60g/m2
- epirubicin >90mg/m2
- ifosfamide ≥2g/m2 per dose
Moderate emetic risk 30-90% freq
Low emetic risk 10-30% feq risk
Minimal emetic risk <10% freq of emesis
emetic risk % for IV and PO
[IV]
high emetic risk >90%
Moderate emetic risk >30-90% freq
Low emetic risk 10-30% feq risk
Minimal emetic risk <10% freq of emesis
[oral]
mod-high ≥30%
minimal - mod <30%
(ANTHRACYCLINE+ CYCLOPHOSPHAMIDE)
for CINV risk
ANTHRACYCLINE
- daunorubicin, doxorubicin, idarubicin and mitoxantrone
CYCLOPHOSPHAMIDE
- bendamustine, busulfan, carmustine, chlorambucil, ifosfamide, lomustine, melphalan, procarbazine, or temozolomide
assess pt emetic risk
- Younger age <50yrs
- F
- Hx of (low prior chronic alcohol intake/ previous chemo induced emesis/ motion sickness/ pregnancy emesis)
- Anxiety
anti-emetic combination for high risk
- Acute, day 1: NK1 + 5HT3 + DEXA
○ +/- OLA - Delayed day 2: DEXA (d2-4), OLA (d2-4 if used on d1)
anti-emetic combination for moderate risk
Acute: 5HT3 + DEXA
Delayed: DEXA d2-3
anti-emetic combination for low risk
Acute: 5HT3 or DEXA or DOPA
multi-day regimen
for D1 HIGH, D2-3 LOW
porphy therapy for expected emetogenicity on each day of chemo admin
delayed prophy for 2-3day after completion of chemo stillable to cover for low risk emetogenic risk
eg: 3day regimen
1st day ACUTE + 2 day DELAYED
Antiemetics for Day 1 : PO Aprepitant 125mg , IV Dexa 8mg , IV Granisetron 1mg
Antiemetics for Day 2 and 3 : PO Aprepitant 80mg , IV Dexa 8mg
NK1 antagonist
aprepitant PO 125mg OD day 1, 80mg OD day 2, 3
Fosaprepitant (150mg IV), (e.g., casopitant, vestipitant, netupitant)
netupitant 300mg (combi)
NK1 antagonist MOA, place in therapy
MOA: Binds to NK1 receptor, prevent sub P from binding.
Attenuate vagal afferent signals and exert antiemeticc effect
acute, delayed CINV
combi NK1 + 5HT3 antagonist
(AKYNZEO) netupitant 300mg + palonosetron 0.5mg
PO 1 cap on day 1
NK1 AE, DDI
AE: fatigue, weakness, N, hiccups
DDI: steroid, warfarin, BZP, chemo (ifosfamide)
SWIB
5HT3 antagonist
IV/PO ondansetron 8-16mg OD day 1
* ondansetron 8mg day 2 onwards (max 16mg)
IV/PO granisetron 1mg OD day 1
* IV/PO 1mg OM day 2 onwards
* 10mg TD patch
5HT antagonist MOA, place
MOA: Block 5HT3 receptors peripherally in GIT and centrally in medulla
acute CINV
5HT AE, DDI
AE: Headache , constipation, QTc prolongation (BBW), SS
DDI: serotonin antagonist, tramadol, meds that affet heart rhythm sotalol, quinidine
dexamethasone dose
IV/PO 12mg OD day 1
8mg OD day 2 onwards
DEXA MOA, place
Unkown - May be activity in central NS
Acute and delayed CINV
DEXA SE
Transient elevation BGL, insomnia (dose earlier in evening), ANX, gastric upset
Less common: psychosis
- Esp in paeds
reactivation of ulcers
- Take after food
dopamine antagonist
IV/PO metoclopramide 10mg OD-TDS
DOPA MOA, place
MOA: Block dopamine receptors in chemoreceptor trigger zone
* Stimulate cholinergic activity in gut
* Incr gut motility
* Antagonism of peripheral 5HT3 receptors in intestine
place: acute (low emetogenic), breakthrough
DOPA SE, DDI
SE: Mild sedation, D, EPSE (dystonia, akathisia)
DDI: Avoid with olanzapine
* Incr EPSE (NMS, tardive dyskinesia)
Olanzapine dose and place
5-10mg OD (day 1-4)
consider lower dose 2.5mg OD for elderly
Acute and delayed CINV, (high emetogenic risk)
olanzapine MOA + SE
MOA: Antagonist of multiple receptors invovled in CINV
(DA, 5HT2, H, Ach)
SE: Fatigue, sedation, postural hypoTEN, Ach SE
adjunctive agents for refractory CINV
Place: not efficacious for upfront anti-emetic ACUTE or DELAYED CINV
○ May be used for refractory CINV
- Butyrophenones (haloperidol APS)
- Phenothiazines (prochlorperazine, chlorpromazine, promethazine)
Butyrophenones (haloperidol APS)
MOA: block DA receptors in CTZ
Dose: PO/IV 0.5-2mg Q4-6H
AE: sedate, EPSE
Phenothiazines (prochlorperazine, chlorpromazine, promethazine)
MOA: block DA receptors in CTZ
Dose: prochlor PO 10mg TDS/ QDS PRN
AE: drowsy, hypoTEN, akathisia, dystonia, EPSE
breakthrough CINV
- GIVE ADDITIONAL AGENT from a diff drug class
○ Choice based on assessment of current prevention strategies used
○ Use of several agents ultilising diff MOA if necessary - If PO not feasible (from NV), consider IV route
- Hydration and fluuid repletion for losses
- Reassess for NEXT cycle’s antiemetic to ensure regimen is appropriate
anticipatory CINV
- Prevention is key (optimal anti-emetic therapy DURING every cycle of tx)
- Behavioural therapy
○ Relaxation, systematic desentisation
○ Hypnosis/ guided imagery
○ Music therapy - Acupuncture/ acupressure
- BZP night before & 2-3hr before tx
BZP dose and place
PO alprazolam 0.5mg-1mg
PO lorazepam 0.5 - 2mg (night before tx; 1-2hr before chemo)
Anticipatory CINV
Caution in elderly (risk of falls, use lowest effective dose)
BZP MOA and SE
MOA: Binds to BZP receptors on postsynaptic GABA neuron to enhance inhibitory effect of GABA
* Lead to sedation
* Reduce ANX
* Possible depression of vomiting centre
SE: Drowsy, dizzy, hypoTEN, anterograde amnesia, PARADOXICAL RXN (hyperactive, aggressive)
non-pharm for CINV
- Take small freq meals, avoid heavy meals
- Avoid greasy, spicy, VERY sweet/ salt food
- Food with strong flavour/ smell
- Sip small amount of fluids often > full glass
- Avoid caffeinated beverages
- Avoid lying flat for 2hrs after eating
CID pathophysiology
Direct damage and inflammation to epithelial cells in mucosa of intestine, leading to imbalance between absorption and secretion
potential CID causes by chemo tx
Targeted therapy: tyrosine kinase inhibitor, EGFRi
* PO targeted therapy
* Cisplatin/ oxaliplatin
* Cyclophosphamide
* Cytarabine
* 5FU/ capecitabine
* Gemcitabine
* Methotrexate
* Doxorubicin/ daunorubicin
* Taxanes
*Irinotecan/ topotecan
pt risk factor for CID
- Age >65yrs
- Female
- Eastern cooperative oncology group (ECOG) performance status (PS) of at least 2 – ambulatory, all DALY
- Bowel inflammation or malabsorption
- Bowel malignancy
- Biliary obstruction
CID predictive factor
- First cycle of chemo
- Cycle duration >3wks
- Concomitant neutropenia
- Sx of mucositis, NV, anorexia, anemia
MAAV
Severity grading (Common Terminology Criteria for Adverse Events (CTCAE) version for CID)
Grade 1: Incr of <4 stools/d above baseline
Grade 2: limit ADLs
= Incr of 4-6 stools/day above baseline
Grade 3: hospitalisation needed, limiting self care
= Incr of ≥7 stools/d above baseline
Grade 4: life threatening = Urgent, intervention need
grade 5: death
CID uncomplicated vs complicated
!!!!!!!
NSF CBD 2P
UNCOMPLICATED:
* Grade 1 or 2 + No complicating s&sx
COMPLICATED:
* Grade 3 or 4
- Grade 1 or 2 w/ any of the 7 s&sx
- Cramp
- > grade 2 NV
- Decr performance status
- Fever
- Sepsis, neutropenia
- Frank bleeding (anus)
- Dehydration
goals of CID
- Decr morbidity and mortality from CID
- Improve QOL and ADL
- Improve recover of intestinal mucosa
- Decr hospitation
uncomplicated CID tx
- Diet modifications
- Oral hydration
- Withhold chemo for grade2
- Resume when sx resolve
- Dose reduction if needed
- Loperamide 4mg; 2mg Q4h/ after ep
- Continue until 12h free of D
uncomplicated CID progression after 12-24hr
- Improve: continue with diet mod, begin solid foods
- Persists: Lop 2mg BD
○ Add PO abx
○ (if lop not working) Octreotide/ 2nd line agent - Worsen severe/ complicated: tx as such
complicated CID tx
- Withhold chemo (resume when sx resolve)
- Restart at decr dose
- Administer
- SC Octreotide 100-150mcg TDS
- IV with dose escalation up to 500mcg TDS
IV fluid hydration
IV abx (ciprofloxacin x7d)
loperamide dose and MOA
- Dose: 4mg –> 2mg every 2-4hr/ after D
Max 16mg/d - MOA: binds to u-opioid receptor in intestine, decr Ach
Inhibit smooth muscle conc, decr motility
LOP place and AE
- Place: reduce fecal incontinence, freq of bowel movements and stool weight
- AE: constipation, ab pain, dizzy, rash, bloat, NV, dry mouth, drowsy
○ High dose: paralytic ileus
octreotide MOA
MOA: dcr hormone secretion, incr transit time within intestine, decr secretion of fluid and incr absorption of fluid and electrolytes
octeotride dose
- Dose: SC 100 - 150mcg TDS; IV 500mcg TDS; continuous IV infusion 25-50mcg/hr
○ May incr dose at 50mcg after 24h to 500mcg TDS
○ Dose-response r/s
octreotide SE and place
- AE: bradycardia, arrhythmia, NVC, ab pain, headache, dizzy, enlarged thyroid
- Place: pt on 5FU and irinotecan
○ Resolution by day 3
Irinotecan-associated diarrhea
Irinotecan –> SN38 (active metabolite) –> SN38G
SN38G –> SN38 (reactivated by gut bacteria)
- early: 24h of admin, sx 30mins, dose dependent
- late: after 24hr, onset 6d. any dose or freq
early Irinotecan-associated diarrhea tx
SC/ IV Atropine 0.25-1mg (max 1.2mg)
○ MOA: Inhibit Ach at muscarinic receptor as competitive antagonist
○ AE: insomnia, dizzy, tachy, blurred vision, blurred mouth, C
○ CI: close angle glaucoma
late Irinotecan-associated diarrhea tx
Loperamide 4mg –> 2mg Q2H/ 4mg Q4H (until 12h passed w/o bowel movement)
4+ (2x12) = 28mg. OR 4 + (4x6)=28mg
(vs usual max of 16mg)
take note of medications for CID
Tyrosine kinase inhibitor
○ ~50% experience CID. Grade 3 CID in 30%
○ Dose dependent
Epidermal growth factor receptor inhibitors [subclass of TK proteins]
Incr EGFR in inflamed mucosa
○ Occur within 2-3d of therapy
○ Grade 3-4 diarrhea in <10%
○ Grade 2 in 20% for cetuximab, panitumumab
○ Grade 3 6-9%, any grade 60% for small-mole inhibitors (erlotinib, gefitinib, lapatinib)
Neratinib requires antidiarrheal prophylaxis with LOPERAMIDE for first 2 cycles
non pharm for CID
- Probiotics (Lactobacillus) prevent Chemo/ radiation induced D
- Diet modifications
- Avoid caffeine, alcohol, fruit juice, foods with lactose, spicy/ high fat food
- Avoid high osmolarity fiber, dietary suppl
- Avoid Lactose containing foods
○ Avoided at least 1 wk after CID resolved
○ 5FU induced lactose intolerance, as lactase activity lost temporarily - Eat small, freq meals
- BRAT diet
- Hydration 3L of clear fluids (salt, sugar, electrolyte)
CIC pathophysiology
can cause dehydration
affect the nerve supply to the gut
medication risk for CIC
- Pain relievers: opioid narcotic (morphine, codeine)
- Chemo: vinca alkaloids (vincristine vinblastine, vinorelbine)
- AntiN drug (ondansetron, granisetron, anticonvulsant drugs)
CIC risk factors
- Low fluid intake and dehydration
- LOA (anorexia)
- Lack of fibre or bulk forming foods in diet
- Vit or mineral suppl (Fe, Ca pills)
- Overuse laxatives
- Low PA/ lots of bed rest
- Thyroid problems
- Depression
- High lvl of Ca/ K in blood
- cancer growing into Large intestine or pressing on spinal cord
sx of constipation
- Bloat, feeling of fullness. Swollen/ distended abdomen
- Cramp/ pain
- Gas/ flatulence
- Belching
- LOA
- No regular bowel movement for ≥2d
- Straining bowel movement
- Small hard stools, difficult to pass
- Rectal P
- Leakage of small amt of stool resembling D
- NV
PO tx for CIC
- Stool softeners: macrogol (forlax 1 sachet BD)
- Help stool hold water to keep it soft
- Stimulant laxatives: senna 15mg ON, sennosides, mineral oil, lactulose 10ml TDS
- Promote, stimulate bowel activity
- Bulk forming laxative: Psyllium 1 sachet BD
- incr fibre, bulk
(not preferred) inserts for CIC
Inserts not recommended when WBC, PLT are low, risk of infection/ bleed
- Suppositories: glycerine, bisacodyl
- Promote bowel activity
- Enema: phosphate enema (fleet), tap water
- clean out bowel or deliver laxatives
non pharm for CIC
- More fibre
- May not be advisable for CRC – large bulk
- Prunes may not be advised – sugar
- Natural laxatives
- Incr PA (gravity)
- Regular meals
mucositis pathophysiology
- Cancer tx: damage to mucosa of oral cavity, pharynx, larynx, esophagus, GIT
- Chemo/ radiation: direct damage to epithelial stem cells
- Targeted therapies: cetuximab, bevacizumab, rituximab, small mole inhibitors potential to cause GI toxicities
- EGF role to maintain mucosal integrity. (EGFR found in esophagus, incr in inflamed mucosa)
- Tissue response varies by seasonal and circadian changes
pt risk factors for mucositis
- Autoimmune factors
- DM
- Female (5-FU induced); Caucasian > african american
- Folic acid of vit b12 deficiency
- Genetic predisposition to tissue damage
○ Deficiency in genes produce enzymes responsible for metabolising chemo
tx risk factors for mucositis
- Chemo
○ Varies by agent and regimen
○ S-phase specific agents have highest risk
○ Duration, dose intensity, schedule
○ Prolonged or repetitive lower doses > risk > bolus doses
○ Incr with n.o. of cycles
○ CL of chemo delayed by renal/ hep impairment
○ Previous therapies toxic to mucosa
○ Previous ep of mucositis - Radiation (added to chemo)
○ Radiation source (throat area vs prostate), dosage, dose intensity, vol of mucosa irradiated - Smoking and alcohol
- Xerostomia, infection
mucositis grading
- Grade 0: no evidence of mucositis
- Grade 1: erythema, soreness
○ Asx or mild sx. No intervention - Grade 2: ulcer, eating solids
○ Mod pain; modified diet - Grade 3: ulcers, require lq diet
○ Severe pain, interfere with PO intake - Grade 4: ulcers, unable to take PO
○ Life threatening - Grade 5: Death
mucositis progression with time
Day 0-5: asx, redness, swell, burn, incr sensitivity
Day 0-7: desquamation, white patches (mistaken for candidiasis)
Day 6-12: contiguous pseudomembranes
Day 7-16: painful erosions, ulceration
goals for mucositis
- Prevent or decr severity of mucositis
- Manage pain and other associated sx
- Prevent chemo delays or dosage reductions
pharm to prevent oral mucositis
- Palifermin $$$$$21,900/ box of 3vials
- Benzydamine Hcl mouthwash
○ After radiation - Low level laser therapy.
○ After high dose chemo +/- TBI - Oral cryotherapy (ice chips)
○ After bolus 5FU - Oral hygiene
Palifermin
- Dose: IV 60mcg/kg/d x3doses BEFORE & AFTER tx
○ 6 doses (3 doses prior. 3rd dose 24-48hr before therapy. Last 3 doses start on same day as tx) - MOA: keratinocyte growth factor, reduce duration and severity of oral mucositis
- Place: high dose chemo/ total body irradiation (TBI). Hematological malignancies (myelotoxic therapy, requiring HSCT)
supportive care for mucositis (gargles)
- Oracare susp (Nystatin 125,000U, tetracycline 62.5mg, hydrocortisone 5mg, diphenhydramine 11.5mg/10ml)
○ Antifungal, Abx, steroid (inflam), antihist (itch)
○ Swallow, after food to kill bacteria - Mylocaine susp (diphenhydramine 11.5mg, lignocaine 16.7mg/10ml)
○ Antihist (itch), pain relief
○ Can swallow Before food to reduce pain from swallowing - Morphine sulfate sol 1mg/ml
○ Swallow before food
supportive care for mucositis (others)
- Oracort-E: lidocaine, triamcinolone
- Soregel: choline salicylate
- Medijel: aminacrine (antiseptic), lidocaine
- Difflam gargle/ spray: benzydamine
* Alc as preservative, gargle and spit out
non pharm for mucositis (mouthwash – gargle and spit out)
prevent dry mouth
Avoid alcohol based mouthwash (xerostomia –> mucositis)
* Oral 7 mouthwash: alc free, natural enzymes, neutral pH
* bioXtra mouthwash: natural enzymes, neutral pH
