CID + Constipation Flashcards
Risk factors for CID
- Age >65y
- Female
- ECOG PS >=2
- Bowel inflammation or malabsorption
- Bowel malignancy
- Biliary obstruction
Other predictive factors:
- First cycle of chemotherapy
- Cycle duration >3w
- Concomitant neutropenia
- Other symptoms such as mucositis, vomiting, anorexia, anemia
Which targeted therapy reports a lot of CID?
Tyrosine kinase inhibitors, esp Epidermal Growth Factor Receptors (EGFR)
E.g., 60% Erlotinib, Gefitinib, Lapatinib, Neratinib
E.g., 20% Cetuximab, Panitumumab
*Neratinib - requires antidiarrheal prophylaxis with Loperamide for first 2 cycles
CID grading
Grade 1: incr of <4 stools per day
Grade 2: incr of 4-6 stools per day, limiting ADL
Grade 3: incr of >= 7 stools per day, hospitalization
Grade 4: life-threatening, urgent
Grade 5: death
Uncomplicated CID
Grade 1 or 2
Complicated CID
Grade 3 or 4
OR
Grade 1 or 2 with any of the following:
- Mod-severe cramping
- > = Grade 2 N&V
- Decreased PS (incr number)
- Fever
- Sepsis
- Neutropenia
- Frank bleeding
- Dehydration
CNPFSNFD
Loperamide
- MOA
MOA
- Mu-opioid receptor agonist, binds to u-opioid receptor on the gut wall and inhibits acetylcholine and prostaglandin release, reduce peristaltic activity (inhibit smooth muscle contraction), slows GI motility, increase intestinal transit time
SEs:
- Constipation
- Stomach cramps, bloating
- Sedation, fainting
- Rapid or irregular heartbeat
- High doses can cause paralytic ileus, toxic megacolon
DDI:
- Loperamide is a PGP substrate (inhibitors: quinidine, ritonavir) => may enhance CNS depressant effects of Loperamide
*Limited efficacy in Grade 3-4 complicated diarrhea
Octreotide
- MOA
MOA:
- Somatostatin analog, blocks release of several hormones (5-HT and other active peptides such as VIP - vasoactive intestinal peptide) => prolong intestinal transit time, reduce secretion, and incr absorption of fluids and electrolytes
SEs:
- Bradycardia, arrhythmias
- Constipation
- Abdominal pain
- Enlarged thyroid
- Headache
- Dizziness
- N&V
- Cholelithiasis (gallstones in gallbladder)
- Steatorrhea
Approach to treating uncomplicated
Conservative management
- Withhold chemotherapy for Grade 2 CID, resume when symptoms resolve and consider dosage reduction
- Diet modification (e.g., avoid caffeine, alcohol, spicy or high fat food, lactose-containing food, high osmolar supplements; eat small frequent meals, BRAT diet; ORS >3L)
- Oral hydration (8-10 large glasses)
- Loperamide (max 16mg/day) - PO 4mg for first dose, then 2mg after each loose stool or q4h
- to continue until 12h diarrhea free
Uncomplicated
- diarrhea improves after 12-24h
Stop loperamide, continue with diet modification and begin o add solid foods
Uncomplicated
- diarrhea persists after 12-24h
Persistent uncomplicated diarrhea:
- Loperamide 2mg q2h
- Start oral antibiotics (e.g., Ciprofloxacin x7d)
Still unresolved after another 12-24h:
- Add second-line agents such as Octreotide SC 100-150mcg TDS (up 500mg TDS) / Budesonide / Tincture of opium
If progress to complicated, treat as per complicated
Approach to treating complicated
Aggressive management
- ADMIT TO HOSPITAL
- Withdraw chemotherapy (resume when all symptoms resolve, restart at decreased dose)
- Administer Octreotide 100-150mcg SC/IV TDS, with dose escalation up to 500mcg TDS (at 50mcg intervals after 24h) or continuous IV infusion 25-50mcg/h
- Start IV fluid hydration
- Start IV antibiotics (7d)
Evaluation of unresolved diarrhea
- Check stool workup (blood, fecal leukocyte, bacteria)
- Check CBC (neutropenia)
- Check electrolytes profile
- Perform abdominal exam
- Replace fluids and electrolytes as appropriate
Non-pharmaco for CID
- Probiotics with lactobacillus
- Diet modification
- Avoid caffeine, alcohol, lactose-containing food (avoid for at least a week after CID resolved), high osmolarity supplements, food that are spicy or high in fat or fibre
*Lactase activity may be lost temporarily after 5-FU treatment
- Small, frequent meals
- BRAT diet (banana, rice, applesauce, toast)
- More than 3L of fluids with electrolytes (ORS)
Irinotecan-induced diarrhea
What is Irinotecan?
Irinotecan
MOA: inhibits topoisomerase 1, induce replication arrest and double-stranded breaks in DNA
Place in therapy: first and second line tx of metastatic colorectal cancer
Irinotecan-induced diarrhea
Describe how the pathology contributes to CID
- Irinotecan primarily converted in the liver to active metabolite SN-38
- SN-38 is deactivated via glucuronidation by UDP-GT1A1 to inactive SN-38G
- SN-38G is secreted through the bile into the gut. Bacteria in gut produce B-glucuronidases that reactivate (via deconjugation) SN-38G to toxic active SN-38
- SN-38 may induce direct mucosal damage during excretion (ablation of crypts, villus blunting, atrophy of epithelium), commensal bacteria in the gut is also altered in the presence of irinotecan, hence allowing other bacteria to proliferate
