2. Diarrhea WHO Definition: The passage of more than 3 unformed stools in 24 hours. Or Frequent passage of loose stools with urgency.

3. NCI Grading of Diarrhea NoneGrade 0 < 4 stools / dayGrade 1 4-6 stools / day Moderate cramping Not interfering with normal activity Grade 2 7- 9 stools / day Sever cramping and incontinence Interfering with normal activity Grade 3 > 10 stools / day Grossly bloody diarrhea Need hospital admission Grade 4

4. Causes of diarrhea in cancer paients  Chemotherapy induced diarrhea  Infectious diarrhea  Entral feeding  Celiac plexus block  Radiotherapy induced diarrhea  Paraneoplastic syndrome

5. Chemotherapy induced diarrhea  The most common CTh agents causing diarrhea are: 1.5 Flu 2.Capecitabine 3.Irinotecan 4.Taxanes 5.Target agents “ Sunitinib, Sorafanib, Erlotinib, Gefitinib …. ”

6. 5- Fluorouracil  Mechanism of action:  5- FLUOROURACIL decrease the biosynthesis of pyrimidine nucleotides by inhibiting thymidylate synthase, the enzyme that catalyzes the rate limiting step in DNA synthesis.  Leucovorin increases binding of 5-FU to thymidylate synthase thereby increasing 5-FU t 1/2

8.  Mechanism of Diarrhea with 5 Flu: 5- Fluorouracil 5-Flu causes mitotic arrest of intestinal crypts cells Abnormal secretion of electrolytes and fluids Increase in the ratio of immature secretory crypt cells to mature villous enterocytes Diarrhea

9. 5- Fluorouracil  Risk factors 1.Older age 2.Coadministration with Leucovorin 3.Bolus rather than infusion 4.Associated bowel disease 5.Female gender

10. DPD deficiency

11.  Life-threatening complication including: 1.Sever diarrhea 2.Sever mucositis 3.Pancytopenia

12. Capecitabine “ Xeloda ”  Capecitabine, a precursor of 5-FU, is an oral fluoropyrimidine cytotoxic agent developed with the aim of providing a more effective, less toxic and oral drug.  It is converted in vivo to 5-FU  The prevelance of diarrhea is 30% - 40%.

13. Irinotecan “ Campto ”  Topoisomerase I inhipitor ( Topoisomerase I relaxes the supercoiled DNA for variety of cellular processes)  2 Types of diarrhea may occur: 1.Acute diarrhea (immediately after drug administration and usually respond to atropine) 2.Delayed diarrhea (24 hrs after drug administration)

14. Irinotecan “ Campto ” cont.  Mechanism of diarrhea: Destructive effect of active agent on the intestinal colonic Epithelium + Production of pro-inflammatory cytokines Disturbance in absorptive and secretory functions of mucosa Diarrhea

15. Assessment  History and physical examination: ( Don ’ t forget Vital signs and signs of dehydration)  Dietary history and medical history  Grading of diarrhea NoneGrade 0 < 4 stools / dayGrade 1 4-6 stools / day Moderate cramping Not interfering with normal activity Grade 2 7- 9 stools / day Sever cramping and incontinence Interfering with normal activity Grade 3 > 10 stools / day Grossly bloody diarrhea Need hospital admission Grade 4

16. Assessment cont.  Complete lab. 1.CBC 2.RFT 3.LFT 4.Bl. Sugar ( Don ’ t forget Electrolytes)  Stool analysis  Blood culture if patient feverish  Imaging according to patient complaint

17. General principles in the management of CTH induced diarrhea 1.Rule out other causes of diarrhea 2.Diet Modification: e.g. * Increase Fluid intake * Fresh diet 3.Anti-diarrheal medications

18. Anti-diarrheal medications A.Loperamide Mech:  Reduces stool frequency  Decrease bowel movement Dose: 4 mg followed by 2mg every 2-4 hrs or after every unformed stool (up to 16 mg /day)

19. Anti-diarrheal medications cont. B.Atropine – diphenoxylate “ Lomotile ” Dose: 1-2 tablets every 4-6 hours

20. Anti-diarrheal medications cont. C.Octreotide “ Sandostatine ” Mech:  Somatostatine analogue  Suppression insulin, glucagone, VAIP and pancreatic exocrine function  Suppress intestinal motility Dose: 100 – 150 mcg SC/IV 3 times /day “ up to 500 mcg /day ” according to response

21. How to manage ?

22. Grade 1-2 Diarrhea Dietary management Loperamide 4mg then 2mg after loose stool (max 16 mg /day) Not resolved High dose loperamide 4mg then 2mg/2hrs Diarrhea resolved Adjust diet and Stop loperamide after 12 hrs without diarrhea Not resolved after 24 hrs Octeroides 100 – 150 mcg + Fulid and elect. reeplacement

23. Grade 3-4 Diarrhea Hospital admition And Loperamide 4mg then 2mg after loose stool (max 16 mg /day) Octeroide 100 – 150 mcg Fluid and elect. Replacement + Consider antibiotic + Not resolved after 24 hrs Increase Octeroide up to 500 mcg / day or 25-50 mcg/hr continuous infusion + High dose loperamide