Colon Cancer

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Colon Cancer
2012-04-28 15:12:04
Regis University

Colon Cancer
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  1. 4 Major layers of cells b/t colon lumen and peritoneum
    • mucosa
    • submucosa
    • muscularis propia
    • serosa
  2. Mucosa layer
    • contains tubular glands (called crypts)
    • consisting of mucin-producing goblet cells and absorptive cells
  3. Submucosa layer
    contains rich lymphatic capillary system
  4. Muscularis propia
    • a rich lymphatic capillary system
    • consists of smooth muscle bands that move colonic material toward anal canal
  5. Serosa
    secretes a fluid that allows the colon to slide easily over nearby structures w/in peritoneum
  6. Risk Factors for Modifiable Colorectal cancer
    • diet high in fats and cholesterol
    • diet low in fiber and vegetables
    • smoking
    • alcohol (>10 drinks/week)
    • physical activity
    • obseity
  7. Risk Factors for Non-Modifiable Colorectal cancer
    • age > 50yrs
    • family history and genetic factors
    • history of adenomatous polyps
    • inflammatory bowel disease
    • prior radiation therapy
    • prior polypectomy
  8. Treat Familial adenomatous polyposis (FAP)
    • surgery
    • sulindac and celecoxib
  9. What are the two key steps in the transformation from adenoma to carinoma
    • hyperproliferation of epithelial cells to form a small benign adenoma in conjunction with
    • cellular mutations that result in transformation to carcinoma
  10. Genetic changes include:
    • activation of oncogenes
    • inactivation of tumor suppressor genes
    • defects in DNA mismatch repair genes
  11. Screening and prevention tests for colorectal cancer
    • Genetic teseting - FAP, HNPCC genetic testing
    • Fecal Occult Blood Testing (FOBT)
    • Stool DNA (sDNA)
    • Colonoscopy
    • Double-contrast barium enema (DCBE)
    • Flexible Sigmoidoscopy
  12. FOBT - Fecal Occult Blood Testing
    • guaiac FOBT: uses chemical guaiac to detect heme in stool
    • Fecal immunochemical test (FIT): uses antibodies to detect the globulin portion of human hemoglobin protein in stool
    • *limitation to FOBT is that many early stage tumors do not bleed, therefore false negatives can occur
  13. Stool DNA (sDNA)
    • testing stool for the presence of DNA alterations that occur during colorectal carinogenesis
    • NOT considered a first-line screening option for colon cancer
  14. Double-contrast Barium Enema (DCBE)
    • a series of x-rays of the entire colon and rectum are taken after the pt is given an enema w/ a barium solution and air is introduced to the colon
    • may miss small polyps
    • not as good as colonoscopy
  15. Clinical staging of Colorectal Cancer
    • stage 0: represents the presence of precancerous polyps that can be removed during a colonoscopy
    • stage III: represents lymph node involvement
    • stage IV: represents metastatic spread
  16. Treat metastatic colorectal cancer
    • bevacizumab
    • cetuximab
    • panitumumab
  17. FOLFOX contains
    • oxaliplatin
    • fluorouracil
    • leucovorin
    • adverse effects: neutropenia, diarrhea, nausea & vomiting, fatigue, sensory neuropathy
  18. Irinotecan
    • topoisomerase I poison/inhibitor
    • used in combo w/fluorouracil as first line agent for metastatic colorectal cancer
    • adverse effects: early diarrhea (treated w/ atropine), delayed diarrhea (treated w/ loperamide)
  19. Topotecan
    • topoisomerase I poison/inhibitor
    • second line agent for ovarian cancer (for platinum resistanat)
    • adverse effects: nausea, vomiting, myelosuppression)
  20. 5-Fluorouracil MOA
    • a prodrug targets thymidylate synthase and acts as a suicide inhibitor
    • nearly identical to endogenous thymidylate synthase difference is a fluorine
    • once bound to enzyme, 5-F-dUMP, unable to deprotonate leading to irreversible covalent modification of both the folate coenzyme and cysteine 146.
    • result in no product formed, no cofactor released, most important thymidylate synthase not regenerated and cells die for lack of thymidine
  21. 5-Fluorouracil adverse effects
    • leukopenia: dose-limiting toxicity of IV bolus 5-FU
    • diarrhea
    • nausea and vomiting
    • stomatitis (inflammation of mucous lining in mouth)
    • *stomatitis reduced w/ use of cryotherapy (ice chewing)
    • continuous 5-FU adverse effects: same as bolus (above), palmar-plantar erythrodysesthesia (hand-foot syndrome)
    • Hand-foot syndrome: reversible by stopping or dose reduction of 5-FU
  22. Capecitabine
    • 1st line agent for colorectal cancer
    • capecitabine is actively converted into 5-FU (prodrug of a prodrug)
    • thymidine phosphorylase is much more active in tumor cells and is responsible for conversion to 5-FU
    • adverse effects: bone marrow suppression, nausea and vomiting, severe diarrhea, and hand & foot syndrome
  23. Leucovorin
    • acts to stabilize the binding of metabolite for 5-FU to thymidylate synthase enahncing inhibition of this enzyme
    • given in combo w/ 5-FU to enhance binding of 5-FU to thymidylate synthase
    • treats methotrexate overdose/toxicity
  24. Oxaliplatin
    • involves intrastrand links between adjacent guanine residues or adjacent guanine-adenine residues
    • used in combo w/ 5-FU/leucovorin
    • adverse effects: less neurotoxic, hematotoxic, ototoxic than cisplatin
  25. Bevacizumab
    • monoclonal antibody
    • binds and neutralizes vascular endothelial growth factor (VEGF)
    • prevents association of VEGF w/ endothelial receptors Flt-1 and KDR. inhibits microvascular growth retarding the growth of all tissues including metastatic tissue
  26. Cetuximab
    • chimeric - contains portions of mouse cells and human antibody
    • binds to the extracellular domain of EGFR preventing the binding of other ligands (EGF - epidermal growth factor, TGF-a - transforming growth factor-a)
    • EGFR then cannot form active dimers and tyrosine kinase is inhibited
    • inhibits cell growth through blockade of EGFR signaling, promoting apoptosis
    • adverse effects: infusion-related, skin rash, diarrhea, asthenia/malaise, nausea and vomiting, lung disease, low Mg
  27. Panitumumab
    • monoclonal antibody
    • targets EGFR, inhibiting binding of EGF and other ligands
    • blocks phosphorylation and activation of intracellular tyrosine kinases
    • results in inhibition of cell survival, growth, proliferation, and transformation
  28. Stage II
    • large tumors (T4)
    • poorly differentiated tumors (grade 3/4)
    • lymphovascular invasion
    • inadequate lymph node sampling
    • perinerual invasion
    • bowel obstruction
    • perforation at presentation
    • positive surgical markers
  29. Decreases Risk of Colon Cancer (BUT NOT reccommended solely for prevention)
    • Calcium supplementation
    • NSAID
    • HRT
    • HMG-CoA reductase inhibitors