Colo-Rectal Carcinomas ICM-9CM Code 154.0 Colo-Rectal Cancer General Considerations A.

Great Majority Of All Cancers Of The Large Intestines Are Adenocarcinomas. B. Almost Always Arise In Adenomatous Polyps. C. Up To 4 % Of Colorectal Cancers Due To Heredity In Polyposis Syndromes Or Hereditary Non-Polyposis Colorectal Cancer D. Generally Curable By Resection E. 134,000 Cases / Year F. 15% Of All Cancer Deaths. 1. Epidemiology: A. Peak Incidence: 60-70 Years Of Age B. Fewer Than 20 % Occur Before The Age of 50 C. Suspect Ulcerative Colitis Or Polyposis Syndromes As Causes In Young People D. Adenomas Are The Presumed Precursor E. Highest Incidence In Developed Countries: USA, Canada, Australia, Scandinavia F. Lowest Incidence India, South America and Africa 2.Risk Factors: A. Dietary Factors : 1. Refined Carbohydrates 2. Low Content Of Unabsorbable Vegetable Fiber 3. Diets Rich In Fat And Red Meat 4. Decreased Protective Nutrients: Vitamin A,C,E B. Age C. History Of Colorectal Cancer, Or Adenomatous Polyps D. Family History Of Colorectal Cancer E. Inflammatory Bowel Diseae: Crohns Disease Or Ulcerative Colitis F. Race: African Americans, Blacks > Whites

3. Pathogenesis: 1. Reduced Fiber Content Leads To Decreased Stool Bulk, Increased Fecal Retention In The Bowel And Altered Bacterial Flora In The Intestines 2. Therefore Toxic Byproducts Of Carbohydrate Degradation By The Bacteria Are Present In the Small Stools And Are Held In Contact With the Colonic Mucosa For Longer Periods Of Time. 3. High Fat Intake Enhances Synthesis Of Cholesterol And Bile Acids By The Liver Which In Turn May Be Converted Into Potential Carcinogens By The Intestinal Bacteria. 4. Refined Diets Also Contain Less Vitamins A,C,E Which May Act As Oxygen Radical Scavengers. 5. Several Recent Studies With Aspirin and Other NSAIDs Suggest They May Play a Protective Role in Preventing Colon Cancer. A. Possible Mechanisms: 1. Induction Of Apoptosis In Tumor Cells 2. Inhibition Of Angiogenesis Through Inhibition Of Cyclooxygenase 2 This Enzyme In Angiogenesis In The Prostaglandin Pathway Seems To Favor Angiogenesis By Enhancing Production Of Vascular Endothelial Growth Factor. 6. On The Basis Of These Findings, The FDA Has Approved COX-2 Inhibitors As Preventive Agents in Patients With Familial Adenomatous Polyposis Syndrome

7. The Adenoma-Carcinoma Sequence: Carcinomas From Adenomas Sequence: A. Populations With High Prevalence Of Adenomas Have A High Prevalence Of Colorectal Cancer B. The Distribution of Adenomas Within The Colorectum Is Comparable To The Colorectal Cancers C. Peak Incidence For Adenomas Antedates Colorectal Cancer By Some Years D. The Risk Of Cancer Is Directly Related To The Number Of Adenomas. Hence The Virtual Certainty Of Cancer In Patients With Familial Polyposis Syndromes E. Programs That Assiduously Follow Patients For The Development Of Adenomas And Remove All That Are Identified Reduce the Incidence Of Colorectal Cancer. H. Carcinogenesis: 1. Two Pathogenetically Distinct Pathways Are Present. 2. Both Involve Stepwise Accumulations Of Multiple Mutations: I. First Pathway: APC/B-Catenin Pathway: A. Cancer Occurs Through First Through Localized Colon Epithelial Proliferation .This Is Followed By Small Adenomas That Eventually Become Dysplastic And Then Turn Into Colon Cancer. B. The Genetic Correlates Of This Pathway: 1. Loss Of The APC Tumor Suppressor Genes 2. Germline Mutations In The APC Gene Gives Rise To Hundreds Of Copies Of Adenomas That Progress To Cancer. Both Copies Of The APC Gene Must Be Lost For The Adenoma To Form. Loss Of APC Function Accumulated B-Catenin Translocates To The Nucleus And Activates Transcription of Several Genes Such As MYC, Cyclin D1 That Promote Cell Proliferation. 3. K-Ras Mutations A. K-Ras Is Trapped In An Activated State That Delivers Mitotic Signals And Prevents Apoptosis. 4. 18q21Deletion: Loss Of Putative Cancer Suppressor Gene Has Been Found In 60-70% Of Patients With Colon Cancer 5. Loss of TP53: Loss of TP53 Tumor Suppressor Gene is Noted in 70-80% of Colon Cancer

II. Second Pathway: 1. Genetic Lesion in DNA Mismatch Repair Genes. Here There Are Accumulations Of Mutations But There Are No Clearly Identifiable Morphologic Correlates 2. Defective DNA Repair Caused By Inactivation Of DNA Mismatch Repair Genes is the Fundamental Pathway in Initiating Colorectal Cancers. 3. DNA Mismatch Repair Genes Give Rise to the Hereditary Non-Polyposis Colon Carcinoma. 4. Loss of DNA Mismatch Repair Genes Gives Rise To Microsatellites (Simple Repetitive DNA Sequences) 5. MSI Pathway: The Resulting Microsatellite Instability (MSI) Is The Molecular Signature Of Defective DNA Mismatch Repair. 6. Some Microsatellite Sequences Are In The Promoter Region Of Genes Involved In Regulation Of Cell Growth. Such Genes Include Type 2 TGF-B Receptor and BAX 7. TGF-B Signaling Inhibits the Growth Of Colonic Epithelial Cells 8. BAX Gene Causes Apoptosis I. Summary: Loss Of Mismatch Repair Genes Leads To The Accumulations of Mutations in These And Other Growth Regulating Genes, Culminating In The Emergence Of Colorectal Carcinoma

3. Pathology: 1. Proximal Colon: Exophytic or Polypoid 2. Distal Colon: Napkin Ring Constriction, Annular Encircling Lesions 4. Clinical Features: A. Cecal And Right Sided Lesions: A. Fatigue B. Weakness From Blood Loss C. Fe Deficiency Anemia B. Left Sided Lesions: A. Occult Bleeding B. Changes In Bowel Habits C. Alternating Diarrhea and Constipation D. Pencil Like Stools, E. LLQ Discomfort F. Stool Streaked With Blood G. Obstructive Symptoms H. Colicky Abdominal Pain C. Rectal Cancer: A. Rectal Tenesmus B. Urgency C. Recurrent Hematochezia D. Metastatic Spread: Suggested By Hepatomegaly 5. Spread: A. Direct Extension B Lymphatics C. Via the Blood 6. Metastases: A. Regional Nodes B. Liver C Lung D. Bones

7. Diagnosis: A. Digital Rectal Examination B Fecal Blood Testing In The Stool C. Barium Enema D. Colonoscopy/ Sigmoidoscopy E. For Metastases: CT /MRI/ PE& PET/CT 8. Laboratory Tests: A. CEA Serum Marker: 1. If High : Disease Already Has Spread 2. Is Diagnostic Of Other Conditions Including: A. Other Cancers B. Alcoholic Cirrhosis C. Ulcerative Colitis D. Pancreatitis B. CBC C. LFT D. Fecal Occult Blood Test Positive E. Prognostic Indication: Stage and TNM Classification

9. Treatment: Colon Cancer A. Surgical: 1. Endoscopic Resection 2. Surgical Resection 3. Hemicolectomy 4. Colectomy B. Medical: Adenocarcinoma 1. 5 FU:Antimetablite: Metastatic Colorectal Carcinoma 1. Capecitabine : Antimetabolite: (Xeloda) 2. FOLFOX: 5- Fluorouracil Leucovorin Oxaloplatin Plus . Bevacizumab (Avastin):Anti VEGF Antibody Cetuximab:Anti EGFR Antibody: (Erbitux) or Panitumumab: (Vectibix) 3. FOLFIR: 5- Fluorouracil Leucovorin Irinotecan Plus: Bevacizumab (Avastin) or Cetuximab (Erbitux) or Panitumumab (Vectibix) 4. Clinical Trials: A. Velcade: Bortezomib B. Oblimersen C. Erlotinib (Tarceva) D. Gefitinib E. Topotecan (Hycamtin)

5. Clinical Trials: A. Trovax Vaccine B. Gene Therapy Vaccine C. BCG : Immunotherapy 10. Treatment: Rectal Cancer: Adenocarcinoma A. Surgical B. Local Ablative Techniques: For Unresectable Hepatic Metastases 1. Cryosurgery 2. Embolization C. Medical: Chemotherapy: 1. 5FU Metastatic Colorectal Cancer: 1. Cetuximab : Anti EGFR Antibody: (Erbitux) Or 2. Bevacizumab : Anti VEGF Antibody: (Avastin) Or 3. Panitumumab: (Vectibix) Plus: 1. 5 FU 2. Leucovorin 3. Oxaliplatin 1. Cetuximab (Erbitux) Or 2. Bevacizumab (Avastin) Or 3. Panitumumab (Vectibix) Plus: 1. 5 FU 2. Leucovorin 3. Irinotecan C. Capecitabine : Antimetabolite (Xeloda) D. Combined : Pre-Operative: Stage 2 And 3 Rectal Cancer 1. Pelvic Radiation 2. Adjuvant 5FU

11. Rx: Anal Cancer: Squamous Cell Carcinoma A. Medical: Chemotherapy 1. Cisplatin (Alklyating Agent) 2. 5 FU (Antimetabolite) (Adrucil) 3. Mitomycin ( Antibiotic) B. Surgical 1. Transanal Excision in Selected Cases 12. Outcome: A. Follow Up: 1. After Resection: A. Evaluations Every 3-6 Months For 3-5 Years With: 1. History 2. Physical Examination 3. Fecal Occult Blood Testing 4. LFTs 5. CEA Determinations 6. Rise in CEA Is Suggestive Of Recurrence 7. Colonoscopy Within 6-12 Months; Then Every 3-5 Years 8. CXR and Abdominal CT: If A. Patient Clinical Picture B. Abnormal LFTs C. Rising CEA Levels 13. Prognosis: A. 5 Year Survival Rates: 1. Stage 1: 80-100% Even Without Adjuvant Therapy 2. Stage 2: T3-T4: Node Negative Disease: 50-75% Consider Study Protocols for Chemotherapy and Radiotherapy 3. Stage 3: Node Positive Disease: 30-50% Without Chemotherapy 65% with Adjuvant Chemotherapy

B. Long Term Survival Rates: 1. Stage 1: 90% 2. Stage 2: Greater Than 70% 3. Stage 3: 67%: With Fewer Than 4 Positive Nodes 4. Stage 3: 33%:: With More Than 4 Positive Nodes 5. Stage 4: Less Than 5 % C. Rectal Cancer: 1. Worse Prognosis 14. Prevention: A. Screening: 40 Years Old: First Degree Members 50 Years Old: General First Screening 60 Years Old Etc B. Chemoprevention: 1. Prolonged Use Of Aspirin Or NSAIDs May Decrease Risk Of Colorectal Neoplasia 2. Routine Chemotherapeutic Agents: Not Recommended Currently 15. Differential Diagnosis: A. Diverticulosis/Diverculitis B. Hemorrhoids C. Adenomatous Polyps D. Ischemic Colitis E. Inflammatory Bowel Disease F. Irritable Bowel Syndrome G. Infectious Colitis H. Other Causes Of Iron Deficiency