1. Colon Cancer Daniel A. Nikcevich, MD, PhD Duluth Clinic Cancer Center January 26, 2009

2. Colon Cancer Diagnosis Diagnosis Staging Staging Treatment Treatment

3. Diagnosis 55 yo female comes to your office with c/o constipation for 4-6 months 55 yo female comes to your office with c/o constipation for 4-6 months Thin-caliber stools, 10 lb weight loss Thin-caliber stools, 10 lb weight loss What’s next? What’s next? Physical exam. Physical exam. Liver non-palpableLiver non-palpable Brown, heme+ stool noted.Brown, heme+ stool noted. HgB 8.5, MCV 69 HgB 8.5, MCV 69

4. Diagnosis Index of suspicion Index of suspicion Differential diagnosis Differential diagnosis Imaging Imaging ColonoscopyColonoscopy Flexible sigmoidoscopyFlexible sigmoidoscopy Virtual colonoscopyVirtual colonoscopy Barium enemaBarium enema

6. Annular constricting or napkin-ring carcinoma of colon ©Copyright Science Press Internet Services

9. Diagnosis Index of suspicion Index of suspicion Differential diagnosis Differential diagnosis Imaging Imaging ColonoscopyColonoscopy Flexible sigmoidoscopyFlexible sigmoidoscopy Virtual colonoscopyVirtual colonoscopy Barium enemaBarium enema Biopsy Biopsy CANNOT diagnose w/o tissueCANNOT diagnose w/o tissue

10. Back to our patient… Biopsy shows adenocarcinoma in mass located in distal sigmoid colon. Biopsy shows adenocarcinoma in mass located in distal sigmoid colon. What’s next? What’s next? CT scan CT scan CEA level CEA level Surgery Surgery

11. DIAGNOSIS: A, B) Mass, distal sigmoid colon/proximal rectum, segmental colonic resection: - Tumor type and grade: Moderately differentiated adenocarcinoma. - Tumor size and location: 3.0 cm, distal sigmoid colon/proximal rectum. - Extent of invasion: Tumor extends through muscularis propria and into subserosal fat, and approaches within less than 1/2 mm of serosa. - Lymph nodes: 5 of 16 lymph nodes involved by metastatic neoplasm. No evidence of extranodal extension by tumor. - Margins: Proximal and distal resection margins uninvolved by neoplasm. Radial margin within proximal rectum of less than 1 mm. Separately submitted anastomotic rings (part B) uninvolved by neoplasm. - Lymphovascular invasion: None seen. - High-risk morphology for microsatellite instability: No. AJCC Stage: Preliminary stage pending clinical review is AJCC pT3, pN2, MX (Stage IIIC). Correlation with clinical and imaging findings is also necessary for accurate staging.

13. Colon Cancer Staging Clinical StagePathologic Stage5 year survival Stage 0TisN0M0> 95% Stage I (A)T1T2N0M085-95% Stage IIA (B)T3N0M060-80% Stage IIB (B2)T4N0M060-80% Stage III (C)T1-4N1-2M030-60% Stage IV (D)M1< 5%

14. Colon Cancer Treatment Surgery Surgery Low-anterior resection (no colostomy)Low-anterior resection (no colostomy) Abdominoperineal resection (permanent colostomy)Abdominoperineal resection (permanent colostomy) Chemotherapy Chemotherapy Radiation (rectal cancer) Radiation (rectal cancer)

15. Who should receive chemotherapy? Stage 1: surgery only. Stage 1: surgery only. Stage IIA/IIB: consider chemotherapy, especially for IIB Stage IIA/IIB: consider chemotherapy, especially for IIB Stage III: chemotherapy is standard of care Stage III: chemotherapy is standard of care Stage IV: chemotherapy is standard of care Stage IV: chemotherapy is standard of care

16. Benefits of adjuvant chemotherapy for colon cancer 40% reduction of recurrence of cancer. 40% reduction of recurrence of cancer. 25% improvement in survival from cancer. 25% improvement in survival from cancer. Based on 5 years from diagnosis. Based on 5 years from diagnosis.

17. Which chemotherapy? Adjuvant chemotherapy Adjuvant chemotherapy 5-FU plus leucovorin5-FU plus leucovorin FOLFOX (5-FU, Oxaliplatin, leucovorin)FOLFOX (5-FU, Oxaliplatin, leucovorin) 33% improvement in disease-free survival for FOLFOX vs 5-FU/LV33% improvement in disease-free survival for FOLFOX vs 5-FU/LV Addition of monoclonal antibody such as bevacizumab or cetuximab in clinical trialsAddition of monoclonal antibody such as bevacizumab or cetuximab in clinical trials Metastatic disease Metastatic disease FOLFOX plus bevacizumab is standard of careFOLFOX plus bevacizumab is standard of care FOLFIRI (substitute irinotecan for oxaliplatin) plus bevacizumab is standard of careFOLFIRI (substitute irinotecan for oxaliplatin) plus bevacizumab is standard of care Irinotecan plus cetuximabIrinotecan plus cetuximab PanitumomabPanitumomab

19. Recommended Follow Up Physical exam every 3 months for 2 years, then every 6 months for 3 years. Physical exam every 3 months for 2 years, then every 6 months for 3 years. CEA every 3 months for 2 years, then every 6 months for 3 years for T2, T3, T4 tumors. CEA every 3 months for 2 years, then every 6 months for 3 years for T2, T3, T4 tumors. Colonoscopy in 1 year Colonoscopy in 1 year Repeat in 1 year if abnormal polyps notedRepeat in 1 year if abnormal polyps noted Repeat every 3-5 years if negativeRepeat every 3-5 years if negative Repeat in 3-6 months after diagnosis if 1 st colonoscopy with “unprepped” bowel.Repeat in 3-6 months after diagnosis if 1 st colonoscopy with “unprepped” bowel.

20. Colon Polyp

21. Metastatic colon cancer Incurable Incurable Treatment goals to improve survival and quality of life Treatment goals to improve survival and quality of life Standard of care is FOLFOX or FOLFIRI with bevacizumab Standard of care is FOLFOX or FOLFIRI with bevacizumab Second-line options include use of cetuximab or panitumomab Second-line options include use of cetuximab or panitumomab Clinical trial option Clinical trial option

22. New approaches Gene profiling Gene profiling Thymidylate synthase expressionThymidylate synthase expression DPD expressionDPD expression Microsatellite instabilityMicrosatellite instability EGF-R expressionEGF-R expression Chemoprevention Chemoprevention AspirinAspirin COX-2 inhibitorsCOX-2 inhibitors Tyrosine kinase inhibitors Tyrosine kinase inhibitors EGF-R inhibitors EGF-R inhibitors CetuximabCetuximab PanitumomabPanitumomab MUST be k-ras wild-type to use either drugMUST be k-ras wild-type to use either drug Antiangiogenesis Antiangiogenesis BevazuzimabBevazuzimab Oral chemotherapy (capecitabine) Oral chemotherapy (capecitabine)

23. Anti-angiogenesis Bevacizumab: a human anti-vascular endothelial growth factor monoclonal antibody. Bevacizumab: a human anti-vascular endothelial growth factor monoclonal antibody. Combination of bevacizumab plus IFL superior to IFL in treatment of patients with metastatic colorectal cancer. Combination of bevacizumab plus IFL superior to IFL in treatment of patients with metastatic colorectal cancer. First human phase III trial to document efficacy of an anti-angiogenesis strategy for treating cancer. First human phase III trial to document efficacy of an anti-angiogenesis strategy for treating cancer.

24. Chemoprevention COX-2 inhibitors used to prevent in adenomas in FAP patients COX-2 inhibitors used to prevent in adenomas in FAP patients Aspirin to prevent adenomas in patients with prior colon cancer or family history of colon cancer. Aspirin to prevent adenomas in patients with prior colon cancer or family history of colon cancer.

25. Sandler, R. S. et. al. N Engl J Med 2003;348:883-890 Kaplan-Meier Estimates of the Time to a First Adenoma

26. Back to our patient… Recovered from surgery (LAR). Recovered from surgery (LAR). Stage IIIC colon cancer. Stage IIIC colon cancer. What to do next? What to do next? Discuss chemotherapy options Discuss chemotherapy options Standard treatment (FOLFOX)Standard treatment (FOLFOX) Clinical trial option (FOLFOX +/- cetuximab)Clinical trial option (FOLFOX +/- cetuximab)

28. Summary Colon cancer is a curable disease. Colon cancer is a curable disease. Chemotherapy improves survival. Chemotherapy improves survival. Indicated for stage III (adjuvant) and stage IV (metastatic disease)Indicated for stage III (adjuvant) and stage IV (metastatic disease) Possible benefit for patients with stage II diseasePossible benefit for patients with stage II disease New treatments based on enhanced knowledge of biology and genetics of colon cancer New treatments based on enhanced knowledge of biology and genetics of colon cancer New treatments in the context of clinical trialsNew treatments in the context of clinical trials Can we afford any of this new stuff?Can we afford any of this new stuff? Colon cancer is a curable disease Colon cancer is a curable disease

29. Questions? Questions? dnikcevich@smdc.org dnikcevich@smdc.org