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CES 2016 02 - Colorectal cancer
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S., with various genetic and environmental risk factors influencing its development. The document discusses the multistep molecular evolution of CRC, emphasizing the importance of screening and understanding polyps, heredity, and treatment strategies based on cancer staging. It outlines the clinical management for different stages of CRC, including surgical interventions and chemotherapy regimens to improve patient outcomes.
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CES 2016 02 - Colorectal cancer
- 1. CES 2016.02: LowerGastrointestinal Cancers Mauricio Lema Medina MD
- 2. Mauricio Luján Piedrahíta,MD Acknowledgments
- 3. Second cause ofcancer death in the US The incidence has decreased recently (in the US) due to screening Mortality has decreased by about 25% POLYPS Grossly visible protrusion fro the mucosal surface Nonneoplastic hamartoma Hyperplastic mucosal proliferation (hyperplastic polyp) Adenomatous polyps Clearly preneoplastic Only a minority of polyps progress to cancer High prevalence: 30% and 50% in middle-aged and elderly adults Only 1% become malignant Multistep molecular evolution through cancer Colon cancer is thought to arise from sequential DNA derrangements in a polyp These may include: Point mutations in the K-ras (KRAS) oncogene Hypomethylation of DNA Allelic loss of a TSG like 5q (APC), 18q (DCC), 17p (p53) Oncogene activation Loss of tumor suppression activity
- 4. Multi-stage carcinogenesis incolon cancer Inspired on: Vogelstein B, 1990
- 5. MAPK pathway (activating)mutations occur in about 60% CRC KRAS: 40-50% NRAS: 10% BRAF: 8%
- 6. POLYPS Pedunculated Flat-based: sessile Higherrisk of cancer development Tubular Villous Tubulovillous Higher risk of cancer development (3x) Small (1.5 cm, or less) Intermediate (1.5-2.5 cm) Substantial (2.5 cm, or more) (2-10% cancer risk) (10% cancer risk or more) The entire bowel should be visualized (1-3 risk of synchronous polyps). Follow-up with colonoscopies: 30-50% risk of another adenoma Adenomas become cancer in about 5 years Colonoscopy need not be more frequent than every 3 years Once a poly is found
- 7. Risk factors forthe development of colorectal cancer Diet: animal fat Hereditary syndromes Inflammatory bowel diseaseStreptococcus bovis bacteremia Upper socioeconomic populations Correlates with per capita consumption of calories, meat protein, dietary fat and oil, high cholesterol, high coronary artery disease Dietary fats change in the microbiome (anaerobes), converting bile-acids into carcinogens High-calorie intake / inactivity cause obesity: insulin resistance, increase in IGF-1, more polyps (and cancer) Fibers and vegetable intake have no been proven to prevent CRC development Up to 25% have a family history Polyposis coli MYH-associated polyposis Nonpolyposis syndromes (Lynch) More with ulcerative colitis Rare during first 10 years Thereafter: 1%/yr incidence Prophylactic colectomy for long active IBD For unknown reason Consider upper and lower GI endoscopies
- 8. Hereditary syndromes Polyposis coli Thousandsof adenomatous polyps through the large bowel Autosomal dominant Deletion of 5q Loss of the APC gene (a TSG) Gardner’s syndrome Soft-tissue and bony tumors Congenital hypertrophy of the retinal epithelium Mesenteric desmoid tumors Ampullary carcinomas Polyposis coli Turcot’s syndrome Malignant tumors of the Central Nervous system Polyposis coli Polyps are rare before puberty But are detectable in most by age 25 Cancer will develop in (almost) all by 40 Once multiple polyps develop, total colectomy must be performed Offspring of affected patients have 50% risk of disease Flexible sigmoidoscopy until 35 should be performed Germ-line APC mutation detection should be considered
- 9. Hereditary syndromes Hereditary nonpolyposiscolon cancer (HNPCC) - Lynch’s syndrome Three or more relatives with documented colorectal cancer; one who is a first-degree relative of the other two; CRC before 50 in at least one; Spanning at least 2 generations. Autosomal dominant Median-age at CRC diagnosis: less than 50 Screening colonoscopy starting on age 25 (q1 to 2 years), with pelvic US/endometrial biopsy for women Poorly-differentiated Mucinous histologies Right-sided preference BETER PROGNOSIS Association with other malignancies (in the family) Ovarian or endometrial carcinomas in women Gastric, small-bowel, pancreaticobiliary, genitourinary cancers sebaceus skin tumors Lynch’s syndrome is associated with mutations of several genes hMSH2 (chromosome 2) hMLH1 (chromosome 3), and others Unable to repair DNA mismatches (MMR) High frequency of microsatellite instability
- 10. Colorectal cancer: presentingsymptoms Right-sided colon tumors May be very large without symptoms Iron-deficiency anemia is characteristic Left-sided tumors Abdominal cramping Intestinal obstruction Intestinal perforation Rectosigmoid tumors Hematochezia tenesmus narrowing of the caliber of stool (similar to hemorrhoids) Anemia is rare
- 11. CRC: Staging, prognosticfactors, and pattern of spread Harrison’s, 19th Ed. Predictors of poor outcome following total surgical resection in CRC Tumor spread to regional lymph nodes Number of lymph nodes involved Tumor penetration to through the bowel wall Poorly differentiated histology Perforation Tumor adherence to adjacent organs Venous invasion Preoperative CEA elevation Aneuploidy Specific chromosomal deletion (BRAF mutation, absence of MSI)
- 12. CRC: Staging, prognosticfactors, and pattern of spread Harrison’s, 19th Ed. Adenocarcinoma
- 13. CRC: Staging AJCC TNM,7th Ed, 2010
- 14. CRC: Staging AJCC TNM,7th Ed, 2010
- 15. CRC: Staging, prognosticfactors, and pattern of spread Harrison’s, 19th Ed. High-risk stage II T4 Perforation Obstruction Lymphovascular invasion non-R0 resection Less than 12 lymph nodes evaluated High-risk recurrence score (in MSS)
- 16. CRC: pattern ofspread Harrison’s, 19th Ed. Most recurrences occur within 4 years of surgery At least 12 lymph nodes need to be evaluated to establish prognosis TNM/Stage is prognostic Regional lymph nodes Supraclavicular lymph nodes Liver metastases Initial site of spread in 1/3 Involved at death in 2/3 Median survival of metastatic CRC is improving: about 2-3 years (2016)
- 17. CRC: Treatment Harrison’s, 19thEd. Pre-surgical work-up H&P Basic labs, including LFTs, CEA Thorax, abdomen and pelvis contrast-enhanced CT Full-length colonoscopy Surgery Colectomy with regional lymph-node dissection Total mesorectal excision for rectal cancer with regional lymph-node dissection At least 12 lymph-nodes need to be assessed Surgery in symptomatic patients, regardless of metastases Adequate surgical margins needed to avoid recurrence in the anastomotic site
- 18. CRC: Treatment Harrison’s, 19thEd. Colon cancer (non-rectal) Surgery Stage I Follow-up Low-Risk Stage II Follow-up High-Risk Stage II/Stage III Stage IVa Resectable Stage IVa Convertible Stage IVb Surgery ChemoT PalliativeCT Follow-up Follow-up Follow-up AdjChemoT Surgery AdjChemoT Surgery Surgery
- 19. CRC: Treatment Harrison’s, 19thEd. Adjuvant chemotherapy in colon cancer Ideally, start within 1 month of surgery, for 6 months Improves survival by 30% in stage III CRC patients May improve survival in high-risk stage II colon cancer patients Based on Fluorouracil (5-FU) Infusional 5-FU both more effective, and less toxic, than bolus Modulation with Folinate (Leucovorin, LV) improves outcomes Addition of Oxaliplatin improves DFS and OS in stage III patients (ie, FOLFOX) Unclear benefit of Oxaliplatin in stage II and older than 70 No benefit of adjuvant 5-FU alone in stage II patients with microsatellite instability
- 20. CRC: Treatment Harrison’s, 19thEd. Rectal cancer Surgery Stage I Follow-up Low-Risk Stage II Follow-up High-Risk Stage II/Stage III Stage IVa Resectable Stage IVa Convertible Stage IVb Surgery ChemoT PalliativeCT Follow-up Follow-up Follow-up AdjChemoT Surgery AdjChemoT Surgery Surgery ChemoRT ChemoRT ChemoRT ChemoRT Pelvic radiation (with radiosensitizing chemotherapy) decreases local- recurrence, but has no impact in overall survival in rectal cancer AdjChemoT
- 21. CRC: Treatment Harrison’s, 19thEd. Adjuvant chemotherapy in rectal cancer Ideally, start within 1 month of surgery, for 6 months Improves survival in stage II-III CRC patients Based on Fluorouracil (5-FU) Infusional 5-FU both more effective, and less toxic, than bolus Modulation with Folinate (Leucovorin, LV) improves outcomes Unclear benefit of Oxaliplatin in stage II and older than 70 Oxaliplatin reasonable in high-risk stage II rectal cancer (ie, FOLFOX) No benefit of adjuvant 5-FU alone in stage II patients with microsatellite instability
- 22. CRC: Treatment Harrison’s, 19thEd. Systemic therapy for metastatic CRC 5-FU-based (or Capecitabine) Each, oxaliplatin and irinotecan improve overall survival Bevacizumab increases overall survival in first- and second-line always with CT Other antiangiogenic agents can be used in second-line (aflibercept, ramicirumab) Anti-EGFR agents are active as single-agents and combination in unmutated RAS Left-sided colon cancer appear to derive greater benefit from anti-EGFR therapy Multikinase inhibitors may afford benefit after all other agents have been used With current therapies, median overall survival for metastatic CRC is abotu 39 mo
- 23. CRC: Clinical pathway- stage III colon cancer Screening Symptoms Colonoscopy / Biopsy Staging CT/CEA/labs Surgery 6 months adjuvant CT (ie, FOLFOX)
- 24. CRC: Clinical pathway- stage III colon cancer Screening Symptoms Colonoscopy / Biopsy Staging CT/CEA/labs Surgery 6 months adjuvant CT (ie, FOLFOX) CRC: Clinical pathway - Stage II/III rectal cancer Surgery 4-6 months adjuvant CT (ie, 5-FULV/FOLFOX) ChemoRT (ie, 5FU/LV)
- 25. CRC: Clinical pathway- stage III colon cancer Screening Symptoms Colonoscopy / Biopsy Staging CT/CEA/labs Surgery 6 months adjuvant CT (ie, FOLFOX) CRC: Clinical pathway - Stage II/III rectal cancer Surgery 4-6 months adjuvant CT (ie, 5-FULV/FOLFOX) ChemoRT (ie, 5FU/LV) CRC: Clinical pathway - Stage IVb CRC mutated RAS Bevacizumab FOLFIRI Bevacizumab FOLFOX Regorafenib
- 26. CRC: Clinical pathway- stage III colon cancer Screening Symptoms Colonoscopy / Biopsy Staging CT/CEA/labs Surgery 6 months adjuvant CT (ie, FOLFOX) CRC: Clinical pathway - Stage II/III rectal cancer Surgery 4-6 months adjuvant CT (ie, 5-FULV/FOLFOX) ChemoRT (ie, 5FU/LV) CRC: Clinical pathway - Stage IVb CRC mutated RAS Bevacizumab FOLFIRI Bevacizumab FOLFOX Regorafenib CRC: Clinical pathway - Stage IVb CRC mutated RAS Cetuximab FOLFIRI Bevacizumab FOLFOX Regorafenib
- 27. CRC: Follow-up Harrison’s, 19thEd. Post-treatment follow-up 3-5% life-time risk of a second CRC, 15% risk of polyps 5-year follow-up H&P q12w x2-3 years. Thereafter, semi-annually until year 5 Triennial colonoscopy CEA q12w x2-3 years. Thereafter, semi-annually until year 5 Contrast-enhanced thorax, abdomen and pelvis CT q1yr until year 3
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