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Colon Cancer

Colon Cancer. Elshami Elamin, MD Medical oncologist central care cancer center www.cccaner.com wichita , ks - usa. COLORECTAL CANCER. >140,000 new cases each yr in the US 3 rd leading cause of death It is curable if detected early. HNPCC (Lynch syndrome). Lynch I:

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Colon Cancer

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  1. Colon Cancer Elshami Elamin, MDMedical oncologistcentral care cancer centerwww.cccaner.comwichita, ks- usa

  2. COLORECTAL CANCER • >140,000 new cases each yr in the US • 3rd leading cause of death • It is curable if detected early

  3. HNPCC (Lynch syndrome) • Lynch I: • No associated other cancers • Lynch II: • Associated with ovarian, uterine cancers • + ve Genetic test : Consider colectomy/TAH/BSO

  4. Familial adenomatouspolyposis (FAP) • Autosomal-dominant • 50% of pts will develop adenomas by age 15 and 95% by age 35. • Left untreated, 100% of pts will develop colorectal cancer. • Invasive cancer occurs at ~ 42Y. • The familial adenomatous polyposis coli (APC) gene localized to chromosome 5q21.

  5. Genetic Tests • HNPCC • COLARIS • FAP/AFAP • COLARIS AP

  6. SCREENING

  7. Work-up • Laboratory: • CBC, Iron profile • LFTs • CEA • Preoperative CT scan • Colon cancer: Adjacent organ invasion/Liver met

  8. PET Scan • Staging • Restaging • 91% sensitivity, ~ 100% specificity for pelvic disease (CT: 52%, 80%) • 95% sensitivity for liver disease (CT 74%)

  9. PET scan • NCCN: • PET only as a pre-op baseline if CT/US indicates potentially surgically curable M1. • Characterization of extent of potentially resectable disease

  10. Staging • Smooth metastatic nodules in pericolic or perirectal fat are considered LN mets (N1) • Irregular met nodules in peritumoral fat are considered vascular invasion • Minimum of 12 LN to accurately identify stage II

  11. TNM • Stage I: T1 (invade submucosa) A T2 (invade muscul propria) B1 • Stage II: T3 (invade through musc propria B2 into subserosa or nonperit. Tissue) T4 (perforate ves perit or B3 invade adjacent structure) • Stage III: N1 (1-3 pericolic/rectal) N2 (> 4) C N3 (along vascular trunk) • Stage IV: M1

  12. 5-Year Survival in CRC

  13. Advances In the management Of Colorectal Cancer

  14. Surgical treatment

  15. Polyps • Pedunculted polyp with invasive cancer (pT1): • single specimen + favorable features + clear margins • Observe • Fragmented, unfavorable features, unclear margins • Colectomy • Sessile polyp with invasive cancer (pT1): • single specimen + favorable features + clear margin • Observe or colectomy • Fragmented, unfavorable features, unclear margin • Colectomy

  16. Laparoscopic vs Conventional Colectomy • Barcelona trial (small trial): • Modest survival advantage of laparoscopic • COLOR trial (1248 pts): • 3Y DFS favor conventional • CLASSIC study (794 pt): • No difference in DFS or OS • COST study (872 pt): • No difference in 5Y recurrence, OS • Meta-analysis: • No difference in local recurrence or OS

  17. Laparoscopic Colectomy: NOT RECOMMENDED in case of: • Tumor in lower and mid rectum • Tumor acutely obstructed or perforated • T4 • Adhesions

  18. Regional LN • Need at least 12 LN to accurately identify stage II colorectal cancer (AJCC and College of American Pathologists) • The number of +ve lymph nodes correlates with survival • At the present time the use of sentinel LN and detection of cancer cells by IHC alone should be considered investigational

  19. SLN • Results are promising • No uniformity in the detection of true clinically relevant positive LN • It is investigational at the present time

  20. Positive margin • Presence of tumor within 1-2 mm from transected margin or within the diathermy margin

  21. Stage II-IIIAdj Therapy

  22. 5-FU • Thymidylate synthase inhibitors • Fluoropyrimidines • 5 days IVP regimen: • Mucositis, diarrhea, neutropenia • Wkly IVP regimen: • Diarrhea • CI regimen: • Hand-foot syndrome, mucositis • Diarrhea or neutropenia • High dose regimen 24-48hrs • Altered MS, angina-like chest pain

  23. New Drugs and Survival !!! • Capecitabine (Xeloda) • Oxaliplatin • Bevacizumab • Cetuximab • Panitumumab (Vectibix)

  24. Oxaliplatin-based Adj Therapy • MOSAIC trial (FOLFOX vs 5-FU/LV): • 2246 pts with stage II and III • 3, 4, and 6 yrs F/U • Stage III: 5Y DFS 66.4% vs 58.9% (P 0.005) • Stage II: 5Y DFS not sig. • Analysis of individual pt data from 20,898 pts on 18 randomized colon adj trials: • OS of stage III treated with FOLFOX sig increased at 6Y f/u (78.5% vs 76%) hazard ratio=0.80; 95% CI, 0.65-0.97; P=0.023

  25. NSABP C-07 (bolus FLOX vs bolus FU/LV): • 2407 pts with stage II, III • 4Y DFS 73.6% vs 67% (P=0.0034)

  26. IRINOTECAN-based Adj therapy • CALGB C89803: • Stage III colon ca • IFL vs 5-FU/LV • No improvement in DFS or OS • IFL: more neutropenia, fever, death • FOLFIRI: • not superior to 5-FL/LV

  27. Oral Fluoropyrimidine (5-FU) derivatives • Capecitabine (Xeloda). • Tegafur (under investigated in Europe and US).

  28. IV 5FU is the standard adjuvant therapy for CRC. Oral xeloda is at least as effective as IV 5FU in mCRC. Can Oral xeloda replace IV 5FU in adjuvant setting? X-ACT

  29. Adjuvant Oral Fluoropyrimidine Capecitabine (Xeloda) = IV 5-FU/L Convenient

  30. ANOTHER REASON Total Cost

  31. XELOX: a new standard of carein the adjuvant setting • XELOX significantly improves DFS and RFS compared with 5-FU/LV • Trend to superior overall survival • XELOX shows similar DFS benefit to FOLFOX4 in a cross-trial comparison With proven efficacy and a favourable safety profile, XELOX is a new standard of care in the adjuvant treatment of early colon cancer

  32. Adj chemo for Stage II colon cancer • Meta-analysis of 5 trials and practice-based studies: • Stage II and III treated with surgery +/- FU/LV • Most of benefits in stage III • Pooled data from 7 randomized trials: • FU/LV sig improves OS in N+, Not in N0 colon ca • SEER databases: • Stage II: Adjvs No Adj chemo • 5Y OS 78% vs 75% not sig • QUASAR adj FU/LV: • 3-4% OS benefit (small but sig)

  33. High Risk Stage II • G3-4 except MSI-H • Lymphatic/vascular invasion • Bowel obstruction • Localized perforation • Intermediate or positive margins • < 12 LNexamined • Perineural invasion • OncotypeDX (recurrence score >41)

  34. MicroSatellite Instability (MSI) • High MSI = deficient mismatch-repair phenotype (dMMR) = pood prognosis. • May not benefit from 5-FU, even could be harmful. • MMR testing for all pts < 50

  35. Stage II MMR status T3 & MMR-D (low risk) T3 & MMR-P (Standard risk) T4 & MMR-P (High risk) Consider observation OncotypeDX Consider chemo

  36. Following surgery NCCN panel recommends • 6 month of adj chemo for stage III (T1-4, N1-2, M0) • Options: • FU/LV/Oxal (standard) or • Capecitabine or FU/LV • No Irinotecan-based adj regimen • 5-FU-based chemo for high risk stage II: • T4, G3-4, lymphovasc inv, BO, localized perforation, close or +ve margins, <12LN • Subset from MOSAIC: No sig DFS benefit of FOLFOX over FU/LV in stage II (but trend for improved DFS in high risk stage II receiving FOLFOX)

  37. Adj RT for colon cancer • Consider concurrent RT with 5-FU for: • T4 tumor penetrating into a fixed structure • Locally recurrent disease

  38. Targeted therapies in adjuvant setting.

  39. CONCLUSION • Adjuvant Bevacizumab: • Did not prolong DFS • Failed to improve the cure rate of patients with resected colon cancer • Did not reach the goal of eradicating occult metastases

  40. SURVEILLANCE • H/P q 3 m for 2 y, then q 6 m for 3 y • CEA q 3 m for 2 y, then q 6 m for 3 y • Annual CT chest/abd/pelvis for high risk pts • Colonoscopy in 1 y: • repeat in 1 y if abnormal • Then q 2-3 y • If no preoperative colonoscopy: • colonoscopy in 3-6 mo.

  41. METASTATIC COLON CANCER

  42. Oral Fluoropyrimidine for mCRC.

  43. ConclusionsXELOX • XELOX is non-inferior to FOLFOX • XELOX and FOLFOX safety profiles are balanced • XELOX offers the advantage of oral fluoropyrimidine administration • XELOX is a good alternative to FOLFOX

  44. Oral Fluoropyrimidine for mCRC. Capecitabine (Xeloda) = IV 5-FU/L Convenient

  45. Targeted therapies in mCRC

  46. Bevacizumab (Avastin) (anti-VEGF)

  47. Conclusions “Bevacizumab” • 1st evidence from 1st line CRC phase III trial that bevacizumab adds • clinically meaningful • statistically superior benefit to oxaliplatin-based chemotherapy • Safety profile overall in line with previous trial experience in colorectal cancer • The outcome of this trial adds to the large body of evidence supporting the use of bevacizumab in combination with standard 1st line chemotherapy

  48. Cetuximab (Erbitux)Panitumumab (Vectibix) ANTI-EGFR THERAPY

  49. OPUS-CRYSTAL Meta-Analysis • Addition of cetuximab to chemotherapy showed PFS benefit in patients with wild-type KRAS • With > 90% of samples collected, addition of cetuximab reduced risk of disease progression by 34% (HR: 0.66; P < .001) • OS results showed an advantage for patients with wild‑type KRAS who received chemotherapy + cetuximab (HR: 0.81; P = .0062) Van Cutsem E, et al. ECCO/ESMO 2009. Abstract P-6077.

  50. K-RAS, BRAF • K-RAS mutations in codon 12 or 13 in exon 2 predict lack of response to anti-EGFR drugs • Wild type K-RAS respond • Consider doing BRAF when K-RAS is non-mutated • Wild type K-RAS and mutated BRAF unlikely respond to ant-EGFR therapy

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