1. CARCINOMA COLON AND IT’S MANAGEMENT Dr. Manoj Kumar B. Moderator: Dr. R. Kapoor 30.10.08

4. Ascending Colon 4% Transverse Colon 8% Descending Colon 14% Sigmoid Colon 35.7% Rectum 39%

7. CARCINOGENESIS: Adenoma to Carcinoma Pathway APC Loss/mutation Ch. 5q Normal Epithelium Early Adenoma Cancer Hyper- proliferation Intermediate Adenoma Late Adenoma K-ras Mutation Ch. 12p (50%) DCC loss Ch. 18q DPC4 Ch. 4 p53 Loss Ch. 17p Loss of DNA methylation

22. AJCC/ UICC STAGING

33. Stage Mean 5 yr survival rate (%) T 1 N 0 97 T 2 N 0 90 T 3 N 0 78 T 2 N + 74 T 4 N 0 63 T 3 N + 48 T 4 N + 38

36. Failure pattern following curative surgery Series Stage n LF (%) Abdominal failure (%) Distant failure(%) Gunderson et al All T3-4 and /or N1-2 91 72 22 17 4 6 7 7 Willet et al All T3-4 and /or N1-2 533 395 6 8 11 14 4 Minsky et al All T3-4 and /or N1-2 284 229 6 4 8 10 3 5

40. Caecum and proximal ascending colon

41. Mid ascending colon

42. Distal descending colon

43. Middle sigmoid colon adherent to left pelvic sidewall or proximal sigmoid

44. Distal ascending colon and hepatic flexure

45. Splenic flexure and proximal descending colon

46. Middle descending colon

47. Palliative - Sigmoid colon adherent to the UB

49. 5 yr Local/Regional failure (%) DFS (%) Group Stage N Surgery Sx+RT Surgery Sx+RT Adjuvant T3N0(B2) 163 10 9 70 72 T4N0(B2) 83 31 7 63 79 T3N1-2 (C2) 100 35 30 44 47 T4N1-2 (C3) 49 53 28 37 53 Perforation/fistula T4N0 21 48 6 43 91 Residual disease All 47 37

55. 5FU 370-400mg/m 2 + LCV 200mg/m 2 D 1 -D 5 x4 weeklyx6 cycles NCCTG/ NCI 3 yr survival (%) RFS(%) Gr 3 toxicity 5FU+LCV(Mayo)x 6 months 83.2 68.6 High PVI 5FU 200mg/ m 2 /d x 12 weeks 87.9 80 Less

58. MOSAIC Trial: LV5FU2 vs LV5FU2 + FOLFOX-4 LV5FU2 (n = 1,123) (%) FOLFOX-4 (n = 1,123) (%) 3 yr DFS stage III 66 72 3 yr DFS stage II 84 87 OS NA NA Grade 3-4 neutropenia 5 41 Neutropenic fever 0 1 Grade 3-4 diarrhea 0 1 Grade 3-4 vomiting 7 11 Neuropathy, any grade 0 92 Neuropathy, grade 3 0 12 Persistent neuropathy, grade 2-3, 1 year after t/t 0 5

59. Commonly Used Fluorouracil (5-FU) Regimens Regimen Reference Schedule Mayo clinic Poon et al., 1989 LV 20 mg/m 2 , followed by bolus 5FU, 425 mg/m 2 each daily d1-d5 repeated 4 weekly for 1 st 2 cycles, than q35d thereafter Roswell Park Haller et al., 1998 LV 500 mg/m 2 over 2 h; 5-FU 500 mg/m 2 bolus 1 h into LV infusion. weekly x 6 wks, every 8 wks Low-dose weekly LV., Jager et al., 1996 LV 20 mg/m 2 over 5-15 min, followed by bolus 5-FU 500 mg/m 2 ; weekly x 6 wks, every 8 weeks Protracted venous infusion Lokich et al., 1989 5-FU 300 mg/m 2 /day by continuous infusion AIO (weekly 24-h infusion) Kohne et al., 1998 LV 500 mg/m 2 over 2 h, followed by 5-FU 2,600 mg/m 2 over 24 h, weekly LV5FU2 de Gramont et al., 1997 LV 200 mg/m 2 over 2 h days 1, 2, followed by bolus 5-FU 400 mg/m 2 /day 1 and 2, f/b 5-FU 600 mg/m 2 over 22 h, day 1 and 2: every 14 days Simplified LV5FU2 Adapted from Andre et al., 1999 LV 400 mg/m 2 over 2 h, followed by bolus 5-FU 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 over 46-48 h; cycles repeated every 14 days

60. Commonly Used Irinotecan/5-FU Combination Regimens Regimen Study Schedule IFL Saltz et al; 2000 Irinotecan 125 over 90 min, followed by LV 20 mg/m 2 by brief infusion, followed by bolus 5-FU 500 mg/m 2 ; weekly for 4 weeks , repeated every 6 weeks FOLFIRI Douillard et al., 2000 Irinotecan 180 mg/m 2 over 2 h; LV 200 mg/m 2 concurrently with irinotecan (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 600 mg/m 2 infusion over 22 h. Irinotecan given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 days FOLFIRI (simplified) Andre et al., 1999 Irinotecan 180 mg/m 2 over 2 h; LV 400 mg/m 2 concurrently with irinotecan (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 infusion over 46-48 h. Cycle repeated every 14 days FUFIRI Douillard et al., 2000 Irinotecan 80 mg/m 2 , then LV 500 mg/m 2 , followed by 5-FU 2,300 mg/m 2 ; all drugs given weekly for 6 weeks, repeated every 7 weeks

61. Selected Commonly Used Oxaliplatin/5-FU Combination Regimens Regimen Study Schedule FOLFOX-4 de Gramont et al., 2000 Oxaliplatin 85 mg/m 2 over 2 h; LV 200 mg/m 2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 600 mg/m 2 infusion over 22 h. Oxaliplatin given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 days FOLFOX-6 Tournigand et al., 2004 Oxaliplatin 100 mg/m 2 over 2 h; LV 400 mg/m 2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 infusion over 46-48 h. Cycle repeated every 14 days Modified FOLFOX-6 (mFOLFOX-6) Widely used in current phase III trials, but not published Oxaliplatin 85 mg/m 2 over 2 h; LV 400 mg/m 2 concurrently with oxaliplatin (can be given in same line through Y connector); followed by 5-FU bolus 400 mg/m 2 , followed by 5-FU 2,400-3,000 mg/m 2 infusion over 46-48 h. Cycle repeated every 14 days FUFOX Grothey et al., 2002 Oxaliplatin 50 mg/m 2 over 2 h, followed by LV 500 mg/m 2 , followed by 5-FU 2,000 mg/m 2 over 24 h, weekly for 5 weeks, repeated every 6 weeks.

62. Single Agents: 5FU/Leucovorin (Mayo, Roswell, DeGramont)‏ Capecitabine Oxaliplatin Irinotecan Combinations: Oxaliplatin + 5FU (FOLFOX)‏ Irinotecan/5FU/Leuco (IFL, Saltz)‏ Irinotecan + 5FU (FOLFIRI)‏ Capecitabine + Oxaliplatin (Capox)‏ Capecitabine + Irinotecan (Capiri)‏ Chemotherapy in CRC

63. 5-Fluorouracil + Leucovorin (Mayo Clinic Schedule) NCCTG 5-FU: 425 mg/m2 IV on d1 – 5 LCV : 20 mg/m 2 IV on d1 – 5 before 5 - FU Repeat cycle every 4 – 5 weeks for a total of 6 cycles Oxaliplatin + 5-Fluorouracil + Leucovorin (FOLFOX4) Oxaliplatin: 85 mg/m 2 IV on day 1 5-Fluorouracil 400 mg/m 2 IV bolus, followed by 600 mg/m 2 IV continuous infusion for 22 hours on days 1 and 2 Leucovorin: 200 mg/m 2 IV on days 1 and 2 as a 2-hour infusion before 5-Fluorouracil Repeat cycle every 2 weeks Chemotherapy as adjuvant in CRC

66. Oxaliplatin + 5-Fluorouracil + Leucovorin (mFOLFOX7) Oxaliplatin: 100 mg/m 2 IV on day 1 5-Fluorouracil: 3000 mg/m 2 IV continuous infusion on days 1 and 2 for 46 hours Leucovorin: 400 mg/m 2 IV on day 1 as a 2-hour infusion before 5-fluorouracil Repeat cycle every 2 weeks Irinotecan + 5-Fluorouracil + Leucovorin (FOLFIRI Regimen) Irinotecan: 180 mg/m2 IV on day 1 5-Fluorouracil: 400 mg/m 2 IV bolus on day 1, followed by 2400 mg/m2 IV continuous infusion for 46 hours Leucovorin: 200 mg/m 2 IV on day 1 as a 2-hour infusion prior to 5-fluorouracil on days 1 – 5 administered before 5 - Fluorouracil Repeat cycle every 2 weeks Capecitabine Capecitabine: 1250 mg/m 2 PO bid on days 1 – 14 Repeat cycle every 21 days for a total of 8 cycles. Dose may be decreased to 850-1000 mg/m 2 PO bid on days 1-14 to reduce the risk of toxicity without compromising clinical efficacy Chemotherapy as adjuvant in CRC

67. Capecitabine + Oxaliplatin (XELOX) Capecitabine: 1000 mg/m 2 PO bid on days 1 - 14 Oxaliplatin: 130 mg/m 2 IV on day 1 Repeat cycle every 21 days. May decrease dose of capecitabine to 850 mg/m 2 PO bid and dose of oxalioplatin to 100 mg/m 2 IV to reduce the risk of toxicity without compromising clinical efficacy Capecitabine + Irinotecan (XELIRI) Capecitabine: 1000 mg/m 2 PO bid on days 1 - 14 Irinotecan: 250 mg/m 2 IV on day 1 Repeat cycle every 21 days. May decrease dose of capecitabine to 850 mg/m 2 PO bid and dose of irinotecan to 200 mg/m 2 IV to reduce the risk of toxicity without compromising clinical efficacy Chemotherapy as adjuvant in CRC

70. Targeted agents in CRC

73. Bevacizumab Anti – VEGF monoclonal antibody

75. E3200: Response Rates 0.7% 3.0% 9.2% 21.8% OR* 0 1.9% CR 29.1% 3.0% 230 Bevacizumab 45.0% 51.7% SD 8.5% 19.9% PR 271 271 FOLFOX4 FOLFOX4 + bevacizumab Giantonio BJ, et al. ASCO 2005 *FOLFOX+B vs FOLFOX: P < 0.0001

79. Cetuximab in EGFR expressing metastatic CRC: first line trials Hoehler T. et al. Proc ESMO 2004 Van Cutsem E. et al. Proc ESMO 2004 Reference 21% resection of livermetastases remarks 21 % 2% PD 24 % 17% SD 55 % 81% (74% conf.)‏ (61-88)‏ CR + PR (95% CI)‏ 38 43 Total patients FUFOX + cetuximab FOLFOX + cetuximab

80. FOLFIRI 5-FU bolus 400 mg/m 2 , infusion 2400 mg/m 2 + Irinotecan 180 mg/m 2 + Leucovorin 400 mg/m 2 every 2 wks (n = 609) Patients with previously untreated EGFR-expressing metastatic colorectal cancer, stratified by geographical region, ECOG PS (N = 1217)‏ FOLFIRI + Cetuximab 5-FU bolus 400 mg/m 2 , infusion 2400 mg/m 2 + Irinotecan 180 mg/m 2 + Leucovorin 400 mg/m 2 every 2 wks Cetuximab 400 mg/m 2 initial dose, then 250 mg/m 2 wkly (n = 608)‏ Van Cutsem E, et al. ASCO 2007. Abstract 4000. CRYSTAL Trial FOLFIRI ± Cetuximab

83. NORMAL CXR RISING CEA COLONOSCOPY FDG-PET CECT

86. THANK YOU