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
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
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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
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
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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
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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.
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
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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