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Overview of Colorectal Cancer, Recent Studies, and Trial Design

Overview of Colorectal Cancer, Recent Studies, and Trial Design. John S. Macdonald, MD Saint Vincent’s Comprehensive Cancer Center. Cancer Incidence/Death. Incidence Death Total (all cancers) 1,220,100 552,200 GI cancers Large bowel 133,600 56,200 Pancreas 28,300 28,200

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Overview of Colorectal Cancer, Recent Studies, and Trial Design

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  1. Overview of Colorectal Cancer, Recent Studies, and Trial Design John S. Macdonald, MD Saint Vincent’s Comprehensive Cancer Center

  2. Cancer Incidence/Death • IncidenceDeath • Total (all cancers) 1,220,100 552,200 • GI cancers • Large bowel 133,600 56,200 • Pancreas 28,300 28,200 • Stomach 21,500 13,000 • Liver 15,300 13,800 • Esophagus 12,300 12,100 • Biliary 6,900 3,400 Greenlee RT, et al. Cancer Statistics 2000. CA: A Journal for Clinicians. 2000;50:7-33.

  3. Colorectal Cancer Etiology Population risk: Lifestyle Dietary Personal risk: Genetic Prevention: Long-term dietary modification Medical model: NSAIDs/ASA/others APC FNPCC

  4. Genetic Alterations Most Commonly Associated With Colorectal Cancer • Dominant oncogenes • •c-src • K-ras • C-myc • Tumor suppressor genes • MCC (mutated in colorectal cancer) • DCC (deleted in colorectal cancer) • APC (adenomatosis polyposis coli) • p53 • DNA repair genes • MSH2 • Prognosis • MSI

  5. Phase III Study Colon Cancer R A N D O M CPT-11 5-FU Leucovorin (222 cases) 5-FU Leucovorin (221 cases) CPT-11 (223 cases) 683 Advanced Colon Cancer Cases Saltz, et al. NEJM 2000;343:905.

  6. Phase III Colon Cancer ToxicityGr 3 RegimenCasesRRPFSDiarrheaMucositisANC Survival (N) (%) (%) (%) (%) (months) CPT-11/ 5-FU/LV 231 39* 7.0** 22 2.2 54 14.8 *** 5-FU/LV 226 21 4.3 13 16.9 66 12.6 CPT-11 226 18 4.2 31 2.2 31 12.0 * P<0.001 ** P =0.004 *** P =0.04 Saltz, et al. NEJM 2000;343:905.

  7. Colorectal CancerCurrent Adjuvant Study R A N D O M 5-FU 500 mg/m2 Leucovorin 500 mg/m2 weekly x6 followed by 2 weeks rest (4 cycles=32 weeks) 5-FU 500 mg/m2 Leucovorin 20 mg/m2 CPT-11 125 mg/m2 weekly x4 followed by 2 weeks rest (5 cycles=30 weeks)

  8. Structure Water-soluble platinum derivative with an oxalato ligand and a 1,2-diaminocyclohexane (DACH) carrier The DACH carrier ligand can exist in 3 stereochemical conformations: oxaliplatin (I-OHP) Pt(oxalato)(trans-I-dach) Pt(oxalato)(1R,2R-dach) MW 397.3

  9. Colorectal Cancer • De Gramont survival and response Survival PFS Response (Months) (Months) (%) 5-FU/Leucovorin 14.7 6.0 28.6 5-FU/Leucovorin/ Oxaliplatin 16.2 8.2 49.5 P=0.0003 P=0.0001 P=NS De Gramont, et al.: JCO 2000;18:2968.

  10. ARM 1 Leucovorin 500 mg/m2/2 hours 5FU 500 mg/m2 bolus 1 hour into leucovorin (GITSG schedule) Weekly, 6 weeks/8 Total of 3 cycles ARM 2 5FU/leucovorin Same as Arm 1 Weeks 1 though 6 of 8 Oxaliplatin 85 mg/m2 Weeks 1, 3, and 5 Total of 3 cycles NSABP C07

  11. Oral Fluorinated Pyrimidines Advantages Oral Route Pharmacokinetics Radiation Sensitization

  12. Oral Fluorinated Pyrimidines UFT 5-FU/776 S-1 Capecitabine 5'-deoxy-5-fluorouridine DPD inhibition Prodrugs

  13. Updated Survival HR*: 0.96 (95.6%; CI=0.83-1.13) * Ratio 5-FU/LV:UFT/LV

  14. Phase III Study Capecitabine Response RegimenCasesPRDurationPFSSAE (N) % months months % Capecitabine 2500 mg/m2/d 26.6 x14 days 301 (2.3% CR) 7.3 5.3 12.5 5-FU/LV Mayo 17.9 Regimen 301 (2.3% CR) 9.6 4.8 17.7 Twelves, et al.Proc ASCO. 1999;18:263.

  15. COLORECTAL CANCER 2000 Cusp of the future Cyanides Arsenicals Heavy metals ID - 1900 Penicillin Tumor suppressor gene products EGFR Anti-angiogenesis Anti-RAS Anti-sense Gene Rx XRT Alkylators Antimetabolites Oncology - 2000

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