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Therapeutic Strategies in Adjuvant Therapy of Colon Cancer

Therapeutic Strategies in Adjuvant Therapy of Colon Cancer. Mohamed Abdulla (M.D.) Prof. of Clinical Oncology, Kasr El-Aini School of Medicine, Cairo University. 01/04/2010. Colon Cancer; Challenging Issues:. Better Understanding of the Molecular Events.

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Therapeutic Strategies in Adjuvant Therapy of Colon Cancer

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  1. Therapeutic Strategies in Adjuvant Therapy of Colon Cancer Mohamed Abdulla (M.D.) Prof. of Clinical Oncology, Kasr El-Aini School of Medicine, Cairo University. 01/04/2010

  2. Colon Cancer; Challenging Issues: • Better Understanding of the Molecular Events. • Better Characterization of Prognostic Groups. • Diagnosis in Younger Age Groups with Aggressive Behavior. • Introduction of Pharmaceuticals Other Than Fluoropyremidines. • Introduction of Targeted Therapies.

  3. The Adenoma-Carcinoma Process: Normal colonic epithelium Mutation in APC Dysplastic aberrant crypt foci Initial adenoma develops Mutation in K-ras Intermediate adenoma Mutation in DCC Late adenoma Mutation in p53 Carcinoma Other alteration? EGFR & VEGF Metastasis Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998:565-87. Vogelstein B, et al. N Engl J Med. 1988;319:525-532. Fearon ER, et al. Cell. 1990;61:759-767.

  4. Who Should Receive Adjuvant Therapy?1. Staging System: LNs = > 12 O’ConnellJB, Maggard MA, Ko CY: Colon Cancer Survival Rates with The New American Joint Committee on Cancer, Sixth Edition Staging. J Natl Cancer Inst 2004;96:1423.

  5. Who Should Receive Adjuvant Therapy?2. Mesentric Nodules: (Contour Role): T-Stage N-Stage Stage III Not IV • V1 (micro). • V2 (macro) • Isolated Tumor Cells & Micrometastases • 0 – 0.2 mm (N0) • 0.2 – 2 mm (N1mi) Cancer 2008;112:50–4.

  6. Who Should Receive Adjuvant Therapy?3. Peri-neural Invasion:An Under-Estimated Variable: 15 – 25% JCO.2009.22.4949

  7. 1/5 : Peritoneal Minimal Residual Disease. 1/7 : Peritoneal Carcinomatois. Who Should Receive Adjuvant Therapy?3. Peritoneal Minimal Residual Disease: • Surgical Techniques. • Intraperitoneal & Intraportal Chemotherapy. • HIPEC. • Prevention of The Inflammatory Response. thelancet.com/oncology Vol 10 January 2009

  8. Who Should Receive Adjuvant Therapy?4. Age Factor: Bouvier et al, CANCER August 15, 2008 / Volume 113 / Number 4

  9. Who Should Receive Adjuvant Therapy?5. Timing of Chemotherapy Initiation: Hershman et al, CANCER December 1, 2006 / Volume 107 / Number 11

  10. Accepted Standards of Care:Stage III Colon Cancer NSABP Co1-6 IMPACT NCCTG 30% NCIC-CTG Lower Toxicity Profile & Better Compliance

  11. Chemotherapeutics Other Than Fluoropyremidines:Stage III Colon Cancer: Oxaliplatin Capecitabine • Effectiveness. • Comparable Toxicity Profiles Irinotecan UFT

  12. Adjuvant FOLFOX4 in Stage II-III Colon Cancer: MOSAIC Study Schema FOLFOX4 Leucovorin 200 mg/m2 IV +5-FU 400 mg/m2 bolus + 5-FU 600 mg/m2 IV over 22 hrs + Oxaliplatin 85 mg/m2 IV (n = 1123) Patients with previously untreated, completely resected stage II-III colon cancer (N = 2246) LV5FU2 Leucovorin 200 mg/m2 IV +5-FU 400 mg/m2 bolus +5-FU 600 mg/m2 IV over 22 hrs (n = 1123) de Gramont A, et al. ASCO 2007. Abstract 4007.

  13. MOSAIC Study: 6-Y OAS; by Treatment Arm: J Clin Oncol. 2009,27:3109-3116

  14. MOSAIC Study: 6-Y OAS; by Treatment Arm & Stage: J Clin Oncol. 2009,27:3109-3116

  15. Final MOSAIC Results (cont’d) • Rate of peripheral sensory neuropathy decreased over time • At 4 yrs • Grade 1: 12.0% • Grade 2: 2.8% • Grade 3: 0.7% • Neutropenia ≥ grade 3 in 41.0% of patients receiving FOLFOX4 vs 4.7% of patients receiving LV5FU2 • Febrile neutropenia in 1.8% of patients receiving FOLFOX4 de Gramont A, et al. ASCO 2007. Abstract 4007.

  16. Final MOSAIC Results (cont’d) • No Significant Survival Advantage for The Following Groups: • Stage II Disease. • Stage III Disease: • Female Sex. • > 65 Years old. • T4 Tumors. • N1 Disease. • Poorly Differentiated Tumors. • CEA > 5. • Vascular Invasion. J Clin Oncol. 2009,27:3109-3116 J Clin Oncol, Vol 27, No 19 (July 1), 2009: pp 3082-3084

  17. Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study: J Clin Oncol.2009,27:3117-3125

  18. Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study: J Clin Oncol.2009,27:3117-3125

  19. Role of Irinotecan in Adjuvant Treatment of Stage III Colon Cancer PETACC-3 Study: After Exclusion of Cases Developed Second Primary in Both Arms J Clin Oncol.2009,27:3117-3125

  20. Oxaliplatin Versus Irinotecan: • Equivalent PFS in Head to Head Comparison in Metastatic Sitting. • Biological Alteration in Metastatic or Recurrent Disease (Topoisomerase I). J Clin Oncol.2005, 23:4866-4875

  21. Capecitabine mode of action:TP-activation – proof of concept at last? Intestine Liver Capecitabine Tumor >> healthy tissue Capecitabine CE 5'-DFCR 5'-DFCR CyD CyD 5'-DFUR 5'-DFUR Thymidine phosphorylase (TP) 5-FU 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase

  22. X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer RANDO MIS ATION Capecitabine 1,250mg/m2 b.i.d. days 1–14 q3w n=1,004 Chemonaïve stage IIIresection 8 weeks Bolus5-FU/LV 5-FU 425mg/m2 + LV 20mg/m2days 1–5 q4w n=983 • Primary endpoint: non-inferiority in DFS • Secondary endpoint: OS Data cut-off: January 2007 b.i.d. = twice daily Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

  23. X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer 5-year DFS (%) Capecitabine 1,004 60.8 5-FU/LV 983 56.7 1.0 0.8 0.6 0.4 0.2 0 n Estimated probability HR=0.88 (95% CI: 0.77–1.01) NI margin 1.20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months Test of non-inferiority p<0.0001 Test of superiority p=0.0682 ITT population Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

  24. X-ACT: 5-year OS (median follow-up 6.8 years) n 5-year OS (%) Capecitabine 1,004 71.4 5-FU/LV 983 68.4 1.0 0.8 0.6 0.4 0.2 0 Estimated probability HR=0.86 (95% CI: 0.74–1.01) NI margin 1.14 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months Test of non-inferiority p=0.000116 Test of superiority p=0.06 Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

  25. X-ACT: 5-year OS (median follow-up 6.8 years) Grade 3/4 adverse events 50 40 30 20 10 0 Capecitabine (n=993) 5-FU/LV (n=974) Patients (%) * * * * HFS Nausea/vomiting Diarrhoea Stomatitis Febrileneutropenia Neutropenia *p<0.001HFS = hand foot syndrome Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

  26. Capecitabine (n=1,004) FOLFOX (n=672) Bolus 5-FU/LV (n=983) LV5FU2 (n=675) X-ACT and MOSAIC: projection of OS in stage III patients X-ACT1 MOSAIC2 1.0 0.8 0.6 0.4 1.0 0.8 0.6 0.4 Estimated probability Estimated probability 0 2 4 6 8 0 2 4 6 8 Years Years 1Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB) 2De Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007) ITT population

  27. CAPOX: a new optionin the adjuvant setting: RANDO MIS ATION CAPOX Capecitabine 1,000mg/m2 b.i.d. days 1–15 Oxaliplatin 130mg/m2 day 1 q3w n=944 Chemo/radiotherapy-naïve stage III colon cancer Bolus 5-FU/LVMayo Clinic or Roswell Park n=942 • Primary endpoint: disease-free survival Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23

  28. Adjuvant CAPOX: favourable toxicity compared with FOLFOX and FLOX: 50 40 30 20 10 0 Grade 3/4 adverse events CAPOX1 (n=938) FOLFOX42 (n=1,108) FLOX3 (n=1,200) Patients (%) * * * HFS Nausea Vomiting Febrileneutropenia Diarrhoea Stomatitis Neutropenia Neurosensory 1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)2André T, et al. N Engl J Med 2004;350:2343–51 3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500) Cross-trial comparison *Not reported

  29. Newly Emerged Strategies:Stage III Colon Cancer:NSABP-C0 - 6: 1608 pts UFT 5-Fu/LV DFS 66.9% 68.3% 78.7% OAS 78.7% Similar Toxicity Profile

  30. EGFR HER2 HER3 HER4 Targeted Therapy in The Adjuvant Sitting

  31. Angiogenesis Is Involved Throughout Tumor Growth and Metastasis Premalignantstage Malignanttumor Tumorgrowth Vascularinvasion Dormantmicrometastasis Overtmetastasis Avasculartumor Angiogenicswitch Vascularizedtumor Tumor cellintravasation Seeding indistant organs Secondaryangiogenesis Stages at which angiogenesis plays a role in tumor progression Poon RT, et al. J Clin Oncol. 2001;19:1207-1225. Reproduced with permission from the American Society of Clinical Oncology.

  32. Trials of bevacizumab/capecitabine/Oxaliplatin in the adjuvant setting

  33. Important adjuvant capecitabine/bevacizumab-based combination trials AVANT 1° efficacy NSABP C-08 1° efficacy QUASAR-2 1° efficacy XELOXA survival follow-up XELOXA 1° efficacy XELOXA final safety 2004 2005 2006 2007 2008 2009 2010 2011

  34. NSABP Protocol C-08: mFOLFOX ± Bevacizumab in Stage II/III CRC Arm A: mFOLFOX6 Q2W x 26 (n = 1356) Pts with stage II or III colon adenocarcinoma with ECOG PS of 0/11 (N = 2710) Arm B: mFOLFOX6 + Bevacizumab 5 mg/kg Q2W x 26 (n = 1354) • Pts stratified by number of positive lymph nodes and randomized between Days 29 and 50 postoperatively • mFOLFOX6 regimen: LV 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-FU 2400 mg/m2 over 46 hours; oxaliplatin 85 mg/m2 IV • Primary endpoint: DFS Wolmark N, et al. ASCO 2009. Abstract LBA4.

  35. NSABP Protocol C-08: 3-Yr DFS Results: 100 80 60 DFS (%) 40 Events291312 3-Yr DFS77.475.5 mFF6 + BmFF6 HR: 0.89 (P = .15) 20 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Yrs Wolmark N, et al. ASCO 2009. Abstract LBA4.

  36. Anti-EGFR in Adjuvant ttt of Stage III Colon Cancer: • Study Duration: 11/05  11/11. • DFS, OAS & Safety. • FOLFOX4+Cetuximab vs FOLFOX4. • ??

  37. Stage II Disease: Stage II Stage II Stage II Stage II Stage II Stage III Stage III Stage III Stage II Stage III

  38. Issues to Be Considered: • 75 – 80% are cured with surgery alone. • No current method to identify the subset of patients at higher risk of recurrence. • Minimal benefit of adding chemotherapy. • The associated significant morbidity.

  39. Stage II Colon Cancer: QUASAR STUDY, 2004 Surgery Surgery + 5-Fu/LV 3300 PTS 5% OAS 5% OAS 5% OAS 5% OAS 1% Mortality 1% Mortality

  40. Stage II Colon Cancer: Kerr D, et al. ASCO 2009. Abstract 4000.

  41. Stage II Colon Cancer:QUASAR Validation Results: • Recurrence score (per 25 units) predictive of DFS and OS • DFS HR: 1.42 (95% CI: 1.09-1.84; P = .010) • OS HR: 1.33 (95% CI: 1.01-1.76; P = .041) • No significant differences in treatment score by treatment interaction in OS, DFS, or relapse-free interval Kerr D, et al. ASCO 2009. Abstract 4000.

  42. Prognostic Value of CRC Biomarkers: Translational Study on PETACC 3 • Study designed to compare the incidence of molecular biomarkers in pts with stage II/III CRC in the PETACC 3 trial (N = 3278). • Frequency of MSI-H significantly higher in stage II (22%) vs stage III (12%) disease (P < .0001). • Higher frequency of MSI detected in N0 tumors compared with N1 or N2 (P < .0001). • Higher tumor stage correlated with increased frequency of MSI (T1/T2 vs T3 vs T4) (P = .037). Roth AD, et al. ASCO 2009. Abstract 4002.

  43. Translational Study on PETACC 3: Results: Strong effect in stage II, decreases in stage III disease Roth AD, et al. ASCO 2009. Abstract 4002.

  44. Stage II Colon Cancer:Preoperative CEA Level: Journal of Surgical Oncology 2009;99:65–70

  45. Keep in Mind: • Number of LNs > 12. • Timing: 4-8 wks. • Age. • Molecular Markers. • 5-Fu/LV is the Backbone. • Stage II Disease: Better Assessment. • Stage III Disease: MOSAIC & X-ACT. • The Role of Adjuvant Targeted Therapy.

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