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: 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. Normal colonic epithelium Dysplastic aberrant crypt foci Initial adenoma develops Intermediate adenoma Late adenoma Carcinoma Metastasis Mutation in APC Mutation in K-ras Mutation in DCC Mutation in p53 Other alteration? EGFR & VEGF

4. Who Should Receive Adjuvant Therapy? 1. Staging System: 60 m30 m0 monthStage % Survival 93.296.1100I 84.791.0100IIa 72.280.2100IIb 83.491.4100IIIa 64.177.3100IIIb 52.367.1100IIIc 43.057.3100IIId 26.843.1100IIIe 8.117.3100IV 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. LNs = > 12

5. Who Should Receive Adjuvant Therapy? 2. Mesentric Nodules: (Contour Role): T-StageN-Stage 1.V1 (micro). 2.V2 (macro) Isolated Tumor Cells & Micrometastases 0 – 0.2 mm (N0) 0.2 – 2 mm (N1mi) Stage III Not IV 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. Who Should Receive Adjuvant Therapy? 3. Peritoneal Minimal Residual Disease:  1/5 : Peritoneal Minimal Residual Disease.  1/7 : Peritoneal Carcinomatois.  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

11. Accepted Standards of Care: Stage III Colon Cancer Stage III Colon Cancer Patients 5- Fu/Leucovorin Mayo ClinicRoswell ParkDe Gramont Lower Toxicity Profile & Better Compliance NSABP Co1-6 IMPACT NCCTG NCIC-CTG 30%

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

13. Adjuvant FOLFOX4 in Stage II-III Colon Cancer: MOSAIC Study Schema de Gramont A, et al. ASCO 2007. Abstract 4007. FOLFOX4 Leucovorin 200 mg/m 2 IV + 5-FU 400 mg/m 2 bolus + 5-FU 600 mg/m 2 IV over 22 hrs + Oxaliplatin 85 mg/m 2 IV (n = 1123) LV5FU2 Leucovorin 200 mg/m 2 IV + 5-FU 400 mg/m 2 bolus + 5-FU 600 mg/m 2 IV over 22 hrs (n = 1123) Patients with previously untreated, completely resected stage II-III colon cancer (N = 2246)

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

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

16. 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.

17. No Significant Survival Advantage for The Following Groups:  Stage II Disease.  Stage III Disease: 1.Female Sex. 2.> 65 Years old. 3.T4 Tumors. 4.N1 Disease. 5.Poorly Differentiated Tumors. 6.CEA > 5. 7.Vascular Invasion. Final MOSAIC Results (cont’d) J Clin Oncol. 2009,27:3109-3116 J Clin Oncol, Vol 27, No 19 (July 1), 2009: pp 3082-3084

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: J Clin Oncol.2009,27:3117-3125

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

21. 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

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

23. X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer Primary endpoint: non-inferiority in DFS Secondary endpoint: OS Bolus 5-FU/LV 5-FU 425mg/m 2 + LV 20mg/m 2 days 1–5 q4w Capecitabine 1,250mg/m 2 b.i.d. days 1–14 q3w Chemonaïve stage III resection  8 weeks n=1, 004 n=983 RANDOMISATIONRANDOMISATION Data cut-off: January 2007 b.i.d. = twice daily Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

24. X-ACT: Xeloda (capecitabine) Adjuvant Chemotherapy Trial of stage III colon cancer Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB) 5-year DFS (%) Capecitabine 1, 004 60.8 5-FU/LV983 56.7 1.0 0.8 0.6 0.4 0.2 0 0642487896 Months HR=0.88 (95% CI: 0.77–1.01) NI margin 1.20 1218243036546066728490 ITT population Estimated probability 102 n Test of non-inferiority p<0.0001 Test of superiority p=0.0682

25. X-ACT: 5-year OS (median follow-up 6.8 years) HR=0.86 (95% CI: 0.74–1.01) NI margin 1.14 06424878961218243036546066728490102 1.0 0.8 0.6 0.4 0.2 0 Estimated probability Test of non-inferiority p=0.000116 Test of superiority p=0.06 5-year OS (%) Capecitabine 1, 004 71.4 5-FU/LV983 68.4 n 0642487896 Months 1218243036546066728490102 Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

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

27. X-ACT and MOSAIC: projection of OS in stage III patients ITT population Estimated probability 0246802468 1.0 0.8 0.6 0.4 Years X-ACT 1 Bolus 5-FU/LV (n=983) Capecitabine (n=1,004) MOSAIC 2 LV5FU2 (n=675) FOLFOX (n=672) 1 Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB) 2 De Gramont A, et al. J Clin Oncol 2007;25:(Suppl. 18):165s (Abstract 4007) Estimated probability 1.0 0.8 0.6 0.4 Years 0246802468

28. Chemo/ radiotherapy-naïve stage III colon cancer Bolus 5-FU/LV Mayo Clinic or Roswell Park CAPOX Capecitabine 1,000mg/m 2 b.i.d. days 1–15 Oxaliplatin 130mg/m 2 day 1 q3w Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23 CAPOX: a new option in the adjuvant setting:  Primary endpoint: disease-free survival n=944 n=942 RANDOMISATIONRANDOMISATION

29. Grade 3/4 adverse events Patients (%) CAPOX 1 (n=938) FOLFOX4 2 (n=1,108) FLOX 3 (n=1,200) Cross-trial comparison *Not reported Neutropenia Nausea Stomatitis Diarrhoea Febrile neutropenia HFS Vomiting Neurosensory 1 Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034) 2 André T, et al. N Engl J Med 2004;350:2343–51 3 Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500) * Adjuvant CAPOX: favourable toxicity compared with FOLFOX and FLOX: ** 50 40 30 20 10 0

30. Newly Emerged Strategies: Stage III Colon Cancer: NSABP-C0 - 6: 1608 pts UFT5-Fu/LV DFS OAS 66.9%68.3% 78.7% Similar Toxicity Profile

31. Targeted Therapy in The Adjuvant Sitting EGFRHER 2 HER 3 HER4

32. Stages at which angiogenesis plays a role in tumor progression Premalignant stage Malignant tumor Tumor growth Vascular invasion Dormant micrometastasis Overt metastasis Avascular tumor Angiogenic switch Vascularized tumor Tumor cell intravasation Seeding in distant organs Secondary angiogenesis Angiogenesis Is Involved Throughout Tumor Growth and Metastasis Poon RT, et al. J Clin Oncol. 2001;19:1207-1225. Reproduced with permission from the American Society of Clinical Oncology.

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

34. Important adjuvant capecitabine/ bevacizumab-based combination trials 20042005200620072008200920102011 XELOXA final safety XELOXA 1° efficacy XELOXA survival follow-up QUASAR-2 1° efficacy AVANT 1° efficacy NSABP C-08 1° efficacy

35. NSABP Protocol C-08: mFOLFOX ± Bevacizumab in Stage II/III CRC Wolmark N, et al. ASCO 2009. Abstract LBA4. Arm A: mFOLFOX6 Q2W x 26 (n = 1356) Arm B: mFOLFOX6 + Bevacizumab 5 mg/kg Q2W x 26 (n = 1354) Pts with stage II or III colon adenocarcinoma with ECOG PS of 0/11 (N = 2710)  Pts stratified by number of positive lymph nodes and randomized between Days 29 and 50 postoperatively  mFOLFOX6 regimen: LV 400 mg/m 2 IV, 5-FU 400 mg/m 2 IV, 5-FU 2400 mg/m 2 over 46 hours; oxaliplatin 85 mg/m 2 IV  Primary endpoint: DFS

36. NSABP Protocol C-08: 3-Yr DFS Results: Wolmark N, et al. ASCO 2009. Abstract LBA4. DFS (%) Yrs 0 20 40 60 80 100 00.51.01.52.02.53.03.5 HR: 0.89 (P =.15) mFF6 + B mFF6 Events 291 312 3-Yr DFS 77.4 75.5

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

38. Stage II Disease: Stage IIStage IIIStage IIStage IIIStage II Stage IIIStage II Stage III

39. 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.

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

41. Stage II Colon Cancer: NSABP C 01, 02, 04, 06 (1851 Pts) 5 Reference Genes 7 Recurrence Genes 6 Treatment Benefit Genes QUASAR Study (1436/3239 Pts) Surgery Surgery + 5- Fu/LV Kerr D, et al. ASCO 2009. Abstract 4000.

42. Clinical or Pathologic VariableHR (95% CI)P Value MMR (deficient vs proficient)0.32 (0.15-0.69)<.001 Tumor stage (T4 vs T3)1.83 (1.23-2.75).005 Tumor grade (high vs low)0.62 (0.40-0.96).026 Number of nodes examined (< vs ≥ 12)1.47 (1.01-2.14).040 LVI (present vs absent)1.40 (0.88-2.23).175 Recurrence score (continuous, per 25 units)1.61 (1.13-2.29).008 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.

43. Prognostic Value of CRC Biomarkers: Translational Study on PETACC 3 Roth AD, et al. ASCO 2009. Abstract 4002.  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).

44. Translational Study on PETACC 3: Results: Strong effect in stage II, decreases in stage III disease Parameter, %HR95% CIP Value Both stage II and III (N = 1233)  RFS0.5690.400-0.811.0018  OS0.5480.357-0.842.006 Stage II (n = 391)  RFS0.2650.107-0.661.0044  OS0.1590.039-0.659.011 Stage III (n = 842)  RFS0.6930.473-1.02.06  OS0.6990.446-1.09.12 Roth AD, et al. ASCO 2009. Abstract 4002.

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

47. 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.