Adjuvant Chemotherapy for Colorectal Cancer

1. Adjuvant Chemotherapy for Colorectal Cancer Ronald L. Burkes, M.D.

2. Historic Synopsis in the Treatment of Colorectal Cancer • 5-FU has anti-tumor activity 1958 • Biochemical modulation of 5-FU with LV 1989 • HAI with FUDR  RR 1993 • Responses seen post bolus 5-FU with • infusional 5-FU 1993 • Adjuvant CT (5-FU/Lev or 5-FU/LV) • for colon cancer 1994 • Adjuvant CT + RT for rectal cancer 1995 • New drugs - CPT-11/Tomudex/Oxaliplatin 1993-2002 • MTD – Cetuximab; Bevacizumab; 2000-2011 Panitumumab

3. Adjuvant Therapy for Stage II Colon Cancer: Yes, No and Maybe So

4. Why is the Situation in Stage II Colon Cancer Less Clear than Stage III • DFS and survival difference is small – relatively low activity of adjuvant treatment • High patient numbers required to show a difference • Stage II is a heterogeneous disease for Clinical factors Pathological factors Molecular factors • Most trials were not stratified for these factors

5. Why is Adjuvant Therapy Effective in Stage III but not Stage II Disease: The Numbers • To detect a 2% survival difference between Rx and controls (90% power with significance level of .05) would require a sample size of 9680 pts per group • To detect an absolute risk reduction of 2.5% at 3 yrs and 4% at 5 (85% & 75% survival) would require a study of 8000 and 4700pts respectively Benson JCO 22:3408, 2004

6. Stage II Colon Cancer: Poor Prognostic factors • Inadequate staging • Clinical/pathological features • Molecular/enzymatic factors

7. Poor Prognostic Factors: Inadequate Staging • Variability of the number of lymph nodes sampled • Rreports have independently recommended that >10 lymph nodes (ideally >12) be examined to classify a colon cancer as truly N0 • Intergroup adjuvant trial • National Cancer Data Base JCO, 2003 Ann Surg Oncology, 2003

8. Clinical/Pathological Features: Subset Analysis for B2 Intergroup Study (7 year survival)

9. Stage II a Heterogeneous Disease: Molecular Factors • Microsatellite instability – MSI-Hi > MSS (stg for stg) • MSI-H vs MSS with CT – ND • MSS with CT - ↑ survival • MSI-H with CT – ND (trend to  survival) • 18q LOH – NO! • DNA ploidy • EGFR+ • P53 • Microarray gene expression profiling • ???KRAS Gryfe NEJM 342:69, 2000 Ribic NEJM 349:247, 2003 Watanabe NEJM 344:1196, 2001 Barrier JCO 24:4685, 2006

10. Other Prognostic Pathological Variables • Grade • Lymphovascular invasion • Perineural invasion • ?Immune response – lymphocytic infiltrate confers a better prognosis; fibrosis a worse prognosis • ? Tumour budding

11. Pooled Analysis of Fluorouracil-Based Adjuvant Therapy for Stage II and III Colon Cancer • 3 factors predict prognosis - nodal status – N0 vs N1-4 vs >5 - depth of invasion – T1/2 vs T3 vs T4 - grade – low vs high • www.mayoclinic.com/calcs • Stage II - 17% relative reduction in risk of recurrence (4% ↑ in 5 yr DFS; 72% vs 76% but overall survival was 80% vs 81%) Gill JCO 22:1797, 2004

12. Adjuvant on Line • Depth of invasion • Histologic grade • # of nodes involved • # of nodes examined • Derived tumor stage • Age • General health (# of comorbid conditions) • Treatment

13. 5-FU + Levamisole for Stage II/Dukes’ B2 Colon Cancer Obs 5-FU/Lev n 159 159 RFS (7 yr) 71% 79% p=.1 OS (7 yr) 72% 72% p=.83 •  recurrence by 31% (p=.1) • disparity secondary to: • - higher rates of non-colon ca deaths with CT • - salvage surgery Moertel JCO 13: 2936, 1995

14. IMPACT B2 Adjuvant Trials (n=1016)(GIVI0, NCIC, FFCD, NCCTG, Siena)Pooled Analysis • 5-FU/FA Control • (370/200) • EFS (5 yrs) 76% 73% • OS (5 yrs) 82% 80% • JCO 17:1356, 1999 (Lancet 345:939,1995)

15. NSABP Colon Trials5 Year Survival

16. Cancer Care Ontario Practice Guidelines for Stage II Colon Cancer • August, 1997 • 31 RCT’s • 3 meta-analysis • 1 evidence-based consensus statement • Update: April, 2000 • 4 meta-analysis • New or updated reports on 19 RCT’s

17. Cancer Care Ontario PracticeGuidelines for Stage II Colon Cancer • Adjuvant therapy is not recommended • Patients with high risk factors have a poorer prognosis and adjuvant CT could be considered - bowel obstruction - tumor adhesion - invasion - perforation - aneuploidy Figueredo Ca Prev Control 1: 379, 1997 CCOPGI: Full Report – April, 2000

18. Systematic Review from the CCO Program in Evidence-Based Care’s GI Disease Site Group: Conclusions • No compelling evidence to use systemic adjuvant therapy. • There probably is a small benefit that present trials have yet to detect as significant. • Additional investigation of newer therapies and more mature data from the available trials should be pursued. Figueredo JCO 22:3395, 2004

19. CCO Guidelines as of April, 2008 • Routine use of adjuvant chemotherapy for all pts is not recommended • High-risk pts who should be considered for adjuvant therapy include – inadequately sampled nodes, T4 lesions, perforation or poorly differentiated histology

20. Conclusions Regarding Adjuvant Therapy: ASCO Guidelines • Adjuvant therapy for low-risk stage II colon cancer is not supported by randomized controlled trials. • Adjuvant therapy for hi-risk stage II disease is recommended - ? regimen.  MSI status important Benson JCO 22:3408, 2005

21. FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07Wolmark PASCO 23&26: 246s/179s (3500/4005), 2005/2008 FULV FLOX 1209 1200 N0 28.8% 28.9% N1-3 45.7% 44.8% N>3 25.3% 25.6% Neuro - all gr - 85% (29% @ 1 yr) - gr 3 - 8% (.5% @ 1 yr) Oxali dose - 765 mg/m2 (1020 in MOSAIC)

22. FULV vs FLOX for Stage II or III Colon Cancer: NSABP C-07Wolmark PASCO 26:179s (4005)2008 • Global test for interaction between stage and Rx was not significant (p = .7)

23. Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC TrialAndre NEJM 350:2343, 2004; de Gramont PASCO 23:246 (3501), 2005 and PASCO 25:#4007, 2007

24. Adjuvant Oxaliplatin + 5-FU + Leucovorin: MOSAIC TrialAndre NEJM 350:2343, 2004; deGramont PASCO 23:246 (3501), 2005 • LV5FU2 FOLFOX4 • 1123 1123 • Stage II/III 40%/60% 40%/60% • Mean # cycles 11.3 10.7 • DI - 5-FU 97.7% 84.4% • - Oxali - 80.5%

25. MOSAIC Trial: 5 Year DFSde Gramont PASCO 25:#4007, 2007

26. MOSAIC Trial: 6 Year Survivalde Gramont PASCO 25:#4007, 2007

27. MOSAIC Trial: Conclusions • DFS benefit seen at 3 yrs is maintained at 5 yrs • At 6 years there is no survival benefit for stage II pts • Despite a DFS benefit with F4 for hi-risk stage II pts this did not translate into a survival benefit • There was no increase in 2nd cancers • There is continued recovery in peripheral neuropathy but 15% of pts still had residual PN at 4yrs (.7% gr 3; 2.8% gr 2; 12% gr 1)

28. DFS (3 yr) vs OS (5 yr) as a Primary Endpoint for Adjuvant Therapy for CRCSargent PASCO 23:249s (3512), 2005/JCO 23:8564, 2005 • 43 Rx arms; n = 20,898 pts • M:F = 54:46 • Stg II:III = 34:66 • 74% of recurrences in 1st 3 yrs • 3 yr DFS & 5 yr OS – cc = .92 for stg III but only .65 for stg II • DFS excellent predictor of OS at 5 yrs (stg III) • ODAC voted 15 to 0 to accept as a surrogate marker (Pazdur)

29. Microsatellites • Short, tandemly repeated DNA sequences • Detected at the molecular level using genomic DNA from either fresh or paraffin-fixed CRC tissues • Insertion or deletions of nucleotides within repeated sequences of DNA = Microsatellite Instability • Frequent alterations in DNA sequence length = MSI-H • MSI is due to defective mismatch repair genes

30. dMMR as a Predictive Marker for Lack of Benefit from 5-FU based Adjuvant Chemotherapy Sargent PASCO 26:180s (#4008), 2008

36. MSI-H in Stage II and III Colon Cancer: PETACC 3Tejpar PASCO 27: #4001, 2009 • Prognostic effect of MSI in stage II remained significant even in pts treated with 5-FU

37. MSI-H vs MSS Treated With 5-FU: 5 yr DFSSargent vs PETACC 3 Sargent PASCO 26: #4008, 2008 Tejpar PASCO 27: #4001, 2009

38. Effect of MSI and Treatment With 5-FU: Sargent vs PETACC 3 Sargent PASCO 26: #4008, 2008 Tejpar PASCO 27: #4001, 2009

40. - closed • CRC.3 in Canada

41. Summary of Adjuvant Therapy for Stage II Colon Cancer: DFS Moertel IMPACT Gray Mosaic 7 yr 5 yr 5 yr 6 yr Obs CT Obs CT Obs CT LV5FU2 F4 71% 79% 73% 76% 73.8% 77.8% 86.8% 86.9%

42. Conclusions: Stage II • Prospective clinical trials and meta-analyses have not yet shown a benefit for adjuvant chemotherapy. • Present guidelines have recommended against the use of such treatment in “standard risk” patients. • The use of adjuvant therapy in subsets of stage II pts with ominous clinical, pathological or molecular characteristics appears reasonable although the value of this strategy has not been prospectivelyvalidated and the regimen to use is controversial. • Should patients with MSI-H tumors even receive adjuvant chemotherapy

43. Stage III Disease

44. Intergroup Trial of Levamisole/5-FU for Stage III Colon Carcinoma (F/U > 5 yrs, med 6.5)

45. IMPACT Trial: Adjuvant 5-FU/FA(GIVI0, NCIC, FFCD)

46. IMPACT Trial: Adjuvant 5-FU/FA(GIVI0, NCIC, FFCD) - cont’d. • decrease recurrence by 33% • decrease mortality by 22% • borderline EFS & none for OS for Dukes’ B Lancet 345: 939, 1995

47. 5-FU/LV vs FU/Lev vs 5-FU/LV/Lev: Low dose vs Hi-dose and 6 months vs 12 months • 6 months of 5-FU + Leucovorin (LD/HD) became the standard adjuvant treatment

48. Capecitabine vs Mayo in Stage III CRC: X-ACT StudyTwelves NEJM 352: 2696, 2005; GI ASCO #274, 2008 Cape Mayo 1004 983 T1/2 10% 10% T3 76% 76% T4 14% 14% 3 yr - DFS 60.8% 56.7% - RFS 65.5% 61.9% - OS 71.4% 68.4% Toxicity - H/F ↑ - Diarrhea ↓ - Stomatitis ↓ - Neutr ↓ Conclusions: • ↑ RFS • Trend to ↑ DFS & OS benefit • ↑ safety

49. X-ACT Trial: Survival Data

50. UFT vs FULV (Roswell) in Stage II & III CRC: NSABP CO6Wolmark PASCO 23:#3508, 2004 Roswell UFT 777 784 II 46% 47% III 54% 54% N1 38% 37% N2 16% 16% RFS 76.4% 74.5% DFS 68.3% 66.9% OS 78.7% 78.7% Diarrhea 28% 29% QOL ND Sx distress ↓ Conclusion • Equitoxic • Equivalent • UFT not available in N.A.