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Advances in the adjuvant treatment of colorectal cancer

Stefano Cascinu Clinica di Oncologia Medica Ancona. Advances in the adjuvant treatment of colorectal cancer . COLON CANCER 2004. Estimated New Cases in Europe and Italy Death UE: 213.000 110.000 I: 32.000 16.000 .

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Advances in the adjuvant treatment of colorectal cancer

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  1. Stefano Cascinu Clinica di Oncologia Medica Ancona Advances in the adjuvant treatment of colorectal cancer

  2. COLON CANCER2004 Estimated New Cases in Europe and Italy Death UE: 213.000 110.000 I: 32.000 16.000

  3. ADJUVANT COLON CANCER:MAIN STEPS FROM 1990 to 2002 • 1990 FU/levamisole better than surgery alone • 1994 FU/LV better than surgery alone • 1996 FU/LV better than FU/levamisole • 1996 6 months FU/LV = 12 months FU/LV • 1996 Levamisole unnecessary • 1996 HD LV = LD LV • 1998 Weekly = monthly schedules • 2001 Elderly benefit from therapy

  4. ADJUVANT COLON CANCER : Questions answered from 2002: Infusional 5-FU? Intraportal + systemic 5-FU? Oral fluoropyrimidines? Oxaliplatin? Irinotecan

  5. Open questions on adjuvant therapy • Patient selection • Stage C • Stage B2 • Treatment choice

  6. MOSAIC RANDOM FOLFOX-4 2246 Patients Stage III 60% LV5FU2 André T, NEJM 2004

  7. MOSAIC: DFS in stage III DFS 3-y FOLFOX4 72.2% LV5FU2 65.3% Hazard ratio: 0.76 (0.62 – 0.92) 24% risk reduction for stage III patients

  8. Benefit of Adjuvant CT in stage III

  9. Trials evaluating LOHP in the adjuvant setting

  10. ROCHE NO16968 RANDOM XELOX q3w x6 mos 1886 Patients Stage III Bolus 5FU/LV qw or q4w x6 mos Schmoll, PASCO 2005

  11. ROCHE NO16968: SAFETY * Data from MOSAIC trial

  12. NSABP C-07 FLOX qw x6 mos RANDOM 2407 Patients Stage III 71% FU/LV qw x6 mos Wolmark N, PASCO 2005

  13. NSABP C-07 vs MOSAIC

  14. ADJUVANT CT FOR STAGE III COLON CANCER TODAY … … is there still a role for mono-therapy?

  15. Adjuvant Infusional or Oral 5FU

  16. Adjuvant Infusional or Oral 5FU • Advantages • Toxicity( ↓ diarrhea, stomatitis, neutropenia) • Duration(3 months 5FU PVI) • Compliance(oral 5FU) • Disadvantages • Efficacy( = 5FU/LV) • CVC complications(infusional 5FU) • Compliance(oral 5FU)

  17. Why consider a monotherapy? • Heterogeneous prognosis of stage III • Weakness of FOLFOX • Patients’ characteristics/preferences

  18. Prognostic factors for stage III • T, N, grade • Number of N removed/examined • MSI, TGF-1 RII, 18q LOH • TS, TP, DPD, p53 • LDH-5, FLK-1 • Gene signature Known Unknown

  19. Prognosis of stage III patients Green FL, Ann Surg 2002

  20. 5y-DFS of resected colon cancer Gill S, J Clin Oncol 2004

  21. Weakness of FOLFOX • Toxicity • Long term safety • Neurotoxicity • Secondary leukemia • Long term efficacy • 3-y DFS vs 5-y OS

  22. MOSAIC: toxicity NCI  Gr 3 (%) FOLFOX4 LV5FU2 Thrombocytopenia 1.7 0.4 Neutropenia 41.1 4.7 Febrile neutropenia 0.7 0.1 Neutropenic sepsis 1.1 0.1 Diarrhoea 10.8 6.7 Stomatitis 2.7 2.2 Vomiting 5.9 1.4 Allergy 3.0 0.2 Alopecia (Gr 2) 5.0 5.0 All cause mortality 0.5 0.5

  23. MOSAIC: Incidence of Grade 3 Neuropathy 13% Median DI: 820 mg/sqm 5% 1% 0.5%* During Treatment 28-Day Follow up 6-Month Follow up 18-Month Follow up * 4% grade 2-3 Andrè T, NEJM 2004

  24. OXALIPLATIN CRHONIC NEUROTOXICITY • Atypical cumulative neurotoxicity • Rare situation described with cumulative doses > 1000 mg/sqm • Presentation: Lhermitte’s sign/Urinary retention • Involvement of dorsal root, spinal cord and parasympathetic • “Coasting” phenomenon • 10-15% of patients symptoms emerge or worsen after oxaliplatin discontinuation • This toxicity is not adequately described • In the MOSAIC 12 patients developed grade 3 sensor neurotoxicity after the end of treatment Taleb S, Cancer 2002

  25. Oxaliplatin-Related Acute Myelogenous Leukemia • 56-year-old woman • FOLFOX-4 (12 cycles) • FOLFOX-6 + BV (9 cycles) • 65-year-old woman • Irinotecan (3 cycles) • FOLFOX-4 (3 cycles) Merrouche Y, Ann Oncol 2005 Carneiro BA, Oncologist 2006

  26. 3-y DFS as surrogate of 5-y OS Analisys of 18 randomized trials (5FU-based) Sargent D, J Clin Oncol 2005

  27. What does DFS means? • Disease Relapse • Death from any cause • Second colorectal cancer • Second non colorectal cancer • Sargent: 1+2 • MOSAIC, X-ACT: 1+2+3 • PETACC-3, ACCORD: 1+2+3+4

  28. What does DFS means? • Disease Relapse • Death from any cause • Second colorectal cancer • Second non colorectal cancer RFS • Sargent: 1+2 • MOSAIC, X-ACT: 1+2+3 • PETACC-3, ACCORD: 1+2+3+4

  29. Trials evaluating IRINOTECAN in the adjuvant setting • No benefit in DFS • Excessive toxicity with IFL

  30. CALGB C89803: IFL vs FL P < .00001 50 LV5FU2 + Irinotecan 43% 40 LV5FU2 alone 30 Patients (%) 20 P < .0005 P < .008 10 5% 4% 2.8% 1% 1% 0 Neutropenia Febrile neutropenia Death during treatment Saltz LB, PASCO 2004

  31. PETACC-3: FOLFIRI-AIOIRI vs FL Results Stage III Van Cutsem E, PASCO 2005

  32. PETACC-3: FOLFIRI-AIOIRI vs FL Results Stage III Risk adjusted for T and N Van Cutsem E, PASCO 2005

  33. PETACC-3 vs MOSAIC: toxicity

  34. Patients preference/attitudes 5FU based FOLFOX www.adjuvantonline.com

  35. Patients preference/attitudes Stefano Bollani … … il jazzista che ama divertire la gente … Gino Castaldo, La Repubblica 2005

  36. Completion of Therapy by Medicare Patients With Stage III Colon Cancer • 3193 stage III colon cancer patients recorded in 1992 – 1996 SEER program • Risk of cancer-related mortality was significantly lower among those completing chemotherapy (5FU based) • relative risk = 0.79 (0.69-0.89) • Factors associated with incomplete adjuvant CT • Physical frailty • Treatment complications • Lack of social and psychological support. Dobie S, JNCI 2006

  37. Relative risks of adjuvant CT completion Age Marital status Comorbidities Dobie S, JNCI 2006

  38. Nessuna differenza tra pazienti con piu’o meno di 65 anni MOSAIC: pazienti anziani

  39. Author (year) (Ref.) Number patients Neurotoxicity (grade 1-4) Neurotoxicity (grade 3-4) Patients younger than 70 years Oxaliplatin/ De Gramont (00) (8) 210 85 mg/m2 5FU ci 68% 18% 5FU dose Andre’ (99) (20) 97 85 mg/m2 5FU ci 94% 28% Goldberg (04) (7) 254 85 mg/m2 5FU ci - 18% Maindrault (01) (21) 48 130 mg/m2 5FU ci 97% 11% Hochster (03) (6) 42 85 mg/m2 5FU bolus 36% 12% Ravaioli (03) (5) 45 130 mg/m2 5FU bolus 42% 2.2% Rothenberg (03) (22) 152 85 mg/m2 5FU ci 51% 5% Patients older than 70 years De Gramont (00) (8) 43 85 mg/m2 5FU ci 96 21% Andre (99) (20) 18 85 mg/m2 5FU ci 45% 29% Aparicio (03) (12) 44 85 mg/m2 5FU ci - 16%

  40. Adjuvant CT for stage III • FOLFOX-4 is the reference treatment • Assessment of long term safety/efficacy is mandatory • Monotherapy could be a reasonable choice considering: • Risk of recurrence • Patients characteristics • Patients preference/attitudes

  41. Ongoing studies for stage III

  42. -mf- Stage II patients – to treat ?

  43. COLON CANCER2004 Stage II CURED 70% UE: 22.365-41748 Italy: 3.360-6.272 RELAPSED: 30% UE:9.585-17.892 Italy: 1.440-2.688 Estimated New Cases in Europe and Italy N- T 3-4 (15-28%) UE: 213.00031.950-59.640 I: 32.000 4800- 8960 Deaths UE: 110.000 I: 16.000

  44. TNM Stage AJCC Stage 2002 Grading 5yrs DFS (Surgery +CT) IIA IIB T3,N0 T4,N0 LOW vs HIGH LOW vs HIGH 82% 79% 74% 70% IIIA IIIB IIIC T1-2,N1 T3-4,N1 any T,N2 LOW vs HIGH LOW vs HIGH LOW vs HIGH 81% 77% 53-68% 46-61% 27-64% 21-59% AJCC Cancer Staging Colorectal Cancer 2002

  45. Adjuvant chemotherapy for stage II colon cancer PROS NSABP metanalysis GILL (ASCO 2003) Dutch trial CONS IMPACT metanalysis Seer – Medicare data INT 0035 QUASAR

  46. Global Mortality RR 0.87(95 % CI = 0.75 – 1.01 p.07) FU + LEV (3 RCT) Mortality RR 0.90(95 % CI = 0.71 – 1.13 p.35) FU + LEV + FUFA (8 RCT) Mortality RR 0.86(95 % CI = 0.73 – 1.01 p.07) I.P. 5-FU (5 RCT) Mortality RR 0.70(95 % CI = 0.44 – 1.11 p.13) CCOPEBC Meta-analysis 2004 4187 pts with stage II colon cancer from 18 RCT Figueredo A, JCO 2004

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