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Adjuvant Therapy of Colon Cancer 2005 Daniel G. Haller, M.D. Abramson Cancer Center at the University of Pennsylvania Philadelphia PA.

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Presentation on theme: "Adjuvant Therapy of Colon Cancer 2005 Daniel G. Haller, M.D. Abramson Cancer Center at the University of Pennsylvania Philadelphia PA."— Presentation transcript:

1 Adjuvant Therapy of Colon Cancer 2005 Daniel G. Haller, M.D. Abramson Cancer Center at the University of Pennsylvania Philadelphia PA

2 Levamisole and Fluorouracil for Adjuvant Therapy of Resected Colon Carcinoma N Eng J Med 322:352-358 February 8, 1990 CG Moertel, TR Fleming, JS Macdonald, DG Haller, JA Laurie, PJ Goodman, JS Ungerleider, WA Emerson, DC Tormey, JH Glick, and et al. Levamisole plus fluorouracil reduced the risk of cancer recurrence. Adjuvant therapy with levamisole and fluorouracil should be standard treatment for Stage C colon carcinoma. This approach should be readily adaptable to conventional medical practice.

3 Adjuvant Therapy for High-Risk Colon Cancer Variations on 5-FU based adjuvant therapy  MOF  Leucovorin  PVI administration  α interferon  Edrecolomab ( Moab 17-1a)

4 Irinotecan and Oxaliplatin with LV5FU2 in Metastatic CRC LV5FU2 ± irinotecan  Douillard LV5FU2 ± oxaliplatin  FOLFOX4 (de Gramont) PETACC-3 MOSAIC

5 Phase III Trial of FOLFIRI/FOLFOX6 in Metastatic Colorectal Cancer RANDOMIZATIONRANDOMIZATION FOLFIRI  FOLFOX6 FOLFIRI  FOLFOX6 FOLFOX6  FOLFIRI FOLFOX6  FOLFIRI Tournigand C et al. JCO 1/15/04 N=113

6 Phase III Trial of FOLFIRI/FOLFOX6 In Metastatic Colon Cancer FOLFIRI FOLFOX FOLFOX FOLFIRI P-value RR % 56% 54%.68 1 st line PFS (mos) 8.5 8.0.26 Median Overall 21.5 20.6.99 Survival (mos) Tournigand C et al. JCO 1/15/04

7 Extending Benefit in Stage II/III Colon Cancer Do combination therapies offer advantages over 5-FU/LV alone?  oxaliplatin-based regimens: MOSAIC, NSABP C0-7  irinotecan-based regimens: CALGB 89803, ACCORD, PETACC-3 The role of biologics:  anti-EGFR (cetuximab)  anti-VEGF (bevacizumab)

8 Objective: Superior OS ( (N=1263 patients)* Objective: Superior OS (65% to 73% at 5 years; HR 1.38) (N=1263 patients)* CPT-11/5-FU/LV (IFL) RANDOMIZATION 5-FU/LV Stage III Intergroup C89803: ASCO 2004

9 C89803: ASC0 2004 Stage III

10 MOSAIC: ASCO 2003 DFS (months) Hazard ratio: 0.77 [0.65 – 0.92] p < 0.01 3-yr DFS FOLFOX4 (n=1123) 77.8% LV5FU2 (n=1123) 72.9% Stage II and III

11 LV5FU2+CPT-11 vs. LV5FU2 in High-Risk Colon Cancer ACCORD: ASCO 2005 High-risk stage III  N2 alone (>3 N+)  N1/N2 detected by occlusion/perforation Primary Endpoint  DFS: time to local recurrence, metastases, second cancer, or deaths

12 FNCLCC ACCORD-02/FFCD 9802, ASCO 2005 3-year DFS: 60% vs. 51% ACCORD: 3-yr DFS p=0.22

13 FUB LV500 FU 500 LV500 OXAL 85 500 Week 1 2 3 4 5 6 7 8 2hr X3X3 R NSABP C-O7: ASCO 2005 RPMI FLOX

14 3-yr DFS FLOX 76.5% FU/LV 71.6% p < 0.004 HR: 0.79 [0.67 – 0.93 ] C-07 DFS: ASCO 2005 Stage II and III

15 3-yr DFS Δ HR C-07 76.5 % 4.9 % 0.79 MOSAIC 77.9 % 5.1 % 0.77 C-07 and MOSAIC 3-yr DFS: Stage II and III

16 Stratification: Stage II vs. III Center RANDOMIZATIONRANDOMIZATION Day 1Day 2 FA 200 mg/m 2 5-FU bolus 400 mg/m 2 5-FU CI 600 mg/m 2 Day 1Day 2 Irinotecan 180 mg/m 2 LV5FU2 as above F IF Repeat q 2 weeks for 12 Cycles PETACC-3 (V307)

17 Study Objectives Primary DFS in Stage III colon cancer patients treated with the LV5FU2 regimen ± irinotecan Relative Dose Intensity, % IFF Irinotecan92 (8-115)- 5-FU91 (31-118) 95 (43-116)

18 Disease Characteristics Stage III IF (n=1044) n (%) F (n=1050) n (%) T Status (tumor depth) T121(2%)18(2%) T2 65(6%)72 (7%) T3776(74%)824(79%) T4180(17%)136(13%) Number of positive lymph nodes <4 (N1) 672(64%) 696(66%)  4 (N2) 372(36%) 354(34%) Number of analyzed lymph nodes <8 186(18%) 174(17%) 8-20 639(61%) 680(65%) >20 219(21%)194(19%)

19 PETACC-3 Results: Stage III HR (95% CI) p-value DFS 0.89 0.091 (0.77-1.11) RFS 0.86 0.045 (0.75-1.00)

20 Duration (months) IF F 0.0 Probability 0.5 0.6 0.7 0.8 0.9 1.0 036912151821242730333639424548 PETACC 3-yr DFS - Stage III F 60.3% IF 63.3% HR= 0.89 (0.77-1.11) P= 0.091

21 Stage III Results Risk Adjusted for T and N HR (95% CI) p-value DFS 0.85 0.021 (0.74-0.98) RFS 0.82 0.009 (0.71-0.95) Outcome within stage III varies by T and N staging Patients not stratified by by T or N, but by stage alone T and N stage were included in the statistical analysis to adjust for these risk factors N stage included prospectively in protocol, whereas T was not

22 What would I have liked to have seen? A positive result based on per-protocol planned analysis of the primary endpoint An adjusted analysis based only on preplanned prognostic factors Overall survival curves Stratification for both T and N stage

23 What else would I have liked to have seen? A Forest plot to visually assess consistency of benefit of IF for all predefined prognostic subgroups. MOSAIC, NEJM 2004

24 Extending Benefit in Stage II/III Colon Cancer Do combination therapies offer advantages over 5-FU/LV alone?  oxaliplatin-based regimens: MOSAIC, NSABP C0-7  irinotecan-based regimens: PETACC-3, CALGB 89803, ACCORD

25 MOSAIC 4-yr DFS: ASCO 2005 1.0 0.9 0.8 0.7 0.6 0.5 0.3 0.4 0.2 0.1 0.0 0 FOLFOX4 LV5FU2 HR [95% CI]: 0.75 [0.62 – 0.89] (0.76 [0.62-0.92]) DFS probability 666121824303642485460 Data cut-off: January 16, 2005 8.6% (6.9%)

26 Clinical Research Issues Targeting the tumor  prognostic and predictive markers Defining the roles of the targeted therapies in the adjuvant setting  Bevacizumab  Cetuximab Defining the optimal duration of treatment  Efficacy  Toxicity  Cost  3 mos PVI 5-FU = 6 mos of Mayo Clinic 5FU/LV ( Chau et al, Ann Oncol 2005) ~

27 E5202: Targeting the Tumor Stage II Colon Cancer mFOLFOX6 mFOLFOX6 + bevacizumab OBSERVATION Low Risk High Risk 18q MSI

28 NSABP C-08 R mFOLFOX6 mFOLFOX6 + bevacizumab Stage II and III

29 AVANT R FOLFOX4 XELOX + bevacizumab FOLFOX4 + bevacizumab Stage II and III

30 N0147 R mFOLFOX6 x 12 mFOLFOX6 x 6 FOLFIRI x 6 FOLFIRI x 12 ± cetuximab Stage III

31 N0147 R mFOLFOX6 x 12 ± cetuximab Stage III

32 N0147 R mFOLFOX6 x 12 mFOLFOX6 x 6 ± cetuximab Stage III


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