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Adjuvant Matters

This presentation highlights the findings from key trials, including NSABP Protocol C-07, focusing on the effectiveness of oxaliplatin combined with fluorouracil and leucovorin (FU/LV) in improving progression-free survival (PFS) and overall survival (OS) for patients with Stage II and III colon cancer. It addresses critical questions surrounding adjuvant therapy durations, optimal oxaliplatin dosage, and management strategies for Stage II patients. The presentation also reviews the role of bevacizumab when combined with FOLFOX, shedding light on toxicity and the impact of longer follow-up periods on survival outcomes.

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Adjuvant Matters

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  1. Adjuvant Matters Richard M Goldberg MD UNC Lineberger Comprehensive Cancer Center Chapel Hill, NC

  2. Disclosures • I have been a paid consultant to • sanofi-aventis • Genentech • Pfizer • Memberships • NSABP (Wolmark, Allegra abstracts) • ACCENT (de Gramont abstract) • Coauthor • Ribic NEJM paper upon which some of the presentation by Sargent is based

  3. NSABP Protocol C-07: A Phase III Trial Comparing FU/LV to FU/LV + Oxaliplatin in Stage II or III Colon Cancer: Survival Data Wolmark, Wieand, Kuebler, Colangelo, O'Connell, Yothers and the NSABP Investigators

  4. Questions • Answered • Does oxaliplatin add to PFS and OS? • Does 5-FU schedule matter? • Is 5 years of follow-up adequate for OS? • Unanswered • What’s the optimal adjuvant therapy duration? • How much total oxaliplatin is optimal? • How do we best manage Stage II patients?

  5. Stage ll + lll Randomize FU/LV FLOX

  6. Critical Statistics • 5.5 year median follow-up • Outcomes better than projected • Expected # deaths 700 • Actual # deaths 560 • Consequent reduction in power • % Stage II: • C-07 28% • MOSAIC 40%

  7. C-07 DFS p = 0.002 HR: 0.81 [0.70 – 0.93] 3y 5y FLOX 76.1% 69.4% FULV 71.5% 64.2%Δ 4.6% 5.2% 19% risk reduction

  8. C-07 Survival D(n) 5y 6y FLOX 259 80.3% 77.7% FULV 301 78.3% 73.5%Δ 42 2.0% 4.2% p = 0.06 HR: 0.85 [0.72 – 1.01] 15% risk reduction

  9. C-07 Survival after Recurrence Median FLOX 17.6 FULV 22.2 P = 0.02 HR: 1.24

  10. Questions • Answered • Does oxaliplatin add to PFS and OS? Yes • Does 5-FU schedule matter? No • Is 5 years of follow-up adequate for OS? No • Unanswered • What’s the optimal adjuvant therapy duration? 3 versus 6 versus other? • How much total oxaliplatin is optimal? May differ in different patients • How do we best manage Stage II patients? TBDNo treatment, 5-FU alone, or FOLFOX

  11. Initial Safety Report of NSABP C-08 Allegra, Yothers, Sharif, O’Connell, Wolmark and the NSABP Investigators

  12. Stage II or III Colon Cancer Stratification Number of + Lymph Nodes Randomization mFOLFOX6 + Bevacizumab mFOLFOX6 NSABP C-08 Schema Disease-free survival: primary endpoint

  13. Questions • Answered • Is the frequency of early deaths different? • What are the relative toxicities of FOLFOX +/- bevacizumab? • Were there any surprises? • Unanswered • Does bevacizumab add to FOLFOX in the adjuvant setting? • Does bevacizumab have any long term toxicity (or benefit)?

  14. Early Mortality with Adjuvant Regimens • C-08 within 18 months of randomization • FOLFOX 1.33% • FOLFOX + bev 1.42% • MOSAIC data within 7 months of randomization • LV5FU2 0.5% • FOLFOX 0.5% • C89803 data within 6 months of randomization • 5-FU/LV 1% • IFL 2.8%

  15. Toxicities (Grade 3+) Significantly Increased with Bevacizumab (%)

  16. Toxicities (Grade 3+) After Chemotherapy

  17. Questions • Answered • Is the frequency of early deaths different? No • What are the relative toxicities of FOLFOX +/- bevacizumab? BP, pain, wounds, proteinuria • Were their any surprises? Pain, a bit more oxaliplatin delivered, no major increase in wound complications • Unanswered • Does bevacizumab add to FOLFOX in the adjuvant setting? No data • 28 months median time on study • Efficacy analysis: 592 events or 4 years after last entry (DMC evaluation every 6 months, latest October 2010) • Does bevacizumab have any long term toxicity (or benefit)? No data

  18. Association between 3 year DFS and OS is delayed with improved survival after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: Findings from the 20,898 patient ACCENT datasetde Gramont for the ACCENT collaborative group

  19. Questions • Answered • Do we need to extend adjuvant trial follow-up beyond 5 years? • Is a survival advantage that is apparent after 5 years still meaningful? • Should trial design be continuously reevaluated? • Unanswered • Do we need to change surveillance plans?

  20. MOSAIC Update: OS with 6 Years Minimum Follow-up 1.0 p=0.996 0.9 0.1% p=0.029 0.8 4.4% 0.7 0.6 Probability 0.5 0.4 HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall survival (months) ASCO 2007

  21. ACCENT: 3yr DFS vs 5yr OS R2 = 0.80 May 2004: ODAC recommends3-yr DFS as new regulatory endpointfor FULL approval in adjuvant colon cancer

  22. Hypothetical – 3yr DFS v. 7yr OS R2 = 0.75

  23. Why Was 6 Years Required for MOSAIC to Become Positive for OS? • Previous analyses with 5FU/LV showed excellent association between 3 yr DFS & 5 yr OS • ACCENT: Median time from recurrence to death: 12 months • MOSAIC: Median ~ 24 months • Improved imaging to detect recurrence earlier • Enhanced treatment post-recurrence • Secondary resections in selected patients

  24. Impact of longer survival following recurrence on clinical trials • Longer follow-up for OS required to observe benefit • improved post-recurrence treatments • DFS even a more important endpoint • Treatments that delay rather than prevent recurrence may send misleading DFS signals

  25. Questions • Answered • Do we need to extend adjuvant trial follow-up beyond 5 years? Yes • Is a survival advantage only apparent after 5 years still meaningful? Absolutely • Should trial design be continuously reevaluated? Absolutely, by clinician & statistician teams • Unanswered • Do we need to change surveillance plans? Probably

  26. Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in Adjuvant Colon Cancer Sargent, Marsoni, Thibodeau, Labianca, Hamilton, Torri, Monges, Ribic, Grothey, Gallinger

  27. Questions • Answered • Should MMR testing be considered prior to 5-FU based Rx for stage II pts? • Unanswered • Should MMR testing be considered prior to 5-FU based Rx for stage III pts? • Should other agents be used in MSI-H pts? • Why are MSI-H different then MSS tumors?

  28. Biology • 15% of CRC pts have MSI-H tumors • Most hypermethylation, not mutation • MSI-H cells have a growth advantage in the presence of 5-FU Carrethers, Gastro, 1999 • MMR cells unable to bind 5-FU modified DNA • MSI-H cell lines • are more sensitive to irinotecan Bras-Goncalves, BJC, 2000 • are not resistant to oxaliplatin Sergent, Canc Chemo Pharmacol 2002

  29. Pooled data (N=1027)

  30. DFS By MMR Status, Pooled Data Treated (N=512) Untreated (N=515) 5 yr DFS HR: 0.79 (0.49-1.25) p=0.30 dMMR 70% pMMR 67% 5 yr DFS dMMR 80% pMMR 56% HR: 0.51 (0.29-0.89) p=0.009

  31. Overall Survival By Treatment, Stage II dMMR Patients N = 55 N = 47 P-value = 0.014 for treatment by MMR status interaction 5 yr OS HR: 3.15 (1.07-9.29) p=0.03 Untreated 93% Treated 75%

  32. Conclusions • dMMR validated as a prognostic marker in untreated patients • No suggestion of benefit from 5-FU based treatment in dMMR patients • Significant OS decrement to 5-FU based treatment in stage II patients

  33. Take Home Message When considering a Stage II patient for 5-FU-based therapy, mismatch repair status, by MSI or IHC, should be used to determine whom not to treat

  34. CALGB 89803: 5-FU/ LV +/- Irinotecan • 854/1264 tumors evaluated for MSI • Patients with samples no different from overall population • 153 (18%) MSI-H by DNA microsatellite analysis • PFS (p=0.04) advantage and OS trend (p=0.17) for IFL over FL treated MSI-H patients • No PFS or OS advantage for MSS patientsBertagnolli, submitted

  35. Disease free survival Overall survival MSI-H tumors p= 0.0391 p = 0.1736 Non- MSI-H tumors p = 0.6681 p = 0.5111

  36. Questions • Answered • Should MMR testing be considered prior to 5-FU based Rx for stage II pts? Yes • Unanswered • Should MMR testing be considered prior to 5-FU based Rx for stage III pts? Unclear • Should other agents be used in MSI-H pts? Needs verification • Irinotecan and oxaliplatin cell line data • CALGB clinical data • Why are MSI-H different then MSS tumors? TBD

  37. ConclusionsAdjuvant Matters • 5-FU/Oxaliplatin standard for adjuvant Rx of Stage III colon cancer • Should be considered in high-risk stage II • No advantage over 5-FU/LV in pooled stage II • Bevacizumab is not standard adjuvant Rx • Adjuvant trials need to be bigger and longer • MSI status appears relevent to likelihood of benefit from 5-FU and possibly other agents • At last we have useful markers of heterogeneity • K-ras and MSI appear to be prognostic and predictive

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