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Adjuvant Matters

Adjuvant Matters. Richard M Goldberg MD UNC Lineberger Comprehensive Cancer Center Chapel Hill, NC. Disclosures. I have been a paid consultant to sanofi-aventis Genentech Pfizer Memberships NSABP (Wolmark, Allegra abstracts) ACCENT (de Gramont abstract) Coauthor

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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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