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D Sargent for the Adjuvant Colon Cancer Endpoints (ACCENT) Group

Time-dependent patterns of failure and treatment benefit from adjuvant therapy for resectable colon cancer: Lessons from the 20,800 patient ACCENT dataset. D Sargent for the Adjuvant Colon Cancer Endpoints (ACCENT) Group. The Adjuvant Colon Cancer Endpoints (ACCENT) database.

jessamine-frederick
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D Sargent for the Adjuvant Colon Cancer Endpoints (ACCENT) Group

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  1. Time-dependent patterns of failure and treatment benefit from adjuvant therapy for resectable colon cancer: Lessons from the 20,800 patient ACCENT dataset D Sargent for the Adjuvant Colon Cancer Endpoints (ACCENT) Group

  2. The Adjuvant Colon Cancer Endpoints (ACCENT) database • Initially established in 2003, to validate disease-free survival (DFS) as an endpoint in adjuvant colon cancer • Individual patient data from large adjuvant clinical trials • Jointly owned by all contributors

  3. No Treatment Control Active Control Trial N Trial N N784852 247 NSABP C03 1081 INT0035 926 NSABP C04 2151 N874651 408 NSABP C05 2176 Siena 239 N894651 915 NCIC 359 N914653 878 FFCD 259 SWOG 9415 1078 NSABP C01 773 INT 0089 3547 NSABP C02 718 GERCOR 905 GIVIO 867 QUASAR 3517 Trials Included Total: 18 trials; 20,898 pts

  4. Mining the ACCENT database • ASCO 2004: DFS surrogate for OS • ASCO 2005: Concordance stronger in stage III than stage II • ASCO 2007 • Survival after recurrence – M O’Connell • Prognostic importance of race – G Yothers • Lessons for trialist

  5. Three questions facing adjuvant colon cancer trialists • Nature and duration of treatment benefit on overall survival (OS), disease free survival (DFS) • Long term recurrence rates • Adequacy of statistical assumptions, using DFS endpoint

  6. Duration of adjuvant therapy benefit • Benefit of adjuvant therapy on OS is durable; long-term OS benefit • ACCENT: 80% of recurrences within first 3 years • Duration of adjuvant therapy benefit for DFS? • Restrict analysis to studies of 5-FU based rx vs no adjuvant rx (N=3305)

  7. Hazard Rates for OS Overall Survival Surgery Alone Arms 0.0006 5-FU Based Rx Arms 0.0004 Hazard Rate 0.0002 0.0 0 2 4 6 8 Follow-up Time (Years)

  8. Hazard Rates for OS and DFS Overall Survival Disease-Free Survival Surgery Alone Arms Surgery Alone Arms 0.0006 0.0006 5-FU Based Rx Arms 5-FU Based Rx Arms 0.0004 0.0004 Hazard Rate Hazard Rate 0.0002 0.0002 0.0 0.0 0 2 4 6 8 0 2 4 6 8 Follow-up Time (Years) Follow-up Time (Years)

  9. Hazard Ratios for Rx vs Control Overall Survival 1.0 0.5 0.0 -0.5 Log hazard ratio -1.0 -1.5 95% pointwise CIs -2.0 0 2 4 6 8 Time in Years

  10. Hazard Ratios for Rx vs Control Disease-Free Survival Overall Survival 1.0 1.0 0.5 0.5 0.0 0.0 -0.5 Log hazard ratio -0.5 Log hazard ratio -1.0 -1.0 -1.5 -1.5 95% pointwise CIs 95% pointwise CIs -2.0 -2.0 0 2 4 6 8 0 2 4 6 8 Time in Years Time in Years

  11. Findings: Duration of benefit • OS • Significant OS chemotherapy benefit consistent over time • DFS • Risk of event spikes in first 2 years in control group, then similar between rx and control • Hazard ratio for treatment only significantly differs between rx and control for first 4 years

  12. 1.0 0.0 Log hazard ratio -1.0 95% pointwise CIs -2.0 0 2 4 6 8 Time in Years Conclusions: Duration of benefit • Long term, constant OS benefit: no detrimental long-term effect of 5-FU based chemotherapy • Treated patients have reduced risk of death every single year

  13. 0.0006 Surgery Alone Arms 5-FU Based Rx Arms 0.0004 Hazard Rate 0.0002 0.0 0 2 4 6 8 Follow-up Time (Years) Conclusions: Duration of benefit • Short term DFS benefits translate into long-term OS benefit • DFS hazards never reverse – 5-FU based chemotherapy prevents, not just delays, recurrence

  14. Long-term recurrence rates

  15. Recurrence Rate by time from randomization (all pts) After 5 years, recurrence rates < 1.5% / year After 8 years, recurrence rates < 0.5% / year

  16. Conclusions: Long-term follow-up • For DFS endpoint, long-term follow-up will provide few events • After 5 years, follow-up for recurrence may be reduced, and increase focus on other factors

  17. Adequacy of Statistical Models • Current methods assume • Constant risk of event • Constant treatment effect • Both assumptions violated for DFS endpoint • Risk of event spikes dramatically in first 2 years • Treatment effect diminishes after 2 years, non-significant after 4 years

  18. Adequacy of Statistical Models • More complex statistical models available, but are they necessary? • Considered trial designed under standard methods to have 90% power to detect HR of 0.77 ( ↑ 3 yr DFS from 68% to 74%) at a = 0.05 • Assumption: event-based analysis, log-rank testing

  19. Power: Constant Rx Effect (HR=0.77)

  20. Power: Non-Constant Rx Effect

  21. Power: Non-Constant Rx Effect

  22. Conclusions: Adequacy of Statistical models • Similar exercises demonstrated < 2% power loss due to non-constant risk of event • Real world impact of DFS endpoint on trial design, for range of treatment effects observed in ACCENT, is minimal • Continued use of standard approaches for sample size determination remains appropriate

  23. Discussion • Continued data mining of large datasets can yield new information • Treatment effects • Trial planning and conduct • Findings should be validated on newer trials • Treatments with different mechanism of action may impact DFS differently

  24. Conclusions: Statistical • Long term follow-up for recurrence will yield few additional events • DFS theoretically violates traditional approach to trial design • Real world impact minor: standard approaches to trial design remain appropriate for DFS endpoint

  25. Conclusions: Clinical • Adjuvant rx provides large short term DFS benefits, long term OS benefit • Recurrence rates after 5 years modest, after 8 years minimal • Adjuvant therapy produces cures • Follow-up for recurrence after 5 years can be minimized

  26. ACCENT Collaborative Group • G Yothers, M O’Connell, N Wolmark, S Wieand– NSABP • J Benedetti, C Blanke – SWOG • R Labianca – Ospedali Riuniti (Italy) • D Haller, P Catalano, A Benson – ECOG • C O’Callaghan – NCIC • JF Seitz – University of the Mediterranean (France) • G Francini – University of Siena (Italy) • A de Gramont, T Andre – GERCOR • R Goldberg – CALGB • M Buyse – IDDI (Belgium) • R Gray, D Kerr – Oxford • D Sargent, A Grothey, E Green, S Alberts - NCCTG

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