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U.S. Food and Drug Administration

U.S. Food and Drug Administration. Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated. .

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U.S. Food and Drug Administration

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  1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

  2. ASCO/FDA Public Workshop onClinical Trials Endpoints inColorectal Cancer Rectal Cancer Endpoints November 12, 2003

  3. Evolution of Adjuvant Treatment • Stage II/III Rectal Cancer (T3/T4, N+) • Surgical Treatment • + Radiation Therapy or Chemotherapy • + Post-operative Chemoradiation Therapy • + Neoadjuvant Chemoradiation Therapy and Post-operative Chemotherapy

  4. Proposed Rectal Cancer Endpoints • Local Control • Sphincter-Sparing Surgery • Pathologic Complete Response

  5. Local-Regional Failure “In contrast to colon cancer, there is a significant risk of local-regional failure as the only or 1st site of recurrence in patients with curative resected rectal cancer.” • Stage I 5% to 10% • Stage II up to 25% to 30% • Stage III up to 50% or higher NIH Consensus Conference on Adjuvant Therapy for Patients with Colon and Rectal Cancer, JAMA, Sept. 19, 1990

  6. Local-Regional Failure Characteristics • Main prognostic determinant is Stage • Local-Regional failure associated with significant morbidity • Major mode of failure(+/- distant metastases) • Most failures within 2-3 yrs and rare after 5 yrs(+/- distant metastases) • Successful salvage is rare

  7. Post-Op ChemoRT vs Surgery K. Hu and L. Harrison – Semin Surg Oncol 19:336-349, 2000

  8. Post-Op ChemoRT vs Single Modality K. Hu and L. Harrison – Semin Surg Oncol 19:336-349, 2000

  9. Short-Term Pre-Op Radiotherapy vs Surgery Alone

  10. Pre-Op vs Post-Op Chemoradiation • NSABP R-03 – Low Accrual • Treatment-related toxicity similar • Sphincter-saving surgery • Pre-op Group (plan 31% to 50%) • Post-op Group (plan 33% vs 33% actual) • INT-0147 – Low Accrual • German Trial – CAO/ARO/AIO-94 • Results presented ASTRO – Oct. 2003

  11. German Trial – CAO/ARO/AIO-94 800+ pts – T3/T4, N+ rectal cancer(CI 5-FU + 50.4 Gy) U Penn Oncolink Report on Plenary Session Presentation – ASTRO 45th Annual Meeting – Oct. 2003 - R. Sauer et al – German Rectal Cancer Group

  12. Pathologic Complete Response • Mix of Retrospective Series, Prospective Series, and Phase 2 Studies • Small Studies • Dependent on pathologic review/QA • Different ChemoRT regimens • Different Stages (usually T3, N+) • Range pCR 9% - 24% • pCR associated with trends in decreased LR, increased sphincter-preserving surgery

  13. Pathologic Assessment: # Lymph Nodes & Outcome US GI Intergroup Adj. Trial INT-0114 (1,664 pts, pT3,T4 or Node+ Rectal Cancer) Pathology Reports with Information on Circumferential Margin Status <10% in this study J. Tepper et al, J Clin Oncol 19:157-163, 2001

  14. Future US Phase III Trials:Rectal Cancer NSABP R-04 Pre-Op ChemoRT Activation 2004 5-FU Capecitabine E3201 Post-Op ChemoRT Activated 10/2003 5-FU/LV CPT-11/5-FU/LV Oxaliplatin/5-FU/LV

  15. DISCUSSION

  16. Rectal Cancer EndpointsNeoadjuvant Therapy-Stage II/III Rectal Cancer

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