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Guidelines for endpoint definitions in cancer trials

Guidelines for endpoint definitions in cancer trials. Bonnetain F DATECAN Project on behalf DATECAN steering committee Statisticians from CRLCC, EORTC, FFCD : Bellara C, Collette L, Dousseau A, Gourgou S, Kramar A, Ouali M, Mathoulin S. Rationale.

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Guidelines for endpoint definitions in cancer trials

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  1. Guidelines for endpoint definitionsin cancer trials Bonnetain F DATECAN Project on behalf DATECAN steering committee Statisticians from CRLCC, EORTC, FFCD : Bellara C, Collette L, Dousseau A, Gourgou S, Kramar A, Ouali M, Mathoulin S

  2. Rationale Review of randomized clinical trials in oncology(Mathoulin et coll. JCO 2008) Medlinedatabases 2004: Cancer / RandomisedClinical Trial : 8 journals: Lancet, JAMA, BMJ, NEJM / BJC, JCO, JNCI, Cancer Review of phase II (11) and phase III (104) randomized clinical trials • 1) Heterogeneity in the selection of ‘survival’ endpoints 2) Non-optimal survival endpoint definition

  3. Rationale

  4. Rationale

  5. Rationale

  6. Summary • Definitions of guidelines in publications: • Without formal consensus (rather expert opinion) • Not often used • Available for only few cancer sites • Heterogeneity in: • The selection of time to event (survival) endpoints • The definitions of these endpoints

  7. Events contributing to DFS in adj Colon Cancer MOSAIC/PETACC8 PETACC-3/ACCORD-02 • Locoregional recurrence EE • Distant metastases EE • Second primary, same cancer E E • Second primary, other cancer IE • (Second primary, colorectal) EE • Death from same cancer EE • Death from other cancer E E • Non-cancer related death E E • Treatment related death E E • Loss to follow-up CC • DFS definitions • MOSAIC/PETACC8 • relapse, death, 2nd colorectal cancer • 2nd cancer other than colorectal (ignored) • PETACC-3/ACCORD-02 • relapse, death, 2nd colon cancer • 2nd cancer other than colon (event / RFS including only 2 nd colon cancer)

  8. Summary • Consequences  Difficulties of interpretation • Comparison between trials • Different conclusions according to different definitions • Example: PETACC 03 • (Van Cutsem E et al. J Clin Oncol 2009)(irinotecan / 5-fluorouracil (5-FU) / folinic acid (FA) versus 5-FU/FA in stage III colon cancer) • DFS (with second primary tumors)  Significant difference • DFS (without second primary tumors)  Non significant difference

  9. Objective To develop guidelines for survival endpoints definitions  standardization: • To define terminology • To define events and censoring process

  10. Methods • Identification of selected cancer sites and relevant endpoints, based on literature review • For each cancer site Develop guidelines with: • Consensus methods based on expert opinion obtained in a systematic manner • European consultation • Consultation of experts with various backgrounds (oncologist, surgeon, radiotherapist, biostatistician, …) • Later contact EMEA etc..

  11. Target cancer sites • First year 2010 - 2011 • Sarcomas • Pancreas cancer • Breast cancer • Following years: • Colo-Rectal cancer • GI cancer (Stomach) ± oesophagus • Kidney & Bladder cancer • Lymphomas • Head & Neck cancer • Lung cancer

  12. Consensus method

  13. Example of questionnaire (GI) • Should the following clinical events be regarded as events in the definition of the endpoint Disease Free survival (DFS)? Please place one tick  on each line. • Table 2 (Setting “no detectable disease” only)

  14. EORTC Group contribution • To provide list of experts: • For participation in the design of the questionnaire (2-3) • Inclusion criteria • Experience in the specialty (>15 years: yes / no) • Principal investigator in clinical trials (>3: yes / no) • Participation in research projects (>3 : yes / no) • Publications in the specialty (>3: Yes / No) • For completion of the questionnaire (15-20) • Inclusion criteria • Experience in the specialty (>10 years: yes / no) (not strict) • Principal investigator in clinical trials (>1: yes / no) • Participation in research projects (>1 : yes / no) • Publications in the specialty (>3: Yes / No)

  15. Schedule • January 2010 – May 2010 • List and agreement of expert for Pilot Group and RC for Pancreatic, Sarcoma and Breast • May – Sept 2010 • Creation of questionnaire forms • Validation and pre-test by pilot group (ongoing for breast) • Database constitution and validation (e-crf) • Since Nov 2010 • First round consensus for Pancreatic and Sarcoma

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