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Guidelines for endpoint definitions in cancer trials

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1 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 DATECAN PROJECT

2 Rationale 1) Heterogeneity in the selection of ‘survival’ endpoints
Review of randomized clinical trials in oncology(Mathoulin et coll. JCO 2008) Medline databases 2004: Cancer / Randomised Clinical 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 184 defined survival endpoints among 104 phase III trials N % Overall survival 101 55 Progression-free survival 27 15 Disease-free survival 18 10 Time to progression 16 9 Relapse-free survival 5 Event-free survival 12 6 DATECAN PROJECT




6 Summary Definitions of guidelines in publications: Heterogeneity in:
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 DATECAN PROJECT

7 Events contributing to DFS in adj Colon Cancer
MOSAIC/PETACC8 PETACC-3/ACCORD-02 Locoregional recurrence E E Distant metastases E E Second primary, same cancer E E Second primary, other cancer I E (Second primary, colorectal) E E Death from same cancer E E Death from other cancer E E Non-cancer related death E E Treatment related death E E Loss to follow-up C C 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 DATECAN PROJECT

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

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.. DATECAN PROJECT

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 DATECAN PROJECT

12 Consensus method DATECAN PROJECT

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) Totally disagree Totally agree 1 2 3 4 5 6 7 8 9 Local relapse/recurrence Regional Relapse/recurrence Appearance/occurrence of distant metastases Appearance/occurrence of liver metastases Appearance/occurrence of non liver metastases Second pancreatic cancer Second non pancreatic cancer Death related to primary cancer Death related to a second cancer Death related to protocol treatment Other cause of death Unknown cause of death End of treatment due to… Occurrence of grade 3-4 WHO PS Loss of follow up Other : specificy and score DATECAN PROJECT

14 DATECAN PROJECT Name Specialty Group Group / Committee
Laurence Collette Biostatistics EORTC Headquarters DATECAN Steering Committee pancreatic cancer pilot Group Franck Bonnetain Epidemiology, Biostatistics CGFL & FFCD & GERCOR Doussau INSERM & CHRU Karin Haustermans Radiation oncologist EORTC ROG, ESTRO Bengt Glimelius Medical oncologist Nordic GI- group /Swedish pancreatic group/ EORTC GI Bert Bonsing Surgical oncologist ESSO Jean Luc Van Laethem GI Oncologist EORTC GI + BGDO (Belgian Group of Digestive Oncology) Thierry Conroy FNCLCC/ PRODIGE/EORTC GI Francois Lacaine FRENCH Manfred Lutz EORTC GI pancreatic cancer Scoring Committee Daniela Aust GI Pathologist Voker Budach ROG EORTC Groups Harun Badakhshi Oscar Matzinger Member of GI and ROG EORTC Groups Erich Gerber Alain Hendlisz Geertjan van Tienhoven Dutch pancreatic Biliary Cancer Group & EORTC ROG Roberto Labianca EORTC GI/ GIVIO (Italy) Josep Tabernero EORTC GI/ TTD (Spain) Teresa Macarulla EORTC GI / TTD (Spain) Marcel Den Dulk David Cunningham UK Hans Joachim Schmoll AIO, EORTC GI John P. Neoptolemos NCRI/ESPAC Claudio Bassi ESPAC Christos Dervenis Debbie Devine clinicians Seema Chauhan Charlotte Rawcliffe Paula Ghaneh Trevor Cox Biostatistician Muriel Mauer Matthias Karrasch Clinician Emmanuel Mitry Gastro-intestinal oncologist FFCD/AGEO/EORTC GI Laetitia Dahan FFCD Thomas Aparicio FFCD/AGEO Philippe Rougier FFCD/EORTC GI Michel Ducreux FNCLCC/ EORTC GI David Malka FNCLCC/AGEO Adenis Antoine FNCLCC/PRODIGE Dromain Clarisse FNCLCC Julien Taieb AGEO/FFCD Benoist Chibaudel GERCOR Aimery de Gramont Pascal Hammel GERCOR/FFCD Jean Robert Delpero FRENCH/FNCLCC Alain Sauvanet Patrick Pessaux Christophe Hennequin SFRO Alice Mege David Azria Veronique Girre GERICO Emmanuel Blot Cécile Mertens Lionel Uwers Aurélien Latouche Biostatistician Epidemologist RFUEC Valérie Jooste Francim Virginie Berger Biostatistician and clinician Group of CRLCC statisticians Emmanuel Chamorey Sophie Dussart Jocelyn Gal DATECAN PROJECT

15 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) 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) DATECAN PROJECT

16 Schedule January 2010 – May 2010 May – Sept 2010 Since Nov 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 DATECAN PROJECT

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