datecan project 1 guidelines for endpoint definitions in cancer trials bonnetain f datecan project...
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DATECAN PROJECT1
Guidelines for endpoint definitionsin cancer trials
Bonnetain F
DATECAN Projecton behalf DATECAN steering committee
Statisticians from CRLCC, EORTC, FFCD : Bellara C, Collette L, Dousseau A, Gourgou S, Kramar A, Ouali M, Mathoulin S
DATECAN PROJECT2
RationaleReview 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 10 5
Event-free survival 12 6
DATECAN PROJECT3
Rationale
DATECAN PROJECT4
Rationale
DATECAN PROJECT5
Rationale
DATECAN PROJECT6
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
Summary
7
Events contributing to DFS in adj Colon Cancer
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
MOSAIC/PETACC8 PETACC-3/ACCORD-02
DFS definitionsMOSAIC/PETACC8 relapse, death, 2nd colorectal cancer
2nd cancer other than colorectal (ignored) PETACC-3/ACCORD-02
relapse, death, 2nd colon cancer2nd cancer other than colon (event / RFS including only 2 nd colon cancer)
DATECAN PROJECT8
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
Summary
DATECAN PROJECT9
Objective
To develop guidelines for survival endpoints definitions standardization:
1. To define terminology
2. To define events and censoring process
DATECAN PROJECT10
Methods
1. Identification of selected cancer sites and relevant endpoints, based on literature review
2. 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 PROJECT11
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 PROJECT12
Consensus methodExperts/Panellists selection
- SC (Steering Committee)
- RC (Rating Committee)
First-round rating process(RC – by mail)
Analysis and synthesis of the questionnaires
(SC)
Formal Consensus Method (« RAND appropriateness method » as proposed by Rand Corp. And UCLA)
For each cancer site
Final report and diffusion of the guidelines
(SC + RC)
Development and diffusion of questionnaire (SC)
SC : Steering CommitteeRC : Rating Committee
In-person meeting lead by the SC :
Presentation to the RC of the first-round results
+ Second-round rating process (RC)
Problem definition(SC : expert sollicitaion + synthesis of literature)
Analysis and synthesis of the questionnaires
(SC)
DATECAN PROJECT13
Example of questionnaire (GI)
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
1.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)
DATECAN PROJECT14
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 Epidemiology, Biostatistics INSERM & CHRU
Karin Haustermans Radiation oncologist EORTC ROG, ESTRO
pancreatic cancer pilot Group
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 Medical oncologist FNCLCC/ PRODIGE/EORTC GI
Francois Lacaine Surgical oncologist FRENCH
Manfred Lutz Medical oncologist EORTC GI
pancreatic cancer Scoring Committee
Daniela Aust GI Pathologist EORTC GI
Voker Budach Radiation oncologistROG EORTC Groups
Harun Badakhshi Radiation oncologistROG EORTC Groups
Oscar Matzinger Radiation oncologist Member of GI and ROG EORTC Groups
Erich Gerber Radiation oncologist ROG EORTC Groups
Alain Hendlisz Medical oncologist EORTC GI
Geertjan van Tienhoven Radiation oncologist Dutch pancreatic Biliary Cancer Group & EORTC ROG
Roberto Labianca Medical oncologist EORTC GI/ GIVIO (Italy)
Josep Tabernero Medical oncologist EORTC GI/ TTD (Spain)
Teresa Macarulla Medical oncologist EORTC GI / TTD (Spain)
Marcel Den Dulk Surgical oncologist EORTC GI
David Cunningham Medical oncologist UK
Hans Joachim Schmoll Medical oncologist AIO, EORTC GI
John P. Neoptolemos Surgical oncologist NCRI/ESPAC
Claudio Bassi Surgical oncologist ESPAC
Christos Dervenis Surgical oncologist ESPAC
Debbie Devine clinicians NCRI/ESPAC
Seema Chauhan clinicians NCRI/ESPAC
Charlotte Rawcliffe clinicians NCRI/ESPAC
Paula Ghaneh clinicians NCRI/ESPAC
Trevor Cox Biostatistician NCRI/ESPAC
Muriel Mauer Biostatistician EORTC Headquarters
Matthias Karrasch Clinician EORTC Headquarters
Emmanuel MitryGastro-intestinal oncologist
FFCD/AGEO/EORTC GI
Laetitia Dahan Gastro-intestinal oncologist
FFCD
Thomas Aparicio Gastro-intestinal oncologist
FFCD/AGEO
Philippe RougierGastro-intestinal oncologist
FFCD/EORTC GI
Michel Ducreux Medical oncologist FNCLCC/ EORTC GI
David Malka Medical oncologist FNCLCC/AGEO
Adenis Antoine Medical oncologist FNCLCC/PRODIGE
Dromain Clarisse Medical oncologist FNCLCC
Julien Taieb Gastro-intestinal oncologist AGEO/FFCD
Benoist Chibaudel Medical oncologist GERCOR
Aimery de Gramont Medical oncologist GERCOR
Pascal Hammel Gastro-intestinal oncologist GERCOR/FFCD
Jean Robert Delpero Surgical oncologist FRENCH/FNCLCC
Alain Sauvanet Surgical oncologist FRENCH
Patrick Pessaux Surgical oncologist FRENCH
Christophe Hennequin Radiation oncologist SFRO
Alice Mege Radiation oncologist SFRO
David Azria Radiation oncologist SFRO
Veronique Girre Medical oncologist GERICO
Emmanuel Blot Medical oncologist GERICO
Cécile Mertens Medical oncologist GERICO
Lionel Uwers Medical oncologist GERICO
Aurélien Latouche Biostatistician Epidemologist RFUEC
Valérie Jooste Biostatistician Francim
Virginie Berger Biostatistician and clinician Group of CRLCC statisticians
Emmanuel Chamorey Biostatistician Group of CRLCC statisticians
Sophie Dussart Biostatistician Group of CRLCC statisticians
Jocelyn Gal Biostatistician Group of CRLCC statisticians
DATECAN PROJECT15
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)
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
DATECAN PROJECT16