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
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DATECAN PROJECT
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Rationale
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
N
%
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
184 defined survival
endpoints among 104
phase III trials
Overall survival
2
2) Non-optimal survival endpoint
definition
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Rationale
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Rationale
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Rationale
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Summary
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Definitions of guidelines in publications:
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Without formal consensus (rather expert opinion)
Not often used
Available for only few cancer sites
Heterogeneity in:
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The selection of time to event (survival) endpoints
The definitions of these endpoints
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Events contributing to DFS in adj
Colon Cancer
MOSAIC/PETACC8 PETACC-3/ACCORD-02
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Locoregional recurrence
Distant metastases
Second primary, same cancer
Second primary, other cancer
(Second primary, colorectal)
Death from same cancer
Death from other cancer
Non-cancer related death
Treatment related death
Loss to follow-up
E
E
E
I
E
E
E
E
E
C
E
E
E
E
E
E
E
E
E
C
DFS definitions
MOSAIC/PETACC8
relapse, death, 2nd colorectal cancer
2nd cancer other than colorectal (ignored)
PETACC-3/ACCORD-02
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relapse, death, 2nd colon cancer
2nd cancer other than colon (event / RFS including only 2 nd colon cancer)
Summary
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Consequences  Difficulties of interpretation
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Comparison between trials
Different conclusions according to different definitions
Example: PETACC 03
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(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)
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DFS (with second primary tumors)
 Significant difference
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DFS (without second primary tumors)
 Non significant difference
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Objective
To develop guidelines for survival
endpoints definitions  standardization:
1.
2.
To define terminology
To define events and censoring process
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Methods
1.
Identification of selected cancer sites and
relevant endpoints, based on literature review
For each cancer site
Develop guidelines with:
2.
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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..
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Target cancer sites
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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
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Consensus method
Experts/Panellists selection
- SC (Steering Committee)
- RC (Rating Committee)
Problem definition
(SC : expert sollicitaion + synthesis of literature)
Formal Consensus Method
(« RAND appropriateness method » as
proposed by Rand Corp. And UCLA)
For each cancer site
Development and diffusion of
questionnaire (SC)
First-round rating process
(RC – by mail)
Analysis and synthesis of the
questionnaires
(SC)
In-person meeting lead by the SC :
Presentation to the RC of the firstround results
+
Second-round rating process (RC)
Analysis and synthesis of the
questionnaires
(SC)
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Final report and diffusion
of the guidelines
(SC + RC)
SC : Steering Committee
RC : Rating Committee
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Example of questionnaire (GI)
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)
Totally
disagree
1
Totally
agree
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
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Name
Laurence Collette
Specialty
Group
Biostatistics
EORTC Headquarters
Group / Committee
DATECAN Steering Committee
Franck Bonnetain
Epidemiology, Biostatistics
CGFL & FFCD & GERCOR
Doussau
Epidemiology, Biostatistics
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
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 pilot Group
pancreatic cancer pilot Group
Jean Luc Van Laethem
Daniela Aust
GI Pathologist
EORTC GI
ROG EORTC Groups
Voker Budach
Radiation oncologist
ROG EORTC Groups
Harun Badakhshi
Radiation oncologist
Oscar Matzinger
Radiation oncologist
Member of GI and ROG EORTC Groups
Erich Gerber
Radiation oncologist
ROG EORTC Groups
Alain Hendlisz
Geertjan van Tienhoven
Medical oncologist
EORTC GI
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
David Cunningham
Medical oncologist
UK
Hans Joachim Schmoll
Medical oncologist
AIO, EORTC GI
John P. Neoptolemos
Surgical oncologist
NCRI/ESPAC
Claudio Bassi
Surgical oncologist
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
EORTC GI
ESPAC
Trevor Cox
Biostatistician
NCRI/ESPAC
Muriel Mauer
Biostatistician
EORTC Headquarters
Matthias Karrasch
Clinician
EORTC Headquarters
Gastro-intestinal oncologist
Emmanuel Mitry
FFCD/AGEO/EORTC GI
pancreatic cancer Scoring Committee
Gastro-intestinal oncologist
Laetitia Dahan
FFCD
Gastro-intestinal oncologist
Thomas Aparicio
FFCD/AGEO
Gastro-intestinal oncologist
Philippe Rougier
FFCD/EORTC GI
Michel Ducreux
Medical oncologist
David Malka
Medical oncologist
FNCLCC/AGEO
Adenis Antoine
Medical oncologist
FNCLCC/PRODIGE
Dromain Clarisse
Medical oncologist
FNCLCC
Gastro-intestinal oncologist
AGEO/FFCD
Julien Taieb
Benoist Chibaudel
Medical oncologist
Aimery de Gramont
FNCLCC/ EORTC GI
GERCOR
Medical oncologist
GERCOR
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
David Azria
Pascal Hammel
SFRO
Radiation oncologist
SFRO
Veronique Girre
Medical oncologist
GERICO
Emmanuel Blot
Medical oncologist
GERICO
Medical oncologist
GERICO
Medical oncologist
GERICO
Cécile Mertens
Lionel Uwers
Aurélien Latouche
Biostatistician Epidemologist
RFUEC
Valérie Jooste
Biostatistician
Francim
Virginie Berger
Biostatistician and clinician
Group of CRLCC statisticians
Biostatistician
Group of CRLCC statisticians
Biostatistician
Group of CRLCC statisticians
Biostatistician
Group of CRLCC statisticians
Emmanuel Chamorey
Sophie Dussart
Jocelyn Gal
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EORTC Group contribution
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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)
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Schedule
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January 2010 – May 2010
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May – Sept 2010
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Creation of questionnaire forms
Validation and pre-test by pilot group
(ongoing for breast)
Database constitution and validation (e-crf)
Since Nov 2010
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List and agreement of expert for Pilot Group
and RC for Pancreatic, Sarcoma and Breast
First round consensus for Pancreatic and
Sarcoma
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