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