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Duration of Disease Control (DDC)or Time to Failure of Strategy (TFS)
to evaluate a chemotherapy strategyin advanced colorectal cancer (ACC).
1,2B Chibaudel, 1,4C Tournigand, 1N Perez-Staub, 1O Bourges, 1F Maindrault-Goebel, 3,4T André, 5G Lledo, 1,4C Louvet, 6F Bonnetain, 1,4A de Gramont
(1) Hôpital Saint-Antoine, APHP, université Paris VI, Paris, France(2) GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie, Paris, France
(3) Hôpital La Pitié-Salpétrière, APHP, université Paris VI, Paris, France(4) INSERM U8106
(5) Clinique Jean Mermoz, Lyon, France(6) Unité de biostatistique et de méthodologie FFCD, INSERM U866, Dijon, France
All GERCOR presentations will be available at http://www.canceronet.com/
Introduction• Therapeutic strategies are needed when several regimens, surgery,
maintenance or chemotherapy-free intervals are available: fixed sequence of two therapies (1), stop & go or alternated therapies (2,3)
• PFS is not an optimal endpoint to evaluate therapeutic strategies (4): Treatment effect on OS, based on the effect on PFS, is predicted extremely well when patients receive no effective second line therapy, but not in patients receiving subsequent lines of treatment→ PFS offers the direct measure of a single treatment course
• Composite endpoints have been proposed to evaluate efficacy of these strategies:– Duration of Disease Control (DDC): previously used as first
endpoint in several randomized studies (2,3)
– Time to Failure of Strategy (TFS) (5)
• Our goal was to compare these two composite endpoints and evaluate if they could be potential surrogate endpoints for OS
(4) Buyse et al, JCO 2007(5) Allegra et al, JCO 2007
(1) Tournigand et al, JCO 2004(2) Tournigand et al, JCO 2006(3) Maindrault et al, ASCO 2007
Methods• Trials :
Pooled analysis of individual patient data from 3 randomized studies evaluating therapeutic strategies
• Groups :The OPTIMOX 1 study was divided in 3 groups according to the number of inclusions per centre, to finally obtain groups of about one hundred patients, like the arms of the other studies
• All endpoints were calculated using the Kaplan-Meier method
• Effect of treatment on PFS, DDC, TFS and OS was quantified through hazard ratios (HRs)
• Coefficient correlation was estimated through a linear regression model
Progression
N=311
N=309
N=104
N=109
N=111
OPTIMOX 1
OPTIMOX 2
C97-3
FOLFOX 4
FOLFOX 7 sLV5FU2
RFOLFOX 7
Reintroduction
R
mFOLFOX 7 sLV5FU2 mFOLFOX 7Reintroduction
mFOLFOX 7 Chemo-Free Interval mFOLFOX 7Reintroduction
R
FOLFIRI 1 FOLFOX 6
FOLFOX 6 FOLFIRI 1
N=98
N=311
N=309
N=104
N=109
N=111
OPTIMOX 1
OPTIMOX 2
C97-3
FOLFOX 4
FOLFOX 7 sLV5FU2
RFOLFOX 7
Reintroduction
R
mFOLFOX 7 sLV5FU2 mFOLFOX 7Reintroduction
mFOLFOX 7 Chemo-Free Interval mFOLFOX 7Reintroduction
R
FOLFIRI 1 FOLFOX 6
FOLFOX 6 FOLFIRI 1
N=98
Definitions (1)Term Interval Delays/Holidays Censoring Rules
Sum of PFS
Except for PD at first evaluation after treatment reinitiation
Complete flexible intervals
1) End of study with no PD
2) Addition of new therapeutic agent with no PD
3) R0-R1 surgery not censored
Time to: (1)
1) addition of a new therapeutic agent (2)
2) PD on full therapy
3) PD during CT holiday and followed by no further therapy within 1 month
4) death
Flexible intervals
Except if treatment delay > 1 month after PD
1) End of study and:
- neither PD,
- nor new therapy intervention
2) R0-R1 surgery not censored
(1) Cessation of therapy as a result of toxicity is not considered as an endpoint(2) Agent not included in the original strategy ; endpoint measured at the first of either PD or initiation of new agent
TFS
DDC
10 Must-have items
Item Definition
Original strategy
(data per course of treatment)
First cycle of the course Date
Last cycle of the course Date
Reason for cessation Progression
Toxicity
Maintenance or break
Other
Progression disease (PD) PD status No PD (0) / PD (1)
Progression Date
PD on full therapy ? No (0) / Yes (1)
New Therapy (NT)
(agent not included in the original strategy)
NT status No (0) / Yes (1)
First cycle Date
Follow-up Survival status Alive (0) / Dead (1)
Last news / Death Date
12
3
456
78
910
General Definitions (2)
Treatmentcourse 1
Uncontrolleddisease
NewAgent
Progression
PFScourse1PFScourse2
Progression
Treatmentcourse 2
DDC = PFScourse1 + PFScourse2
TFS = PFScourse1 + Interval + PFScourse2
Interval
Endpoints & Censoring Rules1. End of study with no PD
PD duringinterval
Course 1
TFS
>1month
Course 1
Censored subjects : 0Event : 1
DDC = PFScourse1 + PFScourse2
TFS = PFScourse1 + Interval + PFScourse2
DDC = PFScourse1 + PFScourse2
TFS = PFScourse1
DDC = PFScourse1
TFS = PFScourse1
No PD No PD
DDC / TFS
No PD No PDPD during
interval
No PD No PD
DDC
0
0
0
0
0
1
DDC / TFS
Course 2
Course 1 Course 2
Endpoints & Censoring Rules2. End of study with PD
Course 2
PD duringinterval
Course 2>1month
TFS = PFScourse1 + Interval + PFScourse2
TFS = PFScourse1
No PD
DDC / TFS
No PDPD during
interval
PD at firstevaluation
DDC TFS
DDC = PFScourse1
PD at firstevaluation
DDC = PFScourse1
Censored subjects : 0Event : 1
1
1
1
1
Course 1
Course 1
Results
• N = 1042 patients• Median potential follow-up : 39.8 months• Median age : 64 years [29-80]
Patients Characteristics
(%)
Correlation between PFSand Overall Survival (OS)
PFS is not an optimal endpoint to evaluate therapeutic strategies
Correlation betweenmedian PFS and median OS
Correlation betweenLog HR PFS and Log HR OS
Survivals
OPTIMOX 1 OPTIMOX 2 C97-3
FOLFOX4 Oxaliplatin Stop & Go
Oxaliplatin Stop & Go
Complete Stop & Go
FOLFIRIFOLFOX6
FOLFOX6FOLFIRI
N=312 N=308 N=98 N=104 N=109 N=111
PFS 8.9 m 9.0 m 8.7 m 6.4 m 8.5 m 8.0 m
P ; HR 0.65 ; 0.96 0.0015 ; 0.61 0.29 ; 1.17
DDC 9.3 m 9.9 m 12.5 m 9.0 m 11.4 m 9.9 m
P ; HR 0.47 ; 1.065 0.013 ; 0.67 0.92 ; 0.99
TFS 9.5 m 10.6 m 12.9 m 9.9 m 14.2 m 11.0 m
P ; HR 0.76 ; 1.03 0.003 ; 0.62 0.61 ; 0.93
OS 19.2 m 20.9 m 24.5 m 19.3 m 21.5 m 20.5 m
P ; HR 0.40 ; 1.08 0.32 ; 0.85 0.92 ; 0.97
DDC vs. TFS
Complete Stop & Go
0 26 52 78 1040
20
40
60
80
100
Survival time (weeks)
FOLFIRI - FOLFOX6
0 26 52 78 1040
20
40
60
80
100
Survival time (weeks)
FOLFOX4
0 26 52 78 1040
20
40
60
80
100
Survival time (weeks)
Oxaliplatin Stop & Go
0 26 52 78 1040
20
40
60
80
100
Survival time (weeks)
OPTIMOX 1 study OPTIMOX 2 study C97-3 study
%
%
%
%
%
%
Oxaliplatin Stop & Go
0 26 52 78 1040
20
40
60
80
100
Survival time (weeks)
FOLFOX6 - FOLFIRI
0 26 52 78 1040
20
40
60
80
100
Survival time (weeks)
Distribution
N (%)
DDC = TFS PFS = DDC = TFS
PFS < DDC = TFS
DDC = TFS < PFS
605
11
4
58.0
1.0
0.5
DDC < TFS PFS = DDC < TFS
PFS < DDC < TFS
206
199
20.0
19.0
TFS < DDC TFS < PFS = DDC 17 1.5
59.5%
39%
1.5%
Advantages & Drawbacks
TFS
DDC
• Exclusion of uncontrolled disease interval
• Exclusion of inactive second course
→ direct measure of treatment effect
• Statistically significant correlation between median DDC and OS
• Median DDC shorter than median TFS
→ smaller sample size
• Based on pragmatic approach
• Uncontrolled disease interval included
• Active treatment delayed ≥1 month after minimal PD not included
• Extension of duration in case of no evaluation between the end of treatment and the following line
Correlation between median endpointsand median Overall Survival (OS)
TFSDDC
Correlation between Log Hazard Ratios Endpointsand Log Hazard Ratio Overall Survival (OS)
(logarithmic scale is used for both axes)
TFSDDC
Conclusions• PFS is not an optimal endpoint when patients can
receive several lines ot treatment
• DDC and TFS achieve roughly the same results in the studies reviewed here.
• However, DDC could capture better the effect of a treatment in a stop and go strategy or a multiline strategy. It is adaptable to every strategies, requires a marginaly smaller sample size and in some cases will require less time to reach the endpoint
• Validation of these composite endpoints as surrogate for OS will require other statistical tests like the surrogate threshold effect