individual patient data-based meta- analysis assessing the interest of pre- operative chemotherapy...
TRANSCRIPT
Individual patient data-based meta-analysis assessing the interest of pre-operative chemotherapy in resectable
oesophageal carcinoma
Abstract: 4512
Thirion P., Michiels S., Le Maître A., Tierney J. The Meta‑Analysis of Chemotherapy in Esophagus Cancer
Collaborative Group
Rational & Background
Improvement of survival of patients with locally advanced resectable oesophageal cancer is warranted
Pre-operative strategies:
Pre-operative radiotherapy IPD-Meta-analysis (Arnott et al., 1998)
Pre-operative chemotherapy Literature-based Review (Cochrane, 2005)
Pre-operative Chemo-radiotherapy Literature-based Review (Gebski et al., 2007)
MethodsObjectives Primary end-point:
OS: Overall Survival
Secondary end-point: DFS : Disease-Free Survival, using a 6-month landmark method RO Complete Resection rate (UICC-AJCC definition) Post-operative mortality rate
Statistical analyses IPD updated / centrally collected, checked & re-analysed
Intention-to-treat analyses Odds Ratio (OR), Hazard ratio (HR) & Logrank test - stratified by trial Kaplan-Meier survival curves Heterogeneity and interaction tests
Planned Sub-group analyses for OS and DFS: Age, gender, initial Performance Status (PS) & histological type
Materials
12 eligible trials identified - 2,290 patients9 available trials (10 comparisons) - 2,102 patients (92%)Median follow up across trials: 5.3 years (range: 4.9 - 6.0)
1st author Country/ Institution Accrual Period
Chemotherapy regime
n
Roth USA / MD Anderson 1982-86 CDDP/Bleo/Vindesine 36
Nygaard 2nd Scandinavian Trial 1983-88 CDDP/Bleo 106 + 111
Giuli International / OESO-2 1985-89 CDDP/Bleo/Vindesine 122
Maipang Thailand / Songkla 1988-90 CDDP/Bleo/Vinblastine 46
Law Hong Kong/Queen Mary 1989-95 CDDP/5FU 147
Kelsen USA / Intergroup RTOG 1990-95 CDDP/5FU 467
Kok NL / Rotterdam E.T.S.G 1990-96 CDDP/VP16 169
Ancona I taly 1992-97 CDDP/5FU 96
MRC UK / MRC OE-02 1992-98 CDDP/5FU 802
Population Characteristics
Patient population characteristics Age > 60 : 54% Male: 79% Initial PS 0-1: 71% (not available in 3 trials, 533 pts)
Squamous Cell Carcinoma: 54% Tumour location:
Middle and lower 3rd: 67% GE junction: 11%
Available outcome variables OS: 9 trials - 2,102 patients DFS: 7 trials - 1,849 patients R0 Complete Resection rate: 7 trials - 1,887 patients Post-operative mortality rate: 7 trials - 1,849 patients
Primary End-point: Overall Survival
Queen Mary 52/74 64/73 -13.3 27.8
StudyNo. Deaths / No. Entered
Chemo preop Control O-E Variance Hazard Ratio HR [95% CI]
Chemo preop better | Control better
Italy 35/48 37/48 -2.4 17.8
Songkla 20/24 16/22 5.7 8.5
MRC EO-02 280/400 316/402 -34.7 148.4
RTOG 8911 204/233 197/234 5.9 100.1
MD Anderson 11/17 16/19 -2.7 6.7
Scandinavia 2 53/56 50/50 -0.9 25.6
Scandinavia 2R 46/53 52/58 0.8 24.2
Oeso-2 44/58 52/64 -3.3 23.7
Rotterdam 61/85 72/84 -14.9 31.9
Total 806/1048 872/1054 -59.8 414.6
Chemo preop effect: p = 0.003
Test for heterogeneity: p = 0.03
0.87 [0.79;0.95]
0.25 1.00 4.00
Primary End-point: Overall Survival
HR = 0.87 [0.79;0.95] , p= 0.003
4.3%20.4%16.1%5 years
5.1%37.5%32.4%2 years
Absolute
benefit
Chemo pre-op
Control
Patients at riskControl 1054 321 144 74 38 20Chemo pre-op 1047 361 153 90 52 31
Su
rviv
al
0.0
0.2
0.4
0.6
0.8
1.0
Time (years)0 2 4 6 8 10
Secondary End-point: DFS
Queen Mary 55/74 68/73 -14.7 29.3
StudyNo. Deaths / No. Entered
Chemo preop Control O-E Variance Hazard Ratio HR [95% CI]
Chemo preop better | Control better
Italy 36/48 41/48 -3.8 19.0
Songkla 20/24 16/22 3.3 8.8
MRC EO-02 296/400 331/402 -38.5 155.3
RTOG 8911 213/233 203/234 -3.1 103.3
Oeso-2 45/58 53/64 -4.1 24.4
Rotterdam 63/85 72/84 -13.3 32.5
Total 728/922 784/927 -74.3 372.6
Chemo preop effect: p = 0.0001
Test for heterogeneity: p = 0.11
0.82 [0.74;0.91]
0.0 1.0 2.0 3.0
Secondary End-point: DFS
HR = 0.82 [0.74;0.91] , p=0.0001
4.4%11.8%7.4%5 years
7.0%30.1%23.1%2 years
Absolute
benefit
Chemo pre-op
Control
Patients at riskControl 927 178 87 43 22 10Chemo pre-op 922 236 111 61 38 20
Dis
ease
fre
e su
rviv
al
0.0
0.2
0.4
0.6
0.8
1.0
Time (years)0-0.5 2 4 6 8 10
Secondary End-point: R0 Resection RateIntention-to-treat Analysis
Queen Mary 48/74 39/73 -4.2 8.9Italy 37/48 35/48 -1.0 4.5
MRC EO-02 233/400 215/402 -9.6 49.5
RTOG 8911 144/233 138/234 -3.3 28.0
MD Anderson 13/17 16/19 0.7 1.4Scandinavia 2 23/56 16/50 -2.4 6.2Scandinavia 2R 28/53 20/58 -5.1 6.9Oeso-2 35/58 40/64 0.7 7.3
Total 561/939 519/948 -24.2 112.7
Study Chemo preopNo. Events / No. Entered
Control O-E Variance Odds ratio OR (95% CI)
Chemo preop effect with p = 0.02
Test for heterogeneity: p = 0.74
0.81 [0.67-0.97]
Chemo preop better | Control better0.0 0.5 1.0 1.5 2.0
Secondary End-point: Post-operative Mortality Rate
Queen Mary 1/74 5/73 -2.0 1.4
Italy 1/48 2/48 -0.5 0.7
Songkla 3/24 0/22 1.4 0.7
MRC EO-02 36/400 40/402 -1.9 17.2RTOG 8911 8/233 5/234 1.5 3.2
Oeso-2 9/58 7/64 1.4 3.5
Rotterdam 4/85 3/84 0.5 1.7
Total 62/922 62/927 0.4 28.5
Study Chemo preopNo. Events / No. Entered
Control O-E Variance Odds ratio OR (95% CI)
No preop Chemo effect p = 0.94 NS
Test for heterogeneity: p = 0.26
1.01 [0.7-1.46]
Chemo preop better | Control better
0.0 0.5 1.0 1.5 2.0
Sub-group Analyses
The overall survival and disease-free survival benefit of the addition of pre-operative chemotherapy was seen across: Age (50<, 50-60, >60) Gender Initial PS Histological Type
Adenocarcinoma 282/385 315/392 -29.5 148.4
Squamous cell 450/564 471/563 -15.0 226.7
CategoryChemo preopNo. Events / No. Entered
Control O-E Var Hazard ratio HR [95% CI]
Test for interaction: p = 0.21Chemo preop better | Control better
0.0 0.5 1.0 1.5 2.0
Conclusions
For patients with resectable oesophageal cancer, pre-operative chemotherapy:
Improves significantly Overall Survival and Disease Free Survival, regardless of age, gender, PS & histological type.
Increases R0 resection rate, without increasing post-operative mortality rate
AcknowledgmentsWriting/Steering Committee: Thirion P., Piedbois Y., Tierney J., Stenning S., Pignon J.P., Buyse M., Piedbois P., Bosset J.F.
Secretariat: Thirion P., Michiels S., Pignon J.P., Piedbois P., Le Maître A.
Collaborators (Investigators & Statisticians): Ancona E., Apinop C., Bancewicz J. , Clark P., De Vathaire F., Giuli R., Hansen H.S., Kelsen D., Kok T.C., Kullathorn T., Law S., Maipang T., Nygaard K., Parmar M., Roth J., Ruol A., Steinberg S., Tierney J, Tilanus H.W., Van der Gaast A., Winter K., Wong J.
Supported by French Cancer Ligue
And the patients.