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.