Poster Pacs 01.indd

PARTICIPATING CENTERS
IN FRANCE : Centre René GAUDUCHEAU, Nantes - Institut Gustave ROUSSY, Villejuif - Institut
Claudius RÉGAUD, Toulouse - Centre François BACLESSE, Caen - Centre Eugène MARQUIS,
Rennes - Centre Paul PAPIN, Angers - Institut Paoli-Calmettes, Marseille - Centre Georges-François
LECLERC, Dijon - Institut Sainte-Catherine, Avignon - Centre Oscar LAMBRET, Lille - Centre Antoine
LACASSAGNE, Nice – CHU Hôpital Civil, Strasbourg - Centre Val d'Aurelle, Montpellier - CH A.
BOULLOCHE, Montbéliard - Centre Paul STRAUSS, Strasbourg - Centre Jean PERRIN, Clermont-
Ferrand - Centre Henri BECQUEREL, Rouen - Institut Jean GODINOT, Reims - CH Bretagne Sud,
Lorient - CH A. Fleyriat, Bourg-en-Bresse - CH L. Pasteur, Colmar - CMC Les Ormeaux, Le Havre
- Institut BERGONIÉ, Bordeaux - CH, Annecy - Centre Alexis VAUTRIN, Nancy - PolyClinique
Bordeaux Nord Aquitaine, Bordeaux - CH, Mulhouse - Clinique Claude BERNARD, Albi – Clinique
Pasteur, Evreux - CHG, Brive-La-Gaillarde - APHP Tenon, Paris - CHU A. Morvan, Brest - CROSF,
Mareuil-Les-Meaux - Clinique Claude BERNARD, Metz - CHU, Fort-de-France - Clinique Saint-
Pierre, Perpignan - Clinique Pont de Chaume, Montauban - CHU, Poitiers - Centre Jean BERNARD,
Le Mans - Clinique Sainte-Clotilde, Ste-Clotilde - Polyclinique de l'Ormeau, Tarbes - Institut privé
de Cancérologie, Grenoble - Centre Etienne DOLET, Saint-Nazaire - CH, Calais - CH. A. Gayraud,
Carcassonne - CH J. Ducuing, Toulouse - Clinique Claude Bernard, Ermont - CH La Beauchée, St-
Brieuc - CH A. Mignot, Le Chesnay - Clinique du Petit Colmoulins, Harfl eur – CH privé Résidence du
Parc, Marseille - CH InterCommunal, Créteil - CHU Hautepierre, Strasbourg - Clinique Saint-Vincent,
Besançon – CHG, Belfort – CHR, Metz-Thionville - CH, Lagny-sur-Marne - Clinique des Cèdres,
Cornebarrieu - Clinique du Cap d'Or, La Seyne-sur-Mer - APHP Paul BROUSSE, Villejuif.
IN BELGIUM : Clinique Saint-Luc, Bruxelles - Clinique Sainte-Elisabeth - CHU Sart-Tilman, Liège -
Hôpital de Jolimont, Haine-Saint-Paul - Clinique Notre-Dame Reine FABIOLA, Charleroi - CH Peltzer-
La Tourelle, Verviers - Clinique Saint-Joseph, Liège - Clinique Notre-Dame, Tournay - Clinique Notre-
Dame Grace, Gosselies - Clinique Saint-Pierre, Ottignies - Clinique Saint-Michel, Bruxelles - CH,
Mouscron - CHR la Citadelle, Liège - Clinique Saint-Joseph, Arlon - Clinique A. RENARD, Herstal
- IMTR Saint-Joseph, Gilly - Centre de Santé des Fagnes, Chimay - CH Hornu, Boussu - CH du Bois
de l'Abbaye, Seraing - Clinique Notre-Dame Bruyères, Eupen - CH Hutois, Huy - Clinique Saint-Luc,
Namur - U.C.L. Mont-Godinne, Yvoir - Clinique Saint-Joseph, Mons .
Benefi t of the sequential administration of Docetaxel after standard FEC regimen for node-positive breast cancer:
long-term follow-up results of the FNCLCC-PACS 01 trial
Bruno Coudert(1), Mario Campone(2), Marc Spielmann(3), Michel Symann(4), Françoise Eichler(5), Daniel Serin(6), Thierry Delozier(7), Gilles Romieu(8), Jean-Luc Canon(9), Hubert Orfeuvre(10), Gilles Piot(11), Thierry Petit(12),
Philippe Chollet(13), Guy Jerusalem(14), Bruno Audhuy(15), Corinne Veyret(16), Marc Beauduin(17), Jean-Christophe Eymard(18), Anne-Laure Martin(19) and Henri Roché(20) on behalf of the FNCLCC Breast Group
(1) Centre Georges-François Leclerc, Dijon, France, (2) Centre René Gauducheau, Nantes, France, (3) Institut Gustave Roussy, Villejuif, France, (4) UCL Saint-Luc, Bruxelles, Belgium, (5) CHRU, Strasbourg, France, (6) Institut Sainte-Catherine, Avignon, France, (7) Centre François Baclesse, Caen, France, (8) Centre Val d'Aurelle, Montpellier, France, (9) Grand Hôpital Charleroi, Charleroi, Belgium, (10) CH Fleyriat, Bourg-en-Bresse, France, (11)
CMC les Ormeaux, Le Havre, France, (12) Centre Paul Strauss, Strasbourg, France, (13) Centre Jean Perrin, Clermont-Ferrand, France, (14) CHU Sart-Tilman, Liège, Belgium, (15) CH, Colmar, France, (16) Centre Henri Becquerel, Rouen, France, (17) Hôpital Jolimont, Haine-Saint-Paul, Belgium, (18) Institut Jean Godinot, Reims, France (19) FNCLCC, Paris, France, (20) Institut Claudius Regaud, Toulouse, France
SABCS 2009 - Poster Discussion Session 6 – Poster 603
INCLUSION CRITERIA
 Operable unilateral breast cancer (T1-T2-T3, M0)
 N+ (at least 5 resected axillary lymph nodes)
 Age ≥ 18 years and ≤ 65 years
 No cardiac, hepatic, hematological, or renal dysfunctions
 Initial screening
- Bilateral mammography
- Chest X-ray, liver ultrasonography, bone scan
- Left ventricular ejection fraction (LVEF) as measured by MUGA
scan or echocardiography
OBJECTIVES
AND STATISTICAL PLAN
 Objective 2004
 To evaluate the benefi t at fi ve years (main endpoint) of the sequential
administration of docetaxel (D) following FEC100 among patients with
node positive, operable breast cancer
 Hypothesis: α = 5%, 1 - β = 90%, two-sided log-rank test;
DFS reference-value = 65%; estimate gain in 5-year DFS = 7.5%
 Secondary endpoints: safety, EFS, OS
 Statistical analysis
 Intent-to-treat analysis
 DFS estimated using the Kaplan-Meier method and the log-rank test,
stratifi ed for the number of axillary lymph nodes and age
 Multivariate analysis using Cox regression model adjusted for age, N,
pT, hormone receptors, and SBR grade
 Objective 2009
 To evaluate the long-term impact on disease-free survival (DFS) and
on overall survival (OS) of the sequential administration of docetaxel
(D) following FEC100.
EFFICACY RESULTS
AT 5 YEARS
 Substituting 3 cycles of docetaxel for 3 cycles of FEC 100 following
3FEC100 signifi cantly improves DFS and OS in N+ breast cancer
patients (1)
 This benefi t was signifi cant for patients older than 50 years
 For younger women, this schedule of docetaxel seems not to offer any
advantage compared to 6 FEC100
 A signifi cant interaction between age and treatment effect might
suggest a heterogeneity between the 2 age groups
(1) Roché H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin-
based and docetaxel chemotherapy for node-positive breast cancer patients: the
FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71.
CONCLUSION
 Substituting 3 cycles of docetaxel for 3 cycles of FEC 100 following 3FEC100
signifi cantly improves DFS and OS in N+ breast cancer patients.
 The 5-year results are fully confi rmed at 8 years with a 15% reduction in the relative
risk of relapse and with a 25% reduction in the relative risk of death with FEC-D.
 This benefi t is more signifi cant :
 for patients older than 50 years than for younger patients.
 for 1-3 positive nodes than for 4 or over positive nodes
 The sequential regimen demonstrates signifi cantly less long term cardiac events.
Benefit of the sequential administration of Docetaxel after standard
FEC regimen for node-positive breast cancer: long-term follow-up
results of the FNCLCC-PACS 01 trial.
 Objective
To evaluate the long-term impact on disease-free survival (DFS) and on
overall survival (OS) of the sequential administration of docetaxel (D)
following FEC100 among patients (pts) with node positive, operable breast
cancer.
 Patients and Methods
Pts with localized, resectable, non pre-treated, unilateral breast cancer
were randomly assigned to receive either Arm A: 6 cycles of FEC100 (5FU/
epirubicin/cyclophosphamide 500/100/500 mg/m² day 1, every 3 weeks), or
Arm B: 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) 100 mg/m²
(day 1, every 3 weeks). First chemotherapy cycle was to be started no more
than 42 days after surgery. Radiotherapy was mandatory after conservative
surgery and hormone therapy was given for 5 years if tumors were positive
for at least one hormone receptor. Main inclusion criteria were: age <
65 years, at least one positive node, no metastasis and normal cardiac,
hematologic and renal functions. The main end-point of this prospective,
non blinded, randomized, multicentre phase III trial was the 5-year DFS.
These results have been already published (Roché et. al. J Clin Oncol.
2006 24(36):5664-71). Since this fi rst analysis, survival data have been
updated.
 Results
Between June 1997 and March 2000, 1999 pts were recruited. Main pts
characteristics were well balanced between the 2 arms: median age 50
years, conservative surgery 57%, grade III 39%, both HR negative 21%,
both HR positive 60%, 1-3 involved nodes 62%. Treatment was completed
for 95% and 93.4% of pts in arms A and B, respectively.As of 15 April 2009,
with a median long term follow-up of 92.8 months, 639 pts have experienced
at least one event: 124 loco regional relapses, 421 metastasis, 68 contra
lateral breast cancer, and 26 deaths as fi rst event. A total number of 71
second cancers and 383 deaths have been registered.8-year DFS rates
were 65.8% with FEC and 70.2% with FEC-D. Cox regression analysis
adjusted for age and number of positive nodes showed a 15% reduction in
the relative risk of relapse with FEC-D (HR = 0.846 [95%CI 0.724 – 0.988],
p=0.03).8-year OS rates were 78% with FEC and 83.2% with FEC-D. Cox
regression analysis adjusted for age and number of positive nodes showed
a 25% reduction in the relative risk of death with FEC-D (HR = 0.754 [95%CI
0.616 – 0.922], p=0.006).
 Conclusion
Initial report of 5-year benefi t in DFS and OS with sequential administration
of FEC followed by D are fully confi rmed at 8 years.
COX MODEL FOR DFS AT 8 YEARS
Cox Adjusted LogRank
P value
HR CI 95% P value
Arm 0.85 0.73 - 0.99 0.035 0.036
Age 0.81 0.69 - 0.94 0.006
Positive node 2.33 1.99 - 2.72 < 0.001
TREATMENT PROTOCOL
S
U
R
G
E
R
YRT HT
RT HT
► RT: Radiotherapy delivered within 4 weeks after the last chemotherapy cycle
► HT: Tamoxifen 20 mg/day for 5 years prescribed in hormone-receptor positive
post-menopausal women after chemotherapy
6FEC100: ARM A
Fluorouracil 500 mg/m² d1
Epirubicin 100 mg/m² d1
Cyclophosphamide 500 mg/m² d1
6 cycles every 21 days
3FEC100-3 Docetaxel: ARM B
3 cycles of FEC 100 every 21 days
followed by
3 cycles of Docetaxel 100 mg/m² d1 every 21 days
Stratifi ed on:
► Center
► Age: < or ≥ 50
► N: 1-3 vs 4 or more
R
8-YEAR EFFICACY RESULTS
LONG TERM ADVERSE
EVENTS
Cox Adjusted
LogRank
P value
HR CI 95% P value
Arm 0.75 0.62 - 0.92 0.006 0.007
Age 0.97 0.79 – 1.19
0.775
0.775
Nr or Positive nodes 2.93 2.38 – 3.60 <0.001
COX MODEL FOR OS AT 8 YEARS
EVENTS, ITT
Patients, n 6FEC100
(N=996) 3FEC100-3D
(N=1,003)
First event 360 317
Loco-regional relapse 73
61
61
Distant relapse 242 215
Deaths 19 18
Contralateral Breast Cancer 42 31
Distant relapse 268 241
Contralateral Breast Cancer 46 36
Deaths 214 169
Second cancer 37 34
CAUSE OF DEATH
Patients, n 6FEC
(N=214) 3FEC-3D
(N=169)
Breast Cancer 189 148
Acute Leukemia 3
2
2
Second Cancer (other) 67
Cardiac death 21
Other 14 11
§ occuring more than 18 months after Chemotherapy * 1 cardiogenic shock, 1 CHF
LONG TERM CARDIAC EVENTS§
Patients, n 6FEC100 3FEC100-3D
Cardiac events
LVEF decline 2
CHF 2
Cardiomyopathy 1
Cardiogenic shock 1
Myocardial infarction 1
Cardiac death 2*
LONG TERM SECOND CANCERS
Patients, n 6FEC100
(N=37) 3FEC100-3D
(N=34)
Acute Leukemia 42
Multiple myeloma
2
2
Lymphoma 2
Other 31 30
STUDY POPULATION
ITT sample 996 1,003
Safety sample
6FEC100 3FEC100-3Docetaxel
995 1,001
1,999 randomized patients between June 1997 and March 2000
in France (n = 1,621) and Belgium (n = 378)
Median follow-up: 92.8 months as of 15 April 2009
DFS BY AGE, ITT
6FEC100 3FEC100-3D
0.00 0.25 0.50
Age <50 (N=1,005)
0.75 1.00
0
500 487 442 410 389 365 330 300 198
505 485 444 411 386 357 317 265 155
Patients
at risk
Arm A
Arm B
Survival Time (years)
12345678
Log-rank P-Value = 0.471
HR (Cox model) = 0.92 [0.75-1.14]
DFS BY NODAL STATUS, ITT
6FEC100 3FEC100-3D
0.00 0.25 0.50
1 to 3 (N=1,237)
0.75 1.00
0
626 617 589 564 539 512 479 433 261
611 600 570 537 514 469 426 382 242
Patients
at risk
Arm A
Arm B
Survival Time (years)
12345678
Log-rank P-Value = 0.181
HR (Cox model) = 0.85 [0.68-1.08]
OS BY AGE, ITT
6FEC100 3FEC100-3D
0.00 0.25 0.50
Age <50 (N=1,005)
0.75 1.00
0
500 497 485 470 457 434 410 378 253
505 499 490 465 451 425 388 322 245
Patients
at risk
Arm A
Arm B
Survival Time (years)
12345678
Log-rank P-Value = 0.149
HR (Cox model) = 0.81 [0.61-1.08]
OS BY NODAL STATUS, ITT
6FEC100 3FEC100-3D
0.00 0.25 0.50
1 to 3 (N=1,237)
0.75 1.00
0
626 625 619 608 601 572 534 504 284
611 609 597 583 568 537 495 425 306
Patients
at risk
Arm A
Arm B
Survival Time (years)
12345678
Log-rank P-Value = 0.022
HR (Cox model) = 0.68 [0.49-0.95]
6FEC100 3FEC100-3D
0.00 0.25 0.50
4 or more (N=762 )
0.75 1.00
Patients
at risk
Arm A
Arm B
0
377 373 351 334 323 308 283 249 176
385 379 364 337 322 291 266 221 151
Survival Time (years)
12345678
Log-rank P-Value = 0.099
HR (Cox model) = 0.81 [0.63-1.04]
6FEC100 3FEC100-3D
0.00 0.25 0.50
Age ≥50 (N=994)
0.75 1.00
0
503 501 484 472 468 448 412 377 218
491 489 471 455 440 402 372 339 216
Patients
at risk
Arm A
Arm B
Survival Time (years)
12345678
Log-rank P-Value = 0.015
HR (Cox model) = 0.70 [0.53-0.94]
6FEC100 3FEC100-3D
0.25 0.50
4 or more (N=762)
0.75 1.000.00
0
377 362 318 288 273 251 228 186 138
385 359 312 279 252 233 208 166 98
Patients
at risk
Arm A
Arm B
Survival Time (years)
12345678
Log-rank P-Value = 0.083
HR (Cox model) = 0.83 [0.67-1.03]
6FEC100 3FEC100-3D
0.00 0.25 0.50
Age ≥50 (N=994)
0.75 1.00
0
503 492 465 442 423 400 369 314 208
491 474 438 405 380 347 316 267 181
Patients
at risk
Arm A
Arm B
Survival Time (years)
12345678
Log-rank P-Value = 0.019
HR (Cox model) = 0.76 [0.61-0.96]
ACKNOWLEDGEMENTS
 The patients who have accepted to participate in the study
 The Independent Data Monitoring Committee
 The Ligue Nationale Contre Le Cancer
 The French Health Ministry (PHRC)
 Sanofi -aventis France, Pfi zer, Amgen France
DFS BY ARM, ITT
6FEC100 3FEC100-3D
0
1003
996
Patients
at risk
Arm A
Arm B
6FEC100: 65.8%
3FEC100-3D: 70.2%
0.00 0.25 0.50
Survival Time (years)
0.75 1.00
979
959
1
907
882
2
852
816
3
812
766
4
763
702
5
696
632
6
601
532
7
397
313
8
HR (Cox model) = 0.85 [0.73-0.99], P-value = 0.035
OS BY ARM, ITT
6FEC100 3FEC100-3D
0
1003
996
Patients
at risk
Arm A
Arm B
6FEC100: 8-year OS = 78.0%
3FEC100-3D: 8-year OS = 83.2%
0.00 0.25 0.50
Survival Time (years)
0.75 1.00
997
988
1
969
961
2
942
920
3
924
890
4
876
825
5
817
760
6
747
643
7
442
444
8
Log-rank unadjusted P-Value = 0.005
Log-rank adjusted P-Value = 0.007
HR (Cox model) = 0.79 [0.65-0.97], P-value = 0.024
Death = 383
Arm B: 169 (16.8%)
Arm A: 214 (21.4%)