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TAC versus FAC as Adjuvant Chemotherapy for High-risk Node-negative Breast Cancer: Results from the GEICAM 9805 Trial

Authors:
TAC versus FAC as Adjuvant
Chemotherapy for High-risk
Node-negative Breast Cancer:
Results from the GEICAM 9805 Trial
Martín M, Lluch A, Seguí MA, Ruiz A, Ramos M,
Adrover E, Rodríguez-Lescure Á, Grosse R, Calvo L,
Anton A, on behalf of the Spanish Breast Cancer
Research Group (GEICAM)
Background (1)
Taxanes improve disease-free survival (DFS)
and overall survival (OS) in node-positive breast
cancer
However, most patients have node-negative
breast cancer at diagnosis, and about 30% of
them are at high-risk of relapse
The role of taxanes in this setting is not fully
established
GEICAM 9805 began in 1998
Disease Free Survival
N0
Months
0 20 40 60 80 100 120 140 160
Probability of DFS
0.0
0.25
0.50
0.75
1.0
FAC Md=N R n=204
Log-rank P = 0.046
CMF Md=NR n=211
Database from GEICAM (1990-1993)
Colomer R et al, JCO 22: 961, 2004
FAC vs CMF as adjuvant chemotherapy
for early breast cancer (GEICAM 8701)
Martin M, et al. Ann Oncol 14:833, 2003
Background (2)
Study design
R
Stratification
• Menopausal status
• Center
6 x TAC
Docetaxel 75 mg/m2
Doxorubicin 50 mg/m2
Cyclophosphamide 500 mg/m2
N=1059
Fluorouracil 500 mg/m2
Doxorubicin 50 mg/m2
Cyclophosphamide 500 mg/m2
6 x FAC
Day 1, every 3 weeks
Additional treatment
• Radiotherapy
Mandatory after conservative surgery and
recommended for patients with tumors >5 cm
• Tamoxifen
For 5 years to all patients with hormone
receptor-positive tumors
Primary prophylactic G-CSF mandatory in TAC arm
Protocol amendment after first 237 patients
randomized
Main inclusion criteria
Age 18–75 years
Curative surgery for unilateral T1–T3 breast
carcinoma
No axillary lymph node involvement
At least 10 lymph nodes examined
At least one St Gallen 1998 high-risk criterion
Tumor grade 2 to 3
Tumors >2 cm
Age <35 years
Hormone-receptor negative
Main exclusion criteria
Previous history of cancer
Abnormal renal, liver, or hematologic function
Other serious illness or medical conditions
Abnormal cardiac function (normal LVEF required)
LVEF, left ventricular ejection fraction
Objectives
Primary
DFS after a minimum follow-up of 5 years
Secondary
OS
Safety
Prognostic and predictive value of molecular markers
Quality of life
Statistical considerations
DFS was defined as the interval from randomization
to the date of breast cancer relapse, contralateral
breast cancer, other primary malignancy or death
from any cause, whichever occurred first
With 511 evaluable patients in each arm, the trial
has a 90% power to detect an absolute 7.5% DFS
increase (87.5% vs 80.0%) with TAC at 5-year
follow-up
Patient characteristics
TAC FAC
Randomized patients, n 539 520
Median age, years (range)
Age <35 y, n (%) 50 (23–74)
42 (7.8) 49 (23–73)
33 (6.4)
Tumor size, %
2 cm
>2 cm 52.9
47.1 47.9
51.9
Tumor grade, %*
1
2
3
7.1
40.1
48.1
6.5
44.2
44.2
Menopausal status, %
Pre-menopausal
Post-menopausal 54.4
45.6 55.0
45.0
Hormone receptor status, %*
ER+ and/or PR+
ER– /PR – 63.8
35.6 67.1
32.5
*Data unknown in a few cases
Safety
Treatment Exposure
TAC-pre
n=114 TAC-post
n=414 FAC
n=519
Completed 6 cycles, n (%) 103 (90.4%) 396 (95.7%) 505 (97.3%)
Relative dose intensity
Median 0.99 0.99 0.98
Median cumulative dose, mg
Docetaxel 445 448
Doxorubicin 298 299 300
Cyclophosphamide 2998 2995 2998
5-FU – 2998
Grade 2 or greater hematologic and
nonhematologic toxicities
TAC-pre
(n=114) TAC-post
(n=414) FAC
(n=519)
P value
(TAC-pre vs
TAC-post)
P value
(TAC-post
vs FAC)
Hematologic toxicity, %
Grade 2–4 anemia
Febrile neutropenia (protocol)*
Febrile neutropenia (NCI-CTC)
47.4
24.6
27.2
27.5
6.5
7.5
7.5
2.3
3.1
<0.0001
0.0001
0.0001
<0.0001
0.0014
<0.0001
Non-hematologic toxicity, %
Asthenia
Anorexia
Myalgia
Dysgeusia
Nail disorder
Stomatitis
64.0
11.4
14.9
7.9
7.9
35.1
48.1
3.6
7.7
3.1
1.4
23.2
33.3
2.9
1.2
2.3
1.3
24.5
0.0025
0.001
0.0193
0.0335
0.0012
0.0101
<0.0001
NS
<0.0001
NS
NS
NS
Toxicity graded by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 1, unless otherwise noted.
*Fever 38.1oC with grade 4 neutropenia requiring intravenous antibiotics and/or hospitalization
Martin M, et al. Ann Oncol 2006;17:1205–1212
Safety
TAC FAC
P value
n % n %
Cardiac toxicity 6 1.1 5 1.0 0.81
Hematologic
neoplasm 1 0.2 1 0.2 1
There were no toxic deaths
Efficacy
DFS events
142 DFS events as of the cut-off (18 April 2008)
58 in the TAC arm
84 in the FAC arm
First DFS event TAC (n) FAC (n)
Breast cancer recurrence 44 58
Second breast malignancy 311
Other second malignancy 812
Deaths without event 33
DFS
Survival distribution function
Disease-free survival (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 0 12 24 36 48 60 72 84 96
HR=0.67 [95% CI, 0.48–0.94]
Stratified log-rank p=0.0181
TAC FAC
539 520
58 (11%) 84 (16%)
Number of patients
Events
91%
86%
Median follow up: 67 months
Survival distribution function
Disease-free survival (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 0 12 24 36 48 60 72 84 96
HR=0.67 [95% CI, 0.48–0.94]
Stratified log-rank p=0.0181
FAC
86%
Median follow up: 67 months
DFS
80%
DFS
Survival distribution function
Disease-free survival (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0 0 12 24 36 48 60 72 84 96
HR=0.67 [95% CI, 0.48–0.94]
Stratified log-rank p=0.0181
TAC
91%
Median follow up: 67 months
89%
Risk reductions
33% reduction in risk of relapse with TAC
(HR for DFS: 0.67; 95% CI, 0.48–0.94; P=0.0181)
30% reduction in risk of death with TAC (HR
for OS: 0.70; 95% CI, 0.41–1.22; P=0.21),
however data not yet mature
53 deaths; TAC 22, FAC 31
DFS subgroup analysis
0.2 Favors
TAC
1.61.41.21.00.80.60.4 Favors
FAC
Number of high-risk features
1 0.64 (0.30, 1.39)
2 0.69 (0.47, 0.99)
Menopausal status
Post-menopausal 0.73 (0.44, 1.20)
Pre-menopausal 0.63 (0.40, 0.99)
Hormone-receptor (HR) status
HR + 0.59 (0.36, 0.95)
HR – 0.73 (0.45, 1.16)
Overall DFS 0.67 (0.48, 0.94)
Hazard ratio (95%, CI)
Conclusions
First trial of purely high-risk, node-negative breast
cancer patients to show an efficacy benefit with taxane
treatment
TAC is superior to FAC, resulting in a 33% reduction in
risk of relapse at 5 years
TAC side effects are mainly hematological and are
manageable with primary G-CSF
GEICAM 9805 confirms BCIRG001 that TAC is proven
effective both in node positive and in high risk node
negative early stage breast cancer
Acknowledgments
We thank the 1059 patients who participated in
this trial
All participating centers and investigators
This trial was co-sponsored by GEICAM and
sanofi-aventis
Participating centers
SPAIN
Arnau de Vilanova (Lérida)
Arnau de Vilanova (Val.)
Arquitecto Marcide
Barbastro
Basurto
C.O. de Galicia
C.S. de Terrasa
Ciudad de Jaén
Clinic
Clínica Corachán
Clínico de Valencia
Clínico San Carlos
Clínico San Cecilio
F.H. de Alcorcón
General de Albacete
General de Elche
General de Elda
Serafín Morales
Vicente Alberola
Laura de Paz Arias
Jesús Florian Gericó
Purificación Mtez del Prado
Manuel Ramos Vázquez
Angels Arcusa Lanza
Margarita Fdez Morales
Montserrat Muñoz
Alfonso Modollel
Ana Lluch
Miguel Martín
José Luis García Puche
Carlos Jara Sánchez
Antonio Fdez Aramburo
Alvaro Rguez Lescure
Cristina Llorca
General de Vic
General Univ. de
Alicante
Germans Trias i Pujol
H. de la Ribera
Insular Las Palmas
IVO
Juan Canalejo
La Fe de Valencia
La Princesa
Lozano Blesa
Marqués de Valdecilla
Miguel Servet
Montecelo
Ntra. Sra. de Aránzazu
Parc Taulí
Puerta del Mar
Puerto Real
Rosa Mª Franquesa
Encarna Adrover
Agustín Barnadas
José Miguel Cuevas Sanz
Adolfo Murias Rosales
Amparo Ruiz
Lourdes Calvo
Blanca Munárriz
Amalia Velasco
Dolores Isla Casado
José Manuel López Vega
Antonio Antón Torres
Manuel Constenla
Isabel Alvarez López
Miguel Angel Seguí
José Manuel Baena
Antonio Lorenzo Peñuelas
Ramón y Cajal
Reina Sofía
Río Carrión
Rodríguez
Chamorro
Ruber Internacional
Sant Joan Reus
Santa María Nai
Universitario de
Salamanca
Virgen Blanca
Virgen de la Luz
Virgen de la Victoria
Virgen de los Lirios
Virgen del Rocío
Xeral Calde de
Lugo
Xeral Cíes de Vigo
Carmen Crespo
Enrique Aranda
Alberto Arizcun
Marta Navalón
Pedro Aramburo
Amadeu Pelegrí
Manuel Rubén Rodríguez
Amalia Gómez Bernal
Andrés García Palomo
Eduardo Martínez de Dueñas
Emilio Alba Conejo
Amparo Oltra
Luis Iglesias Pérez
José Ramón Mel Lorenzo
Javier Castellanos
GERMANY
Klinik und Poliklinik
Klinikum Quedlinburg
GmbH
Kreiskrankenhaus
Donaueschingen
R. Grosse
O. Boldt
M. Eberl
St. Marien-
Kankenhaus
Städtisches Klinikum
Universitätsfrauenkli
nik
Matthias Losch
Med. Melchert
Carsten Oberhoff
Universitätskliniken
Homburg Prof. Schmidt
POLAND
Poznan (Wielkopolskie) Jerzy Zaluski Wojewodzki Szpital Piotr Koralewski
Article
Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.
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