ARTICLE
Auteur(s) : Michel
Héry, Jacques Bonneterre, Henri Roché, Elisabeth Luporsi,
Pierre Kerbrat, Moïse Namer, Pierre Fumoleau, Alain Monnier, Pierre
Fargeot
Centre hospitalier Princesse Grace, avenue Pasteur, 98000
Monaco
Currently, the incidence of newly diagnosed breast cancer is
increasing and breast cancer is the most common cause of death in
females [1]. Mammography screening and therapeutic improvement
explained part of this change. In Europe, nearly 90% of breast
cancer are non metastatic at diagnosis. More than 60 % are
free of axillary lymph node involvement [2]. Node-negative (N-)
breast cancers represent the majority of our patients, requiring a
suitable management. If those patients seem to have a better
prognosis, the incidence of relapse remains not negligible. A
prospective analysis, in patients not receiving adjuvant therapy,
showed that, except for a small favorable subgroup, the rate of
10-year metastatic relapse varied from 15 to 35 % [3].A
crucial question is the definition of N- patients eligible for
adjuvant treatment, especially for chemotherapy. Clinical trials
had selected poor-prognosis disease mainly based on high tumor
size, estrogen-receptor (ER) negative tumor, or high proliferation
index. The first studies used
cyclophosphamide-methotrexate-fluorouracil (CMF) or MF regimens
[4-7]. All these trials showed a significant improvement in
disease-free survival (DFS). This has been confirmed by the Oxford
meta-analysis, which demonstrated a significant advantage of
combination chemotherapy versus no adjuvant treatment, irrespective
of lymph node involvement [8]. Thereafter, anthracyclines were
evaluated in N- disease. As for node-positive disease,
anthracyline-based chemotherapy demonstrated its superiority over
CMF [8, 9].In 1988, when the French Adjuvant Study Group (FASG)
initiated the present trial, FASG-03, anthracycline-based
chemotherapy was not routinely used for N- breast cancer. For this
reason, we decided to select high risk patients. We chose to
compare our timely reference treatment, FEC50 (fluorouracil
500 mg/m2, epirubicin 50 mg/m2,
cyclophosphamide 500 mg/m2, 6 cycles every 21 days), to
the absence of systemic treatment.
Patients and methods
Patients
Operable breast cancer patients were enrolled in 21 institutions in
France. The women had all undergone BCS or modified radical
mastectomy, plus axillary dissection. The study recruited women
aged from 18 to 64 years, with completely resected breast cancer,
and negative axillary lymph nodes involvement (at least five
axillary lymph nodes resected). To be eligible, poor prognostic
factors had to be associated: pathologic tumor size (pT) ≥
4 cm, ER and progesterone-receptor (PR) negative (defined as a
value < 10 fmol/mg proteins). In case of Scarff-Bloom-Richardson
(SBR) grade 2, two of these factors had to be present; in case of
SBR grade 3, one factor was mandatory. The other eligibility
criteria were: World Health Organization (WHO) performance status ≤
2; normal hematologic, hepatic, and renal functions; and no cardiac
dysfunction (LVEF ≥ 50%). Patients were excluded from the study if
they had evidence of metastases; a documented history of cardiac
disease or previous cancer (except treated basal cell and squamous
cell carcinoma of the skin, or cancer of the uterine cervix); a
serious underlying medical illness or psychiatric disorder;
inflammatory or locally advanced breast cancer before surgery;
previous radiation therapy, hormonotherapy or chemotherapy for
breast cancer; or if chemotherapy initiation exceeded 42 days from
initial surgery for breast cancer.
Potentially eligible patients underwent bone scan, chest
radiograph, abdominal ultrasound or computed tomographic scan, and
contralateral mammography. An ethical committee approved the
protocol. A written informed consent was obtained from each patient
in a standard procedure according to the French law.
Treatment
Patients were randomized to receive either FEC50, or no systemic
treatment (control), without any hormonal treatment. Chemotherapy
was started within 42 days after initial surgery. In case of
modified mastectomy, radiotherapy was not mandatory, but was
recommended in case of pT ≥ 4 cm, and in case of central tumor
and/or internal quadrant. It was delivered within 6 weeks after
initial surgery in control group, and within 30 days after the last
chemotherapy cycle in FEC50 group. If required after mastectomy,
radiation to the chest wall, supraclavicular area, internal mammary
chain, and to the axillary area (according to each centre
practices) was delivered and consisted of 50 Gy in 25 fractions for
each target. Patients who underwent BCS received an additionnal
boost of 10 to 15 Gy.
For chemotherapy, preventive use of G-CSF and antibiotics was
prohibited. Antiemetic treatment was prescribed routinely before
each cycle. A cooling cap could be used, according to the usual
practice of each institution. An absolute granulocyte count less
than 2,000/mm3 or a platelet count less than
100,000/mm3 on day 21 led to a treatment interruption of
at least one week. Treatment was stopped if hematologic recovery
took more than 3 weeks. The epirubicin dose was reduced by 50% if
serum bilirubin levels were 35 to 50 μmol/L; treatment was stopped
if bilirubin levels exceeded 50 μmol/L. The tolerability of
chemotherapy was evaluated before each cycle: an electrocardiogram
and an absolute blood count were performed on day 21;
non-hematological toxicity was evaluated during the period between
each cycle, according to WHO criteria. It was recommended to assess
LVEF within 3 to 4 weeks after the last chemotherapy cycle.
Patients underwent clinical and biochemical assessments every 6
months during the 5-year follow-up period, and yearly thereafter. A
radiological assessment was performed yearly during the 5-year
follow-up period, and every two years thereafter.
Statistical analysis
It was an open-label, non controlled study. The primary endpoint
was the 10-year DFS. Assessable patients were entered onto an
intention-to-treat analysis. The χ2 test was used to
compare baseline categorical variables and the incidence of adverse
events in both groups. Continuous variables were compared using
analysis of variance. DFS was defined as the time from
randomization until first relapse (local, regional, and distant). A
contralateral breast cancer was considered a new primary
malignancy. OS was defined as the time from random assignment until
death, whether or not it was related to breast cancer. DFS and OS
rates were computed according to the Kaplan-Meier method, and
survival curves were compared with the log-rank test. The
prevalence of the following prognostic factors was analyzed: age,
menopausal status, surgery, pT, SBR grade, number of examined
nodes, and hormone-receptor status. Cox regression methods were
used to determine whether clinical prognostic variables confounded
the treatment effect.
Results
Patient characteristics
Between 1988 and 1994, 328 patients were enrolled onto the study.
Six were lost to follow-up after randomization and one presented
with an initial metastatic disease; they were excluded from the
efficacy analysis (table 1( Table 1 )).
The safety and compliance analysis involved all treated patients
(table 1). Baseline characteristics were well balanced (table 2(
Table 2 )). Major and minor protocol
violations were included in the analysis and were as follows: age ≥
65 years (9), lack of poor prognostic factors (21), neutrophil
count lower than 2,000/mm3 (9), left ventricular
ejection fraction (LVEF) < 50% (4), and prescription of
tamoxifen (6). The median follow-up was 114 months (range,
6-170).
Table 1 Patients eligible for evaluation
|
Control
|
FEC50
|
Total
|
|
Randomly assigned
|
161
|
167
|
328
|
|
Not eligible and/or not assessable
|
|
|
|
|
- Lost to follow-up
|
2
|
4
|
6
|
|
- Initial metastatic disease
|
1
|
0
|
1
|
|
- Not treated
|
NA
|
6
|
6
|
|
Assessable for safety
|
NA
|
157
|
157
|
|
Assessable for efficacy
|
158
|
163
|
321
|
Table 2 Clinical and pathological characteristics of
the 328 randomized patients
|
Control (n = 161)
|
FEC50 (n = 167)
|
|
|
Characteristics
|
Number of patients (%)
|
Number of patients (%)
|
p
|
|
Age at randomization, years
|
|
|
|
|
Median
|
52
|
49
|
0.32
|
|
Range
|
26-65
|
27-66
|
|
|
< 40
|
22 (13.7)
|
28 (16.8)
|
0.74
|
|
≥ 40
|
135 (83.8)
|
135 (80.8)
|
|
|
Unknown
|
4 (2.5)
|
4 (2.4)
|
|
|
Menopausal status
|
|
|
0.38
|
|
Premenopausal
|
64 (39.7)
|
79 (47.3)
|
|
|
Postmenopausal
|
93 (57.8)
|
84 (50.3)
|
|
|
Unknown
|
4 (2.5)
|
4 (2.4)
|
|
|
Surgery
|
|
|
0.91
|
|
Tumorectomy
|
105 (65.2)
|
111 (66.5)
|
|
|
Mastectomy
|
51 (31.7)
|
52 (31.1)
|
|
|
Unknown
|
5 (3.1)
|
4 (2.4)
|
|
|
Pathologic tumor size
|
|
|
0.97
|
|
≤ 2 cm
|
80 (49.7)
|
84 (50.3)
|
|
|
2-4 cm
|
57 (35.4)
|
61 (36.5)
|
|
|
≥ 4 cm
|
16 (9.9)
|
14 (8.4)
|
|
|
Unknown
|
8 (5.0)
|
8 (4.8)
|
|
|
Number of examined nodes
|
|
|
0.67
|
|
5-9
|
27 (16.8)
|
34 (20.4)
|
|
|
≥ 10
|
129 (80.1)
|
129 (77.2)
|
|
|
Unknown
|
5 (3.1)
|
4 (2.4)
|
|
|
SBR grade
|
|
|
0.78
|
|
2
|
34 (21.1)
|
36 (21.6)
|
|
|
3
|
121 (75.2)
|
127 (76.0)
|
|
|
Unknown
|
6 (3.7)
|
4 (2.4)
|
|
|
HR status
|
|
|
0.52
|
|
ER+/PR+
|
4 (2.5)
|
9 (5.4)
|
|
|
ER+/PR-
|
20 (12.4)
|
16 (9.6)
|
|
|
ER-/PR+
|
16 (9.9)
|
16 (9.6)
|
|
|
ER-/PR-
|
113 (70.2)
|
121 (72.4)
|
|
|
Unknown (ER and/or PR)
|
8 (5.0)
|
5 (3.0)
|
|
Disease-free and overall survival
Among the 321 assessable patients, 53 had relapsed (33.5%) in the
control arm, and 45 (27.6%) in the FEC50 arm. The 10-year DFS rates
were 64.0% (95% confidence interval [CI] = 55.6-72.4) in the
control arm, and 70.7% (95%CI = 63.3-78.1) with FEC50 (p = 0.23; (
figure 1 )). No
significant difference was detected in the pattern of recurrences
between treatment groups, with a low incidence of bone metastases
(11.3 and 15.6%, respectively). Local relapses were observed in 29
(18.4%) patients in the control arm, and in 23 (14.1%) in the FEC50
arm, representing 46.9% of relapses. Of those, 45 occurred after
BCS (table 3( Table 3 ), ( figure 2 )). When a Cox
proportional hazards model was performed, independent prognostic
factors of relapse were premenopausal status, BCS, and less than 10
nodes examined (table 4( Table 4 )). In
this model, the comparison of treatment arms demonstrated an
advantage in favor of FEC50 treatment (table 4).
There were 84 deaths involving 40 patients (25.3%) in the
control arm, and 44 (27.0%) in the FEC50 arm. The 10-year overall
survival (OS) rates were 74.1% (95%CI = 67.0-81.2) in the control
arm, and 70.7% (95%CI = 63.1-78.3) with FEC50 (p = 0.82; ( figure 3 )). Among
these deaths, 7 (4.4%) and 11 (6.7%) were not related to a breast
cancer progression, and were due to traffic accident (3), suicide
(2), second cancer (4), CNS haemorrhage (1), pulmonary embolism
(1), Alzheimer disease (1), alcoholism (1), and unknown reason (5).
After relapse, patients in the control arm received chemotherapy in
77.3% of cases against 62.2% for those who received adjuvant FEC50.
This chemotherapy consisted of an anthracycline-based regimen in
95.1% and 89.3% of cases, respectively.
Table 3 Local relapses after breast-conserving
surgery
|
Control
|
FEC50
|
p
|
|
Breast-conserving surgery
|
105
|
111
|
|
|
Local relapse, n (%)
|
25 (23.8)
|
20 (18.0)
|
|
|
Radiotherapy delivered, n (%)
|
24 (96.0)
|
18 (90.0)
|
|
|
10-year local-DFS, % (95%CI)
|
70.5 (58.9-82.1)
|
79.3 (70.9-87.7)
|
0.27
|
|
Relative risk (95%CI)
|
1.39 (0.80-1.98)
|
Table 4 Factors prognostic of relapse: Cox proportional
hazard model
|
Prognostic factors
|
Hazard ratio
|
95% confidence interval
|
p
|
|
Treatment
|
|
|
|
|
Control
|
1.46
|
1.05-1.87
|
0.06
|
|
FEC50
|
1
|
|
|
|
Menopausal status
|
|
|
|
|
Premenopausal
|
1.51
|
1.12-1.90
|
0.04
|
|
Postmenopausal
|
1
|
|
|
|
Surgery
|
|
|
|
|
Tumorectomy
|
1.84
|
1.37-2.31
|
0.01
|
|
Mastectomy
|
1
|
|
|
|
Number of examined nodes
|
|
|
|
|
5 to 9
|
2.11
|
1.64-2.58
|
0.002
|
|
≥ 10
|
1
|
|
|
Treatment, acute and delayed toxicities
Among the 157 patients who received FEC50, 146 patients (93%)
received 6 cycles. The mean cumulative epirubicin dose received was
285 mg/m2 (intended dose 300 mg/m2). The mean
epirubicin relative dose intensity was 14.8 mg/m2/week
i.e. 89% of the intended dose. Acute toxicity was classical of that
observed with 6 cycles of FEC50. Grade 3-4 neutropenia occurred in
11.3% of the patients without preventive use of granulocyte-colony
stimulating factor (G-CSF), grade 1-2 anemias were reported in
12.3% with one case (0.6%) of grade 3, and no case of
thrombocytopenia was observed. The other severe side effects were:
grade 3-4 nausea-vomiting in 29.9% of patients without anti 5-HT3
prophylaxis, and grade 3 alopecia in 18.2%. During chemotherapy,
five patients presented with transient cardiac events, which
consisted of rhythm and conduction disturbances (4), and thoracic
pain (1). No case of grade 3-4 infections or toxic death occurred.
No case of delayed cardiac toxicity occurred after adjuvant
FEC50. One patient, in the control arm, developed a congestive
heart failure after pleural relapse treated with
vinorelbine-fluorouracil chemotherapy; she died from
progression.
Nineteen patients developed contralateral breast cancer: seven
(4.4%) in the control arm, and twelve (7.4%) in the FEC50 arm.
There was no difference between treatment groups. Second
malignancies occurred in seven patients (control = 3; FEC50 = 4):
uterine cervix (2), colorectal (1), stomach (1), esophagus (1),
gall bladder (1), and basocellular carcinoma (1). No case of
secondary leukemia was reported.
Discussion
In this study, the recruitment was low leading to underpowered
results. In 1986, when the study was initiated, the use of
chemotherapy and of anthracycline-based regimens was not common.
This led us to select very poor prognosis N- patients. The fear of
toxicity and the inclusion criteria, infrequent in N- patients,
could explain the low recruitment. However, FEC50 demonstrated an
advantage over the absence of chemotherapy after a long-follow-up.
Based on our present experience, FEC100 regimen would be preferable
in such patients [10]. Noteworthy, we found an unusual rate of
local relapse after BCS. In the great majority (93%), those
patients had received radiotherapy. The delay in the initiation of
radiotherapy after chemotherapy did not influence the occurrence of
local relapse. Even if not significant, the local-DFS rates were
superior with chemotherapy. This confirmed our previous
observations, performed on all patients randomized in FASG trials
after BCS, showing that a delay in radiotherapy delivery due to
primary chemotherapy did not modify the occurrence of local relapse
[11].
Our findings on the advantage of chemotherapy in N- patients are
in agreement with those previously described in the literature,
which compared chemotherapy to the absence of adjuvant therapy
[4-7, 12-14]. Subsequently, the comparison of anthracycline-based
regimens with CMF demonstrated similar results of those reported in
node-positive disease [8, 9, 15].
The consensus guidelines (NIH, St-Gallen) defined patients
eligible for adjuvant therapy according to the classical prognostic
factors [16, 17]. Their conclusions differed regarding patients who
could benefit from adjuvant treatment. If chemotherapy is
indicated, both recommendations were identical: chemotherapy must
be delivered for 4 to 6 cycles with an anthracycline.
In this setting, we clearly need new markers of recurrence. To
date, the most conclusive markers are uPA/PAI-1 developed by a
German team [13]. The development of micro-arrays technology could
help us in the screening of chemotherapy candidates. Chemotherapy
regimens delivered must display a favorable benefit/risk ratio
based on a long-term experience in adjuvant setting. It is probably
the reason why ongoing clinical trials (PACS-05, NSABP B-36,
AGO-EORTC, NCIC MA-21) use 6 cycles of FEC 100 or CEF 120 as
reference treatment arm. They all include a biological study to
address the question of predictive markers. Nevertheless, the
number of events will be probably low, postponing available
results. For the present time, we should continue the development
of new tumor markers and to treat N- patients with the optimal
regimens based on the present guidelines.
Acknowledgments
Isabelle Chapelle-Marcillac provided editorial assistance in the
preparation of the manuscript.
References
1 Hill C, Doyon F. Frequency of cancer in France. Bull
Cancer 2003; 90: 207-13.
2 Dépistage national du cancer du sein en France.
www.sante.gouv.fr 2001.
3 Hery M, Delozier T, Ramaioli A, Julien JP,
de Lafontan B, Petit T, et al. Natural history of
node-negative breast cancer: are conventional prognostic factors
predictors of time to relapse? Breast 2002; 11: 442-8.
4 Zambetti M, Valagussa P, Bonadonna G. Adjuvant
cyclophosphamide, methotrexate and fluorouracil in node-negative
and estrogen receptor-negative breast cancer. Ann Oncol 1996; 7:
481-5.
5 Mansour EG, Gray R, Shatila AH, Tormey DC,
Cooper MR, Osborne CK, et al. Survival advantage of
adjuvant chemotherapy in high-risk node-negative breast cancer:
ten-year analysis, an Intergroup study. J Clin Oncol 1998; 16:
3486-92.
6 Fisher B, Dignam J, Mamounas EP,
Costantino JP, Wickerham DL, Redmond C, et al.
Sequential methotrexate and fluorouracil for the treatment of
node-negative breast cancer patients with estrogen
receptor-negative tumors: eight-year results from National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of
findings from NSABP B-19 comparing methotrexate and fluorouracil
with conventional cyclophosphamide, methotrexate, and fluorouracil.
J Clin Oncol 1996; 14: 1982-92.
7 Amadori D, Nanni O, Marangolo M, Pacini P,
Ravaioli A, Rossi A, et al. Disease-free survival
advantage of adjuvant cyclophosphamide, methotrexate, and
fluorouracil in patients with node-negative, rapidly proliferating
breast cancer: a randomized multicenter study. J Clin Oncol 2000;
18: 3125-34.
8 Early Breast Cancer Trialists’ Collaborative Group.
Polychemotherapy for early breast cancer: an overview of the
randomised trials. Lancet 1998; 352: 930-42.
9 Martin M, Villar A, Sole-Calvo A,
Gonzalez R, Massuti B, Lizon J, et al.
Doxorubicin in combination with fluorouracil and cyclophosphamide
(i.v. FAC regimen, day 1, 21) versus methotrexate in combination
with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1,
21) as adjuvant chemotherapy for operable breast cancer: a study by
the GEICAM group. Ann Oncol 2003; 14: 833-42.
10 Bonneterre J, Roche H, Kerbrat P,
Bremond A, Fumoleau P, Namer M, et al.
Epirubicin increases long-term survival in adjuvant chemotherapy of
patients with poor-prognosis, node-positive, early breast cancer:
10-year follow-up results of the French Adjuvant Study Group 05
randomized trial. J Clin Oncol 2005; 23: 2686-93.
11 Benchalal M, Le Prise E, de Lafontan B,
Berton-Rigaud D, Belkacemi Y, Romestaing P,
et al. Influence of the time interval between surgery and
radiotherapy on local relapse in node-positive, breast-conserving
surgery, early invasive breast cancer patients: results of French
Adjuvant Study Group. Cancer 2005; (in press).
12 Fisher B, Dignam J, Wolmark N,
DeCillis A, Emir B, Wickerham DL, et al.
Tamoxifen and chemotherapy for lymph node-negative, estrogen
receptor-positive breast cancer. J Natl Cancer Inst 1997; 89:
1673-82.
13 Jänicke F, Prechtl A, Thomssen C,
Harbeck N, Meisner C, Untch M, et al.
Randomized adjuvant chemotherapy trial in high-risk, lymph
node-negative breast cancer patients identified by urokinase-type
plasminogen activator and plasminogen activator inhibitor type 1. J
Natl Cancer Inst 2001; 93: 913-20.
14 Paradiso A, Schittulli F, Cellamare G,
Mangia A, Marzullo F, Lorusso V, et al.
Randomized clinical trial of adjuvant fluorouracil, epirubicin, and
cyclophosphamide chemotherapy for patients with fast-proliferating,
node-negative breast cancer. J Clin Oncol 2001; 19: 3929-37.
15 Fisher B, Anderson S, Tan-Chiu E,
Wolmark N, Wickerham DL, Fisher ER, et al.
Tamoxifen and chemotherapy for axillary node-negative, estrogen
receptor-negative breast cancer: findings from National Surgical
Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001; 19:
931-42.
16 National Institutes of Health Consensus Development Panel.
National Institutes of Health consensus development conference
statement: adjuvant therapy for breast cancer, November 1-3, 2000.
J Natl Cancer Inst 2001; 93: 979-89.
17 Goldhirsch A, Wood WC, Gelber RD,
Coates AS, Thürlimann B, Senn HJ. Meeting
highlights: updated international expert consensus on the primary
therapy of early breast cancer. J Clin Oncol 2003; 21: 3357-65.
|
Printable version
Version PDF
