Annals of Oncology 5: 95-97, 1994.

© 1994 Kluwer Academic Publishers. Printed in the Netherlands.

Short report
FAC (fluorouracil, doxorubicin, cyclophosphamide) as second line
chemotherapy in patients with metastatic breast cancer progressing under
FEC (fluorouracil, epirubicin, cyclophosphamide) chemotherapy*
G. Catimel,1 F. Chauvin,2 J. P. Guastalla,1 P. Rebattu,1 P. B i r o n ^ M. Clavel^1
1
Department of Medicine and 2 Biostatistics unit, Centre Leon Berard, Lyon, France

Summary combination of fluorouracil 500 mg/m2, doxorubicin 50 mg/

m2 and cyclophosphamide 500 mg/m2 every 4 weeks (FAC).
Background: The cross-over resistance between different Results: Five patients achieved partial responses, ranging in
anthracyclines in breast carcinoma has not been largely eval- duration from 5 to 8 months. The main toxicity was cardiac,
uated in clinical trials. with congestive heart failure documented in five patients.
Patients and methods: Nineteen patients with metastatic Conclusion: The findings indicate an absence of cross-
breast cancer who had failed prior first line FEC chemother- resistance of doxorubicin in some epirubicin-resistant patients.
2 2
apy (fluorouracil 500 mg/m , epirubicin 50 mg/m cyclo-
phosphamide 500 mg/m2, every 4 weeks) were treated with a Key words: breast cancer, anthracyclines, cross-resistance

Introduction measurable or evaluable lesions, no brain or leptomeningeal in-

volvement, normal liver and renal functions, WBC >3,000/mm3,
Many different cytotoxic agents are effective against platelets >100,000/mm:!. Prior doxorubicin-based chemotherapy
was accepted if given as adjuvant and if the total cumulative dose of
metastatic breast cancer. Doxorubicin is considered the doxorubicin was OOO mg/m2. Patients with histories of heart dis-
most effective single agent, yielding an objective re- ease, determined by clinical signs of cardiac failure were not includ-
sponse rate of 38% to 50% in previously untreated pa- ed, nor were those with a left ventricular ejection fraction (LVEF) of
tients [1,2]. less than 40% as measured by echography. Only patients progres-
sing after FEC (fluorouracil 500 mg/m2, epirubicin 50 mg/m2,
During the past decade, new analogues of doxorubi- cyclophosphamide 500 mg/m2, every four weeks) first-line chemo-
cin were developed in an attempt to diminish its toxic therapy were eligible for the study.
effects, particularly on the heart. The most thoroughly The therapeutic regimen consisted of fluorouracil 500 mg/m2,
studied of these, epirubicin (4'-epi-doxorubicin), has doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2. Treat-
been shown in experimental models to be significantly ment cycles were repeated at the same intervals as FEC, i.e., every
28 days, with all drugs being administered intravenously on day 1 of
less cardiotoxic than doxorubicin, with comparable each cycle. Physical examination, blood count and toxicities were
antitumor activity [3]. assessed at each cycle. Follow-up LVEF measurement was per-
Several randomised clinical trials have demonstrated formed every 8 weeks. Response to treatment was evaluated every
that epirubicin is effective in metastatic breast cancer two courses using the WHO criteria. Patients continued to receive
and better tolerated than doxorubicin when given as chemotherapy until evidence of disease progression or the onset of
unacceptable toxicity.
single-drug [4] or in combination chemotherapy [5,6|.
To date one of the most frequently used anthra-
cycline-containing combinations has been the fluoro-
uracil, epirubicin and cyclophosphamide regimen Results
(FEC). The objective of the present study was to evalu-
ate the effectiveness of FAC (fluorouracil, doxorubicin, Patient characteristics are detailed in Table 1. Seventy-
cyclophosphamide) chemotherapy in patients with me- nine percent of the patients were postmenopausal, and
tastatic breast cancer progressing after a first-line FEC 42% had previously received doxorubicin-based adju-
regimen, and to determine the degree of cross-resist- vant chemotherapy. A majority of the patients had poor
ance between epirubicin and doxorubicin. prognoses, 58% having liver metastases, and 42% hav-
ing 3 metastatic sites.
Of the 19 patients who entered the study, 2 had pre-
Patients and methods viously achieved partial response during FEC first-line
chemotherapy (for 12 and 14 months) and 6 had ex-
Nineteen patients with metastatic breast carcinoma entered this perienced disease stabilisation (for 6 to 8 months);
trial. Eligibility criteria were: age <70 year, performance status <3 these eight patients were included when progressing.
(ECOG scale), hormono-independent disease, the presence of
The 11 remaining patients had progressive disease after
* This paper is dedicated to the memory of M. Clavel who initiated 3 courses of FEC.
this trial. All patients were evaluable for response and toxicity.
96

Table 1. Patient characteristics.

Patients Age Adjuvant Menopausal Response to Sites of disease Response to

No. (year) chemotherapy status FEC (duration FAC (duration
in months) in months)

1 63 CAF x 6, CMF x 6 Post PD Liver, lung, bone PR (7)

2 39 CAF x 6, CMF x 9 Post PD Liver, bone PR (5)
3 50 None Pre PD Liver, bone, soft tissue PR (8)
4 58 None Post SD(6) Lung, bone PR (5)
5 42 None Pre PD Lymph node, soft tissue, bone PR (5)
6 47 None Post SD(8) Lung, soft tissue SD(4)
7 51 None Pre PR (14) Liver SD(5)
8 39 CAF x 6, CMF x 6 Post SD(6) Liver, bone SD(6)
9 52 None Post PD Liver, bone SD(6)
10 65 CAFX3 Post PD Lung SD(6)
11 54 CAF x 6, CMF x 6 Post SD(6) Liver, soft tissue PD
12 54 CAF x 6, CMF x 6 Post PD Bone PD
13 68 None Post PR (12) Liver, lung, bone PD
14 61 CAF x 6, CMF x 6 Post SD(6) Liver, lung, bone PD
15 55 None Post SD(6) Lung, bone PD
16 38 None Post PD Bone, lung, soft tissue PD
17 47 None Pre PD Soft tissue PD
18 63 CAFX6 Post PD Liver, bone, lung PD
19 48 None Post PD Liver, bone, lung PD

Five partial responses were observed. Sites and dura- were put on the FAC regimen in which the only differ-
tions of response were as follows: liver and lung: 7 ence was the replacement of epirubicin by the same
months; liver: 5 months; liver and soft tissue: 8 months; dose (50 mg/m2) of doxorubicin. All patients had pre-
lung: 5 months; lymph node and soft tissue: 5 months. viously received at least 3 monthly courses of FEC
None of the 5 patients had responded to prior FEC chemotherapy, administered in appropriate doses and
chemotherapy (4 had progressive disease after 3 schedules, and they all had clearly documented pro-
courses and 1 had disease stabilisation for 6 months), gression while receiving FEC. Five of the nineteen pa-
and 2 of them had previously received doxorubicin in tients who entered this trial achieved objective partial
an adjuvant setting. Furthermore, disease stabilisation responses ranging from five to eight months. In this
was observed in 5 patients, with time to progression trial, doxorubicin and epirubicin were given at equi-
ranging from 4 to 6 months. molar doses. Although in metastatic breast cancer
Significant toxicity was primarily cardiotoxicity. Five doxorubin and epirubicin appear equally active at
patients developed congestive heart failure (grade 3 in
4 patients, grade 4 in 1 patient). FAC chemotherapy Table 2. Cumulative anthracycline doses and cardiac toxicity.
had to be discontinued in one patient in partial re-
sponse because of cardiotoxicity. In two patients, car- Patients Epirubicin Doxorubicin cumulative Cardiac
No. cumulative dose (mg/ m2) toxicity
diotoxicity occurred during disease progression. In two dose (OMS
additional patients, the cardiac toxicity was delayed 3 (mg/m2) Adjuvant Advanced Total grade)
and 5 months after the end of FAC chemotherapy. The chemo- disease dose
cumulative administered doses of doxorubicin and epi- therapy
rubicin are described in Table 2, according to cardiac
1 150 300 315 615 Yes (3)
toxicity. 2 150 300 250 550 No
Other chemotherapy-related toxic effects con- 3 200 0 400 400 No
sisted of leukopenia (grade HI-IV: 3 patients), alopecia 4 300 0 250 250 No
(grade HI: 12 patients) and vomiting (grade III: 8 pa- 5 150 0 250 250 No
6 300 0 200 200 No
tients).
7 500 0 300 300 Yes (3)
8 350 300 300 600 Yes (4)
9 150 0 300 300 No
Discussion 10 150 150 300 450 No
11 250 300 100 400 No
12 150 300 200 500 No
Chemotherapy in patients with metastatic breast cancer 13 600 0 150 150 No
is still palliative. The median survival time for such 14 300 300 100 400 Yes (3)
patients is about two years. After failure of a first-line 15 300 0 150 150 No
anthracycline-based chemotherapy, objective re- 16 150 0 150 150 No
sponses occur in fewer than 30% of the patients. 17 150 0 150 150 No
18 150 300 150 450 Yes (3)
In the present study, patients with metastatic breast 19 150 0 50 No
50
cancer progressing after a first-line FEC chemotherapy
 97

equal doses on a mg per m2 basis, reports from dif- Although the results of our trial are of necessity lim-
ferent randomized clinical trials are in conflict: similar ited by the small number of patients, they might suggest
therapeutic results were achieved by equimolar doses that in some cases, there is no cross-resistance between
in some studies [5, 6], and by equimyelotoxic doses in epirubicin and doxorubicin. These data certainly war-
other studies [7-9]. Thus, if 50 mg of epirubicin is not rant further evaluation in clinical trials, taking into
equivalent to 50 mg of doxorubicin, some responses account the potential cardiotoxicity of such an approach.
were still obtained, but based on a dose-effect, when In our opinion, doxorubicin still represents the refer-
epirubicin was replaced with the same dose of doxo- ence chemotherapeutic agent in the treatment of meta-
rubicin. Questions remain concerning the cross resist- static breast cancer. Its systematic replacement by epi-
ance between different anthracycline compounds. rubicin or other anthracycline analogues in first-line
Results of studies performed on in vitro cell cultures chemotherapy regimens is contestable.
and on human tumor xenografts have suggested that
there could be an incomplete cross-resistance between
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patients who did not experience cardiac toxicity. Even Received 25 February 1993; accepted 17 August 1993.
though the cardiotoxic potency of epirubicin is known
Correspondence to:
to be lower than that of doxorubicin, our experience
G. Catimel, M.D.
confirms that a sequential administration of epirubicin Centre Leon Berard
and doxorubicin can induce cumulative dose-depend- 28, rue Laennec
ent heart failure. 69373 Lyon Cedex 08, France