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-

Many different cytotoxic agents are effective against
metastatic breast cancer. Doxorubicin is considered the
most effective single agent, yielding an objective re-
sponse rate of 38% to 50% in previously untreated pa-
tients [1,2].
During the past decade, new analogues of doxorubi-
cin were developed in an attempt to diminish its toxic
effects, particularly on the heart. The most thoroughly
studied of these, epirubicin (4'-epi-doxorubicin), has
been shown in experimental models to be significantly
less cardiotoxic than doxorubicin, with comparable
antitumor activity [3].
Several randomised clinical trials have demonstrated
that epirubicin is effective in metastatic breast cancer
and better tolerated than doxorubicin when given as
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
(FEC). The objective of the present study was to evalu-
ate the effectiveness of FAC (fluorouracil, doxorubicin,
cyclophosphamide) chemotherapy in patients with me-
tastatic breast cancer progressing after a first-line FEC
regimen, and to determine the degree of cross-resist-
ance between epirubicin and doxorubicin.
Patients and methods
Nineteen patients with metastatic breast carcinoma entered this
trial. Eligibility criteria were: age <70 year, performance status <3
(ECOG scale), hormono-independent disease, the presence of
* This paper is dedicated to the memory of M. Clavel who initiated
this trial.
volvement, normal liver and renal functions, WBC >3,000/mm3,
platelets >100,000/mm:!. Prior doxorubicin-based chemotherapy
was accepted if given as adjuvant and if the total cumulative dose of
doxorubicin was OOO mg/m2. Patients with histories of heart dis-
ease, determined by clinical signs of cardiac failure were not includ-
ed, nor were those with a left ventricular ejection fraction (LVEF) of
less than 40% as measured by echography. Only patients progres-
sing after FEC (fluorouracil 500 mg/m2, epirubicin 50 mg/m2,
cyclophosphamide 500 mg/m2, every four weeks) first-line chemo-
therapy were eligible for the study.
The therapeutic regimen consisted of fluorouracil 500 mg/m2,
doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2. Treat-
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
each cycle. Physical examination, blood count and toxicities were
assessed at each cycle. Follow-up LVEF measurement was per-
formed every 8 weeks. Response to treatment was evaluated every
two courses using the WHO criteria. Patients continued to receive
chemotherapy until evidence of disease progression or the onset of
unacceptable toxicity.
Results
Patient characteristics are detailed in Table 1. Seventy-
nine percent of the patients were postmenopausal, and
42% had previously received doxorubicin-based adju-
vant chemotherapy. A majority of the patients had poor
prognoses, 58% having liver metastases, and 42% hav-
ing 3 metastatic sites.
Of the 19 patients who entered the study, 2 had pre-
viously achieved partial response during FEC first-line
chemotherapy (for 12 and 14 months) and 6 had ex-
perienced disease stabilisation (for 6 to 8 months);
these eight patients were included when progressing.
The 11 remaining patients had progressive disease after
3 courses of FEC.
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

equal doses on a mg per m2 basis, reports from dif-
ferent randomized clinical trials are in conflict: similar
therapeutic results were achieved by equimolar doses
in some studies [5, 6], and by equimyelotoxic doses in
other studies [7-9]. Thus, if 50 mg of epirubicin is not
equivalent to 50 mg of doxorubicin, some responses
were still obtained, but based on a dose-effect, when
epirubicin was replaced with the same dose of doxo-
rubicin. Questions remain concerning the cross resist-
ance between different anthracycline compounds.
Results of studies performed on in vitro cell cultures
and on human tumor xenografts have suggested that
there could be an incomplete cross-resistance between
doxorubicin and epirubicin in ovarian carcinoma. In
these studies, two human tumors heterotransplanted in
nude mice were resistant to doxorubicin but sensitive to
epirubicin [10].
To our knowledge, the cross-over resistance between
anthracyclines in breast carcinoma has not been evalu-
ated in clinical trials. Henderson et al. published the
results of a randomized study with a crossover design
comparing mitoxantrone (14 mg/m2/3 weeks) to doxo-
rubicin (75 mg/m2/3 weeks) [11]. In this trial, 4% of the
patients previously treated with doxorubicin had sec-
ondary responses to mitoxantrone, and 11% who had
been previously treated with mitoxantrone (all were pa-
tients without initial response to mitoxantrone) had
secondary responses to doxorubicin. It might be argued
that mitoxantrone, an anthracenedione, exerts its cyto-
toxic activity through two different mechanisms: by
intercalation with DNA, like the anthracyclines, but
also by non-intercalative electrostatic binding. This
would explain the lack of complete cross-resistance be-
tween mitoxantrone and doxorubicin [12].
In a randomized trial testing the efficacy of a three-
week regimen of carminomycin (18 mg/m2) versus
4'-epidoxorubicin (90 mg/m2) as first-line chemother-
apy in advanced breast cancer, patients whose disease
failed to respond to first-line anthracycline received
doxorubicin 60 mg/m2 every three weeks. Significant
antitumor activity was obtained in 4 of 19 patients
(21%) pretreated with carminomycin, and in 1 of 12
patients (8.3%) pretreated with epirubicin [13].
In our study, the high incidence of cardiac toxicity,
with 5 severe cardiac events among 19 patients, is relat-
ed to the high cumulative anthracycline doses admin-
istered. The median cumulative dose was 300 mg/m2
(range 50-615) for doxorubicin and 200 mg/m2 (range
150-600) for epirubicin in the entire patient group.
Furthermore, the median cumulative dose in patients
who developed cardiac heart failure was 300 mg/m2 of
epirubicin and 450 mg/m2 of doxorubicin, whereas it
was only 150 mg/m2 and 250 mg/m2, respectively, in
patients who did not experience cardiac toxicity. Even
though the cardiotoxic potency of epirubicin is known
to be lower than that of doxorubicin, our experience
confirms that a sequential administration of epirubicin
and doxorubicin can induce cumulative dose-depend-
ent heart failure.
97
Although the results of our trial are of necessity lim-
ited by the small number of patients, they might suggest
that in some cases, there is no cross-resistance between
epirubicin and doxorubicin. These data certainly war-
rant further evaluation in clinical trials, taking into
account the potential cardiotoxicity of such an approach.
In our opinion, doxorubicin still represents the refer-
ence chemotherapeutic agent in the treatment of meta-
static breast cancer. Its systematic replacement by epi-
rubicin or other anthracycline analogues in first-line
chemotherapy regimens is contestable.
References
1. Nemoto T, Rosner D, Diaz R et al. Chemotherapy for meta-
slatic breast cancer. Cancer 1978; 41: 2073-7.
2. Hoogstraten B, George SL, Samal B et al. Combination chemo-
therapy and adriamycin in advanced breast cancer. Cancer
1976; 38: 13-20.
3. Ganzina F. 4'-epi-doxorubicin, a new analogue of doxorubicin:
A preliminary overview of preclinical and clinical data. Cancer
Treat Rev 1983; 10:1-22.
4. Brambilla C, Rossi A, Bonfante V et al. Phase II study of doxo-
rubicin versus epirubicin in advanced breast cancer. Cancer
Treat Rep 1986; 70: 261-6.
5. French Epirubicin Study Group. A prospective randomized
phase III trial comparing combination chemotherapy with
cyclophosphamide, fluorouracil and either doxorubicin or epi-
rubicin. J Clin Oncol 1988; 6: 967-88.
6. Italian Multicentre Breast Study with Epirubicin. Phase III
randomized study of fluorouracil, epirubicin and cyclophos-
phamide versus fluorouracil, doxorubicin and cyclophospha-
mide in advanced breast cancer: An kalian multicentre trial. J
Clin Oncol 1988; 6: 976-82.
7. Perez DJ, Harvey VJ, Robinson BA et al. A randomized com-
parison of single-agent doxorubicin and epirubicin as first-line
cytotoxic therapy in advanced breast cancer. J Clin Oncol
1991; 9: 2148-52.
8. Hortobagyi GN, Yap HY, Kau SW et al. A comparative study
of doxorubicin and epirubicin in patients with metastatic breast
cancer. Am J Clin Oncol 1989; 12: 57-62.
9. Jain KK, Casper ES, Geller NL et al. A prospective random-
ized comparison of epirubicin and doxorubicin in patients with
advanced breast cancer. J Clin Oncol 1985; 3:818-26.
10. Casazza AM, Giuliani FC. Preclinical properties of epirubicin.
In Bonadonna G (ed): Advances in anthracycline chemother-
apy: Epirubicin. Masson: Milan 1984; 31-40.
11. Henderson IC, Allegra JC, Woodcock T et al. Randomized
clinical trial comparing mitoxantrone with doxorubicin in pre-
viously treated patients with metastatic breast cancer. J Clin
Oncol 1989; 7: 560-71.
12. Alberts DS, Peng YM, Bowden GT et al. Mechanisms of action
and pharmacokinetics of novantrone in intravenous and intra-
peritoneal therapy. In the current status of novantrone. New
York, John Wiley, 1985; 15-21.
13. Rozencweig M, Ten Bokkel Huinink W, Cavalli F et al. Ran-
domized phase II trial of carminomycin versus 4'-epidoxo-
rubicin in advanced breast cancer. J Clin Oncol 1984; 2:
275-81.
Received 25 February 1993; accepted 17 August 1993.
Correspondence to:
G. Catimel, M.D.
Centre Leon Berard
28, rue Laennec
69373 Lyon Cedex 08, France