Paclitaxel (Taxol) is a taxane known for its high activity in breast
and ovarian cancer. Its effectiveness in breast cancer was originally
observed by Holmes et al and Reichman et al whose impressive study
results indicated that paclitaxel has a high degree of activity compared
with other standard chemotherapies for metastatic breast cancer, as well
as significant activity in patients who had received multiple prior chemotherapies.
In addition, these investigators' studies showed that clinical resistance
to doxorubicin (Adriamycin) does not predict resistance to paclitaxel.
These results motivated evaluation of a combination of paclitaxel and
anthracyclines, which are the other most active drugs available for treatment
of metastatic breast cancer. Holmes et al performed a phase I trial
using paclitaxel given by 24-hour intravenous infusion, followed by doxorubicin
by 48-hour continuous infusion. The dose-limiting toxicity of that trial
was mucositis, which occurred with relatively low doses of both substances.
Sledge et al repored a phase I study using the same regimen, but the
reverse sequence: the doxorubicin infusion was followed after 4 hours by
the 24-hour paclitaxel infusion. The rate of severe mucositis developing
with this schedule was very low. The maximum tolerated doses identified
were doxorubicin 50 mg/m² and paclitaxel 150 mg/m². In other
studies, Dombernowsky et al and Gianni et al reported high response
rates (94%) in patients with previously untreated metastatic breast cancer
treated with paclitaxel combined with doxorubicin. In those studies, paclitaxel
was given as a 3-hour infusion. The main toxicities encountered were neutropenia
and febrile neutropenia, and both studies described severe cardiac toxicities
in 15% to 25% of patients.
Epirubicin (Farmorubicin), the 4'epimer of doxorubicin, is equieffective
but less toxic than its parent compound, particularly with respect to cardiac
toxicity. Medline search recalled eight trials in which patients with
metastatic breast cancer were comparatively treated with doxorubicin vs
epirubicin.[9-17] This phase II study was therefore designed to evaluate
the safety and feasibility of the combination paclitaxel/ epirubicin, with
particular emphasis on cardiac side effects.
Only patients with histologically proven breast cancer were recruited
for this trial. Eligible patients were permitted to have undergone one
adjuvant chemotherapy or hormone therapy course or one palliative hormone
therapy course. The adjuvant therapy could have included anthracyclines
dosed to 300 mg/m². Other eligibility requirements included measurable
metastasis and normal hematologic, renal, and hepatic function. Patients
also were required to be between 18 and 70 years of age and to have a life
expectancy of more than 12 weeks.
The first 57 patients entered (Group A) were treated with epirubicin
60 mg/m² intravenously, given as a 1-hour infusion, followed by paclitaxel
175 mg/m² intravenously over 3 hours. The next 28 patients entered
(Group B) received epirubicin 90 mg/m² intravenously over 1 hour,
followed by the same starting dose and regimen of paclitaxel as was
given to Group A. All patients were premedicated with dexamethasone 20
mg given orally 12 and 6 hours before paclitaxel, and clemastine (Tavist)
2 mg intravenously and ranitidine (Zantac) 50 mg intravenously 30 minutes
prior to paclitaxel. Patients with congestive heart failure were not eligible
for the study.
Cardiac monitoring involved evaluation of left ventricular ejection
fraction after every second cycle. Paclitaxel dose escalation was permitted
in 25 mg/m² steps to a maximum of 225 mg/m², assuming a neutrophil
nadir of 1or more x 109/L, a thrombocyte nadir of 100 or more
x 109/L, and peripheral neuropathy lower than grade 2, without
granulocyte colony-stimulating factor support. In case of higher grades,
the paclitaxel dose could be reduced to 100 mg/m², again in 25 mg/m²
Of 57 and 28 patients enrolled in Groups A and B, respectively, 43 patients
in Group A and 25 patients in Group B were evaluable for response and toxicity.
The median age of patients entered in study groups A and B was 51 and 55
years, respectively, and the median Eastern Cooperative Oncology Group
performance index for all patients was 0. The majority of entered patients
were postmenopausal (Group A, 62%; Group B, 76%), and most had poorly differentiated
tumors (Group A, 63%; Group B, 74%). Adjuvant chemotherapy had been administered
to 51% of patients in Group A and 36% of patients in Group B.
Nearly 20% of patients had primary metastatic breast cancer with a large
tumor at the primary site. The localization of metastases is summarized
in Table 1. More than 80% of the patients
had two or more lesions (Table 2).
The main toxicity encountered was neutropenia. No febrile episodes
occurred in Group A, but there were two episodes in Group B. World Health
Organization grade 3 or 4 neutropenia was reported in 80.9% of the courses
overall. Thrombocytopenia and anemia were observed in less than 1% of the
courses (Table 3). Alopecia was observed
in all patients treated with more than two cycles. No peripheral neuropathy
World Health Organization grade greater than 2 was reported and myalgia
World Health Organization grade 3 was noted in only 1% of cycles. Severe
nausea and emesis were observed in 2% of the cycles (Table
4). No incidence of mucositis was described.
To date, no cardiac toxicity has been seen. The left ventricular ejection
fraction was checked by echocardiography or cardiac scintigraphy in Group
A, but one episode without clinical signs occurred in Group B.
In 15 patients from Group A we were able to escalate the paclitaxel
dose to 200 mg/m² and in seven of these patients further escalation
to 225 mg/m² was possible. In Group B, only one patient could be escalated
to 200 mg/m² and no patient was escalated to 225 mg/m². In Group
A, severe neutropenia necessitated reduction of the paclitaxel dose to
135 mg/m² in 11 patients, and further to 110 mg/m² in four of
them. In Group B, three patients required dose reduction to 135 mg/m²
Response rate was not a primary concern of this study, but it is one
of the checkpoints of oncology treatment. In this poor-prognosis study
group we achieved an overall response rate of 68% in Group A and 71% in
Group B (Table 5). In 50% of patients
who attained a remission, response occurred after the second cycle of treatment,
while 25% of the patients had their best response after the fourth cycle,
and 25% after the sixth cycle.
The median follow-up was 14.1 months in Group A and 8.2 months in Group
B. The median progression-free interval was 8.2 months in both groups with
a range of 5.3 to 11.3 months in Group A and 7.90 to 8.5 months in Group
B. For patients in Group A, the median progression-free interval was 12.5
months (95% confidence interval [CI], 9.7 to 15.3) for those attaining
a complete response and 8.1 months (95% CI 6.7 to 10.3) for those with
a partial response. In Group B, the median progression-free interval for
the patients with a complete response has not been reached, but patients
with a partial response had an interval of 8.2 months (95% CI, 7.8 to 8.5).
The median overall survival for those in Group A was 15.9 months (95% CI,
12.8 to 19), whereas in Group B the median survival has not been reached.
The combination of paclitaxel 175 mg/m²and epirubicin
60 or 90 mg/m² showed remarkable efficacy against metastatic breast
cancer with an overall response of 68% in the group treated with epirubicin
60 mg/m² and 71% in those treated with epirubicin 90 mg/m². The
treatment was generally well tolerated, although the higher epirubicin
dose induced more severe neutro penia and one case of cardiotoxicity. The
nonhematologic toxicities were mild and no cases of severe mucositis or
peripheral neuropathy were reported. The higher epirubicin dose did not
prolong progression-free survival. The observed remission rates were lower
than those reported in the study from Gianni et al, but the progression-free
interval was in the same range.
In October 1996, the German AGO Study Group initiated a phase III trial
comparing the combination of paclitaxel 175 mg/m² and epirubicin 60
mg/m² with the standard combination of epirubicin 60 mg/m² and
cyclophosphamide (Cytoxan) 600 mg/m² as first-line treatment of metastatic
1. Rowinsky EK, McGuire WP, Donehower RC: The current status of Taxol.
Principles and Practice of Gynecology Oncology Updates 1:1-16, 1993.
2. Holmes FA, Walters RS, Theriault RC, et al: Phase II trial of taxol,
an active drug in treatment of metastatic breast cancer. J Natl Cancer
Inst 83:1797-1805, 1991.
3. Reichman BS, Seidman AD, Crown JP, et al: Paclitaxel and recombinant
granulocyte-stimulating factor as initial chemotherapy for metastatic breast
cancer. J Clin Oncol 11:1943-1951, 1993.
4. Holmes FA, Frye D, Valero V, et al: Phase I study of taxol and doxorubicin
for metastatic breast cancer (abstract 66). Proc Am Soc Clin Oncol
5. Sledge GW Jr, Robert N, Sparano JA, et al: Paclitaxel (Taxol)/doxorubicin
combinations in advanced breast cancer: The Eastern Cooperative Oncology
Group experience. Semin Oncol 21(suppl 8):15-18, 1994.
6. Dombernowsky P, Gehl J, Ejlersen B, et al: Treatment of metastatic
breast cancer with paclitaxel and doxorubicin. Semin Oncol 22(suppl
7. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion
in combination with bolus doxorubicin in women with untreated metastatic
breast cancer: High antitumor efficacy and cardiac effects in a dose finding
and sequence finding study. J Clin Oncol 13:2688-2699, 1995.
8. Praga C, Trave F, Petroccione A: Anthracycline-induced cardiotoxicity
and its relevance in cancer treatment, in Nimmo WS, Tucker GT, (eds):
Clinical Measurements in Drug Evaluation. London, Wolfe Publishing,
9. Brunbilla C, Ross A, Bonfonte V, et al: Phase II study of doxorubicin
vs epirubicin in advanced breast cancer. Cancer Treat Rep 70:261-266,
10. Lawton PA, Ostrowski M, Young T: Efficacy and toxicity of single-agent
chemotherapy in advanced breast cancer (abstract). Br J Cancer 61:177,
11. Pervodchikova NI, Valvere VJ: Comparative evaluations of Farmorubicin
and Adriamycin in breast cancer, in Berkada B, et al, (eds): Progress
in Comparative Antimicrobial and Anticancer Chemotherapy, Vol 3. Istanbul
12. Hortobagyi GN, Yu P, Hyikan SW, et al: A comparative study of doxorubicin
and epirubicin in patients with metastatic breast cancer. Am J Clin
Oncol 12:57-62, 1989.
13. Jain K, Casper ES, Geller NL, et al: A prospective randomized comparison
of epirubicin and doxorubicin in patients with advanced breast cancer.
J Clin Oncol 3:818-826, 1985.
14. Taguchi T, Ogawa M, Izuo M, et al: A prospective randomized trial
comparing epirubicin and doxorubicin in advanced recurrent breast cancer.
J Cancer Chemother 13:3498-3507, 1986.
15. van Osteroom AT, Andersson M, Wildinos M, et al: Adriamycin (A)
versus 4-epi-adriamycin (E). Report of a second-line randomized phase II
study in advanced breast cancer (Trial 10811). (abstract 1.6) Proceedings
IV EORTC Breast Cancer Working Conference, London, 1987.
16. Perez DJ, Harvey VJ, Robinson BA, et al: A randomized comparison
of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy
in advanced breast cancer. J Clin Oncol 9:2148-2152, 1991.
17. Mouridsen HT, Alfthan C, Bastholt L, et al: Current status of epirubicin
(F grouporubicin) in the treatment of solid tumors. Acta Oncol 29:257-285,