In the United States each year, more than 180,000 women are diagnosed
with breast cancer and more than 45,000 die of the disease each year.
In spite of major advances in adjuvant therapy, metastatic breast cancer
remains a major clinical problem affecting large numbers of patients.
For many years, standard-dose combination chemotherapy has been the
mainstay of therapy for metastatic disease that is hormone resistant, estrogen-receptor
negative, or associated with life-threatening or visceral disease. The
choice of initial chemotherapy has been combination cyclophosphamide (Cytoxan)/methotrexate/5-fluorouracil
(5-FU) (CMF) or CMF with prednisone (CMFP), with or without vincristine
(Oncovin) followed by anthracycline, or doxorubicin (Adriamycin)-containing
combinations.[2-4] The choice of initial chemotherapy is often complicated
by early relapse in patients who have received adjuvant chemotherapy.
When first described by Cooper, the CMF combination was reported
to induce high response rates. Modern criteria and increasingly sophisticated
imaging procedures for assessment of the extent of disease and response
have shown that the CMF regimen, with or without vincristine and prednisolone,
produces objective responses in about 37% to 59% of patients (Table
1).[2,6-14] Perhaps more significant, median response duration ranges
from 6 to 11 months, and the median survival from initiation of treatment
ranges from 7 to 16 months.
CMF Combinations and Doxorubicin
Doxorubicin alone has been shown to be as active as CMF in randomized
studies of patients with advanced breast cancer.[2,8,15,16] In these studies,
single-agent doxorubicin produced shorter response durations than CMF,
but there was no obvious difference in survival. Survival was difficult
to interpret, however, because patients were often crossed over to the
alternative regimen on progression.
Six randomized studies of cyclophosphamide/doxorubicin/5-FU (CAF) versus
CMF in advanced breast cancer have been reviewed by Henderson.[17-23] Three
of the six showed significantly higher response rates with the CAF combination,
but only two of six showed a statistically significant survival advantage
for the doxorubicin combination.
These studies have been interpreted as showing a slight advantage for
doxorubicin combinations in treatment of metastatic breast cancer.
This interpretation is controversial, and any improvement in outcome with
standard-dose doxorubicin combinations compared to CMF is likely to be
An Australian randomized study compared doxorubicin/cyclophospha
mide (AC) with CMFP in 305 previously untreated patients with metastatic
breast cancer. The response, response duration, and survival were similar
with either CMFP or AC given continuously until relapse. There also was
no difference in the effect of either regimen on life-threatening or visceral
disease. The doxorubicin combination was associated with significantly
more nausea, vomiting, and alopecia than was the CMFP combination. A quality-of-life
assessment by patients on this study revealed that the parameter measuring
nausea and vomiting deteriorated for patients on AC, but not for those
This Australian trial provided a rationale for the use of CMFP as the
control arm of a phase III randomized trial of CMFP versus paclitaxel (Taxol).
Paclitaxel is a novel cytotoxic agent that binds to the beta-tubulin
monomer, inducing permanent microtubular polymerization.[24,25] The resulting
loss of dynamic reorganization of microtubules during mitosis results in
selective blockade of the G2/M phase of cell division. This
action in vitro correlates with clinical activity of paclitaxel.
Paclitaxel, given as a 24-hour infusion, has been found to be active
in previously treated patients with advanced breast cancer. In a single-institution
study conducted at the M.D. Anderson Cancer Center, Holmes reported 6 of
11 previously treated patients responded to paclitaxel therapy with similar
responses seen in 8 of 14 patients who had prior adjuvant chemotherapy
only. Of six patients who were resistant to doxorubicin, two achieved
a partial remission in response to paclitaxel. Since this initial report
there have been a number of studies and reviews confirming that paclitaxel
is active in previously treated and anthracycline-resistant breast cancer.[28-32]
The reported response rates have been quite variable, however, ranging
from 20% to 62% with similar variability in response duration.
The schedule of paclitaxel infusion also has varied, with most of the
earlier studies using 24-hour infusions. Other studies have since reported
1-hour and 3-hour infusion times.[33-35] A large, randomized European-Canadian
study compared two doses of paclitaxel (135 mg/m² vs 175 mg/m²)
and two infusion times (3-hour vs 24-hour) in patients with relapsed ovarian
cancer. In these ovarian cancer patients, there were no differences related
to the two infusion rates. The incidence of hypersensitivity reactions
was low and also was not influenced by dose or schedule. However, this
study clearly demonstrated that the 24-hour paclitaxel infusion is associated
with a significantly greater reduction in neutrophils following each course
compared to the 3-hour infusion. This observation has been confirmed
by a recent randomized study comparing 3-, 6-, and 96-hour infusions of
paclitaxel. Greco and Hainsworth showed that 1-hour paclitaxel
infusions were safe, with the dose-limiting toxicity remaining leukopenia,
as expected. Although numbers were small, approximately 35% of previously
treated patients with breast cancer responded to the 1-hour paclitaxel
regimen, at a dose of 135 mg/m². According to these data, there is
no compelling evidence that longer infusion times are associated with in
creased efficacy, at least in ovarian cancer. Those data and the convenience
of the shorter administration schedule have provided a rationale for exploration
of shorter infusion times for the treatment of breast cancer.
We have reported the preliminary results of a phase III randomized trial
of CMFP versus paclitaxel in previously untreated patients with metastatic
breast cancer. Patients eligible for this study had measurable or evaluable
metastatic breast cancer and had had no prior chemotherapy, except for
adjuvant chemotherapy, for at least 6 months prior to study entry. No prior
radiotherapy was permitted for at least 4 weeks prior to study entry. Patients
were required to have Eastern Cooperative Oncology Group performance status
of 0 to 2, adequate bone marrow function, liver function, and renal function.
Responses and toxicity were evaluated using the criteria of the World Health
Organization (WHO), and patients were required to give written informed
consent prior to enrollment.
Eligible patients were randomized to either paclitaxel or CMFP. Paclitaxel
200 mg/m² was given as a 3-hour continuous intravenous (IV) infusion
every 21 days for a total of 8 courses over 24 weeks. Standard premedication
included dexamethasone 20 mg orally (PO) 12 and 6 hours prior to therapy,
and diphenhydramine 50 mg IV and cimetidine 300 mg IV 30 minutes prior
to paclitaxel. Standard antiemetics including metoclopramide, prochlorperazine,
ondansetron, and dexamethasone were given if required.
CMFP chemotherapy was given as cyclophosphamide 100 mg/m² PO daily
on days 1 to 14, methotrexate 40 mg/m² IV on days 1 and 8, 5-FU 600
mg/m² IV on days 1 and 8, and prednisone 40 mg/m² PO daily days
1 to 14. This schedule was repeated every 4 weeks for six courses, over
24 weeks. Antiemetics were given as for the paclitaxel treatment arm. Upon
completion of 6 months of therapy, chemotherapy was stopped and patients
were observed until relapse.
Appropriate clinical assessment and imaging techniques for tumor evaluation
were carried out at baseline and at 12 and 24 weeks unless the patient
progressed clinically before that time. The routine assessments included
quality-of-life evaluations previously used and reported by this group
of investigators. Patients whose disease progressed were recommended
for subsequent treatment with single-agent epirubicin.
1. American Cancer Society: Cancer statistics. CA Cancer J Clin
2. Brambilla C, DeLena M, Rossi A, et al: Response and survival in advanced
breast cancer after two non-cross-resistant combinations. Br Med
J 1:801-804, 1976.
3. Canellos GP, Pocock S, Taylor S, et al: Combination chemotherapy
for metastatic breast carcinoma. Cancer 38:1882-1886, 1976.
4. Tranum B, Hoogstraten B, Kennedy A, et al: Adriamycin in combination
for the treatment of breast cancer. Cancer 41:2078-2083, 1978.
5. Cooper RG: Combination chemotherapy in hormone-resistant breast cancer
(abstract). Proc Am Assoc Cancer Res 10:15, 1967.
6. Muss HB, White DR, Cooper R, et al: Combination chemotherapy in advanced
breast cancer. A randomised trial comparing a three vs a five-drug program.
Arch Intern Med 137:1711-1714, 1977.
7. Smalley RV, Murphy S, Huguley CM, et al: Combination versus sequential
five-drug chemotherapy in metastatic carcinoma of the breast. Cancer
Res 36:3911-3916, 1976.
8. Hoogstraten B, George SL, Samal B, et al: Combination chemotherapy
and Adriamycin in patients with advanced breast cancer. Cancer 38:13-20,
9. Cebon JS, Bishop JF, Harvey V, et al: Dose intense weekly cyclophosphamide,
methotrexate, 5-fluorouracil, vincristine and prednisolone (CMFP) in advanced
breast cancer. Br J Cancer 61:133-136, 1990.
10. Canellos GP, DeVita V, Gold GL, et al: Combination chemotherapy
for advanced breast cancer: Response and effect on survival. Ann Intern
Med 84:389-392, 1976.
11. Cummings FJ, Gelman R, Horton J: Comparison of CAF versus CMFP in
metastatic breast cancer: Analysis of prognostic factors. J Clin Oncol
12. Coates A, Gebski V, Bishop JF, et al: Optimizing quality of life
during chemotherapy for advanced breast cancer: A comparison of intermittent
and continuous treatment strategies. N Engl J Med 317:1490-1495,
13. Aisner J, Weinberg V, Perloff M, et al: Chemotherapy vs chemoimmunotherapy
(CAF vs CAFVP vs CMF each +/- MER) for metastatic carcinoma of the breast.
J Clin Oncol 5:1523-1533, 1987.
14. Creech R, Catalano RB, Mastrangelo MJ, et al: An effective low-dose
intermittent cyclophosphamide, methotrexate, and 5-fluorouracil treatment
regimen for metastatic breast cancer. Cancer 35:1101-1107, 1975.
15. Carbone PP, Bauer M, Band P, et al: Chemotherapy of disseminated
breast cancer. Cancer 39:2916-2922, 1977.
16. Tormey DC, Gelman R, Band PR, et al: Comparison of induction chemotherapies
for metastatic breast cancer. Cancer 50:1235-1244, 1982.
17. Henderson IC: Principles in the management of metastatic disease,
in Harris JR, Hellman S, Henderson IC, et al (eds): Breast Diseases,
pp 604-673. Philadelphia, Lippincott, 1992.
18. Bull J, Tormey D, Li SH, et al: A randomized comparative trial of
Adriamycin versus methotrexate in combination drug therapy. Cancer 41:1649-1657,
19. Muss HB, White DR, Richards F III, et al: Adriamycin versus methotrexate
in five-drug combination chemotherapy for advanced breast cancer. Cancer
20. Bezwoda WR, de Moor NG, Derman D, et al: Combination chemotherapy
of metastatic breast cancer. Cancer 44:392-397, 1979.
21. Tormey DC, Weinberg VE, Holland JF, et al: A randomized trial of
five and three drug chemotherapy and chemoimmunotherapy in women with operable
node positive breast cancer. J Clin Oncol 1:138-145, 1983.
22. Brincker H, Rose C, von der Maase H, et al: A randomized study of
CAF + TAM (tamoxifen) versus CMF + TAM in metastatic breast cancer (abstract).
Proc Am Soc Clin Oncol 3:113, 1984.
23. Tormey DC, Weinberg VE, Leone LA, et al: A comparison of intermittent
vs continuous and of Adriamycin vs methotrexate 5-drug chemotherapy for
advanced breast cancer. Am J Clin Oncol 7:231-239, 1984.
24. Horwitz SB: Mechanism of action of Taxol. Trends Pharmacol Sci
25. Rao S, Horwitz SB, Ringel I: Direct photoaffinity labelling of tubulin
with Taxol. J Natl Cancer Inst 84:785-788, 1992.
26. Rowinsky EK, Burke PJ, Karp JE, et al: Phase I and pharmacodynamic
study of Taxol in refractory acute leukemias. Cancer Res 49:4640-4647,
27. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of Taxol,
an active drug in treatment of metastatic breast cancer. J Natl Cancer
Inst 83:1797-1805, 1991.
28. O'Shaughnessy JA, Cowan KH: Current status of paclitaxel in the
treatment of breast cancer. Breast Cancer Res Treat 33:27-37, 1994.
29. Seidman AD, Reichman BS, Crown JPA, et al: Paclitaxel as second
and subsequent therapy for metastatic breast cancer: Activity independent
of prior anthracycline response. J Clin Oncol 13:1152-1159, 1995.
30. Gianni L, Capri G, Munzone E, et al: Paclitaxel efficacy in patients
with advanced breast
cancer resistant to anthracyclines. Semin Oncol 21(suppl 8):29-33,
31. Wilson WH, Berg SL, Bryant G, et al: Paclitaxel in doxorubicin-refractory
or mitoxantrone-refractory breast cancer: A phase I/II trial of 96-hour
infusion. J Clin Oncol 12:1621-1629, 1994.
32. Gelmon K, Nabholtz JM, Bontenbal M: Randomized trial of two doses
of paclitaxel in metastatic breast cancer after failure of standard therapy
(abstract 493). Ann Oncol 5(suppl 5):198, 1994.
33. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian
randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus
low-dose and long versus short infusion. J Clin Oncol 12:2654-2666,
34. Schiller JH, Storer B, Tutsch K, et al: A phase I trial of 3 hour
infusions of paclitaxel with or without granulocyte colony-stimulating
factor. Semin Oncol 21(suppl 8):9-14, 1994.
35. Greco AP, Hainsworth JD: One hour paclitaxel infusion schedules:
A 1-hour infusion schedule. Semin Oncol 22(suppl 6):118-123, 1995.
36. Rischin D, Millward M, Toner GC, et al: Cremophor levels in patients
receiving 3, 6 and 96 hour infusions of paclitaxel. J Natl Cancer Inst
1996 (in press).
37. Bishop JF, Dewar J, Tattersall MH, et al: A randomized phase III
study of Taxol (paclitaxel) vs CMFP in untreated patients with metastatic
breast cancer (abstract). Proc Am Soc Clin Oncol 15:110, 1996.
38. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of
cancer treatment. Cancer 47:207-214, 1981.
39. Sledge GW, Robert N, Sparano JA, et al: Eastern Cooperative Oncology
Group studies of paclitaxel and doxorubicin in advanced breast cancer.
Semin Oncol 22(suppl 6):105-108, 1995.
40. 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.
41. Gianni L, Demicheli R, Moliterni A, et al: Pilot study of primary
chemotherapy with doxorubicin/paclitaxel (AT) in women with T2-T3 or locally
advanced breast carcinoma (abstract). Proc Am Soc Clin Oncol 15:A129,
42. Gianni L, Capri G, Tarenzi E, et al: Efficacy and cardiac effects
of 3-hr paclitaxel (P) plus bolus doxorubicin (DOX) in women with untreated
metastatic breast carcinoma (abstract). Proc Am Soc Clin Oncol 15:A128,
43. Gehl P, Goesgaard N, Paaske L, et al: Combined doxorubicin and paclitaxel
in advanced breast cancer: Effective and cardiotoxic. Ann Oncol