The development of a new drug is not only complex but also requires
a major investment in time, resources, patients, and most important, a
collaborative effort between industry and researchers to develop tomorrow's
trials to answer today's clinical challenges. One such agent, docetaxel
(Taxotere), a semisynthetic taxane, has created excitement in the oncology
community. This excitement stems mainly from its unique mechanism of action
and antitumor activity in several cancers.
Confirmation of Efficacy in Metastatic Breast Cancer
Docetaxel promotes abnormal polymerization of tubulin and arrests depolymerization
of microtubule elements necessary for the proper functioning of the mitotic
spindle and other microtubule-based structures.[1,2] As a single agent
used in first-line chemotherapy for patients with metastatic breast cancer,
75 to 100 mg/m² of docetaxel administered as a 1-hour intravenous
infusion once every 3 weeks demonstrates significantly greater antitumor
activity compared with both older agents and newer ones such as vinorelbine
(Navelbine), edatrexate, and gemcitabine (Gemzar) (Table
1). Although reported response rates vary, the taxanes are among
the most active agents available, rivaling doxorubicin, long the most active
first-line agent for patients with metastatic breast cancer.
Numerous clinical trials have demonstrated that docetaxel is also highly
active in anthracycline-resistant tumors.[4-7] Prior to the development
of the taxanes, one of the worst prognostic signs in patients with metastatic
or high-risk primary breast cancer was anthracycline resistance. In the
pre-docetaxel era, patients with anthracycline-resistant metastatic breast
cancer had a median survival of about 4 months. Response to all other treatment
regimens, whether single-agent or combinations, was less than 15%.
Three multicenter studies show that single-agent docetaxel produces
a response rate of approximately 41% and a median survival of 10 months
in anthracycline-resistant patients (Table
2).[4-7] In comparison, paclitaxel (Taxol) achieves response rates
of 6% to 33%, vinorelbine (Navelbine) about 16%, and melphalan (Alkeran),
about 9% in this difficult-to-treat patient population.[8-10]
The first three papers of this supplement provide further confirmation
of the significant antitumor activity of docetaxel as a single agent for
previously treated and untreated patients with metastatic breast cancer.
William J. Gradishar, MD, addresses the use of docetaxel as neoadjuvant
therapy in patients with locally advanced stage III breast cancer. Preliminary
analysis of a phase II study suggests that four cycles of 100 mg/m²
of docetaxel administered as a 1-hour intravenous infusion once every 3
weeks followed by surgery, plus four cycles of standard-dose doxorubicin/cyclophosphamide
(Cytoxan, Neosar) chemotherapy and radiation, with and without tamoxifen
(Nolvadex), achieves a partial response rate of 67%. Complete response
was noted in 18% of patients, with one case being a complete pathologic
response at the time of surgery.
The second article, by Stephen Chan, MD, discusses preliminary data
from a randomized, multicenter phase III trial comparing docetaxel, 100
mg/m², for 1 hour vs doxorubicin, 75 mg/m², for 15 to 20 minutes,
every 3 weeks in patients with metastatic breast cancer who had previously
failed alkylating chemotherapy. In this setting, preliminary data indicate
that docetaxel produced a longer median time to progression, higher response
rates, and fewer cases of disease progression compared with doxorubicin.
The comparative use of docetaxel, 100 mg/m² (1-hour intravenous
infusion every 3 weeks) vs mitomycin (Mutamycin) (12 mg/m² every 6
weeks) plus vinblastine (6 mg/m² every 3 weeks) in patients with anthracycline-resistant
metastatic breast cancer is presented by Jean-Marc Nabholtz, MD. This article
discusses preliminary data from a randomized, multicenter, phase III trial
showing that docetaxel produced a longer median time to progression, higher
response rates, and fewer cases of disease progression compared with the
Although the single-agent activity of docetaxel is exciting, it is not
enough to cure primary breast cancer. Thus, intensive research efforts
seek to develop docetaxel-containing combination regimens for patients
with advanced solid tumors, including those of the breast and lung.
From the preclinical experience, there are numerous reasons to consider
docetaxel in combination therapy--among them is the ability of docetaxel
to act on tubulin, and its ability to act on a different tubulin from that
of paclitaxel, for instance.[1,2] There is incomplete cross-resistance
with several of the major drugs previously used for the management of the
various malignancies, making docetaxel a particularly attractive agent
for combination regimens.
Ascertaining the MTD
In addition, the preclinical work of Bissery and colleagues[1,2] suggests
that there are some synergistic doublets, especially those that include
cyclophosphamide, fluorouracil (5-FU), vinorelbine, methotrexate, and etoposide
(VePesid). Further, even with other drugs that are myelosuppressive and
for which there is partially overlapping toxicity, like doxorubicin, cyclophosphamide,
and methotrexate, Bissery et al[1,2] demonstrated that combinations with
60% to 70% of the maximum tolerated doses can be safely administered.
Veronique Dieras, MD, presents an overview of phase I trials designed
to establish the maximum tolerated doses and toxicity profile of the docetaxel/doxorubicin
combination in patients with metastatic breast cancer. Results from these
trials indicate that the combination is well tolerated and that docetaxel
does not appear to increase the cardiotoxicity associated with doxorubicin.
Further study with this combination is warranted.
Vicente Valero, MD, discusses the preliminary results of a phase I trial
evaluating the maximum tolerated dose and toxicity profile of docetaxel
in combination with cyclophosphamide in patients with advanced solid tumors.
Dr. Valero reports that the recommended doses for phase II study are 700
mg/m² of cyclophosphamide and 75 mg/m² of docetaxel in previously
treated patients and 800/75 mg/m² in previously untreated patients.
The use of docetaxel in a three-drug combination regimen in patients
with metastatic breast cancer is reviewed by Jean-Marc Nabholtz, MD. Based
on the preliminary results of phase I and II trials, the regimen of docetaxel,
doxorubicin, and cyclophosphamide appears to be active without an increase
in the cardiotoxicity of doxorubicin.
Combinations of docetaxel with the platinums--cisplatin (Platinol),
carboplatin (Paraplatin)--in patients with advanced non-small-cell lung
cancer are reviewed by Chandra P. Belani, MD. Favorable response rates
have been reported with docetaxel, 75 mg/m², and cisplatin, 75 mg/m²,
in previously untreated patients with non-small-cell lung cancer. Results
from phase I trials in patients with nonhematologic solid tumors indicate
that the recommended dose of docetaxel in combination with carboplatin
(target area under the curve of 6 mg/mL · min) is 80 mg/m²
without granulocyte colony-stimulating factor (G-CSF) (filgrastim [Neupogen])
support and 90 mg/m2 with G-CSF support.
Matti S. Aapro, MD, presents the preliminary results from phase I and
II studies of the use of docetaxel in combination with vinorelbine in patients
with non-small-cell lung cancer. Encouraging results have been seen, with
partial responses ranging from 27% for non-small-cell lung cancer to 70%
for metastatic breast cancer, warranting further study of docetaxel and
vinorelbine in patients with non-small-cell lung cancer.
Finally, Howard S. Burris, MD, provides a review of phase I and II studies
of docetaxel in combination with 5-FU in patients with advanced solid tumors.
Results from these trials indicate that the recommended dose for phase
II studies of docetaxel/bolus 5-FU is 60/300 mg/m² and for docetaxel/5-day
continuous infusion 5-FU is 85/750 mg/m².
1. Bissery MC, Vrignaud P, Lavelle F: Preclinical profile of docetaxel
(Taxotere): Efficacy as a single agent and in combination. Semin Oncol
22(suppl 13):3-16, 1995.
2. Bissery MC, Guenard D, Gueritte-Voegelein F, et al: Experimental
antitumor activity of Taxotere (RP 56976, NSC 628503), a Taxol analogue.
Cancer Res 51:4845-4852, 1991.
3. Trudeau ME: First-line treatment of metastatic breast cancer. Anticancer
Drugs 7(suppl 2):9-12, 1996.
4. Radvin P, Burris HA, Cook G, et al: Phase II trial of docetaxel in
advanced anthracycline-resistant or anthracenedione-resistant breast cancer.
J Clin Oncol 13:2879-2885, 1995.
5. Valero V, Holmes FA, Walters RS, et al: Phase II trial of docetaxel,
a new, highly effective antineoplastic agent in the management of patients
with anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886-2894,
6. ten Bokkel Huinink WW, Prove AM, Piccart M, et al: A phase II trial
of docetaxel (Taxotere) in second line treatment with chemotherapy for
advanced breast cancer: A study of the EORTC Early Clinical Trials Group.
Ann Oncol 5:527-532, 1994.
7. Guastalla JP, Bonneterre J, Fumoleau P, et al: A phase II trial of
docetaxel in patients with anthracycline-resistant metastatic breast cancer
(MBC) (abstract 348). Eur J Cancer 31A:S75-S76, 1995.
8. Seidman AD, Hudis CA, Norton L: Memorial Sloan-Kettering Cancer Center
experience with paclitaxel in the treatment of breast cancer: from advanced
disease to adjuvant therapy. Semin Oncol 22(suppl 8):3-8, 1995.
9. Vermorken JB, ten Bokkel Huinink WW, Mandjes IA, et al: High-dose
paclitaxel with granulocyte colony-stimulating factor in patients with
advanced breast cancer refractory to anthracycline therapy: A European
cancer center trial. Semin Oncol 22(suppl 8):16-22, 1995.
10. Jones S, Winer E, Vogel C, et al: Randomized comparison of vinorelbine and melphalan
in anthracycline-refractory advanced breast cancer. J Clin Oncol 13:2567-2574,