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(Drug information on 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(Drug information on gemcitabine) (Gemzar) (Table 1). Although reported response rates vary, the taxanes are among the most active agents available, rivaling doxorubicin(Drug information on 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(Drug information on paclitaxel) (Taxol) achieves response rates of 6% to 33%, vinorelbine (Navelbine) about 16%, and melphalan(Drug information on 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(Drug information on 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(Drug information on mitomycin) (Mutamycin) (12 mg/m² every 6 weeks) plus vinblastine(Drug information on 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 combination regimen.
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(Drug information on cyclophosphamide), fluorouracil(Drug information on fluorouracil) (5-FU), vinorelbine, methotrexate(Drug information on methotrexate), and etoposide(Drug information on 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(Drug information on 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(Drug information on 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.