The development of a new drug is not only complex but also requiresa major investment in time, resources, patients, and most important, a
The development of a new drug is not only complex but also requiresa major investment in time, resources, patients, and most important, acollaborative effort between industry and researchers to develop tomorrow'strials to answer today's clinical challenges. One such agent, docetaxel(Taxotere), a semisynthetic taxane, has created excitement in the oncologycommunity. This excitement stems mainly from its unique mechanism of actionand antitumor activity in several cancers.
Confirmation of Efficacy in Metastatic Breast Cancer
Docetaxel promotes abnormal polymerization of tubulin and arrests depolymerizationof microtubule elements necessary for the proper functioning of the mitoticspindle and other microtubule-based structures.[1,2] As a single agentused in first-line chemotherapy for patients with metastatic breast cancer,75 to 100 mg/m² of docetaxel administered as a 1-hour intravenousinfusion once every 3 weeks demonstrates significantly greater antitumoractivity compared with both older agents and newer ones such as vinorelbine(Navelbine), edatrexate, and gemcitabine (Gemzar) (Table1). Although reported response rates vary, the taxanes are amongthe most active agents available, rivaling doxorubicin, long the most activefirst-line agent for patients with metastatic breast cancer.
Numerous clinical trials have demonstrated that docetaxel is also highlyactive in anthracycline-resistant tumors.[4-7] Prior to the developmentof the taxanes, one of the worst prognostic signs in patients with metastaticor high-risk primary breast cancer was anthracycline resistance. In thepre-docetaxel era, patients with anthracycline-resistant metastatic breastcancer had a median survival of about 4 months. Response to all other treatmentregimens, whether single-agent or combinations, was less than 15%.
Three multicenter studies show that single-agent docetaxel producesa response rate of approximately 41% and a median survival of 10 monthsin anthracycline-resistant patients (Table2).[4-7] In comparison, paclitaxel (Taxol) achieves response ratesof 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 confirmationof the significant antitumor activity of docetaxel as a single agent forpreviously treated and untreated patients with metastatic breast cancer.William J. Gradishar, MD, addresses the use of docetaxel as neoadjuvanttherapy in patients with locally advanced stage III breast cancer. Preliminaryanalysis of a phase II study suggests that four cycles of 100 mg/m²of docetaxel administered as a 1-hour intravenous infusion once every 3weeks 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 responsewas noted in 18% of patients, with one case being a complete pathologicresponse at the time of surgery.
The second article, by Stephen Chan, MD, discusses preliminary datafrom a randomized, multicenter phase III trial comparing docetaxel, 100mg/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 previouslyfailed alkylating chemotherapy. In this setting, preliminary data indicatethat docetaxel produced a longer median time to progression, higher responserates, and fewer cases of disease progression compared with doxorubicin.
The comparative use of docetaxel, 100 mg/m² (1-hour intravenousinfusion every 3 weeks) vs mitomycin (Mutamycin) (12 mg/m² every 6weeks) plus vinblastine (6 mg/m² every 3 weeks) in patients with anthracycline-resistantmetastatic breast cancer is presented by Jean-Marc Nabholtz, MD. This articlediscusses preliminary data from a randomized, multicenter, phase III trialshowing that docetaxel produced a longer median time to progression, higherresponse rates, and fewer cases of disease progression compared with thecombination regimen.
Although the single-agent activity of docetaxel is exciting, it is notenough to cure primary breast cancer. Thus, intensive research effortsseek to develop docetaxel-containing combination regimens for patientswith advanced solid tumors, including those of the breast and lung.
From the preclinical experience, there are numerous reasons to considerdocetaxel in combination therapy--among them is the ability of docetaxelto act on tubulin, and its ability to act on a different tubulin from thatof paclitaxel, for instance.[1,2] There is incomplete cross-resistancewith several of the major drugs previously used for the management of thevarious malignancies, making docetaxel a particularly attractive agentfor combination regimens.
Ascertaining the MTD
In addition, the preclinical work of Bissery and colleagues[1,2] suggeststhat there are some synergistic doublets, especially those that includecyclophosphamide, fluorouracil (5-FU), vinorelbine, methotrexate, and etoposide(VePesid). Further, even with other drugs that are myelosuppressive andfor which there is partially overlapping toxicity, like doxorubicin, cyclophosphamide,and methotrexate, Bissery et al[1,2] demonstrated that combinations with60% to 70% of the maximum tolerated doses can be safely administered.
Veronique Dieras, MD, presents an overview of phase I trials designedto establish the maximum tolerated doses and toxicity profile of the docetaxel/doxorubicincombination in patients with metastatic breast cancer. Results from thesetrials indicate that the combination is well tolerated and that docetaxeldoes 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 trialevaluating the maximum tolerated dose and toxicity profile of docetaxelin combination with cyclophosphamide in patients with advanced solid tumors.Dr. Valero reports that the recommended doses for phase II study are 700mg/m² of cyclophosphamide and 75 mg/m² of docetaxel in previouslytreated patients and 800/75 mg/m² in previously untreated patients.
The use of docetaxel in a three-drug combination regimen in patientswith metastatic breast cancer is reviewed by Jean-Marc Nabholtz, MD. Basedon the preliminary results of phase I and II trials, the regimen of docetaxel,doxorubicin, and cyclophosphamide appears to be active without an increasein the cardiotoxicity of doxorubicin.
Combinations of docetaxel with the platinums--cisplatin (Platinol),carboplatin (Paraplatin)--in patients with advanced non-small-cell lungcancer are reviewed by Chandra P. Belani, MD. Favorable response rateshave been reported with docetaxel, 75 mg/m², and cisplatin, 75 mg/m²,in previously untreated patients with non-small-cell lung cancer. Resultsfrom phase I trials in patients with nonhematologic solid tumors indicatethat the recommended dose of docetaxel in combination with carboplatin(target area under the curve of 6 mg/mL · min) is 80 mg/m²without 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 andII studies of the use of docetaxel in combination with vinorelbine in patientswith non-small-cell lung cancer. Encouraging results have been seen, withpartial responses ranging from 27% for non-small-cell lung cancer to 70%for metastatic breast cancer, warranting further study of docetaxel andvinorelbine in patients with non-small-cell lung cancer.
Finally, Howard S. Burris, MD, provides a review of phase I and II studiesof docetaxel in combination with 5-FU in patients with advanced solid tumors.Results from these trials indicate that the recommended dose for phaseII studies of docetaxel/bolus 5-FU is 60/300 mg/m² and for docetaxel/5-daycontinuous 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 Oncol22(suppl 13):3-16, 1995.
2. Bissery MC, Guenard D, Gueritte-Voegelein F, et al: Experimentalantitumor 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. AnticancerDrugs 7(suppl 2):9-12, 1996.
4. Radvin P, Burris HA, Cook G, et al: Phase II trial of docetaxel inadvanced 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 patientswith anthracycline-resistant metastatic breast cancer. J Clin Oncol 13:2886-2894,1995.
6. ten Bokkel Huinink WW, Prove AM, Piccart M, et al: A phase II trialof docetaxel (Taxotere) in second line treatment with chemotherapy foradvanced 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 ofdocetaxel 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 Centerexperience with paclitaxel in the treatment of breast cancer: from advanceddisease to adjuvant therapy. Semin Oncol 22(suppl 8):3-8, 1995.
9. Vermorken JB, ten Bokkel Huinink WW, Mandjes IA, et al: High-dosepaclitaxel with granulocyte colony-stimulating factor in patients withadvanced breast cancer refractory to anthracycline therapy: A Europeancancer center trial. Semin Oncol 22(suppl 8):16-22, 1995.
10. Jones S, Winer E, Vogel C, et al: Randomized comparison of vinorelbine and melphalanin anthracycline-refractory advanced breast cancer. J Clin Oncol 13:2567-2574,1995.