Docetaxel in Breast Cancer and a Rationale for Combination Therapy

ABSTRACT: Development of the taxoids has progressed rapidly in the 1990s. In vitro studies have demonstrated that docetaxel (Taxotere) has a longer residence time and higher accumulation within tumor cells than paclitaxel (Taxol), possibly accounting for its greater cytotoxicity. Animal studies have shown docetaxel to possess high antitumor activity. In clinical studies, docetaxel as a single agent has been shown to be highly active against a variety of solid tumors. It is at least as active in metastatic disease as other agents currently used, and it has demonstrated effectiveness against tumors resistant to anthracyclines or paclitaxel. Docetaxel shows some activity in cell lines resistant to fluorouracil (5-FU), vincristine, cisplatin (Platinol), and etoposide (VePesid). Its unique mechanism of action and lack of cross-resistance or overlapping toxicities with many agents may also contribute to its efficacy and safety in combination therapy. [ONCOLOGY 11(Suppl 6):11-15, 1997]

Introduction

Clinical development of the taxoids began in 1983, when paclitaxel (Taxol)was first used in cancer patients, but progressed slowly until the 1990s.Docetaxel (Taxotere) first entered clinical trials in 1990, with phaseII studies beginning internationally in 1992.[1] Increasing in vitro, invivo, and clinical experience indicate that the two taxoids, although related,are different and should not be considered interchangeable.

In Vitro Studies

The cellular distributions of the taxoids differ in vitro for the sameextracellular concentration. At equilibrium, docetaxel achieves an intracellularconcentration triple that of paclitaxel, with one-third the rate of cellularefflux (Figure 1).[2] The resulting longercell residence time and higher intracellular accumulation may account forits greater in vitro cytotoxicity. As shown in Figure2, docetaxel is a highly potent inhibitor of cell replication in invitro murine and human models.

Animal Models

In vivo comparative data also suggest a higher degree of antitumor activityfor docetaxel. In the rapidly growing murine B16 melanoma model, knownto be sensitive to the taxoids, the increase in tumor burden, followingsubcutaneous implantation of tumor cells in mice, was delayed after treatmentwith docetaxel when compared with treatment with paclitaxel or control(Figure 3).[3]

Clinical Studies of Docetaxel as Monotherapy

Docetaxel has demonstrated high activity as a single agent in first-linetherapy for metastatic breast cancer, as shown in Table1. Its efficacy is comparable with or higher than that of paclitaxel,doxorubicin and other anthracyclines, and vinorelbine (Navelbine).[4-6]

Docetaxel is also highly effective in anthracycline-resistant disease.The historical data are complicated by changes in the definition of resistanceover the past two decades. However, five recent trials demonstrate thatthe taxoids, and docetaxel in particular, are more active than other, olderagents (Table 2).[5,6,15-21]

ClinicalStudies of Docetaxel in Combination Therapy

Requirements for Combination Chemotherapy

• Criteria for using a drug in concurrent combination chemotherapy includethe following:
• High activity against the disease
• Different mechanism of action from other agents in the combination
• No cross-resistance
• No overlapping toxicity
• Capacity to enhance the activity of other components of therapy
• Doses as near as possible to the full dose

Docetaxel demonstrates activity against breast cancer as high as orhigher than that of many commonly used agents, and toxicity is manageable.Preclinical studies have demonstrated its unique mechanism of action: Docetaxelenhances formation of microtubules and stabilizes the polymerization process.No other agent attacks tumors in this way except paclitaxel, which hassmall but important differences in its specific mechanism of action. Exceptfor paclitaxel, no cross-resistance has been found to any other antineoplasticagent used in breast cancer treatment, and the cross-resistance betweendocetaxel and paclitaxel is incomplete.

Docetaxel combinations were shown to be highly active in preclinicalmodels. Synergies, or at least additive effects, were observed in studieswith two- and even three-drug combinations, including docetaxel, cyclophosphamide(Cytoxan, Neosar), fluorouracil (5-FU), vinorelbine, methotrexate, andetoposide (VePesid).[7]

Some of the clinical trials have combined drugs at near their individualmaximum tolerated doses with relatively little increase in overall toxicity.Docetaxel has been combined with the Vinca alkaloids, vincristine, vinblastine,and vinorelbine (at 80% to 100% of the optimal dose), or with doxorubicin,etoposide, cyclophosphamide, 5-FU, and methotrexate (at 60% to 70% of theoptimal dose).[8-11]

Resistance

The mechanisms of resistance to the taxoids are not completely understood,although the mdr gene, abnormal tubulin, and perhaps other factorsmay be responsible. Cell lines resistant to 5-FU, vincristine, cisplatin(Platinol), etoposide, or paclitaxel are not necessarily cross-resistantto docetaxel.

Some mechanisms of resistance to docetaxel and anthracyclines are shared,eg, increased drug efflux and defective apoptotic mechanisms.[8] Othersdiffer, eg, increased topoisomerases and altered tubulin structure.[8]As shown in Table 2, docetaxel exhibitshigh activity in anthracycline-resistant metastatic breast cancer, suggestingpartial cross-resistance between docetaxel and the anthracyclines.

Ongoing and Future Trials

Anthracycline Combinations in First-Line Therapy

A phase I trial, reported more fully in this supplement by Diéraset al, defined the maximum tolerated doses in women with advanced or metastaticbreast cancer as 50 mg/m² of doxorubicin, followed by 85 mg/m²of docetaxel. The dose-limiting toxicity was febrile neutropenia.[13] Sideeffects were tolerable, with no reported congestive heart failure. Responseswere observed at all dose levels, with response rates as high as 90% atthe recommended dose levels, 50 mg/m² of doxorubicin followed by 75mg/m² of docetaxel.

A phase III study of first-line therapy has been initiated to compare50 mg/m² of doxorubicin plus 75 mg/m² of docetaxel, with 60 mg/m²of doxorubicin plus 600 mg/m² of cyclophosphamide, a standard regimenin metastatic and primary breast cancer.

In another phase III trial, 75 mg/m² of docetaxel will be comparedwith 500 mg/m² of 5-FU, each in combination with 50 mg/m² ofdoxorubicin and 500 mg/m² of cyclophosphamide. Nabholtz et al describepreliminary results of a pilot feasibility study for the docetaxel armof this trial in this supplement.[14]

The scheduling of docetaxel/doxorubicin combination therapy will beexplored in a three-arm trial. The first group of patients will receive60 mg/m² of docetaxel plus 60 mg/m² of doxorubicin. The secondgroup will receive 100 mg/m² of docetaxel followed by 75 mg/m²of doxorubicin in a sequential schedule. The third group will receive thetwo agents at the same doses as the second group, but in an alternatingschedule.

Non-Anthracycline-Containing Combinations

There are also trials in development that do not involve anthracyclines.In one trial, 85 mg/m² of docetaxel will be combined with 20 mg/m²of vinorelbine on days 1 and 5 of the course of therapy. In others, docetaxelwill be evaluated in combination with 5-FU, in continuous infusion or asa bolus, and with cisplatin.

Summary

This overview of the clinical development of docetaxel summarizes someof the combination chemotherapy studies that have been conducted or areongoing. The challenge is not only to find effective combinations, strategies,and regimens, but also to determine the optimal role for this agent inrelation to many other active agents in development today.

Early results from phase I combination chemotherapy studies in metastaticor advanced disease demonstrate manageable toxicity at all dose levelsof docetaxel (25 to 100 mg/m²). The most frequent hematologic toxicitywas neutropenia, the incidence of infection was low, and there was generallyno significant cardiotoxicity. Response rates were observed in all studies,ranging from 70% to 90%.

References:

1. Data on file. Rhône-Poulenc Rorer Pharmaceuticals, Inc., Collegeville,PA.

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