The Taxanes: Dosing and Scheduling Considerations

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Introduction

The determination of optimal dosing and scheduling has been an important objective during the development of the taxanes. This issue pertains to both paclitaxel(Drug information on paclitaxel) (Taxol) and docetaxel(Drug information on docetaxel) (Taxotere). The clinical development of docetaxel has largely involved a single administration schedule (1-hour infusion) and a narrow dosing range (60 to 100 mg/m², with most studies using 100 mg/m² over 1 hour every 3 weeks). The range of paclitaxel doses and schedules, on the other hand, has been broad (ranging from 135 to 250 mg/m² over 1 to 96 hours every 3 weeks).

Impressive antitumor activity has been reported recently for paclitaxel on disparate administration schedules, which leads to the question of whether an optimal dosing schedule truly exists for the taxanes. Fortunately, the results of several prospective randomized studies, in addition to retrospective analyses, may shed light on these questions. This review summarizes pertinent preclinical, pharmacologic, and antitumor results pertaining to optimal taxane dosing and scheduling in clinical practice.

In Vitro Cytotoxicity Studies

The results of in vitro studies designed to evaluate taxane dose-response relationships and optimal taxane scheduling have been reviewed previously.[1,2] Many relevant biologic effects in vitro, such as cytotoxicity, formation of microtubule bundles and mitotic asters, increase in tubulin polymer mass, stabilization of microtubules against depolymerization, apoptosis, radiosensitization, antiangiogenesis, and inhibition of chemotaxis and motility, appear to be directly related to the concentration of the taxanes.[3-14]

The taxanes may induce different intracellular effects, depending on the drug concentration. They inhibit proliferation of cells by inducing a sustained mitotic block at the metaphase/anaphase boundary at concentrations much lower than those required to increase microtubule mass and microtubule bundle formation.[15] Half-maximal inhibition of HeLa cell proliferation and 50% blockade of mitotic metaphase occur at 8 nM of paclitaxel, whereas microtubule mass increases half-maximally at 80 nM of paclitaxel, with maximal effect at 300 nM.[15] At high concentrations, the unique effects of paclitaxel in increasing microtubule mass and microtubule bundles have been associated with growth inhibition.[12,15]

Because these effects have not been noted at the lowest effective concentrations, they could not have accounted for the antiproliferative effects observed at low concentrations. Instead, growth inhibition has been associated with the formation of an incomplete metaphase plate of chromosomes and an arrangement of spindle microtubules resembling the abnormal organization that occurs at low concentrations of the Vinca alkaloids.[16]

Plateau and Threshold Concentrations

As paclitaxel concentrations progressively increase, a plateauing of dose-response effects has been observed in various cell lines.[12,17-22] In other words, a situation of diminishing returns occurs as paclitaxel and docetaxel concentrations are increased above specific plateau concentrations, the magnitude of which appears to vary between cell lines. The broad clinical implication of these results is that there may be a critical plateau concentration, ie, a dose above which toxicity, but not efficacy, increases.

The cumulative results of in vitro studies suggest that the precise concentrations at which plateauing occurs depends on the specific treatment schedule and varies according to tumor type. In addition, there appear to be precise threshold concentrations below which drug effects do not usually occur. Like plateau concentrations, the precise level at which threshold effects take place also varies among cell lines. Threshold concentrations typically are inversely related to the duration of treatment. In essence, these preclinical observations resemble clinical observations to date.

Treatment Duration

For both paclitaxel and docetaxel, treatment duration appears to be the most critical determinant of in vitro effect. Prolonging the duration of exposure in vitro generally produces much greater cytotoxicity than increasing drug concentration.[1,2,9,12,14,17,18, 20,23-25] For example, an 11-fold increase in the duration of paclitaxel exposure was more effective in increasing the cytotoxic effect of paclitaxel in an LC8A lymphoma cell line than was a 100-fold increase in paclitaxel concentration.[12] Interestingly, this effect appears to be much more pronounced in taxane-resistant cell lines.[24,26-29] The taxane concentrations at which cell survival curves plateau tend to decrease as the treatment durations are prolonged.

For paclitaxel, and probably docetaxel, the effects of increasing microtubule mass are maximal at drug concentrations that are equimolar with tubulin or when the stoichiometry approaches 1 M of paclitaxel per 1 M of polymerized tubulin dimer.[4,30-33] The binding of paclitaxel to polymerized tubulin is reversible with a binding constant of approximately 0.9 µM. Docetaxel, which most likely shares the same tubulin binding site as paclitaxel, has a 1.9-fold higher effective affinity for the site.[4] The assembly of guanosine diphosphate- or guanosine triphosphate-tubulin induced by docetaxel also proceeds with a critical protein concentration that is 2.1-fold lower than that of paclitaxel.[4] In addition, comparative in vitro cellular pharmacologic studies have demonstrated that higher intracellular levels of docetaxel in P388 murine leukemia cells may also be attributed, in part, to its threefold slower efflux rate.[4]

These differences may explain the varying cytotoxic potencies of the taxanes, with median inhibitory concentrations generally much lower for docetaxel.[4,21,22,33-36] The relative potencies may not necessarily translate into a greater therapeutic index for docetaxel, since greater potency may also result in more severe toxicity at identical drug concentrations in vitro. In addition, the taxanes may
not be completely cross-resistant, although differences in potency may confound the interpretation of both preclinical and clinical studies regarding cross-resistance.

These schedule-dependent effects have also been documented in studies designed to determine the
in vitro interactions of the taxanes with ionizing radiation.[9] In most studies, the radiopotentiating effects of the taxanes have been directly related to the duration of taxane exposure prior to radiation.[9] In one series of studies involving lung cancer cells, a radiosensitizing effect could not be demonstrated for treatment durations of less than 6 hours at any concentration of paclitaxel.[37]

Preclinical Studies

In early studies performed by the National Cancer Institute, paclitaxel was administered as a suspension and antitumor evaluations were limited to studies using intraperitoneally (IP) implanted tumors treated with IP drug administration or human tumor xenografts implanted in the subrenal capsule and treated subcutaneously.[38] In mice-bearing IP-implanted P388 leukemia, paclitaxel administered every 3 hours for three doses (pharmacologically simulating a 24-hour infusion schedule) was more effective than other schedules, including those with multiple-drug treatments on days 1, 5, and 9, or daily treatment for 9 consecutive days.[38] However, these studies were constrained due to the limited solubility of paclitaxel in the formulation vehicles used at that time, thereby precluding the design of proper comparative studies of prolonged schedules and single-dosing schedules.

Lung Cancer Model

When studies designed to evaluate different schedules were later performed by Bristol-Myers Squibb in the M109 lung cancer model using polyoxyethylated castor oil (Cremophor EL) or polysorbate 80 formulations, no schedule-dependent differences were observed.[39] However, neither the optimal schedule demonstrated in the P388 leukemia studies (every 3 hours × 8 doses) nor prolonged (eg, 3 24-hour) infusion schedules were evaluated.

The schedule-finding studies in the M109 model indicated that both daily × 5 and daily × 7 schedules were superior to multiple daily dosing for longer intervals (2 or 3 days between injections). Significantly, maximal antitumor activity was achieved at doses that were substantially lower than the maximum tolerated dose (MTD). This was particularly true for the daily × 7-day schedule, in which dosing at the MTD did not result in any therapeutic advantage over an equally effective, but less toxic, lower dose.[40] These results are consistent with the plateau effects noted in the dose-response curves from a variety of cell lines.

Other Models

Nevertheless, dose-response effects have been observed in many other preclinical in vitro models. Progressive reductions in vertebral metastases were noted in combined immunodeficient mice inoculated with PC-3 ML prostate cancer cells that were previously incubated with increasing paclitaxel concentrations from 0.1 to 1.0 µM [41] and in mice bearing bladder cancer.[42]

Dose-toxicity relationships have been especially profound. Substantially greater toxicity in both rapidly proliferating (lymphoid, myeloid, gastrointestinal) and nonproliferating (peripheral nerve) tissues has been observed on almost all schedules in mice, rats, and dogs.[43-45] The schedule's effects are more profound in that lower total doses are typically required to induce equivalent toxic effects in animals treated with more intermittent dosing schedules or treatment over more prolonged durations.[38,43]

It is difficult to compare paclitaxel and docetaxel with respect to dose and schedule dependency in preclinical studies in animals due to differences in tumor models, dosing schedules, and the proximity of treatment doses to the MTD. Nevertheless, results of limited studies with docetaxel have indicated clear dose-response relationships, particularly with short- and single-dosing schedules. Although one may conclude that the type of administration schedule appears to have minimal impact on docetaxel's antitumor activity, it should be noted that only limited studies with prolonged schedules have been performed.[5,46,47]