Docetaxel in the Integrated Management of Prostate Cancer

The clinical approach to patients with advanced prostate cancer has evolved rapidly with the confirmation that cytotoxic chemotherapy can improve patient outcomes. The documentation that chemotherapy can improve quality of life altered the long-held belief that cytotoxic therapy had no role for hormone-refractory disease. In fact, chemotherapy is used on a routine basis because of such convincing data.[1] The scope of clinical research for chemotherapy in prostate cancer has broadened from initial trials in pretreated patients with advanced disease to neoadjuvant trials in patients with early-stage disease. The current goals of chemotherapeutic research strategies are

• improving the efficacy of existing therapies by optimizing dose and schedule,
• integrating cytotoxic therapy earlier into the treatment of prostate cancer patients in conjunction with surgery, androgen ablation, and/or radiation therapy,
• and combining cytotoxic therapy with agents that possess novel mechanism of action (eg, tyrosine kinase inhibitors, angiogenesis inhibitors, proapoptotic therapies, bone targeting therapies, and proteosome inhibitors).

Summarized in this article is the historical evidence to support the efficacy of chemotherapy in androgen-independent prostate cancer in general. The rationale and specific data to support the clinical efficacy of docetaxel(Drug information on docetaxel) (Taxotere) are presented, and strategies to integrate docetaxel earlier into the management of prostate cancer patients are discussed. Finally, novel investigational combinations with docetaxel under exploration are reviewed.

Historical Development of Chemotherapy in Prostate Cancer

Major changes in the clinical management of patients with advanced, androgen-independent (hormone-refractory) prostate cancer resulted from the demonstration that patient outcome could improve significantly from chemotherapy. A beneficial palliative effect and improved quality of life was demonstrated in symptomatic, androgen-independent prostate cancer patients treated with cytotoxic therapies that utilized mitoxantrone(Drug information on mitoxantrone) (Novantrone) or doxorubicin(Drug information on doxorubicin) in combination regimens. Palliation of disease and/or improved quality of life were demonstrated with mitoxantrone/prednisone and mitoxantrone/hydrocortisone in two phase III randomized trials that compared the chemotherapy-hormone combination vs hormonal therapy alone.[2,3] The findings contrasted with historical data on single-agent cytotoxic therapy, which did not demonstrate a significant evidence of benefit.

The investigation of chemotherapy for prostate cancer has also been substantially influenced by the ability to use serum prostate-specific antigen (PSA) as a surrogate end point for assessment of therapeutic effectiveness.[4,5] As a result of the efficacy of chemotherapy and the ability to use serum PSA to monitor therapeutic outcome, the clinical management of patients with prostate cancer has changed substantially.[6] The medical oncology community has accepted chemotherapy as an effective treatment modality for routine use, and clinical and laboratory investigators are enthusiastically pursuing methods to improve upon the benefits of chemotherapy in prostate cancer.

Molecularly-Based Therapeutic Targets for Prostate Cancer

The further clinical development of chemotherapy for prostate cancer has been the result of a better understanding of the biology of hormone-refractory prostate cancer and the thoughtful investigation of molecular-based therapeutic targets for drugs directed against the disease. One such molecular target is the cytoplasmic microtubule. In fact, the antimicrotubule activity of the taxanes led to their investigation in prostate cancer. The cytotoxic effect of docetaxel is mediated by disruption of the microtubular network essential for mitotic and interphase cellular functions. Docetaxel binds to tubulin, promotes the assembly of tubulin into stable microtubules, and inhibits microtubule depolymerization.[7] A greater and more slowly reversible degree of polymerization has been demonstrated for docetaxel than for paclitaxel(Drug information on paclitaxel).[8] In addition, docetaxel appears to have a higher affinity for tubulin than for paclitaxel and is a more potent inducer of microtubule assembly.[9]

Preclinical Investigations of Docetaxel

Several preclinical studies have demonstrated the potential activity of docetaxel in prostate cancer. In tissue culture, docetaxel is more active than paclitaxel against established prostate cell lines. Recently, the combination of docetaxel and estramustine(Drug information on estramustine) (Emcyt) was shown to exert significant cytotoxic effects in PC-3 and MatLyLu prostatic cell lines.[10]

The topoisomerase II enzyme, nuclear matrix proteins, and modulators of apoptosis (or programmed cell death) are additional molecular targets upon which docetaxel has shown to have an effect. Several pro- and antiapoptotic pathways have been identified in androgen-independent prostate cancer cell lines and tissues. The antiapoptotic protein bcl-2 is expressed in approximately 65% of androgen-independent human prostate cancer specimens.[11] In vitro analyses suggest that docetaxel’s mechanism of action may involve inactivation of bcl-2 by phosphorylation.[12] Results demonstrate 100-fold greater potency of docetaxel over paclitaxel in the induction of bcl-2 phosphorylation, which causes apoptotic cell death.

Of interest was the recent demonstration of different pathways for docetaxel-induced apoptosis between the androgen-responsive (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines.[13] These findings will assist researchers in choosing distinct therapies with activity against localized vs advanced prostate cancer.

Clinical Trials of Docetaxel in Prostate Cancer

Docetaxel has demonstrated beneficial activity in hormone-refractory prostate cancer as a single agent and in combination regimens. Traditionally, the recommended administration schedule of docetaxel has been once every 3 weeks.[7] Data on the weekly administration schedule of docetaxel, compared with the every-3-week schedule, suggest it to be equally efficacious with potentially fewer toxicities.[14] These findings have substantially enhanced investigational strategies for docetaxel in hormone-refractory prostate cancer, a disease in which a number of patients are elderly and unable to tolerate the every-3-week schedule. The results of clinical trials evaluating every-3-week and weekly docetaxel are presented here (Table 1).[15-18]

Single-Agent Docetaxel in Hormone-Refractory Disease

Every-3-Week Regimens

To gain information on the single-agent activity of docetaxel in hormone-refractory prostate cancer, Picus and Schultz investigated every-3-week docetaxel at 75 mg/m² in 35 chemotherapy-naive patients.[15] A > 50% PSA decline was demonstrated in 46% of patients. A full 24% of patients met the National Cancer Institute (NCI) criteria for partial response, defined as a 80% pr more PSA decline in conjunction with a 50% reduction in measurable soft-tissue disease, if present. An additional 46% of patients demonstrated stabilization of their disease. Therapy was generally well tolerated, with primarily hematologic toxicity, including grade 3/4 neutropenia, in 43% of patients.

Friedland and colleagues conducted a similar phase II study of single-agent docetaxel at 75 mg/m² every 3 weeks.[16] A total of 21 hormone-refractory prostate cancer patients with a median age of 69 (range: 55-79 years) were entered into the study. Prior chemotherapy had been administered to 48% of patients. In 16 patients evaluable for response, a 38% overall response rate was observed, with a 50% response rate in chemotherapy-naive patients and a 25% response rate in patients who had received prior chemotherapy. Six of 10 patients with measurable disease had a reduction in disease, and 8 of 11 patients experienced a reduction in bone pain. Hematologic toxicities were predominant, with grade 3/4 neutropenia in 71% of patients.

Weekly Docetaxel

The use of weekly docetaxel in elderly patients with various tumor types has demonstrated a more favorable toxicity profile than every-3-week regimens, while maintaining comparable levels of antitumor activity.[14] Since many men with prostate cancer are elderly and tolerate chemotherapy poorly, investigators have evaluated weekly regimens of docetaxel for hormone-refractory prostate cancer with the aim of reducing side effects.

Berry and colleagues conducted a multi-institution phase II study of weekly docetaxel in 60 heavily pretreated hormone-refractory prostate cancer patients. Patients were scheduled to receive three cycles of therapy with docetaxel at 36 mg/m² per week for 6 weeks, followed by 2 weeks of rest (one cycle).[17] All patients received premedication with oral dexamethasone(Drug information on dexamethasone) (three 8-mg doses at 12-hour intervals starting 12 hours before each infusion of docetaxel). In the 60 patients enrolled, median patient age was 72 years (range: 41-86 years), and 83% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Prior mitoxantrone treatment had been administered in 27% of patients, orchiectomy had been performed in 43%, secondary hormonal therapy had been given to 97%, and palliative radiotherapy had been delivered to 70% of patients. On an intent-to-treat basis, an objective tumor response (50% or more decrease in serum PSA from baseline lasting 4 weeks or longer with a stable or improved performance status) was reported in 24 patients (41%). A total of 16 patients (27%) had a PSA decrease of  80% or more for 2 months or longer. The estimated median time to progression (TTP) from the start of treatment was 5.1 months. The estimated median TTP for patients with a > 50% PSA reduction was 6.6 months vs 4.4 months for patients who did not achieve a > 50% PSA reduction (P < .01). The median overall survival was 9.4 months. Of six patients with measurable soft-tissue disease, two had an objective tumor response, one of which was a CR. Therapy was well tolerated and the dose reduction allowance resulted in grade 3/4 neutropenia in just 3% of patients. Grade 3/4 asthenia and diarrhea were each reported in 10% of patients.

A nearly identical study was conducted by Beer and colleagues; however, eligible patients were not allowed to have received prior chemotherapy for their disease.[18] A total of 25 men with a median age of 72 years (range: 55-81 years) and a median baseline PSA of 201 ng/mL (range: 0.6-1,432 ng/mL) were enrolled in the study. Patients received treatment with single-agent docetaxel at 36 mg/m² weekly for 6 consecutive weeks of an 8-week cycle. The primary end point was palliative response, defined as a pain reduction using the Present Pain Intensity (PPI) scale, or a 50% decrease in analgesic consumption. Secondary end points included PSA response and global quality-of-life assessment. The primary end point of palliative response was demonstrated in 12 of 25 patients (48%). PSA response, defined as > 50% decrease in PSA maintained for two consecutive evaluations at least 4 weeks apart, was achieved in 11 of 24 (46%) evaluable patients. Of the 11 PSA responders, 6 patients achieved a 75% reduction or more in PSA, and 4 of these patients achieved a 90% or more reduction in PSA. No difference in overall quality of life or any quality-of-life domain was detected between patients who responded to treatment and those who did not. Two of five patients with measurable disease demonstrated a partial response to therapy. The median survival for the entire patient cohort was 39 weeks (range: 18-89+ weeks).

Therapy was well tolerated, with 25% of patients experiencing grade 3/4 hematologic toxicity, and 36% of patients experiencing grade 3 nonhematologic toxicity. Grade 3/4 neutropenia was reported in 16% of patients; however, no cases of neutropenic fever were reported. The authors concluded that single-agent weekly docetaxel was efficacious, with activity seen by all relevant measures, including palliation of symptoms, PSA, and measurable disease response.

A retrospective comparison of two studies utilizing weekly or every-3-week docetaxel-containing regimens in hormone-refractory prostate cancer concluded that the PSA response rate was similar with the two regimens and that the weekly regimen represented a practical treatment alternative for elderly men with prostate cancer.[19] The dose consistently tolerated on the weekly schedule represents an increase in dose intensity compared with every-3-week administration.

The question of whether the higher cumulative dose delivered or the unique weekly administration schedule accounts for the potential benefit of weekly schedules remains unclear and is the subject of ongoing investigation. Therefore, while the current overall impression is that weekly regimens possess a higher therapeutic index than every-3-week regimens, this fact must be confirmed in a randomized trial. A prospective randomized phase III study comparing weekly to every-3-week administration of docetaxel is under way (Figure 1). In this comparative study, patients are randomized into one of three arms:

• the control arm of mitoxantrone plus prednisone(Drug information on prednisone),
• every-3-week docetaxel plus prednisone,
• or weekly docetaxel plus prednisone.

The primary end point of this trial is survival.