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Docetaxel in the Integrated Management of Prostate Cancer

Docetaxel in the Integrated Management of Prostate Cancer

ABSTRACT: Docetaxel (Taxotere)-based regimens can be included among the most effective treatment options for the management of patients with advanced, androgen-independent prostate cancer. Results with docetaxel as a single agent and in combination regimens with estramustine (Emcyt) have consistently achieved a palliative response, reduced serum PSA levels by 50% or more, and produced objective responses in patients with measurable disease. In addition, encouraging survival data have been demonstrated in several phase II trials. The ability to administer docetaxel on a weekly basis has substantially enhanced research efforts for treatment in prostate cancer patients. The results of ongoing phase III randomized trials evaluating docetaxel regimens in androgen-independent prostate cancer are eagerly awaited for their potential to definitively demonstrate a beneficial impact on overall patient survival. Docetaxel-containing regimens are likely to demonstrate a substantial role in the management of early-stage prostate cancer patients in the adjuvant and neoadjuvant settings, where clinical investigations are under way. In addition, study results from ongoing trials that integrate docetaxel with hormonal therapies for patients with biochemical recurrence following definitive local treatments will be important in refining the future role of chemotherapy for prostate cancer in general. The preliminary findings from studies conducted with docetaxel are encouraging and await final analysis. Finally, preliminary results from studies exploring combination regimens of docetaxel and novel agents that possess completely different mechanisms of action (eg, proapoptotic agents, angiogenesis inhibitors, and vitamin D analogs) have demonstrated the regimens to be feasible and safe, with promising early response data. These types of investigational studies will likely occupy a dominant position in future research initiatives for patients with advanced prostate cancer. [ONCOLOGY 16(Suppl 6):63-72, 2002]

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 (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 (Novantrone) or
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.[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 (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 (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,
  • every-3-week docetaxel plus prednisone,
  • or weekly docetaxel plus prednisone.

The primary end point of this trial is survival.

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