US Pharm. 2007;32(Suppl 2):20-24.
Prostate cancer is the most common solid tumor
affecting men in the United States. Data from 2005 estimated that
approximately 232,000 men were newly diagnosed with prostate cancer and about
30,000 died from the disease.1 According to the American Cancer
Society, about one third of newly diagnosed prostate cancer is considered
locally advanced. At diagnosis, if the cancer is found to be locally advanced
or metastatic, the standard treatment of choice is hormonal or
androgen-deprivation therapy (ADT), possibly in combination with local
therapy. ADT induces castrated levels of testosterone, which causes epithelial
cells of the prostate gland to undergo apoptosis, and is achieved either via
bilateral orchiectomy or by luteinizing hormone-releasing hormone agonist
injections, such as leuprolide (Lupron, Eligard, Viadur) or goserelin
Initially, most patients respond to ADT. The
androgen-dependent period in patients with metastatic disease is reported to
last about 14–30 months.2 The cancer then progresses to an
androgen-independent stage where even castrate testosterone levels fail to
control the malignancy. Eventually, the cancer no longer responds to any
hormonal therapy and is then referred to as hormone-refractory prostate cancer
(HRPC). HRPC can be defined as an increase in prostate-specific antigen (PSA),
radiologic progression (metastases) or clinical progression (worsening pain,
urinary obstruction).3 The median survival for patients after the
development of metastatic HRPC ranges from nine to 12 months,4 and
treatment options at this point are limited. Radiotherapy may be effective for
painful bony metastasis or managing complications such as spinal core
compression. Hormonal manipulations are sometimes used to decrease PSA level.
Antiandrogens such as bicalutamide (Casodex), flutamide (Eulexin), and
nilutamide (Nilandron) can be added, changed or withdrawn at this time.
Ketoconazole plus corticosteroids can also be used to cause adrenal androgen
synthesis inhibition.5 However, eventually most prostate cancer
becomes refractory to these interventions. The role of chemotherapy, such as
mitoxantrone, has historically been limited to palliation of bone pain.
Recently, docetaxel-based therapy emerged as a new standard of chemotherapy
that not only impacts bone pain and quality of life (QOL), but also shows
improvement in survival.
Mitoxantrone is an anthraquinone derivative that
has less cardiotoxicity than doxorubicin.6 Its usage in combination
with steroids is FDA approved for palliative painful bone metastases in
prostate cancer. Clinical trials with mitoxantrone have demonstrated its
palliative role. A palliative study conducted with mitoxantrone (Canadian
phase III study) randomized 161 hormone-refractory patients with pain to
either mitoxantrone 12 mg/m2 plus prednisone 10 mg daily or
prednisone alone (10 mg daily). The primary end point was palliative response,
observed in 29% of patients on mitoxantrone and prednisone arm versus only 12%
in patients who received prednisone alone (P = .01). The duration of
palliation was also longer in the mitoxantrone and prednisone group: 43 weeks
versus 18 weeks in the prednisone alone group (P <.0001). PSA decreased
in the combination group, but this did not translate to improved survival. In
fact, no differences in overall survival were observed.7
The Cancer and Leukemia Group B (CALGB) also
showed similar results. HRPC patients were randomized to mitoxantrone 14 mg/m
2 plus hydrocortisone 40 mg (MH) or hydrocortisone 40 mg daily alone
(H). Disease progression was slightly better in the MH group (3.7 months)
compared to the hydrocortisone group (2.3 months) (P = .02), but again
there was no difference in survival.8 Phase III trials of
mitoxantrone-based chemotherapy showed an improvement in bone pain but failed
to demonstrate an improvement in survival.7,8
Other chemical agents that have been studied for
the treatment of prostate cancer are the taxanes. Paclitaxel (Taxol) and
docetaxel (Taxotere) are the two examples in this class. They exhibit
antineoplastic activity by stabilization of microtubules bundles that disrupt
the equilibrium between polymerization and depolymerization.9 They
also cause induction of BCL-2 phosphorylation.10 The
progression of prostate cancer and the cause of the hormone-refractory state
have been reported to be due to the over expression of the antiapoptotic gene
BCL-2.11 In vitro, the taxanes have been shown to promote
apoptotic cell death in the prostate by phosphorylating BCL-2.
Docetaxel appears to be the most potent agent in BCL-2 inactivation.
Although there have been no randomized paclitaxel
phase III studies, a phase II study conducted by the US Oncology Group
randomized 163 patients to weekly paclitaxel plus estramustine phosphate (EMP)
or weekly paclitaxel alone. This trial showed that PSA response was better in
the paclitaxel and EMP group than in the paclitaxel group (47% versus 27%, P
<.01). However, the differences in the median survivals were not significant.
Up to this point, chemotherapy's role in prostate
cancer has been only for palliation. Not until recently has chemotherapy been
used as a viable treatment option for patients with HRPC. It now can be used
to decrease pain, and for the first time a chemotherapy-based regimen has been
shown to also increase survival. This is due to the results of the landmark
phase III clinical trials SWOG 99-16 and TAX 327, which used docetaxel-based
In the SWOG 99-16 trial, EMP was used with
docetaxel. EMP has both nitrogen mustard and estradiol components and is
approved for use in patients with metastatic prostate cancer. It has
estrogenic activity that can decrease testosterone to castrate level and it
also exerts cytotoxic effects by interfering with the microtubule structure
and binding to the nuclear matrix.14 EMP also has synergistic
activity with other microtubule-targeting agents, such as the taxanes and
vinca alkaloids, against human prostate cancer cell lines.11 When
EMP was used in combination with docetaxel in phase I and II clinical trials,
it produced impressive results. Although the number of patients studied was
small (ranged from 30 to 46 patients), improved survival (ranged from 14 to 20
months) and a decrease in PSA ranging from 45% to 76% was shown.15-18
In October 1999, the Southwest Oncology Group (SWOG) initiated a phase III,
multicenter, randomized trial comparing docetaxel and EMP with the standard
chemotherapy at the time--mitoxantrone-prednisone in men with HRPC.19
In this study, a total of 770 patients with
androgen-refractory prostate cancer were randomized to either docetaxel 60 mg/m
2 every three weeks (21 days) plus EMP 280 mg three times a day on days
1 to 5 or mitoxantrone 12 mg/m2 every three weeks (21 days) plus
prednisone 5 mg twice a day. Antiandrogens and bisphosphonate therapy were
discontinued at least one month prior to enrollment. The treatment can be
titrated up to 70 mg/m2 docetaxel or 14 mg/m2
mitoxantrone depending on toxicities.
The median follow-up period was 32 months. The
results demonstrated a significant improvement in the median survival in the
docetaxel-EMP group compared to the mitoxantrone-prednisone group (17.5 months
vs. 15.6 months) (TABLE 1). This translates to a death reduction of 20%
in the docetaxel group. Better time-to-disease progression (6.3 months vs. 3.2
months), which is defined as worsening lesion on bone scan and a better PSA
response, was seen in the docetaxel and EMP group compared to the mitoxantrone
and prednisone group. Response of measurable disease and subjective pain
relief rates were not statistically different. Significantly more patients
treated with docetaxel-estramustine had a greater than 50% decrease in PSA.
Further analysis showed that survival benefit was achieved in patients in the
docetaxel-EMP group in the absence of a 50% PSA decrease.
There were significantly greater toxicity rates
observed in the docetaxel-EMP group compared to the mitoxantrone-prednisone
group: gastrointestinal (20% vs. 5%), neutropenic fever (5% vs. 2%),
cardiovascular (15% vs. 7%), metabolic disturbances (6% vs. 1%), and
neurologic events (7% vs. 2%). Discontinued treatment rate was 16% in the
docetaxel-EMP group compared to 10% in the mitoxantrone-prednisone group due
to these adverse events. The study protocol was amended in 2001 to include the
addition of oral coumadin 2 mg a day and aspirin 325 mg a day in the
docetaxel-EMP group to prevent thromboembolic events.
TAX 327 was another phase III, randomized,
international trial looking at survival in men with HRPC treated with
docetaxel or mitoxantrone. One thousand and six patients with HRPC were
randomized to three groups: docetaxel 30 mg/m2 weekly for five
consecutive weeks of a six-week cycle, docetaxel 75 mg/m2 every
three weeks or mitoxantrone 12 mg/m2 every three weeks.20
The two docetaxel regimens were designed to provide the same drug dose
intensity over a six-week period. Docetaxel weekly was studied since it was
associated with less hematologic toxicity compared with the conventional
every-three-weeks schedule. All groups received prednisone 5 mg twice a day.
Median follow up was for 21 months. The survival
benefit was significantly better in the every-three-week docetaxel group
compared to mitoxantrone (TABLE 2), but not in the weekly docetaxel
group relative to the mitoxantrone group. The median survival rates were 18.9,
17.4, and 16.5 months for triweekly docetaxel-prednisone, weekly
docetaxel-prednisone, and mitoxantrone-prednisone group, respectively. This
translates into a 24% reduction in the risk of death for patients in the
triweekly docetaxel-prednisone group compared to the mitoxantrone-prednisone
group. Another secondary end point result found that significantly more
patients in the every-three-weeks docetaxel group experienced a reduction in
pain compared to the mitoxantrone group. Patients in the weekly docetaxel arm
also had a reduction in pain (31%), but the difference was not significant
relative to mitoxantrone (P = .08). PSA response was significantly
better in both docetaxel groups compared to the mitoxantrone group: 45% in
every-three-weeks administration and 48% in the weekly administration arm
versus 32% in mitoxantrone (P<.001). This is an interesting result,
also found in the SWOG 9916 trial, because the improvement in PSA response
does not seem to correlate with survival. Nearly half of the patients in the
weekly docetaxel arm had a PSA response. Again, this did not translate to
improved survival relative to the control arm. QOL was also significantly
better in both docetaxel groups. Compared to patients in the mitoxantrone arm,
22% of patients in the every-three-week and 23% in the weekly docetaxel arms
had a significant improvement in QOL.
Adverse events in this trial were more common in
the docetaxel arm. Grade 3–4 neutropenia occurred in 32% of patients on
triweekly docetaxel, 22% of patients in the mitoxantrone group, and 1.5% of
patients treated weekly with docetaxel. Febrile neutropenia and infection was
uncommon in all groups. The rate of impaired left ventricular ejection
fraction was significantly higher in the mitoxantrone arm (22%) than in the
triweekly docetaxel (10%) and the weekly docetaxel (8%) arms. Weekly docetaxel
was reported to have more clinical side effects (gastrointestinal, tearing,
and epistaxis) than the triweekly dose. (SeeTABLE 3 for a detailed
The role of chemotherapy in advanced prostate cancer has previously been for
palliative care without any survival benefit. This concept has changed with
recent clinical docetaxel trials. In TAX 327, docetaxel every three weeks plus
low-dose prednisone resulted in better survival improvement (2.4 months
improved), decreased pain, better PSA response, and better toxicity profile,
resulting in better QOL. In the SWOG trial, patients treated with docetaxel
and EMP showed a median overall survival prolonged by two months and a median
progression-free survival prolonged by three months. Looking at
the side effects profile, EMP-based therapy with docetaxel resulted in
gastrointestinal and cardiovascular toxicity (deep venous thrombosis and
pulmonary thromboembolism). The SWOG 9916 trial was amended to include
anticoagulation therapy (aspirin and warfarin), but the outcome cannot be
interpreted since this was not in the primary design of the study. At this
time, an EMP-based regimen should not be used since there is no further
benefit of increasing survival compared to docetaxel-based treatment alone.
Treatment of patients with HRPC is not based on
any global algorithm, but should be based on specific patient cases. Things to
consider are the performance status and expectations of the patient, goals of
the treatment, and potential toxicity. Many questions regarding chemotherapy
still remain, and time to initiate chemotherapy is still controversial. Should
it be initiated in symptomatic versus asymptomatic patients? Does docetaxel
have a role in earlier stages of advanced prostate cancer?
Current randomized trials should answer some of
these questions. Although results from these trials are impressive, the
docetaxel-based regimen still only showed improved survival of 2–2.4 months.
The new era of docetaxel therapy has spurred other phase II clinical trials
combining docetaxel with carboplatin,21 thalidomide,22
calcitriol,23 and bevacizumab,24 which have promising
survival results and will hopefully integrate chemotherapy as part of the
standard of care. What is known at this time is that the use of
docetaxel every three weeks plus low-dose prednisone is the standard
chemotherapy treatment for patients with HRPC.
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