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---David C. Smith, M.D.,
Assistant Professor of Internal Medicine
Kenneth J. Pienta, M.D.,
Associate Professor of Internal Medicine and Director of the Urologic Oncology Program
The vast majority of men with
metastatic prostate cancer will respond to hormonal therapy
with a reduction in disease activity and improvement in quality
of life. Unfortunately, the median duration of response is
18 months. Metastatic prostate cancer remains an incurable
disease with a significant impact in terms of morbidity and
mortality. Previous attempts at therapy in patients with hormone-refractory
disease had limited success and were associated with significant
toxicity. This led to skepticism about the role of chemotherapy
in the treatment of advanced prostate cancer (1). This skepticism
has been challenged by new developments resulting from trials
guided by a better understanding of the biology of prostate
cancer and appropriate study endpoints.
Secondary Hormonal Therapy
Secondary hormonal therapy is of limited use in the treatment
of metastatic prostate cancer. Responses to hormonal agents
in this setting are limited in both number and duration (2).
However, two aspects of hormonal therapy continue to play
important roles in hormone-refractory disease. The first is
maintenance of androgen suppression. The growth of metastatic
prostate cancer can be acceler-ated by administration of exogenous
androgens, and review of a large clinical trials database
has shown a superior overall survival for patients in whom
primary androgen deprivation is maintained. Maintenance of
castration levels of testosterone makes sense from a biologic
perspective, since there are likely cells present which can
respond to androgens.
The second issue is antiandrogen withdrawal. Withdrawal responses
have been described with estrogens, progestational agents
and all of the antiandrogens. The response rate to this maneuver
is low (15% to 25%), with a typical duration of a few months.
Nonetheless, withdrawal is required prior to institution of
any additional therapy, since it will complicate the assessment
of response to subsequent therapy (3).
Estramustine-Based Chemotherapy
Estramustine (Emcyt) was initially designed as an alkylating
agent. It has been shown, however, that it acts by binding
to proteins of the nuclear matrix and microtubular assembly.
This observation led to the development of several new combinations
in which estramustine is used with agents that act at these
sites (4). The combination of estramustine and vinblastine
targets the microtubule assembly. Phase II trials of this
combination showed that 30% of patients had sustained decreases
in serum prostate specific antigen (PSA) and 31% of patients
with measurable disease had partial responses. Therapy was
generally well-tolerated, although higher doses of vinblastine
in one trial resulted in greater myelosuppression and neurotoxicity.
Our initial investigations combined estramustine and etoposide,
targeting the nuclear matrix. In sequential phase II trials,
a total of 114 patients were registered. Approximately 50%
of patients had a " 50% decrease in the PSA, and response
was demonstrated in patients with both soft tissue disease
(50%) and disease limited to bone (5,6). Similar studies of
the combination of estramustine and paclitaxel showed that
53% of patients had a " 50% decline in the PSA, and four of
nine patients with measurable disease had objective responses.
This combination acts at the microtubular apparatus. We conducted
a phase II trial using oral estramustine, oral etoposide and
intravenous paclitaxel aimed at both sites of activity (7).
Sixty-three percent of patients enrolled had a " 50% decrease
in PSA, and eight of 15 patients with measurable disease had
at least a partial response. These trials serve as the basis
for an ongoing phase II trial, which adds carboplatin to the
three-drug regimen, and phase III trials currently under development.
Other Chemotherapy
Mitoxantrone plus a glucocorticoid versus a glucocorticoid
alone have now been compared in phase III trials (8). Mitoxantrone
plus prednisone was superior to prednisone alone in terms
of palliative response, although there was no difference in
overall survival. Palliation was seen in 38% of patients randomized
to the combination, compared to 21% of patients randomized
to prednisone alone. Similar preliminary results have been
reported for mitoxantrone plus hydrocortisone versus hydrocortisone
alone.
Suramin has shown activity in the treatment of hormone-refractory
prostate cancer with a promising response rate and significant
toxicity (9). Objective responses have been seen and PSA levels
were reduced > 50% in 60% of patients. Although the toxicities
are reported to be manageable, fatigue, malaise, weakness,
anorexia and wasting are common. A randomized phase III trial
of suramin with palliative endpoints appears to be positive
on initial reports.
Oral cyclophosphamide also has significant activity in prostate
cancer (8). Sixty percent of patients had improvement in symptoms
when treated with 100 mg/m2 per day for 14 days and 30% had
a decrease in PSA levels of " 50%. We have recently used cyclophosphamide,
either with prednisone alone, or with prednisone and diethylstilbestrol
(10). By PSA criteria, the response rate was 40%. This regimen
was extremely well tolerated.
Many new agents are being evaluated in hormone-refractory
prostate cancer. We have recently com-pleted a study of an
oral form of platinum and are in the process of opening a
new trial using an oral 5-FU analog. Other ongoing studies
include novel trials utilizing inhibitors of angiogenesis,
metastasis and tissue invasion.
Conclusion
Until recently, chemotherapy was thought to play little or
no role in the treatment of patients with advanced prostate
cancer. Recent trials have shown that a significant proportion
of patients can have benefit, both in terms of objective response
and palliative effect, when treated with chemotherapy. Ongoing
studies will determine their value and provide a basis for
the development of more effective combinations, which hopefully
will show a significant benefit in terms of survival.
References
- Tannock IF, Boyd NF, De Boer G, Erlichman C, Fine S, Larocque
G, et al. Is there evidence that chemotherapy is of benefit
to patients with carcinoma of the prostate? J Clin Oncol.
3:1013-1021, 1985.
- Smith DC. Secondary hormonal therapy. Sem Urol Oncol.
15:3-12, 1997.
- Scher HI, Kelly WK. Flutamide withdrawal syndrome: its
impact on clinical trials in hormone-refractory prostate
cancer. J Clin Oncol. 11:1566-1572,1993.
- Hudes G. Estramustine-based chemotherapy. Sem Urol Oncol.
15:13-19, 1997.
- Pienta KJ, Redman BG, Bandekar R, Strawderman M, Cease
K, Esper PS, Naik H, Smith DC. A phase II trial of oral
estramustine and oral etoposide in hormone refractory prostate
cancer. Urology. 50:401-6, 1997.
- Pienta KJ, Redman BG, Hussain M, Cummings G, Esper PS,
Appel C, Flaherty LE. A combination of oral estramustine
and oral etoposide for the treatment of hormone refractory
prostate cancer. J Clin Oncol. 12:2005-2011, 1994.
- Smith DC, Esper PS, Todd RF III, Pienta KJ. Paclitaxel,
estramustine, and etoposide in patients with hormone-refractory
prostate cancer (HRPC): A phase II trial. Proc Am Soc Clin
Oncol. 16:310a, 1997.
- Siu LL, Moore MJ. Other chemotherapy regimens including
mitoxantrone and suramin. Sem Urol Oncol. 15:20-27, 1997.
- Eisenberger MA, Sinibaldi VJ, Reyno LM, et al: Phase regimen
of suramin in patients with hormone-refractory prostatecancer.
J Clin Oncol. 13:2174-2186, 1995.
- Pienta KJ, Esper PS, Smith DC. The oral regimen of Cytoxan,
prednisone and diethylstilbesterol (CPD) is an active, non-toxic
treatment for patients with hormone refractory prostate
cancer. Proc Amer Soc Clin Oncol. 16:310a, 1997.
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