Cancer of the prostate is the most common tumor in US men, with well
over 300,000 new cases diagnosed annually. According to the American Cancer
Society, the incidence of this cancer has increased 50% between 1989 and
1993. Paralleling this increase in incidence has been a heightened focus
of the medical and research community on the disease, as demonstrated by
the number of MEDLINE citations on prostate cancer, which rose from 166
in 1966 to a high of 1,643 in 1994 (Figure
Despite this intense public and academic scrutiny, major questions about
prostate carcinoma remain unresolved. In this review, we will briefly examine
some of these issues and also review current studies designed to answer
the most fundamental questions regarding this disease.
Recognizing the public health impact of prostate cancer, several options
for control of this disease are available. At present, the major medical
focus is on early diagnosis and treatment. While this is an attractive
approach, it is associated with several potential confounding factors and
problems. These include: (1) overdiagnosis, (2) unknown impact on mortality,
(3) potential morbidity of treatment, and (4) significant costs of screening
Another potential approach that centers on biologically significant
disease would be to improve the outcomes of therapy for metastatic disease.
Although 50 years have passed since the first description of hormonal therapy
for prostate cancer, there is little evidence that survival of patients
with metastatic disease has improved.
Potential Preventive Approaches
Given the problems inherent in both early detection and treatment and
improving the treatment of metastatic disease, the prevention of prostate
cancer has emerged as a very attractive option. Epidemiologic and observational
evidence suggests a number of potential preventive approaches. These include:
- Dietary PreventionPopulations of patients with diets high in
fiber or low in fat have a lower risk of prostate cancer mortality.
- Vitamin EA recent randomized trial from Finland, originally
designed to determine whether vitamins E and/or A could prevent lung cancer
in heavy smokers, demonstrated a significant reduction in the number of
prostate cancers in patients receiving vitamin E.
- Agents That Block or Suppress MutationOltipraz, selenium, vitamin
C, and isoflavenoids, all of which block or suppress gene mutation, have
been suggested possible chemopreventive agents.
- DifluoromethylorithineRecognizing that the prostate has one
of the highest levels of polyamines in the body, that normal cell proliferation
is enhanced by these agents, and that the first step in mammalian synthesis
of polyamines is catalyzed by ornithine decarboxylase (ODC), difluoromethylorithine
(DFMO), a potent inhibitor of ODC, has been suggested as a potential preventive
Ongoing Clinical Trials
At present, at least two studies are addressing two of these potential
prevention avenues (Table 1). One of
these trials, coordinated through the University of Wisconsin, is designed
to determine whether DFMO can modulate a number of markers for prostate
carcinogenesis. In a model that may be applicable to the testing of a wide
variety of agents, patients with prostate cancer who are scheduled for
radical prostatectomy and those without prostate cancer who are to undergo
cystoprostatectomy (eg, for muscle-invasive bladder cancer) receive DFMO
prior to surgery. Analyses will be performed to ascertain the impact of
treatment on prostate-specific antigen (PSA), as well as a number of cellular
markers of disease.
A second, larger undertaking, the Prostate Cancer Prevention Trial,
is testing the hypothesis that finasteride (Proscar), which prevents the
conversion of testosterone to the more potent dihydrotestosterone via inhibition
of the enzyme 5-alpha-reductase, can prevent the development of prostate
cancer. In this study, 18,000 healthy men over age 55 with a normal
digital rectal examination (DRE) and a PSA level less than 3.0 ng/mL are
randomly assigned to receive either finasteride or placebo. The study end
point is the period prevalence (the number of tumors identified through
biopsy during the 7-year period of the study) of prostate cancer over 7
years. All participants are scheduled to undergo prostate biopsy 7 years
after beginning the study.
Although these two trials will provide tremendous information about
potential methods for preventing prostate cancer, there will almost certainly
be future studies that will examine the impact of other interventions in
this patient population. Hopefully, these trials will identify preventive
strategies that can reduce the morbidity and mortality of this common disease
without the problems associated with treatment.
What is the Best Treatment for Localized Disease?
As stated above, the principal focus of current medical efforts is the
early diagnosis and treatment of prostate cancer. Studies have demonstrated
that the majority of tumors detected by screening tests, including PSA
and DRE, are clinically confined to the prostate (T1-T2 tumors).
There have been conflicting opinions about the relative benefits of
treating these clinically localized tumors. For example, various authors
have provided evidence that, for organ-confined tumors, observation (also
known as "watchful waiting" or "expectant management")
will lead to acceptable outcomes during 5- and 10-year follow-up. A
more recent analysis has suggested, however, that with longer follow-up,
mortality from the disease increases dramatically. Similarly, while
several authors have demonstrated excellent survival among patients with
clinically localized prostate cancer treated with radical prostatectomy,
concerns have been raised about the high rates of positive margins, PSA
recurrence, and patient-reported morbidity.[10,11]
Ongoing Clinical Trials
In an effort to resolve this controversy, the Veterans Administration
and National Cancer Institute are co-sponsoring the Prostate Cancer Intervention
vs Observation Trial (PIVOT), which randomizes patients with clinically
confined prostate carcinoma to either radical prostatectomy or observation.
The arduous study has accrued well over 200 patients to date and is enrolling
over 10 patients per month.
As PIVOT is powered to detect differences in survival, results will
not be forthcoming for many years. Nonetheless, it promises to provide
some of the most important answers regarding the management of early, localized
Another ongoing study that may help resolve the controversy over secondary
prevention (ie, early detection and treatment) of prostate cancer is the
Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) study. The aim of this
trial is to determine whether annual screening will reduce mortality from
prostate, lung, colorectal, and ovarian cancers. In this study of 148,000
men and women, patients randomized to the screening arm undergo PSA and
DRE (prostate), chest x-ray (lung), flexible sigmoidoscopy (colorectal),
and CA-125 and pelvic ultrasound (ovarian) during a screening period of
4 years. This cohort is then compared to a group who undergo whatever regular
testing is available within the community.
Because PLCO does not mandate a specific treatment for detected prostate
cancers, this study dovetails quite well with PIVOT. Possibly, the combination
of the two trials may provide evidence of the relative efficacy of both
screening and treatment.
Numerous trials are currently assessing various treatment modalities
in patients with clinically localized prostate cancer (Table
2). Unfortunately, to the authors' knowledge, no ongoing phase III
trial is evaluating the efficacy of newer treatment modalities; ie, no
head-to-head comparisons are being performed to assess the relative worth
of brachytherapy, cryotherapy, or other modalities compared to either radical
prostatectomy or external-beam radiotherapy. The initial course of many
newly diagnosed prostate cancers is indolent. Thus, it is difficult to
reliably assess efficacy of any treatment from studies in which patients
at relatively low risk of short-term progression are treated and in whom
follow-up is less than 10 years.
What is the Best Treatment For Locally Advanced Disease?
The optimal treatment of patients with locally advanced (T3-T4) disease
has been a polemic for 50 years. Various approaches have been advocated
by many authors. Although external-beam radiotherapy may be the most common
therapeutic modality used in this disease stage, evidence suggests that
its long-term results may be less than satisfactory.[13a]
Ongoing and Recently Completed Clinical Trials
Accordingly, a number of approaches have been employed in the treatment
of T3-T4 disease, some of which are the focus of current clinical trials
(Table 3). These include neoadjuvant
hormonal therapy plus either radiotherapy or radical prostatectomy, increased
doses of radiation (either through hyperfractionation or the use of conformal
therapy), and the addition of systemic agents to radiation.
One very attractive ongoing trial is the JPR3 study of the National
Cancer Institute of Canada, which is being activated in a number of US
groups, including the Southwest Oncology Group (SWOG). This novel study
is designed to determine whether radiation therapy positively contributes
to the ultimate outcome of patients with T3-T4 disease who receive combined
Several authors have explored the possibility of using neoadjuvant hormonal
therapy plus definitive therapy (surgery or radiotherapy) for T3-T4 prostate
carcinoma. A randomized, prospective trial of radiotherapy with or without
neoadjuvant hormonal therapy for localized prostate cancer has recently
been completed. Thus far, results demonstrate that the addition of neoadjuvant
hormonal therapy reduces short-term local and biochemical disease progression.
Whether neoadjuvant hormonal therapy will influence end points of importance
to the patient (eg, metastatic disease-free recurrence and survival) requires
Similarly, a US randomized, prospective trial of patients with T2 disease
has demonstrated that radical prostatectomy plus neoadjuvant hormonal therapy
significantly reduces the rate of pT3 disease (as defined by positive margins).
Of interest, however, are the 1-year follow-up data, which suggest that
the addition of neoadjuvant hormonal therapy does not significantly reduce
the PSA recurrence rate.
A phase II SWOG trial is currently assessing the impact of neoadjuvant
hormonal therapy (a luteinizing hormone-releasing hormone [LHRH] agonist
plus flutamide [Eulexin]) in patients with T3 disease. Although some authors
have suggested that this approach is of limited value in patients with
T3 disease, phase III trials comparing this approach with alternative treatments
will probably be needed to determine the optimal treatment for this disease
What is the Best Treatment for Metastatic Disease?
Since the work of Huggins and Hodges in the 1940s, hormonal therapy
has been the mainstay of therapy for D2 prostate cancer. Unfortunately,
there is little evidence that significant advances in the treatment of
metastatic disease have been made since that time.
A putative major advance was announced by Labrie and colleagues in the
early 1980s: the concept of "combined androgen deprivation"ie,
the use of primary monotherapy (LHRH
agonist or orchiectomy to ablate testicular androgens) plus an antiandrogen
(to block remaining adrenal androgens). In 1989, the National Cancer
Institute (NCI) and SWOG completed a trial comparing LHRH-agonist therapy
with or without antiandrogen therapy. The results of the trial suggested
that combined androgen deprivation significantly improved median time to
progression in patients with metastatic disease.
Ongoing and Recently Completed Clinical Trials
A concern expressed about the NCI-SWOG trial was the fact that, since
LHRH agonist therapy is associated with an initial disease flare (due to
a transient testosterone increase) and that this flare may result in an
exacerbation of the disease, the sole impact of antiandrogen therapy may
be to block this temporary but adverse effect of LHRH agonist therapy.
For this reason, SWOG 8894 was designed and implemented. This study compared
orchiectomy with or without flutamide in patients with metastatic disease.
The results of this trial should be available in the next few months.
Although a number of therapies for metastatic prostate cancer are currently
being tested in clinical trials (Table 4),
perhaps the most intriguing potential approach is the use of intermittent
hormonal therapy. Intermittent therapy is not a new concept. (Whitmore
employed intermittent diethylstilbestrol over 2 decades ago.) However,
the advent of LHRH agonist therapy has afforded a more practical and less
morbid means of achieving intermittent therapy.
Potential advantages of intermittent hormonal therapy include: (1) lower
cost (compared to permanent LHRH therapy); (2) periods during which side
effects are reduced (eg, potency and libido returns to normal after LHRH
therapy is stopped); (3) lower risk of the long-term complications, such
as osteoporosis and anemia; and (4) the possibility that survival may be
enhanced by delaying the development of androgen-independent disease may.
To that end, a recently opened SWOG study is randomizing patients who achieve
an undetectable PSA following initial hormonal therapy to either continuous
therapy or intermittent hormonal therapy. This trial will address one of
the most important new potential treatment approaches for patients with
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