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Combinations of Hormones and Local Therapies in Locally Advanced Prostate Carcinoma

Combinations of Hormones and Local Therapies in Locally Advanced Prostate Carcinoma

ABSTRACT: Locally advanced adenocarcinoma of the prostate (American Urological Association stages B2, C; American Joint Committee on Cancer stages T2c, T3) has been difficult to control by either external-beam irradiation or radical prostatectomy. The combination of local therapies with hormonal manipulation is an innovative strategy to combat this entity. Hormonal regimens have evolved to include total androgen suppression, or maximal androgen blockade. In phase III trials, it appears that the combination of irradiation and hormones is superior to the use of radiotherapy alone. Results of phase III trials comparing surgery to combinations of surgery and hormones have been less encouraging. To date, no prospective randomized trial comparing the combination of hormones plus surgery to hormones plus irradiation has been completed. [ONCOLOGY 10(8):1193-1202, 1996]

Introduction

Carcinoma of the prostate is the most common tumor afflicting
American men. In 1996, it is projected that prostate cancer will
be diagnosed in more than 250,000 patients [1], and locally advanced
prostate cancer that has penetrated beyond the glandular capsule
without distant metastases (American Urological Association [AUA]
stage C; American Joint Committee on Cancer [AJCC] stage T3) will
arise in more than 70,000 patients.

The time-honored management approaches to prostate carcinoma have
included local therapies, such as radical prostatectomy and radiation
treatment, as well as systemic therapies, such as hormonal manipulation.
Locally advanced prostate carcinomas have been especially daunting
to clinicians, who have traditionally used monotherapy to treat
such cases, with local failure rates approximating 50%. The 10-year
clinical survival rates reported for locally advanced disease
range from 33% to 50% in definitive radiation therapy series [2-5]
and from 25% to 40% in surgical series [6,7]. As a result, more
innovative strategies, such as combinations of local therapies
with hormonal manipulation, have been explored during the past
decade.

This review will explain the rationale for combining hormones
with local treatment and summarize available data on these treatment
strategies from prospective and retrospective series. It will
also describe future directions being pursued in ongoing trials
of patients with locally advanced prostate cancer. The published
series have utilized different staging systems--both the traditional
AUA system and the AJCC staging system that has supplanted it.
These different reporting methods create confusion and impose
constraints on interpreting the results. Nonetheless, no attempt
has been made to restage those reports using the older AUA system,
as this would be imprecise and might result in spurious conclusions.
Instead, all data are quoted in the staging system applied by
the primary authors of the respective studies.

Basis for Androgen Deprivation

Since 1941, when Huggins [8] demonstrated that advanced prostate
cancer responded to orchiectomy (observations for which he was
subsequently awarded the Nobel prize in medicine), hormonal manipulation
has been central to the development of new strategies for the
control of prostate cancer. Medical agents that can change the
androgen-dominated hormonal milieu represent alternatives to the
surgical procedures described by Huggins. The earliest trials
of medical hormonal manipulation, conducted by the Veterans Administration
Cooperative Urological Research Group

(VACURG), used high doses of estrogens (up to 5 mg/d of diethylstilbestrol
[DES]) to inhibit intracellular testosterone metabolism. Although
hormonally treated patients showed a delay in time to progression
when compared to untreated controls, their overall survival was
actually decreased due to an excess of cardiovascular deaths.
Reducing the dose of DES (eg, 1 mg/d) minimized this cardiovascular
hazard without compromising survival [9].

Since publication of the VACURG trials, newer hormonal agents
have been developed. It is postulated that androgens act through
receptors that are expressed by prostate cells. Medroxy- progesterone,
megestrol, and cyproterone are progestin-derived compounds that
act as antiandrogens. Although these compounds have improved toxicologic
profiles, compared to DES, they are no more efficacious. Moreover,
they have only weak androgen-blocking ability and actually have
some intrinsic proandrogenic activity.

The nonsteroidal compound flutamide (Eulexin) was the first pure
antiandrogen developed. The clinical import- ance of flutamide
can be appreciated from the observation that intraprostatic testosterone
does not drop to castrate levels following orchiectomy. After
orchiectomy, intraprostatic concentrations of dihydroxytestosterone
synthesized from adrenal precursors reach 40% of the level found
in men with intact testes [10]. Flutamide effectively blocks this
intraprostatic androgen at the level of the androgen receptor.

The concept of total androgen suppression, or maximal androgen
blockade (MAB), simultaneously exploits orchiectomy and extratesticular
androgen blockade. The orchiectomy component of MAB became less
psychologic- ally damaging with the advent of gonadotropin-releasing
hormone (GnRH) analogs, such as leuprolide (Lupron) and goserelin
(Zoladex). The GnRH superagonists cause feedback inhibition of
the pituitary-gonadal axis, rendering the testes hormonally inert.
Although orchiectomy alone had never been shown to prolong patient
survival, MAB significantly lengthened median survival time when
compared to leuprolide alone (16.5 vs 13.9 months; P = .039) among
patients with metastatic disease and good performance status [11].

Rationale for Combining Hormones and Radiation

Recognizing the curative limitations of primary radiotherapy for
stage T3 prostate cancer, clinicians turned their attention to
combinations of hormones and radiotherapy to improve results.
Although androgen deprivation does not cure patients with metastatic
prostate cancer, immediate hormonal manipulation may benefit those
with earlier-stage disease [12]. In addition to treating the patient
at a point when hormonally resistant clonogens may not have evolved,
immediate hormonal manipulation may function as a neoadjuvant
cytoreductive therapy to increase cure rates with radiation.

Theoretical concern has been raised over possible antagonistic
effects of the two modalities [13]. Histologically, hormonally
treated prostate cancer appeared atrophic and lacked significant
degeneration or necrosis. It was suggested that this morphology
represented suppression of tumor growth rather than irreversible
cell death [13]. If androgen deprivation resulted only in the
quiescence of cell division rather than cell death, tumor cells
would be rendered more radioresistant by shifting them into the
G0 phase of the cell cycle.

Possible Favorable Biologic Mechanisms

This concern may be offset by other biologic mechanisms, however.
First, significant tumor shrinkage results in improved blood flow
with a concomitant decrease in tumor cell hypoxia, thereby increasing
radiosensitivity [14]. On the clinical level, Hanks demonstrated
an inverse ratio between tumor volume and control with radiotherapy
[15]. Second, hormonal therapy could provide spatial cooperation
with radiotherapy. This concept implies that hormonal treatment
can sterilize micrometastatic tumor deposits that may not be encompassed
by radiation treatment portals (which are designed to address
bulky local disease). Third, decreased tumor volume alone will
increase radiocurability by reducing the number of viable clonogens.

Apoptosis--Emerging cellular and molecular data indicate
that the mechanism of action of hormonal deprivation is mediated
through an irreversible phenomenon known as apoptosis [16]. Apoptosis,
or programmed cell death, is a morphologically and biologically
distinct mode of cell deletion that is observed in prostate cancer
in response to a variety of antineoplastic therapies, including
androgen deprivation. Apoptosis has been described as a process
comprised of two events: priming and triggering [17]. Priming
includes the expression of calcium-dependent endonucleases that
render cells susceptible to programmed death when appropriate
stimuli are transduced. Once triggered by androgen deprivation,
primed prostate cancer cells undergo a genetically programmed
series of events. These events result in stereotypical DNA degradation
into discrete fragments found in multiples of 180-base pairs corresponding
to single nucleosomes and their oligomers. This is followed by
more generalized DNA degradation, formation of apoptotic bodies,
and, eventually, macrophage clearance.

Radiation therapy can also function as a trigger for apoptosis
[17,18]. Thus, sequential or concomitant application of these
two modalities may have an additive or even supra-additive effect
(Figure 1). Initial hormonal therapy can effectively reduce the
number of androgen-sensitive tumor cells and improve oxygenation.
Subsequent irradiation would then be more effective, with reduced
log-kill requirements and heightened radiosensitivity. Irradiation
kills cells without discrimination to their androgen sensitivity,
but rather, as a distinct trigger of apoptosis, targeting androgen-independent
tumor cells. Androgen deprivation during and following irradiation
may continue to trigger apoptosis of any remaining androgen-responsive
tumor stem cells.

The Spectrum of End Points

Multiple end points have been used to report individual clinical
experiences in the management of locally advanced prostate cancer.
The most important end point is patient survival. However, patients
with prostatic carcinoma often follow indolent courses. This necessitates
the use of other measures of disease control in order to determine,
in a timely fashion, whether new therapies are effective.

A meaningful surrogate end point would fulfill several criteria.
First, it would accurately predict patient survival. Second, relatively
short follow-up would be required. Third, the end point could
be easily applied by independent institutions to ensure its reproducibility.
Because a singularly ideal end point has not been developed, it
is important to review the diverse end points that have been used.

Complete response (CR) is a clinical term that has been used to
describe the resolution of palpable abnormalities on digital rectal
examination (DRE). There are obvious limits to the sensitivity
of this subjective end point. Moreover, the palpated abnormality
may represent benign prostatic hyperplasia, which resolves with
hormonal manipulation, while prostatic cancer remains.

Locoregional failure has also been used and has been variably
defined as a new radiographic or palpable abnormality in the prostate
or regional lymphatics that is confirmed by biopsy. Despite the
development of higher-resolution imaging techniques, quantification
of primary and/or nodal downsizing remains difficult. Consequently,
significant disease progression may be required for local failure
to be detected.

Another potential end point is reassessment of tumor stage in
the surgical specimen. This approach has several limitations.
First, it is difficult to recognize hormonally treated carcinoma,
which is often atrophic and bland [13]. Second, sampling error
is possible. Third, this end point obviously cannot be applied
to irradiated patients. Fourth, series in which T3 disease was
treated by surgery alone indicate that 10% to 30% of patients
were overstaged by clinicians [6], making it difficult to determine
the independent downstaging impact of induction hormonal regimens.
Finally, longer follow-up is needed to determine whether pathologic
downstaging will translate into improved cure rates.

Biochemical Failure

Prostate-specific antigen (PSA) has proven to be a valuable determinant
of relapse after irradiation or radical prostatectomy [19]. Serial
measurements are used to determine biochemical freedom from relapse.
This end point has been reported to increase sensitivity twofold
to threefold over clinically defined failure rates. In addition,
there appears to be a 5- to 7-year lead time between initial biochemical
failure and clinically evident failure [20].

Even PSA levels must be used cautiously in hormonally manipulated
patients, however, because androgen deprivation has been shown
to inhibit PSA expression [21] and secretion [13]. For example,
in surgical patients receiving induction hormonal therapy, serum
PSA values uniformly fall by 98% to normal levels, and yet surgical
specimens rarely show tumor eradication [22]. Thus, when considering
PSA values reported in a randomized trial, it is important to
keep in mind that patients receiving induction hormones may have
spuriously low biochemical relapse rates in comparison to untreated
controls. Nevertheless, the effect of androgen deprivation is
reversible. In viable cancer cells that are not induced into apoptosis,
reintroduction of androgen results in cellular re-expression of
the androgen receptor within 1 hour [23]. Thus, it is quite possible
that any lag in expression of PSA would be of short duration and
that this theoretical concern will be of no clinical relevance.
These caveats notwithstanding, PSA-driven biochemical freedom
from relapse or disease-free survival has emerged as a useful
surrogate for measuring outcome among patients treated by either
surgery or radiotherapy.

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