Combinations of Hormones and Local Therapies in Locally Advanced Prostate Carcinoma

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(Drug information on estrogens) (up to 5 mg/d of diethylstilbestrol(Drug information on 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(Drug information on progesterone), megestrol, and cyproterone(Drug information on 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(Drug information on 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(Drug information on 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.