Contemporary Hormonal Management of Advanced Prostate Cancer

Early in 1997, the American Cancer Society estimated that over 334,500 new cases of prostate cancer would be diagnosed in 1997 in the United States.[1] This incidence figure was later adjusted downward to approximately 210,000 cases as a result of the culling effect of the PSA screening era. If one accepts the assumption that most men with non-organ-confined prostate cancer have advanced disease, then perhaps 60%, or over 100,000 men, will require care for advanced prostate cancer in this year alone.

Since its introduction in 1941,[2] endocrine manipulation by means of orchiectomy or medical hormonal therapy has remained the mainstay of treatment for metastatic adenocarcinoma of the prostate. The availability of new options for hormonal therapy has engendered controversies regarding not only the preferable forms and timing of treatment but also the very definition of “advanced” prostate cancer. These controversies have led some to propose a revised definition of advanced disease. This new definition incorporates recently acquired knowledge about prostate cancer and may influence the treatment and monitoring of various manifestations of advanced disease.

Contemporary Definition of Advanced Prostate Cancer

The term “advanced prostate cancer” is synonymous with “incurable” to most patients and clinicians.[3] Traditionally, the definition of advanced prostate cancer has referred only to disease stage and has included only symptomatic stage D2 disease with bony or soft-tissue metastases. However, patients with extracapsular disease are at increased risk of dying from prostate cancer compared with patients with localized disease.[4] Because a majority of patients with extracapsular disease are otherwise healthy and have no competing morbidity, stages D1 (regional lymph node involvement), T4 (tumor is fixed or invades adjacent structures other than the seminal vesicles),[5] and T3 (tumor has extended through the prostatic capsule)[5] should be included in the revised definition of advanced prostate cancer for most men.

When both clinical and pathologic staging are assessed, T3 disease, in particular, represents a large percentage of the prostate cancers being treated. Approximately one-half of patients with clinically confined T2 cancers are found on pathologic assessment to have T3 cancers.[3,6] Moreover, a 34% incidence of extracapsular extension is noted, even in tumors identified because of elevated prostate-specific antigen (PSA) levels (so-called stage T1c disease).[7]

Patients with a persistent elevation of PSA after prostatectomy or radiation therapy, as well as those with high PSA levels without evidence of metastases, should also be included in the definition of advanced disease in most cases. Prostate-specific antigen is a sensitive marker for monitoring response to therapy.[8-10] After radical prostatectomy, PSA should fall to undetectable levels; a postoperative rise in PSA indicates the presence of residual tumor. Prostate-specific antigen testing also is the best method available for monitoring patients after radiation or androgen deprivation therapy; a post-radio-therapy nadir value < 1.0 ng/mL or < 0.5 ng/mL indicates a good prognosis.[11]

Recent work with prognostic markers has enabled the selection of men at high risk for disease recurrence after treatment of clinically localized prostate cancer. Partin et al studied clinical stage B2 patients undergoing radical prostatectomy and was able to select a subgroup of men at very high risk of recurrence using an equation based on pretreatment PSA, surgical Gleason sum, and organ-confinement status.[12]

Our Department of Defense Center for Prostate Disease Research (CPDR) group has also created and validated a radical prostatectomy recurrence model that appears to be useful for all patients.[13] The equation, given in Table 1, uses four prognostic factors—PSA, Gleason sum, pathologic stage, and race—to derive a risk of recurrence. In the CPDR study, the high-risk group had a 55.5% chance of recurrence at 3 years and an 84.8% chance at 5 years. In our opinion, at least this group may be considered to have advanced prostate cancer, and this can be determined in the immediate postoperative period.

Aside from these equations using traditional prognostic markers, our group and others are using newer markers, such as molecular biomarkers, to establish risk of recurrence and progression to advanced disease. For example, we found that all patients whose radical prostatectomy specimen overexpressed the p53 tumor-suppresser gene protein and the bcl-2 oncogene developed disease recurrence within 5 years of surgery.[14] Similar prognostic models are being developed for irradiated patients.

To summarize, the current definition for advanced prostate cancer should include not only men with widespread osteoblastic metastases, weight loss, and urinary obstruction but also patients with a substantial risk of disease progression and death from prostate cancer, even those who have no symptoms (Table 2).[3]

Treatment Options for Advanced Prostate Cancer

Androgen ablation therapy has been the mainstay of treatment for stage D2 metastatic prostate cancer for over 50 years.[2] Treatment options include orchiectomy, luteinizing hormone-releasing hormone (LHRH) agents, and combination hormonal therapy, which adds an oral nonsteroidal antiandrogen to the testicular ablation. Estrogens(Drug information on estrogens) are rarely used currently because they may cause cardiovascular toxicity.[15]

LHRH Agonists
The use of LHRH agonists has become the preferred method of androgen ablation. In their depot formulations, LHRH analogs are easily administered, rapidly produce castrate serum levels of testosterone, and are not associated with increased cardiovascular risk. Although none of the currently available monotherapies for advanced prostate cancer offers the prospect of a cure, all symptomatic patients with stage D disease should receive hormonal therapy to improve quality of life and relieve symptoms.[16] Open, multicenter studies in patients with stage D2 prostate cancer have demonstrated that treatment with the depot formulations of the LHRH agonists were associated with an objective tumor response (no progression); normalization of, or at least a 50% decrease in, PSA; and improvement in or stabilization of both local disease status and overall performance status in nearly all patients.[17,18]

Orchiectomy vs Medical Hormonal Therapy
Although the outcome of orchiectomy is equivalent to that of LHRH agents, most patients now prefer monthly, quarterly, or every-4-month LHRH injections to the prospect of castration. Past study has shown that patients prefer LHRH agonists to orchiectomy[19] because of the psychological implications of loss of the testicles.

In the late 1990s, an additional concern for patients is that hormonal therapy should be reversible. Even though the efficacy of intermittent hormonal therapy (see below) is as yet unproven, patients have expressed a desire for this approach, should it be proven efficacious, or should hormonal therapy side effects become troublesome.

Combination Hormonal Therapy
Cancer progression during androgen deprivation therapy may be explained by inadequate suppression of adrenal androgens or by the development of androgen-independent tumor cell populations. It appears that the late 1990s will bring continued debate regarding the clinical value of combination hormonal therapy. Since the initial reports of this approach in the early 1980s, the value of adding an antiandrogen to testicular androgen deprivation has been debated.

Because low levels of dihydroxytestosterone produced by the adrenal glands may continue to stimulate androgen-sensitive cells, the use of an antiandrogen, either in addition to an LHRH agonist or after bilateral orchiectomy, may offer an advantage over monotherapy. There is some evidence that combination therapy improves response and survival rates.[20-23] The National Cancer Institute (NCI) study 0036, European Organization for Research and Treatment of Cancer (EORTC) study 30853, Canadian Anandron Study, and Multinational Nilutamide Study all showed a survival benefit of 7 to 15 months with combination hormonal therapy.[24] However, the recently reported NCI intergroup trial 0105 of orchiectomy and flutamide(Drug information on flutamide) (Eulexin) vs orchiectomy and placebo showed no survival benefit from the addition of an antiandrogen to orchiectomy.[25]

Furthermore, even two meta-analyses of combined hormonal therapy studies came to different conclusions. The first analysis, published in the Lancet, [26] found minimal benefit from the use of combination hormonal therapy (2- to 3-month survival advantage); yet, a recently published second meta-analysis found a clear benefit of this approach (7.3- to 7.6-month survival benefit).[24]

In all of the studies included in these meta-analyses, most of the patients were men with late advanced metastatic disease. The benefit of combination hormonal therapy in earlier advanced disease may be less controversial. For example, in patients with minimal metastatic disease, both the NCI 0036 and EORTC 30853 studies showed a more pronounced survival advantage for combination hormonal therapy. However, the minimal-disease subgroup in NCI 0105 did not show a survival benefit from combination hormonal therapy with orchiectomy.[25]