Management of Advanced/Metastatic Prostate Cancer: 2000 Update

The clinical presentation of prostate cancer has been evolving over the past several years, in part due to increased public awareness of the disease and the availability of prostate-specific antigen (PSA) as a screening serologic test in the late 1980s. Currently, approximately 75% of prostate cancer patients present with clinically localized disease, compared with about 50% in the mid-1980s.[1]

Today, fewer patients with prostate cancer present with an abnormal digital rectal exam. In many current series, the most common category at initial presentation is T1C disease. This represents patients who have elevated serum PSA levels without associated nodularities within the prostate gland on rectal exam but are found to have prostate cancer on biopsy. On the other hand, the incidence of metastatic prostate cancer has almost halved over the past 15 years, so that about 10% to 15% of patients currently present with clinical metastatic disease.

Although both prostate cancer incidence and mortality have begun to decline in recent years, 37,000 men in the United States still died from this disease in 1999, making it the second leading cause of US cancer deaths in men. Invariably, prostate cancer deaths are due to progressive, metastatic disease that has failed initial therapies.

Evolving Biological Principles

Dramatic progress has been made in understanding the molecular and biochemical pathways involved in the development and progression of prostate cancer. Before discussing treatment approaches, we will describe a few examples of the evolving biological principles, which can be grouped broadly into several categories that are not mutually exclusive. Many of the following principles are being incorporated into new treatment strategies.

In terms of normal physiology and malignant transformation, the important interactions between the prostate epithelium and the underlying stroma within the prostate gland are being increasingly recognized.[2,3] Dynamic interactions that normally occur between the stroma, endothelial cells, extracellular matrix, and prostate epithelium can be altered as prostate cancer progresses and metastasizes. Potential alterations in intergrin-mediated cell-cell and cell-extracellular matrix interactions/signaling represent one example.[4]

A family of enzymes called matrix metalloproteases (MMPs), as well as tissue inhibitors of MMPs, are involved in the physiologic remodeling of the extracellular matrix.[5] Perturbations in this remodeling process appear to be an important step in tumor growth and invasion.[5] Formation of new blood vessels is a necessary step for the initial tumors to continue increasing in size and subsequently metastasize.[6] Prostate cancer cells can assume angiogenic potential by secreting growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). In turn, endothelial cells recruited during angiogenesis can stimulate tumor growth by secreting growth factors and cytokines such as interleukin (IL)-1 and IL-6.[6-8]

Changes in Cell Signaling

It is now well recognized that changes in intra- and intercellular signaling response to growth factors, cytokines, cell-adhesion molecules, and other ligands are a fundamental aspect of tumor pathogenesis. We are now discovering that significant cross-talk can also occur between the various signaling cascades. The erbB family of receptor tyrosine kinases, which mediate signaling functions of epidermal growth factor (EGF)-like growth factors and other ligands (heregulins), are among the most frequently implicated cell surface receptors in human cancers.[9]

HER2—a member of the erbB family of receptor tyrosine kinases—is overexpressed in a proportion of patients with prostate cancer, and presumably contributes to altered cell functions.[10] Although, to date, no direct ligands for HER2 have been found, it appears to modulate signaling via dimerization with other members of the erbB family. Studies suggest that IL-6 signaling in prostate cancer cells via the IL-6 cytokine receptor requires direct interactions of the latter with HER2, thus implicating cross-talk between cytokine receptors and tyrosine kinase receptors.[11]

Androgen-receptor signaling is fundamental to both normal and malignant prostate physiology. Recent work suggests that ligand (ie, androgen)-independent cross-talk can occur between HER2 and androgen receptors during prostate cancer progression.[12] Androgen-independent cross-talk has also been shown to occur between androgen receptors and the protein kinase A (PKA) signal-transduction pathways in prostate cancer cells.[13] In particular, PSA gene expression can be mediated via PKA-dependent phosphorylation of the androgen receptor/coactivator(s) in an androgen-independent manner.[13]

Other Pathways

In addition to examples of the altered cell signaling noted above, other metabolic/biochemical pathways can be modified as a consequence of malignant transformation. In this regard, a key metabolic pathway involving citrate metabolism has been implicated in prostate cancer. Studies have shown that normal as well as benign hyperplastic prostate tissues accumulate very high levels of citrate and zinc.[14] On the other hand, malignant prostate tissue cannot accumulate zinc or citrate.[14]

Although the mechanisms of differential zinc uptake/transport in the normal prostate gland vs prostate cancer have yet to be clarified, recent work has shown that the high levels of zinc in the normal prostate inhibit the enzyme m-aconitase, which prevents citrate from being oxidized, thus resulting in the high citrate levels in the normal prostate. In contrast, the low accumulation of zinc in prostate cancer cannot inhibit m-aconitase, thereby further metabolizing citrate and leading to low levels of citrate in malignant tissue.[14] Metabolic products of arachidonic acid—generated by the action of 12-lipoxygenase—can activate downstream targets like protein kinase C (PKC). These products have been implicated in prostate cancer progression and invasion.[15,16]

Calcium within cells can serve as an important signaling molecule that modulates many cellular processes. For example, a rise in calcium within the cytosol of cells can occur in response to activation of cell surface receptors, and this, in turn, can trigger a variety of biological functions, including muscle contraction, gene transcription, cell-cycle progression, and apoptosis.[17-19]

In prostate cancer, disruption of intracellular calcium homeostasis is a prominent feature of hormone ablative therapy, which remains the cornerstone of treatment for metastatic disease. In particular, androgen deprivation is associated with an increase in cytosolic calcium levels, which normally are tightly regulated. This, in turn, triggers the apoptotic program that results in cell death.[20]

It has been suggested that a failure to generate such an increase in cytosolic calcium in response to hormone ablation may be one of the mechanisms responsible for the hormone-resistant phenotype that often occurs in prostate cancer, resulting in the eventual failure of androgen ablative therapy in this disease.[21] On the other hand, apoptosis can be induced in hormone-insensitive prostate cancer cells if elevated levels of cytosolic calcium can be generated and sustained for several hours.[21]

Genetic Alterations

Ultimately, genetic alterations form the molecular basis for many of the phenotypic changes in cell biochemistry, cell signaling, and cell-cell interactions that occur as a consequence of malignant transformation. Multiple chromosomal changes have been identified in prostate cancer, and recently, a correlation has been found between tumor grade/tumor invasion and frequency of loss in genetic heterozygosity.[22-24] Examples of genes whose functions may be modified or inactivated during transformation include p53, PTEN, and glutathione S-transferase pi.[25-27]

Hormone Resistance

Another important aspect of prostate tumor biology is the emergence of clinical resistance to initial hormone ablative therapy. Although a majority of patients with metastatic prostate cancer respond to androgen deprivation (see below), most ultimately do not, and consequently, hormone-resistant prostate cancer (which is relatively resistant to chemotherapy drugs) emerges.

Whether androgen-dependent and androgen-independent prostate cancer cells are present at the outset, or only androgen-dependent cells are present initially but androgen-independent cells are selected for during hormone ablation, remains an unresolved issue. However, some preclinical models favor the former hypothesis.[28]

Several mechanisms have been implicated in the development of androgen independence, including changes within the androgen receptor and overexpression of the antiapoptotic protein, bcl-2.[29-31] Overexpression and modification of the latter can partly account for the pleiotropic resistance to cytotoxic agents seen in hormone-resistant prostate cancer.

Evaluation of Response to Treatment

Evaluating the effectiveness of any cancer therapy requires a definition of parameters that can be used to evaluate response. This has been a particularly difficult problem in advanced prostate cancer, because in a majority of patients with metastasis, the dominant sites of involvement are the bones—which are not readily amenable to the classic criteria of response to therapy. These difficulties are reflected in earlier definitions of response used by the National Prostate Cancer Project (NPCP) in the 1970s, where disease "stabilization" was included in the overall response category.[32]

Ever since PSA screening became available, it has been incorporated in most clinical trials as one marker of disease progression or response to treatment. Several reports have indicated a utility to using a 50% or greater decline in PSA posttherapy as a marker of clinical benefit and possibly prolonged survival.[33,34] However, in most studies, definitions vary regarding the incorporation of PSA as a measure of disease progression or response to therapy. Hence, the Prostate-Specific Antigen (PSA) Working Group recently set a series of guidelines defining (1) the different categories of men with metastatic, androgen-independent prostate cancer who might be eligible for clinical trials; and (2) the criteria of disease progression and response (including changes in PSA) to be used in evaluating patients in trials.[35]

Several investigators have sounded a note of caution, however, with respect to using PSA as a marker of response: Some of the newer, "nontraditional" therapies in current clinical testing (including certain differentiation agents, antiangiogenesis drugs, and growth-factor modulators) may actually upregulate PSA gene expression.[36-38] Another aspect regarding the evaluation of therapies is the use of palliative end points, such as quality-of-life (QOL) measures and pain control.[39] These parameters have been incorporated into many of the trials now evaluating the role of chemotherapy in androgen-independent prostate cancer.

First-Line Therapy

Since prostate cancer is primarily dependent on androgens for growth, the initial treatment for advanced/metastatic disease continues to be suppression of testicular androgen production. This therapy was originally described by Huggins 60 years ago in the form of surgical castration (ie, bilateral orchiectomy), which effectively removes 90% of circulating testosterone from the bloodstream.[39a]

Another way of nonsurgically suppressing testicular androgens is via analogs of gonadotropin-releasing hormones [GnRH]), which have been available since the 1970s.[40] The GnRH analogs (leuprolide [Lupron], goserelin(Drug information on goserelin) [Zoladex]) are supra-agonists that, upon binding to the luteinizing hormone-releasing hormone (LHRH) receptor within the pituitary gland, cause an initial surge of LH, and thus, testosterone, release. However, the continued receptor occupancy causes internalization, degradation, and desensitization of the LHRH receptor. This, in turn, leads to decreased testicular androgen synthesis, and hence castrate levels of testosterone within 3 to 4 weeks of drug administration.

Due to the more favorable toxicity profile of the GnRH analogs compared to diethylstilbestrol(Drug information on diethylstilbestrol) (Stilphostrol), the GnRH analogs—despite their expense—have become the treatment of choice for achieving medical castration in the United States. Newer long-acting pure antagonists of GnRH (which avoid the initial LH/testosterone surge) are undergoing clinical trials.[41]

Effective nonsurgical castration can also be achieved with estrogens(Drug information on estrogens) like diethylstilbestrol (administered at 3 to 5 mg/d). However, due to the increased risk of cardiovascular toxicities, this form of therapy has fallen out of favor, at least in the United States.

Approximately 80% of patients with advanced prostate cancer respond initially to either medical or surgical castration. Substantial responses occur in a majority of patients with soft-tissue disease, including normalization of elevated PSA levels in up to 70% of patients as well as stabilization and improvement of bone lesions in a significant proportion. Those with pain resulting from bone metastasis can achieve almost immediate pain relief upon surgical castration.

Although gonadal androgen suppression removes about 90% of circulating testosterone, other androgens (that are primarily adrenally derived) can also potentially exert tumor-promoting effects. Hence, attempts have been made to suppress the action of the remaining circulating androgens via the use of steroidal (cyproterone, megestrol) or nonsteroidal antiandrogens (bicalutamide [Casodex], flutamide(Drug information on flutamide) [Eulexin], nilutamide [Nilandron]).

Particularly with the availability of the nonsteroidal antiandrogens (which act by blocking the peripheral androgen receptor), substantial effort and resources have been devoted to determining whether total androgen suppression (achieved by medical or surgical castration plus the use of antiandrogens) is better than gonadal androgen suppression with respect to response rates and survival in patients with advanced prostate cancer.[42,43] Despite a plethora of prospective, randomized trials addressing this issue (27 such trials conducted to date), any significant advantages of total androgen suppression over gonadal androgen suppression have not been clearly demonstrated. If any survival advantages are seen with total androgen suppression, they are likely to occur primarily in patients with metastatic disease who have minimal tumor burden.[44]

Peripheral androgen blockade refers to the use of antiandrogens in conjunction with inhibitors of 5-alpha reductase (finasteride [Proscar]), an enzyme that converts testosterone to its more active form of dihydrotestosterone. With this approach, serum testosterone levels are less likely to be suppressed to castrate levels, and therefore, some side effects associated with gonadal androgen suppression/total androgen suppression (ie, hot flashes, osteoporosis, anemia, muscle weakness, and impotence) are likely to be less pronounced.

Although peripheral androgen blockade can provide control of advanced prostate cancer, questions remain regarding its overall efficacy. Recent randomized trials comparing antiandrogen monotherapy with gonadal androgen suppression or total androgen suppression confirm the superiority of the latter approaches with respect to survival in patients with metastatic prostate cancer.[45,46] Therefore, gonadal androgen suppression plus or minus antiandrogen therapy remains the most effective first-line treatment in patients with advanced prostate cancer.