Recurrent prostate cancer (CaP) is a disease of years, even decades. In one study, the median time between prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) and death was 13 years. Given this prolonged natural history, CaP can be best understood using a disease state model. This model divides the natural history of CaP into four clinically valuable disease states—(1) clinically localized disease, (2) rising PSA, (3) clinical metastases, noncastrate, and (4) clinical metastases, castration-resistant. This article will review the management of castration-resistant, or hormone-resistant, CaP (HRCaP).
A Biologically and Clinically Heterogeneous Disease
HRCaP is also called androgen-independent CaP but better conceptually thought of as castration-resistant CaP. All refer to the same clinical phenomenon, which is the growth of CaP despite low plasma levels of total testosterone, typically to < 50 ng/dL. Such a reduction in serum testosterone is achieved with either a leutinizing hormone-releasing hormone (LHRH) agonist (eg, leuprolide acetate or goserelin acetate [Zoladex]) or surgical castration. Cancer growth is usually documented radiologically, or with serial increases in serum PSA levels (at least two rises, at least 1 week apart, using the same assay). Checking serum testosterone levels is recommended as an initial evaluation in such patients because at least 5% do not have castrate levels of the androgen, in which case surgical castration should be considered.
One problem with the use of the terms "hormone-refractory" or "androgen-independent" is that many of these tumors are still responsive to therapies that alter the androgen milieu. For example, the addition of exogenous testosterone to patients with HRCaP may shorten their survival. Moreover, therapies that either interfere with the binding of androgens to the androgen receptor or decrease the adrenal androgen contribution produce 20% to 40% response rates in the castrate state. Thus, the term HRCaP denotes a disease state that is not truly refractory. Rather, "hormone -refractoriness" describes a spectrum of sensitivities to further androgen-manipulation.
The clinical observation that responses to secondary hormonal manipulation are heterogeneous is reflected in the underlying biology of HRCaP. While not well elucidated, it seems clear that there are several possible pathways to the acquisition of the castration-resistant phenotype (Table 1). This biologic heterogeneity is further exemplified by the results of rapid autopsy studies. One study demonstrated significant variation in the expression of proteins felt to be important in HRCaP not only between patients but also between metastases to different organs in the same patient. Given this inter- and intrapatient biologic heterogeneity, it is not surprising that response rates to various targeted agents in this disease state are low. The critical question is identifying which HRCaP tumors will respond to any particular therapy.
Clinically, HRCaP is also heterogeneous. With the use of serum PSA tests, the diagnosis of HRCaP can be made long before metastases are diagnosed. Many of these patients are initially asymptomatic and may have many years before any clinical sequellae appear. In a study of 201 patients with HRCaP but without bone metastases, only 33% of men developed bone metastases (as noted by bone scan) at 2 years. Predictors of the development of bone metastases included baseline PSA level and PSA velocity. Thus, patients with HRCaP without metastatic disease can remain asymptomatic for years.
On the other hand, the median survival for patients with metastatic HRCaP is 18 to 22 months.[9,10] The most comprehensive evaluation of prognostic markers for survival in this disease setting was performed by Halabi and colleagues. A dataset of 1,101 men from six different Cancer and Leukemia Group B (CALGB) studies was evaluated. All of these men had HRCaP with metastases. Statistically significant prognostic factors of overall survival in a multivariate analysis included performance status, Gleason sum, serum lactate dehydrogenase (LDH), PSA, hemoglobin, and alkaline phosphatase, and the presence of visceral disease. These prognostic factors have been incorporated into a nomogram.
There are three basic categories of treatment options in HRCaP: supportive care, secondary hormonal manipulations, and chemotherapy. In most centers, clinical trials can be added to this list. Many of these treatment options can be effective in the right patient population, yet the only treatment proven to extend survival in HRCaP is docetaxel chemotherapy.[9,10] Moreover, as described below, the phase III studies of docetaxel were performed in a subset of HRCaP—men with mostly symptomatic, metastatic HRCaP.
Therefore, for an individual patient, we select therapy based on multiple factors, including the patient's age, performance status and comorbidities, PSA velocity, the presence or absence of metastatic disease, the presence or absence of symptomatic disease, and the prognostic factors from the CALGB nomogram. For men with multiple comorbidities and a poor performance status but without evidence of metastases, watchful waiting may be the best option. On the other hand, those with symptomatic, metastatic disease who are otherwise in good health are best managed with chemotherapy. For the vast group of patients with HRCaP and a minimal metastatic burden without symptoms, secondary hormonal manipulation or experimental options are reasonable as initial therapy.
Even with a watchful waiting approach, primary androgen deprivation should be maintained. Clinical trials in HRCaP in which testosterone was added to chemotherapy had inferior outcomes to chemotherapy alone, arguing that even in HRCaP, at least a subset of tumor cells remain sensitive to androgens. Interestingly, though, the return of testosterone is highly variable with the discontinuation of androgen-deprivation therapy. In older men who have been on androgen-deprivation therapy for long periods of time, the return to noncastrate serum testosterone levels after the discontinuation of androgen-deprivation therapy may take a long time if it returns at all. Thus, in patients not on clinical trials, it is not unreasonable to discontinue LHRH use and closely monitor testosterone levels.
Dr. Kantoff is a consultant for Abbott, Pfizer, Sanofi-Aventis, AstraZeneca, Bristol-Myers Squibb, TAP, and Amgen. Dr. Ross has received research grants from Genetech, Sanofi-Aventis, and Novartis.
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