Recent Advances in the Management of Hormone Refractory Prostate Cancer
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Korean J Uro-Oncol 2004;2(3):147-153 Recent Advances in the Management of Hormone Refractory Prostate Cancer Mari Nakabayashi, William K. Oh Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA A typical treatment strategy after AAWD is to use secondary INTRODUCTION hormonal manipulations, although studies have not yet demonstrated a survival benefit with this class of treatment. Prostate cancer is the most common cancer in men in the Options in this category include (1) the secondary use of anti- United States and accounted for 29,900 deaths in 2003.1 androgens (e.g., high-dose bicalutamide, nilutamide), (2) thera- Although most men with advanced prostate cancer respond pies targeted against adrenal steroid synthesis (e.g., ketocona- initially to androgen deprivation therapies (ADT) by either zole, corticosteroids), and (3) estrogenic therapies (e.g. diethy- bilateral orchiectomy or leuteinizing hormone releasing hor- lstilbestrol). Symptomatic improvement and PSA responses mone (LHRH) analogues, patients eventually progress to an (defined as PSA decline ＞50% after treatment) have been androgen-independent state in which the initial ADT no longer reported in approximately 20% to 80% of patients with is adequate to control disease.2 Progression of the disease hormone-refractory prostate cancer (HRPC) with a typical manifests as an increase in serum prostate-specific antigen duration of response of 2 to 6 months. Toxicity is generally (PSA) or may be accompanied by radiographic evidence of mild for these oral therapies, although serious side effects, tumor growth. Here we report a brief summary of recent including adrenal insufficiency, liver toxicity, and thrombosis, advances in the management of hormone refractory prostate may occur (Table 1). cancer (HRPC). 1. Non-steroidal Antiandrogens SECONDARY HORMONAL THERAPIES Bicalutamide is a nonsteroidal antiandrogen, which has a dose-response effect in normalizing PSA levels. Thus, For patients with a rising PSA and/or radiographic evidence high-dose bicalutamide (150 to 200mg) may be associated with of progressive disease despite castration, physicians should first PSA declines ＞50% in up to 20% of patients with HRPC.4,5 consider anti-androgen withdrawal (AAWD). It has been Nilutamide is another nonsteroidal antiandrogen, with PSA reported that 15% to 30% of patients respond to AAWD with responses reported in approximately 40% of HRPC patients. 3 a median duration of response of 3.5 to 5.0 months. The These treatments are orally administrative drugs and well mechanism of AAWD has been attributed to alteration in the tolerated with the most common side effects such as hot flashes androgen receptor (AR) signaling, resulting in the antiandrogen and nausea. However, treatment is expensive ($1,000 US or behaving as an activator of the AR, rather than an inhibitor. more per month). On should wait 4-6 weeks after stopping an antiandrogen and 2. Inhibitors of Adrenal Steroid Synthesis repeat the PSA test. Approximately 5-10% of circulating androgens are produced Corresponding to：William K. Oh, Dana-Farber Cancer Institute, 44 Binney Street, D1230, Boston, MA 02115. Tel: 617-632-4524, by the adrenal glands. In HRPC, some prostate tumor cells may Fax: 617-632-2165, E-mail: [email protected] remain sensitive to lower levels of circulating androgens. 147 148 대한비뇨기종양학회지：제 2 권 제 3 호 2004 Table 1. Secondary hormonal therapies for HRPC ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ PSA response rates Therapy Number of trials References (≥50% decline) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ High dose bicalutamide 2 20-22.5% 4, 5 Nilutamide 2 29-50% 18, 19 Corticosteroids 4 16-22% 8-11 Ketoconazole+Corticosteroids 4 27-62.5% 3, 6, 7, 20 Estrogenic therapies 5 24-81% 12-15, 17 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Ketoconazole has been noted for many years to effectively Table 2. 1st and 2nd generation chemotherapy for HRPC suppress testicular and adrenal androgen production. Recently, ꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚꠚ PSA a phase III clinical trial (CALGB 9583) of high dose Measurable Therapy N decline References ketoconazole (400mg PO TID) and hydrocortisone (30mg PO response ≥50% each morning and 10mg every night) with AAWD demon- ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ strated this treatment has modest activity in 128 HRPC Mitoxantrone+Steroids 199 33% NR 8, 11 Estramustine+Vinblastine 83 41-61% 14-43% 26-28 patients.6 27% of patients responded to this treatment by PSA Estramustine+Docetaxel 131 63-82% 17-57% 29-32 criteria with mild toxicities. A recent phase II study also ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ suggested the similar response rate with half the traditional dose (200mg PO TID) with fewer side effects.7 Ketoconazole should be administered on an empty stomach, as it is better absorbed because of concerns about contamination.15,17 in an acid environment. Low-dose corticosteroids suppress androgens through CYTOTOXIC CHEMOTHERAPY negative feedback on the secretion of adrenocorticotrophic hormone (ACTH). Although inexpensive and well-tolerated, As recently as the early 1990s, cytotoxic chemotherapy for corticosteroids are associated with a modest overall response HRPC was considered to be inactive.21,22 In 1985, Eisenberger rate and a short duration of response compared to other et al. reported a total response of 4.5% of 17 chemotherapy secondary hormonal manipulations.8-11 This therapy is typically studies21, and in 1993 the review of 26 chemotherapy trials combined with ketoconazole, though it could be used alone. performed between 1987 and 1991 reported an overall response Prednisone (10mg PO QD) is an alternative to the hydro- rate of 8.7% (Table 2).23 cortisone dosing noted above. 1. 1st Generation Chemotherapy 3. Estrogenic Therapies Over the past decade, pessimism accompanying chemo- Diethylstilbestrol (DES) is a synthetic estrogen that reduces therapy for HRPC has been replaced by increasing evidence of testicular androgen production by inhibiting the pituitary- clinical efficacy.2 Improvements in measuring response (e.g. by gonadal axis. However, several studies suggest that DES and using PSA endpoints), and in supportive care treatments other estrogenic therapies may also induce PSA responses in including improved antiemetics, have contributed to this trend. 24-81% of HRPC patients, with median durations ranging from The first important milestone for chemotherapy in the manage- 3 to 7 months.12-15 The mechanism for the effect has been ment of HRPC was achieved in 1996 with a Canadian multi- postulated to be from either mitotic arrest or direct cytotoxic institutional phase III trial.11 One hundred sixty one men with effects on the cells.16 The dose of DES that has been studied symptomatic HRPC were randomized to either mitoxantrone has ranged from 1 to 3 mg daily. Similarly, the estrogenic (12mg/m2, every 3 weeks) plus prednisone (10mg daily) versus herbal therapy, PC-SPES, appeared to have similar rates of prednisone alone. The primary end point of the trial was response in HRPC, though this product is no longer available palliative response, and secondary end points included 50% Mari Nakabayashi․William K. Oh：Recent Advances in the Management of Hormone Refractory Prostate Cancer 149 reduction in the total amount of pain medication without an chemotherapy was active in HRPC, though these regimens had increase in pain, duration of responses and survival. Although only modest efficacy. no survival benefit was found, there was a significant decrease 2. 2nd Generation Chemotherapy in pain (29% vs 12%) as well as a significant prolongation in the duration of pain relief(43 wks vs 18 wks) in the Taxanes are among the most active class of drugs tested so mitoxantrone+prednisone arm. Palliation was also significantly far in phase II and III trials.2 Combination chemotherapy more likely in men with a PSA response than those without regimens of estramustine plus paclitaxel demonstrated PSA such a response (50% vs 29%). response rates of 38-53%, and were generally well-tolerated.33,34 In 1999, the Cancer and Leukemia Group B (CALGB) Docetaxel is a semisynthetic taxane with significant activity as reported a comparable phase III trial of 242 HRPC patients a single agent and in combination with estramustine.35-38 randomized to mitoxantrone (14mg/m2, every 3 wks) plus hy- Two landmark phase III studies comparing docetaxel- drocortisone (40mg daily) versus hydrocortisone alone.8 The containing regimens to mitoxantrone were recently reported primary endpoint of this study was overall survival, and (Table 3).39 In SWOG 9916, 674 patients were randomized to secondary end points were time to disease progression, ob- receive docetaxel (60-70mg/m2 every 3 wks) plus estramustine jective and PSA response rates and quality of life (QOL). (280 mg TID for 5 days every 21 days) (n=338) or mito- Though no difference in survival was noted, improvements in xantrone (12-14mg/m2) plus prednisone (5 mg BID daily) pain control and QOL were noted in the mitoxantrone arm. (n=336). Overall survival was longer in the docetaxel plus Based on these 2 randomized trials, mitoxantrone was approved estramustine arm (17.5 months vs 15.6 months), and median in