New Horizons in the Management of Hormone-Refractory Prostate Cancer

New Horizons in the Management of Hormone-Refractory Prostate Cancer

10TH INTERNATIONAL PROSTATE CANCER UPDATE New Horizons in the Management of Hormone-Refractory Prostate Cancer Martin E. Gleave, MD,* Celestia Higano, MD,† L. Michael Glodé, MD,‡ Eric Goluboff, MD,§ Karl Pummer, MD, E. David Crawford, MD¶ *University of British Columbia, Vancouver; †University of Washington, Seattle; ‡University of Colorado Cancer Center, Denver; §Columbia University, New York; Karl-Franzens University, Graz, Austria; ¶University of Colorado Health Sciences Center, Denver Short-term palliation and improved quality of life may be the best that urologists can now offer their patients with hormone-refractory prostate cancer. New options may soon be available, however. The familiar ablation hormones, corticosteroids, chemotherapy, and radiation therapy are being combined effectively. New strategies include use of mitoxantrone, estramustine, taxanes, bisphosphonates, antisense bcl-2 or clusterin oligodeoxynucleotides, and NSAIDs. Key words: Androgen antagonists • Antineoplastic agents • Palliative care • Prostate-specific antigen • Prostatic neoplasms A ndrogen withdrawal is the only effective form of systemic therapy for men with advanced prostate cancer, producing symptomatic and/or objective response in 80% of patients. Unfortunately, androgen-independent (AI) progression and death occur within a few years in most men.1 Hormone-refractory prostate cancer (HRPC) is highly chemoresistant, with an objective response rate of 10% to chemotherapy and no demonstrated survival benefit.2 In 1985, Eisenberger and colleagues3 reviewed 17 randomized clinical trials of 1464 evaluable patients and found an objective response rate of 4.5%. In 1993, Yagoda and Petrylak4 reviewed 26 trials of new chemotherapeutic agents conducted between 1987 and 1991; the overall response rate was 8.7%. Lack of effective management options for HRPC remains the main obstacle to improving the survival and quality of life of patients with advanced disease. Novel therapeutic strategies that target the molecular basis of androgen and chemoresistance are required. HRPC Defined HRPC is commonly defined as demonstration of 2 to 3 serial rises in the serum prostate-specific antigen (PSA) level obtained from samples taken at least 2 weeks apart in patients with castrate serum testosterone levels. Using these criteria, a heterogeneous population of patients is included in this classification. It is helpful, therefore, to subcategorize patients in terms of extent of disease and presence or absence of symptoms, usually bone pain. 40 REVIEWS IN UROLOGY Supplement Hormone-Refractory Cancer Patients with localized prostate cancer, rising PSA levels after definitive surgery or radiotherapy, and no demonstrable metastatic disease often receive hormonal therapy. When the serum PSA level rises again while patients are receiving hormones, restaging studies are often negative for metastases. In this category, sometimes referred to as biochemical HRPC, is a growing population of otherwise asymptomatic patients. There is no standard approach to treatment for these patients, although many clinical trials are now targeting them. Most often, HRPC is thought of in the context of widespread bone metastases. In this setting, it is helpful to distinguish between patients who are asymptomatic and those who have bone pain or other symptoms of metastatic disease. The median time to symptomatic progression after a rise in PSA level of more than 4 ng/mL is approximately 6 to 8 months, while the median time to death from PSA progression is 12 to 18 months.1 Once patients exhibit symptoms, the median survival ranges from 8 to 12 months. Symptomatic patients need immediate attention; palliation of pain and treatment options are varied and are reviewed below. In terms of contemplating treatment options, it is important to consider that AI or hormone refractory is something of a misnomer. In some cases, the prostate cancer may still exhibit some dependence on the hormonal milieu, while in other cases, the disease may function independently. Unfortunately, at present, there is no way to predict which patients may benefit from a second or subsequent hormonal manipulation. Androgen dependence or independence can only be determined retrospectively, based on response to further hormonal manipulation. releasing hormone analog) and who exhibit rising levels of serum PSA should initially have the antiandrogen discontinued for observation of the antiandrogen withdrawal (AAW) response. This phenomenon was first observed after the antiandrogen flutamide was discontinued in a study of 36 patients and the PSA level subsequently declined without other interventions.5 The withdrawal response has now been described with other hormones, such as megestrol acetate and diethylstilbestrol, as well as the other nonsteroidal antiandrogens, bicalutamide and nilutamide.6-9 The AAW response occurs 15% to 30% of the time.5,10,11 Although the median duration of PSA response is only 3.5 months, the range of duration of response is from 1 to 12 or more months. Along with a decline in PSA level, both subjective and objective responses have been reported.5,9,12 Although the precise mechanism of the AAW remains undefined, it probably results from altered structure of the steroid-binding domain of the androgen receptor (ie, mutation or cleavage) or presence of coactivators that permit the antiandrogen to act as an agonist rather than an antagonist, with subsequent transcriptional activation of cell survival– and mitogenesis–signaling pathways.13,14 Discontinuation of the antiandrogen thus disrupts this stimulus. If a patient has not been receiving antiandrogens, a trial of an antiandrogen may result in a PSA response (more than 50% decline) in 15% to 80% of cases; however, the median duration of response is only 4 months.15-17 Subjective responses have been reported as well. The effects of second-line antiandrogen therapy on survival in patients with HRPC remain unknown. Corticosteroids alone are active against prostate cancer and provide significant palliation in terms of anorexia, pain, and depression. The optimal drug and dosage have not been determined, but even prednisone at a dosage of 5 mg bid resulted in subjective and PSA responses in the Canadian randomized trial discussed below.21 Higher dosages of corticosteroids are often reserved for patients with late end-stage disease or those with spinal cord compression, since long-term administration results in manifestations of cushingoid syndrome, including fluid retention, easy bruisability, glucose intolerance, camel hump, facial erythema, and bloating. Second-Line Hormonal Manipulations Ketoconazole Radiation Therapy The combination of ketoconazole (KC) and hydrocortisone (HC) is generally well tolerated and often effective, but the cost (ranging from $300 to $500 Traditionally, external beam radiation therapy (EBRT) has provided successful palliation of bone pain for patients with symptomatic HRPC or impending Patients who are receiving an antiandrogen (in combination with either orchiectomy or a luteinizing hormone– Antiandrogen Addition per month) can be prohibitive. PSA responses (more than 50% decline) have been reported in 62% of patients, and subjective responses have been observed in 20% to 50%.18-20 At a dosage of 400 mg tid, KC blocks production of adrenal hormones (including HC) and, hence, hormone replacement doses of 20 to 25 mg in the morning and 10 to 15 mg at 4 PM are usually prescribed. KC must be taken on an empty stomach and requires an acid stomach environment for adequate absorption. If patients are taking acid-lowering drugs, such as H2 blockers, vitamin C (1000 mg) can be taken with each KC dose to provide acidity. Some drugs should not be given concurrently (terfenadine, astemizole, cisapride, fluconazole, erythromycin) because of drugdrug interactions that can cause arrhythmia. Because KC interacts with the cytochrome P-450 enzyme system, patients receiving agents, such as warfarin, that are metabolized by this pathway should be monitored closely. Side effects of KC include nausea, GI bloating, hepatotoxicity, sticky skin syndrome, and asthenia. Corticosteroids Supplement REVIEWS IN UROLOGY 41 Hormone-Refractory Cancer continued spinal cord compression.22 Radiopharmaceuticals may be indicated for patients with multiple painful bone metastases who are otherwise not eligible to receive chemotherapy. Radiopharmaceuticals, such as strontium chloride 89 and samarium 153, are preferentially taken up and deliver ray irradiation at sites where there is new bone formation.23,24 The exact mechanism of action of pain relief is not known, although, in some studies, the reported PSA level declines after treatment suggest there is some direct cell kill. A randomized trial of EBRT versus EBRT with samarium 153 showed a delay in the appearance of painful new bone metastases, decreased analgesic intake, greater freedom from metastases at 3 months, and improved quality of life, compared with EBRT alone.24 Chemotherapy Options Historically, prostate cancer has not been considered a chemosensitive disease because of the poor survival outcomes reported in older clinical trials. Many of these trials were performed in the pre-PSA testing era, when patients were treated at later and more symptomatic stages and when survival or objective response rates were primary (and often underpowered) end points. Single-agent chemotherapy has been associated with relevant palliative effects, but no single agent has been associated with an objective response rate higher than 30%.3,4 The use of palliation as an end point, along with the availability of PSA testing as an indicator of disease response, has renewed interest in the use of chemotherapy in patients with HRPC and has led to multiple phase II and several phase III trials that demonstrate effective palliation, PSA response, and/or objective response. PSA level as a measure of disease outcome in patients with metastatic HRPC has emerged as an acceptable surrogate end point to evaluate new agents.25 There is also some evidence of correlation between PSA response and survival based on retro- 42 REVIEWS IN UROLOGY Supplement spective data, but a cause-and-effect relationship remains to be confirmed through prospective investigations. Mitoxantrone Palliative effects have been observed in patients with HRPC following administration of corticosteroids26 or of mitoxantrone with either prednisone or HC.27-29 In a phase III Canadian trial, 161 symptomatic patients with HRPC were randomized to receive either best palliative care with prednisone (5 mg bid) or prednisone plus mitoxantrone (12 mg/m2).21 The primary end points were palliation and duration of palliation, with secondary end points of improved time to progression and survival. A reduction of 2 or more points in a 6-point pain scale (lasting for at least 2 evaluations 3 weeks apart without increased analgesic use) was achieved in 29% of patients in the mitoxantrone arm, compared with 12% of those receiving prednisone alone. The median duration of palliation was significantly longer in the mitoxantrone arm: 43 weeks versus 18 weeks in the prednisone-alone arm (P < .0001). Although PSA level was not an end point of the trial, PSA responses were higher in the mitoxantrone arm (44%) than in the prednisone-alone arm (21%). Of 50 patients, 22% crossed over to the mitoxantrone arm at the time of disease progression and achieved a palliative response that lasted a median of 18 weeks. Median time to progression was also better in the mitoxantrone arm: 24 weeks versus 10 weeks (P = .0001). There was, however, no difference in survival between the treatment arms. The Cancer and Leukemia Group B (CALGB) recently published results of a similar trial conducted in the United States.29 Unlike in the Canadian trial, survival was the primary end point of the CALGB study, with palliation a secondary end point; no crossover to the mitoxantrone-containing arm was allowed. Because patients did not need to exhibit symptoms, more than one third of the 242 patients in this trial were asymptomatic at randomization. As in the Canadian trial, there was a significant difference between study arms in time to disease progression (median, 16.1 vs 9.9 weeks, P = .0218). Forty-two (38%) of 112 patients who received mitoxantrone experienced a 50% or higher reduction in PSA level, compared with 25 (22%) of 116 patients who received HC alone (P = .008). Evaluation of survival by PSA level reduction in both groups (n = 228) demonstrated a survival advantage for those patients with a PSA response. Despite the improvement in time to disease progression and PSA response in the mitoxantrone-containing arm, overall survival was not better than the HC-alone arm (median, 12.3 vs 12.6 months, respectively). Based on results from these 2 phase III randomized trials, the combination of mitoxantrone with corticosteroids is recognized now as the reference treatment in metastatic HRPC.21,29 Estramustine Combinations When used alone, estramustine is a relatively ineffective drug that produces such side effects as significant nausea and vomiting, edema, thromboembolic events, and gynecomastia. At a dose of 280 mg tid, the cost is approximately $40/d, making prolonged dosing prohibitive. In combination with other antimicrotubule drugs (including vinblastine, etoposide, paclitaxel, and docetaxel), estramustine appears to be synergistic. Multiple phase I and II trials have evaluated estramustine-based combinations and have demonstrated objective, PSA, and palliative responses in the 40% to 50% range (Table 1).30-33 A phase III trial of vinblastine alone versus vinblastine plus estramustine showed statistically significant improvement in progression-free survival (3.7 vs 2.1 months, respectively), but whether this difference is significant clinically is debatable.34 As reported in phase I and II trials, the combination of estramustine and Hormone-Refractory Cancer Table 1 Estramustine-Based Phase I/II Trials Estramustine combined with Number of patients % With > 50% decline in PSA % With palliative response Median survival (mo) Vinblastine30 Etoposide31 Paclitaxel32 Docetaxel33 36 42 34 32 61 52 53 63 43 — — 53 11.5 10.5 17 22.8 PSA, prostate-specific antigen. docetaxel appears to be active as well as reasonably well tolerated.33 Estramustine at a dosage of 280 mg tid on an empty stomach is administered for 5 days. Side effects include granulocytopenia, thrombocytopenia, nausea, edema, transaminitis, and esophagitis. A new phase III trial will compare this combination with mitoxantrone and corticosteroids. Taxanes Paclitaxel and docetaxel are taxanes that inhibit microtubule formation and that phosphorylate the cell survival oncoprotein, bcl-2. Paclitaxel is indicated in the treatment of patients with metastatic breast and ovarian cancer and has been evaluated alone and in combination for patients with prostate cancer. A phase II trial by the Eastern Cooperative Oncology Group reported minimal activity with single-agent paclitaxel in 23 men with HRPC.35 Increased activity is reported, however, when paclitaxel is combined with other inhibitors of microtubular function. A phase II trial combining paclitaxel with estramustine reported PSA responses in 53% of 32 patients and objective responses in 4 of 9 men with measurable disease.32 In a phase II study of estramustine, oral etoposide, and paclitaxel, 40 men with HRPC had an overall response rate of 45% and a decrease (65%) of 50% or more in PSA level.36 Median duration of response was 3.2 months, and median overall survival was 12.8 months. The regimen was well tolerated, with no significant change in quality of life as a result of therapy. Docetaxel monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy and, in some countries, for the treatment of non–small-cell lung and ovarian cancer. In phase I and II trials in patients with HRPC, docetaxel administration every 7 or 21 days produces significant activity. Docetaxel monotherapy of 75 mg/m2 every 21 days resulted in PSA level declines of more than 50% and 80% in 45% and 20% of patients, respectively, with an objective response in 28% of patients with measurable disease.37 Although the 21-day conventional schedule is the one currently approved (because of extensive clinical experience in the management of solid tumors of the breast, lung, and ovaries), there is increasing clinical experience with the 7-day schedule of docetaxel administration, including for patients with HRPC. Several studies of patients with HRPC suggest that weekly docetaxel administration is a suitable alternative that can result in a higher dose intensity without increased toxicity.33,37-41 The safety profile was acceptable throughout these studies, with objective responses of 10% to 15% and PSA response of 40%. The activity produced by either the 7- or 21-day schedule is similar, but the 7-day schedule has a better safety profile, which is a significant advantage in the elderly. Theoretically, more frequent ex- posure of tumor cells with weekly docetaxel administration may result in enhanced antiangiogenesis and apoptosis (bcl-2 phosphorylation).42 Based on a report of greater-thanadditive cytotoxicity in vitro when docetaxel is combined with estramustine, several clinical trials have tested this combination in patients with HRPC.33 The respective contribution of the 2 drugs in the clinically observed response rate remains unclear. Evidence of the activity of the docetaxel-estramustine combination includes PSA level decline (greater than 50% decline in the range of 31% to 92% of patients), objective response in bidimensionally measurable lesions (17% to 67% of patients), and improved Karnofsky performance score or pain/ symptom control in 53% to 86% of patients (Table 2). Median survival was 22.8 months, reported by Petrylak and colleagues33 but not yet reported by other investigators. The safety of the combination has been assessed as acceptable.33 Two episodes of grade 4 granulocytopenia were observed in patients who received more than 3 cycles of therapy. No myocardial infarctions or pulmonary emboli were reported during the study. GI toxicity was observed, primarily nausea in 29% and vomiting in 12% of patients. Fluid retention, generally of minimal severity, was reported in 65% of patients. Docetaxel is currently being evaluated in a number of phase III trials. The Southwest Oncology Group (SWOG) is Supplement REVIEWS IN UROLOGY 43 Hormone-Refractory Cancer continued comparing mitoxantrone and prednisone with docetaxel and estramustine in patients with HRPC. Both the CALGB and the North Central Cancer Treatment Group will participate in the SWOG phase III trial. A large, international trial comparing mitoxantrone and prednisone to docetaxel (weekly vs every 3 weeks) and prednisone in patients with HRPC has recently been initiated in Europe, Canada, and the United States, with a primary end point of overall survival and secondary end points of time to progression, PSA response, and quality of life. Bisphosphonates Bisphosphonates are stable analogs of calcium pyrophosphate that inhibit osteoclast activity in bone. They have been approved by the FDA for pallia- tion of pain caused by osteolytic bone metastases of breast cancer and myeloma and have been reported to be palliative in small phase II studies of patients with prostate cancer.43,44 A phase III trial evaluating pamidronate in symptomatic patients with HRPC has recently been completed and is currently undergoing evaluation. In addition to the potential for palliation, bisphosphonates may also have an effect on disease progression. In breast cancer, clodronate, a relatively low-potency bisphosphonate available in Europe, produced a reduction in the incidence and number of new bone and visceral metastases.45 A phase III trial randomizing men with HRPC to mitoxantrone and prednisone plus or minus clonidronate is active in Canada. A phase III trial is now in progress with zoled- ronate, one of the most potent bisphosphonates, in asymptomatic patients with early HRPC. Chemohormonal Approaches Progression to androgen independence is a complex process involving variable combinations of clonal selection,46 adaptive up-regulation of antiapoptotic survival genes,47-49 androgen receptor transactivation in the absence of androgen from mutations or increased levels of coactivators,50 and alternative growth factor pathways.51,52 Androgen withdrawal results in a programmatic drift in gene expression and up-regulation of numerous genes, many of which are cell survival genes that help confer resistance to subsequent chemotherapy. Poor responses to chemotherapy result from multiple complex Table 2 Activity of Docetaxel in Combination With Estramustine in HRPC Number of patients evaluable PSA decline > 50% > 75% Objective response* > 50% Improved pain control Median survival (mo) Author Phase Regimen Petrylak33 I Docetaxel 40 80 mg/m2 q21d + estramustine 280 mg tid  5 d 34 70% 40% 28% (5/18) 53% 22.8 Natale38 I/II Docetaxel 20 40 mg/m2 weekly + estramustine 280 - 420 mg tid 3-4d 18 78% 50% 67% (4/6) 86% NA Docetaxel 70 mg/m2 q21d + estramustine 10 mg/kg  5 d 21 58% 64% 56% (5/9) NA NA Docetaxel 40 - 80 mg/m2 q21d + estramustine 14 mg/kg/d 17/17 82% 30% 17% (1/6) NA NA Savarese39 II Kreis41 II HRPC, hormone-refractory prostate cancer; PSA, prostate-specific antigen; NA, not available. *Calculated among patients with bidimensionally measurable lesions. 44 REVIEWS IN UROLOGY Supplement Hormone-Refractory Cancer and interrelated processes, including low proliferation index; high levels of cell survival genes, such as bcl-2,53 bcl-xL,54 and clusterin55; and the presence of comorbities limiting effective chemotherapy dosing in an elderly population. The rationale behind chemohormonal regimens for hormone-naive advanced disease is based on exposing prostate cancer cells to cytotoxic chemotherapy earlier, before clonal expansion of AI cells or constitutive overexpression of cell survival genes becomes established and before patients develop lower performance status associated with aging and HRPC. Preclinical experiments with the Dunning rat model indicated improved outcomes with chemohormonal therapy, compared with either treatment alone.56 Pummer and associates57 randomized 145 men with advanced hormone-naive prostate cancer to total androgen blockade (TAB) with orchiectomy plus flutamide alone or TAB plus weekly epirubicin for 18 weeks. These authors reported that time to progression (18 vs 12 months, P < .02) and overall survival (30 vs 22 months, P = .12) were longer in stage D2 (more than 5 sites of bone metastasis) patients in the TAB plus epirubicin group; differences in overall survival did not reach statistical significance. The European Organization for Research in Cancer Therapy compared orchiectomy with or without mitomycin-C every 6 weeks in 189 men with metastatic prostate cancer and reported no difference in progressionfree survival. In addition, there were better quality of life and overall survival in the orchiectomy-only group.58 These conflicting results illustrate the importance of identifying an active and well-tolerated cytotoxic agent that will balance potential gains in survival with effects on quality of life. Investigational Trials of Novel Agents In addition to the more conventional approaches discussed above, there are many interesting ongoing clinical trials using investigational agents either alone or in combination with chemotherapy. Some of these approaches in- clude gene or vaccine therapy, matrix metalloproteinase inhibitors, antiangiogenesis drugs, telomerase inhibitors, and signal transduction inhibitors. Some selected strategies to enhance chemosensitivity by targeting apoptosis are presented below. Antisense strategies. Targeting cell survival genes up-regulated by androgen withdrawal or cytotoxic chemotherapy may enhance apoptosis and improve response to hormone therapy or chemotherapy. Antisense oligodeoxynucleotide (AS-ODN) therapy is 1 strategy to specifically target functionally relevant genes. AS-ODNs are chemically modified stretches of single-strand DNA that are complementary to messenger RNA (mRNA) regions of a target gene. The AS-ODNs inhibit translation by forming RNA/ DNA duplexes, thereby reducing the mRNA and protein levels of the target gene.59 The specificity and efficacy of AS-ODNs rely on precise targeting afforded by strand hybridization; only a perfect match between the target sequence and the AS-ODN will lead to hybridization and inhibition of transFigure 1. Schema illustrating sequence-specific interaction between testosterone-repressed prostate message2 (TRPM-2) antisense oligonucleotides (ASO) and messenger RNA (mRNA). Following systemic administration, the ASO enters cells through endocytosis and hybridizes with its target message, leading to activation of ribonuclease (RNase) H and enzymatic degradation of TRPM-2 mRNA. Supplement REVIEWS IN UROLOGY 45 Hormone-Refractory Cancer continued 2 3 1.8 2.5 Tumor volume (mm3) 1.6 TRPM-2 + mitoxantrone 1.4 AS TRPM-2 + paclitaxel 1.2 MM TRPM-2 + paclitaxel MM TRPM-2 + mitoxantrone 2 1.5 1 0.8 1 0.6 0.4 0.5 0.2 0 0 0 1 2 3 4 5 6 7 8 0 1 Weeks 2 3 4 5 6 7 8 Weeks Figure 2. Combined use of antisense oligonucleotides targeting human testosterone–repressed prostate message–2 (TRPM-2) significantly enhanced the apoptotic effects of micellar paclitaxel and mitoxantrone in human androgen–independent PC-3 tumors, reducing mean tumor volume by more than 80% and 60%, respectively, by 8 weeks following initiation of treatment. (AS, antisemse; MM, mismatch.) lation (Figure 1). Phosphorothioate ASODNs are water-soluble, stable agents (manufactured to resist nuclease digestion through substitution of a nonbridging phosphoryl oxygen of DNA with sulfur) that become associated after parental administration with highcapacity, low-affinity serum binding proteins.59 AS-ODNs targeting several oncogenes have been reported to specifically inhibit expression of these genes and delay progression in several types of tumors.59-63 Bcl-2. A critical regulator of apoptosis in numerous tissues, bcl-2 has emerged as part of a growing family of apoptosis-regulating gene products. In prostate cancer cells, bcl-2 is up-regulated within months after androgen withdrawal64 and remains increased in AI tumors,65 serving as an adaptive mechanism that helps mediate hormone and chemoresistance. Bcl-2 also blocks proapoptotic signals by a variety of chemotherapy agents, conferring a multidrug-resistant phenotype that may be operative in AI prostate cancer. This evidence raises the possibility that bcl-2 overexpression in AI prostate cancer helps mediate intrinsic chemo- 46 REVIEWS IN UROLOGY Supplement resistance and suggests that modulation of bcl-2 levels may enhance chemosensitivity. Recent reports indicate that bcl-2 AS-ODNs induce apoptosis and enhance chemosensitivity in various types of malignant cell lines, including small-cell lung cancer62 and melanoma.63 Preclinical studies report synergistic activity between bcl-2 AS-ODN and taxanes in several prostate tumor model systems.53,54 Indeed, the concentration that inhibits 50% of taxanes is reduced by a factor of 1 log when combined with bcl-2 AS-ODNs in both LNCaP and Shionogi tumor models.53,66 Adjuvant in vivo administration of bcl-2 AS-ODN and paclitaxel following castration resulted in significant delay in the emergence of AI recurrent tumors, compared with administration of either agent alone. Furthermore, regression of established AI Shionogi tumors was significantly greater with combined bcl-2 AS-ODN plus taxol than with treatment with either agent alone. Synergistic activity between AS-ODN and taxanes results from AS-ODN–induced decreases in bcl-2 mRNA and protein levels and from taxol-induced bcl-2 phosphorylation. Clinical studies using bcl-2 AS-ODNs, either alone or in combination with chemotherapy, in prostate cancer are now under way at several institutions. TRPM-2. Testosterone-repressed prostate message-2 (TRPM-2), also known as clusterin or sulfated glycoprotein-2, is increased in various normal and malignant tissues undergoing apoptosis.67 TRPM-2 inhibits apoptosis in part by functioning as a chaperone-like molecule to prevent protein unfolding during times of cell stress.68 TRPM-2 staining increases in prostate cancer cells after neoadjuvant hormone therapy and in AI tumors. Overexpression of TRPM-2 in LNCaP cells enhances resistance to apoptosis induced by tumor necrosis factor ,69 androgen withdrawal,48 and paclitaxel chemotherapy.55 The up-regulation of TRPM-2 in human prostate cancer tissues after castration serves as an adaptive mechanism that helps mediate hormone and chemoresistance and identifies it as a therapeutic target to enhance castration- and chemotherapy-induced apoptosis. Paclitaxel chemosensitivity is enhanced by a factor of 1 log when Hormone-Refractory Cancer combined with TRPM-2 AS-ODNs both in vitro and in vivo.55 Regression of established AI human PC-3 tumors has been reported as significantly greater with combined TRPM-2 AS-ODN plus paclitaxel than with treatment with either agent alone (Figure 2). Clinical trials using combined docetaxel and TRPM-2 AS-ODN will begin early in 2001. Sulindac sulfoxide. Sulindac, exisulind, and other NSAIDs have been reported to inhibit tumor formation and progression in several experimental tumor systems. Sulindac is a prodrug that is metabolized to either a sulfide or sulfone derivative after oral administration. The sulfide is a cyclooxygenase (COX) II inhibitor, and is responsible for its anti-inflammatory properties. The growth inhibitory effects of sulindac have been reported to be independent of COX inhibition or p53 induction and appear to involve induction of apoptosis via phosphodiesterase inhibition. Sulindac causes regression and prevents recurrence of polyps in patients with familial adenomatous polyposis (FAP)69,70 and inhibits mammary carcinogenesis.71 Phase I and II studies of exisulind in patients with FAP showed a chemopreventive effect with minimal toxicity; phase III trials are under way. In preclinical prostate cancer trials, exisulind delayed LNCaP tumor growth in vivo, presumably via increased apoptosis.72 Ninety-six patients with rising PSA levels after radical prostatectomy were randomized to receive placebo or exisulind for 1 year.73 The drug was well tolerated; after 6 months of treatment, serum PSA levels increased from 2.78 ± 0.4 to 4.76 ± 0.3 ng/mL in the placebo group, compared with 2.16 ± 0.28 to 2.9 ± 0.5 ng/mL in the exisulind group. The attraction of this drug is its oral administration and low toxicity; longer additional trials are under way to assess its efficacy in patients with HRPC and to determine whether it possesses additive or synergistic effects with cytotoxic chemotherapy. Summary Treating patients with HRPC is challenging and requires consideration of multiple disease- and patient-related factors. It is important to individualize the approach to therapy based on the patient’s performance status, other comorbidities, symptoms, logistical issues, and desires and expectations. At the present time, until evidence is obtained that survival can be improved with systemic therapy, maintaining or improving quality of life should be the primary goal of therapy. In the future, there is optimism that, in addition to improving or maintaining quality of life, treatment options for HRPC will also extend survival. ■ References 1. Newling DW, Denis L, Vermeylen K. Orchiectomy versus goserelin and flutamide in the treatment of newly diagnosed metastatic prostate cancer: analysis of the criteria of evaluation used in the European Organization for Research and Treatment of Cancer–Genitourinary Group Study 30853. Cancer. 1993;72(12 suppl):3793-3798. 2. Fowler JE Jr, Whitmore WF Jr. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol. 1981;126:372-375. 3. 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