Lack of prognostic significance of p16 and p27 after radical prostatectomy in hormone-naïve prostate cancer.

BACKGROUND: Loss of normal cell cycle control is an early event in the evolution of cancer. The expression of cyclin-dependent kinase (CDK) inhibitors p16 and p27 has been previously associated with progression of prostate cancer (PC). 70 patients diagnosed with early stage PCwere treated with radical prostatectomy (RP) at our institution and their tumor specimens were immunohistochemically evaluated for expression of p16 and p27. Available clinical data of time to PSA recurrence were correlated with the examined parameters and combined with pre-operative PSA level, Gleason score and pathological TNM (pT) stage assessment. RESULTS: Nuclear overexpression of p16 was not associated with time to biochemical failure (BF) (p = 0.572). Same was the case for nuclear p27 overexpression (p = 1.000). Also, no significant correlations were found between either p16 or p27, and pre-operative PSA level, pT stage and Gleason grade. pT stage emerged as the only independent prognostic factor for biochemical recurrence (p = 0.01). CONCLUSIONS: These data question previously reported data supporting the prognostic relevance of both p16 and p27 proteins in early PC.

CD10 is inversely associated with nuclear factor-kappa B and predicts biochemical recurrence after radical prostatectomy.

INTRODUCTION: The cell surface endopeptidase CD10 (neutral endopeptidase) and nuclear factor-κB (NF-κB) have been independently associated with prostate cancer (PC) progression. We investigated the correlations between these two factors and their prognostic relevance in terms of biochemical (prostate-specific antigen, PSA) relapse after radical prostatectomy (RP) for localized PC. PATIENTS AND METHODS: The immunohistochemical expression of CD10 and NF-κB in samples from 70 patients who underwent RP for localized PC was correlated with the preoperative PSA level, Gleason score, pathological stage and time to PSA failure. RESULTS: CD10 expression was inversely associated with NF-κB expression (p < 0.001), stage (p = 0.03) and grade (p = 0.003), whereas NF-κB was directly related with stage (p = 0.006) and grade (p = 0.002). The median time to PSA failure was 56 months. CD10 and NF-κB were directly (p < 0.001) and inversely (p < 0.001) correlated with biochemical recurrence-free survival, respectively. CD10 expression (p = 0.022) and stage (p = 0.018) were independently associated with time to biochemical recurrence. CONCLUSION: Low CD10 expression is an adverse prognostic factor for biochemical relapse after RP in localized PC, which is also associated with high NF-κB expression. Decreased CD10 expression which would lead to increased neuropeptide signaling and NF-κB activity may be present in a subset of early PCs.

Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.

OBJECTIVES: Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells. METHODS: Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. RESULTS: Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. CONCLUSIONS: These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome.

Nonbacterial thrombotic (marantic) endocarditis in a patient with colorectal cancer.

BACKGROUND: Marantic endocarditis, presently termed nonbacterial thrombotic endocarditis (NBTE), is an infrequent post-mortem diagnosis in the adult population but a not so rare event in the course of neoplastic conditions. CASE REPORT: We describe the case of a 74-year-old woman with advanced sigmoid adenocarcinoma, who developed aseptic vegetations in the right atrium of the heart. Systemic anticoagulation therapy was started, and upon clinical improvement systemic chemotherapy was added, resulting in partial response to antineoplastic therapy along with improvement of her cardiopulmonary status. A new cardiac assessment upon tumor recurrence was unable to distinguish the previously described lesions but disclosed a small mitral valve vegetation, in the absence of any signs or symptoms. The patient was again treated with chemotherapy and remains asymptomatic with stable disease. CONCLUSIONS: Although a hypercoagulable state may be etiologically related to malignant conditions, a strong clinical suspicion of NBTE is required. In these cases, it is often difficult to establish a definite diagnosis; however, immediate anticoagulation treatment is mandatory for the prevention of de novo or further thromboembolic events.

The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 2: transcriptional regulation.

DNA repair is an indispensable part of a cell's defence system against the devastating effects of DNA-damaging conditions. The regulation of this function is a really demanding situation, particularly when the stressing factors persist for a long time. In such cases, the depletion of existing DNA repair proteins has to be compensated by the induction of the analogous gene products. In addition, the arrest of transcription, which is another result of many DNA-damaging agents, needs to be overcome through regulation of transcription-specific DNA repair pathways. The involvement of the ubiquitin-proteasome system (UPS) in cancer- and chemotherapy-related DNA-damage repair relevant to the above transcriptional modification mechanisms are illustrated in this review. Furthermore, the contribution of UPS to the regulation of localization and accessibility of DNA repair proteins to chromatin, in response to cellular stress is discussed.

The ubiquitin-proteasome system in cancer, a major player in DNA repair. Part 1: post-translational regulation.

DNA repair is a fundamental cellular function, indispensable for cell survival, especially in conditions of exposure to environmental or pharmacological effectors of DNA damage. The regulation of this function requires a flexible machinery to orchestrate the reversal of harmful DNA lesions by making use of existing proteins as well as inducible gene products. The accumulation of evidence for the involvement of ubiquitin-proteasome system (UPS) in DNA repair pathways, that is reviewed here, has expanded its role from a cellular waste disposal basket to a multi-dimensional regulatory system. This review is the first of two that attempt to illustrate the nature and interactions of all different DNA repair pathways where UPS is demonstrated to be involved, with special focus on cancer- and chemotherapy-related DNA-damage repair. In this first review, we will be presenting the proteolytic and non-proteolytic roles of UPS in the post-translational regulation of DNA repair proteins, while the second review will focus on the UPS-dependent transcriptional response of DNA repair after DNA damage and stress.

Prospective assessment of systemic therapy followed by surgical removal of metastases in selected patients with renal cell carcinoma.

OBJECTIVE: To prospectively establish objective selection criteria for metastasectomy in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Between 1991 and 1999, 38 patients with mRCC with responsive or stable disease after initial systemic therapy, and with potentially resectable disease, were enrolled. Patients had a metastasectomy with curative intent and received consolidative adjuvant systemic therapy. RESULTS: Of the patients enrolled, 79% had stable disease after initial systemic therapy and 21% had a partial or complete response. Most (84%) had metastasectomy of one organ site. There was surgically no evidence of disease (sNED) in 76%. Operative morbidity and mortality were acceptable and 90% of the patients received adjuvant systemic therapy. The median (95% confidence interval) survival was 4.7 (3.0-7.8) years, and the median time to progression was 1.8 (0.8-3.1) years. Eight of 38 patients (21%) remained free of disease by the end of the study. Significant predictors of outcome were lack of sNED after metastasectomy, and the presence of pulmonary metastases. The median overall survival for those who had sNED was 5.6 years, vs 1.4 years for those who did not (P < 0.001). CONCLUSIONS: Metastasectomy in patients with mRCC not progressing after systemic therapy is feasible, with acceptable morbidity. Predictive factors for long-term outcome include pulmonary metastases and sNED. Future work evaluating treatments that can convert patients into surgical candidates will increase the cure rate of patients with mRCC.

Phase II study of capecitabine single-agent therapy in patients with metastatic renal cell carcinoma.

Fluoropyrimidines are known to have modest activity in the treatment of metastatic renal cell carcinoma (RCC). Capecitabine is an orally administered prodrug that is converted to fluorouracil and is of potential use in the treatment of this disease. We conducted a Phase II clinical trial of capecitabine administered as a single agent to patients with metastatic RCC. The treatment consisted of 1250 mg/m(2) capecitabine orally, twice daily (2500 mg/m(2) per day) days 1-14, repeated every 21 days. There were 15 patients, including 13 men and 2 women, who underwent a total of 67 cycles (median 3.5; range 1-15). Nine patients had undergone prior systemic therapy consisting of interferon-alpha in 3, interleukin-2 in 1, interferon-alpha plus interleukin-2 in 4, and investigational therapy with bryostatin-1 in 1. There were 14 patients assessable for response (one withdrew), and no responses were seen. Median time to progression was 9 weeks (range 1-45). There were 3 patients (21%) who had stable disease for 18, 39, and 45 weeks. Hematologic toxicity was mild. Three patients had grade 3 or 4 gastrointestinal toxicity, and 3 required dose reductions. There were 2 early deaths, including 1 patient with pulmonary edema and 1 with hypotension. The study was terminated because there were no responses in the first 14 assessable patients, indicating that the response rate was likely to be less than 20%. We conclude that single-agent capecitabine has minimal activity for the treatment of metastatic RCC.

Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer.

BACKGROUND: This is a phase I/II trial of thalidomide with estramustine and paclitaxel in men with androgen-independent prostate cancer (AIPC) who underwent previous chemotherapy. PATIENTS AND METHODS: Men with progressive AIPC were treated with oral thalidomide (200 mg, 400 mg, or 600 mg daily), intravenous paclitaxel (100 mg/m2 over 3 hours on days 3 and 10), and oral estramustine (140 mg 3 times daily on days 1-5 and days 8-12) every 21 days. RESULTS: Phase I: first cycle dose-limiting toxicity occurred in 0 of 3 patients at 200 mg thalidomide daily, 0 of 3 at 400 mg daily, and 1 of 3 at 600 mg daily (the designated maximum tolerated dose). Phase II: twenty-nine of 38 evaluable patients (76%; 95% confidence interval, 67%-87%) experienced a 50% decrease in prostate-specific antigen level. Five of 18 patients (28%) with measurable disease exhibited an objective response. Nine of 14 patients (64%) with disease refractory to previous taxane therapy had 50% decreases in prostate-specific antigen level. Grade 3/4 adverse events included neutropenia (9 of 39 [23%]), fatigue (9 of 39 [23%]), dyspnea (8 of 39 [21%]), and thromboembolic events (7 of 39 [18%]). Cumulative dose-limiting toxicity rates were minimal (13%) with thalidomide at 200 mg daily. CONCLUSION: The profile of activity of thalidomide/paclitaxel/estramustine in taxane-refractory AIPC warrants further investigation.

Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate.

PURPOSE: To determine the activity and toxicity of doxorubicin in combination with cisplatin and etoposide in patients with small-cell prostate carcinoma (SCPCa) and to characterize the clinicopathologic features of SCPCa. PATIENTS AND METHODS: Patients with SCPCa (pure or mixed), measurable disease, good organ function, and no prior treatment with doxorubicin, etoposide, or cisplatin were treated every 4 weeks with doxorubicin 50 mg/m(2) as a 24-hour intravenous (IV) infusion followed by etoposide 120 mg/m(2)/d and cisplatin 25 mg/m(2)/d IV on days 2 to 4. RESULTS: Thirty-eight patients (36 assessable for response) were treated for a median of four cycles. Twenty-nine (81%) of 36 patients had prior hormonal therapy. Study patients had visceral metastases, lytic bone disease, and relatively low serum prostate-specific antigen (PSA). We observed 22 partial responses (response rate, 61% in an intent-to-treat analysis); toxicity was severe (grade 3 or 4 neutropenia 100%, thrombocytopenia 66%, mucositis 21%, and infection 68%). Three patients died of toxicity. Median time to progression and overall survival time were 5.8 months and 10.5 months, respectively. Performance status, serum albumin, and number of organs involved (but not PSA, carcinoembryonic antigen, or neuroendocrine markers) were predictors of survival. CONCLUSION: SCPCa presents unique clinicopathologic features. Addition of doxorubicin to the etoposide/cisplatin regimen caused higher toxicity in this patient population and failed to improve outcome. Given these results, we do not recommend further development of this regimen for patients with SCPCa. Improvement in therapy will come from understanding the biology of SCPCa progression and integrating new targeted therapies into the treatment of SCPCa.

Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial.

PURPOSE: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma. PATIENTS AND METHODS: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. RESULTS: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P =.13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P =.021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P =.002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan. CONCLUSION: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.

Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). PATIENTS AND METHODS: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)). RESULTS: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.

Basic Concepts in Metastatic Cardiac Disease.

The involvement of the heart in metastatic cancer is a rare clinical diagnosis, as it may be asymptomatic or symptoms, when present, may be attributed to other causes. Issues regarding incidence, intracardiac location, clinical presentation, diagnosis and treatment of metastatic cardiac tumors will be discussed here.

p53 and cyclooxygenase-2 expression are directly associated with cyclin D1 expression in radical prostatectomy specimens of patients with hormone-naïve prostate cancer.

Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX-2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naïve PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p = 0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p = 0.055 and p = 0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p = 0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP.

Expression of neutral endopeptidase, endothelin-1, and nuclear factor kappa B in prostate cancer: interrelations and associations with prostate-specific antigen recurrence after radical prostatectomy.

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP (P < 0.001), cytoplasmic ET-1 (P = 0.002), and cytoplasmic NFκB (P < 0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P < 0.001) and NFκB (P < 0.001). ET-1 was also correlated with NFκB (P < 0.001). NEP expression (P = 0.017), pT stage (P = 0.013), and SMs (P = 0.036) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.

Employing the treatment-free interval of intermittent androgen ablation to screen candidate prostate cancer therapies.

BACKGROUND: Because neither continuous nor intermittent hormonal therapy is curative, we designed a clinical model to screen new drugs for additive or synergistic effects with hormonal therapy and used IM862, a naturally occurring dipeptide with antiangiogenic and immunomodulatory properties, to test it. METHODS: Patients with prostate cancer who had rising PSA levels after radical prostatectomy and/or radiation therapy were given combined androgen ablation for 3 months. After 2 months' treatment, patients were randomly assigned in a double-blind fashion to receive intranasal IM862 or placebo daily. Treatment continued for 6 months or until disease progression, which was defined by a rising serum PSA level, the appearance of new skeletal or extraskeletal metastatic disease, or new symptoms requiring intervention. RESULTS: Seventy-one patients were evaluable for response. Median time to PSA progression was not reached in either group. At 6 months, disease had progressed in 14 (41%) of the 34 patients receiving treatment and 18 (49%) of the 37 receiving placebo (P = 0.39). No significant toxicities emerged. CONCLUSIONS: The model was demonstrated to be an efficient platform for new drug screening; however, IM862, though well tolerated, failed to demonstrate superiority over placebo in prolonging time to PSA progression.

Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma.

BACKGROUND: In this Phase II study, the authors assessed the toxicity and anti-tumor activity of a combination of oral cyclophosphamide, oral low-dose dexamethasone, and intravenous vincristine (CVD) in patients with metastatic androgen-independent prostate carcinoma (AI-PCa). METHODS: Patients with histologic proof of adenocarcinoma of the prostate progressing despite adequate hormonal therapy and adequate organ function were treated with oral cyclophosphamide, 250 mg/daily (Days 1-14); intravenous vincristine, 1 mg daily (Days 1, 8, 15); and oral dexamethasone, 0.75 mg twice a day (Days 1-14) in 28-day cycles. Study endpoints were toxicity, rate of prostate specific antigen (PSA) decline > 50%, and/or measurable disease response. RESULTS: Fifty-two (95%) of 55 registered patients were evaluable. The majority (65%) of patients had received prior chemotherapy. The median number of treatment cycles given was two (range, one-seven cycles). Twenty-nine percent of the patients were found to have a > 50% decline in PSA level compared with baseline levels, and 25% of the patients with bidimensionally measurable soft-tissue or visceral disease were found to have a partial response. The median progression-free survival duration was 10 weeks, and the median overall survival duration was 10.6 months. There were no thromboembolic events, and hematologic and nonhematologic toxicity was minimal. CONCLUSIONS: CVD was found to be an active and well-tolerated regimen for AI-PCa. The low toxicity profile makes CVD a useful treatment option for patients with significant comorbidities and high risk for treatment-related toxicity, especially thromboembolic events and myelotoxicity.

Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan.

PURPOSE: We examined the effects of atrasentan (endothelin-A receptor antagonist) on bone deposition and resorption markers and on bone scan index. MATERIALS AND METHODS: This double-blind, randomized, placebo controlled clinical trial of hormone refractory prostate cancer patients was done at 74 medical centers in the United States and Europe. A total of 288 asymptomatic patients with hormone refractory prostate adenocarcinoma and evidence of metastatic disease were randomized to 1 of 3 treatment groups, namely 2.5 mg. atrasentan, 10 mg. atrasentan or placebo administered orally daily until disease progression. The main outcomes measures were changes in bone deposition markers (total alkaline phosphatase and bone alkaline phosphatase) and bone resorption (N-telopeptides, C-telopeptides and deoxypyridinoline), and in the bone scan index. RESULTS: At baseline markers of bone deposition and resorption were elevated 1.4 to 2.7-fold above respective upper limits of normal. Subjects receiving placebo experienced a 58% elevation in mean total alkaline phosphatase and a 99% elevation in mean bone alkaline phosphatase (p < 0.001), whereas subjects receiving 10 mg. atrasentan maintained stable mean total alkaline phosphatase and bone alkaline phosphatase values compared with baseline. N-telopeptides, C-telopeptides and deoxypyridinoline elevation from baseline were consistently less in patients receiving 10 mg. atrasentan compared with placebo. Similar trends were observed in subjects who received 2.5 mg. atrasentan. Changes in clinical bone scan studies paralleled bone marker changes. CONCLUSIONS: Atrasentan suppressed markers of biochemical and clinical prostate cancer progression in bone and demonstrates clinical activity for hormone refractory prostate cancer.

A pilot study of thalidomide in patients with progressive metastatic renal cell carcinoma.

BACKGROUND: The highly vascular nature of renal cell carcinoma (RCC) suggests that angiogenesis inhibition may be therapeutic for patients with this disease. Thalidomide inhibits basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-induced angiogenesis. METHODS: In a pilot study, we evaluated the safety and efficacy of escalating doses of thalidomide in patients with progressive metastatic RCC (mRCC), measurable disease, and good organ function. Patients received oral thalidomide starting at 200 mg per day and increasing by 100-200 mg per day weekly until a target dose of 1200 mg per day was reached. Study endpoints were objective tumor response and toxicity. RESULTS: Of the 20 patients enrolled, 19 were evaluable for response. Eighteen achieved the target dose. The most common, but reversible, toxicities were constipation, somnolence, and fatigue. Peripheral neuropathy was seen after prolonged therapy, necessitating dose reduction. Two patients achieved a partial response and nine had stable disease for a median of 14 months (range, 3-17 months). Median time to progression was 4.7 months (range, 0.7-31.3 months). Fifteen patients died (median survival, 18.1 months; 95% lower confidence bound 10.7). Survival was significantly longer in patients with higher hemoglobin level and longer time from first metastasis to start of thalidomide, but significantly shorter in patients with multiple organ involvement and previous treatments. CONCLUSIONS: Thalidomide at this dose is associated with manageable acute toxicities but long-term dose-limiting neuropathy. Objective responses are rare in patients with mRCC and are characterized by delay in achieving maximum tumor reduction. Prolonged stable disease is seen in some patients, but the benefit of thalidomide, as well as other angiogenesis inhibitors, in that setting needs to be studied in controlled, randomized trials.