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We analyzed real-world clinical outcomes of sequential alpha-/beta-emitter therapy for metastatic castration-resistant prostate cancer (mCRPC). Methods: We assessed safety and overall survival in 26 patients who received lutetium-177-prostate-specific membrane antigen ligand (177Lu-PSMA) following radium-223 in the ongoing non-interventional Radium-223 alpha Emitter Agent Safety Study in mCRPC popUlation for long-teRm Evaluation (REASSURE; NCT02141438). Results: Patients received radium-223 for a median 6 injections and subsequent 177Lu-PSMA for a median 3.5 months (≥4th therapy in 69%). The median time between radium-223 and 177Lu-PSMA treatment was 8 months (range 1-31). Grade 3 hematologic events occurred in 9/26 patients (during or after 177Lu-PSMA treatment in 5/9 patients; 8/9 patients had also received docetaxel). Median overall survival was 28.0 months from radium-223 start and 13.2 months from 177Lu-PSMA start. Conclusion: Although the small sample size precludes definitive conclusions, these preliminary data, especially 177Lu-PSMA treatment duration, suggest feasibility of 177Lu-PSMA use after radium-223 in this real-world setting.

The RAdium LUtetium (RALU) study evaluated the feasibility of sequential alpha and beta emitter use in patients with bone-predominant metastatic castration-resistant prostate cancer.This pre-planned, interim, retrospective analysis investigated safety and survival outcomes with lutetium-177-PSMA (Forty-nine patients were evaluated. Patients received a median of 6

What’s known on the subject? and What does the study add? There is little known on how to objectively measure renal ischemia during partial nephrectomy. This study clemonstrates two potentially useful methods to measure renal ischemia during partial nephrectomy. OBJECTIVE • To determine the feasibility of using near-infrared tissue oximetry (TO) and digital image analysis for assessing renal function and to quantify local renal ischaemia in a porcine model. MATERIALS AND METHODS • Tissue oximetry was performed and red/blue (R/B) colour ratios were determined on renal units of Yorkshire swine. • Interval measurements were taken before clamping the renal hilum, during warm ischaemia, and after unclamping using a ViOptix T.OxTM Tissue Oximeter and Matlab® digital image analysis. • Matlab software analysed images from the laparoscopic camera and determined an R/B ratio to track renal ischaemia. • The tissue oximeter used direct infrared light and was placed adjacent to the kidney parenchymal surface. • The data were divided into preclamp, clamp and post-clamp, and compared between methodologies. RESULTS • The R/B ratio showed a higher rate of change compared with TO during clamp time in both the 15-min experiment (R/B = 96.0 vs. TO = 52.1 unit/reference) and the 30-min experiment (R/B = 97.6 vs. TO = 45.9). • The R/B ratio showed a higher rate of change compared with TO at 1 min after clamping in the 15-min experiment (R/B = 80.1 vs. TO = 12.4). • Both detection devices showed similar changes in pre- and post-clamp measurements in the 15- min experiment (R/B = 1.6 vs. TO = 3.8) and the 30-min experiment (R/B = 4.7 vs. TO =−4.5). • In the 30-min experiment the R/B ratio showed a significant difference between preclamp, clamp, and post-clamp states (P= 0.026). CONCLUSIONS • Both TO and digital image analysis were able to calculate an ischaemic drop in tissue oxygen saturation during periods of acute renal ischaemia. • The findings suggest that the R/B ratio observed during histogram analysis shows a greater sensitivity compared with TO in quantifying renal ischaemia.

Prostate cancer is the most common cancer in men in the United States. This is a complex disease with high heterogeneity and the exact causes are unknown in population-specific samples. Family history is a primary risk factor irrespective of race. Identifying prostate cancer families with multiple affected cancer cases is challenging. Herein we document recruitment techniques and present prostate cancer clinical factors described in a cohort of African Americans and Caucasians with or without a strong family history. A total of 521 prostate cancer patients (241 African Americans and 280 Caucasians) were identified using a novel cooperative methodology involving a combination of treating physicians and tumor registries. Higher prostate-specific antigen (PSA, P=0.0269) was found in familial cases as compared to sporadic cases in African-American men. In addition, PSA values for familial cases were higher (P=0.0093) in African-American as compared to Caucasian men. No differences were detected in Gleason score values in either race, regardless of family history. These findings remained the same after adjustment was made for age at diagnosis. In conclusion, methodologies for cohort acquisition, and clinical characteristics, are described for men with and without a family history of prostate cancer using both Caucasian and African-American populations.

New systemic therapies have prolonged the lives of men with metastatic castration-resistant prostate cancer (mCRPC). Use of these therapies in the adjuvant setting when the disease may be micrometastatic and potentially more sensitive to therapies may decrease mortality from prostate cancer. However, the conduct of adjuvant prostate cancer clinical trials is hampered by taking longer than a decade to reach the meaningful endpoint of overall survival (OS) and the fact that many men never die from prostate cancer, even if they relapse. A validated intermediate clinical endpoint (ICE) in prostate cancer that is a robust surrogate for OS has yet to be defined. This paper details the plans, process, and progress of the international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group to pool individual patient data from all available clinical trials of radiation or prostatectomy for localized disease and conduct the requisite analyses to determine whether an ICE can be identified. This paper further details the challenges and the a priori statistical analytical plans and strategies to define an ICE for adjuvant prostate cancer clinical trials. In addition, a brief review of the health economic analyses to model the benefits to patients, society and manufacturers is detailed. If successful, the results from this work will provide a robust surrogate for OS that will expedite the design and conduct of future adjuvant therapy trials using new agents that have proven activity in mCRPC. Moreover, it will also define the health economic benefits to patients and societies.

BACKGROUND: Many physicians now use serum prostate-specific antigen (PSA) to screen for prostate cancer in asymptomatic men. Whether or not a prostate biopsy should also be performed depends on an accurate definition of what constitutes a normal PSA value. Until recently, studies conducted to establish normal serum PSA values have involved study populations that have included few African-American men. PURPOSE: We sought to compare serum PSA levels and PSA density (i.e., serum PSA level/prostate volume ratio) in African-American and white men without histologic evidence of prostate cancer. METHODS: We reviewed the medical records of 826 consecutive men who underwent one or more prostate biopsies at the Veterans Affairs Medical Center in Shreveport, LA, from January 1993 through December 1995. In this retrospective review, we recorded patient's age, race, serum PSA level, digital rectal examination result, ultrasound-determined prostate volume, indications for biopsy, and biopsy results. Data from a total of 752 consecutive men who were either white or African-American and whose indication for biopsy included a serum PSA of greater than 4.0 ng/mL and/or an abnormal digital rectal examination were analyzed. To examine possible differences in serum PSA level, PSA density, prostate volume, and patient age, the two-sided Student's t test was employed. Multivariate linear regression analysis was used to determine if serum PSA levels were associated with the patient's age, race, or prostate volume in men without prostate cancer. RESULTS: Of the 752 men included in this analysis, 254 had histologic evidence of prostate cancer and 498 did not. Of the 498 men without prostate cancer, 367 (74%) men were white and 131 (26%) were black. There were no racial differences in age or calculated prostate volume. Serum PSA levels and calculated PSA density, however, were significantly (both P < .0001) higher in African-American men that in white men. A multivariate linear regression analysis indicated that race and prostate volume were independent variables associated with serum PSA level. For African-American and white men, serum PSA values of greater than 4 ng/mL were associated with prostate cancer with sensitivities of 89.5% and 81.9%, respectively, and specificities of 38.2% and 52.3%, respectively. CONCLUSION: Among biopsied men without histologic evidence of prostate cancer, African-Americans have a significantly higher PSA level and PSA density than similarly aged white men. IMPLICATIONS: Published criteria for normal PSA level and density have been derived primarily from white men and may not be directly applicable to other populations. Race-specific data are needed to fully optimize PSA as a tumor marker in racial populations that are at high risk for prostate cancer death.

Introduction Androgen deprivation therapy (ADT) is commonly utilized in the management of both localized and advanced adenocarcinoma of the prostate. The use of ADT is associated with several adverse events, physical changes, and development of medical comorbidities/mortality. Aim The current article reviews known adverse events associated with ADT as well as treatment options, where available. Current recommendations and guidelines are cited for ongoing monitoring of patients receiving ADT. Methods A PubMed search of topics relating to ADT and adverse outcomes was performed, with select articles highlighted and reviewed based on level of evidence and overall contribution. Main Outcome Measures Reported outcomes of studies detailing adverse effects of ADT were reviewed and discussed. Where available, randomized trials and meta-analyses were reported. Results ADT may result in several adverse events including decreased libido, erectile dysfunction, vasomotor symptoms, cognitive, psychological and quality of life impairments, weight gain, sarcopenia, increased adiposity, gynecomastia, reduced penile/testicular size, hair changes, periodontal disease, osteoporosis, increased fracture risk, diabetes and insulin resistance, hyperlipidemia, and anemia. The definitive impact of ADT on lipid profiles, cardiovascular morbidity/mortality, and all-cause mortality is currently unknown with available data. Treatment options to reduce ADT-related adverse events include changing to an intermittent treatment schedule, biophysical therapy, counseling, and pharmacotherapy. Conclusions Patients treated with ADT are at increased risk of several adverse events and should be routinely monitored for the development of potentially significant morbidity/mortality. Where appropriate, physicians should reduce known risk factors and counsel patients as to known risks and benefits of therapy.

Background Cabazitaxel significantly improves overall survival (OS) versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone. Methods Updated TROPIC data (cut-off 10 March 2010) were used to compare 2-year survival between treatment groups and assess patient demographics and disease characteristics. Factors prognostic for survival ≥2 years were assessed. Pain and Eastern Cooperative Oncology Group performance status were evaluated in the overall patient population. Results Median follow-up was 25.5 months. After 2 years, more patients remained alive following cabazitaxel than mitoxantrone [odds ratio 2.11; 95% confidence interval (CI) 1.33–3.33]. Treatment with cabazitaxel was prognostic for survival ≥2 years. Demographics/baseline characteristics were balanced between treatment arms irrespective of survival. Pain at baseline and pain response were comparable between treatment groups. Average daily pain performance index was lower for cabazitaxel versus mitoxantrone (all cycles; 95% CI –0.27 to –0.01; P = 0.035) and analgesic scores were similar. Grade ≥3 peripheral neuropathies were uncommon and comparable between treatment groups. Conclusions Cabazitaxel prolongs OS at 2 years versus mitoxantrone and has low rates of peripheral neuropathy. Palliation benefits of cabazitaxel were comparable to those of mitoxantrone. The study was registered with www.ClinicalTrials.gov (NCT00417079).

A 61-year-old man with progressive prostate cancer after initial hormonal therapy was treated with TNP-470, an experimental agent with potent antiangiogenesis properties. During the period of TNP-470 treatment, the concentration of serum prostate-specific antigen (PSA) rapidly increased from 28.4 to 89.9 ng/ml. After termination of TNP-470 therapy, the concentration of PSA decreased from 89.9 to 10.3 ng/ml. This pattern of PSA change was previously unanticipated and may eventually provide additional insight into the pharmacological actions of TNP-470.

Although structural features and expression patterns of the src family of tyrosine kinases have been extensively analyzed, there are no direct comparative studies of the putative protein substrates that are tyrosine-phosphorylated by the normal cellular versions of these enzymes. In this report, we have expressed normal and enzymatically activated versions of the fyn, fgr, and src translational products by transfection of appropriate cDNAs into mouse fibroblasts. Because the same parental cell line was used for all transfections, each enzyme was expressed in a similar milieu of potential in vivo substrates. After verification of appropriate expression from each transfected cDNA and assessment of relative transforming potency, a series of putative protein substrates was specifically assayed for expression and tyrosine phosphorylation. Our data indicate that the normal src family kinases display some degree of substrate specificity but that specificity is diminished when these enzymes are constitutively activated. In the course of these studies, tyrosine-phosphorylated proteins were noted to coimmunoprecipitate with some of these putative in vivo substrates. Some of these coimmunoprecipitating proteins have been reported previously, whereas others, such as the presence of p59fyn in anti-p80/85 immunoprecipitates, are heretofore undescribed.

Despite the intensive study of both cellular transformation and src-family protein-tyrosine kinases, there have been no direct comparisons of transforming potency for normal members of this gene-family. In this study, the focus-forming activity of normal c-src, fyn, and lck cDNAs were compared in NIH 3T3 cell transfection assays. Focus formation was studied quantitatively, and individual foci were analyzed for phosphotyrosine content and expression of appropriate translational products. Each foci arising from c-src transfectants had a marked increase in phosphotyrosine content, and the majority of these foci expressed a c-src protein with an aberrant carboxyl terminus. Foci derived from lck transfectants also had a marked increase in phosphotyrosine content, and some foci expressed a lck protein with an aberrant carboxyl terminus. In contrast, foci from fyn-transfected cells were not distinguished from G418-selected mass cultures in terms of total phosphotyrosine content or expression of p59fyn. These studies support the previously published concept that overexpression of the normal fyn protein contributes to focus formation in transfected NIH 3T3 cells but suggest that the focus-forming activity observed after c-src or lck transfections is frequently attributable to mutational events. Because lck mutations have not been previously described in transformed foci, we characterized the lck transcript expressed in two foci and identified a novel point mutation that encodes a lck protein with increased in vivo kinase and focus-forming activity.

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

We have sought to identify candidate substrates for src family protein-tyrosine kinases potentially important for transformation. Transfected NIH/3T3 cells, each overexpressing a normal or activated version of the fyn, fgr, or src translational product, were examined using antibody to phosphotyrosine as a probe. Expression of each cDNA induced similar but distinct patterns of tyrosine phosphorylated cellular proteins, with the extent of phosphorylation being greatest in cells expressing an activated kinase. A 70-kDa tyrosine-phosphorylated protein was found to associate with the activated fyn gene product. A protein designated p130, tyrosine phosphorylated in vitro, and in vivo, was found to physically associate with the activated product of each src family gene examined. Physical interaction of three different highly transforming tyrosine kinases with a common cellular protein suggests that p130 may play an important role in transformation induced by src family kinases.

Aberrant expression of vascular endothelial growth factor (VEGF) is associated with human prostate cancer (PCa) metastasis and poor clinical outcome. We found that both phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and VEGF levels were significantly elevated in patient bone metastatic PCa specimens. A PCa ARCaP progression model demonstrating epithelial-to-mesenchymal transition exhibited increased CREB phosphorylation and VEGF expression as ARCaP cells became progressively more mesenchymal and bone-metastatic. Activation of CREB induced, whereas inhibition of CREB blocked, VEGF expression in ARCaP cells. CREB may regulate VEGF transcription via a hypoxia-inducible factor-dependent mechanism in normoxic conditions. Activation of CREB signaling is involved in the coordinated regulation of VEGF and may pre-dispose to PCa bone metastasis.

Introduction The TROPIC trial (NCT00417079) demonstrated that CbzP improves OS in pts with metastatic castration-resistant prostate cancer (mCRPC) vs mitoxantrone + P (MP) (hazard ratio [HR] 0.70; P Methods OS in pts with poorly differentiated tumour histopathology at diagnosis (Gleason 7–10) and in pts with visceral disease (VD) at baseline was evaluated between treatment groups based on the original and updated analyses of the TROPIC trial data. In addition, the percentage of pts alive at 2 yrs was compared between treatment groups using a χ test. Baseline and treatment characteristics were assessed in pts with OS Results Analysis of the original data showed an OS benefit for CbzP vs MP in pts with Gleason 7–10 (median 15.2 mos CbzP [95% CI 14.1–17.2] vs 12.7 mos MP [95% CI 10.1–14.0], log rank test P Summary of baseline pt characteristics. OS ≥ 2 yrs OS CbzP MP CbzP MP Total population, N (%) 60 (15.9) * 31 (8.2) 318 (84.1) 346 (91.8) Visceral disease (liver and/or lungs), n (%) 9/60 (15.0) 6/31 (19.4) 81/318 (25.5) 83/346 (24.0) Interval from end of prior D to 2L CT, months, median 6.2 6.5 3.7 3.4 Interval from 1st HT to 2L CT, years, median 6.1 5.5 3.9 3.8 Poorly differentiated tumour histopathology at diagnosis, n (%) 40/60 (66.7) 21/31 (67.7) 186/318 (58.5) 190/346 (54.9) * OR 2.10 (95% CI 1.33–3.33) Conclusion The OS benefit of CbzP treatment demonstrated in TROPIC is maintained at 2 yrs and in the subset of pts with poorly differentiated tumours at diagnosis, as well as in mCRPC pts with VD. Baseline factors were similar between treatment groups, suggesting that the difference in OS benefit is likely due to a treatment effect of CbzP. Disclosure S. Oudard: Has acted as an advisor for, and received honoraria from Pfizer Oncology, Bayer Schering Pharma, Roche, GSK, Novartis and Sanofi, J.S. de Bono: Has participated in an advisory board and has acted as a consultant for Sanofi. Has also received honoraria and research funding from Sanofi, M. Ozguroglu: Has acted as an advisor and consultant (compensated) for, and has received research funding from Sanofi, S. Hansen: Has participated in an advisory board for Sanofi, J. Machiels: Has acted as a consultant to Boehringer Ingelheim (uncompensated) and has received research funding from Sanofi, G. Gravis: Has acted as an uncompensated consultant to Sanofi, L. Shen: Is a Sanofi employee (Associate Director) and owns Sanofi stocks and shares, A.O. Sartor: Has acted as a consultant for Sanofi. Has also received honoraria and research funding from Sanofi. All other authors have declared no conflicts of interest.

Several studies have reported racial variation in serum prostate specific antigen (PSA) levels. Many of these studies, however, have included a significant number of men without a documented digital rectal examination (DRE) result or without prostate biopsies if abnormalities in PSA or DRE were detected. Thus, it is not clear that men with prostate cancer have been excluded in these analyses. In this report, data from 9,162 men (3,786 African-American men and 5,376 white men) are reviewed. All men had both serum PSA and DRE testing. Every man in this study had either a documented normal DRE and PSA (4 ng/mL) (3,422 African-American men and 4,795 white men) or a negative prostate biopsy (364 African-American men and 581 white men). Data were analyzed in age-matched decades. African-American men and white men had no difference in serum PSA levels between 30 and 39 years of age. At 40-49, 50-59, 60-69 and 70-79 years of age, African-American men had a statistically higher serum PSA level than white men. From these data, we conclude that racial variation in serum PSA is present in all decades above 40 years of age. Our data are unique in that this cohort included a substantial number of men between 30 and 39 years of age. In this group of young men, no racial differences in serum PSA were detected. These studies indicate, for the first time, that the onset of racial variation in PSA occurs after the fourth decade of life.

Management of prostate cancer progression after failure of initial hormonal therapy is controversial. Recently, the activity of the simple discontinuation of antiandrogen therapy has been established by several groups, as well as the enhanced activity when combined with adrenal suppression (i.e., aminoglutethimide and hydrocortisone). Furthermore, suramin has generated considerable interest following reports of response rates ranging from 17 to 70%. More recently, suramin response rates of 18 and 22% have been reported when the potential confounding variables of flutamide withdrawal and hydrocortisone were prospectively controlled. On the basis of the activity of combining aminoglutethimide with flutamide withdrawal, we designed a protocol in which suramin was combined with aminoglutethimide in two cohorts of patients (those with simultaneous antiandrogen withdrawal compared to those who had previously discontinued antiandrogen therapy). Eighty-one evaluable patients were enrolled in this study between June 1992 and November 1994. Patients were a priori divided into two cohorts, those receiving prior antiandrogen withdrawal (n = 56) and those receiving simultaneous antiandrogen withdrawal (n = 25) at the time the patients were enrolled into the trial. For the group that discontinued antiandrogen prior to enrolling in therapy, the partial response rate (50% decline in PSA for4 weeks) was 14.2%, whereas the partial response was 44% for those patients who discontinued their antiandrogen at the time of starting suramin and aminoglutethimide. The median time to progression was 3.9 months in patients failing prior antiandrogen withdrawal and 5.5 months in those patients having concomitant antiandrogen withdrawal (P = 0.36 for the overall difference). The progression-free survival estimate at 1 year for patients having prior antiandrogen withdrawal was 19.8% [95% confidence interval (CI), 11-32.9%]. For those patients who experienced antiandrogen withdrawal simultaneous with the treatment, the progression-free survival estimates at 1 and 2 years were 27.1 (95% CI, 13.2-47.6%) and 4.5% (95% CI, 0.8-21.6%). The median survival time for those patients having prior antiandrogen withdrawal was 14.2 months, whereas the median survival was 21.9 months for those having concomitant antiandrogen withdrawal (P = 0.029 for the overall difference). In conclusion, the partial response rate of 44% for those who had concomitant flutamide withdrawal with adrenal suppression was consistent with that of other reports using a similar maneuver. Although this study was not randomized and thus we should not over-interpret the results, flutamide withdrawal plus adrenal suppression appears to have greater activity than flutamide withdrawal alone. Furthermore, these data suggest that suramin adds little to the response rate observed for other adrenal suppressive agents in the presence of antiandrogen withdrawal. This interpretation is in agreement with those studies controlling for adrenal suppression and flutamide withdrawal prior to suramin administration, which noted modest activity of short duration. Given that antiandrogen withdrawal is now accepted as an active maneuver for a subset of patients progressing after maximum androgen blockade, we propose that future trials attempting to maximize response rates incorporate this maneuver whenever possible into prospectively designed regimens.

Extraordinarily high serum carcinoembryonic antigen (CEA) values have been reported to be associated with many malignant disorders, including carcinoma with primary sites in the colon, pancreas, stomach, bile duct, lung, and breast. This study was undertaken to determine if a marked elevation of serum CEA levels in androgen-independent prostate cancer patients exists, and to evaluate the potential of using CEA monitoring as a marker for disease progression.Records from 141 patients with progressive androgen-independent prostate cancer who were treated at the National Cancer Institute from 1990 to 1996 were analyzed. Serum CEA concentrations were measured using a micro-particle enzyme immunoassay.Among these cases of prostatic carcinoma, 69 (48.9%) had abnormally elevated plasma CEA values (greater than the normal upper limit of 2.5 ng/mL) at some time during their treatment on a clinical investigation protocol. No correlation was found between the elevated CEA concentrations and prostate specific antigen (PSA). In comparison, 32.5% of patients with elevated CEAs had disease that had metastasized to soft tissue (adenopathy, etc) versus 22.2% with normal CEA who had soft tissue involvement (p = 0.3 X2). We examined the CEA values with respect to survival time, defined as the interval from the date of the earliest CEA level to the date of death and found no association (p0.3).Based on these observations, it appears that in the context of androgen-independent prostate cancer, CEA can be elevated but is an inviable surrogate marker of disease progression with minimal prognostic value.

Combined androgen blockade (CAB) (medical or surgical castration plus antiandrogen therapy) is considered by many to be the optimal endocrine maneuver for patients with metastatic prostate carcinoma. When progression occurs after CAB, the discontinuation of the antiandrogen is recommended. The authors present a patient that had a clinical complete response to flutamide withdrawal plus hydrocortisone that, at last follow-up, had been maintained for more than 46 months.A 71-year-old man with a positive family history of prostate carcinoma presented in 1989 with urinary frequency and a suspicious digital rectal examination. He was found to have a poorly differentiated adenocarcinoma (Gleason 4+4). He was started on CAB and his prostate specific antigen (PSA) concentration declined from 96 ng/mL to the normal range and was maintained for the next 24 months. In 1991 his PSA began to rise, and reached 64 ng/mL by 1993. The patient was enrolled on a clinical trial that discontinued the flutamide administration and hydrocortisone was initiated.Physical examination at the time of enrollment was unremarkable. His PSA declined to below the limits of detection after this maneuver and at last follow-up had been maintained there for more than 46 months. In 1995, the patient underwent a repeat biopsy of the prostate and all six tissue cores were negative for carcinoma. At last follow-up in December 1996, the patient had no evidence of disease and was being followed routinely; however, the authors were continuing treatment with testicular suppression (leuprolide) plus hydrocortisone.The authors believe the residual androgens and steroids produced by the adrenal cortex play a meaningful role in prostate carcinoma cell proliferation. Based on this case and data from trials supporting the activity of flutamide withdrawal plus adrenal suppression, it appears reasonable to evaluate prospectively the discontinuation of antiandrogen versus antiandrogen withdrawal plus adrenal suppression in individuals failing CAB.

Several risk factors for prostate cancer death are well defined. These include age, race (African American), and a family history of prostate cancer. Data also suggest that a family history of breast cancer may provide an additional risk factor for prostate cancer. Despite the fact that these risk factors are well recognized, there are no reports describing a systematic early detection program for prostate cancer in African-American men with an increased familial risk of the disease. In this report, 169 such men between the ages of 40 and 70 are identified. Ninety-five of these men received a prostate-specific antigen and digital rectal examination. The mean age for these 95 men was 52 +/- 8 years; 45.3% were less than age 50. Eighty of these men had a family history of prostate cancer; 15 had a family history of breast cancer. Seventeen men had an abnormal screening test, and 14 subsequently had a prostate biopsy. Four prostate cancers were identified, all within the group of men reporting a positive family history of prostate cancer. In addition to describing the medical aspects of this series, a detailed description of recruiting efforts is also described.

A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide.Fifty-four patients whose disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 micrograms/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and soft-tissue disease response.Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/or a partial response of measurable soft-tissue disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no soft-tissue disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months.Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeutic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin.

The propensity of a cell to undergo apoptosis has been proposed to be a determinant for chemotherapy sensitivity that is not directly dependent on specific drug-target interactions. Androgen-independent prostate cancer is typically refractory to cytotoxic drugs, and we tested whether this is due to a loss of the ability to undergo apoptosis. Exposure of the hormone-insensitive and p53-negative human prostate carcinoma cell line PC-3 to 22 microM cisplatin, 1 microM camptothecin, 10 microM tenoposide, 135 nM vincristine, or 10 microM lovastatin for 72 h caused cell death, internucleosomal DNA fragmentation, and morphological changes typical for apoptosis. One microM cycloheximide prevented anticancer drug-induced apoptosis, whereas high concentration (1 mM) of cycloheximide alone induced apoptosis, indicating that protein synthesis was not needed for these cells to undergo apoptosis. Since cycloheximide affected DNA synthesis and proliferation of PC-3 cells, we tested whether the DNA polymerase inhibitor aphidicolin could also suppress drug-induced apoptosis. In contrast to cycloheximide, aphidicolin inhibited only vincristine-induced apoptosis. Cycloheximide prevented drug-induced changes in cell cycle distribution except for vincristine, while aphidicolin led to an accumulation of cells at the G1-S border independent of the drug used. These data indicate that macromolecular synthesis, active cell cycling, and p53 expression are not required for apoptosis to proceed in this system.

Somatuline, a somatostatin analogue, has proven to be effective in several animal models of prostate cancer. Preliminary clinical studies also have suggested antitumor activity in patients with prostate cancer. The authors conducted a dose-escalation trial of 25 patients with metastatic hormone-refractory prostate cancer.Dosages of 4, 7, 10, 13, 18, and 24 mg/day were administered by continuous intravenous infusion for at least 28 days.Plasma levels of insulin-like growth factor-I (IGF-I), but not those of IGF-II, declined modestly during therapy. Toxicities included grade I diarrhea, bloating, infection, nausea, and flatus. The gastrointestinal side effects were typically self-limiting and occurred during the initial portion of treatment cycles. In addition, three patients experienced grade II catheter-related infections. No clinical response was noted by either radiographic or tumor marker criteria. The maximally tolerated dose of somatuline was not determined.A continuous intravenous infusion of 24 mg/day of somatuline is well tolerated and could be evaluated in other types of cancer or possibly in less advanced prostate cancer, but no clinical activity was noted at this dose in patients with advanced metastatic hormone-refractory prostate cancer.

Introduction Ra-223 is a first-in-class alpha-emitter pharmaceutical that targets bone metastases with high-energy, very short range ( Methods Eligible pts previously received or refused docetaxel, or were docetaxel ineligible, and were randomized 2:1 to receive Ra-223 (50 kBq/kg IV) or Pbo every 4 weeks x 6. After the IA, an updated analysis of all enrolled pts prior to crossover assessed effects of Ra-223 on the primary (OS, using a stratified log-rank test) and secondary (eg, skeletal-related events [SREs], QOL, and safety) endpoints. QOL was assessed with the Functional Assessment of Cancer Therapy—Prostate (FACT-P) and EuroQoL (EQ-5D) instruments. Results The table shows the updated analysis data for 921 pts (Ra-223, n = 614; Pbo, n = 307). Median OS benefit for Ra-223 was 3.6 mos (HR 0.695). Time to first SRE was 6 mos longer with Ra-223. At week 16, Ra-223 pts reported significantly greater well-being (physical, emotional, functional, prostate cancer score, and total score) (FACT-P) and significantly better QOL (EQ-5D) compared to Pbo pts. The incidence of myelosuppression with Ra-223 was low: 2.2% grade 3/4 neutropenia; 6.3% grade 3/4 thrombocytopenia. Parameter Ra-223 + BSC (n = 614) Placebo + BSC (n = 307) P value Hazard ratio (95% CI) Median overall survival, mos 14.9 11.3 .00007 0.695 (0.581, 0.832) Median time to first SRE, mos 15.6 9.8 .00037 0.658 (0.522, 0.830) FACT-P * Physical well-being -0.93 -1.65 0.047 Emotional well-being -0.12 -1.27 Functional well-being -1.15 -2.23 0.011 Prostate cancer score -0.10 -1.74 0.012 Trial outcome index score -2.14 -5.16 0.011 FACT-P total score -2.53 -6.88 0.006 EQ-5D * Single index utility -0.0181 -0.0952 0.003 * Mean change from baseline at week 16. Conclusions The ALSYMPCA updated analysis substantiates that Ra-223 is an effective therapy that significantly improves OS and time to first SRE, with a highly favorable safety profile, in CRPC pts with bone mets. Ra-223 showed significantly better preservation of QOL, with improved functioning and well-being, compared to Pbo. Disclosure C. Parker: C. Parker has served in a consultant or advisory role for Algeta ASA (uncompensated) and Bayer. S. Nilsson: S. Nilsson has served in a consultant or advisory role for Algeta ASA. N. Vogelzang: N. Vogelzang has served in a consultant or advisory role for and has received grant/research support from Algeta ASA and Bayer. K. Staudacher: K. Staudacher is employed by and has an ownership interest in Algeta ASA. R. van Gool: R. Van Gool is employed by and has an ownership interest in Bayer. A.O. Sartor: O. Sartor has served in consultant or advisory roles for Algeta ASA and Bayer. All other authors have declared no conflicts of interest.

Background Androgen deprivation therapy (ADT) is the standard treatment of hormone-sensitive metastatic prostate cancer (HSMPC). We performed a phase III multicentre trial to compare ADT alone with ADT plus docetaxel (D) in HNMPC. Methods Patients (pts) with HSMPC were randomly assigned to either arm A (ADT + D: 75mg/m q3w, up to 9 cycles) or arm B (ADT). The primary endpoint was overall survival (OS). The planned number of pts was 378 to detect an improvement in OS with a hazard ratio (HR) of 0.62, a power of 80% and an alpha risk of 0.05 (two-sided test). Secondary endpoints were biological progression-free survival (PFS) and clinical PFS. Data on toxicity and quality of life have been previously presented. Results From October 2004 to December 2008, 385pts were included. Baseline characteristics were well balanced between the two arms. Median age was 63 years (43-84), median PSA was 26.4 ng/ml (0.1-11900), Gleason score was ≥ 8 in 57%. Prognostic classification was as follows: good prognosis (49%), intermediate (29%) and poor (22%). The majority of pts had metastases at the time of diagnosis (72%), 28% developed metastases after local treatment failure. Median number of D cycles was 8 (range 0-9). The median follow-up was 50 months (mo) [95%CI: 49-54]. At 6 mo, a higher PSA response (≥ 50%) in arm A (94% vs 85%, p = 0.0096) and a higher PSA progression (≥ 25%) in arm B (10% vs 1%, p = 0.0015) were observed. Biological PFS was significantly longer in arm A: 22.9 vs 12.9 mo, HR; 0.72 [95%CI: 0.57-0.91] (p = 0.005). Clinical PFS was increase in arm A: 23.46 vs 15.44 mo, HR: 0.75 [95CI: 0.59-0.94] (0.015). OS was not significantly different (median: 58.9 mo in arm A and 54.2 mo in arm B, HR: 1.01 [95%CI: 0.75-1.36]. The median OS for each prognostic group was 69.1 [95%CI: 60.9-NR], 46.5 [95%CI: 37.7-NR] and 36.6 [95%CI9: 28.5-58.9] mo respectively in the good, intermediate, and poor prognosis groups (p = 0.001), with no difference between the two arms. At the cut-off time, 65% of pts from the ADT arm had received docetaxel since they developed castrate-resistant prostate cancer. Conclusion Combining docetaxel and ADT improves PFS over ADT alone in pts with HSMPC. However, no difference in OS was observed between the two arms. Disclosure G. Gravis: I have expert testimony to disclose: Sanofi Aventis, uncompensated. K. Fizazi: Participation to advisory boards and speaker for Sanofi-Aventis. F. Joly Lobbedez: advisory board/board of directors position: Sanofi, Roche, Pfizer, Novartis, Ferring; compensated consultant relationship: Roche, Novartis; honoraria: Sanofi, Roche, Pfizer, Novartis, Ferring, Ipsen,Takeda; travel remuneration: ASCO by Novartis, ESMO by Janssen. S. Oudard: I have an advisory relationship and honoraria to disclose: Pfizer Oncology, Bayer-Schering Pharma, Hoffman La Roche, Glaxo SmithKline, Novartis Pharma, Sanofi Aventis. D. Pouessel: Consultant role and honoraria: Sanofi, P. Beuzeboc: Presentations: Avantis, All other authors have declared no conflicts of interest.