Design of clinical trials in advanced prostate cancer: avoiding the dead ends

Despite more than 30 years of clinical trials, investigations in prostate cancer have not succeeded in making advances comparable to those in other branches of research, such as breast cancer. Indeed, prostate cancer trials have repeatedly run into a series of "dead ends", as investigators face the problems of inadequate funding for research, treatments that result in only minimal improvements in survival, and lack of treatment options that have sufficient prospects for success. This article briefly reviews the strategies behind clinical investigations into prostate cancer over the last three decades, evaluates the pitfalls that have hindered research, and makes suggestions for the appropriate design of clinical trials that are safe and beneficial to patients while maintaining cost-effectiveness and accountability to patients and society.     

Response criteria for the prostate of the USA national prostatic cancer project

Response criteria developed by the National Prostatic Cancer Project to evaluate chemotherapy for advanced disease and as an adjuvant in early disease are described. Subjective and objective procedures and tests are used to compare pre-and post-treatment disease activity in advanced disease. These patients enter trials in demonstrated progression; hence stabilization of activity was considered a category of objective response. Other response categories include the rare complete response and less rare partial regression, with progression for non-responders. In adjuvant studies response indicators are the incidence of recurring disease and length of disease-free-interval.     

Measurement of factors influencing the participation of patients with prostate cancer in clinical trials: a Canadian perspective

OBJECTIVE

To identify factors that patients with prostate cancer believe to be important determinants in their decisions about future enrolment in clinical trials.

PATIENTS AND METHODS

In all, 122 patients (within 5 years of a diagnosis of prostate cancer) who had never been asked to participate in a clinical trial were asked to complete a 30‐item measure of ‘Factors Influencing Participation’ in clinical trials.

RESULTS

Factor analysis showed that variables influencing participation can be grouped into three areas: acceptability (e.g. recruitment process and altruistic beliefs); awareness (e.g. impact on quality of life, survivorship and randomization process); and accessibility (e.g. costs to patient, influence of family, age, time and need for extra tests). Awareness items were rated significantly more important by patients with T1 or T2 disease (P = 0.002). Patients who had not made a treatment decision also rated awareness (P = 0.05) and acceptability (P = 0.04) items higher. Patients with less than a university education identified access items as more important (P = 0.03). Helping future patients with prostate cancer, the impact of the study protocol on survival, being fully informed about the study, relationship with specialists, and impact of study on quality of life were identified as the five variables having the most influence on future enrolment.

CONCLUSIONS

Men rated items related to awareness and acceptability as being the most important determinants to future enrolment in a clinical trial. Knowledge about what these men believe is important for their future participation in a clinical trial will help researchers to design protocols that address the needs of targeted patient groups.     

Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model

BACKGROUND: Animal models that closely mimic clinical disease can be exploited to hasten the pace of translational research. To this end, we have defined windows of opportunity in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer as a paradigm for designing pre-clinical trials. METHODS: The incidence of cancer, metastasis, and distribution of pathology were examined as a function of time in TRAMP mice. The expression of various markers of differentiation were characterized. RESULTS: The TRAMP model develops progressive, multifocal, and heterogeneous disease. Each lobe of the prostate progressed at a different rate. Cytokeratin 8, E-cadherin, and androgen receptor (AR) were expressed during cancer progression but levels were reduced or absent in late stage disease. A distinct epithelial to neuroendocrine (ENT) shift was observed to be a stochastic event related to prostate cancer progression in TRAMP. CONCLUSIONS: This study will serve as the basis for the rational design of pre-clinical studies with genetically engineered mouse models.     

A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer

PURPOSE: The safety, efficacy and pharmacokinetics of LA-2585, a new 6-month subcutaneous depot of leuprolide acetate (Atrix Laboratories, Fort Collins, Colorado) were investigated in patients with prostate cancer. MATERIALS AND METHODS: In this 12-month, open label, multicenter study 111 patients with adenocarcinoma of the prostate were administered 45.0 mg LA-2585 subcutaneously once every 6 months. The primary efficacy parameter was serum testosterone 50 ng/dl or less. Leuprolide acetate pharmacokinetics were analyzed in a subset of 28 patients. RESULTS: Of the 111 enrolled patients 103 (93%) completed the 12-month study. Eight patients withdrew due to nonmedical reasons in 1, disease progression in 5 and cardiovascular disease in 2. By day 28, 108 of the 109 remaining patients (99%) achieved testosterone suppression, while 1 who never attained suppression was withdrawn at day 85. Mean time to castrate suppression was 21.2 days (median 21). At study completion 102 of 103 patients (99%) were below medical castrate testosterone levels of 50 ng/dl (mean +/- SE 12.3 +/- 2.1 ng/dl) with 91 of 103 (88%) at less than 20 ng/dl. Mean luteinizing hormone decreased from 6.98 +/- 0.48 mIU/ml at baseline to 0.23 +/- 0.14 mIU/ml at month 12. Luteinizing hormone was consistently below 1 mIU/ml. Mean prostate specific antigen decreased 97% from 39.8 +/- 21.5 ng/ml at baseline to 1.2 +/- 0.3 ng/ml at 12 months. No clinically significant flare reactions were observed. The most common treatment related adverse event was mild to moderate hot flashes. CONCLUSIONS: LA-2585 (45.0 mg depot) consistently produced and maintained safe and effective serum testosterone suppression with total serum testosterone well below the medical castrate level of less than 50 ng/dl.     

Preferences for sexual information resources in patients treated for early-stage prostate cancer with either radical prostatectomy or brachytherapy

OBJECTIVE: To identify the preferences for sexual information resources of patients before and after definitive treatment for early-stage prostate cancer with either radical prostatectomy (RP) or brachytherapy. PATIENTS AND METHODS: Two hundred patients (mean age 64 years) treated with either RP or brachytherapy were recruited from radiation oncology (100) and urology (100) outpatient clinics. Patients completed a survey questionnaire to identify the types of information used, preferred sources of information, knowledge of treatments for erectile dysfunction (ED), effect of sexual function on the treatment decision, and the International Index of Erectile Function (IIEF) to assess their current level of sexual function. RESULTS: Urologists were identified as the main source of sexual information. Written information, Internet access and videos were identified as preferred sources of information before and after treatment. The effects of treatment on sexual function had no apparent significant influence on the men's definitive treatment choice. Compared with patients in the brachytherapy group, patients in the RP group reported having significantly higher levels of sexual desire (P < 0.001) after treatment, but otherwise the erectile domains of the groups were remarkably similar. Two-thirds of patients wanted more information on the effects of treatment on sexual function, and on available treatments for ED. CONCLUSIONS: These results support the need for physicians to offer patients access to information on the effect of treatment for early-stage prostate cancer on erectile function before and after treatment.     

Society of Urologic Oncology Biotechnology Forum: new approaches and targets for advanced prostate cancer

PURPOSE: We provide an overview of advances in molecular based therapeutic strategies for prostate cancer and summarize the studies presented at the Society of Urologic Oncology Biotechnology Forum in 2000. MATERIALS AND METHODS: Three promising new treatment strategies are presented, and a critique of the advantages and limitations of each is offered by a leading expert in the field. RESULTS: Treatment results and the current state of dendritic cell based immunotherapy, monoclonal antibody therapy and anti-apoptotic treatment approaches are presented. CONCLUSIONS: Currently patients with advanced prostate carcinoma have expanded therapeutic options available in the form of molecular based phases II and III clinical trials.     

Metabolomic signatures of aggressive prostate cancer

BACKGROUND

Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. This study examined the association of tissue metabolites with other clinically significant findings.

METHODS

A state of the art metabolomics platform analyzed prostatectomy tissues (331 prostate tumor, 178 cancer‐free prostate tissues) from two independent sites. Biochemicals were analyzed by gas chromatography–mass spectrometry and ultrahigh performance liquid chromatography–tandem mass spectrometry. Statistical analyses identified metabolites associated with cancer aggressiveness: Gleason score, extracapsular extension, and seminal vesicle and lymph node involvement.

RESULTS

Prostate tumors had significantly altered metabolite profiles compared to cancer‐free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate‐specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness‐associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NAD+ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement (AUROC from 0.53 to 0.62) and 5‐year recurrence (AUROC from 0.53 to 0.64).

CONCLUSIONS

These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, these data suggest that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests. Prostate 73: 1547–1560, 2013 © 2013 Wiley Periodicals, Inc.     

A narrative review of the role of glucocorticoid receptors in prostate cancer: developments in last 5 years

Background and ObjectiveGlucocorticoids, secreted from the adrenal gland, are commonly used in the treatment of castration-resistant prostate cancer (CRPC) because of their anti-inflammatory and anti-toxic effects. However, glucocorticoids have been reported to have the opposite effects within the course of treatment. Many studies have shown that glucocorticoid receptors (GRs) are involved in the establishment of a dominant population of androgen-independent malignant cells, which may result in CRPC. In this review, we summarized the mechanisms of GRs in CRPC and the clinical application of glucocorticoids based on the present evidence.MethodsWe summarized the isoforms of GRs and the mechanisms involved in CRPC. An updated literature search was performed from the ClinicalTrials database, the National Center for Biotechnology Information database and European Union Drug Regulating Authorities Clinical Trials database. The focus was on the timeframe from 2017 to 2022. At least one primary or secondary outcome [prostate-specific antigen (PSA) response rate, progression-free survival (PFS) or overall survival (OS) and median time to PSA progression] according to studies should be included.Key Content and FindingsThe molecular structures and applications of the isoforms of GR have been intensively researched in the past 60 years. In recent years, researchers have pointed out that GRs may be involved in the development of CRPC via genomic and non-genomic effects. Clinical trials in the past 5 years have focused on the efficacy of drugs regarding CRPC. The use of glucocorticoids during treatments of CRPC follows the guidelines (e.g., NCCN Guidelines^®, guidelines of CSCO, etc.). Based on the collected data, prednisone appears to be the most widely used steroid hormone, followed by dexamethasone. Comparisons of the PSA response rate and the median time to PSA progression revealed that the efficacy of the 2 hormones is similar; however, further research on the effect of steroid hormone in CRPC is still required.ConclusionsVarious GR isoforms may play an important part in the development of CRPC, whose mechanism remains unclear. Most clinical trials have focused on the use of prednisone in the last 5 years. The efficacy of prednisone and dexamethasone is similar.     

Other biomarkers for detecting prostate cancer

Prostate‐specific antigen (PSA) has been used for detecting prostate cancer since 1994. Although it is the best cancer biomarker available, PSA is not perfect. It lacks both the sensitivity and specificity to accurately detect the presence of prostate cancer. None of the PSA thresholds currently in use consistently identify patients with prostate cancer and exclude patients without cancer. Novel approaches to improve our ability to detect prostate cancer and predict the course of the disease are needed. Additional methods for detecting prostate cancer have been evaluated. Despite the discovery of many new biomarkers, only a few have shown some clinical value. These markers include human kallikrein 2, urokinase‐type plasminogen activator receptor, prostate‐specific membrane antigen, early prostate cancer antigen, PCA3, α‐methylacyl‐CoA racemase and glutathione S‐transferase π hypermethylation. We review the reports on biomarkers for prostate cancer detection, and their possible role in the clinical practice.     

A risk index for prostate cancer

BACKGROUND: The aim of the present study was to create a simple numerical index predicting the presence of prostate cancer in a group of high risk patients, for the purpose of selecting those most likely to need prostate biopsy. METHODS: 100 consecutive patients at high risk of having prostate cancer seen at Ramathibodi Hospital, Thailand between November 2000 and February 2002 were prospectively studied. All patients underwent transrectal prostate biopsies. The following predictor variables were obtained: age, digital rectal examination (DRE) findings, prostate specific antigen level, transrectal ultrasonography (TRUS) findings, and prostate volume determined by TRUS. The outcome was the presence of prostate cancer on histological examination of the biopsy specimens. A risk index for prostate cancer based on the linear predictor of a multiple logistic regression model was created. RESULTS: Almost all predictor variables were significantly related to the presence of prostate cancer. The final multiple logistic regression model with four categorized predictors (excluding DRE) was shown to have good discrimination, calibration, and cross-validity. For a cutoff risk index of 10, corresponding to a 10% probability of having prostate cancer, the sensitivity for detecting prostate cancer was 96.2%, with a specificity of 73.0%. Based on this cutoff, 55% of patients in this series might not require prostate biopsy. CONCLUSION: A risk index for prostate cancer was developed. If this index can be externally validated, the potential savings from avoiding unnecessary prostate biopsies, on the basis of selection using the index, could be significant.     

Epstein criteria for insignificant prostate cancer

Study Type – Prognosis (systematic review) Level of Evidence 2b What’s known on the subject? and What does the study add? Overtreatment of prostate cancer is a major problem in contemporary urological practice. The Epstein Criteria reduces overtreatment by identifying insignificant prostate cancers that may be amenable to surveillance therapy. This systematic review of the Epstein Criteria validation studies provides a collective insight into the application and accuracy of the Epstein Criteria to predict for insignificant prostate cancer across different institutions and geographies.

OBJECTIVE

? To review the accuracy of the Epstein Criteria for insignificant prostate cancer and to explore the effect of the modified Gleason classification system on this system.

METHODS

? We searched PubMed, EMBASE and the Cochrane Database using search terms ‘Epstein Criteria’, ‘Prostate Cancer’, ‘Validation’ and ‘Insignificant Cancer’ between 1994 to 2010 for validation articles. ? These were divided into pre‐2005 and post‐2005 and concordances for organ‐confined status, Gleason score ≤6 and insignificant cancer were analysed.

RESULTS

? A pre‐2005 study showed concordance for insignificant prostate cancer, Gleason score ≤6 and organ‐confined status at 84%, 90.3% and 91.6%, respectively. ? Five post‐2005 validation studies were concordant for insignificant cancer, Gleason score ≤6 and organ‐confined status at 37–76%, 54.3–75.9% and 80.0–96.9%, respectively.

CONCLUSIONS

? The Epstein Criteria has a suboptimal accuracy for predicting for insignificant prostate cancer. ? The modification to Gleason scoring may be responsible for a reduced accuracy over time. ? However, significant heterogeneity in the validation studies means better quality validation studies are required.     

Clinical and histopathological characteristics of familial prostate cancer in Finland

Study Type – Aetiology (cohort) Level of Evidence 2b

OBJECTIVE

? To describe clinical and histopathological characteristics of Finnish familial prostate cancer (PCa) through a detailed analysis of cases in families.

PATIENTS AND METHODS

? In total, 202 Finnish families with 617 histopathologically confirmed PCa cases of confirmed genealogy were collected. ? Complete clinical data, including age and prostate‐specific antigen (PSA) at diagnosis, stage, grade and primary treatment, were gathered. The mean (range) number of affected men per family was 3 (2–8). ? All the available diagnostic biopsy samples (n= 323) were collected and regraded by the same uropathologist. ? A population‐based cohort of 3011 hospital district Pirkanmaa PCa patients was used as a control group.

RESULTS

? The mean (range) year of diagnosis of PCa was 1993 (1962–2006) and the mean (range) age at diagnosis was 68 (43–98 years). ? The median (range) primary PSA level was 12.0 (0.8–11 000) ng/mL. After regrading, the Gleason score was ≤6 in 38%, 7 in 37% and ≥8 in 25% of men. ? The subset of familial PCa men diagnosed after 1995 had higher PSA levels (P= 9.9 × 10^?6) and an earlier age of onset (P= 1.7 × 10^?6) than men in the control group, although there were no differences in cancer‐specific survival.

CONCLUSIONS

? We observed an earlier age of onset and higher PSA in familial PCa. ? However, differences between sporadic and familial or hereditary PCa cannot be truly solved until genetic testing of high‐risk genes in addition to family history is used to define PCa families. ? We also emphasize that, when histological samples are collected over a longer study period, reanalysis of the samples by the same experienced uropathologist should be considered. What’s known on the subject? and What does the study add? Previous hospital‐ or population‐based cross‐sectional studies comparing the clinical and histopathological features of hereditary, familial and sporadic PCa either reported weak trends or no differences in features measured except the age of onset. In present study we observed higher PSA and earlier age of onset in the subset of 257 familial PCa menin Finnish PCa families.     

Chemotherapy for androgen-independent prostate cancer

The evolution of taxanes as treatment for androgen-independent prostate cancer hes emerged from both the laboratory and clinic. Docetaxel is a potent in vitro inhibitor of Bcl-2, an antiapoptotic gene. Phase I and II studies with docetaxel alone or in combination with estramustine demonstrated promissing median survivals of 14--23 months, higher than what would have been expected for historic controls. Two randomized trials have proven the superiority of docetaxel based treatment in improving survival in men with androgen-independent prostate cancer. SWOG 99-16 and TAX 327 found that docetaxel-based therapy reduced the risk of death by 20--24% when compared to mitoxantrone-based therapy. Future trials will build on docetaxel-based combinations with novel targeted agents.     

前列腺癌诊断标志物研究进展

前列腺癌是严重危害男性健康的肿瘤,有较高的恶性倾向,在我国发病率逐年上升。前列腺癌患者生存和预后的关键在于早期诊断与有效的治疗。目前临床以前列腺特异性抗原(PSA)及穿刺活检为主要诊断方法,但存在特异度不高、过度穿刺活检等问题。寻找高特异度、高敏感度的前列腺癌诊断标志物是目前研究热点。近年研究发现了长链非编码RNA(lncRNA)、TMPRSS2:ERG融合基因等许多新的肿瘤诊断标志物,对PSA及前列腺癌基因3(PCA3)等诊断标志物的研究也有新的进展,本文针对前列腺癌诊断标志物研究进展作一综述。