Evaluation and treatment of men with biochemical prostate-specific antigen recurrence following definitive therapy for clinically localized prostate cancer

Early detection and monitoring by serum prostate-specific antigen (PSA) measurement has increased the number of men presenting with potentially curable prostate cancer. Most will choose radical prostatectomy or some form of radiation therapy for treatment, but some will have evidence of biochemical disease recurrence following therapy, shown by a rising PSA level without other clinical evidence of disease. Radical prostatectomy involves the removal of all prostate tissue, causing the serum PSA to decline to undetectable levels within four to six weeks following surgery; a subsequent rise in the serum PSA to a detectable level indicates disease recurrence. Patients should be evaluated to assess whether rising PSA levels indicate local recurrence or early metastatic disease. The advantages of salvage radiation, endocrine therapy, and other treatment modalities in local disease recurrence must be weighed against potential side effects and the resulting decrease in quality of life. Radiation therapy does not immediately eradicate all PSA-producing cells; therefore the persistence of a detectable PSA does not necessarily imply residual cancer, but rising PSA levels indicate treatment failure. Salvage surgery can be performed after radiotherapy for the purpose of removing all viable cancer cells, but should be weighed against a higher incidence of surgical complications; cryoablation offers a less invasive therapeutic modality.     

前列腺特异性抗原在前列腺癌诊断中的应用进展

已经证明,前列腺特异性抗原（PSA）是一种有价值的前列腺癌（PCa)肿瘤标记物,血清PSA的广泛使用提高了前列腺癌的检出率,使晚期癌患得明显减少。然而,PSA对PCa的检测缺乏特异性,由于其高的假阳性率,引起许多不必要的活检。为了提高PSA对PCa诊断的特异性,降低不必要的活检,众多学正在探讨与PSA相关的几项参数的临床应用价值,本就此作一综述。     

A stochastic approach to risk management for prostate cancer patients on active surveillance

Screening for prostate cancer (PC) has led to more cancers being detected at early stages, where active surveillance (AS), a strategy that involves monitoring and intervention when the disease progresses, is an option. Physicians are seeking ways to measure progression of the disease such that AS is abandoned when appropriate. A blood test, prostate-specific antigen (PSA), and the concept of doubling time (PSADT) and PSA kinetics are being used as proxies of disease speed of progression. Studies using these proxies report conflicting results. These studies cast doubts on the current rules for stopping AS and recent research concludes that PSADT and PSA kinetics are unreliable triggers for intervention in an AS program. These findings are consistent with stochastic processes being analyzed as if they were “deterministic” (i.e., current models measure disease progression by PSA’s evolution assuming it to be deterministic). A model that best describes PSA evolution is a pre-requisite to the establishment of decision criteria for abandoning AS. This paper suggests modeling PSA evolutions and kinetics as stochastic processes. Consequently, triggers for stopping AS may be different than PSADT and can result in substantially different recommendations, which are likely to have significant impact on patients and the healthcare system.     

The joint modeling of a longitudinal disease progression marker and the failure time process in the presence of cure

In this paper we present an extension of cure models: to incorporate a longitudinal disease progression marker. The model is motivated by studies of patients with prostate cancer undergoing radiation therapy. The patients are followed until recurrence of the prostate cancer or censoring, with the PSA marker measured intermittently. Some patients are cured by the treatment and are immune from recurrence. A joint-cure model is developed for this type of data, in which the longitudinal marker and the failure time process are modeled jointly, with a fraction of patients assumed to be immune from the endpoint. A hierarchical nonlinear mixed-effects model is assumed for the marker and a time-dependent Cox proportional hazards model is used to model the time to endpoint. The probability of cure is modeled by a logistic link. The parameters are estimated using a Monte Carlo EM algorithm. Importance sampling with an adaptively chosen t-distribution and variable Monte Carlo sample size is used. We apply the method to data from prostate cancer and perform a simulation study. We show that by incorporating the longitudinal disease progression marker into the cure model, we obtain parameter estimates with better statistical properties. The classification of the censored patients into the cure group and the susceptible group based on the estimated conditional recurrence probability from the joint-cure model has a higher sensitivity and specificity, and a lower misclassification probability compared with the standard cure model. The addition of the longitudinal data has the effect of reducing the impact of the identifiability problems in a standard cure model and can help overcome biases due to informative censoring.     

Radiation therapy failure in prostate cancer patients: risk factors and methods of detection

Radiation therapy for clinically localized prostatic carcinoma remains one of the mainstays among therapeutic approaches; however, patients continue to fail radiation therapy at too high a rate. This article reviews the risk factors and methods of detection for prostate cancer recurrence. The relative merits of the three major pre-therapy prognostic indicators-TNM staging, Gleason score, and serum prostate-specific antigen (PSA) levels-are discussed. The use of staging and Gleason score, as well as digital rectal examination, transrectal ultrasound, and post-radiation prostate biopsies in detecting failure of radiation therapy is reviewed. Challenges relating to the use of serum PSA levels as an indicator of recurrence are examined. Finally, this article makes recommendations as to procedure for evaluating patients suspected of failing radiation therapy.     

Combining longitudinal studies of PSA

Prostate-specific antigen (PSA) is a biomarker commonly used to screen for prostate cancer. Several studies have examined PSA growth rates prior to prostate cancer diagnosis. However, the resulting estimates are highly variable. In this article we propose a non-linear Bayesian hierarchical model to combine longitudinal data on PSA growth from three different studies. Our model enables novel investigations into patterns of PSA growth that were previously impossible due to sample size limitations. The goals of our analysis are twofold: first, to characterize growth rates of PSA accounting for differences when combining data from different studies; second, to investigate the impact of clinical covariates such as advanced disease and unfavorable histology on PSA growth rates.     

Biochemical (Prostate-Specific Antigen) Relapse: An Oncologist's Perspective

Consensus has not been reached on the exact definition of biochemical relapse after prostatectomy; individual institution definitions of relapse after prostatectomy range from consecutively rising prostate-specific antigen (PSA) values of > 0.2 to > 0.6 ng/mL. PSA measurements after radiation are even less predictable. PSA level is a sensitive marker of occult prostate-cancer relapse and provides early notification of recurrence, but a PSA relapse does not equal a clinical relapse or death from prostate cancer. Data are reviewed from retrospective, single-institution trials that have clarified features of PSA relapse after both prostatectomy and radiation, such as the PSA doubling time and the time to the first PSA elevation, which are associated with clinical progression. Various options for treatment of biochemical relapse are also reviewed; these include hormone therapy, combined chemohormonal therapy, alternative medicine and dietary tactics, new agents, and future strategies, such as vaccination. Currently, there is no standard treatment for biochemical failure with proven benefit in terms of quality of life, time to metastases, or survival. Current options include observation for patients with long PSA doubling times or comorbid medical issues and standard or nontraditional hormone therapy or a clinical trial for men who desire early therapy or who have rapid PSA doubling times (< 10-12 months). Trials combining the early use of chemotherapy with hormone therapy are promising. Patients should be encouraged to enroll in clinical trials to help establish standards of care.     

Stochastic S-system modeling of gene regulatory network

Microarray gene expression data can provide insights into biological processes at a system-wide level and is commonly used for reverse engineering gene regulatory networks (GRN). Due to the amalgamation of noise from different sources, microarray expression profiles become inherently noisy leading to significant impact on the GRN reconstruction process. Microarray replicates (both biological and technical), generated to increase the reliability of data obtained under noisy conditions, have limited influence in enhancing the accuracy of reconstruction . Therefore, instead of the conventional GRN modeling approaches which are deterministic, stochastic techniques are becoming increasingly necessary for inferring GRN from noisy microarray data. In this paper, we propose a new stochastic GRN model by investigating incorporation of various standard noise measurements in the deterministic S-system model. Experimental evaluations performed for varying sizes of synthetic network, representing different stochastic processes, demonstrate the effect of noise on the accuracy of genetic network modeling and the significance of stochastic modeling for GRN reconstruction . The proposed stochastic model is subsequently applied to infer the regulations among genes in two real life networks: (1) the well-studied IRMA network, a real-life in-vivo synthetic network constructed within the Saccharomycescerevisiae yeast, and (2) the SOS DNA repair network in Escherichiacoli.     

Development of a mathematical model that predicts the outcome of hormone therapy for prostate cancer

We propose a mathematical model that quantitatively reproduces the dynamics of the serum prostate-specific antigen (PSA) level under intermittent androgen suppression (IAS) for prostate cancer. Taking into account the biological knowledge that there are reversible and irreversible changes in a malignant cell, we constructed a piecewise-linear dynamical model where the testosterone dynamics are modelled with rapid shifts between two levels, namely the normal and castrate concentrations of the male hormone. The validity of the model was supported by patient data obtained from a clinical trial of IAS. It accurately reproduced the kinetics of the therapeutic reduction of PSA and predicted the future nadir level correctly. The coexistence of reversible and irreversible changes within the malignant cell provided the best explanation of early progression to androgen independence. Finally, since the model identified patients for whom IAS was effective, it potentially offers a novel approach to individualized therapy requiring the input of time sequence values of PSA only.     

Cancer de la prostate : la maladie localisée

Localized prostate cancer is characterized by a tumor confined to the prostate gland at clinical evaluation. Since the onset of PSA screening, the detection of localized prostate cancer has increased. Prognosis factors are clinical stadification, PSA value, PSA doubling time, tumor volume related to needle biopsy pathologic findings (Gleason score, percentage biopsies involved). Treatment depends on tumor prognosis, symptoms and performance status of the patient. Localized prostate cancer can be treated by surgery (radical prostatectomy, high intensity focused ultrasound) or radiotherapy (conformational radiation therapy, brachytherapy). Active follow-up can be proposed to very low risk patients.     

磁共振成像联合血清前列腺特异抗原、上皮钙黏蛋白、早期前列腺癌抗原-2诊断前列腺癌的临床价值探讨

摘要 目的：探究磁共振成像（MRI）联合血清前列腺特异抗原（PSA）、上皮钙黏蛋白（sE-cadherin）、早期前列腺癌抗原-2（EPCA-2）诊断前列腺癌的临床价值。方法：选取潍坊市人民医院2020年1月-2021年7月期间经病理证实的50例前列腺癌患者（前列腺组）以及50例前列腺增生患者（前列腺增生组）展开回顾性研究。100例研究对象均完善了MRI检查并测定血清PSA、EPCA-2、sE-cadherin水平,分析两组患者的MRI影像学特征,比较两组患者的PSA、EPCA-2、sE-cadherin水平以及各项检查方法的诊断准确性差异。结果：前列腺癌的MRI影像学特征为病灶主要位于外周带,外周带T2W呈低信号,病变侵及包膜、膀胱及周围组织具有T1加权消失或者不对称,具有信号异常、肌肉增厚的表现,盆腔淋巴结转移具有淋巴结部分融合或增大表现;前列腺增生的MRI影像学特征为边界清晰、包膜完整并且中央带增生、不均匀信号结节;前列腺癌、前列腺增生均存在不同程度的前列腺体积增大。相比于前列腺增生组,前列腺癌组患者的PSA、sE-cadherin、EPCA-2水平明显更高（P<0.05）。MRI、PSA、sE-cadherin、EPCA-2四项联合鉴别前列腺癌、前列腺增生的诊断符合率为96.00%,明显高于四项单独诊断的88.00%、79%、81%、82%（P<0.05）。结论：MRI联合PSA、sE-cadherin、EPCA-2鉴别诊断前列腺癌的准确性较高,具有作为临床前列腺癌早期诊断指导方案的潜力。     

Treatment options after failure of radiation therapy-a review

Radioresistant or recurrent prostate cancer represents a serious health risk for approximately 20%-30% of patients treated with primary radiation therapy for clinically localized prostate cancer. The majority of patients exhibit large volume and poorly differentiated disease at the time of diagnosis, which limits the ability of salvage therapy to eradicate the cancer. Early detection with serum PSA monitoring and prostate needle biopsy following primary radiation therapy may identify residual adenocarcinoma at an earlier stage and increase the likelihood of successful salvage therapy. Radical prostatectomy, prostate cryoablation, and brachytherapy comprise the options for salvage treatment available for radiorecurrent prostate cancer. The goal of disease eradication must be balanced against the potential for serious treatment-related side effects. As a result, many patients receive noncurative therapy with androgen ablation despite the real risk of disease progression and mortality.     

Prostate cancer risk in testosterone-treated men

Men with classical androgen deficiency have reduced prostate volume and blood prostate-specific antigen (PSA) levels compared with their age peers. As it is plausible that androgen deficiency partially protects against prostate disease, and that restoring androgen exposure increases risk to that of eugonadal men of the same age, men using ART should have age-appropriate surveillance for prostate disease. This should comprise rectal examination and blood PSA measurement at regular intervals (determined by age and family history) according to the recommendations, permanently revisited, published by ISSAM, EAU, Endocrine Society….

Testosterone replacement therapy is now being prescribed more often for aging men, the same population in which prostate cancer incidence increases; it has been suggested that administration in men with unrecognised prostate cancer might promote the development of clinically significant disease. In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found. A percentage (15.2%) of prostate cancer has been found in the placebo group (with normal DRE and PSA) in the prostate cancer prevention study investigating the chemoprevention potential of finasteride.

The hypothesis that high levels of circulating androgens is a risk factor for prostate cancer is supported by the dramatic regression, after castration, of tumour symptoms in men with advanced prostate cancer. However these effects, seen at a very late stage of cancer development, may not be relevant to reflect the effects of variations within a physiological range at an earlier stage.

Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer. A study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing “androgen hypothesis” of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk. Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone. Furthermore, pre-treatment total testosterone was an independent predictor of extraprostatic disease in patients with localized prostate cancer; as testosterone decreases, patients have an increased likelihood of non-organ confined disease and low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy.

A clinical implication of these results concerns androgen supplementation which has become easier to administer with the advent of transdermal preparations (patch or gel) that achieve physiological testosterone serum levels without supra physiological escape levels. During the clinical development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed.     

Effective Testosterone Suppression for Prostate Cancer: Is There a Best Castration Therapy?

Achieving and maintaining effective suppression of serum testosterone levels in men treated with androgen ablation is one of the essential strategies in the management of prostate cancer. Historically, a serum testosterone below 50 ng/dL was considered to be the castrate level. Current data suggest that the new target for either surgical or chemical castration is a serum testosterone level of lower than 20 ng/dL in an attempt to maximize therapeutic outcomes. Testosterone breakthrough and the acute-on-chronic effects of administration of a luteinizing hormone-releasing hormone analogue may cause testosterone levels to periodically rise, sometimes to noncastrate levels. The goal of androgen ablation is to identify those agents that will most consistently achieve and maintain the lowest testosterone levels possible.Key words: Prostate cancer, Androgen ablation, LHRH analogues, LHRH antagonists, TestosteroneThe cornerstone of understanding the basic biology of prostate cancer relies upon the important discovery that prostate cancer is a hormonally responsive tumor. The current use of androgen ablation therapy in prostate cancer includes treatment based on serum prostate-specific antigen (PSA) only or local recurrence; neoadjuvant or adjuvant treatment of high-risk disease, usually in combination with radiation therapy; and treatment of patients with metastatic disease regardless of symptoms. The American Society of Clinical Oncology (ASCO) 2007 guidelines and National Comprehensive Cancer Network (NCCN) 2009 guidelines recommend either luteinizing hormone-releasing hormone (LHRH) agonists or bilateral orchiectomy as first-line therapy for men with advanced prostate cancer.^1,2Medical or chemical castration is almost exclusively performed by the use of injectable LHRH analogues, with a minor role for estrogen and limited experience with LHRH antagonists. Surgical castration through bilateral orchiectomy is infrequently used today.Intermittent hormonal therapy (IHT) is being investigated as an alternative to continuous hormonal therapy with a potential for reduced morbidity and a delay of the progression to hormone-refractory disease.³ Although intermittent therapy may rely upon restoring a normal testosterone level, it is believed that the testosterone level should be as low as possible when the patient is on treatment, thus generating the lowest serum PSA level possible and likely improving outcome.⁴ Although the data on IHT are promising, trials reported thus far are relatively small and somewhat underpowered, and it is likely that its use will increase in the future as trials mature.There is growing recognition that many men may not achieve acceptable levels of testosterone using androgen ablation. This has led to a renewed interest in the significance of the testosterone level in the modern era of prostate cancer management. Can we define the best castration therapy for prostate cancer? Is this the therapy that provides the lowest and most consistent levels of testosterone suppression? To quote Dr. Claude Schulman in a recent editorial: “less is more.”⁵     

Altered glycosylation pattern allows the distinction between prostate-specific antigen (PSA) from normal and tumor origins

Prostate-specific antigen (PSA) is a glycoprotein secreted by prostate epithelial cells. PSA is currently used as a marker of prostate carcinoma because high levels of PSA are indicative of a tumor situation. However, PSA tests still suffer from a lack of specificity to distinguish between benign prostate hyperplasia and prostate cancer. To determine whether PSA glycosylation could provide a means of differentiating between PSA from normal and tumor origins, N-glycan characterization of PSA from seminal fluid and prostate cancer cells (LNCaP cell line) by sequencing analysis and mass spectrometry was carried out. Glycans from normal PSA (that correspond to low and high pI PSA fractions) were sialylated biantennary complex structures, half of them being disialylated in the low pI PSA fraction and mostly monosialylated in the high pI PSA. PSA from LNCaP cells was purified to homogeneity, and its glycan analysis showed a significantly different pattern, especially in the outer ends of the biantennary complex structures. In contrast to normal PSA glycans, which were sialylated, LNCaP PSA oligosaccharides were all neutral and contained a higher fucose content. In 10-15% of the structures fucose was linked alpha1-2 to galactose, forming the H2 epitope absent in normal PSA. GalNAc was increased in LNCaP glycans to 65%, whereas in normal PSA it was only present in 25% of the structures. These carbohydrate differences allow a distinction to be made between PSA from normal and tumor origins and suggest a valuable biochemical tool for diagnosis and follow-up purposes.     

Highly specific expression of luciferase gene in lungs of naïve nude mice directed by prostate-specific antigen promoter

PSA promoter has been demonstrated the utility for tissue-specific toxic gene therapy in prostate cancer models. Characterization of foreign gene overexpression in normal animals elicited by PSA promoter should help evaluate therapy safety. Here we constructed an adenovirus vector (AdPSA-Luc), containing firefly luciferase gene under the control of the 5837 bp long prostate-specific antigen promoter. A charge coupled device video camera was used to non-invasively image expression of firefly luciferase in nude mice on days 3, 7, 11 after injection of 2 x 10(9)PFU of AdPSA-Luc virus via tail vein. The result showed highly specific expression of the luciferase gene in lungs of mice from day 7. The finding indicates the potential limitations of the suicide gene therapy of prostate cancer based on selectivity of PSA promoter. By contrary, it has encouraging implications for further development of vectors via PSA promoter to enable gene therapy for pulmonary diseases.     

A tissue biomarker panel predicting systemic progression after PSA recurrence post-definitive prostate cancer therapy

Background

Many men develop a rising PSA after initial therapy for prostate cancer. While some of these men will develop a local or metastatic recurrence that warrants further therapy, others will have no evidence of disease progression. We hypothesized that an expression biomarker panel can predict which men with a rising PSA would benefit from further therapy.

Methodology/Principal Findings

A case-control design was used to test the association of gene expression with outcome. Systemic (SYS) progression cases were men post-prostatectomy who developed systemic progression within 5 years after PSA recurrence. PSA progression controls were matched men post-prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years. Using expression arrays optimized for paraffin-embedded tissue RNA, 1021 cancer-related genes were evaluated–including 570 genes implicated in prostate cancer progression. Genes from 8 previously reported marker panels were included. A systemic progression model containing 17 genes was developed. This model generated an AUC of 0.88 (95% CI: 0.84–0.92). Similar AUCs were generated using 3 previously reported panels. In secondary analyses, the model predicted the endpoints of prostate cancer death (in SYS cases) and systemic progression beyond 5 years (in PSA controls) with hazard ratios 2.5 and 4.7, respectively (log-rank p-values of 0.0007 and 0.0005). Genes mapped to 8q24 were significantly enriched in the model.

Conclusions/Significance

Specific gene expression patterns are significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence.