Prostate‐specific antigen kinetics in localized and advanced prostate cancer

The successful management of prostate cancer requires early detection, appropriate risk assessment and optimum treatment. To this end, much research has been conducted over many years with the goal of identifying a reliable and easily measurable tumour marker that could be used on a large scale for the diagnosis, staging and monitoring of the disease. Prostate‐specific antigen (PSA) was independently discovered by two groups in the 1960s and 1970s, in semen and prostate tissue, and given different names. It later became evident that these proteins were encoded by the same gene and were the same protein. PSA was then identified as a useful marker for assessing patients with prostate cancer during their follow‐up. In 1986, PSA was approved by the United States Food and Drug Administration to monitor prostate cancer, and in 1994 approved as a tool for detecting the disease in men aged ≥50 years. PSA is now the most widely used serum marker for detecting and monitoring prostate cancer, but its use as a diagnostic marker is controversial because it has several limitations, including its low specificity (PSA levels are also increased in benign prostatic hyperplasia, and in general inflammatory responses) and low sensitivity. Furthermore, PSA levels are highly variable over time, and PSA poorly distinguishes indolent from aggressive cancers. As such, the use of PSA level as a diagnostic tool can lead to over‐detection of cancers that pose little threat to health and/or life. Moreover, the impact of PSA screening on prostate cancer mortality rates remains controversial, and will do so until the results of currently ongoing randomized controlled studies in Europe and the USA become available. To overcome the limitations of using PSA, research on PSA kinetics has developed considerably in the last decade. We review publications on the added value of PSA kinetics compared with single PSA measurements in the early detection of prostate cancer, and in predicting the outcome of patients with localized and advanced disease.     

Early prostate cancer: prevention,treatment modalities,and quality of life issues

Our understanding of the screening, prevention and treatment of early prostate cancer is improving. This is a result of new data from clinical trials and the incorporation of efficacy measures based on risk assessment and quality of life (QoL). This review aims to examine completed and ongoing clinical trials that address issues in early prostate cancer, including screening, prevention, treatment, and QoL. Prostate-specific antigen (PSA) testing has a crucial and evolving role in detecting primary prostate cancer, evaluating prevention interventions and assessing the effectiveness of treatment. Questions remain about the optimal PSA parameters appropriate for primary screening and for diagnosing relapse. Emerging and established data provide evidence that early intervention with hormone therapy, either as immediate or adjuvant therapy, delays progression in prostate cancer patients with intermediate or poor prognosis. The impact of therapeutic modality on QoL has become better characterized, as QoL instruments have been developed, validated and applied.     

PSA—Promoter of Stress and Anxiety or Providentially-Sent Antigen?

Measurement of serum prostate-specific antigen (PSA) levels has revolutionised all aspects of the management of men with prostate cancer. As well as monitoring established disease, PSA testing has an important role in the early detection of prostate cancer. Although some men will undoubtedly benefit from early detection and treatment, concerns are raised by the poor specificity of the PSA test and the lack of conclusive evidence that early detection and treatment of prostate cancer carries survival benefits. As men become more aware of PSA testing through both the media and the Internet, clinicians are being placed under increasing pressure to carry it out. This review explores the arguments for and against PSA screening in asymptomatic men.     

Prostate-specific antigen doubling time and survival in patients with advanced metastatic prostate cancer

The relation between tumor kinetics and disease progression in patients with hormone-refractory prostate cancer (HRPC) has not been well described. Biochemical recurrence of prostate cancer is characterized by detectable prostate-specific antigen (PSA) levels after treatment and occurs in approximately 30% of patients after therapy for apparent localized disease. An increase in PSA almost always occurs before clinical evidence of disease. The ability to identify early biochemical failure in patients to assess disease aggressiveness and guide changes in treatment needs to be examined. We examined serial PSA data from 249 patients with metastatic disease to assess PSA doubling time (PSADT) in hormone-naive prostate cancer (HNPC) and HRPC states. In a subset of patients, the relation of PSADT to Gleason score and survival was studied. PSADT decreased from 37.5 +/- 4.5 weeks to 15.6 +/- 1.6 weeks (mean +/- SEM) in patients with HNPC versus HRPC. In this small study, PSADT did not correlate with Gleason score, survival from start of hormonal treatment, length of time receiving hormone therapy, or survival in the HRPC state. The decrease in PSADT with disease state may help provide insight into understanding the biology of late-stage disease.     

Risk Factors for the Development of Bone Metastases in Prostate Cancer

ObjectivesBone health of men with prostate cancer is threatened throughout the disease course. The majority of patients with advanced prostate cancer will develop bone metastases that can undermine skeletal integrity and result in skeletal complications including pathologic fractures, spinal cord compression, and palliative radiotherapy to bone. The early identification of patients who are at a high risk for bone metastases may enable earlier identification and treatment of bone lesions, thereby preserving patients’ independence throughout the disease course.MethodsCurrent guidelines for bone health maintenance were reviewed and PubMed key word searches performed to identify risk factors for the development of bone metastases in patients with prostate cancer. Additionally, guidelines and consensus recommendations were reviewed to identify bone health issues and their management in patients with early prostate cancer.ResultsCurrent prostate cancer monitoring guidelines recommend bone scans at initial diagnosis for patients with prostate-specific antigen (PSA) levels >20 ng/ml and in patients with chronic bone pain or fractures. Multiple studies have concluded that high baseline PSA levels, rising PSA despite androgen-deprivation therapy (ADT), and high PSA velocity are risk factors for the development of bone metastasis in patients with prostate cancer. In patients with early prostate cancer, bone loss is an emerging concern, and bisphosphonates have been demonstrated to prevent bone loss from ADT. Use of risk factors such as PSA kinetics may optimize screening and enable earlier identification of bone metastases.ConclusionsMonitoring bone mineral density may allow for better preservation of skeletal health in patients undergoing ADT.     

Biochemical markers of bone turnover and clinical outcomes in men with prostate cancer

ObjectivesDisrupted skeletal homeostasis is common in patients with prostate cancer. Low bone density is common at diagnosis, and fracture risk is further elevated by the effects of androgen-deprivation therapy. Later in the disease course, bone metastases can result in skeletal morbidity. Although prostate-specific antigen (PSA) levels can provide important insights into overall disease progression, convenient, noninvasive tools for monitoring skeletal health are lacking. Biochemical markers released into serum and urine as a result of bone turnover might fulfill this unmet need. The objectives of this article are to assess current evidence examining the potential utility of bone turnover markers for monitoring skeletal health, bone disease progression, and response to antiresorptive therapies in the prostate cancer setting.MethodsPublished articles and abstracts from major oncology or urology congresses pertaining to the use of bone turnover markers to monitor skeletal health and disease progression were identified and assessed for relevance and methodologic stringency.ResultsSeveral randomized trials and correlative studies support the utility of bone marker level changes to assess disease progression in the metastatic setting, bone health during hormonal therapy, and response to bisphosphonate therapy. The available data support potential associations between levels of the collagen type I telopeptides (NTX and CTX) and the severity of metastatic bone disease as well as outcomes during antiresorptive therapy. Evidence linking bone marker level changes with early diagnosis of skeletal metastases is emerging. Although several markers have shown promising results in correlative studies, results from ongoing prospective trials are needed to establish the role of bone markers in this setting.ConclusionsBone marker levels reflect ongoing skeletal metabolism and can provide important insights into bone health and response to bisphosphonate therapy in patients with prostate cancer. The data supporting a role for bone markers to monitor skeletal disease progression and response to zoledronic acid therapy are especially strong. Bone marker assessments may complement established diagnostic and monitoring paradigms in prostate cancer.     

PSA and hK2 in the diagnosis of prostate cancer

Serum markers for prostate carcinoma are widely applied for the purpose of early detection of cancer and the differentiation between benign and malignant disease, for the pre-treatment staging of detected prostatic cancers, and for the monitoring of prostate cancer after curative or palliative therapies. Since its discovery in 1979, serum PSA has been the most powerful marker of prostate cancer, but, when used alone, PSA is not sufficiently sensitive or specific to consider it an ideal tool for the early detection or staging of prostate cancer. To optimize the use of PSA, the concepts of PSA velocity, PSA density, and age-related PSA values were developed. Moreover, the molecular forms of PSA, especially the percentage of free PSA, seem to be useful tools for the detection of prostate cancer in men with slightly elevated total PSA. Human kallikrein 2 (hK2), a serine protease closely related to PSA that also is expressed predominantly in the prostate, is a new complementary marker to PSA for early detection of prostate cancer. In this review, we examine PSA testing and its effectiveness in the diagnosis of prostate cancer. Further, we also evaluate recent literature regarding the use of hk2.     

早期前列腺癌的诊断与治疗

随着前列腺癌发病率在我国的逐年升高,泌尿外科医生对此疾病的早期诊断与治疗也越来越关注。尽管美国的资料显示前列腺癌的筛查可以降低前列腺癌相关的死亡率,但对是否开展此项筛查依然存在争议。诊断方面依然以直肠指检(DRE)、前列腺特异性抗原(PSA)和B超引导的经直肠前列腺穿刺活检为主。治疗方面强调对这类患者实施治愈性治疗手段如前列腺癌根治术和放疗。严密的随访可以尽早发现肿瘤复发并及时开始二线治愈性治疗。本文对早期前列腺癌诊断与治疗的现状进行了综述。     

Prostate cancer: Diagnosis and staging

The discovery and the use of serum prostate specific antigen (PSA) has considerably improved the diagnosis of prostate cancer during the past 20 years. Before PSA era, early diagnosis was only based on the digital rectal examination (DRE) of which the Limitations have been evidenced; over half of the tumours diagnosed by such means had already spread out of the prostate and were incurable. Assessment of serum PSA has allowed the diagnosis to be made at an earlier stage of the disease, curable by current treatments. Whichever the diagnostic tools, transrectal ultrasound (TRUS) prostatic biopsies remain necessary for diagnosis ascertainment, taking into account the low specificity of PSA assessment. The feasibility of a diagnosis at an early and curable stage of the disease has logically resulted in screening procedures aimed at reducing the high mortality related to prostate cancer. The numerous publications on prostate cancer screening provide precise information on the accuracy of available diagnostic means (PSA, DRE, TRUS, combined PSA and DRE), on the characteristics of screened tumours (stage and differentiation), and also on the population of men likely to benefit from the screening (age at beginning and end of the screening, frequency of PSA testing, identification of the men with ethnic and/or genetic predisposition). In those early diagnosed prostate cancers, the assessment of loco-regional cancer extension (extracapsular and/or, microscopic nodal involvement), remains unsatisfactory because no imaging technique (ultrasonography, CT scan, MRI,...) allows visualising the tumour itself or microscopic metastases. Nevertheless, the combination of multiple parameters such as DRE data, PSA level, biopsy data and tumour differentiation helps approaching with an increasing precision (nomograms) the true pathologic stage of the disease. Such advances allow distinguishing, among the very heterogeneous group of prostate cancers, tumours that differ from one to another in terms of disease stage, progression and prognosis, which is helpful for the determination of an adapted therapeutic strategy.     

New circulating biomarkers for prostate cancer

The introduction of prostate-specific antigen (PSA) revolutionized prostate cancer (PCa) screening and ushered the PSA era. However, its use as a screening tool remains controversial and changes in the epidemiology of PCa have strongly limited its prognostic role. Therefore, we need novel approaches to improve our ability to detect PCa and foretell the course of the disease. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity and assessment of various isoforms of PSA. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate PCa biomarkers, we have chosen to discuss a select group of candidate blood-based biomarkers including human glandular kallikrein, early prostate cancer antigens, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-2 and IGFBP-3), urokinase plasminogen activation system, transforming growth factor-beta1, interleukin-6, chromogranin A, prostate secretory protein, prostate-specific membrane antigen, PCa-specific autoantibodies and alpha-methylacyl-CoA racemase. While these and other markers have shown promise in early phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, metastasis, and serve as prognosticators, targets and/or surrogate end points of disease progression and response to therapy.     

PSA-based prostate cancer screening: the role of active surveillance and informed and shared decision making

Since the first publication describing the identification of prostate-specific antigen (PSA) in the 1960s, much progress has been made. The PSA test changed from being initially a monitoring tool to being also used as a diagnostic tool. Over time, the test has been heavily debated due to its lack of sensitivity and specificity. However, up to now the PSA test is still the only biomarker for the detection and monitoring of prostate cancer. PSA-based screening for prostate cancer is associated with a high proportion of unnecessary testing and overdiagnosis with subsequent overtreatment. In the early years of screening for prostate cancer, high rates of uptake were very important. However, over time the opinion on PSA-based screening has shifted towards the notion of informed choice. Nowadays, it is thought to be unethical to screen men without them being aware of the pros and cons of PSA testing, as well as the fact that an informed choice is related to better patient outcomes. Now, as the results of three major screening studies have been presented and the downsides of screening are becoming better understood, informed choice is becoming more relevant.     

Does PSA Testing Influence the Natural History of Prostate Cancer?

Prostate-specific antigen (PSA) testing advances the diagnosis of prostate cancer, shifting the stage at diagnosis towards localised disease. However, the widespread application of PSA testing is controversial, due to uncertainties over whether earlier diagnosis of prostate cancer improves the mortality associated with the disease. This article discusses the evidence on the relationship between PSA testing and prostate cancer mortality considering 5-year survival rates, data from randomised, controlled trials and epidemiological trends in disease mortality. Reported improvements in 5-year survival rates for prostate cancer are probably due to lead-time bias (screening leading to earlier diagnosis). Randomised studies evaluating PSA screening are ongoing and will not provide mortality results until the latter part of this decade. Epidemiological data reveal a decline in disease mortality in areas where PSA screening is routine, but the cause of this decline is likely to be multifactorial. In conclusion, an effect of PSA testing on the natural history of prostate cancer is not yet fact, as determined by a randomised controlled trial, but it is certainly more than fiction.     

Prostate cancer in the elderly patient

Although malignant tumours occur at all ages, cancer disproportionately strikes individuals in the age group 65 years and older. The increasing statistical life expectancy of men together with the introduction of prostate specific antigen (PSA) as a screening tool have both contributed to a rising number of elderly men with a diagnosis of prostate cancer. Age is generally considered to be a key prognostic factor in terms of therapeutic decision making, perhaps as important as PSA level and Gleason score. Even in men over 70 years, treatment without curative intent may deprive frail patients of years of life. When considering local treatment, strong consideration should be given to radical surgery. Modern radical prostatectomy is associated with low perioperative morbidity, excellent clinical outcomes as well as long term disease control. Besides, overdiagnosis has led to the concept of expectant management for screening-detected small-volume, low grade disease, with intention of providing therapy for those men experiencing disease progression.     

Papel del antígeno prostático específico ante las nuevas evidencias científicas,una nueva actualización en 2020

ObjectiveTo review and update the latest scientific evidence gathered in recent years regarding prostate-specific antigen (PSA) for better implementation into routine clinical practice.Evidence acquisitionAnalysis of the available evidence on the current role of PSA, based on the experience of an expert panel in the subject under analysis.Evidence synthesisCurrently, PSA cannot be considered only as a guide for the presence or absence of prostate cancer. This determination can also help the urologist to decide on the most convenient treatment for a patient with benign prostatic hypertrophy (BPH) as a criterion for disease progression, and it can also suggest the suspicious existence of a prostatic tumor when there is PSA rise of >0.3 ng/ml over the level reached 6 months after having initiated treatment with 5-alpha-reductase inhibitor. However, the limits of this PSA rise with derivatives of alternative 5-alpha-reductase (5-ARI) inhibitors to dutasteride are controversial. Moreover, PSA is a key factor for the follow-up of patients with prostate adenocarcinoma at any stage who have received treatment (surgery, radiotherapy or focal therapies, hormone therapy), it acts as a guide to identify biochemical recurrence, to suspect the existence of local or distant recurrence, as well as to propose or discard adjuvant treatments. Finally, the role of PSA as a screening tool has been recently reinforced, demonstrating increased mortality rates or the existence of more aggressive cases of prostate cancer in those countries where the use of this tool has declined.ConclusionsWe present new data about the current role of PSA in the management of patients treated for BPH and/or prostate cancer that should be implemented into routine clinical practice, with special emphasis on the relevant role of this biomarker in the screening and follow-up of prostate cancer, as well as in the progression of BPH in dutasteride treatment.     

Diagnosis of localized prostate cancer: 10 years of progress

Advances in the diagnosis of early stage disease, and particularly the introduction of prostate-specific antigen (PSA) testing, have had a dramatic effect on the presentation and clinical management of prostate cancer during the past ten years. As a result, there have been significant epidemiological changes in countries where early diagnosis is recommended. The importance of PSA testing for the diagnosis of localized prostate cancer has become well established in clinical practice and this is reflected by improved outcomes from definitive treatment. The contribution of PSA-related parameters and molecular forms of PSA both to cancer detection and prediction of pathological stage continue to be explored. Concerns about the reliability of the standard sextant biopsy technique for cancer detection relate to the need for re-biopsy in a growing number of patients with negative biopsies and an increasing proportion of patients with low volume, multifocal disease. In men with cancer, additional prognostic information can be derived from biopsy findings, with important therapeutic implications. This relates also to the need for reliable markers indicating pathological stage and risk of progression. The opportunities for the prevention of prostate cancer have grown with improved understanding of its biology and the genetic basis of the early steps associated with malignant transformation. In the future, the need for therapeutic intervention is likely to be most influenced by successful prevention strategies.     

Prostate cancer screening markers

Prostate cancer is the most frequent new cancer diagnosis in the Western world. Prostate-specific antigen (PSA) was shown to be an adequate tool in prostate cancer screening. However, in men with a PSA level between 4.0 and 10 ng/ml its predictive value is low. PSA serum levels are poorly correlated with grade and stage of prostate cancer, and clinically significant prostate cancers have been found in patients with serum PSA levels lower than 4.0 ng/ml. The widespread use of PSA screening programs led to over-diagnosis and unnecessary biopsies. Consequently, there is a need for new instruments that are likely to improve the specificity of serum PSA levels between 4.0 and 10 ng/ml and the screening for prostate cancer in subjects with low PSA. Potential biomarkers related to conventional PSA, such as free PSA, PSA density, PSA velocity and complexed PSA, intact PSA, nicked PSA, benign PSA and pro PSA, as well as insulin-like growth factor 1 and its binding protein, and human glandular kallikrein 2 are reviewed. Promising urinary markers for the early detection of prostate cancer, such as glutathione-S transferase P1 gene (GSTP-1), 8-hydroxydeoxyguanosine (8-OHdG), differential display code 3 (DD3), uPM3, and telomerase, which have been described during the last years are reviewed in this article. The advantages and limitations of screening markers for prostate cancer are discussed.     

Screening for prostate cancer: current recommendations

Recent studies have questioned the efficacy of PSA as a marker for the early detection of prostate cancer, but techniques are being investigated to improve the sensitivity and specificity of screening. It is hoped that new methods can differentiate between lethal and nonlethal cancers, thereby avoiding lead-time bias. Even with the current limitations of PSA, the combination of stage migration seen with screening, the recent Scandinavian study showing decrease of disease progression following surgical extirpation, and the known mortality in patients presenting with advanced disease help support PSA screening for prostate cancer. It is hoped that prospective, randomized, long-term screening studies, such as the PLCO and ERSCP trials, will show improved survival using the admittedly imperfect PSA marker in prostate cancer screening.     

Does screening for prostate cancer identify clinically important disease?

In this study the combination of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) is shown to be effective for detecting early prostate cancer in a urological out-patient setting. PSA provides the means to detect cancer in men with normal DRE that may otherwise present as so-called incidental cancer at transurethral resection of the prostate (TURP) for apparently benign disease or later in the course of its natural history as locally advanced or metastatic disease. PSA progression in men with incidental cancer has been previously demonstrated to be predicted more reliably by residual cancer on needle biopsy after TURP than by tumour in the resected specimen and, therefore re-staging such patients is worthwhile when further treatment would be considered. Among men selected for radical prostatectomy, non-palpable tumours detected with PSA more predictable in pathological extent than incidental cancer and their particular pathological characteristics suggest they include clinically significant tumours that would progress if untreated to palpable and eventually metastatic disease. In view of this progressive behaviour, cancer detected by PSA should be considered clinically significant particularly in men with a life expectancy of at least 10 years. Therefore screening should be offered for such individuals, to detect and treat tumours at a curable stage and thereby eliminate the high mortality and often protracted morbidity commonly associated with metastatic disease.     

早期前列腺癌抗原-2在前列腺癌早期诊治中的应用

PSA在前列腺癌患者筛选、诊治、随访应用中的局限性越来越被临床所证实,人们也在不断寻找新的前列腺癌的标志物,早期前列腺癌抗原-2(EPCA-2)的发现为人们提供了这一依据,具有潜在的临床应用价值,本文对EPCA-2在前列腺癌的早期诊治中的应用进行了综述。     

Managing benign prostatic hyperplasia and prostate cancer – the challenges today

Many men who reach average life expectancy will experience benign prostatic hyperplasia (BPH) or prostate cancer and together these conditions account for a considerable amount of ill-health and distress for men and their partners. Although there is considerable overlap across BPH and prostate cancer in symptom and risk profiles, management approaches are very different for each condition and appropriate diagnostic evaluation is therefore crucial to achieve the best possible outcome. The primary care physician should play a vital role in the diagnosis, management and appropriate referral of men with prostate disease with the ultimate goals being (1) early detection of prostate cancer and (2) effective treatment of benign prostate disease to manage symptoms and reduce the risk of progression.In prostate cancer, although there is debate over the implementation of systematic prostate-specific antigen (PSA) screening and appropriate thresholds, the use of PSA screening in conjunction with digital rectal examination (DRE) may aid earlier detection. The challenge is now to better determine which men are likely to develop aggressive disease so that overtreatment can be avoided. Results of large trials of systematic PSA screening are eagerly anticipated.In BPH, a major challenge is to identify men with bothersome lower urinary tract symptoms. Improved communication, education of patients, and the use of tools such as the International Prostate Symptom Score (IPSS) may help detect men who need treatment. Treatment selection should be driven by an understanding of the risks of disease progression, the impact of the disease on the patient's quality of life, and by the patient's own treatment preferences.Ultimately, we must empower our patients to make informed decisions about their diagnostic and treatment options through open dialogue and provision of appropriate information and education.