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The High Prevalence of Undiagnosed Prostate Cancer at Autopsy: Implications for Epidemiology and Treatment of Prostate Cancer in the Prostate-Specific Antigen-Era
Abstract
Widespread prostate-specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6024 men. Among men aged 70-79, tumor was found in 36% of Caucasians and 51% of African-Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well-recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow-up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential. This article is protected by copyright. All rights reserved.
... Fourth, we restricted analyses to participants who had more than 2, more than 3, and more than 4 years of follow-up to evaluate the potential for reversecausality. Finally, we explored associations with nonfatal prostate cancer risk and prostate cancer-specific mortality separately, given that prostate cancer-specific mortality may serve as an indicator of more aggressive tumors compared with nonfatal prostate cancers (48). Due to the limited number of prostate cancer deaths, models adjusting for age and BMI are presented in addition to fully adjusted models; modifications were also made to covariates in fully adjusted prostate cancer mortality models due to constraints with case counts. ...
... Device-based sleep measures help mitigate measurement error associated with selfreport of typical sleep (27,28,71,72). We attempted to address detection bias of prostate cancer incidence by including PSA testing history as a covariate and as a potential effect modifier (48). We also explored analyses evaluating wakefulness after sleep onset with nonfatal prostate cancers as a potential indicator of cancer aggressiveness and found similar associations with wakefulness after sleep onset and overall prostate cancer incidence. ...
... Covariate data, excluding physical activity, were assessed at baseline and may have changed over time. We cannot rule out potential residual and unmeasured confounding from health-seeking behaviors and PSA testing (48). Nonfatal prostate cancer incidence and prostate cancer-specific mortality were based on prostate cancer deaths accrued over a short follow-up and thus may miss aggressive cancers. ...
Background
Studies of sleep and prostate cancer are almost entirely based on self-report, with limited research using actigraphy. Our goal was to evaluate actigraphy-measured sleep and prostate cancer and to expand on findings from prior studies of self-reported sleep.
Methods
We prospectively examined 34 260 men without a history of prostate cancer in the UK Biobank. Sleep characteristics were measured over 7 days using actigraphy. We calculated sleep duration, onset, midpoint, wake-up time, social jetlag (difference in weekend-weekday sleep midpoints), sleep efficiency (percentage of time spent asleep between onset and wake-up time), and wakefulness after sleep onset. Cox proportional hazards models were used to estimate covariate-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs).
Results
Over 7.6 years, 1152 men were diagnosed with prostate cancer. Sleep duration was not associated with prostate cancer risk. Sleep midpoint earlier than 4:00 am was not associated with prostate cancer risk, though sleep midpoint of 5:00 am or later was suggestively associated with lower prostate cancer risk but had limited precision (earlier than 4:00 am vs 4:00-4:59 am HR = 1.00, 95% CI = 0.87 to 1.16; 5:00 am or later vs 4:00-4:59 am HR = 0.79, 95% CI = 0.57 to 1.10). Social jetlag was not associated with greater prostate cancer risk (1 to <2 hours vs <1 hour HR = 1.06, 95% CI = 0.89 to 1.25; ≥2 hours vs <1 hour HR = 0.90, 95% CI = 0.65 to 1.26). Compared with men who averaged less than 30 minutes of wakefulness after sleep onset per day, men with 60 minutes or more had a higher risk of prostate cancer (HR = 1.20, 95% CI = 1.00 to 1.43).
Conclusions
Of the sleep characteristics studied, higher wakefulness after sleep onset—a measure of poor sleep quality—was associated with greater prostate cancer risk. Replication of our findings between wakefulness after sleep onset and prostate cancer are warranted.
... Disease progression rates are independent of patient age or disease onset, as with other studies. Asymptomatic onset used in the model is estimated from autopsy studies and previously published models [36,[41][42][43]. The model assumes that these adequately reflect the real prevalence of disease in the U.S., although that may be an underestimation of the true amount of latent disease in the population. ...
... Asymptomatic onset used in the model is estimated from autopsy studies and previously published models [36,[41][42][43]. The model assumes that these adequately reflect the real prevalence of disease in the U.S., although that may be an underestimation of the true amount of latent disease in the population. ...
... The main and most important risk factor affecting all types of cancer, except cervical cancer, is getting older. Autopsy studies indicate that prevalence of PCa is an increasing function of age [41][42][43]. Since the real underlying prevalence of PCa is unknown, we use estimates from autopsy studies. ...
In this study, we present a novel simulation model and case study to explore the long-term dynamics of early detection of disease, also known as routine population screening. We introduce a realistic and portable modeling framework that can be used for most cases of cancer, including a natural disease history and a realistic yet generic structure that allows keeping track of critical stocks that have been generally overlooked in previous modeling studies. Our model is specific to prostate-specific antigen (PSA) screening for prostate cancer (PCa), including the natural progression of the disease, respective changes in population size and composition, clinical detection, adoption of the PSA screening test by medical professionals, and the dissemination of the screening test. The key outcome measures for the model are selected to show the fundamental tradeoff between the main harms and benefits of screening, with the main harms including (i) overdiagnosis, (ii) unnecessary biopsies, and (iii) false positives. The focus of this study is on building the most reliable and flexible model structure for medical screening and keeping track of its main harms and benefits. We show the importance of some metrics which are not readily measured or considered by existing medical literature and modeling studies. While the model is not primarily designed for making inferences about optimal screening policies or scenarios, we aim to inform modelers and policymakers about potential levers in the system and provide a reliable model structure for medical screening that may complement other modeling studies designed for cancer interventions. Our simulation model can offer a formal means to improve the development and implementation of evidence-based screening, and its future iterations can be employed to design policy recommendations to address important policy areas, such as the increasing pool of cancer survivors or healthcare spending in the U.S.
... and the lifetime risk of dying of prostate cancer is 2.44% (95% C.I. 2.42-2.46). 1 An estimated 191,930 men will be diagnosed and about 33,330 will die of prostate cancer in 2020. 10 Prostate cancer incidence is highly sensitive to prostate cancer screening patterns. As prostate specific antigen (PSA) screening increased starting in 1991-1992, incidence rates increased as well. ...
... 4 It is important to note that in these intervening years, United States Preventive Services Task Force (USPSTF) revised its screening guidelines in 2008 urging a cautious approach to PSA screening and in 2012, it gave a Grade D recommendation, advising against routine use of PSA screening and discouraging the use of Digital Rectal Examination (DRE) with both PSA and DRE were found to be an ineffective screening modality. 10,23 The rapid increase in incidence in early 1990s brought about radical changes in stage and grade migration with an increasing number of men diagnosed with low risk, localized or indolent prostate cancer. 8 For example, in late 1990s to early 2000s, almost 80-90% of prostate cancer diagnosed was localized prostate cancer. ...
... 3,20 In contrast, before the PSA era, a larger proportion of prostate cancers were diagnosed at an advanced stage. 10 In addition to state migration, surveillance data suggest that PSA testing created age migration as evidenced by the changes in the age distribution of the population diagnosed. 3,11 For example, longitudinal analysis of SEER data reveals that prostate cancer is most frequently diagnosed in men between the ages of 65 and 74 with the median age of 66 at diagnosis. ...
Despite advances in prostate cancer treatment, wide variability in post-operative oncologic and functional outcomes are observed. Effective management of prostate cancer requires accurate prediction of potential outcomes and setting realistic expectations of functional outcomes is an important challenge. Advances in computing are accelerating the development of prediction tools using routine clinical practice and patient reported outcomes data to support the treatment decision-making process; however, variability in post-operative functional outcomes remains despite the advancements. The development, deployment, and evaluation of prediction models in routine urology practices has the potential to enhance the treatment decision-making process and improve the overall quality of prostate cancer care. The objective of this dissertation is to assess the patterns of urinary continence recovery in a statewide registry. To achieve the objective of this dissertation, we conducted a retrospective analysis of urinary continence recovery after radical prostatectomy for individuals who completed the Michigan Urological Surgery Improvement Collaborative (MUSIC) - Patient Reported Outcomes (PRO) questionnaires. We assessed variability in urinary function outcomes at four post-operative time points and quantified the variability attributable to patients and surgeons (Aim 1). We trained pre- and post-operative prediction models that estimated long-term urinary continence recovery by predicting urinary domain scores and pad use at multiple time points (Aim 2). Lastly, we evaluated how temporal changes in practice patterns affect the robustness of models that estimate pad use by assessing various model building strategies (Aim 3). Using MUSIC registry and patient reported outcomes data, we found wide variability in continence recovery, with greater variability attributable to patients than surgeons (66% versus 7%) in mixed-effects models. Models that incorporated post-operative data and predicted outcomes at proximal time points performed better than pre-operative models or models that predicted outcomes at distal time points. Model discrimination remained stable and models while model calibration showed some indication of over-estimation in later years, but no evidence of calibration drift emerged. By conducting a retrospective study of statewide registry data to quantify variability in urinary continence, predicting long-term recovery, and assessing the robustness of prediction models to secular trends in registry data, our aim is to further the understanding of factors associated with urinary continence recovery and advance the science around prediction models using patient reported outcomes data. The results of these analyses fill gaps in our understanding of urinary continence recovery and further advance the goals of the Michigan Urological Surgery Improvement Collaborative to improve the quality of prostate cancer care in Michigan.
... A continuous ratio logistic model was fitted, with the classification of PCa in the aforementioned categories as response variable, and tPSA, f/tPSA% and age as predictors. The choice of this particular class of logistic regression models allowed us to evaluate the ability for discriminating: (1) "high grade PCa" vs. "low grade PCa"; and, (2) "low grade" vs. "No PCa", conditionally to the knowledge that in (2) grade is not high [16]. For fitting the model, at first non linear effects and an interaction effect between f/tPSA% and age were evaluated by likelihood ratio test, and statistical significance was conventionally deemed when p<0.05. ...
... PCa is the sixth leading cause of male cancer death (7.4%), although the largest proportion of PCas are indolent without leading to any complaints or death if left undetected [16]. These are managed by active surveillance, whereas "clinically significant" PCas (i.e. ...
... By considering the nomogram, predicting the probability of having low grade PCa vs. not having the disease, as expected the discriminating capability was lower than the first nomogram but acceptable and also the overestimation for predicted probability >50%, should be accounted, although likely with low clinical impact to recommend active surveillance. The progression is not a major feature of low grade PCa, but cannot be excluded [16,19,25] and preliminary evidence has associated a 1 unit increase of tPSA to an approximately 2 fold increased risk of having high grade disease [9]. ...
Objectives
Clinical practice guidelines endorse the stratification of prostate cancer (PCa) risk according to individual total prostate-specific antigen (tPSA) values and age to enhance the individual risk-benefit ratio. We defined two nomograms to predict the individual risk of high and low grade PCa by combining the assay of tPSA and %free/tPSA (%f/tPSA) in patients with a pre-biopsy tPSA between 2 and 10 μg/L.
Methods
The study cohort consisted of 662 patients that had fPSA, tPSA, and a biopsy performed (41.3% with a final diagnosis of PCa). Logistic regression including age, tPSA and %f/tPSA was used to model the probability of having high or low grade cancer by defining 3 outcome levels: no PCa, low grade (International Society of Urological Pathology grade, ISUP<3) and high grade PCa (ISUP≥3).
Results
The nomogram identifying patients with: (a) high vs. those with low grade PCa and without the disease showed a good discriminating capability (∼80%), but the calibration showed a risk of underestimation for predictive probabilities >30% (a considerable critical threshold of risk), (b) ISUP<3 vs. those without the disease showed a discriminating capability of 63% and overestimates predictive probabilities >50%. In ISUP 5 a possible loss of PSA immunoreactivity has been observed.
Conclusions
The estimated risk of high or low grade PCa by the nomograms may be of aid in the decision-making process, in particular in the case of critical comorbidities and when the digital rectal examinations are inconclusive. The improved characterization of the risk of ISUP≥3 might enhance the use for magnetic resonance imaging in this setting.
... Despite advances in our understanding of the foundational biology of PCa (i.e. pathological risk factors, PSA testing, associated oncogenes), differentiating aggressive and non-aggressive neoplasms prior to treatment initiation remains elusive as symptomology does not present until later stages of disease-with some men never presenting symptoms until the development of wide-spread metastasis [3][4][5] . This situation has led to both over treatment of ultimately indolent disease, with associated treatment-related side effects, and under treatment of aggressive disease, with associated poor outcomes [3][4][5][6] Biomarkers that can differentiate aggressive from indolent PCa are needed and would have high clinical impact. ...
... pathological risk factors, PSA testing, associated oncogenes), differentiating aggressive and non-aggressive neoplasms prior to treatment initiation remains elusive as symptomology does not present until later stages of disease-with some men never presenting symptoms until the development of wide-spread metastasis [3][4][5] . This situation has led to both over treatment of ultimately indolent disease, with associated treatment-related side effects, and under treatment of aggressive disease, with associated poor outcomes [3][4][5][6] Biomarkers that can differentiate aggressive from indolent PCa are needed and would have high clinical impact. ...
... Because of these reasons, PSA testing is no longer recommended by the US Preventative Services Task Force for men over 70 years old, as the harm of treatment outweighs the bene t of therapy 16 . Given that there is no consistent threshold for PSA in predicting tumor aggressiveness, companion assays that better identify refractory tumors are of high demand at the diagnostic stage 5 . ...
Despite advancements in the early-stage detection and expansion of treatments for Prostate Cancer (PCa), patient mortality rates remain high in patients with aggressive disease, and overtreatment of indolent disease remains a major issue. Prostate Specific Antigen (PSA), a standard PCa blood biomarker, is limited in its ability to differentiate disease subtypes resulting in the overtreatment of non-aggressive indolent disease. Recently Cancer Associated Macrophage-Like cells (CAMLs), a cancer-specific polyploid circulating stromal cell was found in the blood of patients with PCa. Further, it has been suggested that circulating CAMLs ≥50μm in cytoplasmic diameter are associated with aggressive tumor subtypes and worsened patient outcomes, which may aid PSA for patient stratification. To expand upon previous research, we hypothesized that monitoring CAML size, in combination with PSA, may aid in differentiating indolent, non-aggressive, and highly aggressive PCas by adding biological information that complements traditional clinical biomarkers, thereby guiding treatment for PCa.
... However, we question its validity. It was estimated that among 70-79 year old people, more than one-third of Caucasian men and half of African American men have indolent prostate cancer that would not cause harm if not diagnosed and untreated [87]. The detection of indolent prostate cancer has obvious adverse consequences [88]. ...
... If this prevalence rate is added with the clinically diagnosed prevalence rate, one would expect to see a unity for those of 85 or above. Projected based on the age and racial distribution, life expectancy and total U.S. population in 2015, these data suggest roughly 45 million cases of potentially detectable prostate cancer in the U.S. [87]. ...
... This was to avoid the significant risk of having control patients who may be undiagnosed with asymptomatic prostatic disease or cancer in older age groups, which would invalidate our findings. Notably, the prevalence of undiagnosed PCa at autopsy is estimated at 36% for Caucasians and 51% for African-Americans among men aged 70-79 (Jahn et al. 2015). We have, therefore, used a younger control cohort who are well outside the age range of having significant risk of a prostatic condition, such that we can have greater confidence on the CRPC markers identified in this study. ...
... We have, therefore, used a younger control cohort who are well outside the age range of having significant risk of a prostatic condition, such that we can have greater confidence on the CRPC markers identified in this study. Although potential differences exist in global protein expression between the control and CRPC samples due to age, these difference are likely related to normal physiological processes (Jahn et al. 2015) rather than affecting PCa-related marker expression. In addition, the control group in our study had a relatively small sample size. ...
Purpose
Extracellular vesicles (EV) secreted from cancer cells are present in various biological fluids, carrying distinctly different cellular components compared to normal cells, and have great potential to be used as markers for disease initiation, progression, and response to treatment. This under-utilised tool provides insights into a better understanding of prostate cancer.
Methods
EV from serum and urine of healthy men and castration-resistant prostate cancer (CRPC) patients were isolated and characterised by transmission electron microscopy, particle size analysis, and western blot. Proteomic and cholesterol liquid chromatography-mass spectrometry (LC–MS) analyses were conducted.
Results
There was a successful enrichment of small EV/exosomes isolated from serum and urine. EV derived from biological fluids of CRPC patients had significant differences in composition when compared with those from healthy controls. Analysis of matched serum and urine samples from six prostate cancer patients revealed specific EV proteins common in both types of biological fluid for each patient.
Conclusion
Some of the EV proteins identified from our analyses have potential to be used as CRPC markers. These markers may depict a pattern in cancer progression through non-invasive sample collection.
... Nineteen international studies, spanning from 1935 to 2014 and including countries such as Scandinavia, Caucasus, France, Hungary, Greece, Japan, China, Singapore, and North America, examined the histopathological evidence of PC in autopsies of 6024 males aged between 50-59, regardless of the cause of death. These studies found that approximately half of the individuals had histopathological evidence of prostate cancer, although only 3.8% died from PC [8]. ...
Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients’ quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocyte-derived and TAM-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.
... Early screening plays a crucial role not only in detecting the disease but also in reducing morbidity and mortality and improving the quality of life for patients. A study by Jahn et al. demonstrated an increase in the incidence of prostate cancer following the use of prostatic specific antigen (PSA) as a screening method, but the incidence returned to baseline after a decrease in PSA testing [32]. Another study conducted by Ilic et al., which involved 162,243 men aged between 50 and 69 years with a median follow-up of 12 years, revealed a lower incidence of metastatic prostate cancer in regularly screened patients compared to those who were not screened [33]. ...
In melanoma patients, distant metastases frequently manifest in the skin, lung, brain, liver, bone, and intestine. Notably, bone metastasis predominantly occurs within the axial skeleton, with the lumbar and thoracic spines being the most affected regions. Conversely, prostate cancer often disseminates to the bone, lung, liver, pleura, and adrenal glands. The spinal column, particularly the lumbar region, frequently harbors metastases in prostate cancer cases. Given the proximity of axial lesions to the spinal cord, patients commonly experience pain, weakness, and urinary dysfunction. This article presents a compelling case report of a patient initially diagnosed with metastatic prostate cancer, who later exhibited a metastatic lesion in the thoracic spine, subsequently identified as originating from acral melanoma on the plantar surface of the right foot. Histopathological examination confirmed the presence of acral melanoma in both the spine and the right foot. The patient received comprehensive treatment for advanced melanoma from a multidisciplinary team comprising medical and radiation oncologists. Considering the overlapping pathophysiology of prostate cancer and melanoma, simultaneous screening for both diseases in cases where one is detected could yield significant benefits, including enhanced morbidity and mortality outcomes and the facilitation of early detection for secondary malignancies.
... This restriction seems tolerable since rapid tumor progression is not to be expected in these cases. Multiple autopsy data show that 36-51% of men harbored an undiagnosed PCa that did not limit their life expectancy and-if detected-would have been considered in need of therapy [36]. Recent studies have shown that it is also reasonable to offer delayed treatment to some patients with an intermediate-risk PCa [37]. ...
The standard procedure for the diagnosis of prostate carcinoma involves the collection of 10–12 systematic biopsies (SBx) from both lobes. MRI-guided targeted biopsies (TBx) from suspicious foci increase the detection rates of clinically significant (cs) PCa. We investigated the extent to which the results of the TBx predicted the tumor board treatment decisions. SBx and TBx were acquired from 150 patients. Risk stratifications and recommendations for interventional therapy (prostatectomy and radiotherapy) or active surveillance were established by interdisciplinary tumor boards. We analyzed how often TBx alone were enough to correctly classify the tumors as well as to indicate interventional therapy and how often the findings of SBx were crucial for therapy decisions. A total of 28/39 (72%) favorable risk tumors were detected in TBx, of which 11/26 (42%) very-low-risk tumors were not detected and 8/13 (62%) low-risk tumors were undergraded. A total of 36/44 (82%) intermediate-risk PCa were present in TBx, of which 4 (9%) were underdiagnosed as a favorable risk tumor. A total of 12/13 (92%) high-risk carcinomas were detected and correctly grouped in TBx. The majority of csPCa were identified by the sampling of TBx alone. The tumor size was underestimated in a proportion of ISUP grade 1 tumors. Systematic biopsy sampling is therefore indicated for the next AS follow-up in these cases.
... A common issue with PSA screening is over-staging indolent disease [7] and high prevalence of false positives (upwards 70%) [54], causing the overtreatment of non-aggressive neoplasms. This results in increased adverse biopsy events (i.e., hematuria, pain, septicemia) and worse toxicities (i.e., vomiting, diarrhea, anemia) to standard of care treatment [5,7,21,55,56]. These issues have left a need for a companion biomarker to PSA to help in screening early PCa and for stratifying patients with more aggressive diseases. The high presence of CAMLs prior to resection and first-line treatment suggests that CAMLs might be useful in conjunction with PSA and could increase specificity in the diagnostic setting. ...
Despite advancements in the early-stage detection and expansion of treatments for prostate cancer (PCa), patient mortality rates remain high in patients with aggressive disease and the overtreatment of indolent disease remains a major issue. Prostate-specific antigen (PSA), a standard PCa blood biomarker, is limited in its ability to differentiate disease subtypes resulting in the overtreatment of non-aggressive indolent disease. Here we assess engorged cancer-associated macrophage-like cells (CAMLs), a ≥50 µm, cancer-specific, polynucleated circulating cell type found in the blood of patients with PCa as a potential companion biomarker to PSA for patient risk stratification. We found that rising PSA is positively correlated with increasing CAML size (r = 0.307, p = 0.004) and number of CAMLs in circulation (r = 0.399, p < 0.001). Over a 2-year period, the presence of a single engorged CAML was associated with 20.9 times increased likelihood of progression (p = 0.016) in non-metastatic PCa, and 2.4 times likelihood of progression (p = 0.031) with 5.4 times likelihood of death (p < 0.001) in metastatic PCa. These preliminary data suggest that CAML cell monitoring, in combination with PSA, may aid in differentiating non-aggressive from aggressive PCas by adding biological information that complements traditional clinical biomarkers, thereby helping guide treatment strategies.
... Nineteen international studies, spanning from 1935 to 2014 and including countries such as Scandinavia, Caucasus, France, Hungary, Greece, Japan, China, Singapore, and North America, examined the histopathological evidence of PCa in autopsies of 6,024 males aged between 50-59, regardless of the cause of death. These studies found that approximately half of the individuals had histopathological evidence of prostate cancer, although only 3.8% died from PCa [8]. ...
Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocytes-derived and TAMs-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.
... A different association has been observed, analyzing several risk factors for indolent compared to lethal disease [25]. Hence, it is mandatory to distinguish between risk factors for overall PCa and those for aggressive disease. ...
Background:
PSA density and an elevated PI-RADS score are among the strongest predictors of prostate cancer (PCa) in a fusion biopsy. Positive family history, hypertension, diabetes, and obesity have also been associated with the risk of developing PCa. We aim to identify predictors of the prostate cancer detection rate (CDR) in a series of patients undergoing a fusion biopsy.
Methods:
We retrospectively evaluated 736 consecutive patients who underwent an elastic fusion biopsy from 2020 to 2022. Targeted biopsies (2-4 cores per MRI target) were followed by systematic mapping (10-12 cores). Clinically significant PCa (csPCa) was defined as ISUP score ≥ 2. Uni- and multi-variable logistic regression analyses were performed to identify predictors of CDR among age, body mass index (BMI), hypertension, diabetes, positive family history, PSA, a positive digital rectal examination (DRE), PSA density ≥ 0.15, previous negative biopsy status, PI-RADS score, and size of MRI lesion.
Results:
The median patients' age was 71 years, and median PSA was 6.6 ng/mL. A total of 20% of patients had a positive digital rectal examination. Suspicious lesions in mpMRI were scored as 3, 4, and 5 in 14.9%, 55.0%, and 17.5% of cases, respectively. The CDR was 63.2% for all cancers and 58.7% for csPCa. Only age (OR 1.04, p < 0.001), a positive DRE (OR 1.75, p = 0.04), PSA density (OR 2.68, p < 0.001), and elevated PI-RADS score (OR 4.02, p = 0.003) were significant predictors of the CDR in the multivariable analysis for overall PCa. The same associations were found for csPCa. The size of an MRI lesion was associated with the CDR only in uni-variable analysis (OR 1.07, p < 0.001). BMI, hypertension, diabetes, and a positive family history were not predictors of PCa.
Conclusions:
In a series of patients selected for a fusion biopsy, positive family history, hypertension, diabetes, or BMI are not predictors of PCa detection. PSA-density and PI-RADS score are confirmed to be strong predictors of the CDR.
... Accurately identifying aggressive prostate tumors and studying them as a separate outcome are crucial from an etiology and preventive perspective . The risk factors for aggressive prostate cancer are frequently different from those for early stage or complete prostate cancer, depending on the disease stage, grade, or long-term prognosis (Jahn et al., 2015). ...
Summary
This study aimed to identify the most common bacterial isolation that were
correlated with patients suffering from prostate cancer, study antibiotic susceptibility
pattern. During the period extending between (November 2021 to April 2022) from the
Imam Hussain Center for Oncological and Hematological Diseases Directorate, urine
samples were obtained from so suspected patients suffering from prostate cancer, their
age were ranged from 51 to 80 years. Collected 50 urine sample. The Vitek 2 system
was the method that used for identification of bacterial species. The results showed that
out of 50 urine samples, (58%) had non-significant bacteria growth, (42%) were found
with significant bacterial growth.
The result of bacterial isolates was (81%) of Escherichia coli, (14.3%) of
Enterobacter cloacae and (4.7%) of Klebsiella pneumoniae. The most growth of E.
coli isolates was within 8-10 Gleason score group (56%), this indicates that this
category (Gs 8-10) is a risk factor and an encouragement for the growth of E. coli in
prostate patients. The results of the present study showed that E. coli and Enterococcus
are present in large number relatively in the urine of subjects with prostate cancer.
Increased levels of these two types of bacteria in urine may indicate that a significant
degree of inflammation occurs in those with prostate cancer.
Current study showed that Gleason score (8-10) with 25 patients (50%); and
documented increasing prostate specific antigen in age group (70-79) years. also, the
results revealed there were 17 (34%) patients within the overweight group and severe
Gleason scores (8-10) that may indicate that being overweight is a risk factor for the
severity of prostate cancer. Vitek 2 compact system was used to check for antibiotic
sensitivity among all of the identified isolates. The extracted data show that out of 46
antibiotics tested, E. cloacae isolates (A10: 33, A18 and A39: 11) were resistant to
antibiotics and (A10: 5, A18 and A39: 21) sensitive to antibiotics with different
percentage, K. pneumoniae was resistant to 3 antibiotics and sensitive to 22 antibiotics
and E. coli isolates was resistant to 29 antibiotics, intermediate to 3 antibiotics and
sensitive to 32 antibiotics with different percentage among isolates.
... Risk factors for aggressive PC, as defined by advanced stage and poorer prognosis, often differ from those for earlystage PC in epidemiological studies and this may indicate that indolent and aggressive PC have distinct aetiologies [10][11][12]. To increase knowledge about PC aetiology and improve targeted prevention, it has been recommended to study aggressive PC as a distinct outcome. ...
Background:
The Prostate Cancer Cohort Consortium (PC3) Working Group proposed a definition for aggressive prostate cancer (PC) for aetiologic epidemiologic research. We aimed to validate this definition as well as a second approach utilising only information on stage at diagnosis.
Methods:
First primary PCs diagnosed 2004 - 2009 in the population-based Janus Serum Bank (JSB) cohort were identified by linkage to the population-based Cancer Registry of Norway (CRN) (n = 3568). The CRN and Norwegian Prostate Cancer Registry provided clinicopathological data for these cases. Approach 1 classified PC as aggressive if it was clinically T4, or N1, or M1, or had a Gleason score ≥8 at diagnosis (as proposed). Approach 2 classified PC as aggressive if CRN stage at diagnosis was 'regional spread' or 'distant metastases'. Both approaches were validated by calculating the sensitivity and positive predictive value (PPV) against PC-death within 10 years of diagnosis.
Results:
Overall, 555 died from PC within 10 years. Approach 1 classified 24.7% of cases as aggressive and 13.6% were unclassified due to missing information. Approach 2 classified 19.6% as aggressive and 29% were unclassified. Sensitivity was highest for Approach 1 (0.76, 95% CI: 0.72 - 0.80 vs 0.69, 95% CI: 0.64 - 0.73), while PPVs were similar for both approaches (0.43, 95% CI: 0.40 - 0.46 and 0.40, 95% CI: 0.36 - 0.44). We observed similarly high sensitivity and higher PPVs than those reported by the PC3 Working Group.
Conclusions:
The proposed definition of aggressive PC was applicable and valid in the JSB cohort. Stage at diagnosis can be useful if data on cTNM or Gleason score is unavailable.
... Aggressive prostate cancer cases have increased validity through reduced sensitivity to variations in diagnostic practices (i.e. the prostate-specific antigen test) 18,19 and its definition has been suggested for aetiological studies. 19 The Norwegian Offshore Petroleum Workers (NOPW) cohort contains detailed work histories for over 25 000 male offshore workers employed on the Norwegian continental shelf during 1965-98. ...
Background
Night shift work may acutely disrupt the circadian rhythm, with possible carcinogenic effects. Prostate cancer has few established risk factors though night shift work, a probable human carcinogen, may increase the risk. We aimed to study the association between night shift work and chlorinated degreasing agents (CDAs) as possible endocrine disrupters in relation to aggressive prostate cancer as verified malignancies.
Methods
We conducted a case-cohort study on 299 aggressive prostate cancer cases and 2056 randomly drawn non-cases in the Norwegian Offshore Petroleum Workers cohort (1965–98) with linkage to the Cancer Registry of Norway (1953–2019). Work history was recorded as years with day, night, and rollover (rotating) shift work, and CDA exposure was assessed with expert-made job-exposure matrices. Weighted Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for aggressive prostate cancer, adjusted for education and year of first employment, stratified by 10-year birth cohorts, and with 10, 15, and 20 years of exposure lag periods.
Results
Compared with day work only, an increased hazard of aggressive prostate cancer (HR = 1.86, 95% CI 1.18–2.91; P-trend = 0.046) was found in workers exposed to ≥19.5 years of rollover shift work. This persisted with longer lag periods (HR = 1.90, 95% CI 0.92–3.95; P-trend = 0.007). The exposure-hazard curve for a non-linear model increased linearly (HRs ≥1.00) for 18–26 years of rollover shift work. No association was found with CDA exposure.
Conclusions
Long-term exposure to rollover shift work may increase the hazard of aggressive prostate cancer in offshore petroleum workers.
... Case-Cohort Men who reported sleep problems had lower morning urinary 6-sulfatoxymelatonin (aMT6s) levels; compared to men with morning urinary aMT6s levels above the median, 4-fold increase in risk for advanced PC in men with aMT6s levels below the median (HR: 4.04; 95% CI: 1. 26 Prostate cancer is a leading cause of death in men with a 60% incidence in men over the age of 65 [1]. While confirmed diagnoses are significant, a systematic review reporting on autopsies of 6024 men found undiagnosed prostate cancer in 36% and 51% of Caucasians and African Americans aged 70-79, respectively [16], accentuating the true age-related risk of prostate cancer. In addition to this clear age-related risk is an association between prostate cancer risk and diminished levels of endogenous melatonin [17,18], described further in the next section. ...
Melatonin is an endogenous indoleamine that has been shown to inhibit tumor growth in laboratory models of prostate cancer. Prostate cancer risk has additionally been associated with exogenous factors that interfere with normal pineal secretory activity, including aging, poor sleep, and artificial light at night. Therefore, we aim to expand on the important epidemiological evidence, and to review how melatonin can impede prostate cancer. More specifically, we describe the currently known mechanisms of melatonin-mediated oncostasis in prostate cancer, including those that relate to the indolamine's ability to modulate metabolic activity, cell cycle progression and proliferation, androgen signaling, angiogenesis, metastasis, immunity and oxidative cell status, apoptosis, genomic stability, neuroendocrine differentiation, and the circadian rhythm. The outlined evidence underscores the need for clinical trials to determine the efficacy of supplemental, adjunct, and adjuvant melatonin therapy for the prevention and treatment of prostate cancer.
... Our patient had similar symptoms of difficulty in urination for 1 year, which was serious but not life-threatening in the long term. This was consistent with an autopsy report, which reported that > 33% of men aged 70 to 79 years who died of other causes had PC prior to their death (Jahn et al., 2015). Therefore, we focused on alleviating the patient's symptoms and controlling the disease progression. ...
Prostate cancer (PC) is the most common malignancy of the male genitourinary system. For patients with advanced progressive PC, the treatment strategies include second-line endocrine therapy, chemotherapy, and immunotherapy. Such therapeutic techniques are either too expensive or too toxic for some patients, and traditional Chinese medicine (TCM) has become an alternative for its low cost and low toxicity. The application of Shi-pi-san and Gui-zhi-Fu-ling-wan in PC has never been reported. We report their application on a 71-year-old male patient, who was diagnosed with PC and was undergoing endocrine therapy. He originally chose chemotherapy, and experienced acute renal failure, which required hemodialysis during hospitalization. He felt weak and opted for Chinese herbal medicine treatment. After treatment with Shi-pi-san and Gui-zhi-Fu-ling-wan, the patient's tumor and other symptoms were significantly reduced, and he reported feeling "refreshed." This case indicates that TCM treatment has unique advantages and is more tolerable than endocrine therapy and chemotherapy. Considering that the patient was undergoing hemodialysis treatment and using low-molecular-weight heparin (LMWH) to prevent blood coagulation while taking TCM, whether LMWH has a synergistic anticancer effect remains to be explored.
... CaP, de manera que un tratamiento radical solo se aplique en aquellos pacientes que lo precisen. El CaP es un tumor con una alta prevalencia, como lo muestra la elevada presencia de tumores no diagnosticados en las autopsias, especialmente a partir de los 70 años(33). Su pronóstico es, por tanto, muy heterogéneo, puesto que incluye desde tumores indolentes con una muy baja probabilidad de progresión, que incluso pueden no haber sido diagnosticados en vida del paciente, hasta tumores agresivos que requieren un tratamiento precoz.La disponibilidad de indicadores que permitan clasificar el CaP en función de su riesgo de progresión ha permitido individualizar el tratamiento para cada situación. ...
... Unlike other malignancies, prostate cancer is relatively unique because its natural progression is more protracted [6]. It is relatively prevalent, with up to 50% of the male population in the 70-79 years age group likely having histologically abnormal/cancerous but previously undiagnosed prostate cancer diagnosed by autopsy [7]. ...
Cryotherapy is one of the recognised ablative modalities for both primary and salvage therapy for prostate cancer. It presents an alternative, less invasive treatment for an organ-confined disease, improved preservation of surrounding tissue and a more suitable option for patients who are unfit for radical prostatectomy. Nevertheless, the currently available literature is relatively too scarce to provide definite conclusions regarding the treatment outcomes in cryotherapy. The present study aimed to review current oncological and survival outcomes in cryotherapy for primary and recurrent prostate cancer. Furthermore, this study aimed to establish the complications and functional outcomes of cryotherapy for prostate cancer. A literature search was performed on the PubMed, Cochrane and Google Scholar databases. Current guidelines and recommendations from the European Association of Urology were also reviewed. The search keywords used included 'Cryotherapy, Prostate Cancer', 'Cryoablation, Prostate Cancer' and 'Cryosurgery, Focal Prostate Cancer'. Truncations and Boolean operators were used with the keywords. All relevant studies from after 2015, including abstracts and non-English research assessing oncological and functional outcomes and complications, were included. Twenty-six studies consisting of 11,228 patients were reviewed. Fifteen studies assessed the outcomes of primary cryotherapy, whereas 11 studies reported the outcomes in salvage therapy. The patient's age ranged 55-85 years, and the pre-procedural prostate-specific antigen (PSA) ranged 0.01-49.33 ng/mL. A total of 2031 patients were classified to be at low risk, 2,995 were at moderate risk and 253 were at high risk on the D'Amico prostate cancer risk classification system. Follow-ups ranged from 9.0 to 297.6 months. The disease-specific survival rate was 65.5%-100.0%, overall survival was 61.3%-99.1%, the PSA nadir was 0.01-2.63 ng/mL and the overall biochemical recurrence rate was 15.4%-62.0%. The complications included erectile dysfunction (3.7%-88.0%), urinary retention (2.13%-25.30%) and bladder neck stricture/stenosis (3.0%-16.7%). The functional assessment showed a mixture of improved, unchanged or worsened post-procedural outcomes in primary therapy. This systematic review did not find significant differences in the cancer-specific, overall and biochemical-free survival rate between the primary and salvage cryotherapy cohorts. The most common complications encountered in both cohorts were erectile dysfunction, urinary incontinence, lower urinary tract/bladder neck stricture and infection. More prospective and double-arm studies are critically needed to provide guidance on the careful selection of patient cohorts for cryotherapy, whether for curative or salvage intent.
... • Invasive sampling procedure that is only indicated in certain settings. Serum prostate-specific antigen (PSA) is routinely used for both screening and disease monitoring in men with suspected or known prostate cancer; however, this biomarker comes with a high risk of overdiagnosis, especially when used in isolation, and ucfDNA might provide a more accurate alternative 60 . A real-time PCR-based assay designed to detect >250 bp fragments of the genes encoding MYC, HER2 and AR showed promising levels of sensitivity (0.79) and specificity (0.84) in a pilot study comparing ucfDNA from 29 patients with prostate cancer with that obtained from 25 volunteers without cancer; however, the diagnostic performance of this assay was lower than that of serum PSA when tested in a larger cohort that included patients with benign urogenital conditions 33,61 . ...
Over the past decade, various liquid biopsy techniques have emerged as viable alternatives to the analysis of traditional tissue biopsy samples. Such surrogate 'biopsies' offer numerous advantages, including the relative ease of obtaining serial samples and overcoming the issues of interpreting one or more small tissue samples that might not reflect the entire tumour burden. To date, the majority of research in the area of liquid biopsies has focused on blood-based biomarkers, predominantly using plasma-derived circulating tumour DNA (ctDNA). However, ctDNA can also be obtained from various non-blood sources and these might offer unique advantages over plasma ctDNA. In this Review, we discuss advances in the analysis of ctDNA from non-blood sources, focusing on urine, cerebrospinal fluid, and pleural or peritoneal fluid, but also consider other sources of ctDNA. We discuss how these alternative sources can have a distinct yet complementary role to that of blood ctDNA analysis and consider various technical aspects of non-blood ctDNA assay development. We also reflect on the settings in which non-blood ctDNA can offer distinct advantages over plasma ctDNA and explore some of the challenges associated with translating these alternative assays from academia into clinical use.
... Prostate cancer is a heterogeneous disease, so to anticipate the behavior of cancer, evaluating risk factors is very important [41]. Epidemiological studies have consistently emphasized the notion that naturally-occurring dietary agents possess chemopreventive properties and could easily suppress several malignancies, including that of the prostate [15]. ...
Prostate cancer is a heterogeneous disease, the second deadliest malignancy in men and the most commonly diagnosed cancer among men. Traditional plants have been applied to handle various diseases and to develop new drugs. Medicinal plants are potential sources of natural bioactive compounds that include alkaloids, phenolic compounds, terpenes, and steroids. Many of these naturally-occurring bioactive constituents possess promising chemopreventive properties. In this sense, the aim of the present review is to provide a detailed overview of the role of plant-derived phytochemicals in prostate cancers, including the contribution of plant extracts and its corresponding isolated compounds.
... Prostatic adenocarcinoma is the second-most common cancer in men and the fifth most common cause of cancer death [1]. Its incidence increases with age; 75% of patients are 65 years and older [2]. Environmental and hereditary features play a part in the pathogenesis; males associated with 1 st -degree families have 10 times higher risk [3]. ...
Prostatic adenocarcinoma is the second-most common cancer in men and the fifth most common cause of cancer death. Its incidence increases with age; 75% of patients are 65 years and older. The aim of the study was to assess epithelial membrane antigen (EMA) expression in prostatic adenocarcinoma as a poor prognostic marker and its correlation to some pathological parameters. The formalin-fixed, paraffin-surrounded tissue blocks were retrospectively collected from 40 men diagnosed with prostate carcinoma. All cases were collected from Al Hilla Teaching Hospital and some private labs between October 2018 - November 2020, with ages ranging from 30-89 years. Statistical analysis was done using SPSS 22, frequency and percentage were used for categorical data, and Chi-square was used to evaluate connotation between variables. P-value ≤0.05 was significant. The blocks were sectioned for EMA immunohistochemical staining using monoclonal mouse anti-human EMA protein. EMA protein overexpression was detected in 75% (n=30/40) of prostatic adenocarcinoma cases. EMA expression showed no correlation with the patient's age (P=0.09) and a positive correlation with the cancer grade (P=0.003). In prostatic adenocarcinoma patients, EMA could be seen as a potential prognostic predictor for disease progression.
... While conclusive etiological hints linking prostate cancer progression to occurrence have been difficult to establish, numerous studies have connected the disease to common risk factors, such as ethnicity, age, diet, and physical activity [218]. Since prostate cancer is such a diverse condition, it's important to assess risk factors to predict how it will behave [219,220]. Natural-occurring food agents have long been thought to have chemopreventive effects and could effectively inhibit a variety of cancers, including prostate cancer, according to epidemiological research [221]. However, there has been some discrepancy in the recommendations for a diet that is plant-based, phytochemicals, associated minerals,and prostate health. ...
Background:Cancer-induced mortality is increasingly prevalent globally which skyrocketed the necessity to discover new/novel safe and effective anticancer drugs. Cancer is characterized by the continuous multiplication of cells in the human which is unable to control. Scientific research is drawing its attention towards naturally-derived bioactive compounds as they have fewer side effects compared to the current synthetic drugs used for chemotherapy.
Objective:Drugs isolated from natural sources and their role in the manipulation of epigenetic markers in cancer are discussed briefly in this review article.
Methods:With advancing medicinal plant biotechnology and microbiology in the past century, several anticancer phytomedicines were developed. Modern pharmacopeia contains at least 25% herbal-based remedy including clinically used anticancer drugs. These drugs mainly include the podophyllotoxin derivatives vinca alkaloids, curcumin, mistletoe plant extracts, taxanes, camptothecin, combretastatin, and others including colchicine, artesunate, homoharringtonine, ellipticine, roscovitine, maytanasin, tapsigargin,andbruceantin.
Results:Compounds (psammaplin, didemnin, dolastin, ecteinascidin,and halichondrin) isolated from marine sources and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates. They have been evaluated for their anticancer activity on cells and experimental animal models and used chemotherapy.Drug induced manipulation of epigenetic markers plays an important role in the treatment of cancer.
Conclusion:The development of a new drug from isolated bioactive compounds of plant sources has been a feasible way to lower the toxicity and increase their effectiveness against cancer. Potential anticancer therapeutic leads obtained from various ethnomedicinal plants, foods, marine, and microorganisms are showing effective yet realistically safe pharmacological activity. This review will highlight important plant-based bioactive compounds like curcumin, stilbenes, terpenes, other polyphenolic phyto-compounds, and structurally related families that are used to prevent/ ameliorate cancer. However, a contribution from all possible fields of science is still a prerequisite for discovering safe and effective anticancer drugs.
Keywords: Bioactive, cancer, chemotherapy, neoplasm, vincristine, curcumin
Background:
Previously suggested modifiable risk factors for prostate cancer could have resulted from detection bias because diagnosis requires a biopsy. We investigated modifiable risk factors for a subsequent cancer diagnosis among men with an initially negative prostate biopsy.
Methods:
In total, 10,396 participants of the Health Professionals Follow-up Study with an initial negative prostate biopsy after 1994 were followed for incident prostate cancer until 2017. Potential risk factors were based on previous studies in the general population. Outcomes included localised, advanced, and lethal prostate cancer.
Results:
With 1851 prostate cancer cases (168 lethal) diagnosed over 23 years of follow-up, the 20-year risk of any prostate cancer diagnosis was 18.5% (95% CI: 17.7-19.3). Higher BMI and lower alcohol intake tended to be associated with lower rates of localised disease. Coffee, lycopene intake and statin use tended to be associated with lower rates of lethal prostate cancer. Results for other risk factors were less precise but compatible with and of similar direction as for men in the overall cohort.
Conclusions:
Risk factors for future prostate cancer among men with a negative biopsy were generally consistent with those for the general population, supporting their validity given reduced detection bias, and could be actionable, if confirmed.
Understanding prostate carcinogenesis is crucial not only for identifying new treatment targets but also for developing effective strategies to manage the asymptomatic form of the disease. There is a lack of consensus about predicting the indolent form of the disease prostate cancer, leading to uncertainties regarding treatment initiation. This review aims to enhance the assessment and management of early prostate cancer by providing a comprehensive picture of the molecular anatomy of the prostate, synthesising current evidence, highlighting knowledge gaps, and identifying future directions. It presents evidence for the efficacy of active surveillance as an alternative treatment strategy and its potential benefits in specific patient groups through androgen receptor disruption. Overall, an improved understanding of prostate carcinogenesis and its molecular underpinnings can pave the way for tailored and precise management approaches for this common cancer. Further development and validation of molecule-based assessment tools are needed. Integrating genomic, proteomic, and phenotypic models, as well as functional approaches, can help predict outcomes. This facilitates selecting candidates for active surveillance and targeting interventions for higher-risk cases, contributing to more precise management strategies.
Globally, prostate cancer (PCa) is regarded as a challenging health issue, and the number of PCa patients continues to rise despite the availability of effective treatments in recent decades. The current therapy with chemotherapeutic drugs has been largely ineffective due to multidrug resistance and the conventional treatment has restricted drug accessibility to malignant tissues, necessitating a higher dosage resulting in increased cytotoxicity. Plant‐derived bioactive compounds have recently attracted a great deal of attention in the field of PCa treatment due to their potent effects on several molecular targets and synergistic effects with anti‐PCa drugs. This review emphasizes the molecular mechanism of phytochemicals on PCa cells, the synergistic effects of compound‐drug interactions, and stem cell targeting for PCa treatment. Some potential compounds, such as curcumin, phenethyl‐isothiocyanate, fisetin, baicalein, berberine, lutein, and many others, exert an anti‐PCa effect via inhibiting proliferation, metastasis, cell cycle progression, and normal apoptosis pathways. In addition, multiple studies have demonstrated that the isolated natural compounds: d‐limonene, paeonol, lanreotide, artesunate, and bicalutamide have potential synergistic effects. Further, a significant number of natural compounds effectively target PCa stem cells. However, further high‐quality studies are needed to firmly establish the clinical efficacy of these phytochemicals against PCa.
Background
Prostate cancer (PC) is the most diagnosed cancer in African American men (AAM), yet PC screening regimens in this group are poorly guided by existing evidence, given underrepresentation of AAM in prostate cancer screening trials. It is critical to optimize PC screening and early detection in this high-risk group since underdiagnosis may lead to later stage cancers at diagnosis and higher mortality while overdiagnosis may lead to unnecessary treatment.
Methods
We performed a review of the literature related to PC screening and early detection specific to AAM to summarize the existing evidence available to guide healthcare practice.
Results
Limited evidence from observational and modeling studies suggests that AAM should be screened for PC. Consideration should be given to initiating screening AAM at younger ages (eg, 45-50 years) and at more frequent intervals relative to other racial groups in the U.S. Screening intervals may be optimized through use of a baseline PSA measurement in midlife. Lastly, no evidence indicated that AAM would benefit from screening beyond age 75 years, and AAM may experience higher rates of overdiagnosis at older ages.
Conclusions
The evidence base for PC screening in AAM is limited by the lack of large, randomized studies. Our literature search supported the need for AAM to be screened for PC, for initiating screening at younger ages (45-50 years) and perhaps at more frequent intervals among AAM relative to men of other racial groups in the U.S.
Background:
Circadian disruption is a potential risk factor for advanced prostate cancer, and light at night (LAN) exposure may disrupt circadian rhythms. We evaluated whether outdoor LAN increases the risk of prostate cancer.
Methods:
We prospectively followed 49,148 participants in the Health Professionals Follow-up Study from 1986 through 2016. We estimated baseline and cumulative time-varying outdoor LAN with ~1 km2 resolution using data from the US Defense Meteorological Satellite Program's Operational Linescan System, which was assigned to participants' geocoded addresses. Participants reside in all 50 US states and reported a work or home address. We used multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between outdoor LAN and risk of overall (7,175 cases) and fatal (915 cases) prostate cancer adjusting for individual and contextual factors.
Results:
There was no association between the interquartile range increase in cumulative LAN and total (HR:1.02, 95% CI 0.98, 1.06) or fatal (HR: 1.05, 95% CI: 0.96, 1.15) prostate cancer in adjusted models. However, there was a positive association between baseline LAN and total prostate cancer among non-movers (HR: 1.06, 95% CI:1.00,1.14) including among highly screened participants (HR: 1.11, 95% CI:1.01,1.23).
Conclusions:
There was a suggestive positive association between baseline outdoor LAN and total prostate cancer. Additional studies with different measures of outdoor LAN and in more diverse populations are necessary.
Impact:
To our knowledge, this is the first longitudinal cohort study exploring the relationship between outdoor LAN and prostate cancer.
Objective:
To review biochemical parameters, clinical characteristics, demographics, radiological and histopathological findings, treatment modalities and outcomes used to examine patients with coexisting multiple myeloma and prostate adencocarcinoma.
Methods:
The systematic review comprised search on PubMed, Google Scholar, Science Direct and the Directory of Open Access Journal databases for case reports published till June 1, 2022. The search was done in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using appropriate key words. Case reports included were those dealing exclusively with human subjects, were published in the English language and had free, full-text, public access. Quality assessment was done using Joanna Briggs Institute's Critical Appraisal Checklist for Case Reports. Data was extracted and the case reports were evaluated for demographic, diagnostic and treatment parameters.
Results:
Of the 515 studies initially identified, 5(0.97%) were analysed; all males with mean age 68.6±10.78 years. The most common symptom reported at presentation was low back pain 3(60%), Osteolytic lesions were seen in 4(80%) patients on imaging with elevated prostate surface antigen levels. Anaemia was found in 3(60%) patients and 2(40%) had thrombocytopenia.
Conclusion:
Multiple myeloma and prostate adenocarcinoma can coexist although it is rare. Awareness regarding the possible coexistence of the two prominent cancer types may further help clinicians during their practice in considering multiple myeloma as a differential diagnosis when encountered with patients having osteolytic bony lesions along with elevated levels of prostate-specific antigen.
Prospero registration number:
CRD42022334906.
Increased androgen receptor (AR) signaling brought on by higher intratumoral androgen production and AR amplification is associated with castrate-resistant prostate cancer (CRPC). Cell proliferation in this case continues even during low expression of testosterone in the body. Aldo-keto reductase family 1 member C3 (AKR1C3) is one of the most elevated genes in CRPC and catalyzes the formation of powerful AR ligands from inactive forms. The current work aimed to use the x-ray method to investigate the ligand's crystal structure while also conducting molecular docking and molecular dynamics tests on the synthesized molecules against AKR1C3. As per the results obtained, the MM-PBSA binding energies of inhibitors 2,2'-((4-methoxyphenyl)methylene)bis(3,4-hydroxy-5,5-dimethylcyclohex-2-en-1-one is -132.456 kJ mol-1 and 2,2'-(phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-en-1-one is -81.017 kJ mol-1 . These results create a promising approach to drug design based on its fit to the structures of the receptor site rather than basing it on analogies to other active structures.
Prostate cancer is the most common cancer among men in Montana and the second-most-common cause of cancer deaths. In 2014, prostate cancer incidence in Montana started increasing significantly, even as incidence in the United States overall stayed about the same. The increased incidence was not accompanied by an increase in prostate cancer mortality. Trends in local stage incidence and incidence among men aged 65 to 79 years mirrored the trends in overall prostate cancer incidence and suggest that changes are due to screening behavior. However, it is difficult to determine what may have caused increased screening among Montana men since 2014. Monitoring prostate cancer incidence and mortality is an important tool in determining if there is a change in prostate cancer disease burden or in overdiagnosis, and informs planning for possible public health intervention.
Despite the innovations made to enhance smarter screening and conservative management for low-grade prostate cancer, overdiagnosis, and overtreatment remains a major health care problem. Driven by the primary goal of reducing harm to the patients, relabeling of nonlethal grade group 1 (GG 1) prostate cancer has been proposed but faced varying degrees of support and objection from clinicians and pathologists. GG 1 tumor exhibits histologic (invasive) and molecular features of cancer but paradoxically, if pure, is unable to metastasize, rarely extends out of the prostate, and if resected, has a cancer-specific survival approaching 100%. Most of the arguments against relabeling GG 1 relate to concerns of missing a higher-grade component through the unsampled area at biopsy. However, the designation of tumor benignity or malignancy should not be based on the shortcomings of a diagnostic procedure and sampling errors. This review explores possible solutions, mainly the feasibility of renaming GG 1 in radical prostatectomy (RP) with ramifications in biopsy diagnosis, acceptable for both pathologists and clinicians. One workable approach is to rename GG 1 in RP with a cautious neutral or nonbenign non-cancer term (eg, acinar neoplasm) using "defined criteria" that will stop the indiscriminate reporting of every GG 1 in biopsy as carcinoma including eventual insignificant microtumors in RPs. Use of a corresponding noncommittal term at biopsy while commenting on the possibility of an undersampled nonindolent cancer, might reduce the pathologist's concerns about upgrading. Dropping the word "carcinoma" in biopsy preempts the negative consequences of labeling the patient with cancer, including unnecessary definitive therapy (the root cause of overtreatment). Renaming should retain the status quo of contemporary grading and risk stratifications for management algorithms while trying to minimize overtreatment. However, the optimal approach to find answers to this issue is through multidisciplinary discussions of key stakeholders with a specific focus on patient-centered concerns and their ramifications in our practices. GG 1 renaming has been brought up in the past and came up again despite the continued counterarguments, and if not addressed more comprehensively will likely continue to reemerge as overdiagnosis, overtreatment, and patient's sufferings persist.
Purpose of the study . Evaluation of the diagnostic characteristics of the CA‑62 marker for epithelial carcinomas for detecting early‑stage prostate cancer in a double‑blind clinical study. This study is also focused on the possibility of using the CA‑62 antigen as an auxiliary tool for decision‑making in prostate cancer diagnosis.
Patients and methods . A blinded clinical study was conducted on 325 clinically verified blood serum samples. This includes 144 prostate cancer samples, 79 generally healthy volunteers‑men and 102 samples from patients with benign prostatic hyperplasia (BPH). Quantitative determination of the total and free prostate specific antigen (PSA) levels, as well as the CA‑62 marker of serum samples was performed using the electrochemiluminescent immunoassay ECLIA Elecsys Total and Free PSA (COBAS, Roche Diagnostics GmbH, Germany, EU) and the chemiluminescent immunoassay CLIA‑CA‑62 (JVS Diagnostics LLC, Moscow, RF).
Results . A comparison of the CA‑62 level with the results for total and free PSA, as well as other diagnostic methods (PCA3, PHI) for the analysis of the BPH and prostate cancer groups was performed. The results show that the CA‑62 marker has the highest PPV (94.4 %) and NPV (93.1 %). This may increase the reliability of the decision related to the presence of PC and be used by doctors as an argument as an argument for a prostate biopsy referral. It has been demonstrated that using the novel cancer marker CA‑62 makes it possible to detect up to 90 % of the early‑stage prostate cancer with 97.2 % specificity (AUC = 0.969).
Conclusion . Using the CA‑62 marker as an auxiliary diagnostic method within the PSA “grey zone” (from 2.5 to 10 ng/ml) made it possible to significantly increase the accuracy of detecting the PC early stages at biopsy up to 93.1 %. It will help the doctors to effectively differentiate between prostate cancer and benign prostatic hyperplasia.
Importance:
Active surveillance (AS) is endorsed by clinical guidelines as the preferred management strategy for low-risk prostate cancer, but its use in contemporary clinical practice remains incompletely defined.
Objective:
To characterize trends over time and practice- and practitioner-level variation in the use of AS in a large, national disease registry.
Design, setting, and participants:
This retrospective analysis of a prospective cohort study included men with low-risk prostate cancer, defined as prostate-specific antigen (PSA) less than 10 ng/mL, Gleason grade group 1, and clinical stage T1c or T2a, newly diagnosed between January 1, 2014, and June 1, 2021. Patients were identified in the American Urological Association (AUA) Quality (AQUA) Registry, a large quality reporting registry including data from 1945 urology practitioners at 349 practices across 48 US states and territories, comprising more than 8.5 million unique patients. Data are collected automatically from electronic health record systems at participating practices.
Exposures:
Exposures of interest included patient age, race, and PSA level, as well as urology practice and individual urology practitioners.
Main outcomes and measures:
The outcome of interest was the use of AS as primary treatment. Treatment was determined through analysis of electronic health record structured and unstructured clinical data and determination of surveillance based on follow-up testing with at least 1 PSA level remaining greater than 1.0 ng/mL.
Results:
A total of 20 809 patients in AQUA were diagnosed with low-risk prostate cancer and had known primary treatment. The median age was 65 (IQR, 59-70) years; 31 (0.1%) were American Indian or Alaska Native; 148 (0.7%) were Asian or Pacific Islander; 1855 (8.9%) were Black; 8351 (40.1%) were White; 169 (0.8%) were of other race or ethnicity; and 10 255 (49.3%) were missing information on race or ethnicity. Rates of AS increased sharply and consistently from 26.5% in 2014 to 59.6% in 2021. However, use of AS varied from 4.0% to 78.0% at the urology practice level and from 0% to 100% at the practitioner level. On multivariable analysis, year of diagnosis was the variable most strongly associated with AS; age, race, and PSA value at diagnosis were all also associated with odds of surveillance.
Conclusions and relevance:
This cohort study of AS rates in the AQUA Registry found that national, community-based rates of AS have increased but remain suboptimal, and wide variation persists across practices and practitioners. Continued progress on this critical quality indicator is essential to minimize overtreatment of low-risk prostate cancer and by extension to improve the benefit-to-harm ratio of national prostate cancer early detection efforts.
Introdução: O câncer de próstata é o segundo mais comum entre os homens (atrás apenas do câncer de pele não-melanoma), sendo a obesidade um importante fator de risco de câncer de próstata. Espera-se que até 2025, cerca de 167 milhões estejam com sobrepeso ou obesidade. Objetivo: avaliar o impacto da obesidade sobre o risco do desenvolvimento de câncer de próstata. Métodos: Trata-se de revisão de literatura integrativa, que utilizou buscas nas bases de dados e indexadores como: Scientific Electronic Library Online (SciELO), PUBMED e Biblioteca Virtual em Saúde (BVS) publicados no período correspondente de 2010 a 2021. publicados em inglês e português, sob os seguintes descritores: " obesidade" e " Câncer de próstata" . Resultados e Discussão: Os valores de Índice de Massa Corporal (IMC) quando em níveis de sobrepeso e obesidade tem demonstrado influenciar na carcinogênese, mas ainda com resultados conflitantes, enquanto que a circunferência da cintura, parece ter uma forte relação no risco para desenvolver da patologia. Conclusão: A obesidade tem demonstrado exercer um papel carcinogênese do câncer de próstata, mas que pode ser desencadeado por vários fatores inerentes a obesidade, sendo o profissional da nutrição uma peça fundamental para minimizar esse impacto.
There is no doubt that prostate cancer is a disease. Then, according to hyperfunction theory, menopause is also a disease. Like all age-related diseases, it is a natural process, but is also purely harmful, aimless and unintended by nature. But exactly because these diseases (menopause, prostate enlargement, obesity, atherosclerosis, hypertension, diabetes, presbyopia and thousands of others) are partially quasi-programmed, they can be delayed by slowing aging. Is aging a disease? Aging is a quasi-programmed disease that is partially treatable by rapamycin. On the other hand, aging is an abstraction, a sum of all quasi-programmed diseases and processes. In analogy, the zoo consists of animals and does not exist without animals, but the zoo is not an animal.
Prostate cancer, with its remarkably high prevalence, frequently creates clinical problems in terms of screening and diagnosis, as well as identifying the optimal window for treatment. Moreover, the prostate-specific antigen (PSA) blood test, despite being easy to perform, is routinely carried out without the patient’s informed consent. Although PSA-based screening for prostate cancer can reduce cancer-specific mortality, informed decision-making is mandatory; however, the clinician’s daily routine often neglects this critical discussion before performing a PSA blood test. This narrative review discusses the main questions regarding PSA screening and provides information on the epidemiological, clinical, and pathological aspects of prostate cancer.
Background:
In China, the incidence and mortality of prostate cancer are increasing. In this study, we analyzed the spatial-temporal distribution characteristics of prostate cancer incidence and mortality in China and explored the potential associations of socioeconomic, ecological, and meteorological conditions.
Methods:
Spatial-temporal scan statistics were used to analyze the spatial-temporal patterns of prostate cancer in China from 2012 to 2016. Spatial regression models and the Geodetector method were used to explore the potential associations of anthropogenic and natural factors with prostate cancer.
Results:
The incidence and mortality of prostate cancer in China from 2012 to 2016 rapidly increased. The high incidence and mortality clusters were concentrated in the economically developed Yangtze River Delta region along the southeast coast. Among the 14 selected environmental factors, gross domestic product (GDP) per capita, population density, comprehensive index of environmental pollution discharge, accessibility of health care resources, urbanization rate, and nitrogen dioxide (NO2) had significant positive correlations with prostate cancer incidence and mortality. GDP per capita, urbanization rate, and population density had high explanatory power.
Conclusion:
The high-concentration areas for prostate cancer are located in more economically developed cities. The index of environmental pollution discharge, NO2, and prostate cancer incidence and mortality were positively correlated. The government should advocate increasing the use of clean energy while strengthening the regulation of industrial production to reduce pollutant emissions.
Impact:
To inform the development of prevention and control strategies for prostate cancer in China.
Introduction:
Elderly men are underrepresented in prostate cancer (PCa) literature, with management based on individualized care pathways and life expectancy. Reports have shown survival benefit with radiation (XRT), surgery, and hormone (ADT) in localized disease. The objective of this study was to assess treatment trends and overall survival (OS) among men 75 years of age and older with cT1c PCa.
Methods:
The National Cancer Database was queried to identify patients with cT1c PCa, aged 75 years and older, between 2004 and 2016. We excluded individuals with N1/NX or M1/MX disease, unknown treatment, treatment with both XRT and surgery, surgery other than radical prostatectomy (RP), or PSA > 10 ng/ml. We described 4 treatment cohorts: observation, XRT, surgery, and ADT alone. Treatment trends and OS were analyzed using SPSS.
Results:
Among 49,843 patients, 7% had surgery, 66% had XRT, 5% had ADT alone, and 22% were observed. From 2004-2016, a large decline in XRT was noted, with an increase in surgery and observation. Men receiving ADT alone were significantly older, with higher Gleason's score, and lower incomes. Cox regression revealed survival benefit for surgery and XRT (HR 0.44 and 0.69, P < .001 respectively); ADT had worse survival than observation (HR 1.23, P < .001).
Conclusion:
Fewer men 75 years of age and older with cT1c PCa are being diagnosed and treated. Rates of XRT have declined, with rises in surgery and observation. Survival benefit was seen for surgery and XRT among elderly men, which highlights the importance of proper patient selection for improved outcomes in a highly individualized sphere.
Purpose
Despite the high incidence of false positives, prostate specific antigen (PSA) screening remains a widely used diagnostic test for prostate cancer, driving an urgent need for the discovery of better biomarkers for early prostate cancer detection. Extracellular vesicles (EV) secreted from cancer cells are present in various biological fluids, carrying distinctly different cellular components compared to normal cells, and have great potential to be used as a source of biomarkers.
Methods
EV from serum and urine of healthy men and prostate cancer patients were isolated, and characterised by transmission electron microscopy, particle size analysis, and western blot. Proteomic and cholesterol liquid chromatography-mass spectrometry (LC-MS) analyses were conducted.
Results
There was a successful enrichment of exosomes isolated from serum and urine. EV derived from biological fluids of prostate cancer patients had significant differences in composition when compared with those from healthy controls. Analysis of matched serum and urine samples from six prostate cancer patients revealed specific EV proteins common in both types of biological fluid for each patient.
Conclusion
Some of the EV proteins identified from our analyses have potential to be used as prostate cancer biomarkers, either to depict cancer progression or for disease diagnosis through non-invasive testing.
Medicine fails to find predictable cures for cancer in more than a century, and we explored the feasibility of controlling cancer growth speed by using lifestyle factors. After conducting an extensive literature review, we conducted simulations for cancer growth courses to see the feasibility of controlling cancer growth speeds. We found that (1) medical treatments are often accompanied by three to four lethal factors: treatment side-effects, emotional distress, and chronic stress, reduced exercises and physical inactivity, and excessive nutrition in some cases; (2) clinical trial exaggerates treatments short-term benefits and underestimates the slow-delivering adverse side effects as a result of statistical averaging, interfering effects of personal lifestyle factors and insufficient follow-up times; (3) the benefits of medical treatments are limited by chain comparisons, where surgery may work as a negative standard relative to the best alternatives for resolving cancer; (4) the strategy of destroying the tumor or killing all cancer cells is unworkable; (5) medical treatments can turn natural cancer growth curve into approximately doubly exponential curve; (6) multiple-factor non-medical measures are potentially much more powerful than medical treatments in controlling cancer growth and metastasis speeds; and (7) cancer early diagnosis and over treatments are unwise strategies in light of discoveries. Based on huge increases in cancer growth rate constants, substantial loss of vital organ functional capacity, and severe systemic aging-like cellular damages, we concluded that medical treatments may promote cancer growth and metastasis speeds and shorten patient lives in most situations, and the claimed benefits are caused by triple biases of clinical trials. By using the same method to explore how several lifestyle factors affect cancer growth rates, we concluded that the better strategy for ending the global cancer epidemic in the future is changing caner treatment strategy from killing cancer cells to slowing down cancer growth rates by using various lifestyle factors in combination. This study in part explains why cancer can self-resolve.
Drug industry, controlling medical publishers and large media promote flawed medicine for their revenues by systematically laundering medical knowledge in decades. They maintain and promote flawed research models and suppress disruptive discoveries, thereby precluding reform of medicine. In this study, I will deeply explore how the wrong life model, population-based research model, misused clinical trials, flawed statistical models, the symptom-based research methods, binary disease classification, failure to address the massive vital organ capacities, failure to correct biased caused by expected delay in realizing side effects, and failure to address the interference effects of non-controllable factors affect the conclusions of “effectiveness and safety” for mRNA vaccines. I will directly analyze three studies that have been relied upon by FDA in approving mNRA use authorizations: one BNT162b2 effectiveness study published in NEJM, one booster shot study published in NEJM and a Seven Integrated Health Care Organizations study published by CDC. I will expose fatal flaws in the frequency risk concept, effectiveness rate, and hazard reduction ratios, and show why 3% death rate, 95% effectiveness rate and 90% mortality reduction are all meaningless and misleading, and should never have been used as treatment guidance. I will also examine common biases that can be easily practiced by sponsors’ researchers to alter conclusions in favor of approval. By relying on laundered medical “knowledge”, FDA has consistently failed to predict latent drug side effects for any drugs and vaccines in its history. FDA approved disastrous DES in 1941, Swine Flu vaccine in 1976, and mRNA vaccines in 2020. The vaccines are used to deliver short-term benefits on a small percent of persons at the costs of damaging health, causing deaths that would be avoided, and shortening lifespans for all people in the population. I thus urge FDA to reevaluate all mRNA vaccines and revoke their use authorizations.
The role of lycopene in prostate cancer prevention remains controversial. We examined the associations between dietary lycopene intake and prostate cancer, paying particular attention to the influence of prostate-specific antigen screening, and evaluated tissue biomarkers in prostate cancers in relation to lycopene intake.
Among 49898 male health professionals, we obtained dietary information through questionnaires and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Cox regression was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Tissue microarrays and immunohistochemistry were used to assess tumor biomarker expression in a subset of men. Two-sided χ(2) tests were used to calculate the P values.
Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: HR = 0.72; 95% CI = 0.56 to 0.94; P trend = .04). In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; P trend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential.
Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor. Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening.
Background:
The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized screening trial demonstrated no mortality effect of screening. Here we analyze prostate cancer specific survival in PLCO and its relation to screening.
Methods:
76,693 men aged 55-74 were randomized to usual care (n = 38,350) or intervention (n = 38,343). Intervention arm men received annual prostate-specific antigen (6 years) and digital rectal exam (4 years). Men were followed for cancer diagnosis and mortality through 13 years. Medical record abstractors confirmed prostate cancer diagnoses, stage and grade. Prostate-specific survival in PLCO cases was analyzed using Kaplan-Meier analysis and proportional hazards modeling. We utilized data from the Surveillance, Epidemiology and End Results (SEER) program to compute expected survival in PLCO and compared this to observed.
Results:
There was no significant difference in prostate-specific survival rates between arms; 10 year survival rates were 94.7% (intervention, n = 4250 cases) versus 93.5% (usual care, n = 3815 cases). Within the intervention arm, cases never screened in PLCO had lower 10 year survival rates (82%) than screen detected or interval (following a negative screen) cases, both around 95.5%. The ratio of observed to expected 10 year prostate-specific death (1-survival) rates was 0.59 (95% CI: 0.51-0.68) for all PLCO cases, 0.66 (95% CI: 0.51-0.81) for Gleason 5-7 cases and 1.07 (95% CI: 0.87-1.3) for Gleason 8-10 cases.
Conclusion:
Prostate cancer specific survival in PLCO was comparable across arms and significantly better than expected based on nationwide population data. How much of the better survival is due to a healthy volunteer effect and to lead-time and overdiagnosis biases is not readily determinable.
Substantial geographical differences in prostate cancer (PCa) incidence and mortality exist, being lower among Asian (ASI) men compared with Caucasian (CAU) men. We prospectively compared PCa prevalence in CAU and ASI men from specific populations with low penetrance of prostate-specific antigen screening.
Prostate glands were prospectively obtained during autopsy from men who died from causes other than PCa in Moscow, Russia (CAU), and Tokyo, Japan (ASI). Prostates were removed en-block and analyzed in toto. We compared across the 2 populations PCa prevalence, number and Gleason score (GS) of tumour foci, pathological stage, spatial location, and tumor volume using χ(2), Mann-Whitney-Wilcoxon tests, and multiple logistic regression. All statistical tests were two-sided.
Three hundred twenty prostates were collected, 220 from CAU men and 100 from ASI mean. The mean age was 62.5 in CAU men and 68.5 years in ASI men (P < .001). PCa prevalences of 37.3% in CAU men and 35.0% in ASI men were observed (P = .70). Average tumor volume was 0.303cm(3). In men aged greater than 60 years, PCa was observed in more than 40% of prostates, reaching nearly 60% in men aged greater than 80 years. GS 7 or greater cancers accounted for 23.1% and 51.4% of all PCa in CAU and ASI men, respectively, (P = .003). When adjusted for age and prostate weight, ASI men still had a greater probability of having GS 7 or greater PCa (P = .03).
PCa is found on autopsy in a similar proportion of Russian and Japanese men. More than 50% of cancers in ASI and nearly 25% of cancers in CAU men have a GS of 7 or greater. Our results suggest that the definition of clinically insignificant PCa might be worth re-examining.
Studies of dietary ω-3 fatty acid intake and prostate cancer risk are inconsistent; however, recent large prospective studies have found increased risk of prostate cancer among men with high blood concentrations of long-chain ω-3 polyunsaturated fatty acids ([LCω-3PUFA] 20:5ω3; 22:5ω3; 22:6ω3]. This case-cohort study examines associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial.
Case subjects were 834 men diagnosed with prostate cancer, of which 156 had high-grade cancer. The subcohort consisted of 1393 men selected randomly at baseline and from within strata frequency matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. All statistical tests were two-sided.
Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response.
This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.
Objective. To examine prostate cancer trends by demographic and tumor characteristics because a comprehensive examination of recent prostate cancer incidence rates is lacking. Patients and Methods. We described prostate cancer incidence rates and trends using the 2001-2007 National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program data (representing over 93% of US population). Because of coding changes in cancer grade, we restricted analysis to 2004-2007. We conducted descriptive and trend analyses using SEER∗Stat. Results. The overall prostate cancer incidence rate was stable from 2001 to 2007; however, rates significantly increased among men aged 40-49 years (APC = 3.0) and decreased among men aged 70-79 years (APC = 2.3), and 80 years or older (APC = -4.4). About 42% of localized prostate cancers diagnosed from 2004 to 2007 were poorly differentiated. The incidence of poorly differentiated cancer significantly increased among localized (APC = 8.0) and regional stage (APC = 6.1) prostate cancers during 2004-2007. Conclusions. The recent trend in prostate cancer incidence was stable but varied dramatically by age. Given the large proportion of poorly differentiated disease among localized prostate cancers and its increasing trend in more recent years, continued monitoring of prostate cancer incidence and trends by demographic and tumor characteristics is warranted.
The relationship between obesity and risk of prostate cancer (PCa) is unclear; however, etiologic heterogeneity by subtype of PCa (localized, advanced) related to obesity was suggested. Therefore, we conducted a dose-response meta-analysis of prospective studies to assess the association between body mass index (BMI) and risk of localized and advanced PCa.
Relevant prospective studies were identified by a search of Medline and Embase databases to 03 October 2011. Twelve studies on localized PCa (1,033,009 men, 19,130 cases) and 13 on advanced PCa (1,080,790 men, 7067 cases) were identified. We carried out a dose-response meta-analysis using random-effects model.
For localized PCa, we observed an inverse linear relationship with BMI [Ptrend<0.001, relative risk (RR): 0.94 (95% confidence interval, 95% CI, 0.91-0.97) for every 5 kg/m2 increase]; there was no evidence of heterogeneity (Pheterogeneity=0.27). For advanced PCa, we observed a linear direct relationship with BMI (Ptrend=0.001, RR: 1.09 (95% CI 1.02-1.16) for every 5 kg/m2 increase); there was weak evidence of heterogeneity (Pheterogeneity=0.08). Omitting one study that contributed substantially to the heterogeneity yielded a pooled RR of 1.07 (95% CI 1.01-1.13) for every 5 kg/m2 increase (Pheterogeneity=0.26).
The quantitative summary of the accumulated evidence indicates that obesity may have a dual effect on PCa-a decreased risk for localized PCa and an increased risk for advanced PCa.
Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer.
We conducted a prospective analysis of 47,911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests.
The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, P(trend) = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, P(trend) = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (≥6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years.
We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.
In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.
From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.
During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).
Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment. (Funded by the Swedish Cancer Society and the National Institutes of Health.).
Insulin may play a role in prostate cancer tumorigenesis. Postprandial blood glucose and insulin responses of foods depend importantly on the carbohydrate quality and quantity, represented by glycemic index (GI), glycemic load (GL), fiber and whole-grain content, but are also influenced by intake of protein and other characteristics. The recently developed insulin index (II) quantifies the postprandial insulin secretion, also taking into account these additional characteristics.
We investigated the association between dietary GI, GL, II, fiber, and whole grains and risk of total prostate cancer (n = 5,112) and subgroups of prostate cancer as defined by stage or grade in 49,934 male participants of the Health Professionals Follow-up Study. Multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression.
Dietary GI, GL, II, or fiber was not associated with risk of total or subgroups of prostate cancer. We observed a positive association between dietary intake of whole grains and total prostate cancer (HR highest versus lowest quintile 1.13, 95% CI 1.03-1.24), which was attenuated after restriction to PSA-screened participants (HR 1.03, 95% CI 0.91-1.17).
These results suggest that long-term exposure to a diet with a high insulin response does not affect prostate cancer incidence.
Prostate cancer incidence varies 60-fold globally, which suggests the roles of lifestyle and dietary factors in its cause. To our knowledge, a comprehensive assessment of the association between fish consumption and prostate cancer incidence and mortality has not been reported.
We conducted a meta-analysis of fish intake and prostate cancer by focusing on the incidence of prostate cancer and prostate cancer-specific mortality and included subgroup analyses based on race, fish type, method of fish preparation, and high-grade and high-stage cancer.
We searched MEDLINE and EMBASE databases (May 2009) for case-control and cohort studies that assessed fish intake and prostate cancer risk. Two authors independently assessed eligibility and extracted data.
There was no association between fish consumption and a significant reduction in prostate cancer incidence [12 case-control studies (n = 5777 cases and 9805 control subjects), odds ratio (OR): 0.85; 95% CI: 0.72, 1.00; and 12 cohort studies (n = 445,820), relative risk (RR): 1.01; 95% CI: 0.90, 1.14]. It was not possible to perform a meta-analysis for high-grade disease (one case-control study, OR: 1.44; 95% CI: 0.58, 3.03), locally advanced disease (one cohort study, RR: 0.80; 95% CI: 0.61, 1.13), or metastatic disease (one cohort study, RR: 0.56; 95% CI: 0.37, 0.86). There was an association between fish consumption and a significant 63% reduction in prostate cancer-specific mortality [4 cohort studies (n = 49,661), RR: 0.37; 95% CI: 0.18, 0.74].
Our analyses provide no strong evidence of a protective association of fish consumption with prostate cancer incidence but showed a significant 63% reduction in prostate cancer-specific mortality.
Purpose
Gleason grading is an important predictor of prostate cancer (PCa) outcomes. Studies using surrogate PCa end points suggest outcomes for Gleason score (GS) 7 cancers vary according to the predominance of pattern 4. These studies have influenced clinical practice, but it is unclear if rates of PCa mortality differ for 3 + 4 and 4 + 3 tumors. Using PCa mortality as the primary end point, we compared outcomes in Gleason 3 + 4 and 4 + 3 cancers, and the predictive ability of GS from a standardized review versus original scoring.
Patients and Methods
Three study pathologists conducted a blinded standardized review of 693 prostatectomy and 119 biopsy specimens to assign primary and secondary Gleason patterns. Tumor specimens were from PCa patients diagnosed between 1984 and 2004 from the Physicians' Health Study and Health Professionals Follow-Up Study. Lethal PCa (n = 53) was defined as development of bony metastases or PCa death. Hazard ratios (HR) were estimated according to original GS and standardized GS. We compared the discrimination of standardized and original grading with C-statistics from models of 10-year survival.
Results
For prostatectomy specimens, 4 + 3 cancers were associated with a three-fold increase in lethal PCa compared with 3 + 4 cancers (95% CI, 1.1 to 8.6). The discrimination of models of standardized scores from prostatectomy (C-statistic, 0.86) and biopsy (C-statistic, 0.85) were improved compared to models of original scores (prostatectomy C-statistic, 0.82; biopsy C-statistic, 0.72).
Conclusion
Ignoring the predominance of Gleason pattern 4 in GS 7 cancers may conceal important prognostic information. A standardized review of GS can improve prediction of PCa survival.
The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers.
We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54-80 years in 1985-2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model.
The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively.
The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.
Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer.
To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men.
A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer.
Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years.
Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer.
As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group.
Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men.
clinicaltrials.gov identifier: NCT00006392.
Fish and seafood n-3 fatty acids may prevent or delay the progression of prostate cancer, but epidemiologic studies do not uniformly support this hypothesis.
We examined the relation of fish and seafood n-3 fatty acid intakes with prostate cancer incidence and mortality.
We conducted a prospective cohort study among 20,167 men participating in the Physician's Health Study who were free of cancer in 1983.
During 382 144 person-years of follow-up, 2161 men were diagnosed with prostate cancer and 230 died of prostate cancer. Fish intake was unrelated to prostate cancer incidence. Survival analysis among the men diagnosed with prostate cancer revealed that those consuming fish >or=5 times/wk had a 48% lower risk of prostate cancer death than did men consuming fish less than once weekly [relative risk (RR) = 0.52; 95% CI: 0.30, 0.91; P for trend = 0.05]. A similar association was found between seafood n-3 fatty acid intake and prostate cancer mortality (RR(Q5 versus Q1) = 0.64; 95% CI: 0.42, 0.99; P for trend = 0.02). These associations became stronger when the analyses were restricted to clinically detected cases.
These results suggest that fish intake is unrelated to prostate cancer incidence but may improve prostate cancer survival.
Background
The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years.
Methods
ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55–69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50–74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years’ follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736.
Findings
With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83–1·99) after 9 years (1·64 [1·58–1·69] including France), 1·66 (1·60–1·73) after 11 years, and 1·57 (1·51–1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70–1·03) after 9 years, 0·78 (0·66–0·91) after 11 years, and 0·79 (0·69–0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490–1929) men invited for screening or one per 27 (17–66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61–0·88).
Interpretation
In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening.
Funding
Each centre had its own funding responsibility.
Importance
Up-front treatment of older men with low-risk prostate cancer can cause morbidity without clear survival benefit; however, most such patients receive treatment instead of observation. The impact of physicians on the management approach is uncertain.Objective
To determine the impact of physicians on the management of low-risk prostate cancer with up-front treatment vs observation.Design, Setting, and Participants
Retrospective cohort of men 66 years and older with low-risk prostate cancer diagnosed from 2006 through 2009. Patient and tumor characteristics were obtained from the Surveillance, Epidemiology, and End Results cancer registries. The diagnosing urologist, consulting radiation oncologist, cancer-directed therapy, and comorbid medical conditions were determined from linked Medicare claims. Physician characteristics were obtained from the American Medical Association Physician Masterfile. Mixed-effects models were used to evaluate management variation and factors associated with observation.Main Outcomes and Measures
No cancer-directed therapy within 12 months of diagnosis (observation).Results
A total of 2145 urologists diagnosed low-risk prostate cancer in 12 068 men, of whom 80.1% received treatment and 19.9% were observed. The case-adjusted rate of observation varied widely across urologists, ranging from 4.5% to 64.2% of patients. The diagnosing urologist accounted for 16.1% of the variation in up-front treatment vs observation, whereas patient and tumor characteristics accounted for 7.9% of this variation. After adjustment for patient and tumor characteristics, urologists who treat non–low-risk prostate cancer (adjusted odds ratio [aOR], 0.71 [95% CI, 0.55-0.92]; P = .01) and graduated in earlier decades (P = .004) were less likely to manage low-risk disease with observation. Treated patients were more likely to undergo prostatectomy (aOR, 1.71 [95% CI, 1.45-2.01]; P < .001), cryotherapy (aOR, 28.2 [95% CI, 19.5-40.9]; P < .001), brachytherapy (aOR, 3.41 [95% CI, 2.96-3.93]; P < .001), or external-beam radiotherapy (aOR, 1.31 [95% CI, 1.08-1.58]; P = .005) if their urologist billed for that treatment. Case-adjusted rates of observation also varied across consulting radiation oncologists, ranging from 2.2% to 46.8% of patients.Conclusions and Relevance
Rates of management of low-risk prostate cancer with observation varied widely across urologists and radiation oncologists. Patients whose diagnosis was made by urologists who treated prostate cancer were more likely to receive up-front treatment and, when treated, more likely to receive a treatment that their urologist performed. Public reporting of physicians’ cancer management profiles would enable informed selection of physicians to diagnose and manage prostate cancer.
Although prostate cancer (PCa) screening reduces the incidence of advanced disease and mortality, trade-offs include overdiagnosis and resultant overtreatment.
To review primary data on PCa overdiagnosis and overtreatment.
Electronic searches were conducted in Cochrane Central Register of Controlled Trials, PubMed, and Embase from inception to July 2013 for original articles on PCa overdiagnosis and overtreatment. Supplemental articles were identified through hand searches.
The lead-time and excess-incidence approaches are the main ways used to estimate overdiagnosis in epidemiological studies, with estimates varying widely. The estimated number of PCa cases needed to be diagnosed to save a life has ranged from 48 down to 5 with increasing follow-up. In clinical studies, generally lower rates of overdiagnosis have been reported based on the frequency of low-grade minimal tumors at radical prostatectomy (1.7-46.8%). Autopsy studies have reported PCa in 18.5-38.5%, although not all are low grade or low volume. Factors influencing overdiagnosis include the study population, screening protocol, and background incidence, limiting generalizability between settings. Reported rates of overtreatment vary widely in the literature, although contemporary international studies suggest increasing use of conservative management.
Epidemiological, clinical, and autopsy studies have been used to examine PCa overdiagnosis, with estimates ranging widely from 1.7% to 67%. Correspondingly, estimates of overtreatment vary widely based on patient features and may be declining internationally. Careful patient selection for screening and reducing overtreatment are important to preserve the benefits and reduce the downstream harms of prostate-specific antigen testing. Because all of these estimates are extremely population and context specific, this must be considered when using these data to inform policy.
Screening reduces spread and death from prostate cancer (PCa) but overdiagnoses some low-risk tumors that may not have caused harm. Because treatment has potential side effects, it is critical that not all patients with PCa receive aggressive treatment.
To review the process and rationale for the American Urological Association (AUA) guideline on prostate cancer detection. The AUA guideline on detection of prostate cancer involved a systematic literature review of >300 studies that evaluated outcomes important to patients (prostate cancer, incidence/mortality, health-related quality of life, diagnostic accuracy and harms of testing). A multidisciplinary panel interpreted the evidence and formulated statements to assist the urologist and the asymptomatic average-risk man in decision-making about prostate cancer detection. Other than prostate-specific antigen (PSA)-based prostate cancer screening, there was no evidence to address the outcomes of interest to patients. The strongest evidence that benefits may outweigh harms was in men aged 55-69 years undergoing PSA-based screening. This led the panel to recommend shared decision-making for these men at average risk, but recommend against routine screening for other age groups at average risk. Further, to reduce the harms associated with screening (false positive tests, over diagnosis, over treatment), the panel recommended against annual screening for those who choose to be screened. A panel under the auspices of the AUA recommended shared decision-making for the average risk asymptomatic man aged 55-69 years considering PSA-based screening for prostate cancer detection.
A world-wide comparative study of the frequency and characteristics of latent carcinoma of the prostate was undertaken in seven areas, using standardized methods and “blind” microscopic evaluation in order to reduce selection and observer bias. The morphological features of 350 latent carcinomas found in 1,327 prostates were examined. Two Chinese populations, from Hong Kong and Singapore, showed a low frequency of latent carcinoma in comparison with western Europeans in Sweden and the Federal Republic of Germany and negroes from Jamaica; an intermediate position was found for Israelis and black Ugandans. The frequency of small latent carcinomas was about 12% in all the areas investigated and did not vary with age. Rates for larger latent carcinomas increased sharply with age and showed an area-to-area variation resembling that of clinical carcinoma of prostate. The small carcinomas were almost exclusively situated in the outer half of the prostate and latent carcinomas of all sizes were evenly distributed between the anterior and posterior halves of the prostate and the right and left sides of the outer prostatic shell. Certain disagreements in diagnosis were noted when the sections from each area were evaluated independently by a different pathologist. Most of these disagreements were resolved by re-reading the sections; their occurrence had no significant effect on the geographical comparisons.
Description:
Prostate cancer is an important health problem in men. It rarely causes death in men younger than 50 years; most deaths associated with it occur in men older than 75 years. The benefits of screening with the prostate-specific antigen (PSA) test are outweighed by the harms for most men. Prostate cancer never becomes clinically significant in a patient's lifetime in a considerable proportion of men with prostate cancer detected with the PSA test. They will receive no benefit and are subject to substantial harms from the treatment of prostate cancer. The American College of Physicians (ACP) developed this guidance statement for clinicians by assessing current prostate cancer screening guidelines developed by other organizations. ACP believes that it is more valuable to provide clinicians with a rigorous review of available guidelines rather than develop a new guideline on the same topic when several guidelines are available on a topic or when existing guidelines conflict. The purpose of this guidance statement is to critically review available guidelines to help guide internists and other clinicians in making decisions about screening for prostate cancer. The target patient population for this guidance statement is all adult men.
Methods:
This guidance statement is derived from an appraisal of available guidelines on screening for prostate cancer. Authors searched the National Guideline Clearinghouse to identify prostate cancer screening guidelines in the United States and selected 4 developed by the American College of Preventive Medicine, American Cancer Society, American Urological Association, and U.S. Preventive Services Task Force. The AGREE II (Appraisal of Guidelines, Research and Evaluation in Europe) instrument was used to evaluate the guidelines.
Guidance statement 1:
ACP recommends that clinicians inform men between the age of 50 and 69 years about the limited potential benefits and substantial harms of screening for prostate cancer. ACP recommends that clinicians base the decision to screen for prostate cancer using the prostate-specific antigen test on the risk for prostate cancer, a discussion of the benefits and harms of screening, the patient's general health and life expectancy, and patient preferences. ACP recommends that clinicians should not screen for prostate cancer using the prostate-specific antigen test in patients who do not express a clear preference for screening. GUIDANCE STATEMENT 2: ACP recommends that clinicians should not screen for prostate cancer using the prostate-specific antigen test in average-risk men under the age of 50 years, men over the age of 69 years, or men with a life expectancy of less than 10 to 15 years.
On step cross sections of the entire prostate gland in 100 patients aged 70 to 79, carcinoma was identified in 41. Of these, 17 were diffuse and 24 were focal. The site of origin of the diffuse carcinomas could not be ascertained though one half of the gland usually was involved more extensively. The location of focal carcinomas was usually at the periphery of the gland. While the microscopic patterns of diffuse and focal carcinomas were reasonably distinct, it appears that their biologic behavior is similar, and that focal carcinoma may be a stage in the development of diffuse carcinoma of the prostate.
Description:
Update of the 2008 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for prostate cancer.
Methods:
The USPSTF reviewed new evidence on the benefits and harms of prostate-specific antigen (PSA)-based screening for prostate cancer, as well as the benefits and harms of treatment of localized prostate cancer.
Recommendation:
The USPSTF recommends against PSA-based screening for prostate cancer (grade D recommendation).This recommendation applies to men in the general U.S. population, regardless of age. This recommendation does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer; the use of the PSA test for this indication is outside the scope of the USPSTF.
Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.
Lead-time is defined as the time by which screening advances the diagnosis compared with absence of screening. A sufficiently long lead-time needs to be achieved so that cancer can be detected while still curable. A very short lead-time may indicate poor sensitivity of the screening test, while a very long lead-time suggests overdiagnosis.
In the first screening round, a total of 56,294 men aged 55-74 years were screened with serum prostate specific antigen (PSA) in five countries of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with an overall detection rate (prevalence) of 2.8% (1972 prostate cancers). Prostate cancer incidence among 92,142 men randomly allocated to the control arm of the trial was also assessed. Lead-time was estimated as the time required to accumulate a similar cumulative risk of prostate cancer in the control arm to the detection rate in the intervention arm, i.e. from the ratio of detection rate (prevalence of screen-detected cases) and expected incidence (cumulative risk).
Using a serum PSA cut-off of 4 ng/ml, the mean lead-time in the whole study population was estimated as 6.8 years (95% confidence interval (95% CI) 7.9-8.4). It was 8 years in The Netherlands, 6 in Sweden and Finland, 5 in Italy and 4 in Belgium. The mean lead-time was similar, 6-7 years, at ages 50-64 years, but close to 8 years among men aged 65-74 years. A lower PSA cut-off level of 3 ng/ml used in Sweden and The Netherlands prolonged the mean lead-time by approximately 1 year. Lead-time based on advanced prostate cancer only was slightly shorter, mean 5.3 years (95% CI 4.6-6.0). The lead-time for the second screening round was slightly shorter than that for the first (5.9, 95% CI 5.4-6.4), reflecting a similar relation between detection rate and control group incidence.
The lead-time for prostate cancer found in ERSPC substantially exceeded that found for breast, cervical and colorectal cancer screening. One round of prostate cancer screening can advance clinical diagnosis by 4-8 years. Overdiagnosis or detection of non-progressive tumours may contribute substantially to the lead-time.
Prostate cancer is one of the leading causes of death from malignant disease among men in the developed world. One strategy to decrease the risk of death from this disease is screening with prostate-specific antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate.
In December, 1994, 20,000 men born between 1930 and 1944, randomly sampled from the population register, were randomised by computer in a 1:1 ratio to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group not invited (n=10,000). Men in the screening group were invited up to the upper age limit (median 69, range 67-71 years) and only men with raised PSA concentrations were offered additional tests such as digital rectal examination and prostate biopsies. The primary endpoint was prostate-cancer specific mortality, analysed according to the intention-to-screen principle. The study is ongoing, with men who have not reached the upper age limit invited for PSA testing. This is the first planned report on cumulative prostate-cancer incidence and mortality calculated up to Dec 31, 2008. This study is registered as an International Standard Randomised Controlled Trial ISRCTN54449243.
In each group, 48 men were excluded from the analysis because of death or emigration before the randomisation date, or prevalent prostate cancer. In men randomised to screening, 7578 (76%) of 9952 attended at least once. During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer, resulting in a cumulative prostate-cancer incidence of 12.7% in the screening group and 8.2% in the control group (hazard ratio 1.64; 95% CI 1.50-1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17-0.64), from 0.90% in the control group to 0.50% in the screening group. The rate ratio for death from prostate cancer was 0.56 (95% CI 0.39-0.82; p=0.002) in the screening compared with the control group. The rate ratio of death from prostate cancer for attendees compared with the control group was 0.44 (95% CI 0.28-0.68; p=0.0002). Overall, 293 (95% CI 177-799) men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death.
This study shows that prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over-diagnosis is substantial and the number needed to treat is at least as high as in breast-cancer screening programmes. The benefit of prostate-cancer screening compares favourably to other cancer screening programs.
The Swedish Cancer Society, the Swedish Research Council, and the National Cancer Institute.
The incidence of prostate cancer is approximately 60% higher and the mortality rate is 2 to 3 times greater in black than in white American men. We propose that a more rapid prostate cancer growth rate and/or earlier transformation from latent to aggressive prostate cancer in black than in white men contribute to this disparity.
We evaluated entirely embedded prostate glands on autopsy from 1,056 black and white men who died of causes other than prostate cancer. We also reviewed data from our radical prostatectomy database and from the Detroit Surveillance, Epidemiology and End Results database.
Autopsy data indicated that subclinical prostate cancer in black and white men starts at early age and clinical characteristics do not differ by race at early ages. Radical prostatectomy specimen data revealed that prostate cancer volume and Gleason grade were greater in black than in white men. Advanced or metastatic prostate cancer occurred at a 4:1 ratio in black and white men, respectively, in the Detroit Surveillance, Epidemiology and End Results registry database.
Results showed that age at prostate cancer initiation and clinical characteristics did not differ by race in our autopsy series, prostate cancer volume after radical prostatectomy was greater in black than in white men and disease became distant disease at a ratio of 4 black men to 1 white man in the Detroit Surveillance, Epidemiology and End Results population. These findings support the concept that prostate cancer grows more rapidly in black than in white men and/or earlier transformation from latent to aggressive prostate cancer occurs in black than in white men.
We evaluated the relationship between smoking and adenocarcinoma of the prostate.
We pooled data from 24 cohort studies enrolling 21 579 prostate cancer case participants for a general variance-based meta-analysis. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated separately for mortality and incidence studies. We tested the robustness of effect measures and evaluated statistical heterogeneity with sensitivity analyses.
In the pooled data, current smokers had no increased risk of incident prostate cancer (RR = 1.04; 95% CI = 0.87, 1.24), but in data stratified by amount smoked they had statistically significant elevated risk (cigarettes per day or years: RR = 1.22; 95% CI = 1.01, 1.46; pack years of smoking: RR = 1.11; 95% CI = 1.01, 1.22). Former smokers had an increased risk (RR = 1.09; 95% CI = 1.02, 1.16). Current smokers had an increased risk of fatal prostate cancer (RR = 1.14; 95% CI = 1.06, 1.19). The heaviest smokers had a 24% to 30% greater risk of death from prostate cancer than did nonsmokers.
Observational