Prostate cancer detection among men with prostate specific antigen levels of 2.5 to 4.0 ng/ml in a Japanese urological referral population

PURPOSE: Prostate cancer detection at levels of 2.5 to 4.0 ng/ml in a Japanese urological referral population has not been elucidated. The purpose of this study is to investigate the cancer detection rate and clinical relevance of prostate cancer in this PSA range. MATERIALS AND METHODS: All urological patients 70 years or younger tested for prostate cancer were studied. There were 550, 97, 112 and 52 patients with a PSA of less than 2.5, 2.5 to 4.0, 4.1 to 10.0 and more than 10.0 ng/ml, respectively. Transrectal 10-core prostate biopsy was performed in 80 (82%) of the 97 patients with a PSA of 2.5 to 4.0 ng/ml and 102 (91%) of the 112 patients with a PSA of 4.1 to 10.0 ng/ml. RESULTS: Cancer detection rates in patients who underwent biopsy were 26.3% and 34.3% at PSA levels 2.5 to 4.0 and 4.1 to 10.0 ng/ml, respectively. High grade cancers with Gleason score 7 or more were found in 19.0% and 22.9% of patients with cancer with PSA 2.5 to 4.0 and 4.1 to 10.0 ng/ml, respectively. No significant difference was found between the 2 groups in pathological findings on biopsy, including percent positive cores (16.7% vs 20.0%, p = 0.10), maximum cancer length (25.0% vs 30.0%, p = 0.28) and maximum percent cancer length (2.0 vs 3.0 mm, p = 0.17). CONCLUSIONS: Japanese urological referral patients develop prostate cancer quite commonly even if their serum PSA levels are 2.5 to 4.0 ng/ml. Since these cancer cases include high grade, clinically significant cancer, prostate biopsy might be considered at least for selected cases in this PSA range.     

Examination of prostate biopsy among Japanese with less than 4.0 ng/ml prostate specific antigen--usefulness of free/total PSA ratio

The low specificity of the prostate specific antigen (PSA) test is considered to be a problem when PSA measurement alone is performed to detect cancer. Therefore, we examined a method to decrease the number of unnecessary biopsies while maintaining the power of the test by using PSA, PSA free/total ratio (PSAf/t), and digital rectal examination (DRE). The subjects were 232 patients with PSA levels of 4.0 ng/ml or less who underwent biopsy for prostate cancer. An endorectal ultrasound perineal biopsy was conducted, and the average biopsy core number was 21. Cancer was detected in 37 of the 232 subjects. Receiver operating characteristic curves of PSA and PSAf/t were subsequently determined. Although the area under the curve (AUC) was 0.56 for PSA alone, the AUC increased to 0.75 when the factor of positive data in DRE was taken into account. Although the AUC was 0.62 for PSAf/t alone, when the factor of positive data in DRE was added as for PSA, the AUC increased to 0.79. In addition, as a result of examining the combination of PSA, PSAf/t and DRE, the condition of the biopsy for prostate cancer in the cases with PSA of 4.0 ng/ml was determined as follows: PSA should be 3.1 ng/ml or more and PSAf/t 27% or less, or the result of DRE should be positive. Based on these criteria, the sensitivity, specificity and detection rate of cancer increased to 0.919, 0.436 and 23.2%, respectively. We consider that this approach will be useful.     

Early detection of prostate cancer in Germany: a study using digital rectal examination and 4.0 ng/ml prostate-specific antigen as cutoff

OBJECTIVE: While international screening studies for prostate cancer are by now almost reaching the estimated number of recruitments mandatory for the necessary power to investigate an effect on mortality of prostate cancer, no statistical figures on the detection of prostate cancer in Germany - apart from historical data before the use of prostate-specific antigen (PSA) are available. In order to generate a database and to investigate the diagnostic efficacy of the primarily practice-based urological care system, a case finding study designed as a nationwide longitudinal early detection trial was initiated. METHODS: In one week in November 1997, 963 urologists prospectively examined 11,644 men between 45 and 75 years of age by digital rectal examination (DRE) and PSA with 4.0 ng/ml as cutoff. Data of family history and physical examination were collected by questionnaire. At this time participants were not aware of their PSA value. PSA was determined in the study center. Indication for sextant biopsy was a PSA value above 4.0 ng/ml or a suspicious lesion on DRE. Any indicated biopsy not performed had to be clarified. In a second questionnaire results of prostate biopsy, treatment and tumor status were documented. RESULTS: The mean age of the study population was 62 years (median 62). The PSA median was 1.4 ng/ml with 82.8% presenting with < 4.0 ng/ml, 12.8% with 4-10 ng/ml and 4.4% with >10 ng/ml. From 1,115 men (47.7%) biopsied, 262 cancers were detected resulting in a detection rate of 23.5%. While 399 men refused biopsy, further investigation was not recommended in 387 men by their urologist, because prostatitis or benign hyperplasia was thought to be the cause for elevated PSA. From the 143 patients undergoing radical prostatectomy, 93 (65%) cancers were organ confined. T(1c) cancers with elevated PSA > 10 ng/ml could be treated with curative intent in 44% only. The positive predictive value (PPV) was estimated to be 16% for DRE alone (14/90), 17% for PSA alone (143/819) and 51% for the combination of both (105/206). In that cohort, use of age-adjusted PSA values and PSA density increased the PPV of PSA testing nonsignificantly. CONCLUSIONS: Significant higher PPV indicated that utilizing a combination of both DRE and PSA is most effective in the early detection of prostate cancer. Unnecessary biopsies can be avoided using either age-adjusted PSA value or PSA density, but the PPV is not significantly changed and potentially curable cancer is missed in up to 25%. Given the substantial variability of the diagnostic approach despite the study design, uniform guidelines are necessary to ensure countrywide sufficient screening.     

Predictors of subsequent prostate cancer in men with a prostate specific antigen of 2.6 to 4.0 ng/ml and an initially negative biopsy

PURPOSE: Almost 75% of men with a prostate specific antigen (PSA) of 2.6 to 4.0 ng/ml have no evidence of prostate cancer on biopsy. Deciding whether and when to repeat the biopsy is challenging. We determined if patient specific variables might identify men at increased risk for the subsequent detection of prostate cancer. MATERIALS AND METHODS: We analyzed the records of 24,893 men from a community based prostate cancer screening study. Our study group consisted of 1,202 men with PSA 2.6 to 4.0 ng/ml and a previously negative prostate biopsy. Patient specific variables were analyzed for their value in predicting a future diagnosis of prostate cancer. RESULTS: Of 1,011 men with adequate followup 136 (13.5%) were subsequently diagnosed with prostate cancer. Mean followup +/- SD in men without prostate cancer was 72 +/- 36 months. Prostate cancer was subsequently diagnosed in 35% of men with high grade prostatic intraepithelial neoplasia (HGPIN) on initial biopsy (p <0.0001), in 18% with abnormal or suspicious digital rectal examination (DRE) (p = 0.02) and 16% with an annual PSA velocity of 0 ng/ml (p = 0.002). Multivariate analysis identified HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, family history of prostate cancer and annual PSA velocity 0 ng/ml as predictors of prostate cancer. CONCLUSIONS: Men with a PSA of 2.6 to 4.0 ng/ml and negative biopsy should be advised to undergo repeat biopsy if they have HGPIN, initial PSA 3.6 to 4.0 ng/ml, abnormal DRE, a family history of prostate cancer or a PSA velocity of 0 ng/ml or greater.     

Histological characteristics and clinical significance of Japanese prostate cancer with low levels of prostate specific antigen of 4.0 ng/ml or lower]

PURPOSE: They set a normal limit of prostate specific antigen (PSA) to 4.0 ng/ml in Tandem R assay at most institutions. We investigated clinical and histological characteristics of prostate cancer based on whole mount step-section histology of radical prostatectomy specimens, and taking notice of Japanese prostate cancer whose levels of PSA are less than 4.0 ng/ml in normal levels. MATERIALS AND METHODS: One hundred and twenty-two patients underwent radical prostatectomy for clinically resectable prostate cancer at University Hospital from February 1992 to April 1997. Clinicopathological findings were stratified according to the preoperative PSA levels in 111 patients without preoperative endocrine therapy. Immunohistochemical study for PSA was conducted in 7 randomly selected patients. RESULTS: Of the patients 22 (19.8%) had normal (4.0 ng/ml or lower) preoperative serum PSA. Mean tumor volume in this PSA range was 1.5 cm3 with one pT 0 case included. Pathologically organ confined, potentially curable disease (< pT 3) was found in 17 (77.3%) patients and extracapsular extension and seminal vesicle invasion in 5 (23.8%), respectively. No patients had positive pelvic lymph nodes. Well differentiated tumors of Gleason scores 2-4 were found in 9 (40.9%) of the patients, moderately differentiated tumors (Gleason scores 5, 6) in 5 (22.7%) and poorly differentiated histology (Gleason scores 7-10) in 7 (31.8%). Sixteen (72.7%) patients had clinically significant tumors (> 0.5 cm3, Gleason score > or = 7). All 7 patients had positive staining for PSA, but its intensity did not correlate with serum PSA levels. CONCLUSIONS: Many prostate cancers found in surgical specimens were clinically significant despite the low levels of PSA and potentially curable by definitive treatment. Age, co-morbidity and other clinicopathological variables as well as PSA levels should all be taken into account when treatment options are discussed.     

Patients with low prostate-specific antigen levels (< or =4 ng/ml) would benefit from a twelve-core biopsy protocol for prostate cancer detection

INTRODUCTION: Prostate biopsy protocols using twelve cores rather than the standard six cores have consistently shown improved prostate cancer detection rates. The aim of our study was to evaluate whether the improved rate of prostate cancer detection in patients with low prostate-specific antigen levels warrants the standardization of a twelve-core biopsy protocol in this group. PATIENTS AND METHODS: The clinical and pathological records from 241 patients treated between 2000 and 2003 were evaluated, and the impact of a twelve-core biopsy protocol on the prostate cancer detection rate relative to prostate-specific antigen levels compared to the standardized six-core biopsies was analyzed. RESULTS: Prostate cancer was detected in 34% (81/241) of the patients who underwent transrectal ultrasound-guided biopsy. An additional 23.5% (19/81) of the carcinomas were diagnosed using the twelve-core biopsy protocol, and 84.2% (16/19) of these fulfilled the clinical significance criterion developed by Epstein and coworkers (see text). Interestingly, the greatest increase was found in the patient group with prostate-specific antigen levels < or =4 ng/ml. CONCLUSIONS: Patients with low prostate-specific antigen levels (< or =4 ng/ml) would benefit from the standardized use of a twelve-core biopsy protocol using peripheral cores.     

Evaluation of proprostate specific antigen for early detection of prostate cancer in men with a total prostate specific antigen range of 4.0 to 10.0 ng/ml

PURPOSE: In contemporary screening populations a major drawback of prostate specific antigen (PSA) is its relative lack of specificity, especially in the range of 4 to 10 ng/ml, where prostate cancer is found 25% of the time. ProPSA is a derivative of free PSA (fPSA) consisting of the truncated forms (eg [-2]proPSA, [-4]proPSA or the full-length [-7]proPSA). There is increasing evidence that proPSA is associated preferentially with prostate cancer. The objective of this study was to determine whether proPSA can influence the detection of early prostate cancer. MATERIALS AND METHODS: Archival serum samples obtained from 93 men who underwent a systematic 12-core prostate biopsy (total PSA range 4.0 to 10.0 ng/ml) were assayed for percent free PSA, total PSA and the 3 forms of proPSA (Hybritech Tandem Assays Beckman Coulter Access, Beckman Coulter, Inc., Brea, California). Free PSA, the cumulative sum of individual proPSA forms ([-2], [-4] and [-7], or sum-proPSA) and derivatives were determined. Of the 93 men assessed 41 (44%) had evidence of prostate cancer (76% Gleason 5/6, 19% Gleason 7 and 5% Gleason 8). Prostate volume was measured at systematic 12-core biopsy for the detection of prostate cancer. Results were analyzed using univariate and multivariate logistic regression (LR) nonparametric statistical methods. RESULTS: Using univariate LR, fPSA, percent fPSA (%fPSA), percent sum-proPSA and prostate volume significantly (p <0.05) differentiated men with prostate cancer from those with benign disease. However, applying stepwise backward multivariate LR, total PSA, %fPSA and sum-proPSA were retained and generated a receiver operator characteristic curve with an area under the curve of 76.6%. At 90% sensitivity these 3 variables collectively achieved a specificity of 44% for the detection of prostate cancer. Individually, the 3 retained variables had a specificity of 23% (total PSA), 33% (%fPSA) and 13% (sum-proPSA). CONCLUSIONS: Sum-proPSA, total PSA and %fPSA in combination improve the specificity of early prostate cancer detection in men with a total PSA of 4 to 10 ng/ml compared with the results of individual PSA molecular forms measured.     

Characteristics of prostatic cancer in men with a serum prostate-specific antigen level of < or =4.0 ng/ml

Fifteen out of 140 men (median age 67 years, range 62-75) had a serum prostate-specific antigen (PSA) level of < or = 4 ng/ml before radical prostatectomy which was performed without preoperative neoadjuvant hormonal therapy between 2001 January and 2004 September. Demographic and clinical data were analyzed. Pathological specimens were evaluated by routine hematoxylin and eosine staining and immunohistochemistry with anti-PSA antibody, for both pathological staging and grading, and for the presence of PSA production. Pathological data were compared between patients with PSA < or = 4 ng/ml and those with 4 < PSA < or = 10 ng/ml. Clinically insignificant cancer was defined as a cancer volume of < 0.5 ml and the Gleason score < or = 6. The median PSA level was 3.0 ng/ml (range 1.4-3.9). Thirteen tumors (87%) were pT2. One tumor had a Gleason score of 7 and 14 tumors had a final Gleason score of < or = 6. Nine (60%) tumors were clinically insignificant. Comparison of pathological variables, PSA < or = 4 ng/ml cancer had a significantly lower Gleason score (p = 0.0029), and a smaller cancer volume (p = 0.0451) than 4 < PSA < or = 10 ng/ml cancer. All tumors were stained strongly for PSA. During a median follow-up of 24 (9-36) months, no patient showed elevated PSA (PSA > or = 0.1 ng/ml). Most prostate cancers in men with a PSA level of < or = 4 ng/ml were pT2, and about half of them were clinically insignificant. All cancers produced PSA.     

Prostate cancer detection in the "grey area" of prostate-specific antigen below 10 ng/ml: head-to-head comparison of the updated PCPT calculator and Chun's nomogram, two risk estimators incorporating prostate cancer antigen 3

Background

Prostate cancer antigen 3 (PCA3) holds promise in diagnosing prostate cancer (PCa), but no consensus has been reached on its clinical use. Multivariable predictive models have shown increased accuracy over individual risk factors.

Objective

To compare the performance of the two available risk estimators incorporating PCA3 in the detection of PCa in the “grey area” of prostate-specific antigen (PSA) <10 ng/ml: the updated Prostate Cancer Prevention Trial (PCPT) calculator and Chun's nomogram.

Design, setting, and participants

Two hundred eighteen patients presenting with an abnormal PSA (excluding those with PSA >10 ng/ml) and/or abnormal digital rectal examination were prospectively enrolled in a multicentre Italian study between October 2008 and October 2009. All patients underwent ≥12-core prostate biopsy.

Measurements

PCA3 scores were assessed using the Progensa assay (Gen-Probe, San Diego, CA, USA). Comparisons between the two models were performed using tests of accuracy (area under the receiver operating characteristic curve [AUC-ROC]), calibration plots, and decision curve analysis. Biopsy predictors were identified by univariable and multivariable logistic regression. In addition, performance of PCA3 was analysed through AUC-ROC and predictive values.

Results and limitations

PCa was detected in 73 patients (33.5%). Among predictors included in the models, only PCA3, PSA, and prostate volume retained significant predictive value. AUC-ROC was higher for the updated PCPT calculator compared to Chun's nomogram (79.6% vs 71.5%; p = 0.043); however, Chun's nomogram displayed better overall calibration and a higher net benefit on decision curve analysis. Using a probability threshold of 25%, no high-grade cancers would be missed; the PCPT calculator would save 11% of biopsies, missing no cancer, whereas Chun's nomogram would save 22% of avoidable biopsies, although missing 4.1% non–high-grade cancers. The small number of patients may account for the lack of statistical significance in the predictive value of individual variables or model comparison.

Conclusions

Both Chun's nomogram and the PCPT calculator, by incorporating PCA3, can assist in the decision to biopsy by assignment of an individual risk of PCa, specifically in the PSA levels <10 ng/ml.     

The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng/ml: relation to biopsy strategy

PURPOSE: It has recently been suggested that the diagnostic threshold for the prostate specific antigen (PSA) assay be lowered to enhance prostate cancer detection. A 22% incidence of prostate cancer has been reported in men with PSA between 2.5 and 4.0 ng/ml. We designed a study to confirm this observation. MATERIALS AND METHODS: Men who participated in our free early detection program and who had serum PSA between 2.5 and 4.0 ng/ml were asked to undergo prostate biopsy. Of 268 eligible men 151 (56%) agreed to participate in this free trial. All men underwent biopsy using an 11-core multisite directed biopsy scheme. All biopsy cores were color coded for location specificity and examined by 1 pathologist. RESULTS: Cancer was identified in 24.5% (37 of 151) of the men biopsied. The median age of men with cancer was 62 years (range 43 to 74). Conventional systematic sextant biopsies, which accounted for 6 of the 11 cores, detected 73.0% (27 of 37) of the cancers and the alternate site biopsies identified the remaining 10. Gleason score was 6 in 25 men, 3 + 4 in 5, 4 + 3 in 4 and 8 or greater in 3 (median Gleason score 6). There were 14 men who had 1 core positive for cancer, 9 had 2 and 14 had more than 2 (median number of positive cores 2). Of the 14 men with 1 positive core 11 had a less than 3 mm focus of cancer and 8 had only a positive alternate site biopsy. There were 11 cases of abnormal results on digital rectal examination, 5 of which were cancer, and 31 cases of abnormal results on ultrasonography, 13 of which were cancer. Median biological variability in PSA was +/-15% (range 0.4% to 440.0%). CONCLUSIONS: We found a significant incidence of cancer (24.5%, 37 of 51) in men with serum PSA between 2.5 and 4.0 ng/ml. In our study 67.6% of the detected cancers were significant based on the biopsy data. If the PSA threshold is lowered the conventional systematic sextant technique may be preferable to an extended strategy.     

The incidence of prostate cancer in men with prostate specific antigen greater than 4.0 ng/ml: a randomized study of 6 versus 12 core transperineal prostate biopsy

PURPOSE: The prostate cancer detection rate in patients with elevated prostate specific antigen (PSA) increases with extended needle biopsy protocols. Transperineal biopsy under transrectal ultrasound guidance is rarely reported, although notable cancer diagnoses are obtained with this technique. We describe the results of 6 and 12 core transperineal biopsy. MATERIALS AND METHODS: A total of 214 patients with PSA greater than 4.0 ng/ml were prospectively randomized to undergo 6 or 12 core transperineal biopsy. Each group of 107 patients was comparable in terms of clinical characteristics. The procedure was performed on an outpatient basis using local anesthesia. Specimens were obtained with a fan technique with 2 puncture sites slightly above the rectum (1 per lobe) under transrectal ultrasound guidance. Cores were taken from all peripheral areas, including the far lateral aspect of the prostate. RESULTS: The overall cancer detection rate was 38% and 51% for 6 and 12 core biopsy, respectively. In patients with PSA between 4.1 and 10 ng/ml the cancer detection rate was 30% and 49% for 6 and 12 core biopsy, respectively. CONCLUSIONS: The 12 core transperineal prostate biopsy is superior to 6 core biopsy. The technique provides optimal prostate cancer diagnosis. About half of the patients with PSA greater than 4.0 ng/ml and a slightly lower percent with PSA between 4.1 and 10 ng/ml have prostate cancer.     

血清PSA〈4．0ng/ml的人群中前列腺癌集团筛查的病理学特征

目的探讨血清PSA<4.0ng/ml的人群中前列腺癌的病理学特征。方法对长春市15192名男性进行血清前列腺特异性抗原(PSA)检测,其中46名血清PSA<4.0ng/ml伴有直肠指诊检查异常者接受了经直肠超声引导下前列腺6点活检穿刺,并应用组织病理学、免疫组织化学及统计学等方法进行系统的病理学研究和分析。结果(1)血清PSA<4.0ng/ml者有13886名,46人进行了前列腺活检穿刺,活检率为0.33%(46/13886)。(2)46名男性血清PSA值在0.03～3.84ng/ml之间,主要分布在0～1.9ng/ml间,占60.9%。(3)46例前列腺活检病理诊断:良性前列腺增生29例,占63.1%;前列腺癌10例,占21.7%;炎症性病变与肉瘤各3例,分别占6.5%;转移癌1例占2.2%。10例血清PSA<4.0ng/ml的前列腺癌中普通型腺癌5例,以中分化(3/5)、器官内癌(4/5)为主,且血清PSA值较靠近4ng/ml;特殊类型前列腺癌5例,占50%,均为进展期癌,血清PSA值相对较低。结论(1)血清PSA<4.0ng/ml的人群中有前列腺癌存在。(2)血清PSA<4.0ng/ml的人群中前列腺癌以中分化器官内腺癌和特殊类型进展期前列腺癌为主。(3)应用直肠指诊检查(DRE)能检出血清PSA<4.0ng/ml的前列腺癌,且检出率与血清PSA值成正相关,两者联合应用可以提高前列腺癌的检出率。     

Prostate cancer detection in men with prostate specific antigen 4 to 10 ng/ml using a combined approach of contrast enhanced color Doppler targeted and systematic biopsy

PURPOSE: Transrectal gray scale ultrasound guided biopsy is the standard method for diagnosing prostate cancer (PC). Improved cancer detection with ultrasound contrast agents is related to better detection of tumor vascularity. We evaluated the impact of a combined approach of contrast enhanced, color Doppler targeted biopsy (CECD) and systematic biopsy (SB) for the PC detection rate in men with prostate specific antigen (PSA) 4.0 to 10 ng/ml. MATERIALS AND METHODS: We examined 380 screening volunteers with a total PSA of 4.0 to 10 ng/ml (percent free PSA less than 18). CECD was always performed before SB. Another investigator blinded to contrast enhanced findings performed 10 SBs. The cancer detection rate for the CECD, SB and combined approaches was assessed. RESULTS: PC was detected in 143 of 380 patients (37.6%, mean total PSA 6.2 ng/ml). The PC detection rate for CECD and for SB was 27.4% and 27.6%, respectively. The overall cancer detection rate with the 2 methods combined was 37.6%. For targeted biopsy cores the detection rate was significantly better than for SB cores (32.6% vs 17.9%, p <0.01). CECD in a patient with cancer was 3.1-fold more likely to detect PC than SB. CONCLUSIONS: CECD allows for the detection of lesions that cannot be found on gray scale ultrasound or SB. CECD allows for assessment of neovascularity associated with PC. However, the combined use of CECD and SB allows for maximal detection of PC with a detection rate of 37.6% in our patients with PSA 4 to 10 ng/ml.