Evaluation of prediagnostic prostate‐specific antigen dynamics as predictors of death from prostate cancer in patients treated conservatively

Prostate‐specific antigen (PSA) dynamics have been proposed to predict outcome in men with prostate cancer. We assessed the value of PSA velocity (PSAV) and PSA doubling time (PSADT) for predicting prostate cancer‐specific mortality (PCSM) in men with clinically localized prostate cancer undergoing conservative management or early hormonal therapy. From 1990 to 1996, 2,333 patients were identified, of whom 594 had two or more PSA values before diagnosis. We examined 12 definitions for PSADT and 10 for PSAV. Because each definition required PSA measurements at particular intervals, the number of patients eligible for each definition varied from 40 to 594 and number of events from 10 to 119. Four PSAV definitions, but no PSADT, were significantly associated with PCSM after adjustment for PSA in multivariable Cox proportional hazards regression. All four could be calculated only for a proportion of events, and the enhancements in predictive accuracy associated with PSAV had very wide confidence intervals. There was no clear benefit of PSAV in men with low PSA and Gleason grade 6 or less. Although evidence that certain PSAV definitions help to predict PCSM in the cohort exist, the value of incorporating PSAV in predictive models to assist in determining eligibility for conservative management is, at best, uncertain.     

Time to prostate‐specific antigen nadir independently predicts overall survival in patients who have metastatic hormone‐sensitive prostate cancer treated with androgen‐deprivation therapy

BACKGROUND:

The objective of this study was to evaluate the relation between the kinetics of prostate‐specific antigen (PSA) decline after the initiation of androgen‐deprivation therapy (ADT) and overall survival (OS) in men with metastatic, hormone‐sensitive prostate cancer (HSPC).

METHODS:

The authors' institutional database was used to identify a cohort of men with metastatic HSPC who were treated with ADT. Patients were included if they had at least 2 serum PSA determinations before PSA nadir and at least 1 serum PSA value available within 1 month of ADT initiation. Patient characteristics, PSA at ADT initiation, nadir PSA, time to PSA nadir (TTN), and PSA decline (PSAD) in relation to OS were analyzed.

RESULTS:

One hundred seventy‐nine patients were identified, and they had a median follow‐up after ADT initiation of 4 years. The median OS after ADT initiation was 7 years. The median PSA level at ADT initiation and PSA nadir were 47 ng/mL and 0.28 ng/mL, respectively. On univariate analysis: TTN <6 months, PSAD >52 ng/mL per year, PSA nadir ≥0.2 ng/mL, PSA ≥47.2 ng/mL at ADT initiation, and Gleason score >7 were associated with shorter OS. On multivariate analysis, TTN <6 months, Gleason score >7, and PSA nadir ≥0.2 ng/mL independently predicted shorter OS.

CONCLUSIONS:

To the authors' knowledge, this was the first report to demonstrate that a faster time to reach a PSA nadir after the initiation of ADT was associated with shorter survival duration in men with metastatic HSPC. These results need confirmation but may indicate that a rapid initial response to ADT indicates more aggressive disease. Cancer 2009. © 2009 American Cancer Society.     

Australian prostate‐specific antigen outcome and toxicity following radiation therapy for localized prostate cancer

The objective of the present study was to examine prostate‐specific antigen relapse free survival (PSA‐RFS) and morbidity following ‘conventional’ radical radiation therapy for prostate cancer in two Australian regional treatment services. Four hundred and eighty men with clinically localized prostate cancer were treated between 1993 and 1997 at Liverpool and Westmead Hospitals using a standardized 4‐field, CT‐planned radiotherapy technique. Principal endpoints were PSA‐RFS (American Society for Therapeutic Radiology and Oncology guidelines definition) and late rectal and urinary morbidity (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria). The median follow up of patients from the end of RT was 55 months. Prospectively, they were divided into three prognostic categories: (i) high risk T3 or 4 and/or PSA > 20 ng/mL and/or Gleason score 8?10 (40% of cohort); (ii) intermediate risk T1 or 2 and PSA 10?20 ng/mL and/or Gleason score 7 (33% of cohort); and (iii) low risk T1 or 2 and PSA < 10 ng/mL and Gleason score < 6 (27% of cohort). The 5‐year actuarial PSA‐RFS was 53% for the whole patient group. The 4‐year rates were 32, 56 and 75% for high, intermediate and low risk groups, respectively. On multivariate analysis, T‐stage, Gleason score, pre‐RT‐PSA were strong independent predictors of PSA‐defined outcome. Late (grade 2) rectal and urinary morbidity occurred at some point in time in the post‐RT period in 8.0 and 5.8% of patients, respectively. These results confirm that low Gleason score, low T stage, presenting PSA < 10 ng/mL and nadir < 1 ng/mL remain the strongest predictors of a good outcome. Long‐term toxicity was very acceptable. However, further improvement in outcome is desirable, and with the adoption of new technology allowing escalation of radiotherapy doses such an expectation might be achieved.     

Time to an undetectable prostate-specific antigen (PSA) after androgen suppression therapy for postoperative or postradiation PSA recurrence and prostate cancer-specific mortality

BACKGROUND: For men receiving androgen-suppression therapy (AST) for a rising postoperative or postradiation prostate-specific antigen (PSA) recurrence, whether the time to an undetectable (u) PSA was significantly associated with prostate cancer-specific mortality (PCSM) was evaluated. METHODS: The study cohort comprised 585 men with a rising PSA and negative bone scan after surgery (n = 415) or radiation therapy (n = 170) that were treated with AST and achieved a uPSA. Gray's regression was used to evaluate whether the time to a uPSA after AST was significantly associated with the time to PCSM after the uPSA adjusting for known prognostic factors. RESULTS: The median time (interquartile range) to achieve a uPSA was 4.6 (range, 2.8-7.8) months. There were 23 deaths, 4 of which were from prostate cancer. An increasing time to a uPSA (adjusted hazard ratio [HR]: 9.2, 95% confidence interval [CI]: 3.8, 22.1; P < .0001), a decreasing PSA doubling time (DT) (HR: 0.58, 95% CI: 0.43, 0.80; P = .0007), and Gleason score 8 to 10 cancers (HR: 8.6, 95% CI: 1.04, 77; P = .05) were significantly associated with a shorter time to PCSM. CONCLUSIONS: Despite achieving a uPSA after AST, the risk of PCSM increased significantly as the time to the uPSA lengthens, especially in men with a short pre-AST PSA DT and high-grade prostate cancer. These men should be considered for randomized studies evaluating immediate vs delayed chemotherapy after the achievement of the uPSA.     

Clinical significance of the LacdiNAc‐glycosylated prostate‐specific antigen assay for prostate cancer detection

To reduce unnecessary prostate biopsies (Pbx), better discrimination is needed. To identify clinically significant prostate cancer (CSPC) we determined the performance of LacdiNAc‐glycosylated prostate‐specific antigen (LDN‐PSA) and LDN‐PSA normalized by prostate volume (LDN‐PSAD). We retrospectively measured LDN‐PSA, total PSA (tPSA), and free PSA/tPSA (F/T PSA) values in 718 men who underwent a Pbx in 3 academic urology clinics in Japan and Canada (Pbx cohort) and in 174 PC patients who subsequently underwent radical prostatectomy in Australia (preop‐PSA cohort). The assays were evaluated using the area under the receiver operating characteristics curve (AUC) and decision curve analyses to discriminate CSPC. In the Pbx cohort, LDN‐PSAD (AUC 0.860) provided significantly better clinical performance for discriminating CSPC compared with LDN‐PSA (AUC 0.827, P = 0.0024), PSAD (AUC 0.809, P < 0.0001), tPSA (AUC 0.712, P < 0.0001), and F/T PSA (AUC 0.661, P < 0.0001). The decision curve analysis showed that using a risk threshold of 20% and adding LDN‐PSA and LDN‐PSAD to the base model (age, digital rectal examination status, tPSA, and F/T PSA) permitted avoidance of even more biopsies without missing CSPC (9.89% and 18.11%, respectively vs 2.23% [base model]). In the preop‐PSA cohort, LDN‐PSA values positively correlated with tumor volume and tPSA and were significantly higher in pT3, pathological Gleason score ≥ 7. Limitations include limited sample size, retrospective nature, and no family history information prior to biopsy. LacdiNAc‐glycosylated PSA is significantly better than the conventional PSA test in identifying patients with CSPC. This study was approved by the ethics committee of each institution (“The Study about Carbohydrate Structure Change in Urological Disease”; approval no. 2014‐195).     

Body mass index in relation to serum prostate‐specific antigen levels and prostate cancer risk

High Body mass index (BMI) has been directly associated with risk of aggressive or fatal prostate cancer. One possible explanation may be an effect of BMI on serum levels of prostate‐specific antigen (PSA). To study the association between BMI and serum PSA as well as prostate cancer risk, a large cohort of men without prostate cancer at baseline was followed prospectively for prostate cancer diagnoses until 2015. Serum PSA and BMI were assessed among 15,827 men at baseline in 2010–2012. During follow‐up, 735 men were diagnosed with prostate cancer with 282 (38.4%) classified as high‐grade cancers. Multivariable linear regression models and natural cubic linear regression splines were fitted for analyses of BMI and log‐PSA. For risk analysis, Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) and natural cubic Cox regression splines producing standardized cancer‐free probabilities were fitted. Results showed that baseline Serum PSA decreased by 1.6% (95% CI: ?2.1 to ?1.1) with every one unit increase in BMI. Statistically significant decreases of 3.7, 11.7 and 32.3% were seen for increasing BMI‐categories of 25 < 30, 30 < 35 and ≥35 kg/m², respectively, compared to the reference (18.5 < 25 kg/m²). No statistically significant associations were seen between BMI and prostate cancer risk although results were indicative of a positive association to incidence rates of high‐grade disease and an inverse association to incidence of low‐grade disease. However, findings regarding risk are limited by the short follow‐up time. In conclusion, BMI was inversely associated to PSA‐levels. BMI should be taken into consideration when referring men to a prostate biopsy based on serum PSA‐levels.     

Impact of recent screening on predicting the outcome of prostate cancer biopsy in men with elevated prostate‐specific antigen

BACKGROUND:

Risk models to predict prostate cancer on biopsy, whether they include only prostate‐specific antigen (PSA) or other markers, are intended for use in all men of screening age. However, the association between PSA and cancer probably depends on a man's recent screening history.

METHODS:

The authors examined the effect of prior screening on the ability to predict the risk of prostate cancer by using a previously reported, 4‐kallikrein panel that included total PSA, free PSA, intact PSA, and human kallikrein‐related peptidase 2 (hK2). The study cohort comprised 1241 men in Gothenburg, Sweden who underwent biopsy for elevated PSA during their second or later visit for the European Randomized Study of Screening for Prostate Cancer. The predictive accuracy of the 4‐kallikrein panel was calculated.

RESULTS:

Total PSA was not predictive of prostate cancer. The previously published 4‐kallikrein model increased predictive accuracy compared with total PSA and age alone (area under the curve [AUC], 0.66 vs 0.51; P < .001) but was poorly calibrated and missed many cancers. A model that was developed with recently screened men provided important improvements in discrimination (AUC, 0.67 vs 0.56; P < .001). Using this model reduced the number of biopsies by 413 per 1000 men with elevated PSA, missed 60 of 216 low‐grade cancers (Gleason score ≤6), but missed only 1 of 43 high‐grade cancers.

CONCLUSIONS:

Previous participation in PSA screening dramatically changed the performance of statistical models that were designed to predict biopsy outcome. A 4‐kallikrein panel was able to predict prostate cancer in men who had a recent screening history and provided independent confirmation that multiple kallikrein forms contribute important diagnostic information for men with elevated PSA. Cancer 2010. © 2010 American Cancer Society.     

Evaluation and management of prostate-specific antigen recurrence after radical prostatectomy for localized prostate cancer

A radical prostatectomy has been established as one of the standardmanagement options for localized prostate cancer. However, asubstantial proportion of patients who undergo a radical prostatectomydevelop prostate-specific antigen (PSA) recurrence which iscommonly defined as a PSA cut-off point value of 0.2 ng/ml.Although the management of PSA recurrence after radical prostatectomymay depend on the site of recurrence, it is quite difficultto identify the recurrent lesion accurately based on the currentlyavailable imaging technology. Patients who have surgical margininvolvement or a Gleason score 7 based on the radical prostatectomyspecimens, who do not have nodal or seminal vesicle involvement,and who develop a PSA recurrence >1–2 years after surgerywith a doubling time of >1 year, and whose pre-treatmentPSA is <1.0–1.5 ng/ml are considered to benefit fromlocal treatment with at least 64 Gy of salvage radiotherapy.Patients with different characteristics are considered to havedistant metastases or both local lesions and distant metastases,and thus may be candidates for hormonal manipulation ratherthan radiotherapy. Since local recurrent lesions are consideredto be quite small at the early stage of PSA recurrence, hormonalmanipulation may be sufficient to prevent disease progressioninstead of radiotherapy. However, the optimal type and timingof hormonal manipulation remain to be elucidated. As a result,no consensus regarding the treatment for PSA recurrence afterradical prostatectomy has yet been reached.     

Incidental finding of ileal gastrointestinal stromal tumour during prostate cancer staging with prostate‐specific membrane antigen scan

Prostate‐specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is used in managing and staging prostate cancer, but can identify other non‐prostate pathology. We present the first reported case where small bowel gastrointestinal stromal tumour (GIST) has been incidentally identified on PSMA‐PET scan and highlight the need for awareness of other pathology being identified on PSMA‐PET/CT.