Change In Serum Prostate-specific Antigen Research Articles

LONG-TERM OUTCOME FOR MEN WITH ANDROGEN INDEPENDENT PROSTATE CANCER TREATED WITH KETOCONAZOLE AND HYDROCORTISONE

The combination of high dose ketoconazole and hydrocortisone (HDK) is active against androgen independent prostate cancer (AIPC). Median response times with HDK tend to be brief but a significant minority of AIPC patients benefit with extended responses. Well characterized response and survival information, especially in the cohort of patients who experience these longer, more durable, responses has not been previously reported. Characterization of this subgroup is of particular interest since men with long-term responses derive the greatest benefit from HDK therapy. The medical records of 78 patients with AIPC treated with HDK between March 1991 and February 1999 were retrospectively reviewed. Baseline clinical and laboratory factors predictive of prolonged response and survival were identified. The median baseline prostate specific antigen (PSA) before the initiation of HDK was 25.1. The number of patients with zero, 1 to 3, and more than 3 lesions on bone scan were 25, 35 and 18, respectively. Median and mean time to PSA progression was 6.7 and 14.5 months. Median and mean survival time was 38.0 and 42.4 months, respectively. Response time and survival were highly correlated (r = 0.799). A total of 34 (44%) men had a greater than 75% decrease in PSA. The median survival times in men with more vs less than a 75% decrease were 60 vs 24 months, respectively. In a Cox proportional hazard regression, prolonged survival was predicted by percent PSA decrease, extent of disease on bone scan and baseline PSA. Ketoconazole can induce prolonged responses, occasionally lasting for years. Long responses are more likely to occur in men initiating HDK earlier in the course of disease before the cancer burden becomes excessive.

The Prognostic Importance of Prostate-Specific Antigen in Monitoring Patients Undergoing Maximum Androgen Blockage for Metastatic Prostate Cancer

The changes in serum prostate-specific antigen (PSA) concentrations can be used as a prognostic factor in patients undergoing maximum androgen blockage for metastatic prostate cancer. A total of 149 patients followed in our department were classified into 4 groups on the basis of PSA changes: group 1, those with normalisation of PSA levels within the first 3 months; group 2, those with normalisation of PSA between months 3 and 6; group 3, those with a decrease in PSA, but not reaching normal range; group 4, those with no decrease. The gleason scores and the number of bone metastases were also compared between the groups. Again time to progression in patients with Gleason scores 5-7 (grade 2) and over 7 (grade 3) whose PSA levels decreased between first and 3rd months (mean 21.2 months) were significantly longer than the patients with same gleason scores whose PSA levels decreased between 3rd and 6th months (mean 13.4 months) (p < 0.001). The decrease in PSA level is more important than gleason scores in determining the time to progression. Early normalisation of PSA delays the time to progression and when combined with gleason scores, PSA is an important prognostic factor in predicting the success of the therapy.

Recreational and Master Athletic Activity Does Not Affect Free and Total Prostate-specific Antigen Levels but Lowers the Free-to-total Prostate-specific Antigen Ratio

Prostate-specific antigen (PSA) and the ratio of free-to-total PSA are widely used tumour markers, but the effect of exercise on these parameters is unclear. We aimed to determine whether long-term physical training was associated with changes in serum PSA by comparing PSA concentrations in middle-aged master athletes (n = 12), recreational athletes (n = 12) and sedentary controls (n = 12). Serum total PSA and free PSA concentrations were assessed using an electrochemiluminescence immunoassay; there were no significant differences among the groups. The free-to-total PSA ratio was significantly lower statistically in master athletes compared with recreational athletes, but this is not clinically significant as both values (0.22 versus 0.31, respectively) were within the normal range. These results indicate that the free-to-total PSA ratio may be affected by long-term athletic training, and could be important when evaluating athletes with prostate-related disorders.

Phase I study of the novel, oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK): Evaluating the pharmacokinetic effect of a high-fat meal in patients with hormone-refractory prostate cancer (HRPC)

4689 Background: PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known VEGF receptors, important mediators of tumor growth and metastasis. This phase I study in patients (pts) with HRPC assessed the effect of food on the pharmacokinetics (PK) of PTK/ZK and evaluated safety and preliminary efficacy (defined as changes in serum prostate-specific antigen [PSA] levels). Methods: Pts with HRPC received 1,000 mg/day PTK/ZK and were randomized to fed or fasted conditions on days 15, 18, 22, and 25. Blood was collected over 24 hr to assess the PK of PTK/ZK and PSA levels. Results: Of 23 pts treated, 1 pt discontinued due to disease-related adverse event (AE), and 3 due to drug-related AEs. PK data from 19 evaluable pts showed that administration of PTK/ZK with food resulted in a delay in absorption (Tmax increased from 2.0 to 4.0 hr; P < .001), decreased Cmax by 12% (fed:fasted ratio of 0.88; 90% CI = 0.72, 1.08), and increased AUC by 27% (fed:fasted ratio of 1.27; 90% CI = 1.07, 1.52). PK variability was moderate with intrapatient CV% of 21% - 25% and interpatient CV% of 42% for Cmax and AUC; variability was slightly higher under fed conditions. Commonly reported AEs were mostly grades 1/2: nausea (70%), dizziness (52%), headache (52%), hypertension (39%), vomiting (39%), arthralgia (35%), fatigue (30%), constipation (26%), anorexia (17%), back pain (17%), bone pain (13%), and cough (13%). Grade 3 AEs (> 5%) were hypertension (17%) and syncope (9%). The incidence of AEs was similar on fasting and fed days. Overall median time to PSA progression (TTP) was 2 mo. One pt had a 68% reduction from baseline in serum PSA level and TTP of 12 mo; 2 other pts demonstrated > 40% reductions in PSA and TTP of 4 and 5 mo, respectively. Conclusions: The small food effect observed in this study was not associated with higher frequency or severity of AEs on fed vs fasted days, suggesting that the small but statistically significant food effect is not clinically significant, and that PTK/ZK may be taken with or without food. PTK/ZK also exhibited clinical activity in pts with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Schering AG

Phase I study of the novel, oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK): Evaluating the pharmacokinetic effect of a high-fat meal in patients with hormone-refractory prostate cancer (HRPC)

4689 Background: PTK/ZK is a novel, oral angiogenesis inhibitor that potently inhibits all known VEGF receptors, important mediators of tumor growth and metastasis. This phase I study in patients (pts) with HRPC assessed the effect of food on the pharmacokinetics (PK) of PTK/ZK and evaluated safety and preliminary efficacy (defined as changes in serum prostate-specific antigen [PSA] levels). Methods: Pts with HRPC received 1,000 mg/day PTK/ZK and were randomized to fed or fasted conditions on days 15, 18, 22, and 25. Blood was collected over 24 hr to assess the PK of PTK/ZK and PSA levels. Results: Of 23 pts treated, 1 pt discontinued due to disease-related adverse event (AE), and 3 due to drug-related AEs. PK data from 19 evaluable pts showed that administration of PTK/ZK with food resulted in a delay in absorption (Tmax increased from 2.0 to 4.0 hr; P < .001), decreased Cmax by 12% (fed:fasted ratio of 0.88; 90% CI = 0.72, 1.08), and increased AUC by 27% (fed:fasted ratio of 1.27; 90% CI = 1.07, 1.52). PK variability was moderate with intrapatient CV% of 21% - 25% and interpatient CV% of 42% for Cmax and AUC; variability was slightly higher under fed conditions. Commonly reported AEs were mostly grades 1/2: nausea (70%), dizziness (52%), headache (52%), hypertension (39%), vomiting (39%), arthralgia (35%), fatigue (30%), constipation (26%), anorexia (17%), back pain (17%), bone pain (13%), and cough (13%). Grade 3 AEs (> 5%) were hypertension (17%) and syncope (9%). The incidence of AEs was similar on fasting and fed days. Overall median time to PSA progression (TTP) was 2 mo. One pt had a 68% reduction from baseline in serum PSA level and TTP of 12 mo; 2 other pts demonstrated > 40% reductions in PSA and TTP of 4 and 5 mo, respectively. Conclusions: The small food effect observed in this study was not associated with higher frequency or severity of AEs on fed vs fasted days, suggesting that the small but statistically significant food effect is not clinically significant, and that PTK/ZK may be taken with or without food. PTK/ZK also exhibited clinical activity in pts with HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals; Schering AG

Followup Interval Prostate Biopsy 3 Years After Diagnosis of High Grade Prostatic Intraepithelial Neoplasia is Associated With High Likelihood of Prostate Cancer, Independent of Change in Prostate Specific Antigen Levels

Repeat biopsy has been advocated following the diagnosis of high grade prostatic intraepithelial neoplasia to exclude coexisting prostate cancer. We further define the natural history of high grade prostatic intraepithelial neoplasia by determining the incidence of prostate cancer 3 years following diagnosis. A total of 31 men underwent followup interval biopsy 3 years after high grade prostatic intraepithelial neoplasia diagnosis in 1996 to 1997, regardless of change in serum prostate specific antigen (PSA) or digital rectal examination findings. A single pathologist reviewed all biopsy specimens. All men had a minimum of 12 biopsy cores taken at the time of diagnosis. A 3-year followup interval biopsy eight (25.8%) men had prostate cancer, 11 (35.5%) had high grade prostatic intraepithelial neoplasia only and 12 (38.7%) had no disease. Mean serum PSA at diagnosis and before the followup biopsy was 6.88 and 9.69 ng./dl., respectively (p = 0.008). Of the men 48% had less than a 1.0 unit increase in serum PSA. Upon univariate regression analysis change in serum PSA was not associated with the detection of prostate cancer (p >0.10). All 4 patients who subsequently underwent radical prostatectomy had organ confined disease. In a high proportion of men with high grade prostatic intraepithelial neoplasia prostate cancer will develop in a 3-year interval. Our findings support the concept that high grade prostatic intraepithelial neoplasia is a precursor to prostate cancer and that repeat biopsy at a delayed interval is recommended regardless of changes in PSA.

PSA response to finasteride challenge in men with a serum PSA greater than 4 ng/ml and previous negative prostate biopsy: preliminary study

Objectives. To determine, in a prospective study, the prostate-specific antigen (PSA) response to finasteride challenge in men with a serum PSA greater than 4 ng/mL who had undergone previous biopsy. Patients with a serum PSA level greater than 4 ng/mL who have undergone repeated prostate biopsy with prostate cancer (CaP) that was not detected present a diagnostic dilemma. The magnitude of PSA reduction after administration of finasteride has been well documented. In addition, doubling of the PSA value after 1 year of finasteride has been touted to be a more useful paradigm for diagnosing CaP than PSA alone. Methods. Thirty-eight men with a baseline serum PSA level greater than 4 ng/mL and a normal digital rectal examination who had been previously biopsied a minimum of two times, with CaP not detected, were given 5 mg finasteride daily. The PSA level was measured at 6 and 12 months with repeat transrectal ultrasonography and biopsy (12 cores) performed at 1 year. Changes in prostate volume, serum PSA, PSA density, and the incidence of CaP at 1 year were assessed. Results. The mean age of the group was 60.5 years (±7.6). For the group, the average number of previous biopsies performed was 2.9 (range 2 to 6). The baseline PSA level for the entire group was 6.32 ng/mL (±3.2), and the baseline prostate volume was 37.3 cm 3 (±12.4). At 1 year, the PSA level had decreased to 3.73 ng/mL (−41.0%), and the prostate volume had decreased to 30.4 cm 3 (−18.5%). In the 11 men (29%) in whom CaP was detected, the serum PSA decreased from 7.3 to 5.2 ng/mL (−28.8%) and the prostate volume decreased from 37.3 to 32.3 cm 3 (−13.4%). CaP was detected in 0 of 10 men with a serum PSA decrease of 50% or higher, in 6 (32%) of 19 men with a PSA decrease between 33% and 50%, and in 5 (56%) of 9 men who had a PSA decrease of less than 33%. Conclusions. The data in this preliminary study suggest that the magnitude of change in serum PSA after 1 year of finasteride challenge may be useful in diagnosing CaP in patients with elevated PSA levels and prior negative prostate biopsy.

Evaluation of the effect of spinal cord injury on serum PSA levels

Objectives. Prostatic structure and secretory activity are thought to be influenced by autonomic innervation of the prostate. Prostatic denervation is especially likely in patients with spinal cord injury (SCI) at the level of the cauda equina or the conus medullaris, where the peripheral nerve supply to the prostate may be specifically damaged. This may result in changes in serum prostate-specific antigen (PSA) levels, either directly or indirectly. Therefore, we measured serum PSA levels and also studied the influence of factors such as age, catheterization, duration of SCI, urinary tract infection, and history of cystitis on serum PSA values in men with SCI. Methods. Serum PSA levels were determined in 79 men with SCI (age older than 40 years) using banked sera by the Abbott MEIA PSA assay. Variables such as age, catheterization, duration of SCI, urine culture results, and history of cystitis were obtained from a review of patient records. Comparisons were made with a randomly selected, non-SCI control population of 501 men, 40 to 89 years old, who underwent serum PSA determination at our institution. Statistical comparisons were performed using the Mann-Whitney U test (nonparametric), since the populations were not normally distributed. Multivariate logistic regression analysis was used to assess the correlation between the various factors and the serum PSA levels in men with SCI. Results. No statistically significant differences were found in the median serum PSA values between the SCI group and the non-SCI control population. The age-specific PSA values obtained in the SCI group were also comparable to those reported for the general population at large. Age ( P <0.03) and the presence of a catheter ( P <0.0002) were the only two factors that were correlated with higher serum PSA values in the SCI group by regression analysis. Conclusions. Men with SCI tended to have serum PSA value distributions that were similar to those of the general population. However, those in the SCI group who had indwelling catheters were more likely to have higher PSA values at baseline, as were older men with SCI.

Early castration‐induced upregulation of transforming growth factor β1 and its receptors is associated with tumor cell apoptosis and a major decline in serum prostate‐specific antigen in prostate cancer patients

BACKGROUND The mechanism behind castration-induced apoptosis in prostate cells is unknown, but data from other species suggest that transforming growth factor β1 (TGF-β1) may be involved. METHODS By using quantitative RT-PCR and immunohistochemistry, expression of TGF-β1 and its receptors type I and II (RI and RII) was studied in normal and tumor areas of core biopsies taken before and 2–11 days after castration therapy. The TGF-β responses were related to changes in apoptotic index and to changes in serum prostate-specific antigen (PSA). RESULTS In normal prostate tissue, apoptosis was generally increased by castration, and apoptosis was accompanied by an increase in TGF-β1 and RII mRNA levels (P < 0.05). In tumors, apoptosis was seen only in 44% of the cases and in these, but not in the others, TGF-β1, RI, and RII mRNA levels were increased (P < 0.05). In the patients showing a prognostically favorable PSA response (nadir PSA <5 ng/ml), but not in the others, RI and RII mRNA levels were significantly upregulated (P < 0.05). CONCLUSIONS Short-term upregulation of TGF-β1 and its receptors is associated with apoptosis in human prostate and prostate cancer, and possibly with a favorable clinical outcome after castration therapy. Prostate 38:268–277, 1999. © 1999 Wiley-Liss, Inc.

Early castration-induced upregulation of transforming growth factor beta1 and its receptors is associated with tumor cell apoptosis and a major decline in serum prostate-specific antigen in prostate cancer patients.

The mechanism behind castration-induced apoptosis in prostate cells is unknown, but data from other species suggest that transforming growth factor beta1 (TGF-beta1) may be involved. By using quantitative RT-PCR and immunohistochemistry, expression of TGF-beta1 and its receptors type I and II (RI and RII) was studied in normal and tumor areas of core biopsies taken before and 2-11 days after castration therapy. The TGF-beta responses were related to changes in apoptotic index and to changes in serum prostate-specific antigen (PSA). In normal prostate tissue, apoptosis was generally increased by castration, and apoptosis was accompanied by an increase in TGF-beta1 and RII mRNA levels (P < 0.05). In tumors, apoptosis was seen only in 44% of the cases and in these, but not in the others, TGF-beta1, RI, and RII mRNA levels were increased (P < 0.05). In the patients showing a prognostically favorable PSA response (nadir PSA <5 ng/ml), but not in the others, RI and RII mRNA levels were significantly upregulated (P < 0.05). Short-term upregulation of TGF-beta1 and its receptors is associated with apoptosis in human prostate and prostate cancer, and possibly with a favorable clinical outcome after castration therapy.

Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer.

With an hypothesis that post-chemotherapy changes in serum prostate-specific antigen (PSA) levels might serve as a surrogate marker for assessing prostate cancer outcome (i.e., survival), we studied the relationship between pretherapy and post-therapy prognostic factors and survival in patients with androgen-independent prostate cancer. A prognostic model for survival based on pretherapy and post-therapy parameters was developed from the clinical data on 254 patients with androgen-independent prostate cancer treated with 11 different protocol therapies at Memorial Sloan-Kettering Cancer Center. The model was validated by use of an independent dataset of 541 patients enrolled in two randomized phase III trials. In multivariate analysis, a post-therapy decline in PSA levels of 50% achieved in 12 weeks was a statistically significant factor associated with survival (two-sided P = .0012). A similar outcome was obtained with the use of an 8-week time frame. Elevated pretherapy level of serum lactate dehydrogenase (two-sided P = .0001), lower pretherapy level of hemoglobin (P = .0001), and younger age (two-sided P = .0430) had a statistically significant negative impact on outcome. Median survival times were 23, 17, and 9 months for low-, intermediate-, and high-risk groups of patients defined by the prognostic model, respectively. This study confirms the prognostic value of a post-therapy decline in PSA of 50% or greater from baseline in relation to survival in patients with androgen-independent prostate cancer treated with a variety of therapies. Two consecutive determinations at 4-week intervals can be used as an end point for efficacy in phase II trials of therapies in this disease.

Targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 inhibits the growth of PC-82 human prostate cancer in nude mice.

Receptors for luteinizing hormone-releasing hormone (LH-RH) found in prostate cancers might be used for targeting of chemotherapeutic agents. Doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) can be linked to carrier analog [D-Lys6]LH-RH to form the targeted cytotoxic analog of LH-RH, AN-207. We evaluated the effects of AN-207 and its components on the growth of LH-RH receptor-positive human prostate cancer PC-82 xenografted into nude mice. Analog AN-207, radical AN-201, carrier [D-Lys6]LH-RH, or a mixture of [D-Lys6]LH-RH and AN-201 were injected intravenously once at doses of 200 nmol/kg. Tumor growth, body weight, total WBC counts, and serum prostate-specific antigen (PSA) were determined. Receptors for LH-RH on PC-82 tumors were evaluated, and the expression of mRNA for LH-RH receptors was assessed by RT-PCR. Eight weeks after administration of cytotoxic analog AN-207, there was a 67.8% reduction in tumor volume (P < 0.01), 70.7% decrease in tumor burden (P < 0.01), and 36.5% decrease in serum PSA levels (P < 0.01) as compared with controls. Only one of 8 animals treated with AN-207 died. Cytotoxic radical AN-201 caused a 34.2% (not significant, NS) reduction in tumor volume with no change in serum PSA, and killed 3 of 8 mice due to toxicity. Carrier [D-Lys6]LH-RH and the unconjugated mixture of [D-Lys6]LH-RH and AN-201 had no effect on tumor growth. LH-RH receptors as well as the expression of their mRNA were found in PC-82 tumors.

Serial prostate-specific antigen measurements in men with clinically benign prostatic hyperplasia during a 12-month placebo-controlled study with terazosin

Objectives To prospectively analyze whether the treatment of men with clinically benign prostatic hyperplasia (BPH) with alpha blocking agents affects the serum prostate-specific antigen (PSA) levels, and to determine the magnitude of such effect. Methods Serial PSA measurements were performed using the Abbott IMx assay over 1 year in 134 men over the age of 55 years participating in the Hytrin Community Assessment Trial (HYCAT). HYCAT is a 1 -year, randomized, placebo-controlled, double-blinded study of the alpha 1-adrenergic antagonist terazosin. All men had lower urinary tract symptoms and a clinical diagnosis of BPH with an American Urological Association (AUA) symptom index of 13 points or more, an AUA bother score of 8 points or more, and a peak urinary flow rate of less than 15 mL/s. PSA was measured at baseline and at 8, 26, 39, and 52 (end of study) weeks. Results Baseline serum PSA levels weakly correlated with patients' age at study entry, and modestly with residual urine (positive correlation) and peak flow rate (negative correlation), although none of the levels were statistically significant. Changes of serum PSA during the course of the study did not correlate with either one of the symptom severity or bother assessment tools, residual urine, or peak flow rate. Mean PSA increased from a baseline of 2.5 ± 0.22 ng/mL (mean ± SE) by 0.5 ± 0.11 ng/mL in the placebo- and from 2.7 ± 0.23 ng/mL by 0.3 ± 0.11 ng/mL in the terazosin-treated patients ( P = 0.36 by ANOVA). There were no differences in the changes in serum PSA when patients were stratified by decade of life according to the age-specific PSA reference ranges, or by the final dose of terazosin (2, 5, or 10 mg daily). Conclusions The treatment of men with lower urinary tract symptoms and clinical BPH with the alpha 1-adrenergic antagonist terazosin does not affect serum PSA concentration, and thus does not confound longitudinal monitoring of serum PSA levels in patients at risk for prostate carcinoma.

Immunohistochemical analysis of estramustine binding protein with particular reference to proliferative activity in human prostatic carcinoma.

The estramustine binding protein (EMBP) specifically binds to estramustine and was first discovered in the rat ventral prostate. However, the physiological property of EMBP in the human prostate still remains to be elucidated. To elucidate whether EMBP is interrelated with cellular proliferation in human prostatic carcinoma (PC), the change in EMBP immunostaining during luteinizing hormone-releasing hormone (LH-RH) analog administration or during Cis-platinum-based chemotherapy, and the difference in EMBP immunostaining between hormone refractory (hr-PC) and untreated PC were analyzed. Forty-six patients with histologically proven untreated PCs (34 were treated with LH-RH analog and 12 were treated with chemotherapy as an initial therapy) and 14 with hr-PC were used in this study. PC tissues were obtained before and 3 months after the initial therapy. The changes in immunostainings for EMBP, proliferating cell nuclear antigen (PCNA), and nm23 protein were compared with the change in serum prostate-specific antigen (PSA) level and the histological response during the treatment. The increased EMBP expression was observed in tumors with high histological grade and high clinical stage as well as in hr-PC. In untreated PC, EMBP expression weakly correlated with PCNA or nm23 protein immunoreactivity. In PC receiving LH-RH analog, EMBP expression was significantly reduced after treatment, however, no significant changes were observed in PCNA or nm23 protein immunoreactivity. In addition, EMBP expression before the treatment significantly correlated with the serum PSA change, while PCNA expression and nm23 protein immunoreactivity did not. On the other hand, no significant relationship was observed between histological changes induced by the LH-RH analog and immunostainings for EMBP, PCNA, and nm23 protein before treatment. In PC patients receiving chemotherapy, immunostainings for EMBP, PCNA, and nm23 protein were not significantly changed during the treatment. EMBP immunoreactivity was significantly higher in hr-PC than in untreated PC with paralleled change of PCNA expression and nm23 protein immunoreactivity. These observations indicate that EMBP is androgen regulated in some PCs. However, EMBP expression is demonstrated even in hr-PC and is interrelated with cellular proliferation especially in hr-PC.

Detection of Prostate Cancer Relapse With Prostate Specific Antigen Monitoring at Levels of 0.001 to 0.1 micro g./l

The development of prostate specific antigen (PSA) assays with detection limits of approximately 0.001 microgram./l. is technically feasible. We examined if serum PSA changes of 0.001 to 0.1 microgram./l. for up to 3 years after radical prostatectomy have any clinical value. We studied 148 patients with a postoperative PSA of less than 0.1 microgram./l. by a conventional PSA assay. At least 3 serial serum samples were collected per patient along with detailed clinicopathological features. Serial serum samples were analyzed for PSA with the ultrasensitive method. Associations between increase in serum PSA and clinicopathological features were analyzed with the unconditional logistic regression model. After establishing a set of interpretative criteria, we divided the patients into 51 with biochemical relapse, 93 who were free of relapse and 4 with equivocal status. Between the groups with and without relapse there was no difference in year of surgery, age at operation or length of followup. Compared to patients without relapse, those with biochemical relapse were likely to have positive surgical margins (p < 0.01), larger tumor volumes (p < 0.01), greater preoperative PSA (p = 0.03) and disease extending outside the prostate (p = 0.02). The relative risks for biochemical relapse estimated by a univariate logistic regression model were 3.1 (95% confidence interval 1.39 to 6.82, p < 0.01) for positive surgical margin, 3.4 (95% confidence interval 1.46 to 8.13, p < 0.01) for tumor volume, 2.3 (95% confidence interval 1.08 to 5.02, p = 0.03) for high preoperative PSA and 2.7 (95% confidence interval 1.12 to 6.26, p = 0.03) for extraprostatic tumor extension. At multivariate analysis with the same model the associations between positive surgical margins and biochemical relapse (relative risk 2.95, p = 0.04) and tumor volume (relative risk 3.36, p = 0.03) remained significant. These associations were still observed when we analyzed a subset of patients classified as having biochemical relapse based on PSA changes of 0.001 to 0.08 microgram./l. Increases in postoperative serum PSA at levels of 0.001 to 0.1 microgram./l. after radical prostatectomy are associated with clinicopathological features of poor prognosis. Monitoring postoperative cases with a highly sensitive PSA assay (detection limit 0.001 microgram./l.) could offer a simple and effective means of detecting clinically important biochemical relapse early after radical prostatectomy. These patients may be suitable for early intervention when effective treatments for relapse become available.

The Influence of Ejaculation on Serum Levels of Prostate Specific Antigen

While prostatic manipulation and surgery have been shown to increase serum prostate specific antigen (PSA), the influence of ejaculation on serum PSA remains controversial. We examined the effect of ejaculation on serum PSA levels. We evaluated 100 men 25 to 35 years old with no history of surgery or inflammatory disease of the urogenital tract. Serum PSA was evaluated 1 and 24 hours after ejaculation, and serum testosterone and seminal fluid PSA levels were determined. In all men a baseline PSA level was detected. There were no statistically significant changes in serum PSA and testosterone 1 and 24 hours after ejaculation. Mean PSA concentration was significantly higher in seminal plasma than in serum. However, we did not observe a correlation between serum and seminal plasma PSA levels. Based on our data ejaculation does not affect serum PSA concentration in young men, and there seems to be no physiological relationship between ejaculation and PSA level.

PSA divergence. A new parameter for the accurate longitudinal assessment of prostatic disease.

Prostate-specific antigen (PSA) and the various parameters derived utilizing this marker have increased our ability to diagnose early prostatic disease; however, their accuracy in identifying the etiology of the disease remains somewhat limited. We propose a new PSA derivative, termed "PSA divergence" (PSADI), defined as the change in serum PSA over time (years) divided by the change in prostatic volume over time (years), to more accurately distinguish benign, premalignant, and malignant prostatic diseases. In this study, we evaluated 160 subjects with a PSA >4.0 ng/ml who were found by transrectal ultrasound-guided biopsy (TRUS) to have either benign prostatic hyperplasia or prostatic intraepithelial neoplasia. These men were followed at 6 or 12 months with serial PSA, digital rectal exam (DRE), and TRUS with rebiopsy. Data analysis demonstrated a statistically significant (p < 0.05) correlation between PSADI and each final pathologic outcome, suggesting that PSADI is useful in distinguishing among intraepithelial neoplasia and benign and malignant prostatic disease.

Ejaculation increases the serum prostate-specific antigen concentration

To determine the effect of ejaculation on the serum prostate-specific antigen (PSA) concentration in men at risk for developing prostate cancer. A prospective, community-based study was conducted in which 64 men, aged 49 to 79 years, underwent a serum PSA determination immediately before ejaculation (baseline) and at 1 hour, 6 hours, and 24 hours following ejaculation. The serum PSA also was measured 48 hours and 1 week after ejaculation if the concentration had not returned to the baseline value by the previous time interval. All subjects abstained from ejaculation for a minimum of 7 days prior to the study and until the PSA concentration returned to the baseline level. Absolute and relative change in serum PSA concentration, as well as the time to return to baseline PSA concentration following ejaculation, were assessed. The serum PSA concentration increased following ejaculation in 87% of the subjects. The mean baseline PSA was 1.8 ng/mL (median, 0.7 ng/mL). The mean absolute PSA change +/- standard deviation 1 hour, 6 hours, 24 hours, and 48 hours after ejaculation was 0.8 +/- 1.32 ng/mL, 0.3 +/- 0.66 ng/mL, 0.2 +/- 0.33 ng/mL, and 0.4 +/- 0.40 ng/mL, respectively. The mean relative PSA change +/- standard error 1 hour, 6 hours, 24 hours, and 48 hours after ejaculation was 41 +/- 4%, 9 +/- 1.5%, 8 +/- 1.3%, and 10 +/- 2.3%, respectively. The absolute and relative changes in PSA concentration noted 1 hour, 6 hours, and 24 hours after ejaculation were statistically significant (P = 0.0001). A strong correlation was observed between absolute change in PSA and baseline serum PSA, at each time interval (1 hour: r = 0.68, 6 hours: r = 0.77, 24 hours: r = 0.70; P < 0.0001) after ejaculation. Similarly, a significant correlation was noted between absolute change in PSA and patient age at each time interval (1 hour: r = 0.37, 6 hours: r = 0.38; P = 0.002, 24 hours: r = 0.55; P < 0.0001). Ninety-two percent of subjects returned to baseline by 24 hours (95% confidence interval (Cl) = 83% to 97%), whereas 97% of subjects returned to baseline by 48 hours (95% Cl = 89% to 99%). Ejaculation causes a significant increase in the serum PSA concentration in men between 49 and 79 years of age that may persist for up to 48 hours. This change appears to correlate with age and baseline PSA. It is recommended that men abstain from ejaculation for 48 hours prior to having a serum PSA determination.

Predicted and actual change in serum PSA following prostatectomy for BPH

Objective. To determine the relationship between prostatic adenoma volume and serum prostate-specific antigen (PSA) levels in patients with benign prostatic hyperplasia (BPH), and to compare the predicted change in serum PSA following prostatectomy with the actual change observed. Methods. Transrectal ultrasound (TRUS) estimation of prostatic adenoma (transition zone) and total gland volumes were calculated in 96 patients prior to prostatectomy. BPH was confirmed histologically following transurethral prostatectomy (in 86) and open prostatectomy (in 10). Serum PSA was measured preoperatively in all patients and post-operatively in 87 patients. Results. Correlation coefficients of 0.607 and 0.614 were observed between PSA and adenoma and total gland volumes, respectively. The geometric mean ratio of PSA to adenoma volume was 0.120 μg/L/cc with 95% CI (0.104, 0.139) and to total gland volume was 0.068 μg/L/cc with 95% CI (0.058, 0.078). TRUS-determined adenoma and total gland volumes correlated well (r = 0.915), as did TRUS-determined adenoma volume and resected weight (r = 0.878). The mean ratio of change in PSA to resected weight was −0.096 μg/L/g with 95% CI (−0.128, −0.064). Neither total gland volume nor operation type affected the relationship between change in serum PSA and resected weight. Conclusions. The adenoma should be the main determinant of serum PSA levels in patients with BPH. TRUS adenoma volume measurement is therefore the most appropriate preoperative measure when one is interpreting elevated levels of serum PSA in men thought clinically to have BPH.

Effect of cystoscopy, prostate biopsy, and transurethral resection of prostate on serum prostate-specific antigen concentration

To assess the effect of cystoscopy, prostate biopsy, and transurethral resection of the prostate (TURP) on the serum prostate-specific antigen (PSA) concentration, 101 patients were evaluated. For cystoscopic examination, 69 men were randomized in a prospective manner to one of three groups: flexible cystoscopy, rigid cystoscopy, and a control cohort. The median change in serum PSA was 0.1 ng/mL following flexible cystoscopy, 0.05 ng/mL after rigid cystoscopy, and 0.05 ng/mL for the control group, in which two serum PSA determinations were obtained without an intervening cystoscopy. The differences between the three groups were not statistically significant. The effect of prostate biopsy and TURP was examined in 32 men. Prostate biopsy caused an immediate elevation in the serum PSA level, with a median increase of 7.9 ng/mL (p < 0.0001). Similarly, TURP produced an elevation in the serum PSA concentration, with a median change of 5.9 ng/mL (p < 0.001). The median time required for the serum PSA value to return to a stable level after prostate biopsy was fifteen days (range: 5–21 days) for men with prostate cancer and seventeen days (range: 3–30 + days) for men without cancer, and eighteen days (range: 12–30+ days) for men who underwent TURP These findings indicate that a serum PSA determination after either a flexible or a rigid cystoscopy is accurate and reliable. Both biopsy and TURP cause an immediate increase in the serum PSA level, which usually returns to a stable, baseline level within three weeks. However, because in some patients the serum PSA still remained elevated after four weeks, it is recommended that a serum PSA determination not be obtained for at least six weeks after either a prostate biopsy or TURP.