Association of prostate‐specific antigen doubling time and cancer in men undergoing repeat prostate biopsy

Objectives: To analyze the association between prostate‐specific antigen doubling time with prostate cancer risk and grade among men with prostate‐specific antigen levels ≥4.0 ng/mL undergoing repeat prostate biopsy. Methods: A total of 286 patients with prostate‐specific antigen ≥4 ng/mL and available prostate‐specific antigen doubling time data, who underwent repeat prostate biopsy from 1996–2009, were included in this analysis. Prostate‐specific antigen doubling time was divided into three groups: >9 years, 3–9 years and <3 years. Multivariate analyses of prostate‐specific antigen doubling time with cancer risk and grade (≤3 + 4 vs≥4 + 3) were carried out using logistic regression adjusting for prebiopsy prostate‐specific antigen, race, age, digital rectal examination, year of biopsy and number of prior negative biopsies. Results: The median prostate‐specific antigen doubling time before biopsy was 4.5 years (interquartile range = 2.5–10). Shorter prostate‐specific antigen doubling time was associated with higher prostate‐specific antigen (P < 0.001), but it was unrelated to age, digital rectal examination or race. Shorter prostate‐specific antigen doubling time as a continuous variable was associated with greater prostate cancer risk in both uni‐ (hazard ratio = 0.99, 95% confidence interval = 0.98–0.99, P = 0.001) and multivariate analysis (hazard ratio = 0.99, 95% confidence interval = 0.98–0.99, P = 0.004). The prevalence of cancer among prostate‐specific antigen doubling time groups (>9, 3–9, <3 years) was 17%, 37% and 40%, respectively. Shorter prostate‐specific antigen doubling time groups were associated with higher cancer risk (P = 0.001). Stratified by grade, short prostate‐specific antigen doubling time as a continuous variable significantly predicted both low‐ (P = 0.010) and high‐grade disease (P = 0.049). The inclusion of prostate‐specific antigen doubling time groups in a multivariate model to predict biopsy positivity increased its accuracy from 0.69 to 0.74. Conclusion: Prostate‐specific antigen doubling time seems to provide further cancer risk assessment in men undergoing repeat biopsy for prostate‐specific antigen ≥4.0 ng/mL. If validated in future studies, the present findings support the use of prostate‐specific antigen doubling time in the risk stratification of this patient population.     

Implications of prostate-specific antigen doubling time as indicator of failure after surgery or radiation therapy for prostate cancer

OBJECTIVES: To review the methodology of PSA doubling time (PSA DT) calculations and the implications of PSA DT for the follow-up of prostate cancer patients curatively treated with surgery or radiation therapy. METHODS: A literature search of the most recent articles on PSA DT (those published after 2000) led to the selection of six studies with the largest and best-documented cohorts of patients treated with surgery or irradiation with curative intent. RESULTS: PSA kinetics, in the form of PSA DT, is the most effective parameter for identifying patients at significant risk for mortality specific to prostate cancer. Thresholds of 3, 6, and 12 mo have shown prognostic significance both in surgical and radiation series, notwithstanding differences in treatment selection, definition of biochemical recurrence, and methods of DT calculation. CONCLUSIONS: In retrospective studies, PSA DT is a reliable predictor of prognosis; however, prospective validation studies are needed to determine the cut points of PSA DT. Optimal time intervals for calculation and optimal thresholds are still to be determined.     

The interpretation of serum prostate specific antigen in men receiving 5alpha-reductase inhibitors: a review and clinical recommendations

PURPOSE: We reviewed the effects of 5alpha-reductase inhibitors on prostate specific antigen and clarified the adjustments that should be made to compensate for these effects to ensure that the usefulness of prostate specific antigen for detecting prostate cancer is maintained. MATERIALS AND METHODS: We reviewed articles published in the scientific literature with relevance to the effects of 5alpha-reductase inhibitors on the usefulness of prostate specific antigen for detecting prostate cancer. RESULTS: A total serum prostate specific antigen of 4.0 ng/ml has traditionally been used as the threshold for triggering prostate biopsy. However, clinical trials of finasteride and dutasteride have shown that 5alpha-reductase inhibitors decrease serum prostate specific antigen in patients with and without prostate cancer. To compensate, the doubling rule has been applied in clinical trials and clinical practice. However, doubling serum prostate specific antigen may overestimate actual prostate specific antigen in some patients receiving 5alpha-reductase inhibitors for up to 6 to 9 months, accurately estimate prostate specific antigen from 1 to 3 years and underestimate it thereafter. An increase in prostate specific antigen of 0.3 ng/ml from nadir as a trigger for biopsy maintains 71% sensitivity for prostate cancer in men receiving dutasteride with 60% specificity, similar to the 4.0 ng/ml prostate specific antigen cutoff using placebo. CONCLUSIONS: We propose that a prostate specific antigen increase from nadir of 0.3 ng/ml or greater could represent an alternative to the doubling rule for monitoring prostate specific antigen in patients on 5alpha-reductase inhibitors. The prostate specific antigen increase from nadir appears to be a more accurate cancer indicator than a doubled value in some patients.     

A pilot study of the liposomal MUC1 vaccine BLP25 in prostate specific antigen failures after radical prostatectomy

PURPOSE: Men with biochemical failure after radical prostatectomy have few therapeutic options other than androgen deprivation therapy. Targeted therapies in this group are appropriate because the optimal timing of the initiation of hormonal therapy in this patient population is unknown. A single institution pilot trial was performed using BLP25 liposome vaccine in hormone na?ve patients with prostate specific antigen failure after radical prostatectomy to determine if prostate specific antigen progression could be halted. MATERIALS AND METHODS: Men with biochemical failure after radical prostatectomy were enrolled. Primary end points were efficacy and safety of the MUC1 BLP25 liposomal vaccine. Changes in prostate specific antigen doubling time were also evaluated. Patients received a single intravenous dose of cyclophosphamide, followed by vaccinations with BLP25 liposome vaccine for up to 1 year. Prostate specific antigen was measured at baseline and during treatment, and prostate specific antigen doubling time was calculated for these intervals. RESULTS: A total of 16 patients with a median age of 60 years were enrolled. All patients received cyclophosphamide and 15 of 16 completed the primary treatment period. Ten patients completed the maintenance period. After the 8-week primary treatment period 8 of 16 patients had stable or decreased prostate specific antigen. At the last on-study prostate specific antigen measurement 1 patient maintained stable prostate specific antigen but all others had progression. However, 6 of the 16 patients had greater than 50% prolongation of prostate specific antigen doubling time compared to pre-study prostate specific antigen doubling time. CONCLUSIONS: BLP25 liposome vaccine shows promise for prolonging prostate specific antigen doubling time in hormone na?ve men with biochemical failure after prostatectomy and little morbidity. This could potentially translate into the deferral of hormonal therapy. Further testing in this population of patients is warranted.     

Prostate-specific antigen kinetics in clinical decision-making during active surveillance for early prostate cancer--a review

CONTEXT: The kinetics of prostate specific antigen (PSA) are generally assumed to be indicative of tumour progression and are therefore used in clinical decision-making in men on active surveillance for early prostate cancer. OBJECTIVE: This review aims to provide support for exploiting PSA kinetics in an active surveillance setting. EVIDENCE ACQUISITION: We searched the Medline database and reviewed the evidence on both the relation between PSA kinetics before radical treatment for prostate cancer and outcome, as well as the role of PSA kinetics during active surveillance. Furthermore, the benefits and setbacks of different derivatives of PSA kinetics, minimum required time interval and number of measurements, practical recommendations, and pitfalls of their use in clinical practice are discussed. EVIDENCE SYNTHESIS: The evidence concerning the prognostic value of the PSA velocity (PSA-V) and PSA doubling time (PSA-DT) is sparse, especially in active surveillance. PSA kinetics should therefore be combined with other diagnostic measures as the trigger for deferred radical treatment or repeat prostate biopsies. There seems to be consensus among several reports on the unfavourable outcome relating to a PSA-DT <3-4 yr and on the favourable prognostic value of a PSA-DT >10 yr or a decreasing PSA level. Online tools provide help with calculations and insight on disease development. The best method of calculation, number of measurements, and time interval between measurements is unknown for now. CONCLUSIONS: Despite the current deficits in our understanding of the natural behaviour of early prostate cancer and its relation to serum PSA levels, and despite several secondary factors playing a role in PSA kinetics, PSA kinetics are a practical parameter we can offer men on active surveillance to assess the status of their disease.     

Detectable prostate specific antigen between 60 and 120 days following radical prostatectomy for prostate cancer: natural history and prognostic significance

PURPOSE: Following radical retropubic prostatectomy for prostate cancer, if the serum prostate specific antigen fails to become undetectable, occult micrometastatic disease is suspected. We assessed the natural history of disease progression, and predictors of recurrence and survival in this group of patients. MATERIALS AND METHODS: We identified 303 men treated with radical retropubic prostatectomy for prostate cancer between 1990 and 1999, who had a detectable prostate specific antigen between 60 and 120 days postoperatively. Systemic recurrence-free and cancer specific survival were estimated using the Kaplan-Meier method, and analyzed using Cox proportional hazards models. RESULTS: Clinical and pathological features were more adverse among men whose postoperative prostate specific antigen was detectable. These men had poorer systemic recurrence-free survival and cancer specific survival compared to men with an undetectable postoperative prostate specific antigen, and even men whose prostate specific antigen subsequently became detectable. These differences persisted after multivariate adjustment for preoperative prostate specific antigen, specimen Gleason score, seminal vesicle and margin status. With a median followup of 8.5 years, 50 systemic recurrences and 26 deaths from cancer were observed. Gleason score and the prostate specific antigen doubling time were multivariate predictors of systemic recurrence, while Gleason score, margin status and seminal vesicle invasion were predictors of death from cancer. CONCLUSIONS: A detectable prostate specific antigen immediately following radical retropubic prostatectomy confers an increased risk of progression and death, but only in a subset of patients, who may be identified on the basis of pathological features and prostate specific antigen doubling time. In future such patients may be suitable for trials of systemic therapy.     

ROLE OF EARLY ADJUVANT HORMONAL THERAPY AFTER RADICAL PROSTATECTOMY FOR PROSTATE CANCER

PURPOSE: Recent prospective randomized studies have shown that adjuvant hormonal therapy combined with local treatment can significantly improve overall survival in patients with locally advanced disease. This finding challenges the previous belief that adjuvant hormonal therapy may not be beneficial for minimal stages TxN + M0 or less prostate cancer, particularly when combined with local treatment. We reviewed the benefits of adjuvant hormonal therapy in patients at risk for disease progression, especially when administered after radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed the current literature and evaluated clinical information on stage pT3b cancer from a large single institution prostate cancer database to determine the current role of adjuvant hormonal therapy after radical prostatectomy for prostate cancer. RESULTS: Retrospective experimental and clinical studies have proved the impact of adjuvant hormonal therapy for decreasing prostate specific antigen (PSA) and clinical disease progression in patients with regionally limited prostatic cancer. This finding applies to stage pT3b as well as to lymph node positive cancer. Our literature review and current data from the Mayo Clinic database show that adjuvant hormonal therapy after prostatectomy has a significant impact on prostate specific antigen (PSA) progression but it also decreases systemic progression and cause specific death in patients with stage pT3b and lymph node positive disease. After adjusting for preoperative PSA, margins, grade, ploidy and patient age the risk ratio for stage pT3b disease in 707 cases was 0.3 (95% confidence interval 0.2 to 0.7). A recent prospective randomized trial showed a significant decrease in cancer death in N+ cases when adjuvant hormonal therapy was administered after radical prostatectomy, supporting previous Mayo Clinic data on N+ disease that favors combination therapy. In the PSA era, that is 1987 and after, our database data on stage pTxN+ cancer indicates that radical prostatectomy and hormonal therapy for single node positive disease resulted in 94% 10-year cause specific survival, which was not significantly different from the rate in patients with N0 disease after adjusting for local stage, Gleason grade, margins, ploidy, PSA and adjuvant hormonal therapy. CONCLUSIONS: Our literature review, including prospective randomized studies, and more recent results in the PSA era from our database indicate that early adjuvant hormonal therapy has a significant impact on time to progression and cause specific survival in patients with seminal vesicle invasion and limited lymph node disease who undergo radical prostatectomy, although in a retrospective nonrandomized study. Future prospective studies with longer followup are needed to evaluate the potential benefit of adjuvant treatment in regard to survival for stages pT2 and pT3a disease with unfavorable pathological variables.     

Wide variation of prostate-specific antigen doubling time of untreated, clinically localized, low-to-intermediate grade, prostate carcinoma

OBJECTIVE: To assess the prostate specific antigen (PSA) doubling time of untreated, clinically localized, low-to-intermediate grade prostate carcinoma. PATIENTS AND METHODS: A prospective single-arm cohort study has been in progress since November 1995 to assess the feasibility of a watchful-observation protocol with selective delayed intervention for clinically localized, low-to-intermediate grade prostate adenocarcinoma. The PSA doubling time was estimated from a linear regression of ln(PSA) against time, assuming a simple exponential growth model. RESULTS: As of March 2003, 231 patients had at least 6 months of follow-up (median 45) and at least three PSA measurements (median 8, range 3-21). The distribution of the doubling time was: < 2 years, 26 patients; 2-5 years, 65; 5-10 years, 42; 10-20 years, 26; 20-50 years, 16; >50 years, 56. The median doubling time was 7.0 years; 42% of men had a doubling time of >10 years. CONCLUSIONS: The doubling time of untreated clinically localized, low-to-intermediate grade prostate cancer varies widely.     

PSA Velocity and Doubling Time in Diagnosis and Prognosis of Prostate Cancer

Cancer is a growth process and it is natural that we should be concerned with how the routinely used marker of prostate cancer tumour burden - PSA - changes over time. Such change is measured by PSA velocity or PSA doubling time, described in general as "PSA kinetics". However, it turns out that calculation of PSA velocity and doubling time is far from straightforward. More than 20 different methods have been proposed, and many of these give quite divergent results. There is clear evidence that PSA kinetics are critical for understanding prognosis in advanced or relapsed prostate cancer. However, PSA kinetics have no value for men with an untreated prostate: neither PSA velocity nor doubling time have any role in diagnosing prostate cancer or providing a prognosis for men before treatment.     

Long-term outcome following radical prostatectomy in men with clinical stage T3 prostate cancer

PURPOSE: We evaluated patients at our institution who underwent radical prostatectomy for clinical stage T3 prostate cancer to determine their long-term clinical outcomes. MATERIALS AND METHODS: We reviewed our prospective surgical database and identified 176 men who underwent radical retropubic prostatectomy for clinical stage T3 prostate cancer from 1983 to 2003. Clinical and pathological data were reviewed and evaluated in a Cox proportional hazards model to determine preoperative predictors of biochemical recurrence. Clinical progression following biochemical recurrence was evaluated and clinical failure was defined as the development of clinical metastases or progression to hormone refractory prostate cancer. RESULTS: Of the 176 patients with cT3 prostate cancer 64 (36%) received neoadjuvant hormonal therapy. At a mean followup of 6.4 years 84 (48%) patients had disease recurrence with a median time to biochemical recurrence of 4.6 years. The actuarial 10-year probability of freedom from recurrence was 44%. On multivariate analysis biopsy Gleason score, pretreatment serum prostate specific antigen and year of surgery were independent predictors of biochemical recurrence. Neoadjuvant hormonal therapy was not a significant predictor of biochemical recurrence. Following biochemical recurrence clinical failure developed in 30 of 84 (36%) men with a median time of 11 years. Overall the 5, 10 and 15-year probabilities of death from prostate cancer were 6%, 15% and 24%, respectively. CONCLUSIONS: More than half (52%) of our patients remained free of disease recurrence following radical prostatectomy. In our series neoadjuvant hormonal therapy offered no advantage with respect to disease recurrence. Radical prostatectomy remains an integral component in the treatment of select patients with clinical stage T3 prostate cancer.     

Delayed therapy with curative intent in a contemporary prostate cancer watchful-waiting cohort

OBJECTIVE: To identify predictors of delayed therapy with curative intent, an increasingly common option in contemporary patients with prostate cancer who initially choose watchful waiting. PATIENTS AND METHODS: The characteristics of all patients at one institution and diagnosed with T1-4NXM0 prostate cancer between 1993 and 2000 were prospectively recorded. Factors recorded included: age, tumour stage, histological type, Gleason score, serum prostate specific antigen (PSA) level, prostate volume, PSA density (PSAD), percentage of positive biopsy cores, and the initial treatment selection. Outcomes, including all cancer-directed interventions, all serum PSA values, and initial outcomes of all interventions with curative intent, were determined by review of all medical records and cancer registry data. RESULTS: Of 187 patients on watchful waiting, 175 had stage T1 or T2 cancer and were analysed primarily. Thirty-eight (22%) of these patients received delayed intervention with curative intent (15 radical prostatectomy, 17 external beam radiotherapy, six brachytherapy). Age (P < 0.001) and percentage of positive biopsy cores (P = 0.042) were significant independent predictors of intervention with curative intent. When the PSA doubling time was added to the model it became a significant predictor (P = 0.018), with percentage positive biopsy cores (P = 0.022) and age (P < 0.001). CONCLUSIONS: Therapy with curative intent is common in contemporary patients with prostate cancer who initially choose watchful waiting. Age and percentage positive biopsy cores are independent predictors of such intervention, with PSA doubling time also an independent predictor.     

Mean time to cancer-specific death of apparently clinically localized prostate cancer: policy implications for threshold ages in prostate-specific antigen screening and ablative therapy

OBJECTIVE: To assess the mean time to cancer-specific death in patients with prostate cancer, using a minimum follow-up of 14 years at one institution, and thus evaluate the minimum life-expectancy for eligibility for radical surgery, radiotherapy and, implicitly, prostate specific antigen (PSA) screening. PATIENTS AND METHODS: The tumour registry of the authors' institution was searched for the records of patients with prostate cancer (stages T1 and nonmetastatic T2-3) over the period 1976-1983, chosen to give a maximum follow-up with sufficient numbers of patients. Kaplan-Meier curves and the mean time to death to 1995 for palpable and impalpable cancers were calculated. Deaths not from cancer and from unknown causes were censored. Patients still alive were also censored, except for in the calculation of mean time to death. RESULTS: Patients with both stages of disease had a steep increase in mortality at 16 years. The mean (SEM) time to prostate cancer-specific death for T1 disease was 17 (1.8) years and for T2-T3 (palpable) was 11.7 (1.2 years). CONCLUSION: These results suggest that, if there is to be one at all, the upper age limit for prostate cancer screening should be 62 years.     

Long-term prognostic significance of primary Gleason pattern in patients with Gleason score 7 prostate cancer: impact on prostate cancer specific survival

PURPOSE: We determined the long-term clinical significance of primary Gleason pattern in patients with Gleason score 7 prostate cancer. MATERIALS AND METHODS: We reviewed the records of all patients who underwent bilateral pelvic lymph node dissection and radical retropubic prostatectomy for Gleason score 7 prostate cancer at our institution. All patients who underwent adjuvant hormonal or radiation therapy were excluded from analysis. Patients were monitored for biochemical failure, that is PSA progression, systemic recurrence and cancer specific survival. RESULTS: We identified 1,688 patients who met admission criteria, of whom 1,256 (74.4%) had primary Gleason pattern 3 and 432 (25.6%) had primary Gleason pattern 4. Median followup was 6.9 years. At 10 years primary Gleason pattern 3 was associated with increased biochemical recurrence-free survival (48% vs 38%, p <0.001), lower systemic recurrence (8% vs 15%, p <0.001) and higher cancer specific survival (97% vs 93%, p = 0.013) for Gleason primary grades 3 and 4, respectively. All of these end points remained significant on multivariate analysis when controlling for preoperative PSA, seminal vesicle involvement, margin status, DNA ploidy and TNM staging. PSA doubling time was shorter in patients with primary Gleason pattern 4 (1.64 vs 1.01 years). Systemic recurrence and cancer specific survival were associated with a PSA doubling time of less than 1 year. CONCLUSIONS: Gleason score 7 prostate cancer is a heterogeneous entity. We should continue to stratify patients according to primary Gleason pattern. Patients with Gleason score 4 + 3 prostate cancer have more aggressive disease and experience higher rates of biochemical failure, systemic recurrence and cancer specific death.     

Prostate specific antigen density correlates with features of prostate cancer aggressiveness

PURPOSE: An increased prostate specific antigen density (serum prostate specific antigen divided by prostate volume) is an established parameter to help determine the need to perform prostate biopsies. A man with a high prostate specific antigen and a normal size prostate gland is more likely to have cancer than a man with the same prostate specific antigen and a large gland. Prostate specific antigen in relation to prostate size should also reflect the volume of cancer in the gland. One group defined clinically unimportant prostate cancer as tumor volume less than 0.5 cc, organ confined disease and Gleason less than 7. Another group noted that at the time of biopsy, a prostate specific antigen density less than 0.15 ng/ml/cc combined with low risk clinical tumor features predicted insignificant cancer. There are limited published validating data on the association of prostate specific antigen density with the criteria for prostate cancer aggressiveness. We tested the association of prostate specific antigen density with features of tumor aggressiveness in a screened and in a nonscreened cohort of patients with clinically localized prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: The screened patient cohort included 1,280 patients with screen detected prostate cancer treated from 1990 to 2002 at Washington University, and the nonscreened cohort included 382 patients treated from 2003 to 2004 at Northwestern University. We recorded the clinical and pathological tumor parameters in a prospective database. Parameters evaluated were pathological tumor stage, Gleason sum, tumor volume, biochemical progression and the previously mentioned 2 criteria for clinically unimportant cancers. We grouped patients into 4 prostate specific antigen density categories of less than 0.1, 0.1 to 0.14, 0.15 to 0.19 and greater than 0.19 ng/ml/cc. RESULTS: There was a significant trend for worsening clinicopathological prognostic features as prostate specific antigen density increased. There were 357 (82%), 283 (75%), 171 (75%) and 192 (55%) men with organ confined disease with clear surgical margins if prostate specific antigen density was less than 0.1, 0.1 to 0.14, 0.15 to 0.19 and greater than 0.19 ng/ml/cc, respectively (p <0.001). There were 86 (20%), 102 (27%), 64 (28%) and 157 (45%) men with a Gleason sum greater than 7 when grouped into each increasing PSA density category, respectively (p <0.001). There were 91 (21%), 91 (25%), 74 (33%) and 157 (46%) men with a total cancer volume greater than 0.5 cc when grouped into each increasing PSA density category, respectively (p <0.001). Prostate specific antigen velocity was greater than 2 ng/ml per year in 11%, 30%, 27% and 46% of men if prostate specific antigen density was less than 0.1, 0.1 to 0.14, 0.15 to 0.19 and greater than 0.19 ng/ml/cc, respectively (p <0.001). CONCLUSIONS: Prostate specific antigen density measurements are useful in helping to determine the aggressiveness of clinically localized prostate cancer, and can be used as an adjunct in predicting insignificant cancer and outcomes after local therapy.     

Prostate biopsy: indications and technique

PURPOSE: The last decade has seen numerous modifications in the way prostate cancer is diagnosed. We review the current indications for and methods of prostate biopsy. MATERIALS AND METHODS: The English language literature was reviewed regarding major indications for and methods of prostate biopsy. Pertinent peer reviewed articles were collated and analyzed. RESULTS: The most widely accepted indication for prostate biopsy is a prostate specific antigen (PSA) value of greater than 4.0 ng./ml. However, some investigators advocate prostate biopsy for men with a PSA value in the 2.5 to 4.0 ng./ml. range, believing that use of this parameter results in detection of a greater number of cases of curable disease. Age specific PSA range, percent free PSA and presence of prostatic intraepithelial neoplasia or atypia are all considered to be relative indications for prostate biopsy. The current literature describes a trend toward increasing the number of cores obtained and the sites biopsied beyond those of the standard sextant technique. The additional cores in many series are obtained from more lateral regions of the gland. CONCLUSIONS: Although several criteria are used as indications for initial prostate biopsy, all are based on PSA level and/or abnormal digital rectal examination. Future improvements in currently used prostate cancer markers may result in better selection of cases to biopsy. There is no universally accepted technique of prostate gland biopsy. The current literature supports use of more extensive biopsy techniques to increase the likelihood of prostate cancer detection.     

The effects of 5alpha-reductase inhibitors on the natural history, detection and grading of prostate cancer: current state of knowledge

PURPOSE: The Prostate Cancer Prevention Trial (PCPT) showed that the 5alpha-reductase inhibitor (5ARI) finasteride significantly decreased the 7-year period prevalence of prostate cancer vs placebo. However, Gleason score 7-10 tumors were significantly more common in the finasteride vs the placebo group. We considered data on the effects of 5ARIs on prostate cancer natural history and detection. MATERIALS AND METHODS: A detailed review was performed of the literature identified from the MEDLINE database examining the effects of 5ARIs on prostate cancer prevalence and tumor histopathology. RESULTS: In PCPT there were fewer biopsies performed for cause in the finasteride vs the placebo group and the proportion of high grade tumors in the treatment groups did not diverge with time. Given that finasteride has an effect on prostate specific antigen and prostate volume, which are key factors in triggering prostate biopsies, they may be significant confounders of Gleason score results. Prostate shrinkage in the finasteride treated group may minimize biopsy sampling error. Furthermore, histological studies have shown that 5ARIs have a significant effect on prostate architecture, which can make the interpretation of prostate specimens in men treated with 5ARIs difficult. Further evaluation of PCPT findings will help determine the true nature of these observations. CONCLUSIONS: 5ARIs decrease the risk of prostate cancer but also alter the detection of disease through effects on prostate specific antigen, and prostate volume and histology. The weight of evidence suggests an artifactual effect of finasteride on Gleason grading in the PCPT. The role of 5ARIs for prostate cancer chemoprevention needs further examination before it can be considered for wide recommendation.     

Prostate-specific antigen doubling time as a prognostic marker in prostate cancer

Prostate cancer has a varied natural history. Men with similar serum prostate-specific antigen (PSA) levels, clinical stages, and histologic features in their tissue specimens can have markedly different outcomes. While prostate cancer is lethal in some patients, most men die with cancer rather than because of it. Moreover, histologically apparent cancer can be found in the prostate glands of approximately 42% of men over 50 years of age who die from other causes, but the lifetime risk that a man in the US will be diagnosed with prostate cancer is estimated to be 11% and the risk of dying from the disease is only 3.1%. Consequently, appropriate disease management requires risk assessment. How likely is it that a given man's cancer will progress or metastasize over his remaining lifetime? What is the probability of successful treatment? What are the risks of adverse effects and complications of each treatment? Physicians use a variety of clinical and pathologic parameters to assess the risk that a given cancer poses to an individual patient. In addition to the accepted parameters of serum PSA level, clinical staging, and pathologic grading and staging, PSA doubling time has emerged as an important factor in the evaluation of men with newly diagnosed prostate cancer or prostate cancer that recurs after treatment. PSA doubling time can also be used as a surrogate marker for prostate cancer-specific death. This review summarizes current knowledge regarding the role of PSA doubling time as a prognostic marker in men with prostate cancer.     

ERA SPECIFIC BIOCHEMICAL RECURRENCE-FREE SURVIVAL FOLLOWING RADICAL PROSTATECTOMY FOR CLINICALLY LOCALIZED PROSTATE CANCER

PURPOSE: We retrospectively reviewed a large series of men with clinically localized prostate cancer who underwent surgery to define the extent of stage migration and its influence on biochemical recurrence in 3 different eras of prostate cancer management. MATERIALS AND METHODS: A total of 2,370 men were treated with radical prostatectomy from 1982 to 1998. We analyzed the freedom from biochemical (prostate specific antigen) progression after radical prostatectomy. We compared the distribution of pathological stage by the year of surgery. We then compared the biochemical recurrence-free survival rate according to the different eras that reflect a change in prostate cancer management. RESULTS: There was a significant downward stage migration of prostate cancer and an increasing proportion of men who presented with organ confined disease in recent years. The actuarial biochemical recurrence-free rate was significantly different for patients who underwent surgery between 1982 and 1988, compared with those between 1989 and 1998 (p <0.001). These changes may have reflected the benefits of early detection with prostate specific antigen and digital rectal examination, better preoperative selection of patients for surgery as well as the effect of lead time. CONCLUSIONS: Widespread early detection programs for prostate cancer resulted in downward stage migration in men presenting with prostate cancer at our institution during the last 18 years. Also, we have demonstrated a biochemical recurrence-free survival advantage, probably secondary to an improved therapeutic outcome as well as lead time bias, in men who underwent surgery between 1989 and 1998, compared with those between 1982 and 1988. When trying to compare the efficacy of different treatment modalities for prostate cancer, the era in which patients underwent therapy is an important factor to be considered.     

Prognostic factors for PSA relapse of prostate cancer after endocrine therapy

PURPOSE: Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to endocrine therapy with lowering of serum prostate specific antigen (PSA) level but later showing PSA relapse. MATERIALS AND METHODS: In prostate cancer patients newly diagnosed from January 1992 to December 2004 at our institution, there were 93 patients in that the PSA level of 10 ng/ml or more before therapy initially dropped below 10 ng/ml by endocrine therapy, but showed PSA relapse thereafter. We investigated the relationship between clinical stage, pathological differentiation, initial PSA, duration between initiation of therapy and PSA nadir, the value of PSA nadir, duration between initiation of therapy and PSA relapse, PSA doubling time (PSA-DT) at relapse, PSA response three months after initiation of second line therapy and prognosis after PSA relapse. RESULTS: In Kaplan-Meier method, between all or some categories investigated showed significant difference in prognosis after PSA relapse. In multivariate analysis, the factors that significantly affected prognosis after PSA relapse were clinical stage, pathological differentiation, PSA nadir value, duration between initiation of therapy and PSA relapse and PSA response three months after initiation of second line therapy. CONCLUSION: We investigated the prognostic factors refractory to endocrine therapy. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and families.     

Prostate cancers scored as Gleason 6 on prostate biopsy are frequently Gleason 7 tumors at radical prostatectomy: implication on outcome

PURPOSE: Differentiation between Gleason score 6 and 7 in prostate biopsy is important for treatment decision making. Nevertheless, under grading errors compared with the actual pathological grade at radical prostatectomy are common. We compared the characteristics and outcomes of tumors that were scored 6 on prostate biopsy but were 7 on subsequent radical prostatectomy pathological evaluation to those in tumors with a consistent rating of Gleason score 6 or 7 at biopsy and surgery. MATERIALS AND METHODS: We performed a retrospective database analysis from our referral center (1989 to 2004). We compared pre-prostatectomy characteristics, radical prostatectomy pathological features and the post-radical prostatectomy prostate specific antigen failure rate, defined as any 2 consecutive detectable prostate specific antigen measurements, in 3 subgroups of patients, including 156 with matched Gleason score 6 in the prostate biopsy and radical prostatectomy, 205 with upgraded Gleason score 6/7, that is prostate biopsy Gleason score 6 and radical prostatectomy Gleason score 7, and 412 with matched Gleason score 7 in the prostate biopsy and radical prostatectomy. RESULTS: Radical prostatectomy Gleason score matched the prostate biopsy score in 38.2% of biopsy Gleason score 6 and 81.4% of biopsy Gleason score 7 cases. Higher prostate specific antigen was associated and an increased percent of cancer in the prostate biopsy was predictive of discordance between the prostate biopsy and radical prostatectomy Gleason scores (p <0.001). Margin (p = 0.0075) or seminal vesicle involvement (p = 0.0002), cancer volume (p <0.001) and the prostate specific antigen failures rate (p = 0.014) were significantly higher in under graded Gleason score 7 cancer compared to those in matched Gleason score 6 cases. However, they were comparable to those with a matched Gleason score 7 tumor grade (p = 0.66). CONCLUSIONS: Almost half of tumors graded Gleason score 6 at biopsy are Gleason score 7 at surgery. Upgraded Gleason score 6 to 7 tumors have outcomes similar to those of genuine Gleason score 7 cancer. For prostate biopsy Gleason score 6 tumors clinicians should consider the overall likelihood of tumor upgrading as well as specific patient characteristics, such as prostate specific antigen and the percent of tumor in the prostate biopsy, when contemplating treatments that are optimized for low grade tumors, including watchful waiting or brachytherapy.