Perspectives on prostate cancer diagnosis and treatment: a roundtable.

This roundtable was held September 30, 2000. It addressed, first of all, the accuracy and proper interpretation of the available prostate-specific antigen assays. Dr. Brawer presented data to demonstrate the specificity of the complexed prostate-specific antigen assay. Dr. Stamey counterpoised evidence that pretreatment prostate-specific antigen levels less than 9 ng/mL are attributable to benign prostatic hyperplasia and therefore are of little value as an indicator of when to initiate treatment for prostate cancer. The other roundtable participants offered reviews and new data regarding hormonal therapy as primary or adjunctive treatment of prostate cancer. Dr. Fowler presented a large retrospective series of men with locally advanced prostate cancer for whom androgen ablation was the primary therapy. Dr. Droller discussed his center's experience in integrating hormonal therapy with brachytherapy. Finally, Dr. Messing reviewed and critiqued the evidence that the combination of hormonal and radiation therapy improves survival.

Modern brachytherapy for localized prostate cancers: the northwest hospital (Seattle) experience.

Modern ultrasound-guided prostate brachytherapy is rapidly changing the way localized prostate cancer is managed. With routine use of prostate-specific antigen screening, prostate cancer is being diagnosed in younger men, who are understandably concerned about the morbidity of radical treatments that may significantly decrease their quality of life. Numerous studies of prostate brachytherapy have shown the excellent disease control rates achieved while maintaining low levels of urinary and erectile difficulties. This report examines a modern implant method of brachytherapy; describes patient selection for brachytherapy, alone and in combination with external beam therapy; and presents results from a series of men followed for 12 years.

Evaluation and treatment of men with biochemical prostate-specific antigen recurrence following definitive therapy for clinically localized prostate cancer.

Early detection and monitoring by serum prostate-specific antigen (PSA) measurement has increased the number of men presenting with potentially curable prostate cancer. Most will choose radical prostatectomy or some form of radiation therapy for treatment, but some will have evidence of biochemical disease recurrence following therapy, shown by a rising PSA level without other clinical evidence of disease. Radical prostatectomy involves the removal of all prostate tissue, causing the serum PSA to decline to undetectable levels within four to six weeks following surgery; a subsequent rise in the serum PSA to a detectable level indicates disease recurrence. Patients should be evaluated to assess whether rising PSA levels indicate local recurrence or early metastatic disease. The advantages of salvage radiation, endocrine therapy, and other treatment modalities in local disease recurrence must be weighed against potential side effects and the resulting decrease in quality of life. Radiation therapy does not immediately eradicate all PSA-producing cells; therefore the persistence of a detectable PSA does not necessarily imply residual cancer, but rising PSA levels indicate treatment failure. Salvage surgery can be performed after radiotherapy for the purpose of removing all viable cancer cells, but should be weighed against a higher incidence of surgical complications; cryoablation offers a less invasive therapeutic modality.

Prostate cancer: serum and tissue markers.

The detection of prostate cancer, its clinical staging, and the prediction of its prognosis remain topics of paramount importance in clinical management. The digital rectal exam, although once the "gold standard," has been largely supplanted by a variety of techniques including serum and tissue-based assays. This article reviews recent progress in the development of prostate-specific antigen assays with greater specificity; molecular markers for prostate cancer (DNA ploidy, nuclear morphometry, markers of proliferation, and cell adhesion molecules); the link between vitamin D deficiency and the clinical emergence of prostate cancer; the possible correlation of serum insulin-like growth factor levels with the risk for developing prostate cancer; and the latest advances in radiologic staging.

Prostate cancer: risk assessment and diagnostic approaches.

The successful treatment of prostate cancer relies on detection of the disease at its earliest stages. Although prostate-specific antigen (PSA)-based screening has been a significant advance in the early diagnosis of prostate cancer, identifying specific genetic alterations in a given family or patient will allow more appropriate screening for early disease. Mapping and identification of specific prostate cancer susceptibility genes is slowly becoming a reality. Other prostate cancer risks include a family history, race, and possibly serum markers such as insulin-like growth factor-I (IGF-I). Once a high-risk man is identified, transrectal ultrasound (TRUS)-guided biopsies are the standard to diagnose prostate cancer. Although TRUS is an advance over traditional digitally directed biopsies, it represents a random sampling of the prostate since most lesions cannot be visualized. Newer modalities such as ultrasound contrast agents, pattern recognition, and artificial neural networks (ANNs), applied to TRUS images, may improve diagnostic accuracy. If a man at risk for prostate cancer has undergone a negative TRUS biopsy, the decision for the need for additional biopsies is problematic. Use of PSA derivatives such as free and total PSA and the initial biopsy abnormalities such as atypia or high-grade prostatic intraepithelial neoplasia may define those patients in need of follow-up biopsy.

Androgen deprivation and other treatments for advanced prostate cancer.

Among the issues discussed at this year's meeting on prostate cancer in Vail, Colorado, were several that specifically relate to the patient with advanced disease. Dr. E. David Crawford addressed the issue of the timing of hormone therapy, specifically reviewing several important trials that give a glimpse at the potential outcome of aggressive treatment in stage D1.5. The efficacy of antiandrogens, flutamide, bicalutamide, and nilutamide, when combined with chemical or surgical castration, was reviewed. Dr. Arturo Mendoza-Valdes reviewed the rationale behind intermittent (versus continuous) total androgen blockade, especially as related to quality of life. Dr. Paul Miller gave an update on the role of bisphosphonates as adjuvant therapy for prostate cancer. Also discussed was an important new agent for androgen deprivation, Abarelix, a sustained-release GnRH antagonist with low histamine-releasing potential which avoids testosterone and other hormone surge and flare.

The evolution of hormonal therapy for prostatic carcinoma.

It is well recognized that testosterone has a number of untoward effects on prostatic carcinoma and that castration is associated with significant tumor shrinkage and resolution of symptoms of advanced prostatic carcinoma. Approaches to hormonal therapy have evolved significantly over the last several decades. Initially castration was utilized, which provided effective reduction of testicular androgens, but with adverse psychological factors. The next approach was utilization of diethylstilbestrol, but with significant cardiovascular toxicity in higher doses. The development of the luteinizing hormone-releasing hormone agonists provided an improvement in pharmacologic castration; however, they are associated with a transient testosterone surge and the potential for exacerbation of clinical manifestations of advanced prostate carcinoma (the so-called "testosterone flare"). Recently, gonadotropin-releasing hormone (GnRH) antagonists have been investigated. Abarelix is a pure GnRH antagonist that blocks the anterior pituitary receptor, resulting in prompt and significant reduction not only of luteinizing hormone but also follicle-stimulating hormone. This results in castrate levels of testosterone while avoiding the testosterone surge.

Prostate cancer: where we have been, where we are, where we are going.

Prostate cancer has generated more debate over the last decade than perhaps any other malignancy. This stems from many factors, not the least of which is the fact that the histologic incidence far exceeds clinically manifested disease. Despite this fact, prostate cancer remains the most common male malignancy and the second most common cause of cancer-related mortality in most Western societies. Significant advances have occurred in virtually all domains surrounding prostate cancer, including increased understanding of the molecular and genetic basis of the disease, improved methods of early detection and screening, refinement of biopsy techniques, and advances in staging and therapeutic approaches. Even with these advances, the sobering mortality statistics clearly underscore the need for further insight and progress.

Comparison of percent free PSA, PSA density, and age-specific PSA cutoffs for prostate cancer detection and staging.

OBJECTIVES: Various methods have been proposed to increase the specificity of prostate-specific antigen (PSA), including age-specific PSA reference ranges, PSA density (PSAD), and percent free PSA (%fPSA). In this multicenter study, we compared these methods for their utility in cancer detection and their ability to predict pathologic stage after radical prostatectomy in patients with clinically localized, Stage T1c cancer. METHODS: Seven hundred seventy-three men (379 with prostate cancer, 394 with benign prostatic disease), 50 to 75 years old, from seven medical centers were enrolled in this prospective blinded study. All subjects had a palpably benign prostate, PSA 4.0 to 10.0 ng/mL, and a histologically confirmed diagnosis. Hybritech's Tandem PSA and free PSA assays were used. RESULTS: %fPSA and age-specific PSA cutoffs enhanced PSA specificity for cancer detection, but %fPSA maintained significantly higher sensitivities. Age-specific PSA cutoffs missed 20% to 60% of cancers in men older than 60 years of age. %fPSA and PSAD performed equally well for detection (95% sensitivity) if cutoffs of 25% fPSA or 0.078 PSAD were used. The commonly used PSAD cutoff of 0.15 detected only 59% of cancers. %fPSA and PSAD also produced similar results for prediction of the post-radical prostatectomy pathologic stage. Patients with cancer with higher %fPSA values (greater than 15%) or lower PSAD values (0.15 or less) tended to have less aggressive disease. CONCLUSIONS: The results of this study demonstrated that cancer detection (sensitivity) is significantly higher with %fPSA than with age-specific PSA reference ranges. %fPSA and PSAD provide comparable results, suggesting that %fPSA may be used in place of PSAD for biopsy decisions and in algorithms for prediction of less aggressive tumors since the determination of %fPSA does not require ultrasound.

Percentage of free PSA in black versus white men for detection and staging of prostate cancer: a prospective multicenter clinical trial.

OBJECTIVES: In predominately white populations, measurement of the percentage of free prostate-specific antigen (%fPSA) has been shown to enhance the specificity of total PSA testing for prostate cancer while maintaining high sensitivity and to aid in prostate cancer staging. This study evaluated whether the %fPSA cutoff that maintained a 95% sensitivity in a white population yielded the same sensitivity and specificity in a black population and whether %fPSA was useful in predicting postoperative pathologic features in blacks. METHODS: We evaluated 647 white and 79 black men, prospectively enrolled at prostate cancer screening and surgical referral centers. Subjects were 50 to 75 years old with digital rectal examination findings that were not suspicious for prostate cancer and total PSA values between 4.0 and 10.0 ng/mL. All had undergone needle biopsy of the prostate. Hybritech's Tandem total and free PSA assays were used. RESULTS: Ninety-five percent sensitivity was attained with a %fPSA cutoff of 25% in both races. Use of this cutoff could have avoided unnecessary biopsies in 20% of white and 17% of black subjects (P = 0.69). In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for %fPSA was significantly higher than for total PSA in both blacks (0.76 versus 0.56, P <0.01) and whites (0.70 versus 0.54, P <0.001). In both races, higher %fPSA values indicated a lower risk of cancer and also predicted favorable pathologic features in radical prostatectomy specimens. CONCLUSIONS: A 25% fPSA cutoff detected 95% of cancers and reduced unnecessary biopsies in both races. Higher %fPSA values were associated with favorable postoperative histopathologic findings in both races.

Evaluation of prostate cancer patients receiving multiple staging tests, including ProstaScint scintiscans.

BACKGROUND: Multiple serum tests were performed on archival samples from patients who participated in trials to assess the ProstaScint scan staging ability. Traditional statistical analysis as well as artificial neural network (ANN) analysis were employed to evaluate individual patients and the group as a whole. The results were evaluated so that each factor was tested for prognostic value. METHODS: Data obtained from serum tests, bone scans, and ProstaScint scans were evaluated by traditional statistical methods and ANN to determine the individual value in clinical staging of prostate cancer. RESULTS: Two hundred seventy-five patients (180 postprostatectomy, 95 intact prostate) with prostate cancer (14 with distant metastases) were available for analysis. Data available included: clinical state (remission or progression), most recent clinical TNM stage, bone scan, and ProstaScint scan. Serum was tested for prostate-specific membrane antigen(PSMA), prostate-specific antigen(PSA), free PSA (fPSA), and complexed PSA (cPSA). Additional calculations included percent free PSA, and percent complexed PSA. Spearman individual statistical assessment for traditional group evaluation revealed no significant factors for T-stage. The free PSA and complex PSA had a significant association with node (N)-status. The distant metastases (M) stage correlated well with the bone scan and clinical stage. ANN analysis revealed no significant T-stage factors. N-stage factors showed a 95% sensitivity and 49% specificity. These factors included the presence or absence of a prostate, PSA serum levels, bone scan, and ProstaScint scans as major associated indicators. ANN analysis of the important variables for M-stage included ProstaScint scan score, and PSA levels (total, percent complexed, percent free, and fPSA). These factors were associated with a 95% sensitivity and 15% specificity level. CONCLUSIONS: Two hundred seventy-five patients receiving treatment for prostate cancer were evaluated by ANN and traditional statistical analysis for factors related to stage of disease. ANN revealed that PSA levels, determined by a variety of ways, ProstaScint scan, and bone scan, were significant variables that had prognostic value in determining the likelihood of nodal disease, or distant disease in prostate cancer patients.

Screening for prostate cancer.

Screening for prostate cancer has shown great promise in its ability to detect prostate cancer at a curable stage; however, significant problems exist with respect to our knowledge of its impact on prostate cancer mortality. For the properly informed patient with at least a 10-year life expectancy, it would seem that early detection efforts utilizing digital rectal examination (DRE) and serum prostate-specific antigen (PSA) determination are beneficial. Considerable controversy abounds about early detection and screening and will continue until definitive proof of decreased prostate cancer mortality as a result of effective early detection and treatment regimens is demonstrated. Until then, all men with at least a 10-year life expectancy should be counseled as to the potential benefits and risks. The salient literature is reviewed and commentary made as to the benefits of screening methods that can be invoked as well as their limitations and potential liabilities.

Prostate-specific antigen.

Prostate-specific antigen (PSA) has revolutionized the diagnosis and management of men with prostate cancer. Significant advances have been made since the early development of immunoassays. While PSA is useful for staging and monitoring of established disease, it has shown the greatest utility in the realm of early detection realm. PSA is the most important tumor marker; its importance in evaluating men for the possibility of prostate cancer is irrefutable. Enhancing specificity is a pressing need. In this regard, the recognition of the molecular forms of free PSA and complex PSA have shown the most promise and undoubtedly will result in fewer false-positive PSA test results. The salient literature is reviewed and commentary made on the current status of PSA with particular emphasis on methods to enhance its specificity in early detection and applications.

Polyamine depletion therapy in prostate cancer.

The prostate gland has among the highest level of polyamines in the body and prostate carcinomas have even greater elevated polyamine levels. These ubiquitous molecules synthesized by prostate epithelium are involved in many biochemical processes including cellular proliferation, cell cycle regulation, and protein synthesis. These properties have made polyamines a potential target for therapeutic intervention in diseases of excessive cell proliferation such as cancer. However, attempts to limit tumor growth by inhibition of polyamine synthesis have not been very successful since cells have the capacity to take up polyamines from the bloodstream. We report here studies utilizing polyamine depletion by means of a combination of blockade of polyamine synthesis with DFMO (alpha-difluoromethylornithine), an inhibitor of ornithine decarboxylase, the rate limiting enzyme in the polyamine synthetic pathway, and ORI 1202, a novel inhibitor of polyamine transport into the cell. This cytostatic combination, even in the presence of excess extracellular polyamines, significantly slowed the growth of the human tumor cell line PC-3 grown in tissue culture with an EC(50) in the &mgr;M range. Other prostate cell lines were similarly growth inhibited including LNCaP.FGC and DU145. Growth of the PC-3 tumor cell line as a xenograft in nude mice was also slowed significantly by this combination of compounds. Polyamine levels in the tumor were lowered from control tumor levels. This combination therapy could provide an effective and potentially non-toxic therapy for prostate tumors.Prostate Cancer and Prostatic Diseases (2000) 3, 275-279