Computer modeling of prostate biopsy: tumor size and location--not clinical significance--determine cancer detection.

PURPOSE: Sampling error is an inherent problem of prostate biopsy, and the determination of clinical significance based on biopsy results is problematic. We quantify the dimensions of these problems by computer simulation. MATERIALS AND METHODS: We constructed 3-dimensional solid computer models of 59 autopsy prostates containing clinically undetected prostate cancer, and performed simulations of the standard prostate biopsy method. RESULTS: Biopsy simulation detected 19 tumors from the 59 prostates, the majority of which were in the most accessible portion of the prostate, the posterior peripheral zone. Using 0.5 cc or greater tumor volume or less than 0.5 cc and Gleason sum 7 or greater as criteria of significance, the model detected 58% (11 of 19) significant tumors and 20% (8 of 40) insignificant tumors. With 0.25 cc or greater tumor volume or less than 0.25 cc and Gleason sum 7 or greater as criteria 15 of 29 significant (52%) and 4 of 30 insignificant (13%) tumors were detected. Among significant tumors defined by either volume criterion there was a statistical difference between detected and undetected tumors in terms of mean tumor volume and mean ratio of tumor volume-to-prostate volume. Among insignificant tumors defined by either criterion there was no such difference. CONCLUSIONS: As much as 20 to 40% of currently detected prostate cancer may be histologically insignificant, as 4 of 19 cancers were detected when 0.25 cc was used as volume determinant of clinical significance and 8 of 19 were detected when 0.5 cc volume was used. These tumors are detected randomly. On the other hand, perhaps only one-half to three-fourths of clinically significant prostate cancers are being detected, and then only because the volume and anatomic location make them hard to miss.

Morphological analysis and classification of latent prostate cancer using a 3-dimensional computer algorithm: analysis of tumor volume, grade, tumor doubling time and life expectancy.

PURPOSE: We estimate the potential clinical significance of prostate cancers found at autopsy provided the individual had lived to the projected lifespan based on life expectancy tables. MATERIALS AND METHODS: We used 3-dimensional computer models of 59 autopsy prostates that contained clinically undetected carcinoma to determine tumor volumes. Using doubling times of 2, 3, 4 and 6 years, carcinoma volumes at autopsy were extrapolated through patient projected lifespans. The carcinomas were then classified as clinically insignificant or significant according to Mayo Clinic criteria. RESULTS: In 13 patients less than 60 years old, using doubling times of 2, 3, 4 and 6 years, clinically significant tumors were identified in 13 (100%), 10 (77%), 7 (54%) and 7 (54%), respectively. In 46 patients 60 years old or greater significant tumors were identified in 32 (70%), 22 (48%), 21 (46%) and 18 (39%), respectively. A statistical difference (p <0.0001) was found between the mean tumor volume (0.20 +/- 0.10 cc) of 43 organ confined carcinomas and the mean tumor volume (3.26 +/- 3.58 cc) of 16 extracapsular tumors. No capsule perforation was found in tumors with Gleason sums of 4 or less. However, capsule perforation was present in 8 of 31 tumors (25.8%) with Gleason sums of 5 or 6, and 8 of 11 tumors (72.7%) with Gleason scores of 7 or 8. CONCLUSIONS: Prostatic carcinomas that remain clinically insignificant throughout life are likely to have doubling times greater than 4 years. The subset of carcinomas that emerge as clinically significant are likely to have doubling times less than 3 years. Therefore, an accurate method to measure doubling time at diagnosis could, provide an objective indicator to guide clinical management.

Prevalence and natural history of urinary symptoms in a longitudinal national prostate cancer screening (community-based) study.

The AUA Symptom score (AUASS) was administered for three consecutive years to participants in a national prostate cancer screening study. Although the prevalence symptom free (AUSS=0) individuals was very low (<7%) in this cohort of 16 000 men, mean AUASS and proportion of men in the mild, moderate and severe categories are equivalent to community-based studies from around the world. Across all ages and races, AUASS drops after 12 months but returns to original levels at 24 months. No differences in AUASS were noted for race when adjusted for age. Age is most strongly correlated to the increase in AUASS and to the severity of urinary symptoms.

Eight years of "Prostate Cancer Awareness Week": lessons in screening and early detection. Prostate Cancer Education Council.

BACKGROUND: Prostate Cancer Awareness Week began in 1989 to raise public awareness of the disease and impact on its clinical dynamics. Prior to 1990, prostate carcinoma was usually diagnosed in symptomatic men as advanced and ipso facto incurable. METHODS: A 5-year longitudinal study of screening and early detection was initiated in 1992, involving 250 centers that tested over 50,000 men annually. The study analyzed the following: 1) the efficacy of digital rectal examination and prostate specific antigen (PSA) tests for the early detection of prostate carcinoma, 2) the impact of serial screening on stage of disease at diagnosis and cancer detection, 3) age and race specific reference ranges for PSA, 4) prostate carcinoma risk factors, and 5) psychosocial variables that influence the appropriateness and acceptability of both screening and treatment. RESULTS: Community-based screening for prostate carcinoma is as effective as programs conducted at academic centers, but annual testing may not be necessary for all men. Participants in community screening programs may require more prescreening information and education regarding the potential risks and benefits of screening, and also regarding the cascade of diagnostic and treatment decisions that follow an abnormal digital rectal examination or an elevated PSA finding. CONCLUSIONS: Community-based prostate carcinoma screening programs have contributed to the shift in the diagnosis of prostate carcinoma at an earlier stage. They provide data that are useful in studying the natural course of prostate carcinoma and in designing studies of the effect that prostate carcinoma screening has on mortality from the disease.

Prostate cancer clinical trials of the Southwest Oncology Group.

The changing clinical dynamics of prostate cancer have resulted in a broadening of the research focus of the Genitourinary (GU) Cancer Committee of the Southwest Oncology Group (SWOG). Beginning with an emphasis on hormone-refractory disease in its early years, SWOG prostate cancer trials now cover the entire spectrum of the disease: localized, locally advanced, metastatic and hormone-refractory disease. As the world's largest GU cancer research group, the GU committee of SWOG has pioneered studies in combined androgen therapy for metastatic disease, quality-of-life (QOL) assessments for patients with localized and advanced disease, adjuvant therapy models, and prostate cancer chemoprevention. The committee has also formed the GU Global Group, whose purpose is to convene the chairs of the GU committees of all the major national and international oncology cooperative groups. Meeting semiannually, this group discusses activities within their respective organizations, plans collaborative strategies and protocols, and establishes global strategy in prostate cancer clinical research. The future directions of national and international prostate cancer trials will build on this broad foundation of well-conceived, logically sequenced studies.

Age-specific reference ranges for PSA in the detection of prostate cancer.

An association between age and prostate-specific antigen (PSA) has been documented: As men age, their serum PSA value increases. Currently, a single demarcation between normal and elevated PSA values, 4.0 ng/mL, is used as an indication for biopsy among men of all ages. The use of age-specific reference ranges might address several shortcomings of the PSA test. First, age-specific reference ranges could improve the sensitivity of PSA by detecting curable, organ-confined tumors in younger men when the threshold of 4.0 ng/mL is lowered. Second, age-specific reference ranges could improve the specificity of the PSA test by raising the PSA threshold for normal among older men. This would modulate PSA interpretation by taking into account the increasing prevalence of both benign prostatic growth and incidental, non-life-threatening cancers among successively older cohorts of men. Furthermore, many unnecessary (false-positive) biopsies would be avoided. However, the association between PSA values and age is not entirely clear, and whether age-specific reference ranges represent the best interpretive index for PSA remains problematic.

Combined androgen blockade: the gold standard for metastatic prostate cancer.

There is no debate that both the earlier diagnosis and the treatment of men with cancer of the prostate (CaP) are having an impact on patients with this disease. In many practices there are fewer and fewer patients presenting with the classic diagnosis of 'advanced disease', i.e., stage M (D2). Only a few years ago, a large percentage of men with CaP had bony metastases when they presented to a physician. Hormonal ablation was the optimal treatment, and the only question was whether bilateral orchiectomy or medical castration should be used. The median time to progression with either type of monotherapy was 12-18 months, and the median time to survival was 24-36 months. Unfortunately, in many parts of the world, this scenario is still the norm. In the United States, Europe, and an increasing number of other countries, improved methods of detection with transrectal ultrasound and prostate-specific antigen (PSA) have resulted in a dramatic shift in the stage of disease at diagnosis. It is safe to say that in these countries the majority of prostate cancers are now being clinically diagnosed while still localized, and many organ-confined tumors are being definitively treated and cured. Nevertheless, many of these patients will be understaged at the time of diagnosis and will show progression following definitive therapy. In most surgical series approximately one half of patients will be found on pathologic examination to have pT3 disease. The use of PSA in the diagnosis of CaP has been mentioned, and it is being used extensively to monitor recurrent/residual disease. Hormonal therapy is being employed earlier in numerous clinical situations, and its use is no longer reserved solely for patients with metastatic disease. In this context combined androgen blockade has become the gold standard of treatment in neoadjuvant situations as well as for advanced CaP. Newer advances, including 3-month depot formulations of luteinizing hormone-releasing hormone analogues, the reversibility of medical castration, the preference of most patients to have medical castration, and the approval of other antiandrogens in the United States, all have further strengthened the use of combined androgen blockade. Hormonal therapy in adjuvant settings, when there is a high likelihood of disease recurrence, is also being used in many clinical situations. In addition, there appears to be a role for certain types of hormonal therapy in chemoprevention.

A cross-sectional study of vasectomy, time since vasectomy and prostate cancer.

Past studies of the association of vasectomy and prostate cancer have reported inconsistent results. Our objective was to investigate whether vasectomy and time since vasectomy are associated with a higher risk of prostate cancer. We conducted a cross-sectional study on unduplicated records of >95 000 participants in a longitudinal study (1993-1995) of prostate cancer screening conducted during Prostate Cancer Awareness Week. Vasectomy was reported by 28%, and there were 2530 biopsies. (chi)(2) tests and logistic regression analyses were used and found that vasectomy and an increased length of time since vasectomy are not associated with a higher risk of prostate cancer.

Age- and race-specific reference ranges for prostate-specific antigen from a large community-based study.

OBJECTIVES: To analyze the relationship of age and race to prostate-specific antigen (PSA) levels among participants in a community-based study. METHODS: A total of 77,700 records of men aged 40 to 79 years were analyzed from a longitudinal study of PSA conducted during Prostate Cancer Awareness Week 1993 and 1994. Records from 1994 were not included for men who were tested in 1993. All cases of prostate cancer were excluded. Records with outlier PSA values greater than 20 ng/mL were eliminated from the analysis (n = 190; 24%). RESULTS: Mean PSA values (ng/mL) of 10-year age groups differed significantly (P < 0.0001) between each group (ages 40-49, 0.83; 50-59, 1.23; 60-69, 1.83; 70-79, 2.31). In each successively older age group, PSA variance increased significantly (P = 0.0001). Standard deviations (SD) by age group were: 40-49, 0.79; 50-59, 1.33; 60-69, 1.94; and 70-79, 2.35. Significant differences in mean PSA by race were found. Pairwise differences in mean PSA were found between whites and blacks, whites and Latinos, blacks and Asians, and Asians and Latinos (P < 0.0001). No statistically significant differences in PSA variance between racial groups were found. Age-within-race analysis resulted in consistent statistical significance when comparing variance among age cohorts in each race. CONCLUSIONS: Age-specific PSA reference ranges are a result of the increasing mean PSA and increasing PSA variance in successively older cohorts of men. Mean PSA values differ significantly by race, but differences in PSA variance do not. The clinical significance of race-specific PSA reference ranges has yet to be determined.

Serum prostate-specific antigen and digital rectal examination for early detection of prostate cancer in a national community-based program. The Prostate Cancer Education Council.

OBJECTIVES: This study analyzed methods of prostate cancer early detection in community settings throughout the United States against standards and findings of earlier studies conducted at academic medical centers. METHODS: The study was conducted at 148 clinical centers during Prostate Cancer Awareness Week in September 1993 and continued through June 1994. A total of 31,953 eligible subjects were tested by both digital rectal examination (DRE) and prostate-specific antigen (PSA). PSA was tested with the Abbott IMx PSA assay and reported by Roche Biomedical, Inc. RESULTS: The study confirmed that elevated PSA levels (greater than 4.0 ng/mL) aid in the detection of organ-confined prostate cancer when used in conjunction with the DRE. Reflecting more conservative biopsy decision-making practices, study results nonetheless are comparable to earlier reports. Among 1307 subjects who underwent biopsy, 322 cancers were detected. The cancer detection rate was 3.6% for PSA, 3.0% for DRE, and 4.7% if either test result was positive. The positive predictive value (PPV) for elevated PSA levels (greater than 4.0 ng/mL) was 3l.6%, significantly better (P < 0.0001) than the PPV for abnormal DRE results (25.5%). Nearly 90% (88.9%) of staged cancers were diagnosed as localized. Elevated PSA levels detected more localized cancers (76 of 105 [72.4%]) than the DRE (72 of 105 [68.6%]). Of localized tumors, 33 (31.4%) were missed by DRE and detected solely by PSA, and 29 (27.6%) were missed by PSA and detected solely by DRE. The combined use of the two methods detected 33 additional localized tumors. CONCLUSIONS: Community practice throughout the United States demonstrates that PSA and DRE are consistently effective and efficient in the early detection of prostate cancer.

The role of prostate-specific antigen in the chemoprevention of prostate cancer.

An understanding of the natural history of changes in prostate-specific antigen (PSA) may be valuable as a surrogate view of prostate dynamics, as a method to differentiate between benign and malignant growth, and as a means to assess the use of PSA as a tool for monitoring activity of chemoprevention agents. Although PSA appears to be useful as a noninvasive marker of prostatic growth, PSA changes should not be confused with a direct measure of tumor growth. Serum PSA levels are a function of tumor volume but are also influenced by the volume of benign epithelium, grade of carcinoma (if any), inflammation, androgen levels, growth factors, and the extracellular matrix. The biological functions of PSA in the prostate and in its secretions need to be more completely elucidated in order that PSA measurements may more accurately describe prostate dynamics. The expression of PSA is androgen-regulated. It is one of the most abundant prostate-derived proteins in the seminal fluid. Seminogelin, a major protein in seminal fluid, is cleaved by PSA, and this cleavage is important in the liquefaction of semen. Less is known about other PSA substrates. Current PSA studies indicate that cancer cases exhibit an early slow linear PSA phase followed by a rapid exponential phase, and that PSA levels begin to increase exponentially approximately 7-9 years before diagnosis. The establishment of age-specific PSA reference ranges (ASRR) and of PSA velocity (PSAV) rates provide elements of a baseline from which prediction models could measure malignant potential of a prostatic carcinoma. Moreover, recent discoveries of different molecular forms of PSA in serum may allow a much more accurate differentiation of benign and malignant growth as well as a more potent measure of the impact of chemoprevention agents. If PSA doubling time is approximately 2.4-3.0 years and accurately reflects tumor doubling time, and if the average man has less than 0.5 ml of latent prostatic tumor tissue and the average stage T2 cancer is approximately 4 ml when detected, then the available PSA data suggest that the 3 doublings necessary to change from 0.5-4.0 ml, would take 7-12 years for a typical small volume tumor to reach the size of most stage T2 tumors. The findings that histologic cancers appear at much younger ages than previously known is disturbing. It indicates that disease initiation may begin sooner than ever thought likely. "Normal" PSA levels for younger men (< 40 years of age) may need to be studied, and an emphasis upon premalignant lesions in this age group may be necessary. Younger men may represent the most appropriate population and premalignant lesions the most relevant clinical factor for prostate cancer chemoprevention studies and trials. The molecular composition and molecular changes of PSA derived from premalignant lesions have yet to be elucidated, but such investigations may lead to a more complete understanding of the possible progression or transformation of normal prostate cells to premalignancy and subsequently to carcinoma. High grade prostatic intraepithelial neoplasia (PIN) in and of itself does not account for elevated serum PSA levels, but subtle changes in the molecular dynamics of PSA may reveal the influence of androgens and the impact of chemopreventive agents.

Current status of combined androgen blockade: optimal therapy for advanced prostate cancer.

CAB represents the gold standard of treatment for patients with advanced prostate cancer. The treatment is well-tolerated with the only increased side effect being a 6% increase in diarrhea. Ninety-five percent of patients benefit, and those having minimal metastatic disease show a marked benefit. Since maximal androgen blockade seems to be of major benefit for patients with good performance status and minimal disease, its role needs to be investigated in patients with earlier stages of prostate cancer including stages B, C, and D1. Important trials are underway to address these provocative issues. Progress in the treatment of patients who relapse with metastatic prostate cancer after initial CAB will probably come to rely on the discovery and development of novel drugs or innovative drug delivery systems. Immunomodulatory drugs to enhance the body's natural defenses, monoclonal antibodies directed against prostate specific cellular antigens and tagged with radioisotopes or cytotoxic agents, and bone-seeking radiopharmaceuticals may represent the breakthrough that is needed. Exciting advances in gene therapy may represent the ultimate chance for a cure.

Screening strategies: a clinical perspective.

Prostate cancer is increasing in incidence, particularly because of the control of competing causes of death and the lengthening life span of western men. Screening and early detection initiatives among symptom free men show that the disease can be detected at earlier stages when hope for cure is reasonable. Prostate specific antigen is the most useful marker for prostate cancer. Analytical methods to improve its sensitivity and specificity include PSA density, age specific PSA reference ranges and PSA velocity or the rate of change in PSA. Older paradigms of the natural history of prostate cancer have been heavily influenced by characteristics of clinical disease. However, improved detection of the disease through better diagnostic tools and heightened public awareness may be changing the dynamics of the disease. The prevalence of advanced disease is falling, and more knowledge is accumulating on the identification of clinically significant disease. The most appropriate definition of clinically significant disease today must be based on a new paradigm, one that can build on but not be bound by older models.

Southwest Oncology Group strategies in prostatic carcinoma.

The Southwest Oncology Group Genitourinary Committee evolved in 1978 from a combined gynecologic-urologic cancer committee. A significant catalyst in this development was the growing interest in prostatic carcinoma, with an initial focus on hormone refractory disease. Clinical studies have expanded into combined androgen blockade, untreated metastatic disease and localized prostate cancer. Since 1978, more than forty trials in prostatic carcinoma have been conducted. Currently, seven are in progress or under development. Conclusions and future directions are reviewed.

Pretreatment of metastatic disease. Prostate cancer in the older male.

Prostate cancer is a disease of older men, with more than 80% of cases being diagnosed in men 65 years of age and older. Broader participation in screening and early detection programs has resulted in many diagnoses being made earlier in the course of the disease. However, an estimated 25-30% of cases among older men will be diagnosed as metastatic disease. These will be men initially diagnosed with metastatic disease as well as men previously treated for localized disease that has progressed to metastatic disease. The treatment of metastatic prostate cancer has been straightforward. Objective prognostic factors are assessed, and recommendations for the most suitable hormonal therapy are made. Androgen withdrawal, androgen blockade, or combination therapy are current first-line treatment modalities. Patients with good prognostic factors will generally do well for a long time, even experiencing a time-limited remission. Patients with a poor prognosis will die of their disease, with median survival being 18 months. Pretreatment assessment of men diagnosed with metastatic prostate cancer should include prognostic factors (tumor volume, histologic grade, DNA ploidy, and prostate specific antigen), health status (comorbidity and performance status), quality of life factors (as a baseline against which to evaluate subjective response and to predict subjective progression), and psychosocial dimensions (sexuality and sexual function, self image, sociability, and social support). Each of these assessment areas will provide important predictors for suitable treatment, response and progression, and survival. The challenge presented is the time and difficulty involved in weighing all these areas and in making an informed physician-patient decision on the most appropriate treatment plan. The physician must direct a health care team to treat metastatic prostate cancer effectively. This team includes oncology nurses, dietitians, social workers, spouses, significant others, and the patient himself.

PSA as a screening test for prostate cancer.

With an expected rise in the incidence of prostate cancer, the major challenge of the 1990s is to establish standards and procedures for the screening and early detection of prostate cancer so that mortality is reduced. Prostate-specific antigen (PSA) lacks sufficient sensitivity and specificity to be used alone as a screening test for prostate cancer. However, in conjunction with the digital rectal examination and transrectal ultrasound, PSA can greatly improve detection rates.

Chemoprevention of prostate cancer: guidelines for possible intervention strategies.

The "natural history" of prostate cancer may bedevil the development of guidelines for chemoprevention interventions. Can strategies be designed to direct agents to those lesions which have the potential to develop localized extension that may become symptomatic or metastatic disease? Of necessity our interventions will focus on the identification and quantification of appropriate biomarkers as intermediate endpoints, although no reliable endpoints for prostate cancer have yet been identified. The reduction of prostate cancer incidence may be the ultimate objective, but a decrease in the progression of microfocal or "latent" cancer may well be just as effective as prevention when the age of the target population and competing causes of death are taken into account. Early intervention strategies must focus on the analysis of the interactions of the chosen chemopreventive agents upon precancerous and cancerous cellular dynamics in the prostate. Whether the requirements of such molecular epidemiology necessitate a more deliberate strategy of Phase II studies or a high risk-high gain strategy of a broad Phase III study is open to debate. Factorial designs for proposed randomized chemoprevention trials may be desirable to test multiple chemopreventive agents simultaneously, provided knowledge of the biochemical synergism of the agents is solid. Stratification of study participants by degree of risk will ameliorate concerns regarding the precision targeting of lesions at different stages in the precancer/cancer continuum.