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Current controversies in screening: cholesterol, breast cancer, and prostate cancer.

Physicians must make decisions in day-to-day practice even when the balance of benefit and harm is not yet known. Adopting a clinical policy about screening is a case in point. Three controversies in screening healthy adults illustrate different aspects of resolving a dispute when the evidence is incomplete. The major controversy in cholesterol screening is whether to screen young adults. There has never been a randomized trial of treatment, let alone a trial of screening, in young adults. However, a patchwork of evidence strongly suggests that, because the baseline risk of coronary heart disease (CHD) is very small in young adults, the absolute reduction in risk from treatment would be very small. In breast cancer screening, randomized trials do not show conclusively that periodic mammography for women aged 40-49 years reduces breast cancer mortality. A 7-10 year delay between the first mammogram and a reduction in deaths from breast cancer suggests the hypothesis that the only benefit of screening women aged 40-49 years occurs from mammograms performed after age 50. There is no high quality evidence that early detection and treatment reduce the death rate from prostate cancer. In lieu of randomized trial data, we must depend on a decision analysis that shows that screening middle-aged men is cost-effective relative to other preventive services. However, this result depends on using optimistic survival data in the decision model, and most organizations do not recommend routine screening. The best strategy is to discuss the harms and benefits, and let the patient decide.

Adult↗

Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study.

PURPOSE: Studies reporting effects of radiotherapy for prostate cancer on sexual, bowel, and urinary function have been conducted primarily in referral centers or academic institutions. Effects of external-beam radiotherapy for prostate cancer among a population-based cohort were assessed. PATIENTS AND METHODS: The study population included 497 white, Hispanic, and African-American men with localized prostate cancer from six US cancer registries who were diagnosed between October 1, 1994, and October 31, 1995, and treated initially with external-beam radiotherapy. They were interviewed at regular intervals, and medical records were reviewed. Distributions of responses for bowel-, urinary-, and sexual-related functions at 6, 12, and 24 months after diagnosis and adjusted mean composite change scores for each domain were analyzed. RESULTS: Declines of 28.9% in the sexual function score and 5.4% in the bowel function score occurred by 24 months, whereas at this time, the urinary function score was relatively unchanged. A total of 43% of those who were potent before diagnosis became impotent after 24 months. More than two thirds of the men were satisfied with their treatment and would make the same decision again. CONCLUSION: Sexual function was the most adversely affected quality-of-life domain, with problems continuing to increase between 12 and 24 months. Bowel function problems increased at 6 months, with partial resolution observed by 24 months. Despite the side effects, satisfaction with therapy was high. These results are representative of men in community practice settings and may be of assistance to men and to clinicians when making treatment decisions.

Aged↗

The association between local atherosclerosis and prostate cancer.

OBJECTIVE: To morphometrically compare local atherosclerotic changes in cancerous prostate with those in noncancerous prostate specimens, as epidemiological studies report a positive association between the prevalence of general atherosclerosis and prostate cancer. MATERIALS AND METHODS: The intima-to-media-ratio (IMR) of 538 prostate capsular tissue arteries was measured in 50 prostate cancer-positive and 29 prostate cancer-negative specimens (including 26 with benign prostatic hyperplasia and three with normal prostatic tissue). RESULTS: An IMR of >1 was significantly associated with prostate cancer and a greater risk of prostate cancer (odds ratio 2.28). The IMR was >1 in cancer-positive specimens about twice as often as in cancer-negative tissue. CONCLUSION: Local atherosclerosis (measured by the IMR) was more pronounced in prostate cancer-positive than in prostate cancer-negative specimens. The results support the view that men with local atherosclerotic lesions are at higher risk of prostate cancer.

Atherosclerosis↗

Correlation between extent of metastatic lesions in whole body bone scintigraphy of patients with prostatic cancer and prostatic acid phosphatase in serum with Eiken PAP RIA kit.

The whole body bone scintigraphy of 13 patients whose prostatic cancer were histologically confirmed, was processed in four colors, and the bone metastases were quantitatively estimated. On the basis of this estimation, the extent of bone metastases was classified into 4 divisions (grades 0, 1, 2 and 3). And then, the correlation between the extent of bone metastases and prostatic acid phosphatase, acid phosphatase, and alkali phosphatase levels in serum were investigated.

Acid Phosphatase↗

Comparison of dihydrotestosterone levels in prostatic cancer metastases and primary prostate cancer.

Dihydrotestosterone (DHT) concentration, a marker for biochemical differentiation and possible clonal origin of prostate tumors, was measured in cancer present in lymph nodes (LN) from patients with untreated metastatic prostate cancer and compared to levels in untreated primary prostate cancer. The mean DHT of 2.23 ng/g in LN (S.E. = 0.28, N = 22) was significantly less (P less than .001) than the mean DHT of 4.8 ng/g in primary cancer (S.E. = 0.52, N = 20). Since primary prostate cancer may be admixed with stromal tissue, while lymph node represents pure epithelial cell tumor, we chose for this comparison only the 20 prostate cancer tissues that were judged by our pathologist to contain 90% or more epithelial cell tumor. Using this selection criteria, we found that prostate stroma, which has an average DHT concentration 1.18 times higher than prostate epithelia, would have an insignificant effect on primary prostate tumor DHT concentration. These data suggest that the decreased DHT in prostate tumor cells present in LN metastases may be a marker for a clone of cells with metastatic potential. These findings are consistent with previous reports from this laboratory indicating that DHT concentration less than 2.4 ng/g in primary prostate cancer is a predictor of a reduced disease-free interval following androgen blockade in advanced prostate cancer.

Dihydrotestosterone↗

Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans.

Prostate cancer (PCA), the most commonly diagnosed cancer in males in the United States, is the second leading cause of cancer-related deaths of males in this country. Because of the poor success rate in the treatment of PCA, an intervention at an early stage may reduce the progression of small carcinoma to large metastatic lesion, thereby reducing PCA-related deaths. Concerted efforts are needed to establish mechanism-based approaches to develop: (a) the markers for early detection of the disease as well as toward monitoring the efficacy of treatment(s); and (b) novel chemopreventive strategies against PCA. Using unique samples of pair-matched benign and cancer tissue obtained from the same PCA patient, we showed that ornithine decarboxylase (ODC) activity is significantly (P < 0.001) elevated in PCA (1142 +/- 100; mean +/- SE) than in paired benign tissue (427 +/- 51; mean +/- SE). The immunoblot analysis also showed a significant elevation in the protein expression of ODC in the PCA tissues as compared with the paired benign tissue. Furthermore, our data showed that the ODC activity in the prostatic fluid obtained by a digital rectal massage from the patients with PCA (3847 +/- 162; mean +/- SE) was significantly higher than in the patients with benign prostatic hyperplasia (2742 +/- 167; mean +/- SE) or normal individuals (1244 +/- 67; mean +/- SE). This observation might be of significance because the prostatic fluid could be obtained noninvasively by digital rectal massage. We suggest that ODC could serve as a target for early detection of human PCA as well as for monitoring the efficacy of treatment(s). The development of ODC as a target for novel chemopreventive strategies against PCA is an intriguing possibility.

Biomarkers↗

Practice patterns of Canadian urologists in benign prostatic hyperplasia and prostate cancer. Canadian Prostate Health Council.

PURPOSE: We reviewed the practice patterns of Canadian urologists in benign prostatic hyperplasia (BPH) and prostate cancer, and assessed the changes that occurred between 1995 and 1998. MATERIALS AND METHODS: In 1995 and 1998 questionnaires were mailed to all active members of the Canadian Urological Association who practiced adult urology in Canada. Many questions were similar, allowing for the assessment of changes in practice patterns. RESULTS: A number of changes were observed between 1995 and 1998. Cystoscopy and imaging of the upper urinary tract were used less often to evaluate uncomplicated cases of BPH. However, 39% of respondents continued to perform cystoscopy routinely. Finasteride was no longer administered in men with a smaller prostate. In 1998 before radical prostatectomy 28% of respondents routinely performed a bone scan, 29% cystoscopy and 57% chest x-ray. The number believing that maximal androgen blockade is the most effective hormonal therapy decreased from 90% to 62%, while 24% reported in the 1998 survey that they frequently administered intermittent hormonal therapy. Comparison with an American study from 1995 indicated that American urologists used the American Urological Association symptom score and performed a prostate specific antigen test more frequently than Canadian urologists. However, Canadian urologists performed cystoscopy more frequently. CONCLUSIONS: These surveys provide a useful insight into the variations in clinical practice of Canadian urologists and help to determine whether changes are occurring in regard to the development of practice guidelines. They also indicate the need to develop further guidelines, and ensure that these guidelines are widely promoted and accepted by the urological community.

Adult↗

Flutamide--an antiandrogen inhibiting prostatic cancer and prostatic secretion with retention of potency.

Ten men with prostatic cancer, stage T3M0 Nx or more, who were anxious to maintain sexual potency, were treated with flutamide. The eight metastasis-free tumours remained stable during treatment periods of 3-48 months. The two tumours with metastasis at the start of treatment showed growth inhibition for 3 and 7 months, respectively, but thereafter progressed, leading to change of treatment. Nine of the ten men claimed maintained potency during flutamide therapy. Seven delivered ejaculate for biochemical analysis during or after flutamide therapy, as further evidence of potency. Biochemical analyses of the pre-flutamide ejaculates revealed higher values for markers of prostatic secretion in cases with high level of tumour differentiation. Significant reduction in the secreted amount of prostatic and seminal vesicle parameters was found in all the studied cases during flutamide therapy.

Adenocarcinoma↗

Prostatic intraepithelial neoplasia and prostate cancer.

Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate specific antigen. PIN is characterized by progressive abnormalities of phenotype which are intermediate between normal prostatic epithelium (NP) and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High-grade PIN is considered the most likely precursor of prostatic carcinoma (PCa), according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via the suppression of vascular endothelial growth factor (VEGF) production. It is likely that PCa might also arise from precursor lesions other than high-grade PIN (low-grade PIN, atypical adenomatous hyperplasia, malignancy-associated foci, and atrophy).

Androgen Antagonists↗

Evaluation of plasma hormone concentrations in relation to clinical staging in patients with prostatic cancer. British Prostate Study Group.

Plasma concentrations of testosterone, oestradiol-17 beta, luteinising hormone (LH), follicle stimulating hormone (FSH), prolactin and growth hormone (GH) were measured in patients with histologically proven prostatic cancer, before any form of therapy was given for this disease. Patients were categorised according to UICC classification. No systemic change in the group means of any of these hormones was associated with the progression of the disease from the T0 to the T4 stage. When multivariate analysis was applied to the combined intraprostatic (T0 + T1 + T2) and extraprostatic (T3 + T4) tumour category in patients without clinically evident metastases (M0) a discrimination was observed, GH substantially contributing to the separation of the 2 groups. When plasma hormone data from patients classified as M0 (without metastases) were compared with M1 patients (with metastases), mean GH values were significantly larger (P less than 0.02) in patients with metastases. GH was also a major contributory factor to the discrimination between the M0 and M1 groups, using multivariate analysis. Testosterone group means for M0 versus M1 were also significantly different (P less than 0.02).

Age Factors↗

Immunohistochemical expression of BRCA2 protein and allelic loss at the BRCA2 locus in prostate cancer. CRC/BPG UK Familial Prostate Cancer Study Collaborators.

Many epidemiological studies have reported an association between breast and prostate cancer. BRCA2 functions as a tumour-suppressor gene in about 35% of large familial breast-cancer clusters; its role in the pathogenesis of sporadic breast cancer is less clear. We have evaluated immunohistochemical expression of BRCA2 protein and allelic loss of markers at the BRCA2 locus in tissue derived both from sporadic and from familial cases of prostate cancer. Immunohistochemical analysis was performed in 167 paraffin-embedded archival specimens. Normal prostate and 75% (120/160) of prostate-cancer tissue did not express BRCA2 protein. However, 25% (40/160) of cancer cases did express patchy staining; of these, 17% (2711 60) expressed positive nuclear staining in normal glandular tissue adjacent to tumour (either in addition to, or, independent of tumour). Allelic loss is the hallmark of a tumour-suppressor gene. Markers flanking (D13S267, D13S260) and within (D13S171) the BRCA2 gene indicated allelic loss in at least one locus in 23% (17/73) of tumours analyzed. There was no difference in the rates of allelic loss between sporadic and familial tumours, nor was there any association between immunohistochemical staining and allelic loss. Although immunohistochemical staining provided no useful prognostic information, allelic loss at BRCA2 was shown in univariate analysis to be associated with poorer survival (log-rank test, p = 0.046).

BRCA2 Protein↗

The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.

Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.

Adult↗

Transrectal ultrasound and core biopsies for the diagnosis of prostate cancer. A study of pretreatment investigation strategy for patients with suspected prostate cancer.

Prostate cancer is the most common malignancy among Swedish men. In order to select patients to appropriate treatment, transrectal ultrasound (TRUS) and guided core biopsies is commonly used. The aim of this study was to define prognostically important factors in prostate cancer and the accuracy of TRUS and core biopsies as diagnostic tools. Fifty-one patients with localized prostate cancer were prostatectomized and followed up after a mean observation time of 73 months. The adverse influence on progression by tumor volume, Gleason grade, seminal vesicle invasion and lymph node metastases was statistically significant in the univariate analyses. However, tumor volume was the only parameter with an independent prognostic impact on progression. It is important to find a diagnostic method which can accurately determine these parameters in the pretreatment work-up. Thirty-four patients with localized prostate cancer were examined with TRUS prior to radical surgery. The ultrasound examination failed to detect 24% of the tumors, and was not reliable for the determination of tumor size and capsular penetration. TRUS can not be used as the sole method for the diagnosis of prostate cancer. Biopsies might improve the results. Ultrasound-guided core biopsies targeting hypoechoic lesions suspicious for prostate cancer in combination with systematic biopsies sampling the whole gland were performed on 251 men. By adding the results of systematic biopsies to the results of target biopsies, additional information was obtained for the detection of cancer, on tumor volume and seminal vesicle invasion. Grading was not improved. By taking multiple TRUS-guided biopsies considerable trauma is inflicted to the patient. A 1.2-mm cutting needle is commonly used for sampling. A thinner needle may possibly cause less pain. It was shown that a 0.9-mm core biopsy needle can be used without compromising diagnostic accuracy. The results obtained with two thinner needles, 0.8- and 0.7-mm, were unsatisfactory. Complications following TRUS-guided biopsies are infections, bleeding and urinary retention. A total of 347 consecutive men were extensively biopsied. We studied the impact of patient age, final diagnosis, number of biopsies taken, and different regimes for prophylactic norfloxacin treatment. The administration of antibiotics for 3 days, when the first dose was given before the examination began, was the only parameter statistically associated with a reduced risk for complications. Multiple biopsies can be taken without an increased risk for complications if prophylactic antibiotic treatment is given.

Aged↗

Pathology review in an early prostate cancer detection program: results from the American Cancer Society-National Prostate Cancer Detection Project.

Biopsy materials obtained in the American Cancer Society National Prostate Cancer Detection Project were reviewed at the Central Pathology Laboratory at the Armed Forces Institute of Pathology. Of 265 cases submitted, 177 were diagnosed as prostatic carcinoma, 7 as prostatic intraepithelial neoplasia (PIN), 13 as atypical glands or atypical hyperplasia, and the remaining 68 were benign hyperplasias. Irrespective of the means of detectin or the grading system used (Gleason or WHO-Mostofi), a large majority of the cancers were detected as low-grade tumors. Of 27 cases of PIN reported, 20 were associated with cancer, leaving 7 cases with the sole diagnosis of PIN. These data may indicate the increased use of prostate-specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasound (TRUS) in the United States is shifting the spectrum of prostate cancer pathology toward early low-grade tumors.

Biopsy↗

Adjuvant hormonal treatment for prostate cancer: the bicalutamide early prostate cancer program.

Adjuvant hormonal therapy has been demonstrated to be able to delay disease progression in nonmetastatic prostate cancer. To date, however, a favorable impact on survival has only been demonstrated in lymph-node-positive disease and in external-beam radiotherapy series with locally advanced and probably mainly micrometastatic tumors. The Bicalutamide Early Prostate Cancer Program is the largest study under way to define the role of adjuvant treatment in early prostate cancer and identify subgroups of patients likely to benefit from immediate hormonal therapy. At the time of the most recently published analysis, the risk of objective clinical progression was significantly reduced in the bicalutamide arm (hazards ratio 0.58, 95% confidence interval 0.51-0.66, p < 0.0001). However, further maturation of data is needed to see whether this difference will lead to a survival advantage.

Androgen Antagonists↗

Prostatic volume and ratio of free-to-total prostate specific antigen in patients with prostatic cancer or benign prostatic hyperplasia.

PURPOSE: We correlated prostatic volume with the ratio of free-to-total prostate specific antigen (PSA) in serum from patients with prostatic cancer or benign prostatic hyperplasia (BPH) to evaluate how prostatic volume influences the ratio. MATERIALS AND METHODS: We evaluated sera from 395 patients (mean age 65 years, range 45 to 88) with prostate cancer (239) or BPH (156) for total PSA, free PSA and ratio of free-to-total PSA. For detection of total and free PSA we used an Immulite free and total PSA assay. Prostatic volume was determined with transrectal ultrasonography. Prostatic volume in BPH and prostate cancer patients was divided into 10 ml. groups, and mean ratio of free-to-total PSA was calculated for each volume group and both diseases. For statistical analysis Mann-Whitney U and Kruskal-Wallis tests were performed in addition to calculation of sensitivity and specificity, and receiver operator curves for prostates 60 ml. or less and greater than 60 ml. RESULTS: For BPH patients the mean ratio of free-to-total PSA was 14.64 to 25.14% without a close relation to prostatic volume. In prostate cancer patients a proportional increase from 8.45 to 19.37% in the ratio of free-to-total PSA with volume was found. Mann-Whitney U analysis revealed significant differences in prostate cancer versus BPH only in patients with prostates of 60 ml. or smaller (p = 0.0008 to 0.029). No significant differences were seen when prostate cancer and BPH patients with prostates larger than 60 ml. were compared (p = 0.082 to 0.868). Kruskal-Wallis test confirmed independence of the ratio of free-to-total PSA from prostatic volume in BPH patients (p = 0.285) but dependence in prostate cancer patients (p <0.0001). Sensitivity was higher in patients with prostates 60 ml. or smaller (86.72%) than in patients with prostates larger than 60 ml. (66%), and specificity was lower at 45.78 and 56.16%, respectively. CONCLUSIONS: We have shown that the ratio of free-to-total PSA is influenced by prostatic volume in patients with prostate cancer. The ratio of free-to-total PSA provides useful information for differentiate BPH from prostate cancer in patients with small prostates but it is less useful in patients with larger prostates, probably because of the larger proportion of benign hypertrophic tissue.

Aged↗

Effects of false-positive prostate cancer screening results on subsequent prostate cancer screening behavior.

OBJECTIVES: Little is known about screening behavior following a false-positive prostate cancer screening result, which we have defined as a screening result with "abnormal/suspicious" labeling that did not result in a prostate cancer diagnosis within 14 months. The purpose of this analysis was to examine whether age, race, education, or previous false-positive prostate cancer screening results via prostate-specific antigen or digital rectal exam predict decision to obtain subsequent prostate cancer screening. METHODS: Data were drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The study sample consisted of 2,290 older men (mean age, 62.8 years; range, 55-75 years) who had false-positive (n = 318) or negative (n = 1,972) prostate-specific antigen or digital rectal exam baseline prostate cancer screening results. Multivariable logistic regression was used to assess the effect of false-positive results on subsequent prostate cancer screening behavior, adjusting for all covariates. RESULTS: The multivariable model showed that being African American (P = 0.016), and having a high school education or less (P = 0.007), having a previous false-positive prostate cancer screening result (P < 0.001), were predictive of not returning for prostate cancer screening in the following screening trial year. CONCLUSION: The study results highlight the importance of shared decision making between patients and their providers regarding the risks and benefits of prostate cancer screening, and follow-up options for abnormal prostate cancer screening results. Shared decision making may be especially important for African American men, whom prostate cancer disproportionately affects.

Black or African American↗

[Prostate cancer screening (II): is prostate cancer a public health problem? Update of incidence and mortality figures in France from 1982 to 1990].

OBJECTIVE: To describe the epidemiological situation of prostatic cancer in France on the basis on a large population sample. MATERIAL AND METHODS: This study uses incidence data derived from French cancer registers, and mortality data obtained from death certificates. Crude rates and rates standardized for the world population are calculated. The variation of these rates is analysed by a log-linear model (adjusted for age, department and period). RESULTS: The incidence of prostatic cancer in France in 1990 was 200 to 300/100,000 between the ages of 60 and 70 years and more than 600/100,000 after the age of 70 years. 73% of cases were diagnosed after the age of 70 years. The incidence increased annually by 8.76% between 1982 and 1990. An estimated 22,600 cases were diagnosed in France in 1990. The increased incidence of localized or local stages is due to the use of diagnostic tests (PSA and ultrasound-guided biopsies), as this increase accelerated after 1987. The crude mortality rate was 33.4/100,000 (384/100,000 between the ages of 75 and 85 years). It increased by 2.56% per annum from 1982 to 1990, but essentially for men over the age of 75 years. CONCLUSION: These findings tend to make prostatic cancer a public health priority, but this affirmation must be moderated by the fact that this disease has a low impact on loss of life expectancy.

Age Distribution↗