Benign and Malignant Neoplasms of the Prostate

0022-534 7/94/1514-1116$03.00/0 Vol. 151, 1116-1152, April 1994 Printed in U.S. A.

THE JOURNAL OF UROLOGY Copyright© 1994 by AMERICAN UROLOGICAL ASSOCIATION, INC.

ABSTRACTS BENIGN AND MALIGNANT NEOPLASMS OF THE PROSTATE A Prospective Study of Dietary Fat and Risk of Prostate Cancer

E. GIOVANNUCCI, E. B. RIMM, G. A. COLDITZ, M. J. STAMPFER, A. ASCHERIO, C. C. CHUTE AND WILLETT

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J. Natl. Cancer Inst., 85: 1571-1579, 1993 Background: The strong correlation between national consumption of fat and national rate of mortality from prostate cancer has raised the hypothesis that dietary fat increases the risk of this malignancy. Case-control and cohort studies have not consistently supported this hypothesis. Purpose: We examined prospectively the relationship between prostate cancer and dietary fat, including specific fatty acids and dietary sources of fat. We examined the relationship of fat consumption to the incidence of advanced prostate cancer (stages C, D, or fatal cases) and to the total incidence of prostate cancer. Methods: We used data from the Health Professionals Follow-up Study, which is a prospective cohort of 51529 U.S. men, aged 40 through 75, who completed a validated food-frequency questionnaire in 1986. We sent follow-up questionnaires to the entire cohort in 1988 and 1990 to document new cases of a variety of diseases and to update exposure information. As of January 31, 1990, 300 new cases of prostate cancer, including 126 advanced cases, were documented in 47855 participants initially free of diagnosed cancer. The Mantel-Haenszel summary estimator was used to adjust for age and other potentially confounding variables. Multiple logistic regression was used to estimate relative risks (RRs) when controlling simultaneously for more than two covariates. Results: Total fat consumption was directly related to risk of advanced prostate cancer (age- and energy-adjusted RR= 1.79, with 95% confidence interval [CI] = 1.04-3.07, for high versus low quintile of intake; P [trend] = .06). This association was due primarily to animal fat (RR= 1.63; 95% CI= 0.95 -2.78; P [trend]= .08), but not vegetable fat. Red meat represented the food group with the strongest positive association with advanced cancer (RR = 2.64; 95% CI= 1.21-5.77; P = .02). Fat from dairy products (with the exception of butter) or fish was unrelated to risk. Saturated fat, monounsaturated fat, and a-linolenic acid, but not linoleic acid, were associated with advanced prostate cancer risk; only the association with a-linolenic acid persisted when saturated fat, monounsaturated fat, linoleic acid, and a-linolenic acid were modeled simultaneously (multivariate RR= 3.43; 95% CI = 1.67-7.04; P [trend] = .002). Conclusion: The results support the hypothesis that animal fat, especially fat from red meat, is associated with an elevated risk of advanced prostate cancer. Implications: These findings support recommendations to lower intake of meat to reduce the risk of prostate cancer. The potential roles of carcinogens formed in cooking animal fat and of a-linolenic acid in the progression of prostate cancer need to be explored.

Editorial Comment: In this series the intake of animal fat was not associated with the overall development of prostate cancer but was associated with the presence of advanced prostate cancer. Red meat represented the food group with the strongest positive association, producing a relative risk of 2.6. This suggests that animal fat may act as a promoter producing progression of disease. Patrick C. Walsh, M.D.

Serum Pituitary and Sex Steroid Hormone Levels in the Etiology of Prostatic Cancer-A Population-Based Case-Control Study S.-0. ANDERSSON, H.-0. ADAMI, R. BERGSTROM AND L. WIDE, Department of Urology, Orebro Medical Center Hospital, Orebro, Cancer Epidemiology Unit and Department of Clinical Chemistry, Uppsala University Hospital and Department of Statistics, Uppsala University, Uppsala, Sweden Brit. J. Cancer, 68: 97-102, 1993 The hypothesis that serum concentrations of pituitary hormones, sex steroid hormones, or sex hormonebinding globulin (SHBG) affect the occurrence of prostatic cancer was tested in a consecutive sample of 93 patients with newly diagnosed, untreated cancer and in 98 population controls of similar ages without the disease. Cases did not differ significantly from controls regarding serum levels of luteinising hormone (LH) or follicle stimulating hormone (FSH). Remarkably close agreement was found for mean values of total testosterone (15.8 nmol 1- 1 in cases and 16.0 in controls), and free testosterone (0.295 and 0.293 nmol 1-1, respectively), with corresponding odds ratios for the highest vs lowest tertile of 1.0 (95% confidence interval 0.5-1.9) for testosterone and 1.2 (95% confidence interval 0.6-2.4) for free testosterone. Similar close agreement between cases and controls was found for serum concentrations of estradiol, androstenedione and SHBG, although the mean estradiol level was non-significantly (P = 0.30) lower among cases. Changes secondary to the disease 1116

BENIGN AND MALIGNANT NEOPLASMS OF THE PROSTATE

were unlikely to have affected the results materially, since only LH and FSH were associated with stage of disease and this relationship was weak. Our findings suggest that further analyses of serum hormone levels at the time of diagnosis are unlikely to improve our understanding of the etiology of prostatic cancer.

Editorial Comment: This study fails to demonstrate an association between serum hormone levels at the time of diagnosis and the presence of prostate cancer. Patrick C. Walsh, M.D.

Production of Alpha-1-Antichymotrypsin by PSA-Containing Cells of Human Prostate Epithelium A. BJARTELL, T. BJORK, M.-T. MATIKAINEN, P.-A. ABRAHAMSSON, A. DISANT'AGNESE AND H. LILJA Departments of Urology and Clinical Chemistry, Lund University, Malmo General Hospital, Malmo, Sweden, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York and Department of Biotechnology, University of Turku, Turku, Finland Urology, 42: 502-510, 1993 Prostate-specific antigen (PSA) is a chymotrypsin-like serine protease exclusively produced by the prostate epithelium, and abundant in seminal fluid. In serum, PSA is predominantly complexed to a liver-derived serine protease inhibitor, alpha-1-antichymotrypsin (ACT). A higher proportion of serum PSA is complexed to ACT in prostate cancer than in benign prostate hyperplasia. Since the molecular basis for this is unclear, we have investigated whether or not ACT may be produced in the prostate gland. Immunocytochemistry, using either monoclonal or polyclonal lgGs, demonstrated specific immunostaining for ACT in normal PSA-containing prostate epithelium. Production of ACT in the normal PSA-producing prostate epithelium was demonstrated by means of nonradioactive in situ hybridization using 30-mer anti-sense DNA probes for ACT and for PSA. The ACT and PSA coding transcripts, as detected by in situ hybridization, were distributed perinuclearly, in contrast to the specific immunostaining for ACT and PSA which was most intense in the apical portion of the secretory cells. The results strongly suggest local production and release of ACT by the normal prostate epithelium that may be important for interaction between PSA and ACT in extracellular compartments.

Editorial Comment: PSA is a powerful protease that is inactivated in the serum by binding to 2 major protease inhibitors, al-antichymotrypsin and a2-macroglobulin. Some PSA also circulates in the plasma unbound in a free form; presumably this form is not enzymatically active. Preliminary evidence suggests that there is more free PSA in the serum of men with benign prostatic hyperplasia. This finding potentially could improve the specificity of serum PSA in distinguishing benign prostatic hyperplasia from prostate cancer. This article and a recent report by Lilja 1 expand upon these observations and the potential underlying mechanisms. 1. Lilja, H.: Significance of different molecular forms of serum PSA. The free, noncomplexed form of PSA

versus that complexed to alpha-I antichymotrypsin. Urol. Clin. N. Amer., 20: 681, 1993.

Serum Prostate-Specific Antigen in a Community-Based Population of Healthy Men: Establishment of Age-Specific Reference Ranges J.E. OESTERLING, s. J. JACOBSEN, C. G. CHUTE, H. A. GUESS, C. J. GIRMAN, L.A. PANSER AND M. M. LIEBER, Department of Urology, Section of Clinical Epidemiology, Mayo Clinic and Foundation, Rochester, Minnesota and Department of Epidemiology, Merck Research Laboratories, Blue Bell, Pennsylvania J.A.M.A., 270: 860-864, 1993 Objective.-To define the characteristics of serum prostate-specific antigen (PSA) in a population of healthy men without clinically evident prostate cancer, but who are at risk for developing the malignancy. The influence of patient age and prostatic size on the serum PSA concentration was assessed in order to use PSA more appropriately to detect clinically significant prostate cancer at an early, potentially curable stage. Design.-Prospective, community-based study. Participants.-Between December 1989 and March 1991, 2119 healthy men aged 40 to 79 years from Olmsted County, Minnesota, were entered into a prospective study to assess the natural history of benign prostatic hyperplasia. Of these, 537 (25%) were randomly chosen to participate in a detailed clinical examination that included a serum PSA determination (Tandem-R PSA assay), digital rectal examination, and transrectal ultrasonography. Four hundred seventy-one (88%) completed the prostatic evaluation and had no evidence of prostate cancer by any of these three diagnostic tests; these men formed the study population on which all analyses were performed. Main Outcome Measure.-Serum PSA concentration, prostatic volume, and PSA density (serum PSA level/ prostatic volume) as a function of patient age.

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Results.-The serum PSA concentration is correlated with patient age (r = .43; P <.0001) and prostatic volume (r = .55; P <.0001). Prostatic volume, in turn, is directly correlated with patient age (r = .43; P <.0001), whereas the PSA density value is only weakly correlated with patient age (r = .25; P <.001). For a healthy 60year-old man with no evidence of prostate cancer, the serum PSA concentration increases by approximately 3.2% per year (0.04 ng/mL per year). The recommended reference range for serum PSA (95th percentile) for men aged 40 to 49 years is 0.0 to 2.5 ng/mL; for 50 to 59 years, 0.0 to 3.5 ng/mL; 60 to 69 years, 0.0 to 4.5 ng/ mL; and 70 to 79 years, 0.0 to 6.5 ng/mL. Conclusions.-The serum PSA concentration is directly correlated with patient age and prostatic volume, the latter of which also is directly related to age. Thus, rather than rely on a single reference range for men of all age groups, it is more appropriate to have age-specific reference ranges. These age-specific reference ranges have the potential to make serum PSA a more discriminating tumor marker for detecting clinically significant cancers in older men (increasing specificity) and to find more potentially curable cancers in younger men (increasing sensitivity). Editorial Comment: The authors have made a logical suggestion that the reference range for PSA should vary with patient age. It is well recognized that prostate size increases as men age and correction of serum PSA for prostate size (PSA density) can be useful. The authors suggest that age provides a useful surrogate for prostate size and age specific ranges for PSA provide a more discriminating marker, detecting more curable cancers in younger men by increasing sensitivity and reducing unnecessary diagnostic tests in older men by increasing specificity. However, it has yet to be shown whether the loss of sensitivity in older men will decrease the diagnosis of curable cancers in men in their sixties. Prospective evaluation of this concept in a large cohort of men is certainly warranted. Patrick C. Walsh, M.D.

Effect of Patient Age on Early Detection of Prostate Cancer With Serum Prostate-Specific Antigen and Digital Rectal Examination

J. P. RICHIE, W. J. CATALONA, F. R. AHMANN, M. A. HUDSON, P. T. SCARDINO, R. C. FLANIGAN, J. B. DEKERNION, T. L. RATLIFF, L. R. KAVOUSSI, B. L. DALKIN, W. B. WATERS, M. T. MACFARLANE AND P. C. SOUTHWICK, Division of Urologic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, Divisions of Urology and Hematology-Oncology, University of Arizona College of Medicine and Tucson VA Medical Center, Tucson, Arizona, Scott Department of Urology, Baylor College of Medicine, Houston, Texas, Department of Urology, Loyola University Medical Center, Chicago, Illinois, Division of Urology, UCLA School of Medicine, Los Angeles and Department of Clinical Research and Regulatory Affairs, Hybritech Incorporated, San Diego, California Urology, 42: 365-374, 1993 This study was designed to determine the effects of age by decade on the efficacy of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) for early detection of prostate cancer in men aged fifty and over. A prospective multicenter clinical trial was conducted at six university centers. All 6,630 male volunteers underwent a serum PSA (Hybritech, Tandem) determination and DRE. Quadrant biopsies of the prostate were performed if PSA was> 4 ng/mL or DRE suspicious. A total of 1,167 biopsies were performed, and 264 cancers were detected. The cancer detection rate increased from 3 percent in men aged fifty to fifty-nine to 14 percent in men eighty years or older (p < 0.0001). PSA detected significantly more of the total cancers than DRE at all age ranges (p < 0.05). The positive predictive values (PPV) for PSA were 32 percent (50-59 years), 30 percent (60-69 years), 34 percent (70-79 years), and 38 percent (80+ years). The corresponding PPVs for DRE were 17 percent, 21 percent, 25 percent, and 38 percent. Eighteen percent of the cancers were detected solely by DRE, whereas 45 percent of cancers were detected solely by PSA. Thus, the use of both tests in combination provided the highest rate of detection in all age groups. One hundred-sixty patients underwent radical prostatectomy and pathologic staging. Cancer was organ-confined in 74 percent (25/34) of men aged fifty to fifty-nine, 76 percent (65/86) of men aged sixty to sixty-nine, and 60 percent (24/40) of men aged seventy or over (x 2 , < 70 vs.~ 70, p < 0.05). Early detection programs yield a lower, yet still substantial, cancer detection rate in younger men, and there is a greater likelihood for detection of organ-confined disease in this age range. Younger men have the longest projected life expectancy and, therefore, the most to gain from early prostate cancer detection. Editorial Comment: The authors present evidence that PSA screening detects more organ confined cancers in younger men, who have the most to gain from early prostate cancer detection, than in men who are older than 70 years. Patrick C. Walsh, M.D.

BENIGN AND MALIGNANT NEOPLASMS OF THE PROSTATE

Detection of 0:rgsm-Co.nfined Pro§tate Cancer is Increased Th.rough Prostate-Specific AntigenBased Screening

W. J. CATALONA, D. S. SMITH, T. L. RATLIFF AND J. W. BASLER, Division of Urologic Surgery, Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri J.A.M.A., 270: 948-954, 1993 Objective.-To determine whether prostate-specific antigen (PSA)-based screening alters the proportion of organ-confined prostate cancers detected. Design.-A prospective, nonrandomized, serial PSA-based screening trial (follow-up from 6 to 37 months), and a concurrent comparison group. Setting.-General community outpatient screening program based at a university center. Patients.-The study group consisted of 10251 men aged 50 years and older (mean and median age, 63 years; mean and median age of patients who underwent biopsies, 66 years) who presented to a prostate cancer screening program and consented to phlebotomy. The comparison group consisted of 266 concurrently studied private patients in the same age range (mean and median age, 68 years) who were referred for prostatic ultrasonography and biopsy because of an abnormal digital rectal examination (DRE). Main Outcome Measure.-Proportion detected with clinically or pathologically advanced prostate cancer. Results.-The men were divided into three groups: the comparison group, the initial PSA-based screening group, and the serial PSA-based screening group. The proportions of prostate cancers detected that were clinically or pathologically advanced were as follows: comparison group, 57% (27/47); initial FSA-based screening group, 37% (91/244); and serial PSA-based screening group, 29% (37/129). Screened patients had a lower proportion of advanced cancers than the comparison group (x 2 [2] = 12.3; P = .002); this advantage was observed principally in patients younger than 70 years. Surgical staging revealed that the cancer was microscopically focal and well differentiated (possibly latent cancer) in 2.5% (1/40) of the nonscreened group, 2.9% (7 /244) of the initially screened group, and 7.8% (10/129) of the serially screened group (generalized Fisher's Exact Test, P = .08). Conclusion.-Screening based on PSA identifies some men with prostate cancer who have a significantly increased proportion of organ-confined tumors compared with those detected through evaluation for an abnormal DRE alone. Editorial Comment: This study demonstrates that in men who are diagnosed by serial PSA screening, 71 % will have organ confined disease at surgery, nearly double the p:ropo:rtion of prostate cancers that a:re organ confined when detected by an abnormal digital rectal examinationo Patrick Co Walsh, MoD.

Characteristics of Prostate Cancers Detected in a Multimodality Early Detection Program

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P. J. LITTRUP, A. CHESLEY, R. BABAIAN, R. BADALAMENT, R. A. KANE Center Institute, Buffalo, New York, American Cancer Society, Atlanta, Georgia, Radiology Prostate Research Group, Ypsilanti, St. Joseph Mercy Hospital, Ann Arbor, Michigan, St. Joseph Hospital, Prostate Cancer Detection Clinic, St. John, New Brunswick, Canada, M. D. Anderson Cancer Center, University of Texas, Houston, Texas, Ohio State University, University Hospitals, Columbus, Ohio, New England Deaconess Hospital, Boston, Massachusetts and Armed Forces Institute of Pathology, Department of Genitourinary Pathology, Washington, D. C. METTLIN, G. P. MURPHY, F. LEE, AND F. K. MOSTOFI, Roswell Park

Cancer, 72: 1701-1708, 1993 Background. Few data are available to describe the clinical and pathologic characteristics of prostate cancers detected through early detection programs. The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) is a multimodality, multicenter study of the feasibility of early prostate cancer detection using digital rectal examination (DRE), transrectal ultrasound (TRUS), and prostate specific antigen (PSA). One hundred fifty-six prostate cancers are available from this project for analysis. Methods. The ACS-NPCDP is a prospective, comparative study of a cohort of 2,999 men between 55 and 70 years of age not suspected of having prostate cancer. DRE, TRUS, and PSA are performed for each subject on an annual basis for as long as 5 years. Biopsies are performed on the basis of recommendations from DRE or TRUS results. Although elevated PSA alone was not typically a basis for biopsy, in some instances biopsies were recommended because of the degree of elevation in PSA. Diagnoses are confirmed by participating pathologists and by pathologic analysis. Results. A small proportion of cancers detected were advanced in terms of the clinical stage at time of diagnosis. A total of only six cancers were stage Cl to Dl, and five of these were preexisting cancers detected at the first examination. Cancers detected by DRE tended to be more advanced than those found on the basis of only TRUS or PSA. A large proportion of patients received curative therapy, involving radical prostatectomy for 67.9% and radiation therapy for 17.9%. Of 100 men presumed to have organ confined disease and treated by prostatectomy, 64 actually proved to have localized cancer, a rate of upstaging of 36.0%. PSA level and PSA

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density were associated with the detection of organ confined cancer, but several advanced cancers had PSA levels in the normal range, limiting the usefulness of these measures for staging. Conclusions. The cancers resulting from this multimodality detection effort represented a spectrum of pathologic findings. These data, however, suggest that early detection interventions in men not suspected to have prostate cancer will yield tumors with a favorable stage distribution that are likely to benefit from treatment. Further follow-up evaluation is needed to determine whether these benefits are reflected in longterm mortality and survival experience. Editorial Comment: With slightly different methodology, this group of investigators found similar improvement in the identification of organ confined cancers using a sequential screening program. Patrick C. Walsh, M.D.

Prostate Cancer Screening: What We Know and What We Need to Know B.

S. KRAMER, M. L. BROWN, P. C. PROROK, A. L. POTOSKY AND J. K. GOHAGAN, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland

Ann. Intern. Med., 119: 914-923, 1993 Objective: To critically evaluate the evidence for recommending the screening of asymptomatic men for prostate cancer with a blood test to detect a prostate-specific antigen (PSA). Data Sources: Relevant articles on screening for prostate cancer were identified from MEDLINE searches, from the authors' files, and from the bibliographies of identified articles. Study Selection: In the absence of controlled prospective trials, the studies are primarily retrospective and contain information about the sensitivity, specificity, and predictive values of tests used to screen for prostate cancer; the natural history of untreated prostate cancer; the morbidity, mortality, and costs of definitive treatment; and reviews of screening study biases. Data Extraction: Potential treatment-related mortality and costs that could be incurred by screening were estimated using defined assumptions. Results: Although screening for prostate cancer has the potential to save lives, because of possible overdiagnosis, screening and subsequent therapy could actually have a net unfavorable effect on mortality or quality of life or both. Given the performance characteristics of the test, widespread screening efforts would probably cost billions of dollars. Conclusions: The net benefit from widespread screening is unclear. A randomized prospective study of the effect of screening on prostate cancer mortality has therefore been initiated by the National Cancer Institute. Editorial Comment: I classify this article in the category of misinformation. In an accompanying editorial, I did my best to try to set the record straight. 1 I pointed out that many men older than 50 years present with urinary symptomatology and in these men PSA functions as a diagnostic test, not a screening test. For this reason and for many others I do not agree with their estimate of the economic impact. Next, I pointed out that the optimal use of PSA in the diagnosis of prostate cancer has not yet been defined and that there are many refinements in progress which may improve its diagnostic accuracy, for example age specific ranges, PSA velocity and measurement of free versus bound PSA. Their discussion of the management of localized prostate cancer in this article focuses on studies of no treatment, which indicated little benefit. However, other studies were ignored, such as the recent series by Adolfsson et al that showed that radical prostatectomy reduces metastases and death from prostate cancer by 50% at 10 years. 2 The purpose of this article is to discourage screening for prostate cancer, which might interfere with the major screening trial of the National Cancer Institute (NCI) called the Prostate, Lung, Colon-Rectum and Ovary trial (PLCO). This study will involve 4 years to recruit patients and 12 years of followup. The cost is estimated to be $89 million. I believe that this study is so severely flawed that it will never answer the question. Men will be screened once a year for only 4 years, which is similar to the screening intervals used in the study that showed a benefit for mammography in diagnosing breast cancer, and will then be followed with no further testing. However, the doubling time of breast cancer is much more rapid than that of prostate cancer and, thus, a similar protocol is unlikely to produce similar results. Furthermore, I believe that 4 years is too short a time to test whether a yearly rate of change in PSA will prove as valuable as I believe it will be. I also am concerned about the lack of mandated treatment. Once a diagnosis is made the choice of treatment is left up to the patient and his physician. The end point in this study will be death from prostate cancer. If screened patients are not required to receive effective therapy, how will this study answer any question? Furthermore, to recruit enough patients the NCI has decided that they must enroll men up to age 74 years. Urologists are criticized for performing radical prostatectomy on men who are older than 70 years but the NCI has included these older men in this study.

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Fo:r all of these reasons I believe that the NCI study should. he stopped until the results of ongrning trials provide info:rmation about the optimal use of PSA measurements for the identification of significant tumors that need to be treated. During this delay the study should undergo major modifications to exclude older patients from the study and to :randomize study patients to an effective treatment arm in the event that a diagnosis of prostate cancer is made. Patrick C. Walsh, M.D. L Walsh, P. C.: Using prostate-specific antigen to diagnose prostate cancer: sailing in uncharted waters. Ann. Intern. Med., 119: 948, 1993. 2. Adolfsson, J., Steineck, G. and Whitmore, W. F., Jr.: Recent results of management of palpable clinically localized prostatic cancer. Cancer, 72: 310, 1993.

Fast Spin-Echo MR Images of the Pelvis Obtained With a Phased-Ar:ray Coil: Value in Localizing and Staging Prostatic Carcinoma R. KIER, S. WAIN AND R. TROIANO, Department of Radiology, Yale University School of Medicine, New Haven and Department of Pathology, Griffin Hospital, Derby, Connecticut

AJR, 161: 601-606, 1993 OBJECTIVE. The fast spin-echo pulse sequence allows T2-weighted MR images to be acquired more rapidly than is possible with conventional spin-echo sequences, and phased-array coils can provide a higher signal-tonoise ratio than is possible with the body coil. The combination of these methods permits higher resolution images to be obtained with more signal averages despite shorter imaging times. In this study, initial technical comparisons designed to confirm the advantage of combining fast spin-echo pulse sequences with a pelvic phased-array multicoil were followed by an assesment of the value of these methods for the localization and staging of prostatic carcinoma. SUBJECTS AND METHODS. Seventy-one men with known (60) or suspected (11) prostatic carcinoma were imaged with T2-weighted fast spin-echo pulse sequences in the axial and coronal planes with a phased array of four surface coils (multicoil) for signal reception. Four of these men also were imaged with fast spinecho sequences and the body coil, and six of these men also were imaged with T2-weighted conventional spin echo sequences and the multicoil; image qualities achieved with these techniques were compared. The use of IV glucagon (42 of 71 studies) before fast spin-echo sequences was correlated with the subsequent presence or absence of peristaltic artifacts on MR images. MR images were analyzed for the presence or absence ofprostatic cancer in the right and left sides of the gland and for evidence of spread either through the capsule, into the seminal vesicles, or to lymph nodes or bone. Findings at MR imaging were compared with results of radical prostatectomy (20), lymph node dissection without prostatectomy (seven), and biopsy (67). RESULTS. Image quality obtained with the combination of the fast spin-echo sequence with the multicoil was judged superior to that obtained with either the conventional spin-echo sequence with the multicoil or the fast spin-echo sequence with the body coil. Significant motion artifacts were noted in 45% of studies (13/29) performed without glucagon vs 7% of studies (3/42) performed with glucagon. In the 58 patients for whom information concerning the location of tumor in either the right or left side of the gland was obtained from biopsy (39) or surgery (19), MR images allowed cancer to be detected with 89% sensitivity and 77% specificity. Among the 20 patients undergoing prostatectomy and seven others undergoing lymph node dissection, MR imaging permitted high accuracies in predicting involvement of the seminal vesicles (100%), local transcapsular spread (85% ), and involvement of pelvic lymph nodes (85% ). CONCLUSION. Fast spin-echo imaging with a pelvic phased-array multicoil provides high-resolution images of the prostate that may obviate an endorectal coil for the detection, localization, and staging of prostatic carcinoma. Editorial Comment: The auUwn, report on a new technique that may improve imaging of the prostate without using an en.do-rectal coil. Patrick C. Walsh, M.D.

Effect of Cystoscopy, Prostate Biopsy, and Transurethral Resection of Prostate on Serum ProstateSpecific Antigen Concentration

J. E. OESTERLING, D. C. RICE, w. J. GLENSKI AND E. J. BERGSTRALH, Department of Urology, Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota Urology, 42: 276-282, 1993 To assess the effect of cystoscopy, prostate biopsy, and transurethral resection of the prostate (TURP) on the serum prostate-specific antigen (PSA) concentration, 101 patients were evaluated. For cystoscopic examination, 69 men were randomized in a prospective manner to one of three groups: flexible cystoscopy, rigid cystoscopy, and a control cohort. The median change in serum PSA was 0.1 ng/mL following flexible cystoscopy,

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

Editorial Comment: This report is a reminder that serum PSA usually returns to baseline levels within 3 weeks after a needle biopsy but it can remain elevated for longer than 3 weeks. For this reason the authors recommend that PSA should not be measured for at least 6 weeks after a prostate biopsy or transurethral resection of the prostate. Patrick C. Walsh, M.D.

Analysis of Variation in Prostate-Specific Antigen Values

M. RIEHMANN, P. R. RHODES, T. D. COOK, G. S. GROSS AND R. C. BRUSKEWITZ, Department of Surgery, Division of Urology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Urology, 42: 390-397, 1993 This retrospective study analyzes variation in prostate-specific antigen (PSA) levels in 129 males who were not diagnosed with prostate cancer or other known malignancies. The extent to which the assay and the biologic variation contributed to the variation in PSA concentration was evaluated from analysis of slopes characterizing PSA concentration as a function of time. The mean coefficient of variation on observations was 58.0 percent. The estimated mean biologic coefficient of variation was 55.3 percent versus a mean assay coefficient of variation of 13.2 percent, indicating that the assay variation contributed negligibly to variation compared with the biologic variation. The concept that a PSA level which rises more than that attributable to assay variation indicates the need for invasive testing for prostate cancer is questionable. A decreasing PSA level was seen as often and of the same magnitude as an increasing level within a relatively narrow window of approximately one year. We are aware of no reason why this variability in PSA values would not be observed in patients with occult prostate cancer.

Editorial Comment: The authors attempted to evaluate the concept of PSA rate of change (PSA velocity) using historical controls. Using the Yang assay they were unable to confirm the findings of Carter et al. 1 However, they readily admit that in their hands the Yang assay is less precise than the Hybritech assay used by Carter et al. Furthermore, the authors defined elevations of PSA by single point elevations. In the study by Carter et al elevations were defined based upon an average increase over 3 determinations obtained an average of 2 years apart. More recently, Catalona and Snow confirmed the findings of Carter et al using a neural network, which is a mathematical pattern recognition paradigm that "learns" complex interactions among input variables and has the ability to recognize subtle patterns of association in multiple data points. 2 This allowed Catalona and Snow to analyze findings from a longitudinal study of 999 men who on initial screening with digital rectal examination and PSA were found to be free of prostate cancer. In these men followed at 6-month intervals a consistent increase in serum PSA of 0. 72 ng./ml. per year over 3 determinations was the single most predictive parameter to identify prostate cancer. However, Catalona and Snow make the.-point that these increases must be consistent. Patrick C. Walsh, M.D. 1 Carter, H.B., Pearson, J. D., Metter, E. J., Brant, L. J., Chan, D. W., Andres, R., Fozard, J. L. and Walsh, P. C.: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. J.A.M.A., 267: 2215, 1992. 2. Catalona, W. J. and Snow, P. D.: Artificial neural networks for predicting prostate cancer: a pilot study. Presented at annual meeting of the American Association of Genito-Urinary Surgeons, Phoenix, Arizona, April 16-18, 1993.

BENIGN AND MALIGNANT NEOPLASMS OF THE PROSTATE

Relationship Between Changes in Prostate-Specific Antigen. and Prognosis of P:rostate Cancer J. A. CADEDDU, J. D. PEARSON, A. W. PARTIN, J. I. EPSTEIN AND H.B. CARTER, Departments of Urology and Pathology, Johns Hopkins University School of Medicine, James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Longitudinal Studies Branch, Gerontology Research Center, National Institute of Aging, Baltimore, Maryland Urology, 42: 383-389, 1993 Changes in prostate-specific antigen (PSA), used to estimate PSA doubling times, may reflect prostate cancer growth. To determine if PSA doubling time prior to diagnosis predicted outcome in men with prostate cancer, we evaluated 16 men with prostate cancer who had (1) serial PSA determinations (mean 9.9) on frozen sera from twleve to twenty-six years before diagnosis; (2) at least five years of follow-up in those subjects without metastatic disease (range 5.5-12.3 years); and (3) archival material from diagnosis available for pathologic evaluation. PSA doubling time prior to diagnosis was investigated with relation to patient outcome (regardless of treatment) and the known predictors of tumor behavior, Gleason score and nuclear morphometry. In 5 of 16 men who had evidence of metastatic disease at diagnosis, metastasis developed or they died of prostate cancer during follow-up (group 1). Eleven of 16 had no evidence of metastatic disease during follow-up (group 2). Both Gleason score and variance of nuclear roundness (VNR) were significantly greater for group 1 (p <0.05). There was no significant difference between the two groups with respect to PSA doubling time, and the PSA level at diagnosis did not correlate with the development of metastatic disease. One of 5 men with no PSA level greater than 4.0 ng/mL prior to diagnosis died within two years of diagnosis. These data suggest that (1) a normal PSA at diagnosis does not exclude an aggressive cancer, and (2) changes in PSA that occur before the diagnosis of prostate cancer may not always predict outcome. Since PSA level is influenced by tumor grade, an inability to correct PSA for tumor grade could have influenced the results.

Editorial Comment: This is an important report th.at every urologist who uses watchful waiting should understand. A normal PSA does not exclude aggressive cancer and prostate cancer can progress without any significant increase in serum PSA. For example, in this series 1 man with no PSA level greater than 4 ng./ml. prior to diagnosis died within 2 years of diagnosis with no increase in serum PSA! Thus, a low level of PSA with no significant increase does not indicate that the cancer is not growing. Patrick C. Walsh, M.D.

Negative Repeat Trammrethral Resection of Prostate Fails to Identify Patients With Stage Al Prostatic Carcinoma at Lower Risk of Progression: A Long-Term Study A. INGERMAN, G. BRODERICK, R. D. WILLIAMS AND P. R. CARROLL, Departments of Urology, University of California, School of Medicine, San Francisco, California, University of Pennsylvania, Philadelphia, Pennsylvania and University of Iowa, Iowa City, Iowa Urology, 42: 528-532, 1993 Stage Al (low-grade and low-volume) adenocarcinoma is associated with a low likelihood of progression. Repeat transurethral resection has been used to identify patients at increased risk (residual cancer noted) as well as those at low risk of progression (no residual cancer noted). We recently evaluated the ability of this technique to define a low-risk patient population. We reviewed the records of 24 patients who underwent repeat transurethral resection after they were identified as having Stage Al prostatic cancer on initial resection (Gleason score <5, tumor volume comprising <5% of the resection specimen). Despite no evidence of residual carcinoma on repeat resection, 3 patients (13%) progressed at a mean follow-up of seven years (2 locally, 1 locally and distantly). We conclude that repeat resection does not effectively evaluate the risk of progression and that other techniques including transrectal ultrasonography and serial prostate-specific antigen measurements should be similarly evaluated.

Editorial Comment: Men with stage A prostate cancer are being seen less frequently. However, they still present a dilemma. This article suggests that a repeat transureth:ral :resection of the prostate does not provide useful information in predicting the prognosis of men with stage Al (Tla) disease. Patrick C. Walsh, M.D.

Radical Prostatectomy for Pathologic Stage C Prostate Cancer: Influence of Pathologic Variables and Adjuvant Treatment on Disease Outcome

8. CHENG, M. FRYDENBERG, E. J. BERGSTRALH, J. J. LARSON-KELLER AND H. ZINCKE, Department of Urology, Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

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Urology, 42: 283-295, 1993

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A retrospective analysis was performed on 1,035 patients with pathologic Stage C prostate cancer treated with bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. Of these patients, 661 received no immediate adjuvant treatment, 131 adjuvant radiotherapy only, and 103 postoperative adjuvant orchiectomy only. Overall crude survival at five, ten, and fifteen years was 91 percent, 68 percent, and 46 percent, respectively, comparable to the expected survival of 84 percent, 66 percent, and 46 percent, respectively. Cause-specific survival was 96 percent, 81 percent, and 66 percent and overall nonprogression survival was 78 percent, 56 percent, and 48 percent at five, ten, and fifteen years, respectively. Patients with margin-positive and residual disease, high-grade tumors, large tumor bulk, and seminal vesicle involvement were more likely to receive adjuvant treatment. However, both univariately and multivariately, only tumor grade and increasing tumor volume correlated significantly with cause-specific survival and local and systemic progression. Adjuvant treatment significantly decreased local, systemic, and overall progression but did not improve cause-specific or crude survival. Orchiectomy and radiation appeared to demonstrate similar efficacy in controlling local recurrences: five-year local recurrence-free survival in this retrospective analysis was > 95 percent for both treatments compared with 84 percent for those without adjuvant treatment.

Editorial Comment: This important article from the Mayo Clinic demonstrates that early hormonal therapy does not prolong life in men with stage C disease. If it does not work in stage C disease, why should it work in stage Dl disease? Patrick C. Walsh, M.D.

Thromboembolic Complications Following Radical Retropubic Prostatectomy: Influence of External Sequential Pneumatic Compression Devices

L. J. C1SEK AND P. C. WALSH, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland Urology, 42: 406-408, 1993 The influence of external sequential compression devices (SCD) on the development of postoperative thromboembolic events was studied in 1,300 consecutive men undergoing radical retropubic prostatectomy. Of the 784 men whose perioperative management did not involve the SCD, in 9 (1.1%) thromboembolic complications developed: 7 (0.9%) pulmonary emboli (PE), and 2 (0.3%) deep venous thrombosis (DVT). In the 516 patients with SCD prophylaxis there were 12 (2.3%) thromboembolic complications: 9 (1.7%) PE, and 3 (0.6%) DVT. In patients with SCD prophylaxis, the delay from the time of surgery to the onset of thromboembolic symptoms averaged 20 ± 12 days, and all but 1 patient suffered the complication while an outpatient; this was significantly longer than in men without SCD (11 ± 5 days; p <0.05). This delay in thromboembolic events was the only benefit we could demonstrate with SCD. Recognizing that most thromboembolic complications occur after discharge, new strategies for prophylaxis may be needed during this period, and patients should be well informed about the signs and symptoms of PE and DVT to avoid a delay in diagnosis and treatment.

Editorial Comment: This report makes an important point that all urologists should know. Today, most thromboembolic phenomena occur after a patient has been discharged from the hospital. For this reason a patient should be well informed about the signs and symptoms of pulmonary embolism and deep venous thrombosis to avoid a delay in diagnosis and treatment once he is home. All future studies evaluating prophylaxis should focus on the interval after the patient has been discharged from the hospital. Using this criterion we were unable to demonstrate improvement with external sequential pneumatic compression devices. Patrick C. Walsh, M.D.

Transrectal Ultrasound-Guided Percutaneous Radical Cryosurgical Ablation of the Prostate G. M. ONIK, J. K. COHEN, G.D. REYES, B. RUBINSKY, Z. CHANG AND J. BAUST, Departments of Neurosurgery and Urology, Allegheny General Hospital, Pittsburgh, Pennsylvania, Department of Mechanical Engineering, University of California Berkeley, Berkeley, California and Cryomedical Sciences, Inc., Rockville, Maryland Cancer, 72: 1291-1299, 1993 Background. The two major treatments for prostate cancer, radical prostatectomy and radiation therapy, are associated with considerable morbidity and variable results. This article presents the preliminary results using percutaneous radical cryosurgical ablation under ultrasound guidance to treat prostate cancer. Methods. The patient group consisted of all patients with localized prostate cancer who underwent cryosurgery between June 1, 1990 and May 1, 1992. Patients in Group 1 were treated by freezing of the tumor with two cryoprobes placed multiple times. Group 2 patients were treated by freezing of the tumor with five

BENIGN AND MALIGNANT NEOPLASJ:vIS OF THE PROSTATE

simultaneously. Cryoprobes (3 mm in diameter) were placed percutaneously with a transperineal approach. Cryoprobe placement and freezing were monitored using the transrectal ultrasound. Results. Of the 55 patients (68 procedures) undergoing treatment, 23 have 3 months of follow-up with associated biopsy (Group 1, 8 patients; Group 2, 15 patients). In Group 1, three (37.5%) patients had residual disease. In Group 2, one (6.7%) patient had residual disease, whereas 14 (93.3%) patients did not. Combining both groups, 19 (82.6%) patients had no residual disease, whereas 4 (17.4%) patients had positive results on postoperative biopsy. Complications included rectal freezing, urethrorectal fistula, sloughing urethral tissue, impotence, perinea! ecchymosis, penile edema, and ileus. Conclusions. Preliminary results indicate that percutaneous transperineal ultrasound-guided prostate cryosurgery may be an effective treatment for prostate cancer with minimal associated morbidity.

Editorial Comment: This is the first .report in a peer :reviewed medical journal on the results of transrectal ultrasound guided cryosurgical ablation of the prostate for prostate cancer. The authm.-s report on 2 groups of patients. In the first group of 8 patients a system was used with only l probe pe:r instrument and the probe was placed foto the gland multiple times. Because early biopsy and PSA results indicated that total gland destruction was not occurring, the current procedure was undertaken in which multiple cryoprobes are placed simultaneously. Of the 15 patients in group 2 only 1 has a positive biopsy at 3 months; however, 80% have detectable levels of serum PSA. Potency :returned in only 35% of the patients. I have been critical of this approach because I thought that there was too little animal experimentation before clinical application. If I were one of the first 8 patients I would want to know why this lesson was not learned on dogs rather than on me. It is well recognized that prostate cancer is multi.focal and that to cu.re the disease it is necessary to destroy the entire prostate. They have yet to demonstrate that this is possible in experimental animals. This technique is not approved by the Food and Drug Administration for the treatment of prostate cancer and everyone should be aware that it is still under investigation. Patrick C. Walsh, M, D.

Prostate-Specific Antigen: An Important Marker for Prostate Cancer Treated by External Beam Radiation Therapy G. K. ZAGARS AND A. C. VON ESCHENBACH, Departments of Clinical Radiotherapy and Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Cancer, 72: 538-548, 1993 Background. Prostate-specific antigen (PSA) is a valuable serum marker for prostate cancer. However, the prognostic importance of baseline PSA values in relation to other prognostic factors has not been elucidated. The incidence of postradiation rising PSA values has not been documented, and the extent to which PSA influences the assessment of radiation therapy is unclear. This study was designed to address these issues. Methods. Three hundred and fourteen consecutive patients with baseline PSA values who were treated between 1987 and 1991 with external beam radiation alone were reviewed for disease outcome and posttreatment PSA levels. Results. Clinical stages at diagnosis were: Stage A2, 87 (28%); Stage B, 108 (34%); and Stage C, 119 (38%). At a mean follow-up of 21 months, 25 patients had relapsed, 53 had developed rising PSA profiles, and 58 had either relapsed or had rising PSA profiles, and 58 had either relapsed or had rising PSA profiles. The actuarial relapse rate was 20% at 4 years, the incidence of rising PSA profiles was 38% at 4 years, and the incidence of either relapse or rising PSA was 40% at 4 years. In multivariate analysis, baseline PSA value was the single most important factor predicting for local relapse, metastatic relapse, any disease relapse, and posttreatment rising PSA values. Using relapse or rising PSA as endpoints, the following four prognostic groupings based on baseline PSA and M.D. Anderson (MDA) grade were delineated: I, PSA less than or equal to 4 ng/ml, any grade; II, PSA greater than 4 but less than or equal to 10 ng/ml, Grades 1 and 2; III, PSA greater than 4 but less than or equal to 10 ng/ml, Grades 3 and 4 or PSA greater than 10 but less than or equal to 30 ng/ml, Grades 1 and 2; and IV, PSA greater than 10 but less than or equal to 30 ng/ml, Grades 3 and 4 or PSA greater than 30 ng/ml, any grade. The actuarial incidence of relapse or rising PSA in these groups was: I, less than 10% at 3 years; II, 20% at 3 years; III, 55% at 3 years; and IV, 90% at 30 months. When using traditional endpoints of disease outcome, the patients in this series had an outcome equivalent to that in 799 patients treated in our institution in the pre-PSA era; when using rising PSA profiles as endpoints, treatment was significantly less effective. Conclusions. Pretreatment serum PSA level is the single most significant predictor of disease outcome after radiation therapy for local-regional prostate cancer. Moreover, postirradiation PSA values may potentially serve as an early endpoint to evaluate treatment efficacy. Using a rising posttreatment PSA profile as an index of treatment failure reveals that total and permanent eradication of prostate cancer with radiation therapy

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alone is not achieved as often as previously believed and that multimodal treatment approaches to prognostically unfavorable early stage disease need investigation.

Editorial Comment: Multiple institutions are now recognizing that external beam radiotherapy was not as effective as they previously thought. This relates to the selection of candidates and to the failure of radiation therapy to sterilize organ confined cancers. Patrick C. Walsh, M.D.

Patient Compliance in Treatment of Prostate Cancer With Luteinizing Hormone-Releasing Hormone (LHRH) Agonist J. A. SHAHEEN, M. AMIN AND J. I. HARTY, Division of Urology, Department of Surgery, University of Louisville School of Medicine and Veterans Administration Medical Center, Louisville, Kentucky Urology, 42: 533-535, 1993 Luteinizing hormone-releasing hormone (LHRH) agonist therapy is commonly used as a form of hormonal ablative therapy in patients with advanced prostate cancer. It is important to administer LHRH agonist every four weeks. Any delay of more than two weeks is associated with the risk of disease flare. A retrospective review of two groups of patients were compared. Twenty-five patients treated at the Veterans Administration Medical Center, Louisville, Kentucky, showed that 44 percent missed one or more injections and 24 percent had a delay of more than two weeks after the scheduled time for another injection. Twenty-three patients were treated by a private practice group in Louisville, Kentucky. There were no problems with compliance. An office nurse kept a separate register for patients receiving LHRH agonist therapy and their appointments. For LHRH therapy to be effective, we believe that the level of compliance one could expect from an individual should be determined before instituting LHRH agonist therapy. If good compliance is not assured, alternative forms of hormone ablative therapy may be preferable for patients with advanced prostate cancer.

Editorial Comment: Compliance is a major factor to consider when choosing among the various forms of hormonal therapy that are available. Many patients are not anxious to remind themselves to have an expensive, painful monthly shot. Patrick C. Walsh, M.D. Recommended Reading Lepor, H.: Medical therapy for benign prostatic hyperplasia. Urology, 42: 483, 1993. Oesterling, J.E.: Prostate tumor markers. Urol. Clin. N. Amer., vol. 20, No. 4, November 1993.

IMAGING Measurement of Normal Renal Artery Blood Flow: Cine Phase-Contrast MR Imaging vs Clearance of p-Aminohippurate

R. L. WOLF, B. F. KING, V. E. TORRES, D. M. WILSON AND R. L. EHMAN, Departments of Diagnostic Radiology and Nephrology, Mayo Clinic and Foundation, Rochester, Minnesota AJR, 161:995-1002, 1993 OBJECTIVE. The purpose of this study was to compare cine phase-contrast MR imaging with renal clearance of p-aminohippurate for measuring normal renal blood flow. A reliable technique for evaluation of renal hemodynamics would be useful for studying renal vascular diseases and the effects of treatment. Measurements of renal blood flow based on renal clearance of p-aminohippurate are limited in that the kidneys are not studied separately, temporal resolution is poor, and normal renal function is required. SUBJECTS AND METHODS. Bilateral oblique sagittal cine phase-contrast MR images were obtained simultaneously in 10 healthy adult volunteers, with the imaging planes oriented perpendicular to the left and right renal arteries in order to measure through-plane flow. Velocity encoding was 150 cm/sec (seven of 10 volunteers) and 100 cm/sec (eight of 10 volunteers). Axial cine phase-contrast images of the abdominal aorta above and below the origins of the renal arteries were obtained in six volunteers. In these cases, renal blood flow was determined by measuring the difference between suprarenal and infrarenal aortic flow. For all volunteers, renal clearance of p-aminohippurate was determined immediately after MR measurements. RESULTS. Renal blood flow measurements determined by using cine phase-contrast MR imaging were in close agreement with those determined by using clearance of p-aminohippurate. At a velocity encoding of 150 cm/sec, the mean difference was 69 ml/min (95% confidence interval, -31 to 169 ml/min). At a velocity encoding of 100 cm/sec, the mean difference was 39 ml/min (95% confidence interval, -100 to 177 ml/min).