Prostate Cancer Markers and Treatment Ranging From Gene Therapy to Cryosurgery Examined at AUA

American Urological Association Annual Meeting

MEETING REVIEW Prostate Cancer Markers and Treatments Ranging From Gene Therapy to Cryosurgery Examined at AUA Highlights from the American Urological Association 93rd Annual Meeting May 30-June 4, 1998, San Diego, Calif. [Rev Urol 1(2):82-91, 1999] While the media focused on the “little blue pill”—sildenafil citrate (Viagra®)—at the 93rd annual meeting of the American Urological Association (AUA), a great deal of original and exciting work was presented, reflecting advances and improvements of our understanding of the diagnosis, staging, monitoring, and treatment of localized and advanced prostate cancer. Nearly 250 presentations were directly related to either clinical or basic science investigation of prostate cancer. Here are highlights from just a few of these important presentations. Evaluating New and Existing Markers The major focus of presentations on prostate cancer screening and diagnosis was on progress in the search for new markers, evaluation of such existing early-detection modalities as PSA density, age-specific PSA reference ranges, biopsy technique, and the use of neural networks (eg, ProstAsure Index, Horus Global HealthNet, Hilton Head Island, SC) to aid in detection of prostate cancer. Prostate cancer markers. Three markers received particularly high at- Alan W. Partin, MD, PhD, The Johns Hopkins Medical Institutions, Baltimore. 82 REVIEWS IN UROLOGY SPRING 1999 Key words Cancer, prostate • Prostate specific antigen (PSA) • Prostatectomy • Interleukin-2 (IL-2) Main Points √ Of the 3 markers gaining the most attention at the AUA, only percent free-PSA is presently recommended for clinical use in diagnosis and screening. Further investigation regarding HK-2 and cPSA will be required before recommendations regarding actual clinical utility can be made. √ One longitudinal study demonstrated that men with PSA levels <2.0 ng/mL and a normal DRE may not need annual prostate cancer screening, but men with an abnormal DRE and/or PSA values between 2.1 and 4.0 ng/mL require annual prostate cancer screening. √ One group concluded that no imaging modality could detect lymph node metastasis to add staging information when the PSA is <4 ng/mL, but positron emission tomography imaging can detect lymph node metastasis in many men with PSA levels ≥4 ng/mL. √ On the treatment front, several studies investigating phase I and phase II clinical trials of gene therapy for prostate cancer were reported. One study investigated the use of intraprostatic interleukin-2 gene therapy in a phase I clinical trial for locally advanced prostate cancer. √ Short-term data from these studies of antiandrogen and a 5α-reductase inhibitor for the treatment of recurrent prostate cancer demonstrate that this combination is well tolerated and effective in short-term reduction in serum PSA. However, long-term survival or quality-of-life benefits have yet to be demonstrated. tention: percent free-PSA, human glandular kallikrein-2 (HK-2), and complexed PSA (cPSA). Percent free-PSA was initially introduced at the 1997 annual meeting in New Orleans. In the period between the 1997 and 1998 AUA meetings, the Food and Drug Administration had approved a percent free-PSA (Hybritech, San Diego) assay for early detection of prostate cancer. Clinicians, however, need to be savvy about interpreting results of percent free–PSA assays. The published results regarding the actual recommended “cutoff” for use of percent free-PSA vary among the different commercially available assays. Prostate Cancer In general, whichever commercially available assay is used, percent free-PSA has shown clinical utility by increasing the specificity without decreasing the sensitivity for detection of prostate cancer. Studies have documented as much as a 30% increase in specificity (with a concomitant decrease in unnecessary biopsies), while maintaining a 95% sensitivity (or ability to detect cancer) when percent free-PSA is used as an adjunct to the total PSA for men who have total PSA values ranging between 2 and 20 ng/mL, depending upon the assay. Presentations at the AUA meeting continued to fine-focus the clinical utility of this important marker of prostate cancer. Further characterization of the role of prostate volume, appropriate reference ranges for the population, racespecific recommendations, acute and chronic prostatitis, and further characterization of the utility of percent free-PSA for men with “low total PSA” were highlighted at the San Diego meeting. In summary, researchers reported the following findings: 1. Prostate volume provided discriminant ability to detect prostate cancer detection only for men with PSA values below 4 ng/mL.1 2. Percent free-PSA most often diagnosed prostate cancer in men who had undergone a prior prostate evaluation and continued to have either an abnormal digital rectal examination (DRE) or an elevated total PSA. Men found to have a percent freePSA of less than 15% should undergo repeat biopsy, whereas those who have percent free-PSA above 25% could be followed. Little diagnostic information was provided for men with percent free-PSA values between 15% and 25%, and the investigators of this study recommended further evaluation on an individual basis.2 3. One team of investigators demonstrated that percent free-PSA tends to be lower among black men with histologic benign prostatic hyperplasia (BPH) than among white men. This finding suggests that percent free-PSA as a prostate screening tool may be less useful in black men with BPH.3 4. One investigation revealed that acute prostatitis elevates the level of percent free-PSA. Further, the same study also documented that men who have chronic prostatitis had levels of total PSA and percent free-PSA that were similar to the levels in men who had prostate cancer. That finding effectively eliminates the ability of percent free-PSA to distinguish between prostate cancer and chronic prostatitis. 5. Another study demonstrated that investigating the clinical utility of HK-2 for early detection of prostate cancer are important. However, multicenter prospective clinical trials will be required to bring the clinical utility of this prostate cancer marker into sharper focus. The bound or complex fraction of PSA was also introduced as a potential “single test” marker for diagnosis of prostate cancer. Two studies presented results of independent clinical trials evaluating an investigative assay for complexed PSA (cPSA) (Bayer Corporation, West Haven, Conn) and its utility for prostate cancer.7,8 In the first study, a prospective evaluation of 300 randomly chosen archival se- Men who have chronic prostatitis had levels of total PSA and percent free-PSA that were similar to the levels in men who had prostate cancer. combining a total PSA with a cutoff of 3.0 ng/mL plus percent free-PSA with a cutoff of 18% or less could increase the total detection rate of prostate cancer.4 Two presentations focused on preliminary results of the first clinical information regarding the use of HK-2 for detection of prostate cancer.5,6 One of the 2 studies demonstrated added value for early detection of prostate cancer when a ratio between percent free-PSA and total HK-2 was calculated.5 The added value for early detection with this ratio was most apparent among men who had percent free-PSA values between 15% and 25% (which covers 65% of the population, according to results of a recently published prospective trial). This ratio, termed “the good kallikrein divided by the bad kallikrein,” will require furth– er investigation in a multicenter prospective trial to elucidate its clinical utility. The other study characterized the elimination of HK-2 from the bloodstream following radical prostatectomy.6 These initial studies rum samples, representing a standard office-based population of men undergoing sextant biopsy for elevated PSA or abnormal DRE, demonstrated that cPSA had an advantage in detection over total PSA and percent freePSA. Using the cPSA provided a 26.5% specificity and a 95% sensitivity for early detection.7 The second study investigated the same assay in a group of nearly 300 men with similar characteristics; it, too, demonstrated improvement in cancer detection by cPSA when compared with total PSA, and showed that percent free-PSA was more useful than cPSA alone.8 These results dictate the need for further investigation comparing these 2 methods. In summary, of the 3 markers gaining the most attention at the AUA meeting, only the percent free-PSA is recommended for clinical use in diagnosis and screening. Further investigation of HK-2 and cPSA will be required before recommendations can be made regarding actual clinical utility. SPRING 1999 REVIEWS IN UROLOGY 83 ms 4/2/99 riu5851/partin pp7/ 84 Prostate Cancer continued Questioning Age-and RaceSpecific Reference Ranges While previous AUA meetings have highlighted the clinical utility of agespecific and race-specific PSA reference ranges for detection of prostate cancer, at the 1998 meeting only race-specific PSA reference ranges were highlighted. The general consensus of investigators at these presentations is that the differences between both total and percent freePSA among white and black men are poorly understood.3,9 One study demonstrated no racial difference between total PSA in a group of agematched black and white men.9 Another important study demonstrated PSA reference ranges, while intuitively useful, in practice do not provide the optimal means for detecting prostate cancer. Race-specific PSA reference ranges will require further investigation to determine their full clinical potential. Two studies documented that PSA-TZ provided superior detection when compared with other PSA indices; such studies further support the clinical utility of PSA density.12,13 One of the 2 studies used multivariate analysis to document that a combination of TZ-corrected total PSA density plus percent free-PSA significantly enhanced the detection of prostate cancer in a group of more than 900 Longitudinal follow-up of a cohort of more than 8000 men taking part in Prostate Cancer Awareness Week demonstrated that men with PSA levels less than 2.0 ng/mL and a normal DRE may not need annual prostate cancer screening. that the total PSA cutpoint for indicating and recommending a prostate biopsy for black men should not be higher than that for white men.10 Three studies further questioned the clinical utility of age-specific PSA reference ranges. One study demonstrated that older men are more likely to have extensive disease when compared with younger men with similar PSA levels.11 Thus, the concept for higher PSA thresholds for older men could compromise the cure of disease further, bringing into question the use of age-specific PSA reference ranges. Another study demonstrated that age-specific PSA reference ranges provided the worst sensitivity and specificity for detection of prostate cancer when compared with a PSA reference of 4.0 ng/mL, the ProstAsure Index, volume-reference PSA values, percent free-PSA, and PSA corrected for transition-zone volume (PSA-TZ).12 In summary, overwhelming evidence now suggests that age-specific 84 REVIEWS IN UROLOGY SPRING 1999 men taking part in an early-detection program.13 The other study demonstrated that TZ-corrected total PSA density was the most accurate determinant of the presence of prostate cancer when compared with age-specific PSA reference ranges, the ProstAsure Index, total PSA, volumereference PSA, and percent free-PSA alone. These exciting studies, while limited in widespread clinical utility by the need for accurate determination of TZ prostate volume, provide useful information and further clarify the clinical utility of PSA density.12 Screening Intervals and Strategies Studies investigating the appropriate screening intervals and the appropriate end points for PSA screening provided new and clinically useful information. One study documented the results of a longitudinal follow-up of a cohort of more than 8000 men taking part in Prostate Cancer Awareness Week. This study demonstrated that men with PSA levels less than 2.0 ng/mL and a normal DRE may not need annual prostate cancer screening.14 The investigators also recommend that men who have had an abnormal DRE with a history of negative biopsy and/or PSA values between 2.1 and 4.0 ng/mL require annual prostate cancer screening. Another study likewise investigated longitudinal data. Reviewing data from the Baltimore Longitudinal Study of Aging, the research team concluded that if PSA testing were eliminated in men aged 65 years and older who have low PSA values, few cancer cases would be missed and the number of PSA tests and unnecessary prostate biopsies could be greatly reduced.15 These studies, while requiring validation by other investigators, provide some of the most exciting and clinically useful information regarding early detection of prostate cancer. Further investigation will be required to identify definitive recommendations regarding screening intervals and appropriate indications for use of early-detection techniques. Using neural networks in screening. Neural networks are rapidly demonstrating clinical utility in genitourinary oncology. The first neural network (ProstAsure Index) demonstrating clinical utility in prostate cancer was further evaluated by 2 studies at the AUA meeting.16,17 One study compared percent free-PSA and the ProstAsure Index for detection of prostate cancer in men with PSA levels between 2.5 and 4.0 ng/mL. This study suggested that the ProstAsure Index may be superior to percent free-PSA in men whose PSA is <4.0 but >2.5 ng/mL.17 Another study from the same research team further documented, in an independent group of more than 450 men, the clinical utility of the ProstAsure Index.16 Researchers concluded that the ProstAsure Index was Prostate Cancer superior to the free over total PSA ratio in distinguishing prostate cancer both from BPH and from normal prostate at PSA below 4 ng/mL. In summary, neural networks are rapidly weaving their way into clinical practice for genitourinary oncology. It is becoming evident that this complex statistical technique can provide clinically useful information for both diagnosis and staging of patients with prostate cancer. We, as urologists, must learn to better understand these techniques as they become an important part of our decision-making process in urologic oncology. ent modalities work. Longer followup for surgical, external-beam radiation, and interstitial radiation series were presented. In addition, modifications of molecular techniques for “gene therapy” for prostate cancer were introduced in phase I and phase II trials. Several studies were also presented regarding variations in the delivery method and timing of androgen-deprivation therapy for advanced disease. An exciting recent study suggests that a cavernousal nerve stimulator can be used to identify and guide the surgical planes along the lateral aspect of the prostate during a nerve- AUA meeting demonstrate actuarial biochemical disease-free rates and cancer-specific survival rates similar to those published by Patrick Walsh, MD, from Johns Hopkins Hospital. Radiation therapy. Several papers regarding appropriate outcome measures (eg, PSA nadir) following external-beam radiation therapy also were presented. One study was an assessment of a group of more than 450 men who had prostate cancer who had been treated with external-beam monotherapy since 1970.25 They reported that a PSA nadir of <0.5 ng/mL 5 years following therapy documented a low risk of subsequent Prostate Biopsy Techniques Another exciting area for early detection of prostate cancer involves techniques and methods for prostate biopsy. Computer analysis and prospective trials are further refining biopsy of the prostate to increase and optimize our detection rates for prostate cancer. One study presented an elegant computer-simulation analysis of various methods of prostate biopsy of 180 digitally reconstructed radical-prostatectomy specimens.18 This analysis recommended an 11-core scheme that provided the highest sensitivity for detection of prostate cancer. Another study utilized a 3-dimensional probability map to increase the accuracy rate of sextant biopsies.19 A third study stressed the need for additional lateral biopsies of the prostate to increase the sensitivity for detection.20 And, finally, 1 team introduced the use of ultrasonic spectrum analysis to improve transrectal ultrasound (TRUS)-guided biopsy techniques.21 Advances in Treatment No new techniques were introduced at the AUA convention for treating either clinically localized or advanced prostate cancer. Several presentations, however, increased the current understanding of why and how pres- An exciting recent study suggests that a cavernousal nerve stimulator can be used to identify and guide the surgical planes along the lateral aspect of the prostate during a nerve-sparing radical prostatectomy. sparing radical prostatectomy.22 The results of long-term randomization of this technique await publication. One study examined cancer-control rates following anatomic radical retropubic prostatectomy (RRP) with long-term follow-up.23 This study represents a single surgeon’s experience of an anatomic RRP in more than 1700 men. With a median follow-up of 42 months, the 7-year actuarial biochemical recurrence-free survival rate was 81% for pathologic stage or case pT1-2, 60% for pT3ab, and 26% for pT3c. Biochemical recurrence-free actuarial survival of 7 years for lymph node-positive patients was 21%. Overall, cancer-specific survival was 96%. Another team reported on cancer control and survival rates for the 10year follow-up of 1368 men treated with RRP.24 Overall, cancer-specific survival at 10 years for this group was 98% and biochemical diseasefree survival was 71%. Both of these large surgical series presented at the failure. However, a PSA nadir between 0.5 and 1.0 ng/mL at 5 years demonstrated a higher risk of recurrence. Neoadjuvant androgen-deprivation therapy may affect these outcomes. Another group also documented the importance of the PSA nadir postexternal-beam radiation therapy as a predictor of failure following subsequent therapy.26 This study demonstrated a beneficial effect of “early” x-ray therapy for adverse pathology, as compared with “PSA-triggered” external-beam radiation therapy. Adjuvant hormone therapy. A compelling study by Bolla and associates27 further documented the efficacy of adjuvant hormonal therapy initiated at the onset of external-beam radiation therapy. The investigators focused on a group of 415 men treated between 1987 and 1995 who were randomized to receive, for a period of 3 years, external-beam radiation therapy alone or combined with androgen-deprivation therapy. At 5 SPRING 1999 REVIEWS IN UROLOGY 85 Prostate Cancer continued PET and RT-PCR in Staging Several papers reported on studies investigating the clinical utility of positron emission tomography (PET) and monoclonal antibody scanning (ProstaScint, Cytogen, Trenton, NJ) for staging prostate cancer. One group introduced PET scanning as a noninvasive method for staging prostate cancer and demonstrated its ability to increase the accuracy for detection of lymphatic spread.47 Another group evaluated men with low PSA levels and concluded that no imaging modality could detect lymph node metastasis to add staging information when the PSA is <4 ng/mL.48 For patients with PSA levels ≥4 ng/mL, however, imaging with PET detected metastases in a high percentage of patients. Monoclonal antibody scanning, used in combination with multivariate staging algorithms, proved better than methods not using imaging techniques in predicting lymph node involvement in high-risk prostate cancer patients.49 As was done in early-detection algorithms, the techniques for staging prostate cancer have been adapted for analysis by neural network technology. Three abstracts demonstrated the use of neural networks to improve staging of prostate cancer.50-52 In addition, percent free-PSA has also been suggested in preliminary studies to be useful for staging of disease in men with clinically localized prostate cancer.53 These early staging modalities (PET, neural networks, and percent freePSA) will require large, multicenter, prospective trials to further delineate the clinical potential for prostate cancer. Using RT-PCR as a cancer staging tool. Recent work evaluating reverse transcriptase polymerase chain reaction (RTPCR) as a staging tool for prostate cancer was presented at the AUA. One study prospectively enrolled 100 men into a trial to evaluate the clinical utility of RT-PCR for preopera- years, local control was increased from 77% to 97%. Disease-free survival increased from 36% to 74% in those treated with combined therapy, and there was a significant increase in 5-year overall survival (from 62% to 79%; P<0.001) in favor of the combined modality. Two studies documented complication rates and need for adjuvant therapy following interstitial brachytherapy for prostate cancer. The first looked at a group of 2124 men in the Medicare population who underwent prostate brachytherapy in 1991.28 Overall, 8.3% underwent a surgical procedure for bladder-outlet obstruction during the follow-up period. Only 7 men (0.3%) required a colostomy for complications related to the tive and postoperative staging of prostate cancer.54 These investigators reported that RT-PCR for PSA demonstrated excellent molecular sensitivity for detecting PSA-producing cells; however, its clinical sensitivity and the prediction of extracapsular penetration and postoperative recurrence were limited. Another study used RT-PCR for both PSA and prostate-specific membrane antigen (PSMA) to determine surgical margin status following radical retropubic prostatectomy.55 Molecular assessment of the prostatic fossa following radical prostatectomy may provide evidence to help in the prediction of extracapsular spread, which cannot be identified by conventional pathology. One group evaluated RT-PCR for both PSA and PSMA and documented improved sensitivity of PSMA compared with PSA for detection of tumor spread for men with clinically localized prostate cancer.56 Another group examined whether the combination of a RTPCR assay for PSA plus serum PSA values would enhance the clinical ability to predict pathologic stage for a group of 300 men undergoing radical prostatectomy for clinically localized prostate cancer.57 This group demonstrated a sensitivity for RT-PCR alone for detecting extracapsular disease of 60%. They also found that factoring in the preoperative serum PSA level allowed for enhanced prognostic capabilities. Several groups evaluated the utility of using RT-PCR from bone marrow aspirates for staging of prostate cancer.58-60 One group suggested that PSA-producing cells, presumably of prostate origin, are frequently found in the bone marrow of patients prior to radical prostatectomy.59 To date, the follow-up on these patients has not demonstrated a correlation with biochemical tumor recurrence. brachytherapy, and just 0.2% needed an artificial urinary sphincter placed following therapy. While not addressing efficacy of therapy, this study documents a low complication rate for this mode of therapy. In the second study, Scherr and associates29 looked at complication rates in more than 690 men treated between 1990 and 1997 with brachytherapy for localized prostate cancer. At a mean follow-up of 45 months, only 3% of the men required surgical intervention for morbidity. Irritative symptoms occurred in 13%, and 90% of the patients who were sexually potent prior to therapy remained potent in their posttreatment evaluation. Just 10% of the men experienced erectile dysfunction following im- plantation. Radiation proctitis occurred in 2% of the patients, rectal ulceration was noted in 1 man, and tenesmus was experienced by 15% of those treated. Thus, brachytherapy again has proven a safe and well-tolerated procedure for treatment of localized prostate cancer. Investigation into the appropriate nadir PSA value following brachytherapy was presented, as well. One study suggested a PSA nadir goal for radiotherapy (external beam or brachytherapy) of ≤0.2 ng/mL.30 These investigators suggest that, with few exceptions, only men who achieve and maintain PSA nadirs <0.5 ng/mL will actually be cured of prostate cancer by irradiation. The same group presented actuarial 5continued on page 89 86 REVIEWS IN UROLOGY SPRING 1999 Prostate Cancer continued from page 86 and 10-year disease-free survival rates of 79% and 67%, respectively, for men receiving either a combination of external-beam radiation therapy and interstitial seed placement, compared with those receiving external-beam radiation alone.31 Another group demonstrated 5-year actuarial biochemical disease-free survival rates of 80% with a PSA nadir of <1 ng/mL and 71.2% with a PSA nadir of <0.5 ng/mL.32 Treating advanced prostate cancer. Therapies for advanced prostate cancer—including androgen-suppression or -deprivation therapy, cryosurgery, and salvage therapy following definitive surgery or radiation therapy— were likewise presented at last year’s meeting. The age-old question of early hormonal therapy as opposed to initiation of androgen deprivation at the time of symptoms was again addressed at the AUA meeting. Several investigators reported on such long-term side effects of androgen-deprivation therapy as osteoporosis.33-36 In particular, researchers documented a measurable and significant decrease in bone density for men treated with androgen-deprivation therapy for prostate cancer. Final recommendations regarding how to avoid this complication are pending. One interesting study documented the use of medroxyprogesterone acetate (Depo-Provera®) to treat hot flushes associated with androgendeprivation therapy for advanced prostate cancer.37 Techniques for long-term dosing of leutinizing hormone-releasing hormone (LHRH) analogues were also successfully tested and presented. These delivery systems will allow a continuous administration of LHRH agonists38 or an LHRH analogue39 for treatment of advanced prostate cancer. Other investigators are also evaluating the combined use of an antiandrogen and a 5α-reductase inhibitor for the treatment of recurrent prostate cancer following therapy.40 Short-term data from these studies demonstrate that this combination is well tolerated and effective in shortterm reduction in serum PSA. However, long-term survival or quality-oflife benefits have yet to be demonstrated. Intermittent administration of androgen-suppression therapy continues to be a major area of focus. Bruchovsky and colleagues41 reported on phase II studies of intermittent androgen-deprivation therapy for men with rising PSAs, which suggests inadequate response to radiation therapy. The researchers demonstrated that more than 90% of the men who had a PSA below 4 ng/mL after 36 weeks of deprivation were able to interrupt their androgen-suppression radiation gene-therapy trial for advanced prostate cancer demonstrated that introduction of the BRCA1 retrovirus in a phase I clinical trial of 21 men by direct injection into the prostate appears to be safe.43 Phase II studies are pending regarding the efficacy of this treatment. Cryosurgery. The 5-year biochemical and biopsy-confirmed outcomes following cryosurgery as primary treatment for localized prostate cancer were presented at the AUA, as well. In one study, 729 patients underwent cryosurgical ablation of the prostate as primary treatment for adenocarcinoma of the prostate.44 Patients underwent serial PSA and prostate biopsies at 3, 24, and 60 months. At 60 months, the negative Investigators suggest that, with few exceptions, only men who achieve and maintain PSA nadirs less than 0.5 ng/mL will actually be cured of prostate cancer by irradiation. therapy for approximately 9 months before PSA began to rise.41 The goal behind intermittent androgen-deprivation therapy is to provide improved quality of life. It remains to be elucidated what the long-term effects this modification of androgen-deprivation therapy may have on survival. Gene therapy. Several studies investigating phase I and phase II clinical trials of gene therapy for prostate cancer were presented at the annual AUA meeting. One study investigated the use of intraprostatic interleukin-2 (IL-2) gene therapy in a phase I clinical trial for locally advanced prostate cancer.42 These investigators demonstrated the feasibility and safety of this technique. Transient decreases in serum PSA were noted in several of the participants in this phase I study. Further trials, however, are needed to determine long-term efficacy with respect to cancer control. Another phase I biopsy rate was 72%. Only 43% and 60% of the patients maintained PSA levels of <0.4 and 1.0 ng/mL, respectively. Complications such as incontinence and sloughing of tissue ranged between 1% and 6%. The results of these early studies clearly demonstrate that cryosurgery as a primary therapy should only be reserved for patients with unfavorable presentations. Using PSA recurrence as an end point, cryosurgery did not demonstrate comparable disease-free rates with other surgery or external-beam radiation. Salvage Radiotherapy One group investigated salvage radiotherapy for men with pT3N0M0 prostate cancer. The long-term data from this study demonstrated no improvement in either biochemical, local, or distant recurrence rates when salvage radiotherapy was administered for unfavorable pathologic findings.45 SPRING 1999 REVIEWS IN UROLOGY 89 Prostate Cancer continued In summary, early results of brachytherapy are now demonstrating similar biochemical recurrence rates when compared with surgical and external-beam radiation therapy reported series. Questions remain unanswered as to whether these early brachytherapy results will continue to be comparable when stage-matched comparisons are performed. The optimal PSA nadir for both brachytherapy and external-beam radiation therapy trials should be 0.2 to 0.5 ng/mL. A combination of adjuvant andro- cancer at the AUA meeting exemplify this dynamic new research. Summary The 93rd American Urological Association annual meeting in San Diego has provided many novel studies advancing the understanding of the diagnosis, staging, treatment, and basic science issues regarding prostate cancer. As urologists, we presently find ourselves in the middle of a very important era regarding all aspects of the diagnosis and treatment of pros- A combination of adjuvant androgen-deprivation therapy and external-beam radiation therapy has now demonstrated a survival advantage over external-beam radiation therapy alone for clinically localized prostate cancer. 8. 9. 10. 11. 12. 13. gen-deprivation therapy and external-beam radiation therapy has now demonstrated a survival advantage over external-beam radiation therapy alone for clinically localized prostate cancer. Finally, long-term results from large radical prostatectomy series continue to demonstrate the clinical applicability for treating localized prostate cancer. Basic Science of Prostate Cancer At least 50 prostate cancer basic science abstracts were chosen for poster presentation at the AUA annual meeting.46 The 6 major categories for basic science abstracts at the AUA fell under the following headings: (1) studies investigating cell growth and death kinetics (apoptosis), (2) gene therapy basic science investigations, (3) investigation of novel prostatecancer genes, (4) inhibitors and inducers of prostate cancer, (5) genetic studies, and (6) evaluation of new and existing tumor markers. New and exciting work with both the investigation of the etiology and pathophysiology of prostate cancer are ongoing. The abstracts presented with the basic science poster session for prostate 90 REVIEWS IN UROLOGY SPRING 1999 tate cancer. I hope this review will help foster ideas for further research toward the ultimate goal of developing a cure for prostate cancer. References 1. VanCangh PJ, De Nayer PP, Lorge F, et al: Influence of prostate volume on the discriminating power of free over total prostate specific antigen ratio (F/T PSA). AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S178, 1998. Abstract 684. 2. Beduschi MC, Beduschi R, Vashi A, et al: Percent free-PSA distribution in male populations with normal and abnormal prostate evaluations: Determination of reference ranges. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S234, 1998. Abstract 892. 3. Kilambi NK, Fowler JE, Sanders J, et al: Percent free-PSA in black and white men with histologic BPH and histologic prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S234, 1998. Abstract 893. 4. Tornblom M, Norming U, Becker C, et al: The diagnostic value of percent free-PSA in men with low total PSA and the variation with prostate volume and age in a randomized population. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S235, 1998. Abstract 897. 5. Partin A, Catalona W, Brawer M, et al: Human glandular kallikrein (hK2) correlates with detection and pathologic features of prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S71, 1998. Abstract 269. 6. Lilja H, Huland E, Haese A, et al: Elimination of complexed and non-complexed prostate-specific antigen forms (PSA) and human glandular kallikrein 2 (HK2) following radical prostatectomy (RP). AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S72, 1998. Abstract 270. 7. Meyer GE, Brawer MK, Letran JL, et al: Alpha-1 antichymotrypsin complexed PSA in men undergoing prostate biopsy offers significant 14. 15. 16. 17. 18. 19. 20. 21. 22. advantage for the detection of carcinoma over total PSA and free-to-total PSA. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S72, 1998. Abstract 273. Bruzek DJ, Cox JL, Partin AW, et al: Is complexed PSA alone clinically useful? AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S234, 1998. Abstract 895. Sartor O, Eastham JA, Venable DD, et al: Racial variation in PSA in a well-defined cohort of men without known prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S234, 1998. Abstract 894. Powell IJ, Banerjee M, Novallo M, et al: Should the age specific PSA cut-point for prostate biopsy be higher among African American vs. American Caucasian men above age 50 years. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S74, 1998. Abstract 280. Carter HB, Epstein JI, Walsh PC, et al: Age, PSA and the chance of curable prostate cancer among men with non-palpable disease. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S74, 1998. Abstract 279. Kamoi K, Troncoso P, Ramirez EI, et al: Comparison of prostate specific antigen (PSA) density of the transition zone with percent free PSA and other PSA indexes in the detection of prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S235, 1998. Abstract 899. Djavan B, Marberger M, Zlotta A, et al: PSA, f/tPSA, PSAD, PSA-TZ and PSA-velocity for prostate cancer prediction: A multivariate analysis. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S235, 1998. Abstract 898. Leewansangtong S, Crawford ED, Gordon SG, et al: Longitudinal follow-up from Prostate Cancer Awareness Week (PCAW): Screening intervals. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S177, 1998. Abstract 680. Pearson JD, Landis P, Fozard JL, et al: When is PSA testing no longer necessary? AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S178, 1998. Abstract 681. Stamey TA, Barnhill SD, Zhang Z, et al: A neural network (ProstAsure) with sensitivity and specificity of 75% in detecting prostate cancer in men with a PSA < 4.0ng/mL. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S72, 1998. Abstract 271. Zhang Z, Stamey TA, Oesterling JE, et al: A comparison of percent free-PSA and ProstAsure index in separating prostate cancer from BPH and normal in men with a PSA level between 2.5-4.0ng/mL. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S109, 1998. Abstract 418. Chen MF, Troncoso P, Johnson D, et al: Comparison of prostate schemes by computer simulation. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S179, 1998. Abstract 685. Kaplan CR, Lynch JH, Zeng J, et al: Comparison of sextant to 5 region biopsy technique using a three dimensional computer simulation of actual prostate specimens. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S179, 1998. Abstract 687. Chang JJ, Shinohara K, Hovey RM, et al: Prospective evaluation of lateral biopsies of the prostate for cancer detection. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S179, 1998. Abstract 688. Feleppa EJ, Tsai H, Porter C, et al: Ultrasonic spectrum analysis for improved TRUS-guided biopsies. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S179, 1998. Abstract 686. Klotz L, Jewett M, Goldenberg L, et al: Randomized evaluation of intraoperative cavernosal nerve stimulation with penile tumescence mon- Prostate Cancer 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. itoring during nerve sparing radical prostatectomy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S223, 1998. Abstract 864. Catalona WJ, Smith DS: Cancer control after anatomical radical retropubic prostatectomy: An update. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S253, 1998. Abstract 970. Abbas F, Kattan MW, Wheeler TM, et al: Survival and cancer control for patients with cT1-T2 prostate cancer with intent to treat by radical prostatectomy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S252, 1998. Abstract 964. Davis JW, Kolm P, Wright GL, et al: The durable effect of external beam radiation therapy for prostate cancer. Can it be identified? AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S64, 1998. Abstract 240. Newhall PM, Iselin CE, Aslan P, et al: Prognostic factors of PSA failure after radiation therapy following radical prostatectomy for prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S179, 1998. Abstract 688. Bolla M, Gonzalez D, Kurth KH, et al: Adjuvant hormonal therapy with goserilin improves survival in patients with locally advanced prostate cancer treated with radiotherapy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S131, 1998. Abstract 496. Benoit RM, Cohen JK, Miller RJ, et al: Complications and adjuvant therapy after prostate brachytherapy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S63, 1998. Abstract 235. Scherr D, Bosworth J, Potters L, et al: Complications of brachytherapy in 692 men treated for localized prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S65, 1998. Abstract 243. Critz FA, Levinson K, Williams WH, et al: The PSA nadir goal for radiotherapy of prostate cancer is ≤0.2ng/mL. AUA 93rd Annual Meeting, San Diego, Calif. J Urology 159(55):S218, 1998. Abstract 844. Levinson AK, Critz FA, Williams WH, et al: Prostate cancer treated by simultaneous radiotherapy: I-125 prostate implant followed by external-beam radiation. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S63, 1998. Abstract 236. Radge H, Blasko J, Grimm P, et al: 5 year observed biochemical disease-free survival in T1/T2 prostate cancer patients treated with brachytherapy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S63, 1998. Abstract 237. Levis L, Krongrad A, Soloway MS, et al: Bone loss after androgen deprivation for prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. Abstract 489. J Urol 159(55):S130, 1998. Cheon J, Sung B-M, Kim J-J, et al: Osteoporosis in patients receiving total androgen blockade therapy for prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S336, 1998. Abstract 1291. Suzuki Y, Oishi Y, Yamazaki H, et al: Cross-sectional measurement of bone density in patients with prostatic carcinoma receiving LHRH-analogue with and without estrogen. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S337, 1998. Abstract 1297. Bernhard PH, Niewoehner C: Effects of early hormonal therapy on bone in asymptomatic men with prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S338, 1998. Abstract 1298. Ellsworth JB, O’Reilly KJ, Thrasher JB: DepoProvera therapy for hot flushes associated with 38. 39. 40. 41. 42 43. 44. 45. 46. 47. 48. 49. 50. 51. hormonal treatment of advanced carcinoma of the prostate. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S132, 1998. Abstract 498. Jungwirth A, Gomahr A, Joos H, et al: Potent LHRH-agonist for testosterone deprivation (new mode of application). AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S131, 1998. Abstract 494. Fowler JE, Gottesman JE, Bardot SF, et al: A phase III dose ranging study of Duros (leuprolide) implantable therapeutic system in patients with advanced prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S335, 1998. Abstract 1289. Harding P, Moul JW, McLeod D: Combination flutamide and finasteride in PSA-only recurrence after prior local prostate cancer therapy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S130, 1998. Abstract 491. Bruchovsky N, Kotz LH, Crook JM, et al: A phase II study of intermittent androgen suppression (IAS) in men with a rising serum PSA after radiation for localized prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S335, 1998. Abstract 1287. Naitoh J, Tso CL, Kaboo R, et al: Intraprostatic interleukin-2 (IL-2) gene therapy: Preliminary results of a phase I clinical trial for the treatment of locally advanced prostate cancer (CaP). AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S254, 1998. Abstract 973. Steiner MS, Lerner J, Greenberger M, et al: Clinical phase I gene therapy trial using BRCA1 retrovirus is safe. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S130, 1998. Abstract 491. Cohen JK, Miller R, Benoit R, et al: Five year outcomes of PSA and biopsy following cryosurgery as primary treatment for localized prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S252, 1998. Abstract 967. Hudson ML, Akduman B: Radiotherapy following radical prostatectomy for pT3N0M0 prostate cancer: Long term results. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S335, 1998. Abstract 1288. J Urol 159(55): S1-S13, 1998. Abstracts 1-50. Carlin BI, Resnick MI, Faulhaber PF, et al: Alteration in PET scanning technique increases accuracy in detecting the lymphatic spread of prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S289, 1998. Abstract 1113. Seltzer M, Naitoh, Cangiano T, et al: Comparison of computed tomography (CT), positron emission tomography (PET), and monoclonal antibody scan (MAB) for evaluation of lymph node (LN) metastases in patients with PSA relapse after treatment for localized prostate cancer (CAP). AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S288, 1998. Abstract 1109. Polascik TJ, Gurganus RT, Partin AW, et al: Comparison of staging algorithms and a monoclonal antibody scan (ProstaScint) to predict lymph node involvement in high-risk prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S289, 1998. Abstract 1112. Partin AW, Zhang Z, Zhang H, et al: The development of a neural network-based staging index for predicting organ-confined disease in men with newly diagnosed prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S294, 1998. Abstract 1133. Tewari A, Calvanese C, Carlson G, et al: An artificial intelligence based genetic adaptive neural network model to predict pathological stage of prostate cancer in patients undergoing radical prostatectomy. AUA 93rd Annual Meeting, San 52. 53. 54. 55. 56. 57. 58. 59. 60. Diego, Calif. J Urol 159(55):S294, 1998. Abstract 1135. Snow PB, Levine RF, Ziada AM, et al: Impact of different variables on outcome of treatments for clinically confined prostate cancer: Prediction of response and pathological stage of the disease using a neural network. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S295, 1998. Abstract 1136. Subong E, Pannek J, Chan DW, et al: The use of percent-free prostate-specific antigen for staging of men with clinically localized prostate cancer. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S294, 1998. Abstract 1132. Hedican SP, Nelson JB, Marshke P, et al: Evaluation of preoperative prostate cancer staging and postoperative detection of recurrence utilizing the reverse transcriptase polymerase chain reaction (RT-PCR). AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S289, 1998. Abstract 1115. Theodorescu D, Frierson HF, Mills SE, et al: Molecular determination of surgical margins following radical prostatectomy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S290, 1998. Abstract 1117. Grasso YZ, Gupta MK, Levin HS, et al: Combined nested RT-PCR assay for prostate specific antigen (PSA) and prostate specific membrane antigen (PSM) in prostate cancer patients: Correlation with pathological stage. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S291, 1998. Abstract 1120. Nejat RJ, Katz AE, Benson MC, et al: Enhanced RT-PCR for PSA combined with serum PSA predicts pathologic stage and outcome in 300 radical prostatectomy patients. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S291, 1998. Abstract 1121. Gao C-L, Dean R, Pinto A, et al: Detection of PSA-expressing prostatic cells in bone marrow of radical prostatectomy patients by sensitive reverse transcriptase-polymerase chain reaction (RT-PCR). AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S290, 1998. Abstract 1118. Ellis WJ, Corey E, Melchior SW, et al: PSA RTPCR in bone marrow aspirates following radical prostatectomy. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S290, 1998. Abstract 1119. Grasso YZ, Gupta MK, Levin HS, et al: Combined nested RT-PCR assay for prostate specific antigen (PSA) and prostate specific membrane antigen (PSM) in prostate cancer patients: Correlation with pathological stage. AUA 93rd Annual Meeting, San Diego, Calif. J Urol 159(55):S291, 1998. Abstract 1120. COMING IN THE BEST OF THE 1999 AUA ANNUAL MEETING SPRING 1999 REVIEWS IN UROLOGY 91