Comparison of percent free prostate specific
antigen and prostate specific antigen density as
methods to enhance prostate specific antigen
specificity in early prostate cancer detection in
men with normal rectal examination and
prostate specific antigen between 4.1 and
Morote J, Raventos CX, Lorente JA, LopezPacios MA, Encabo G, deTorres I, Andreu J Journal of Urology, 1997, Vol 158, Iss2, pp 502-504
Univ Autonoma Barcelona, Vall Dhebron Hosp,
Dept Urol, E-08193 Barcelona, SPAIN
Purpose: We analyzed the behavior of prostate specific antigen (PSA) density and percent free PSA to enhance the specificity of PSA in the early diagnosis of prostate cancer in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. Materials and Methods: PSA serum level, PSA density and percent free PSA were analyzed in 74 men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. All men underwent systematic prostate biopsy, and the diagnosis was benign prostate hyperplasia in 52 and prostate cancer in 22. Furthermore, we determined the decrease in unnecessary biopsies and the cancer detection rate using 0.10 versus 0.15 as cut points for PSA density, and 20 versus 25 as cut points for percent free PSA. Results: In patients with benign prostatic hyperplasia and prostate cancer, respectively, the median PSA level was 6.7 and 7.0 ng./ml. (p > 0.05), median prostate volume was 50 and 37 cc (p < 0.04), median PSA density was 0.14 and 0.19 (p < 0.007) and median percent free PSA was 18.9 and 10.1 (p < 0.005). Using PSA density cut points of 0.15 and 0.10, the decrease in negative biopsies was 53.8 and 36.5% with a sensitivity of 86.4 and 90.9%, respectively. However, using percent free PSA cut points of 20 and 25, the decrease in negative biopsies was 36.5 and 26.9% with a sensitivity of 77.3 and 95.5%, respectively. Conclusions: Although both methods could minimize unnecessary biopsies in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml., the percent free PSA was more cost-effective since transrectal ultrasound was not required. In this small series of symptomatic patients a percent free PSA cut point of 25 could detect at least 95% of prostate cancers and decrease 26.9% of negative biopsies.
Prevalence and predictors of a positive
repeat transrectal ultrasound guided needle
biopsy of the prostate
NE Fleshner, M O'Sullivan, WR Fair Journal of Urology, 1997,
Vol 158, Iss 2, pp 505-508
Fleshner NE, Mem Sloan Kettering Canc Ctr,
Urol Serv, New York,NY 10021 USA
Purpose: We determined the prevalence of and risk factors for carcinoma in patients with 1 previously negative prostate biopsy. Materials and Methods: Transrectal ultrasound guided prostate needle biopsies were repeated in 130 men. Risk factors analyzed included age, pathological result of initial biopsy, inter-biopsy interval, prostate specific antigen (PSA), PSA density, PSA velocity, digital rectal examination, abnormal transrectal ultrasound and family history of prostate cancer. Results: A total of 39 patients (30%) had positive biopsies for cancer. Univariate analysis revealed that PSA more than 20 ng./ml. And abnormal transrectal ultrasound were more frequent in men with positive second biopsies. Using multivariate logistic regression analysis only PSA more than 20 ng./ml. Was a significant risk factor (adjusted odds ratio 4.48, 95% confidence interval 1.02 to 20.1). We determined the incidence of carcinoma in patients who represent the lowest risk group as defined by PSA less than 10 ng./ml., PSA density less than 0.15 mg./ml./cm.(3), PSA velocity less than 0.75, ng./ml. Per year, no prostatic intraepithelial neoplasia plus negative transrectal ultrasound, digital rectal examination and family history. Of 21 patients who fit this cohort 5 (23.8%) had carcinoma on repeat biopsy. Conclusions: A significant false-negative rate for initial transrectal ultrasound guided prostate biopsies exists. Baseline risk in lowest risk patients is sufficiently high such that one cannot define a subset of patients for whom repeat biopsy is unnecessary. We recommend repeat biopsy in all patients who meet the criteria for a transrectal ultrasound guided biopsy and in whom the initial biopsy is negative.
Accelerated tumor proliferation rates in
locally recurrent prostate cancer after
JA Connolly, JC Presti, ML Cher, K Chew, K Shinohara, PR Carroll
Journal of Urology, 1997, Vol 158, Iss 2, pp 515-518
Carroll PR, Univ Calif San Francisco, Dept Urol, Sch Med, Program Urol Oncol, Mt Zion Canc Ctr, U-575, San Francisco,CA 94143 USA
Purpose: We compared the growth rates of primary cancer and prostatic fossa recurrence after radical prostatectomy. Materials and Methods: Tumor proliferative rates were studied in 26 patients with biopsy proved prostatic fossa recurrences after radical prostatectomy. Proliferation was calculated in the prostatectomy specimens and in recurrent cancer using Ki-67 antibody to detect dividing cells. Results: Mean and median labeling indexes for radical prostatectomy specimens were 2.96 and 2.51, respectively. Labeling indexes in locally recurrent tumors were significantly higher (mean 6.47, median 5.59, p < 0.001). The increase in labeling index between parent and recurrent tumors was unrelated to pathological staging at prostatectomy or interval from radical prostatectomy. Conclusions: Tumors that recur locally after radical prostatectomy appear to have a higher proliferative rate compared to parent tumors.
Improved survival in patients with locally
advanced prostate cancer treated
with radiotherapy and goserelin
M Bolla, D Gonzalez, P Warde, JB Dubois, RO
Mirimanoff, G Storme, J Bernier, A Kuten, C Sternberg,
T Gil, L Collette, M Pierart
New England Journal of Medicine, 1997, Vol 337, Iss 5, pp 295-300
Bolla M, Univ Hosp, Dept Radiotherapy, BP 217,
F-38043 Grenoble 9, FRANCE
Background We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer. Methods From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin. Results Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P=0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001). Conclusions Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer. (C) 1997, Massachusetts Medical Society.
Relative effects of demographic,
clinical, histologic, and MR imaging variables
on the accuracy of staging
DJ Getty, SE Seltzer, CMC Tempany, RM Pickett, JA Swets, BJ McNeil
Radiology, 1997, Vol 204, Iss 2, pp 471-479
Getty DJ, Bbn Syst & Technol Corp,
10 Moulton St, Cambridge,MA 02138 USA
PURPOSE: To determine the effects on the accuracy of staging prostate gland cancer of diagnostic prediction rules based on demographic, clinical, histologic, and magnetic resonance (MR) image variables. MATERIALS AND METHODS: A total of 200 cases from four medical centers were evaluated by nine radiologists experienced in MR imaging. The accuracies of the four diagnostic variables (age, prostate specific antigen level, Gleason tumor grade, and MR imaging findings) were measured, both singly and combined in a particular sequence, by calculating the area index of the receiver operating characteristic curve. RESULTS: The accuracy of staging with single variables (age, 0.58; prostate specific antigen level, 0.74; Gleason grade 0.73, MR image findings, 0.74) increased as the variables were optimally merged. The first two variables combined to yield an accuracy of 0.74; the first three combined to yield an accuracy of 0.81; and all four variables resulted in an accuracy of 0.86. In a clinically important subset of 69 cases for which antigen level and Gleason grade together were inconclusive for the purposes of staging, the addition of MR imaging findings resulted in an increase in accuracy from 0.55 to 0.73. CONCLUSION: Optimal merging of diagnostic test results yields an improvement in the accuracy of prostate cancer staging.
Results of 3D conformal radiotherapy in
the treatment of localized prostate cancer
N FukunagaJohnson, HM Sandler, PW McLaughlin,
MS Strawderman, KH Grijalva, KE Kish, AS Lichter
International Journal of Radiation Oncology
Biology Physics, 1997, Vol 38, Iss 2, pp 311-317
FukunagaJohnson N, Univ Michigan Hosp,
Dept Radiat Oncol, Ann Arbor,MI 48109 USA
Purpose: 3D conformal radiotherapy (3D CRT) has been shown to decrease acute morbidity in the treatment of prostate cancer. Therapeutic outcome and late morbidity data have been accumulating. To evaluate the results of 3D CRT for the treatment of prostate cancer, we analyzed the outcome of a large series of patients treated with conformal techniques. Material and Methods: From January 1987 through June 1994, 707 patients with localized prostate cancer were treated with 3D CRT. Patients with pathologically-confirmed pelvic lymph node metastasis, treated with preirradiation (preRT) androgen ablation, or treated post-prostatectomy were excluded. All had CT obtained specifically for treatment planning, multiple structures contoured on the axial images, and beam's-eye view conformal beams edited to provide 3D dose coverage. Median follow-up is 36 mos; 70 patients have been followed longer than 5.5 Sears. Six hundred three had T1-T2 tumors. PreRT prostate specific antigen (PSA) was available for 649 patients: median preRT PSA was 12.9 ng/ml, 209 patients had preRT PSA > 20 ng/ml. The median dose of radiation was 69 Gy; 102 patients received greater than or equal to 69 Gy. Biochemical failure was defined as: 1) two consecutive PSA rises over 2.0 ng/ml if nadir PSA less than or equal to 2.0 ng/ml, 2) two consecutive PSA rises over nadir if nadir PSA > 2.0 ng/ml, or 3) initiation of hormonal therapy after RT. Complications were graded using the RTOG system. Results: PreRT PSA and Gleason score emerged as independent indicators of biochemical control (bNED). Patients with preRT PSA > 10 had a significantly worse bNED at 5 years than patients with preRT PSA less than or equal to 10. Five-year bNED was determined according to preRT PSA: PSA less than or equal to 4, 88%; PSA > 4 less than or equal to 10, 72%; PSA > 10 less than or equal to 20, 43%; and PSA > 20, 30%. Patients with Gleason score greater than or equal to 7 also had a significantly worse bNED than patients with Gleason score < 7. Patients were divided into two prognostic groups: a favorable group with PSA less than or equal to 10, Gleason score < 7, and T1-T2 tumors, and an unfavorable group with PSA > 10, Gleason score greater than or equal to 7 or T3-T4 tumors and studied for the effect of dose on bNED status. The bNED at 5 years was 75% for the favorable group and 37% for the unfavorable group. In addition, a group that might be considered a surgical subset was reviewed: patients with PSA less than or equal to 10, Gleason score less than or equal to 7, and T1-T2 tumors who were <70 years old. This subset had an 84% 5-year bNED rate and 98% 5-year overall survival. Complications with the techniques used here are very low: 3% risk at 7 years of Grade 3-4 complications and 1% risk at 7 years of Grade 3 bladder complications (no Grade 4). Conclusion: 3D CRT allows for treatment of prostate cancers with a very low risk of complications. Patients with relatively early disease as defined by preRT PSA, Gleason score < 7, and T1-2 tumors and patients who are candidates for radical prostatectomy have excellent 5-year bNED rates. Patients with adverse prognostic factors have a high risk of biochemical recurrence and are candidates for innovative therapy. (C) 1997 Elsevier Science Inc.
Induction of apoptosis and altered
nuclear/cytoplasmic distribution of the
androgen receptor and prostate-specific
antigen by 1 alpha,25-dihydroxyvitamin
D-3 in androgen-responsive LNCaP cells
TC Hsieh, JM Wu
Biochemical and Biophysical Research Communications, 1997,
Vol 235, Iss 3, pp 539-544
Wu JM, New York Med Coll, Dept Biochem
Mol Biol, Valhalla,NY 10595 USA
In addition to suppressing prostate cell growth, vitamin D also up-regulates the expression of androgen receptor (AR) and prostate-specific antigen (PSA). To study the mechanism involved in the control of these proteins, LNCaP cells were treated with 10 nM 1 alpha,25-dihydroxyvitamin D-3 and separated into cytosol and nuclear fractions. AR and PSA were analyzed by western blot analysis. A second approach involved incubating control and treated cells with [H-3]R1881, fractionating the cells into the cytosolic and nuclear components, and quantifying the amount of radioactivity associated with the respective fractions. Alternatively, immunohistochemical assays were performed by staining cells with cognate antibodies for AR and PSA, Both biochemical and immunohistochemical analyses show proportionately greater increased presence of AR in the nucleus, accompanied by relatively reduced AR in the cytosol, following treatment of LNCaP cells with vitamin D-3. Surprisingly, PSA was found to be present in the nuclear fraction in both control and treated cells. These results suggest that vitamin D-3 promotes the translocation of AR from the cytosol to the nucleus. The presence of PSA in the nucleus of LNCaP cells raises the possibility of an autogenous mode of control of PSA gene expression. (C) 1997 Academic Press.
Effects of endocrine therapy on the
primary lesion in patients with prostate
carcinoma as evaluated by endorectal
magnetic resonance imaging
Nakashima J.; Imai Y.; Tachibana M.; Baba S.; Hiramatsu K.; Murai M.
Cancer (USA) , 1997, 80/2 (237-241)
Dr. J. Nakashima, Department of Urology, Keio University School of Medicine,
35 Shinanomachi, Shinjuku-ku, Tokyo 160 Japan
BACKGROUND. Little effort has been made at the quantitative and qualitative evaluation of patients with prostate carcinoma, including downsizing and downstaging of the primary lesion, after conservative therapy. The current study was undertaken to investigate the qualitative and quantitative effects of endocrine therapy on the primary prostate carcinoma using magnetic resonance imaging (MRI). METHODS. The primary prostate carcinoma was evaluated by endorectal MRI approximately 4 months after the initiation of endocrine therapy in 48 patients with histologically confirmed prostate carcinoma detected by endorectal MRI before therapy. RESULTS. The volumes of the prostate gland, the carcinoma, and the noncarcinomatous components were reduced to 60.2 plus or minus 2.7%, 25.5 plus or minus 2.9%, and 83.2 plus or minus 6.3% of their pretreatment volumes respectively after endocrine therapy, indicating that the tumors are more susceptible to endocrine therapy than the nontumorous components. The number of prostate carcinomas that demonstrated low signal intensity compared with the normal peripheral zone on T2-weighted images decreased after endocrine therapy and the number of carcinomas with enhancement of T1-weighted contrast-enhanced images increased after therapy. Seven of the 48 patients underwent downstaging after endocrine therapy, based on the endorectal MRI evaluation. CONCLUSIONS. The results of the current study suggest that downsizing and occasionally downstaging of the carcinoma may occur after endocrine therapy in patients with prostate carcinoma. In addition, the androgen sensitivity of the prostate carcinoma tissue is relatively high compared with the residual noncancerous prostate gland.
Ischemic damage to the prostate
during cardiac surgery: A clinical model
C Coker, RA Sherwood, T Crayford, F Saadeh,
D Mulvin, E Brakenbury, MJ Coptcoat
Prostate, 1997, Vol 32, Iss 2, pp 85-88
BACKGROUND. To determine if altered tissue perfusion during cardiac surgery results in ischemic tissue damage to the prostate, as suggested by a rise in prostatic-specific antigen (PSA). METHODS. Twenty-nine male patients undergoing elective coronary artery bypass grafting were studied. Ten male patients undergoing elective gastrointestinal surgery served as controls. PSA levels were determined preoperatively and six hourly intervals postoperatively for 48 hr. All patients underwent urethral catheterization at induction of anesthesia. RESULTS. All patients (100%) who had undergone cardiac bypass surgery showed rises in serum PSA during 48 hr of postoperative follow-up. At the 6-hr postoperative interval, the mean PSA was significantly different from the mean baseline value (paired two tailed Student's t test, P < 0.001) in 27 of the 29 (93%) patients. In contrast, the PSA values in the 10 gastroenterological controls did not change at 6 hr (P > 0.2) or during the next 48 hr. One patient in the cardiac group showed a very marked elevation in serum PSA of greater than 50 times normal preoperative levels. CONCLUSIONS. Statistically significant rises in PSA levels are seen following coronary bypass surgery. This rise may be caused by ischemic nontrauma related damage to the prostate and suggests a possible pathophysiological mechanism for the clinically episodic symptoms of prostatism seen in elderly men. (C) 1997 Wiley-Liss, Inc.
prostate cancer (stage T1c): an analysis
of whole-mount prostatectomy specimens.
Douglas TH; McLeod DG; Mostofi FK;
Mooneyhan R; Connelly R; Moul JW; Sesterhenn IA
Prostate (UNITED STATES) Jun 15 1997, 32 (1) p59-64,
Department of Surgery, Walter Reed Army Medical Center,
Washington, DC 20307-5001, USA.
BACKGROUND: Clinical and pathological staging of prostate cancer has been, and remains, problematic. Since prostate-specific antigen (PSA)-detected tumors are often discerned during "screening," what are their significance? METHODS: We analyzed 67 consecutive patients with stage T1c prostate cancer undergoing radical prostatectomy at our institution from August 1, 1991-September 12, 1995, and who had whole-mount specimen processing. Diagnosis was determined in all cases by transrectal ultrasound-guided biopsy. RESULTS: The mean age of our patients was 63 years, and the mean PSA at time of diagnosis was 8.6 ng/ml (median, 7.2 ng/ml). There was organ-confined cancer in 31/67 (46%) patients; 17/67 (25%) had periprostatic fat infiltration, and of these 5(7%) had seminal vesicle involvement. Thirty-one of 67 (46%) had positive surgical margins. Twenty-two (33%) had a Gleason sum of > or = 7 in the final pathological specimen. Insignificant tumors (dominant tumor volume < 0.20 cc) were found in only 4 cases. Smaller tumors were more likely to be found when the PSA was < 10 ng/ml. Multifocal disease was found in 64/67 (96%) prostate specimens. CONCLUSIONS: This study adds impetus to the growing realization that nonpalpable prostate cancer, detected because of elevated PSA, is rarely insignificant. Our findings add further emphasis to the fact that patients diagnosed by PSA elevation have, for the most part, significant cancer that should be treated aggressively.
Early stage prostate cancer treated
with radiation therapy:
Stratifying an intermediate risk group
JP Lattanzi, AL Hanlon, GE Hanks
International Journal of Radiation Oncology
Biology Physics, 1997, Vol 38, Iss 3, pp 569-573
Lattanzi JP, Fox Chase Canc Ctr, Dept Radiat Oncol,
7701 Burholme Ave, Philadelphia,PA 19111 USA
Purpose: This study identifies two early prostate cancer populations within the T1/T2AB, Gleason 2-7, pretreatment prostate specific antigen (PSA) 4-15 ng/ml grouping. By demonstrating different outcomes we may be able to more appropriately select a subgroup for whom adjuvant therapy trials or altered treatment techniques are indicated. Materials and Methods: One hundred forty-six patients with T1/T2AB, Gleason score 2-7, PSA 4-15 ng/ml prostate cancer were treated with external beam radiotherapy alone from November 1987 to October 1993. The median pretreatment PSA was 8.6 and the mean 8.7. Minimum follow-up was 2 years with a median of 38 months (mean 42 months, range 24-87). The median age was 70 years (range 58-83) and the median central axis dose delivered was 7240 cGy (mean 7273, range 6541-7895 cGy). Eleven patients received conventional radiotherapy while 135 were treated using conformal techniques. As there is evidence that a low PSA nadir is an early marker for long term biochemical control, time to post treatment PSA < 1 ng/ml was actuarially analyzed by Gleason score, pretreatment PSA, radiation dose, stage, and the presence of perineural invasion. Pretreatment PSA was the only patient characteristic predictive of achieving a PSA level < 1.0 ng/ml. Biochemical relapse free (bNED) control (non rising PSA) was then compared for patients above and below the approximate median pretreatment PSA level of 8 ng/ml. BNED control rates and the time to PSA <1.0 ng/ml were estimated using Kaplan-Meier methodology, and differences in bNED control and PSA <1.0 ng/ml according to PSA level were evaluated using the log-rank test. Results: Results from actuarial analysis revealed that pretreatment PSA was the only significant variable predictive of a PSA <1.0 ng/ml. Ninety-eight percent of patients with pretreatment PSA <8 achieved a PSA level <1.0 ng/ml within 3 years compared to 78% for patients with a PSA >8 ng/ml (p = 0.0003). BNED control for the two groups separated at a pretreatment PSA of 8 ng/ml confirms a favorable outcome, 88% bNED control at 5 years for <8 ng/ml and 74% for a pretreatment PSA greater than or equal to 8 ng/ml (p = 0.007 for overall curve comparison). Conclusion: For early prostate cancer patients (T1/T2AB, Gleason 2-7, pretreatment PSA 4-15) there is a significant break in bNED control following external beam radiation at a pretreatment PSA level of 8 ng/ml. Patients with pretreatment PSA <8 have a very favorable bNED response with radiation alone while those with a pretreatment PSA 8-15 have a significant decrease in bNED response. The 27% failure rate at 5 years in the PSA 8-15 ng/ml patients may justify altered treatment techniques or clinical trials of adjuvant androgen deprivation in this group. (C) 1997 Elsevier Science Inc.
Enhancement of prostate tumor volume
definition with intravesical contrast:
A three-dimensional dosimetric evaluation
R Sharma, M Duclos, PJ Chuba, F Shamsa, JD Forman
International Journal of Radiation Oncology
Biology Physics, 1997, Vol 38, Iss 3, pp 575-582
prostate cancer; intravesical contrast; three-dimensional treatment planning Pergamon-Elsevier Science Ltd,
The Boulevard, Langford Lane, Kidlington, Oxford, England OX5 1GB
Purpose: To assess the impact of intravesical contrast during computed tomography (CT) simulation on prostate tumor volume definition and dose distribution. Methods and Materials: Sixteen patients with localized adenocarcinoma of the prostate underwent CT-based virtual simulation in preparation for definitive radiotherapy, Patients were immobilized with a foam cradle and an initial CT was performed after oral but without intravesical contrast (noncontrast scan), A second scan was performed following administration of intravesical contrast (contrast scan), Beam apertures were designed on the noncontrast scans and digitized into the contrast scan file, Beam apertures were also designed on the contrast scans, Isodose plans were generated for several beam apertures and arrangements. Results: There was enhanced visualization of the prostate at the cephalad portion of the field for 15 of the 16 cases, The mean differences between the noncontrast and contrast volumes was significant (p = 0.0001), The mean percent underdosage to the prostate ranged from 3.9% to 18.6%, depending upon the target volume and beam arrangement. Conclusion: This study demonstrates the necessity of using intravesical contrast for defining the location of the prostate during CT simulation, The underestimation of the extent of the prostate when omitting intravesical contrast leads to significant underdosage, The value of intravesical contrast is most evident when small (prostate only) conformal fields are used. (C) 1997 Elsevier Science Inc.
Arachidonic acid stimulates prostate cancer
cell growth: Critical role of 5-lipoxygenase
J Ghosh, CE Myers
Biochemical and Biophysical Research Communications,
1997 Vol 235, Iss 2, pp 418-423
Ghosh J, Univ Virginia, Ctr Canc, POB 334, Charlottesville,VA 22908 USA
Arachidonic acid (5,8,11,14-eicosatetraenoic acid), a member of the omega-g poly-unsaturated fatty acids, was found to be an effective stimulator of human prostate cancer cell growth in vitro at micromolar concentrations, Selective blockade of the different metabolic pathways of arachidonic acid (e.g. Ibuprofen for cyclooxygenase, SKF-525A for cytochrome P-450, baicalein and BHPP for 12-lipoxygenase, AA861 and MK886 for 5-lipoxygenase, etc.) revealed that the growth stimulatory effect of arachidonic acid is inhibited by the 5-lipoxygenase specific inhibitors, AA861 and MK886, but not by others. Addition of the eicosatetraenoid products of 5-lipoxygenase (5-HETEs) showed stimulation of prostate cancer cell growth similar to that of arachidonic acid, whereas the leukotrienes were ineffective, Moreover, the 5-series of eicosatetraenoids could reverse the growth inhibitory effect of MK886. Finally, prostate cancer cells fed with arachidonic acid showed a dramatic increase in the production of 5-HETEs which is effectively blocked by MK886. These experimental observations suggest that arachidonic acid needs to be metabolized through the 5-lipoxygenase pathway to produce 5-HETE series of eicosatetraenoids for its growth stimulatory effects on human prostate cancer cells. (C) 1997 Academic Press.
Induction of cyclo-oxygenase-2 mRNA by
prostaglandin E-2 in human prostatic carcinoma cells.
Tjandrawinata RR, Dahiya R, HughesFulford M
Br J Cancer 1997 APR;75(8):1111-1118
HughesFulford M, Vet Affairs Med Ctr, Lab Cell Growth 151F,
4150 Clement St, San Francisco,CA 94121 USA
Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclo-oxygenases: COX-I (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E-2 (dmPGE(2)) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE(2) to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE(2) concentration. DmPGE(2) also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE(2) regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE(2) concentration, with maximum stimulation seen at 5 mu g ml(-1). The non- steroidal anti-inflammatory drug flurbiprofen (5 mu M), in the presence of exogenous dmPGE(2), inhibited the up- regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE(2) has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE(2), perhaps resulting from changes in local cellular PGE(2) concentrations.
Mitoxantrone: A review of its pharmacology
and clinical efficacy in the management of
hormone-resistant advanced prostate cancer.
Wiseman LR, Spencer CM
Drug Aging 1997 JUN;10(6):473-485LA - English
Wiseman LR, Adis Int Ltd, 41 Centorian Dr,
Private Bag 65901, Auckland 10, NEW ZEALAND
The antineoplastic agent mitoxantrone in combination with a corticosteroid (either prednisone or hydrocortisone) hasshown clinical efficacy as palliative treatment for a proportion of patients (about 35 to 40%) with hormone-resistant advanced prostate cancer; a disease which predominantly affects elderly men and for which few systemic treatment options are available. Palliative end-points including pain relief decreased analgesic use and reduced prostate specific antigen levels (a marker of tumour response) are reached in a greater percentage of patients receiving combination therapy than corticosteroid alone. In addition, there are generally greater improvements in quality-of-life parameters in mitoxantrone recipients. However, combined treatment offers no survival advantage over corticosteroid monotherapy.Neutropenia is the most common toxicity associated with mitoxantrone therapy and may necessitate dosage reduction in some patients. Otherwise, mitoxantrone generally has a more favourable tolerability profile than has been established for other cytotoxic agents such as doxorubicin with regard to acute adverse events (e.g. Nausea/vomiting, anorexia, constipation, alopecia, malaise/fatigue, oedema) and cardiac toxicity.In conclusion, administration of mitoxantrone plus a corticosteroid can provide palliation for some elderly patients with hormone-resistant advanced prostate cancer, and is thus a valuable first-line treatment for this indication.
Molecular and cellular biology of
Lalani EN, Laniado ME, Abel PD
Cancer Metastasis Rev 1997 JUN;16(1-2):29-66
Lalani EN, Hammersmith Hosp, Royal Postgrad Med Sch, Dept
Histopathol, du Crane Rd, London W12 0NN, ENGLAND
Prostate cancer is an enigmatic disease. Although prostatic-intraepithelial neoplasia appears as early as the third decade and as many as 80% of 80 year old men have epithelial cells in their prostate that fit the morphological criteria for cancer, only about 10% of men will ever have the clinical disease and less than 3% will die from it. There have been no significant proven interventions which have al tered the natural history of the disease since hormone down regulation was introduced in the 1940s and new research has been poorly supported. There is however an urgent need to develop new criteria to distinguish those patients with localised disease who will benefit from intervention from those that do not require it or who will have occult extra prostatic metastases. Similarly, there is an urgent need to develop new treatments for those in wham the disease is extra- prostatic and therefore incurable by conventional treatments. This review covers the latest developments in epidemiology, cellular and molecular biology including new areas such as ion channels in the field of prostate cancer.
Antiproliferative effect of Pygeum africanum
extract on rat prostatic fibroblasts.
Yablonsky F, AU - Nicolas V, Riffaud JP, Bellamy F
J Urol 1997 JUN;157(6):2381-2387
Yablonsky F, Labs Debat, Grp Fournier, 153 Rue Buzenval, F
92380 Garches, FRANCE
The effect of a Pygeum africanum extract (Tadenan(R)) (Pa), used in the treatment of micturition disorders associated with BPH, has been examined on the proliferation of rat prostatic stromal cells stimulated by different growth factors. EGF, bFGF, and IGF-I but not KGF are mitogenic for prostatic fibroblasts in culture. Pygeum africanum inhibits both basal and stimulated growth with IC50 values of 4.5, 7.7 and 12.6 mu g./ml. For EGF, IGF-I and bFGF, respectively, compared to 14.4 mu g./ml. For untreated cells, the inhibition being stronger towards EGF. Pygeum africanum inhibited the proliferation induced by TPA or PDBu in a concentration-dependent manner with IC50 values of 12.4 and 8.1 mu g./ml. Respectively. The antiproliferative effects of Pa were not ascribed to cytotoxicity. These results show that Pygeum africanum is a potent inhibitor of rat prostatic fibroblast proliferation in response to direct activators of protein kinase C, the defined growth factors bFGF, EGF and IGF-I, and the complex mixture of mitogens in serum depending on the concentration used. PKC activation appears to be an important growth factor-mediated signal transduction for this agent. These data suggest that therapeutic effect of Pygeum africanum may be due at least in part to the inhibition of growth factors responsible for the prostatic overgrowth in man.
Flutamide withdrawal plus hydrocortisone
resulted in clinical complete response
in a patient with prostate carcinoma.
Figg WD, Kroog G, Duray P, Walther MM, Patronas N, Sartor O, Reed E
Cancer 1997 MAY 15;79(10):1964-1968
Figg WD, NCI, Med Branch, Bldg 10, Room 5A01,
9000 Rockville Pike, Bethesda,MD 20892 USA
BACKGROUND. Combined androgen blockade plus (CAB) (medical or surgical castration plus antiandrogen therapy) is considered by many to be the optimal endocrine maneuver for patients with metastatic prostate carcinoma. When progression occurs after CAB, the discontinuation of the antiandrogen is recommended. The authors present a patient that had a clinical complete response to flutamide withdrawal plus hydrocortisone that, at last follow-up, had been maintained for more than 46 months. METHODS. A 71-year-old man with a positive family history of prostate carcinoma presented in 1989 with urinary frequency and a suspicious digital rectal examination. He was found to have a poorly differentiated adenocarcinoma (Gleason 4+4). He was started on CAB and his prostate specific antigen (PSA) concentration declined from 96 ng/mL to the normal range and was maintained for the next 24 months. In 1991 his PSA began to rise, and reached 64 ng/mL by 1993. The patient was enrolled on a clinical trial that discontinued the flutamide administration and hydrocortisone was initiated. RESULTS. Physical examination at the time of enrollment was unremarkable. His PSA declined to below the limits of detection after this maneuver and at last follow-up had been maintained there for more than 46 months. In 1995, the patient underwent a repeat biopsy of the prostate and all six tissue cores were negative for carcinoma. At last follow-up in December 1996, the patient had no evidence of disease and was being followed routinely; however, the authors were continuing treatment with testicular suppression (leuprolide) plus hydrocortisone. CONCLUSIONS. The authors believe the residual androgens and steroids produced by the adrenal cortex play a meaningful role in prostate carcinoma cell proliferation. Based on this case and data from trials supporting the activity of flutamide withdrawal plus adrenal suppression, it appears reasonable to evaluate prospectively the discontinuation of antiandrogen versus antiandrogen withdrawal plus adrenal suppression in individuals failing CAB. (C) 1997 American Cancer Society.
Quality of life and treatment outcomes:
Prostate carcinoma patients' perspectives
after prostatectomy or radiation therapy.
ShraderBogen CL, Kjellberg JL, McPherson CP, Murray CL
Cancer 1997 MAY 15;79(10):1977-1986
ShraderBogen CL, Healthsyst Minnesota, Inst Res
Educ, 3800 Pk Nicollet Blvd, 2 S,
Minneapolis,MN 55416 USA
BACKGROUND. Of the estimated 317,000 men in the United States diagnosed with prostate carcinoma in 1996, 57% will have localized disease, and their 5-year relative survival rate will be 98%. Limited information exists on patient- reported quality of life (QOL) and the incidence and severity of treatment-related side effects. The purpose of this study was to identify and compare patients' self- reported QOL and treatment side effects 1-5 years after radical prostatectomy or radiotherapy. METHODS. Data collection for this cross-sectional study included a mailed, self-administered survey with three parts: a demographic survey, the Functional Assessment of Cancer Therapy-General (FACT-G), and a newly developed Prostate Cancer Treatment Outcome Questionnaire (PCTO-Q). The FACT-G measured the effect of prostate carcinoma on overall QOL in the two treatment groups. The PCTO-Q assessed the patients' perceptions of the incidence and severity of specific changes in bowel, urinary, and sexual functions. The test-retest reliability of the PCTO-Q in a pilot study was 91.2%. RESULTS. Two hundred seventy-four eligible men completed the questionnaires; 132 (48%) reported having undergone prostatectomy and 142 (52%) reported having undergone radiotherapy. After age adjustment, the radiotherapy group reported more bowel dysfunction (P = 0.001), whereas the prostatectomy group reported more urinary problems (P = 0.03) and more sexual dysfunction (P = 0.001). Scores for the FACT-G were similar in the two treatment groups. CONCLUSIONS. Men undergoing treatment for clinically localized prostate carcinoma continue to experience difficulty long after treatment. In this study, the prostatectomy group fared worse in regard to sexual and urinary functions, whereas the radiotherapy group experienced more bowel dysfunction. Survivor-reported QOL and treatment outcomes can assist physicians in counseling patients in the selection of the preferred course of treatment. (C) 1997 American Cancer Society.
Prostate cancer detection in men with
serum PSA concentrations of 2.6 to 4.0 ng/mL
and benign prostate examination:
Enhancement of specificity with
free PSA measurements.
Catalona WJ Smith DS Ornstein DK
JAMA 1997 MAY 14;277(18):1452-1455
Catalona WJ, Washington Univ, Sch Med, Dept Surg,
Div Urol Surg, 4960 Childrens Pl,
St Louis,MO 63110 USA
Objective.-To determine the detection rate of prostate cancer in a screening population of men with prostate- specific antigen (PSA) concentrations of 2.6 to 4.0 ng/mL and a benign prostate examination, to assess the clinicopathological features of the cancers detected, and to assess the usefulness of measuring the ratio of free to total PSA to reduce the number of prostatic biopsies. Design.-A community-based study of serial screening for prostate cancer with serum PSA measurements and prostate examinations. Setting.-University medical center. Subjects.-A total of 914 consecutive screening volunteers aged 50 years or older with serum PSA levels of 2.6 to 4.0 ng/mL who had a benign prostate examination and no prior screening tests suspicious for prostate cancer, 332 (36%) of whom underwent biopsy of the prostate. Main Outcome Measures.-Cancer detection rate, clinical and pathological features of cancers detected, and specificity for cancer detection using measurements of percentage of free PSA. Results.-Cancer was detected in 22% (73/332) of men who underwent biopsy. All cancers detected were clinically localized, and 81% (42/52) that were surgically staged were pathologically organ confined. Ten percent of the cancers were clinically low-volume and low-grade tumors, and 17% of those surgically staged were low-volume and low- grade or moderately low-grade tumors (possibly harm less). Using a percentage of free PSA cutoff of 27% or less as a criterion for performing prostatic biopsy would have detected 90% of cancers, avoided 18% of benign biopsies, and yielded a positive predictive value of 24% in men who underwent biopsy. Conclusions.-There is an appreciable rate of detectable prostate cancer in men with serum PSA levels of 2.6 to 4.0 ng/mL. The great majority of cancers detected have the features of medically important tumors. Free serum PSA measurements may reduce the number of additional biopsies required by the lower PSA cutoff.
Prostate-specific antigen failure despite
pathologically organ-confined and
margin-negative prostate cancer:
The basis for an adjuvant therapy trial.
DAmico AV, Whittington R, Malkowicz SB, Schultz D,
Tomaszewski JE, Wein A,
J Clin Oncol 1997 APR;15(4):1465-1469
DAmico AV, Harvard Univ, Sch Med, Joint Ctr Radiat Therapy,
330 Brookline Ave, Boston,MA 02215 USA
Purpose: A multivariable analysis to evaluate the potential clinical and pathologic factors that predict for early biochemical failure in patients with pathologically organ-confined and margin-negative disease was performed to define patients who may benefit from adjuvant therapy. Patients and Methods: Three hundred forty-one prostate cancer patients treated with a radical retropubic prostatectomy between January 1989 and June 1995 and found to have pathologically organ-confined and margin-negative disease comprised the study population. A logistic regression multivariable analysis to evaluate the predictive value of the preoperative prostate-specific antigen (PSA) level, pathologic (prostatectomy) Gleason score, and pathologic stage on PSA failure occurring during the first postoperative year was performed. Results: Predictors of PSA failure during the first postoperative year in patients with pathologically organ- confined disease included pathologic Gleason score greater than or equal to 7 (P = .0007) and preoperative PSA level greater than 10 (P .0001). Corresponding 3-year freedom- from-PSA-failure rates for these pathologic organ-confined patients with both, one, or neither of these factors were 60%, 75% to 84%, and 95%, respectively (P .0001). Conclusion: Prostate cancer patients with pathologically organ-confined and margin-negative disease and a preoperative PSA level greater than 10 ng/mL or a pathologic Gleason score greater than or equal to 7 have significant decrements in short-term PSA-failure-free survival. Therefore, these patients should be considered for adjuvant therapy in the setting of a phase III clinical trial. (C) 1997 by American Society of Clinical Oncology.
Family history of prostate cancer in
patients with localized prostate cancer:
An independent predictor of treatment outcome.
Kupelian PA, Kupelian VA, Witte JS, Macklis R, Klein EA,
J Clin Oncol 1997 APR;15(4):1478-1480
Kupelian PA, Cleveland Clin Fdn, Dept Radiat Oncol,
Desk T28, Cleveland,OH 44195 USA
Purpose: To determine if familial prostate cancer patients have a less favorable prognosis than patients with sporadic prostate cancer after treatment for localized disease with either radiotherapy (RT) or radical prostatectomy (RP). Patients and Methods: One thousand thirty-eight patients treated with either RT (n = 583) or RP (n = 455) were included in this analysis, These patients were noted as having a positive family history if they confirmed the diagnosis of prostate cancer in a first-degree relative, The outcome oi: interest was biochemical relapse-free survival (bRFS). We used proportional hazards to analyze the effect of the presence of family history and other potential confounding variables (ie, age, treatment modality, stage, biopsy Gleason sum [GS], and initial prostate-specific antigen [iPSA] levels) on treatment outcome. Results: Eleven percent of all patients had a positive family history, The 5-year bRFS rates for patients with negative and positive family histories were 52% and 29%, respectively (P .001). The potential confounders with bRFS rates were iPSA levels, biopsy GS, and clinical tumor stage; treatment modality and age did not appear to be associated with outcome. After adjusting for potential confounders, family history of prostate cancer remained strongly associated with biochemical failure. Conclusion: This is the first study to demonstrate that the presence of a family history of prostate cancer correlates with treatment outcome in a large unselected series of patients. Our findings suggest that familial prostate cancer may have a more aggressive course than nonfamilial prostate cancer, and that clinical and/or pathologic parameters may not adequately predict this course. (C) 1997 by American Society of Clinical Oncology.
Phase II trial of suramin, leuprolide,
and flutamide in previously untreated
metastatic prostate cancer.
Dawson NA, Figg WD, Cooper MR, Sartor O, Bergan RC,
Senderowicz AM, Steinberg SM,
Tompkins A, Weinberger B, Sausville EA, Reed E, Myers CE,
J Clin Oncol 1997 APR;15(4):1470-1477
Dawson NA, Walter Reed Army Med Ctr,
Washington,DC 20307 USA
Purpose: To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. Patients and Methods: patients with stage D2 and poor- prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 mu g/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. Results: Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease, The median age was 59 years (range, 42 to 79) and 31 patienf 5 had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease, Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%, Eighteen patients have died, The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. Conclusion: The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone, Toxicity was moderate and reversible.
The antiandrogen withdrawal syndrome.
Wirth MP, Froschermaier SE
Urol Res 1997 APR;25:S67-S71
Wirth MP, Tech Univ Dresden, Dept Urol,
Fetscherstr 74, D 01307 Dresden, GERMANY
In 1989 the unanticipated agonist effect of antiandrogens on LNCaP prostate cancer cells was detected. A ''flutamidewithdrawal syndrome'' was first described by Kelly andScher , who reported a decrease in serum prostate-specific antigen (PSA) levels after the removal offlutamide from the treatment regimen. In the last fewyears the paradoxical response to antiandrogens has alsobeen reported for bicalutamide, chlormadinone acetate andothers. Therefore the name of the syndrome has changed to''antiandrogen withdrawal syndrome.'' Several reasons suchas mutations in the androgen receptor or a directstimulatory effect of the antiandrogen for this effecthave been discussed, but the exact molecular mechanismremains unclear. However, in patients with hormonallyrelapsed prostate cancer, a trial of ''withdrawaltherapy'' is required prior to the initiation of toxictherapies.