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Staging of early prostate cancer: a proposed tumor volume-based prognostic index.
Bostwick DG, Graham SD Jr, Napalkov P, Abrahamsson PA, di Sant'agnese PA, Algaba F, Hoisaeter PA, Lee F, Littrup P, Mostofi FK, et al
Mayo Clinic Department of Pathology, Rochester, Minnesota 55905.
Urology 1993 May;41(5):403-11

Current staging of early prostate cancer separates patients into two groups: those with palpable and non-palpable tumors. Such staging relies on digital rectal examination in making this separation, despite the low sensitivity, low specificity, and low positive predictive value of this method. As an alternative, tumor volume may be useful for staging because of its powerful prognostic ability and its potential to be assessed clinically due to recent advances in imaging techniques such as transrectal ultrasound. In this study, we evaluate the utility of tumor volume in predicting progression of early prostate cancer based on the composite published evidence from nine pathologic studies of serially-sectioned prostates. Logistic regression revealed that tumor volume was a good positive predictor of all measures of tumor progression. There was a 10 percent probability of capsular invasion in tumors measuring about 0.5 cm3; 10 percent probability of seminal vesicle invasion in tumors measuring about 4.0 cm3; and 10 percent probability of metastases in tumors measuring about 5.0 cm3. These composite results suggest that tumor volume is a significant predictor of cancer progression. A volume-based prognostic index is proposed as an adjunct to staging for early prostate cancer.

Tumor volume and prostate specific antigen: implications for early detection and defining a window of curability.
Babaian RJ, Troncoso P, Steelhammer LC, Lloreta-Trull J, Ramirez EI
Department of Urology, University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
J Urol 1995 Nov;154(5):1808-12

PURPOSE: We attempted to determine the relationship between tumor volume and extent of localized prostate cancer, as well as the interrelationships of tumor volume with prostate specific antigen (PSA) level, grade and stage.

MATERIALS AND METHODS: Serial whole mount sections from 128 patients who underwent radical prostatectomy were analyzed using a computer assisted volumetric program. Statistical evaluations were performed using logistic and simple regression analyses.

RESULTS: The median tumor volume for patients with organ confined disease was significantly lower than for those with extraprostatic extension (1.25 versus 2.94 cc, p < 0.001). A significant incidence (32%) of small volume cancers (0.51 to 1.5 cc) exhibited extraprostatic extension while that of extraprostatic disease increased to 66% for patients with tumor volumes greater than 1.5 cc (p < 0.001). Of men with clinically significant (greater than 0.5 cc, or Gleason score 7 or more) pathological stage B disease 31% had a serum PSA value of 4 ng./ml. or less. Multivariate regression analysis of tumor volume as a function of PSA, grade and stage demonstrated that log PSA had the strongest association with tumor volume. Goodness-of-fit analysis (coefficient of determination) revealed that only 40 to 50% of the PSA levels are explained by tumor volume.

CONCLUSIONS: These data suggest that the window of curability for prostate cancer decreases significantly once the tumor grows to a volume greater than 1.5 cc, and that grade and tumor volume are more significantly related to stage than PSA.

The development of human benign prostatic hyperplasia with age.
Berry SJ, Coffey DS, Walsh PC, Ewing LL
J Urol 1984 Sep;132(3):474-9

In this study we report the prevalence and growth rate of human benign prostatic hyperplasia with age by combining and analyzing data from 10 independent studies containing more than 1,000 prostates. The normal prostate reaches 20 plus or minus 6 gm. in men between 21 and 30 years old, and this weight remains essentially constant with increasing age unless benign prostatic hyperplasia develops. The prevalence of pathological benign prostatic hyperplasia is only 8 per cent at the fourth decade; however, 50 per cent of the male population has pathological benign prostatic hyperplasia when they are 51 to 60 years old. The average weight of a prostate that is recognized at autopsy to contain benign prostatic hyperplasia is 33 plus or minus 16 gm. Only 4 per cent of the prostates in men more than 70 years old reach sizes greater than 100 gm. An analysis of a logistic growth curve of benign prostatic hyperplasia lesions removed at prostatectomy indicates that the growth of benign prostatic hyperplasia is initiated probably before the patient is 30 years old. The early phase of benign prostatic hyperplasia growth (men between 31 and 50 years old) is characterized by a doubling time for the tumor weight of 4.5 years. In the mid phase of benign prostatic hyperplasia growth (men between 51 and 70 years old) the doubling time is 10 years, and increases to more than 100 years in patients beyond 70 years old.

Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease.
Carter HB, Pearson JD, Metter EJ, Brant LJ, Chan DW, Andres R, Fozard JL, Walsh PC
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD.
JAMA 1992 Apr 22-29;267(16):2215-20

OBJECTIVE--To evaluate longitudinal changes in prostate-specific antigen (PSA) levels in men with and without prostate disease.

DESIGN--Case-control study of men with and without prostate disease who were participants in a prospective aging study.

SETTING--Gerontology Research Center of the National Institute on Aging; the Baltimore (Md) Longitudinal Study of Aging.

PATIENTS--Sixteen men with no prostate disease (control group), 20 men with a histologic diagnosis of benign prostatic hyperplasia (BPH), and 18 men with a histologic diagnosis of prostate cancer.

OUTCOME MEASURES--Multiple PSA and androgen determinations on serum samples obtained from 7 to 25 years prior to histologic diagnosis or exclusion of prostate disease.

RESULTS--Changes in androgen levels with age did not differ between groups. Control subjects did not show a significant change in PSA levels with age. There was a significant difference in the age-adjusted rate of change in PSA levels between groups (prostate cancer greater than BPH greater than control; P less than .01). At 5 years before diagnosis when PSA levels did not differ between subjects with BPH and prostate cancer, rate of change in PSA levels (0.75 micrograms/L per year) was significantly greater in subjects with prostate cancer compared with control subjects and subjects with BPH. Also, rate of change in PSA levels distinguished subjects with prostate cancer from subjects with BPH and control subjects with a specificity of 90% and 100%, respectively.

CONCLUSIONS-The most significant factor affecting serum PSA levels with age is the development of prostate disease. Rate of change in PSA levels may be a sensitive and specific early clinical marker for the development of prostate cancer.

Prostate specific antigen progression rates after radical prostatectomy or radiation therapy for localized prostate cancer.
Fowler JE Jr, Pandey P, Braswell NT, Seaver L
Division of Urology, University of Mississippi Medical Center, Jackson 39216.
Surgery 1994 Aug;116(2):302-5; discussion 305-6

BACKGROUND. The purpose of the study was to determine whether a difference is noted in the rate of prostate specific antigen (PSA) elevation after radical prostatectomy or radiation therapy for localized prostate cancer.

METHODS. PSA doubling times were calculated by linear regression analysis in 50 patients who had been treated by radical prostatectomy and who had three or more increasing PSA levels and in 55 patients who had been treated with radiation therapy and who had three or more increasing PSA levels.

RESULTS. No significant difference was noted in the mean PSA doubling times in the two patient groups when stratified by the site of tumor recurrence or by pretreatment tumor stage, tumor grade, or acid phosphatase level.

CONCLUSIONS. Because the PSA doubling time probably parallels the tumor growth rate, these data suggest that the malignant potentials of recurrent tumor after radical prostatectomy and after radiation therapy are equivalent.

Prostate specific antigen regression and progression after androgen deprivation for localized and metastatic prostate cancer.
Fowler JE Jr, Pandey P, Seaver LE, Feliz TP, Braswell NT
Division of Urology, University of Mississippi Medical Center, Jackson, USA.
J Urol 1995 Jun;153(6):1860-5

To identify prostate specific antigen (PSA) functions of prognostic significance in regard to treatment with androgen deprivation for prostate cancer we analyzed the pretreatment PSA, PSA half-life, PSA nadirs, times to PSA elevation and PSA doubling times in 245 patients with localized and 78 with metastatic disease who were treated with this modality. There was a direct correlation between the pretreatment PSA and the time to PSA elevation in patients with localized cancer (p = 0.000003) but no significant correlation in those with metastatic cancer. The PSA half-life was highly variable and did not correlate with other PSA functions of prognostic significance. Incremental increases in the PSA nadir correlated with the time to PSA elevation in patients with localized and metastatic cancer (p < 0.000001 and p = 0.00009, respectively), and with other parameters of prognostic significance. The median PSA doubling time in 26 patients with localized cancer in whom distant metastases did not develop (7.5 months) was significantly longer than that in 7 in whom new metastases developed (2.5 months) and in 43 with preexisting metastatic cancer (2.5 months) (p < 0.05 and p < 0.0001, respectively). In the 7 patients with localized cancer in whom metastases developed the median of the ratios of the PSA when the metastases were manifest and the pretreatment PSA was 0.14, and in 24 patients with preexisting metastatic cancer the median of the ratios of the antemortem PSA and the pretreatment PSA was 1.2. These data show that PSA synthesis by prostate cancer is reduced after androgen deprivation but that the PSA nadir and PSA doubling time following treatment provide important prognostic information.

Early stage prostate cancer treated with radiation therapy: stratifying an intermediate risk group.
Lattanzi JP, Hanlon AL, Hanks GE
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Int J Radiat Oncol Biol Phys 1997 Jun 1;38(3):569-73

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 > or = 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.

Prostate specific antigen and gleason grade: an immunohistochemical study of prostate cancer.
Aihara M, Lebovitz RM, Wheeler TM, Kinner BM, Ohori M, Scardino PT
Matsunaga-Conte Prostate Cancer Research Center, Scott Department of Urology, Baylor College of Medicine, Houston, Texas.
J Urol 1994 Jun;151(6):1558-64

Prostate cancer is histologically heterogeneous as reflected in the 5 patterns of the Gleason grading system. Gleason grade correlates with volume, extent and prognosis. Serum prostate specific antigen (PSA) levels also correlate with tumor volume but the degree to which grade correlates with PSA has not been precisely defined. To quantify this relationship further, we prepared maps of each grade of cancer in 86 radical prostatectomy specimens from patients with clinical stage T2 cancer. The median per cent of the volume of cancer per prostate composed of grade 1 was 0%, while it was 1% for grade 2, 84% for grade 3, 5% for grade 4 and 0% for grade 5. We stained 95 cancer foci (grades 1 to 5) in 40 of these specimens for PSA. The presence and intensity (0 to 3+) of staining in more than 33,000 acini (or cells) correlated inversely with grade (p < 0.0001). Nearly all acini in grade 1 and most in grade 2 stained positive (2 to 3+) for PSA; 87% were positive but with less intensity in grade 3. While many grade 4 (79%) and grade 5 (49%) cells were positive, the intensity of staining was weak. Serum PSA levels correlated with total tumor volume (r = 0.67) but serum PSA levels per cm.3 of cancer decreased with increasing grade (r = -0.24 and p < 0.02). These studies confirm the strong inverse correlation between Gleason grade and the PSA content of prostate cancer. Since more than 85% of grade 3 acini stained for PSA and grade 3 made up the largest portion (84%) of cancer, the predominant contributor to serum PSA levels from prostate cancer was Gleason grade 3. The other grades contribute relatively little to the serum PSA levels either because of the small volume (grades 1 and 2) or the diminished PSA content (grades 4 and 5).

Prostate cancer volume adds significantly to prostate-specific antigen in the prediction of early biochemical failure after external beam radiation therapy.
D'Amico AV, Propert KJ
Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA 02747, USA.
Int J Radiat Oncol Biol Phys 1996 May 1;35(2):273-9

PURPOSE: A new clinical pretreatment quantity that closely approximates the true prostate cancer volume is defined.

METHODS AND MATERIALS: The cancer-specific prostate-specific antigen (PSA), PSA density, prostate cancer volume (VCa), and the volume fraction of the gland involved with carcinoma (VCafx) were calculated for 227 prostate cancer patients managed definitively with external beam radiation therapy. 1. PSA density = PSA/ultrasound prostate gland volume. 2. Cancer-specific PSA = PSA - [PSA from benign epithelial tissue] 3. VCa = Cancer-specific PSA/[PSA in serum per cm3 of cancer] 4. VCafx = VCa/ultrasound prostate gland volume A Cox multiple regression analysis was used to test whether any of these clinical pretreatment parameters added significantly to PSA in predicting early postradiation PSA failure.

RESULTS: The prostate cancer volume (p = 0.039) and the volume fraction of the gland involved by carcinoma (p = 0.035) significantly added to the PSA in predicting postradiation PSA failure. Conversely, the PSA density and the cancer-specific PSA did not add significantly (p > 0.05) to PSA in predicting postradiation PSA failure. The 20-month actuarial PSA failure-free rates for patients with calculated tumor volumes of < or = 0.5 cm3, 0.5-4.0 cm3, and > 4.0 cm3 were 92, 80, and 47%, respectively (p = 0.00004).

CONCLUSION: The volume of prostate cancer (VCa) and the resulting volume fraction of cancer both added significantly to PSA in their ability to predict for early postradiation PSA failure. These new parameters may be used to select patients in prospective randomized trials that examine the efficacy of combining radiation and androgen ablative therapy in patients with clinically localized disease, who are at high risk for early postradiation PSA failure.

Calculated prostate cancer volume: the optimal predictor of actual cancer volume and pathologic stage.
D'Amico AV, Chang H, Holupka E, Renshaw A, Desjarden A, Chen M, Loughlin KR, Richie JP
Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02215, USA.
Urology 1997 Mar;49(3):385-91

OBJECTIVES: A new clinical pretreatment quantity called the calculated prostate cancer volume has been defined. The correlation between the calculated parameter and the actual prostate cancer volume, and its ability to predict for pathologic Stage T3 disease in patients with clinically localized disease, is tested.

METHODS: Prostate cancer volume measurements were obtained using a 3-dimensional computerized morphometric reconstruction technique on 104 whole-mounted radical prostatectomy specimens. The calculated prostate cancer volume was determined based on pretreatment clinical parameters (prostate-specific antigen [PSA], biopsy Gleason score, and prostate ultrasound volume). Linear regression was used to determine the Pearson correlation coefficients (r) between the PSA, the calculated prostate cancer volume, and the measured prostate cancer volume. Logistic regression multivariable analysis evaluating the predictive value of the pretreatment PSA, biopsy Gleason score, clinical stage, and calculated prostate cancer volume in predicting pathologic Stage T3 disease in patients with clinically organ-confined disease was performed.

RESULTS: The calculated prostate cancer volume (r 0.71 to 0.96) was superior to PSA (r 0.12 to 0.67) in predicting the measured prostate cancer volume over a wide range (0.02 to 9.5 cm3) of cancer volumes. The calculated prostate cancer volume was the only significant predictor (P = 0.02) of pathologic Stage T3 disease in patients with clinical Stage T1 to T2 disease on multivariable analysis.

CONCLUSIONS: The calculated volume of prostate cancer is superior to PSA in predicting both the pathologic prostate cancer volume and pathologic Stage T3 disease in patients with clinical Stage T1 and T2 disease. Therefore, it may be useful in determining the optimal candidates for radical prostatectomy.

Morphometry of the prostate: I. Distribution of tissue components in hyperplastic glands.
Marks LS, Treiger B, Dorey FJ, Fu YS, deKernion JB
Department of Surgery/Urology, UCLA School of Medicine.
Urology 1994 Oct;44(4):486-92

OBJECTIVES. Morphometry, or quantitative image analysis, offers great promise in characterizing the various histologic types of benign prostatic hyperplasia (BPH), but to date, a systematic study of the tissue components is lacking. Thus we employed morphometry to examine the distribution of primary BPH tissues throughout whole human prostates.

METHODS. The prostate glands of 20 men with BPH were removed for low-volume carcinoma and subjected to a uniform, comprehensive, systematic quantification of the primary BPH tissue components using the technique of digitization and point-count morphometry.

RESULTS. We found the following average volumes among the 20 glands: epithelium, 19.9% (S.D. 5.1%, range 11.7% to 30.8%); fibromuscular stroma, 50.4% (S.D. 9.4%, range 32.2% to 74.4%); glandular lumina, 29.7% (S.D. 8.9%, range 11.9% to 47.5%). Within the individual prostates, we found symmetry in primary BPH tissue distribution, except that the outer prostate was on average 25% richer in epithelium than the inner prostate (p < 0.05). When tissue composition was determined in simulated biopsy specimens, corrected for radial (ie, inner vs outer gland) orientation, the correlation with whole-organ composition was statistically significant for "percentage epithelium" (r = 0.72, p < 0.01) and for "stromal/epithelial ratio" (r = 0.63, p < 0.01).

CONCLUSIONS. Major differences in primary tissue composition may separate different hyperplastic prostates. Primary BPH tissues are rather symmetrically distributed within individual prostates. Quantitative histologic differences between prostates, potentially important in clinical decision-making may be accurately diagnosed by morphometry of radially oriented biopsy specimens.

Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin.
Dehmlow C, Erhard J, de Groot H
Institut fur Physiologische Chemie, Universitatsklinikum, Essen, Germany.
Hepatology 1996 Apr;23(4):749-54

The flavonoid silibinin, the main compound extracted from the milk thistle Silybum marianum, displays hepatoprotective properties in acute and chronic liver injury. To further elucidate the mechanisms by which it acts, we studied the effects of silibinin on different functions of isolated rat Kupffer cells, namely the formation of superoxide anion radical (02-), nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), and leukotriene B(4) (LTB(4)). Production of 02- and NO were inhibited in a dose-dependent manner, with an 50 percent inhibitory concentration (IC(50)) value around 80 micro mol/L. No effect on TNF-alpha formation was detected. Opposite effects were found on the cyclooxygenase and 5-lipoxygenase pathway of arachidonic acid metabolism. Whereas no influence on PGE(2) formation was observed with silibinin concentrations up to 100 micro mol/L, a strong inhibitory effect on LTB(4) formation became evident. The IC(50)-value for inhibiting the formation of this eicosanoid was determined to be 15 micro mol/L silibinin. The strong inhibition of LTB(4), formation by silibinin was confirmed in experiments with phagocytic cells isolated from human liver. Hence, while rather high concentrations of silibinin are necessary to diminish free radical formation by activated Kupffer cells, significant inhibition of the 5-lipoxygenase pathway already occurs at silibinin concentrations which are achieved in vivo. Selective inhibition of leukotriene formation by Kupffer cells can at least partly account for the hepatoprotective properties of silibinin.

Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade.
Strum SB, McDermed JE, Scholz MC, Johnson H, Tisman G
Daniel Freeman Marina Medical Centre, Marina del Rey, California, USA.
Br J Urol 1997 Jun;79(6):933-41

OBJECTIVE: To describe the incidence, time to onset and extent of anaemia occurring in patients with prostate cancer receiving combined hormone blockade (CHB) and the timing and extent of recovery from anaemia in those patients where CHB was discontinued.

PATIENTS AND METHODS: Patients with prostate cancer were evaluated prospectively by physical examination and laboratory tests at baseline and at routine intervals while receiving CHB. Of 142 patients who received CHB, 133 were evaluable for the assessment of anaemia; CHB was discontinued in 76 patients, of whom 64 were assessable for recovery from their anaemia.

RESULTS: Haemoglobin levels declined significantly in all patients from a mean baseline of 149 g/L to means of 139 g/L, 132 g/L and 131 g/L at 1, 2 and 3 months, respectively. Haemoglobin levels continued to decline during CHB to a mean nadir of 123 g/L at a mean of 5.6 months of CHB, representing a mean absolute haemoglobin decline at nadir of 25.4 g/L. In 120 of the 133 (90%) patients, the relative decline in haemoglobin at nadir was > or = 10% and was > or = 25% in 17 (13%) others, representing a mean absolute haemoglobin decline in this subset of 42.7 g/L. Significant symptoms related to anaemia occurred in 17 patients (13%). Anaemia and symptoms in these patients were easily corrected with the subcutaneous administration of recombinant human erythropoietin.

CONCLUSIONS: The anaemia associated with androgen deprivation is significant and occurs routinely in men receiving CHB. It is normochromic, normocytic, temporally-related to the initiation of androgen blockade and usually resolves after CHB is discontinued. We suggest that patients receiving CHB undergo haematological testing at baseline, 1-2 months after initiating CHB and periodically thereafter. Patients developing anaemia should be questioned about symptoms reflecting physiological compromise (e.g. angina, dyspnoea on exertion). In the absence of other causes, CHB should be suspected in the development of anaemia in patients receiving this treatment.

Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.
Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L, Pierart M
University Hospital, Grenoble, France.
N Engl J Med 1997 Jul 31;337(5):295-300
Comment in: N Engl J Med 1997 Jul 31;337(5):340-1
Comment in: N Engl J Med 1997 Dec 4;337(23):1693; discussion 1694

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.

Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy.
Zelefsky MJ, Lyass O, Fuks Z, Wolfe T, Burman C, Ling CC, Leibel SA
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021-6007, USA.
J Clin Oncol 1998 Oct;16(10):3380-5

PURPOSE: To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized prostatic cancer treated with neoadjuvant androgen deprivation (NAAD) and three-dimensional conformal radiotherapy (3D-CRT).

MATERIALS AND METHODS: Between 1989 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD in these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 15.3 ng/mL (range, 1 to 560 ng/mL). The median 3D-CRT dose was 75.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years).

RESULTS: The significant predictors for improved outcome as identified in a multivariate analysis included pretreatment PSA level < or = 10.0 ng/mL(P < .00), NAAD-induced preradiotherapy PSA nadir < or = 0.5 ng/mL (P < .001), and clinical stage < or = T2c (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels < or = 10 ng/mL, 10 to 20 ng/mL, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels < or = 0.5 ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .001).

CONCLUSION: For patients treated with NAAD and high-dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with NAAD-induced PSA nadir levels greater than 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies.

Stage T1-2 prostate cancer with pretreatment prostate-specific antigen level < or = 10 ng/ml: radiation therapy or surgery?
Keyser D, Kupelian PA, Zippe CD, Levin HS, Klein EA
Department of Radiation Oncology, Cleveland Clinic Foundation, OH 44195, USA.
Int J Radiat Oncol Biol Phys 1997 Jul 1;38(4):723-9

PURPOSE: To detect differences in biochemical failure rates by treatment modality (radiation therapy or radical prostatectomy) in patients with early-stage prostate cancer presenting with pretreatment prostatic-specific antigen (PSA) levels < or = 10.0 ng/ml.

METHODS AND MATERIALS: A total of 1467 consecutive patients with prostate carcinoma were treated with either radiotherapy (RT) or radical prostatectomy (RP) between January 1987 and June 1996. Patients with the following were excluded from the present study: initial PSA (iPSA) level > 10 ng/ml (n = 444), clinical Stage T3 disease (n = 73), adjuvant or neoadjuvant treatment (n = 173), no available iPSA level (n = 31), no available biopsy Gleason score (GS) (n = 33), incomplete pathologic information (n = 16), and no available follow-up PSA levels (n = 90). The analysis was performed on 607 cases: 354 treated with RP and 253 with RT (median dose 68.4 Gy). The outcome of interest was biochemical relapse-free survival (bRFS), with biochemical relapse being defined as either a detectable PSA level after RP or elevation in PSA levels of > or = 1.0 ng/ml above the nadir after RT. Proportional hazards were used to analyze the effect of treatment modality and confounding variables (i.e., age, stage, biopsy GS, iPSA levels) on treatment outcome.

RESULTS: Seventy-nine percent of patients (n = 478) had clinical Stage T1 or T2A disease at presentation (RP vs. RT: 84% vs. 71%, p < 0.001). Twenty-one percent of patients (n = 127) had iPSA levels < or = 4 ng/ml (RP vs. RT: 24% vs. 17%, p = 0.027). Seventy-six percent of patients (n = 460) had biopsy GS < or = 6 (RP vs. RT: 79% vs. 71%, p = 0.014). The median follow-up time was 24 months (range 3-110). For the 607 patients, the 5-year bRFS rate was 76%. The 5-year RFS rates for RP versus RT were 76% versus 75%, respectively (p = 0.09). After adjustment for all confounding variables, iPSA levels (p < 0.001) and biopsy GS (p = 0.001) were the only independent predictors of relapse, whereas age, clinical stage, and treatment modality were not (p = 0.20; p = 0.09; and p = 0.10, respectively).

CONCLUSION: In patients with clinical Stage T1-2 prostate cancer and pretreatment PSA < or = 10 ng/ml, there is no difference in biochemical failure rates between those treated with radiation and those treated with surgery.

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer.
Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, Wilding G, Sears K, Culkin DJ, Thompson IM Jr, Bueschen AJ, Lowe BA
Johns Hopkins Hospital, Baltimore, MD, USA.
N Engl J Med 1998 Oct 8;339(15):1036-42

BACKGROUND: Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy.

METHODS: We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status.

RESULTS: Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease.

CONCLUSIONS: The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

Major advantages of "early" administration of endocrine combination therapy in advanced prostate cancer.
Labrie F, Dupont A, Cusan L, Gomez JL, Diamond P
Endocrine Research Clinic, CHUL Research Center, Quebec City, Quebec, Canada.
Clin Invest Med 1993 Dec;16(6):493-8

Combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or orchiectomy was administered to 268 patients with previously untreated metastatic stage D2 prostate cancer for an average of 1,191 d (3.26 y). Only 17 of the 268 evaluable patients (6.5%) showed no objective positive response to the combination therapy assessed according to the National Prostatic Cancer Project objective criteria of response. The median duration of the disease-free response was 2.23 y and median overall survival was 3.58 y. The median survival for patients with only 1-5 bone metastases was not yet reached at 8 y, but for patients with 6-10 bone lesions, 11-40 bone lesions, and multiple bone metastases (superscan), median survival was markedly reduced to 3.56, 2.36, and 1.76 y, respectively. Analysis of patients according to general symptomatology, pain, and performance status showed median survivals of 5.47, 2.71, and 2.1 y for minimal, moderate, and severe symptoms, respectively. The present data demonstrate that administration of combination therapy to stage D2 prostate cancer patients having 1-5 bone metastases adds a minimum of 4.4 y of good quality life compared with patients whose disease is slightly more advanced. Our findings clearly demonstrate the major importance of starting combination therapy as soon as possible after diagnosis of metastatic prostatic cancer.

Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center.
Denis LJ, Keuppens F, Smith PH, Whelan P, de Moura JL, Newling D, Bono A, Sylvester R
Department of Urology, A.Z. Middelheim, Antwerp, Belgium.
Eur Urol 1998;33(2):144-51

OBJECTIVES: This prospective, randomized phase III study was initiated to compare the efficacy and side effects of bilateral orchiectomy versus a combination of a luteinizing hormone-releasing hormone agonist depot formulation, goserelin acetate (3.6 mg s.c. once every 4 weeks) and flutamide (250 mg 3 x daily) in patients with metastatic prostate cancer.

METHODS: Relative treatment efficacy was assessed by comparing the two treatment groups with respect to response, time to first progression, progression-free survival, duration of survival and time to death due to malignant disease.

RESULTS: There was a difference in response only with respect to a more frequent decrease to normal of the serum prostate acid phosphatase in patients assigned to maximal androgen blockade treatment. Additionally, maximal androgen blockade treatment showed significantly better results for duration of survival (p = 0.04), time to death due to malignant disease (p = 0.008), time to first progression (p = 0.009) and progression-free survival (p = 0.02). The most frequent side effects for both treatments included hot flushes and gynaecomastia.

CONCLUSIONS: Increased time to progression and duration of survival is achieved by the combination of flutamide and goserelin when compared to bilateral orchiectomy.

Treatment with finasteride following radical prostatectomy for prostate cancer.
Andriole G, Lieber M, Smith J, Soloway M, Schroeder F, Kadmon D, DeKernion J, Rajfer J, Boake R, Crawford D, et al
Merck Research Laboratories, Rahway, New Jersey.
Urology 1995 Mar;45(3):491-7

OBJECTIVES. The objective of this study was to evaluate the effect of finasteride (10 mg/d) or placebo on serum prostate-specific antigen (PSA) and recurrence rates in men with detectable PSA levels after radical prostatectomy.

METHODS. A total of 120 men, 48 to 89 years old, previously treated with radical prostatectomy for prostate cancer within the past 10 years, with serum PSA levels between 0.6 and 10.0 ng/mL, with no evidence of skeletal metastasis on bone scan, and with no previous androgen deprivation therapy, were treated with 10 mg finasteride or placebo in a double-blind fashion for 12 months. After the first year, all patients were treated with finasteride for an additional 12 months. Primary endpoints were serum PSA levels and recurrence rates defined as positive bone scan or positive biopsy.

RESULTS. Patients treated with finasteride had a delayed increase in serum PSA compared with placebo of approximately 9 months in the first year and 14 months by the end of the second year. Patients with baseline PSA levels less then 1.0 ng/mL had no significant increase in serum PSA during the 2 years of treatment. Fewer recurrences were observed in the finasteride group, but these differences were not statistically significant. Finasteride was well tolerated, and side effects were balanced between treatment groups.

CONCLUSIONS. The results of this study indicate that treatment with finasteride delays but does not prevent the rise in serum PSA observed in untreated patients with detectable PSA levels after radical prostatectomy. The reduction in local and distant recurrences in the finasteride group suggests that the effect on PSA reflects a direct effect on tumor growth without affecting the initial response to subsequent hormonal therapy. These data require confirmation by studies that are longer and larger, focused on demonstrating significant differences in progression rates and survival before the use of finasteride can be considered as an option for men with detectable PSA levels after radical prostatectomy.

Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate.
Brufsky A, Fontaine-Rothe P, Berlane K, Rieker P, Jiroutek M, Kaplan I, Kaufman D, Kantoff P
Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Urology 1997 Jun;49(6):913-20

OBJECTIVES: Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide.

METHODS: Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride, 5 mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first and second nadir PSA values.

RESULTS: The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 +/- 38.2 ng/mL at baseline and 7.8 +/- 2.7 and 4.7 +/- 2.2 ng/mL at the first and second PSA nadir values, respectively (P = 0.034). Mean percent decline in PSA value from baseline was 87.0 +/- 3.1% with flutamide alone and 94.0 +/- 1.9% with both flutamide and finasteride (P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 +/- 14.7% of baseline (P = 0.0001), DHEA fell a mean of 32.4 +/- 4.6% (P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 +/- 6% (P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 +/- 4.7% (P = 0.0009).

CONCLUSIONS: Finasteride and flutamide were safe and well tolerated as AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.

A case for synchronous reduction of testicular androgen, adrenal androgen and prolactin for the treatment of advanced carcinoma of the prostate.
Rana A, Habib FK, Halliday P, Ross M, Wild R, Elton RA, Chisholm GD
University Department of Surgery/Urology, Western General Hospital, Edinburgh, U.K.
Eur J Cancer 1995 Jun;31A(6):871-5

The present study was undertaken mainly to investigate whether prolactin manipulation combined with maximal androgen blockage improves the effectiveness of treatment in advanced prostatic cancer. The efficacy of oral hydrocortisone as an alternative to commercial anti-androgens in reducing the adrenal androgens, and of bromocriptine in reducing the prolactin level were also examined. A consecutive series of 30 patients with untreated and advanced prostatic cancer were entered into a three-arm prospective randomised trial. 10 patients received subcapsular orchiectomy alone (arm 1), another 10 had subcapsular orchiectomy plus flutamide (arm 2), and the remaining 10 had subcapsular orchiectomy plus oral hydrocortisone and bromocriptine (arm 3). Clinical and biochemical parameters, including trans-rectal ultrasound-determined prostatic volumes, hormonal profiles and radionuclide bone scan were evaluated at regular intervals. At 12 months, serum testosterone was reduced by more than 90% in all arms, however, maximum suppression of androstenedione, prolactin, and reduction of prostatic volumes were only observed in arm 3; this was reflected by the significant improvement in clinical response in arm 3 compared with other arms. This study suggests that a combined maximal suppression of androgens and prolactin offers a significant improvement in response over conventional treatments without prolactin suppression in the treatment of advanced prostatic cancer. Importantly, a better clinical outcome in arm 3 was still apparent at the end of 36 months.

Anemia associated with advanced prostatic adenocarcinoma: effects of recombinant human erythropoietin.
Beshara S, Letocha H, Linde T, Wikstrom B, Sandhagen B, Nilsson S, Danielson BG
Department of Medicine, University Hospital, Uppsala, Sweden.
Prostate 1997 May 15;31(3):153-60

BACKGROUND AND METHODS: Nine patients with hormone-refractory metastatic prostatic adenocarcinoma and anemia were treated with recombinant human erythropoietin (rHuEpo) at a median dose of 150 U/kg BW 3 times a week subcutaneously. Baseline hemoglobin (Hb) ranged from 70 to 116 g/L, and the study duration was 12 weeks (median patient participation period was 8 weeks).

RESULTS: Four patients demonstrated a median Hb increase of 20 g/L and were considered responders. Three patients showed a median increase of 17 g/L but required blood transfusion once, and were therefore considered as partial responders. Baseline erythropoietic status showed a significant correlation between serum Epo and Hb. Inadequate Epo production, evaluated by the observed/predicted log Epo ratio, was found in two patients. Defective bone marrow activity, demonstrated by low transferrin receptor (TfR), and hypoferremia in spite of abundant iron stores were also shown. Hemorheological investigations showed elevated plasma viscosity.

CONCLUSIONS: Our results indicate that suppression of erythropoiesis can be mainly explained by the depressed marrow activity. The altered hemorheology might contribute to the anemia. This anemia could possibly be corrected with rHuEpo.

Recent advances on PSA and cancer growth.
Stamey TA
International Symposium on Recent Advances in Diagnosis and Treatment of Prostate Cancer
September 21-23, 1995, Quebec City, p. 14, 1995.

No abstract.

Anemia associated with androgen deprivation(AAAD) due to combination hormone blockade (CHB) responds to recombinant human erythropoietin (r hu-EPO).
Strum S, McDermed JE, Scholz MC, Tisman G, Johnson H
J Urol 157:232A 1997.

No abstract.

Intermittent androgen deprivation (IAD) with finasteride (F) during induction and maintenance permits prolonged time off IAD in localized prostate cancer (LPC).
Scholz M, Strum S, McDermed J
J Urol 161:156A, 1999.

No abstract.

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