|
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.
ADAMICO@JCRT.dfci.harvard.edu
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.
zelefskm@mskcc.org
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.
|