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Prostate specific antigen levels during radical radiation therapy and the
prediction of outcome in localized carcinoma of the prostate.

The use of prostate-specific antigen (PSA) for the monitoring of
radiation therapy in prostate cancer.

Kinetics of serum prostate-specific antigen after external beam radiation
for clinically localized prostate cancer.

Fifteen-year survival and recurrence rates after radiotherapy for
localized prostate cancer.

Analyzing Predictive Models following Definitive Radiotherapy for Prostate Carcinoma (Movsas)

AU - McLean M; Panzarella T; Warde PR; Gospodarowicz M; Duncan W; Catton C;
Bissett R

TI - Prostate specific antigen levels during radical radiation therapy and the
prediction of outcome in localized carcinoma of the prostate.
SO - Clin Oncol (R Coll Radiol) 1997;9(4):226-33
AD - Princess Margaret Hospital/University of Toronto, Ontario, Canada.
AB - There has been substantial interest in the effect of radiation
therapy upon serum prostate specific antigen (PSA) levels in patients
managed by radiation therapy and their ability to predict the
eventual outcome. At our institute, an observational prospective
longitudinal study was begun in 1989 to identify prognostic factors
for biochemical relapse from among several variables, including PSA
levels measured prior to treatment, during treatment, and post-
treatment, and to summarize what happens to PSA levels over the
course of treatment with radical radiation therapy. A total of 142
patients with adenocarcinoma of the prostate (T1-4, N0, M0) were
radically irradiated (6-7 weeks) between February 1989 and January
1991. Serum PSA levels were recorded weekly during radiation therapy
in 117 patients. Of these 117, weekly PSA measurements ranged in
completeness from 95 to 113 cases. A number of statistical tests were
performed on the data with investigative/ exploratory intent. There
were 60 biochemical relapses documented in the whole group of 142
patients, with a maximum follow-up of 4.6 years and median follow-up
of 3.3 years. Of the candidate prognostic variables tested by
univariate analysis, the following emerged as statistically
significant (i.e. P < 0.05): each of the four pretreatment factors
(absolute PSA value, dichotomous PSA (normal versus above normal), T
category and Gleason score); the treatment variables namely, the
end-of-treatment PSA, the slope of PSA, and the absolute change in
PSA from pretreatment to the end of treatment; and, among post-
treatment variables, the first follow-up PSA, the absolute change in
PSA from pretreatment to first follow-up, and the return to normal of
an above-normal pretreatment PSA by first follow-up. The majority of
these factors were then subjected to multivariate Cox proportional
hazards (PH) regression analyses. The end-of-treatment PSA and T
category were consistently identified as independently statistically
significant factors associated with biochemical relapse. The Gleason
score was selected less consistently, and never when defined on a
categorical scale. Therefore, using a Cox PH model with the variables
of end-of-treatment PSA and T category, both defined on a categorical
scale, we developed three prognostic groups with good, intermediate
and poor prognoses (chi 2 TREND = 40.7; P < 0.0001). Their 3-year
biochemical relapse-free rates, for example, were: 91%, (standard
error (SE) 5%); 64% (SE 9%); and 24% (SE 6%), respectively. However,
substitution of the baseline value of PSA, which was also strongly
associated with outcome, and using the data from all 142 patients,
provided similarly distinct prognostic groups (chi 2 TREND = 41.6; P
< 0.0001), with corresponding 3-year relapse-free rates of: 92% (SE
4%); 79% (SE 7%); and 30% (SE 6%). Mean weekly PSA levels measured
during treatment were found to have a negatively sloping or
decreasing tendency. A statistically significant decrease in PSA
occurred from pretreatment to the end of treatment (t116 = 7.5; P <
0.0001); the geometric mean of the ratio of end-of-treatment PSA to
PSA at pretreatment was 0.7 (95% CI 0.6-0.8). The end-of-treatment
PSA and T category emerged as independently statistically significant
prognostic variables predicting biochemical relapse. Using the fitted
Cox PH model with these two variables, three distinct prognostic
groups were identified. The results using pretreatment PSA instead of
end-of-treatment PSA produced similarly distinct prognostic groups.
Mean weekly PSA levels measured during treatment exhibited a
decreasing tendency, and a statistically significant decrease in PSa
from pretreatment to the end of treatment was observed.

AU - Schafer U; Micke O; Hampel G; Brandt B; Bovenschulte A; Semjonow A;
Willich N

TI - The use of prostate-specific antigen (PSA) for the monitoring of
radiation therapy in prostate cancer.
SO - Anticancer Res 1997;17(4B):2983-6
AD - Klinik und Poliklinik fur Strahlentherapie-Radioonkologie, Westfalischen
Wilhelms-Universitat Munster, Germany.
AB - BACKGROUND: The classic methods for surveilling the efficacy of
radiotherapy in prostate cancer are not accurate enough. The
objective of this analysis was to determine whether prostate-specific
antigen could perform this task. MATERIALS AND METHODS: From 1/95 to
10/95, 16 patients were treated at our clinic. 7 of these underwent
primary irradiation, 4 treatment for local recurrence, and 5 had
adjuvant radiotherapy. Radiotherapy was carried out with a total dose
of 60 Gy in 30 fractions, 10 fractions per week, to the prostate bed
plus 2 cm safety margin. RESULTS: PSA levels usually start to decline
between the 3rd and the 4th week of radiotherapy with a half-life of
2.5 months. Five patients had equal or rising PSA levels, including
all three patients with recurrent tumor. DISCUSSION: In most cases,
PSA declined continuously from the 3rd week of therapy. Our median
half-life was similar to other reported results. Persisting or rising
PSA levels are an indicator for local or distant recurrence; all our
patients who developed a recurrence showed a corresponding PSA
increase.

TI - Kinetics of serum prostate-specific antigen after external beam radiation
for clinically localized prostate cancer.

SO - Radiother Oncol 1997;44(3):213-21

AU - Zagars GK; Pollack A
AD - Department of Radiation Oncology, The University of Texas, M.D. Anderson
Cancer Center, Houston, USA.
AB - BACKGROUND AND PURPOSE: To determine the kinetics of serum prostate-
specific antigen (PSA) after radiation therapy of localized prostate
cancer and to evaluate whether such kinetics provide prognostic
information. MATERIALS AND METHODS: Eight hundred forty-one men with
serial PSA determinations who underwent external beam radiation
without androgen ablation were analyzed to determine postradiation
PSA kinetic parameters (half-life and doubling time) and to correlate
these parameters with disease outcome. Non-linear regression
techniques were used to determine half-lives and doubling times.
RESULTS: The postradiation serum PSA data fitted well to first order
kinetic models. The median PSA half-life was 1.6 months (range
0.5-9.2 months). There was no correlation between half-life and
T-stage or Gleason grade. A significant but quantitatively weak
correlation was present between the pretreatment PSA level and
half-life; lower pretreatment levels were associated with longer
half-lives. Half-life did not correlate with disease outcome whether
the endpoint was local recurrence, distant metastasis or rising PSA.
In 263 men with a rising postradiation PSA profile the median PSA
doubling time was 12.2 months (range 0.8-80.2 months). Faster
doubling times were significantly associated with higher T-stage,
higher Gleason grade and higher pretreatment PSA levels. Thus,
patients with initially adverse disease developed faster rising PSA
values after treatment than patients with less adverse disease. The
most striking correlation was between rapid doubling time and the
likelihood of metastatic relapse. Patients who developed metastases
had a median PSA doubling time of 4.2 months compared to a median
doubling time of 11.7 months in patients who developed local
recurrence. Overall, patients with a PSA doubling time of less than 8
months had a 7-year actuarial metastatic rate of 54%, while patients
with a PSA doubling time exceeding 8 months had only a 7% metastatic
rate. Particularly ominous was the combination of a doubling time
shorter than 8 months which began to rise within the first year; by 3
years 50% of these men had metastases and all were actuarially
projected to develop such relapse by 6.5 years. CONCLUSIONS: Overall,
the clinical utility of postradiation serum PSA kinetics was small.
There were no discernible uses for PSA half-life. In patients with a
rising PSA profile the faster the kinetics the more adverse the
disease. Doubling times shorter than 8 months, especially if the rise
begins in the first year, predict for metastatic relapse. However, in
the absence of decisively useful treatment for metastatic prostate
cancer the virtues of the early detection of metastases remain
unclear.

AU - Eastham JA; Kattan MW; Groshen S; Scardino PT; Rogers E; Carlton CE Jr;
Lerner SP

TI - Fifteen-year survival and recurrence rates after radiotherapy for
localized prostate cancer.
SO - J Clin Oncol 1997;15(10):3214-22

AD - Scott Department of Urology and the Information Technology Program,
Baylor College of Medicine, Houston, TX 77030, USA.
AB - PURPOSE: To determine 15-year survival and recurrence rates after
radiotherapy for localized prostate cancer. METHODS: One hundred
thirty-six patients with clinically localized prostate cancer treated
from 1966 to 1974 with interstitial gold seed and external-beam
irradiation were evaluated to determine the probability of recurrence
and survival > or = 15 years after therapy. All patients were
surgically staged with pelvic lymphadenectomy and none received
hormonal therapy before relapse. RESULTS: Overall, 60 patients (44%)
have never recurred, although 57% (34 of 60) of these same patients
have died of causes other than prostate cancer. Local progression
developed in 39% of patients and distant metastases in 42%. At 15
years, the probability of dying of prostate cancer was 33%+/-8% (%
+/- 2SE) and of all causes was 72%+/-8%. In clinical stage A2 and B,
29%+/-9% of patients died of their cancer within 15 years, compared
with 57%+/-21% in stage C1, while only 18%+/-8% with clinical stage
A2 and B and negative lymph nodes died of cancer within this period.
In contrast, the prostate cancer mortality rate at 15 years was high
for patients with positive nodes regardless of the stage of the
primary tumor (73% for A2 and B; 71% for C1). Patients with nodal
metastases, poorly differentiated tumors, and advanced local disease
all had a significantly (P < .0001) increased risk of cancer death.
CONCLUSION: The cancer-specific mortality rate for patients with
stage A2 and B tumors and negative nodes compares favorably with
other series of patients treated with radiation therapy and > or = 15
years' follow-up evaluation. While local progression rates are high
and associated with a substantial risk of prostate cancer death, many
patients live with the disease and ultimately die of causes other
than prostate cancer.

Analyzing Predictive Models following Definitive Radiotherapy for Prostate Carcinoma

Benjamin Movsas, M.D.1, Alexandra L. Hanlon, M.S.1, Teruki Teshima, M.D.2, Gerald E. Hanks, M.D.1

Cancer 80:1093-102, 1997

1 Fox Chase Cancer Center, Department of Radiation Oncology, Philadelphia,
Pennsylvania. 2 Osaka University Medical School, Department of Radiation
Oncology, Osaka, Japan.

ABSTRACT

BACKGROUND. As we approach the 21st century, clinically useful predictive models for prostate carcinoma are urgently needed to stratify patients reliably for future strategies. Recently, many investigators have developed models that employ prostate specific antigen (PSA)-based constructs or groupings in an attempt to predict outcome accurately following definitive radiotherapy. This investigation was conducted to determine which of these models provides the closest "fit" to independent clinical outcome data measuring biochemical freedom from failure (bNED control), thereby warranting further exploration.

METHODS. Six models were analyzed in a definitive radiotherapy series of 421 patients with localized prostate carcinoma treated with a median dose of 74 Gray (Gy) between March 1988 and November 1994. A stepwise Cox proportional hazards multivariate analysis (MVA) was performed to predict for bNED control using the following covariates: PSA, Gleason's score, stage, dose, PSA density, and perineural invasion. Subsequent MVAs were performed for each model incorporating the new construct or prognostic groupings. The adequacy of the models was confirmed using plots of score residuals against time to bNED failure and comparisons were made used Akaike's Information Criteria (AIC) in which a smaller value corresponds to a statistically improved model based on explained variation and the number of predictors. Because PSA was distributed in a log-normal fashion in the current study population, the model-building process was duplicated using a logarithmic transformation analysis. Biochemical failure was defined as 2 consecutive elevations in the PSA 1.5 ng/mL. The median follow-up time was 34 months (range, 2-87 months).

RESULTS. Initially, the model developed by Pisansky et al. appeared the most predictive due to the parsimony in their risk estimate, which is the sole predictor of outcome, as well as its associated lowest AIC value. However, after the logarithmic transformation analysis, all the models appeared to be equally predictive of bNED outcome.

CONCLUSIONS. A plethora of accurate models for predicting outcome following definitive radiotherapy for prostate carcinoma recently have been engineered, all of which are essentially equally predictive in this data base (via a logarithmic conversion process). This analysis should be corroborated in other large radiotherapy series.