Pretreatment Pretreatment Prostate-specific Antigen Research Articles

Race and Survival of Men Treated for Prostate Cancer on Radiation Therapy Oncology Group Phase III Randomized Trials

We assessed the impact of race on survival in men treated with external beam radiotherapy with or without hormonal therapy for localized prostate cancer in Radiation Therapy Oncology Group randomized trials. Between 1975 and 1992, 2,048 men were treated for clinically localized prostate cancer in 1 of 4 consecutive prospective phase III randomized trials. After excluding nonblack and nonwhite men 2,012 remained for analysis. Patients were included in this analysis if they were deemed evaluable and eligible for the trial, and followup information and centrally reviewed pathological results were available. Short-term hormonal therapy consisted of goserelin acetate and flutamide administered 2 months before and during radiotherapy. Long-term hormonal therapy consisted of adjuvant goserelin acetate, which was generally given for 2 years or more. Pretreatment prostate specific antigen (PSA) findings were available in 430 cases (21%), including 213 treated with radiotherapy alone, 60 treated with short-term hormonal therapy and 157 on long-term hormonal therapy. Mean pretreatment PSA was 68.8 and 35.2 ng./ml. in black and white patients, respectively. Cox proportional hazards models were used to identify the impact of previously defined risk groups on overall and disease specific survival. Multivariate analysis was done for the significance of race using a stratified Cox model. Median followup in patients treated in early and late studies exceeded 11 and 6 years, respectively. On univariate analysis black race was associated with lower overall and disease specific survival (p = 0.04, RR = 1.24 and p = 0.016, RR = 1.41, respectively). After adjusting for risk group and treatment type (with or without short-term or long-term hormonal therapy) race was no longer associated with outcome (p >0.05). The trend for a persistent difference in survival was likely due to the higher tumor burden in black men, as reflected in higher PSA. As previously reported, tumor grade (Gleason score), palpation T stage, lymph node status, pretreatment PSA and treatment type are major predictors of overall and disease specific survival. We noted no evidence that race has independent prognostic significance in patients treated for prostate cancer in Radiation Therapy Oncology Group prospective randomized trials.

Relative influence of Gleason score and pretreatment PSA in predicting survival following brachytherapy for prostate cancer

Purpose: To evaluate 10-year survival rates after prostate brachytherapy and to assess the relative importance of pretreatment prostate-specific antigen (PSA) and Gleason score in predicting cancer death. Materials and Methods: A retrospective review was performed on all patients treated with permanent brachytherapy for stage T1 or T2 primary prostate cancer at a single institution from December 1988 through June 30, 1998. The study cohort consisted of 1266 patients with a median follow-up of 4.1 years and a maximum of 12.6 years. Actuarial survival and cause-specific survival rates were calculated as the primary endpoints, and compared at 5 and 10 years. Groups studied consist of PSA≤4, PSA 4.1–10, and PSA≥10 as well as Gleason 2–4, 5–6, and 7–10. Multivariate and univariate analysis were performed looking at stage, grade, PSA, and risk group as variables. Results: The median age at the time of treatment was 73 years and at the time of analysis 603 patients were known to be alive. Overall survival is 38% at 10 years, however most deaths were unrelated to prostate cancer. Cause specific survival at 5 and 10 years is 98% and 87%. Both grade (≥Gleason 7) and PSA (≥10 ng/ml) predict adversely for cancer death within 10 years. Patients with low grade or PSA at presentation reveal prostate cancer-specific survival of 91% and 98%, respectively. By contrast, men with high grade or high PSA presentation have survival of 66% and 69% at 10 years. In multivariate analysis, the presence of one of these adverse features carries a hazard ratio of cancer death of 4.7 and 6.4, while the presence of multiple risk factors places patients in an unfavorable risk group with a hazard ratio of 27. Conclusions: Biochemical disease-free survival is a useful tool to assess prostate cancer treatments and is predicted based on established pretreatment risk groups. Long-term cancer-specific survival is ultimately a more important endpoint. Brachytherapy is reported here to be an excellent therapeutic alternative for selected early stage patients with prostate cancer. This is based on 10-year cause specific survival, which may also be predicted by stage, grade, PSA, and risk group. Of these, the risk group remains the most powerful parameter to identify those patients at highest risk of biochemical failure and death from prostate cancer.

Percentage of Positive Biopsy Cores as Predictor of Clinical Outcome in Prostate Cancer Treated With Radiotherapy.

The clinical significance of pretreatment biopsy characteristics is not well understood relative to known prognostic factors. We performed a complete pathology analysis of pretreatment biopsy specimens in an attempt to clarify their impact on clinical outcome following radiotherapy. From 1991 to 1999, 160 patients with locally advanced prostate cancer were prospectively treated with external beam radiotherapy in combination with high dose rate brachytherapy at our hospital and had pretreatment biopsy material available for complete pathological review. Patients with pretreatment prostate specific antigen (PSA) 10.0 ng./ml. or greater, Gleason 7 or greater or clinical stage T2b-T3c N0 M0 disease were eligible for study entry. Pelvic external beam radiotherapy (46.0 Gy.) was supplemented with 3 (1991 to 1995) or 2 (1995 to 1999) ultrasound guided transperineal interstitial iridium high dose rate implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy. per implant. All pretreatment biopsy specimen slides from each case were reviewed by a single pathologist (N. S. G.). Median followup was 4.2 years. Biochemical failure was defined as 3 consecutive PSA increases. On univariate analysis pretreatment PSA, Gleason score, clinical T classification, percentage of positive biopsy cores, dose per implant and total radiotherapy dose (equivalent in 2 Gy. fractions) were significantly associated with biochemical failure. Perineural invasion was of borderline significance (p = 0.07). On univariate analysis for clinical failure only Gleason score and percent positive cores were significant. Percent positive cores was associated with biochemical and clinical failure whether analyzed in subgroups or as a continuous variable. Patients with less than 33% positive cores had a 5-year biochemical control rate of 83% and 5-year clinical failure rate of only 7%. Conversely, patients with more than 67% positive cores had a 5-year biochemical control rate of only 57% and 25% had clinical failure at 5 years. Since percent positive cores correlated with biochemical and clinical failure, an analysis was performed to determine which other prognostic factors were associated with percent positive cores. Pretreatment PSA level, Gleason score, clinical T classification and perineural invasion were significantly associated with a higher percent positive cores. Nevertheless, on Cox multiple regression analysis higher percent positive cores, pretreatment PSA and Gleason score remained independently associated with biochemical failure but not T classification. On Cox multiple regression analysis for clinical failure only Gleason score remained independently significant with percent positive cores maintaining borderline significance (p = 0.07). Percent positive pretreatment biopsy cores is a powerful predictor of biochemical and clinical outcome for prostate cancer treated with radiotherapy, independent of other known prognostic factors. Percent positive cores should be seriously considered as a primary factor in risk group stratification for prostate cancer.

Dose response in prostate cancer with 8–12 years’ follow-up

Purpose: This communication reports the long-term results of the original group of prostate cancer patients who participated in the first prospective Fox Chase Cancer Center radiation dose escalation study for which 8–12 years of follow-up is now available.Methods and Materials: Between March 1, 1989 and October 31, 1992, 232 patients with clinically localized prostate cancer received three-dimensional conformal radiotherapy only at Fox Chase Cancer Center in a prospective dose-escalation study. Of these patients, 229 were assessable. The 8-, 10-, and 12-year actuarial rates of biochemical control (biochemically no evidence of disease [bNED]), freedom from distant metastasis (FDM), and morbidity were calculated. The Cox proportional hazards model was used to assess multivariately the predictors of bNED control and FDM, including pretreatment prostate-specific antigen (PSA) level (continuous), tumor stage (T1/T2a vs. T2b/T3), Gleason score (2–6 vs. 7–10), and radiation dose (continuous). The median total dose for all patients was 74 Gy (range 67–81). The median follow-up for living patients was 110 months (range 89–147). bNED control was defined using the American Society for Therapeutic Radiology and Oncology consensus definition.Results: The actuarial bNED control for all patients included in this series was 55% at 5 years, 48% at 10 years, and 48% at 12 years. Patients with pretreatment PSA levels of 10–20 ng/mL had statistically significant differences (19% vs. 31% vs. 84%, p = 0.0003) in bNED control when stratified by dose (<71.5, 71.5–75.6, and > 75.6 Gy, respectively) on univariate analysis. For the 229 patients with follow-up, 124 (54%) were clinically and biochemically without evidence of disease. Sixty-nine patients were alive at the time of last follow-up, and 55 patients were dead of intercurrent disease. On multivariate analysis, radiation dose was a statistically significant predictor of bNED control for all patients and for unfavorable patients with a pretreatment PSA <10 ng/mL. For the patients with a pretreatment PSA level of 10–20 ng/mL, the radiation dose was a statistically significant predictor across all groups. No radiation dose response was seen for those patients with a pretreatment PSA level >20 ng/mL, although large numbers of patients are required to demonstrate a difference. The radiation dose, Gleason score, and palpation T stage were significant predictors for the entire patient set, as well as for those with pretreatment PSA levels between 10 and 20 ng/mL. The FDM rate for all patients included in this series was 89%, 83%, and 83% at 5, 10, and 12 years, respectively. For patients with pretreatment PSA levels <10 ng/mL, all four covariates (radiation dose, Gleason score, pretreatment PSA, and palpation T stage) were significant predictors of distance metastasis. Using the Radiation Therapy Oncology Group morbidity scale, no difference was noted in the frequency of Grade 2 and 3 genitourinary and Grade 3 gastrointestinal morbidity when patients in this data set were stratified by radiation dose. However, a significant increase occurred in Grade 2 gastrointestinal complications as the radiation dose increased.Conclusion: The long-term results of the original Fox Chase radiation dose escalation study with >9 years of median follow-up confirm the existence of a dose response for both bNED control and FDM. The dose response in prostate cancer is real, and the absence of biochemical recurrence after 8 years demonstrates the lack of late failure and suggests cure.

Using PSA, biopsy Gleason score, clinical stage, and the percentage of positive biopsies to identify optimal candidates for prostate-only radiation therapy

Purpose: An identification of prostate cancer patients most likely to benefit from prostate-only radiation was made based upon the pretreatment prostate-specific antigen (PSA), biopsy Gleason score, clinical stage, percentage of positive biopsies, and the 5-year postoperative PSA outcome.Methods: Between 1989 and 2000, 2099 patients underwent radical prostatectomy for clinically localized prostate cancer. The primary end points were pathologic evidence of seminal vesicle invasion 2(SVI), extracapsular extension (ECE) with or without positive surgical margins, and the 5-year postoperative PSA outcome.Results: Pretreatment PSA, biopsy Gleason score, and clinical stage were used to assign patients to low-, intermediate-, and high-risk groups. These risk groups were stratified by the percentage of positive biopsies and the primary pathologic and biochemical outcomes examined. The rates of SVI, ECE with positive margin, and no biochemical evidence of disease (bNED) for low-risk patients with ≤50% positive biopsies were 2%, 7%, and 93%, respectively. Patients with >50% positive biopsies had higher rates of SVI and ECE (5% and 11%, respectively) and 52% bNED (p < 0.0001). For intermediate-risk patients with ≤17% positive biopsies, the rates of SVI, ECE with positive margin, and bNED were 3%, 9%, and 90%, respectively. As the percentage of positive biopsies increased above 17% in intermediate-risk patients, there was a statistically significant increase in SVI and ECE and a significant decrease in bNED.Conclusions: Low-risk patients with ≤50% positive biopsies and intermediate-risk patients with ≤17% positive biopsies had a very low risk of SVI and ECE with positive surgical margins. Given that the presence of SVI and ECE with positive surgical margins was uncommon (<10%) with a ≥90% PSA failure-free survival after radical prostatectomy, these patients may be optimal candidates for radiation therapy directed at the prostate only (prostate gland + 1.5-cm margin).

Independent prognostic significance of HER-2 oncoprotein expression in pN0 prostate cancer undergoing curative radiotherapy.

Existing prognostic algorithms for localized prostate cancer (PC) are hampered by poor validation for endpoints other than biochemical relapse such as clinical disease progression or survival. Therefore, the prognostic relevance of Her-2 (Her-2/neu, c-erbB2) protein expression in patients undergoing curative radiotherapy (RT) was compared to widely accepted prognostic factors such as pretreatment prostate-specific antigen (PSA) levels, biopsy Gleason score and T category of the primary tumor. Biopsies from 112 homogeneously treated patients with T1-4pN0M0 PC were examined by immunohistochemistry and 37% of cases showed membrane-bound Her-2 expression in more than 10% of cancer cells. No definite membrane staining was seen in normal prostate epithelium. With 25 patients dead of PC and a median follow-up of surviving patients of 71 months (range 48-144), the prognostic relevance of Her-2 expression was univariately associated with adverse outcome in terms of biochemical or clinical progression-free survival (B/C-PFS; p = 0.04), clinical progression-free survival (C-PFS; p = 0.02) and disease-specific survival (DSS; p = 0.02). In multivariate analysis, Her-2 expression, T category and Gleason score were independently associated with C-PFS, whereas only Her-2 expression and Gleason score were associated with DSS. Her-2 expression and Gleason score together discriminated 2 groups of patients with 5-year DSS of 95% and 79%, respectively (p < 0.001). Pretreatment PSA levels were associated only with B/C-PFS but not with C-PFS or DSS. Together the data show for the first time that expression of Her-2 is of prognostic relevance in localized PC undergoing RT and suggest that analysis for Her-2 may improve prognostic algorithms for clinically relevant endpoints other than biochemical relapse.

Relationship between percent positive biopsies and biochemical outcome after permanent interstitial brachytherapy for clinically organ-confined carcinoma of the prostate gland

Purpose : Recently, the percentage of positive prostate biopsies has been reported to be statistically significant in predicting the biochemical outcome after either radical prostatectomy or 3-dimensional conformal external beam radiotherapy. In this study, we evaluated the impact of the percentage of positive prostate biopsies in predicting the 5-year biochemical outcome for patients with clinically organ-confined prostate cancer undergoing permanent interstitial brachytherapy. Methods and Materials : Two hundred sixty-two hormone naive patients underwent transperineal ultrasound-guided permanent prostate brachytherapy with generous periprostatic margins, using either 103Pd or 125I for clinical T1b/T2b NXM0 (1997 AJCC) adenocarcinoma of the prostate gland from April 1995 to October 1999. No patient was lost to follow-up. The actual percentage of positive biopsies (number of positive biopsies/total number of biopsies) was determinable for 255 of the 262 patients. Of the evaluated cases, 133 patients were implanted with 103Pd and 122 patients with 125I. The median patient age was 68 years (range 48–81). The median follow-up was 38.6 months (range 6–73). Follow-up was calculated from the day of implantation. Patients were stratified by the percentage of positive biopsies into the following groups: <34%, 34–50%, and >50%. Additional clinical parameters evaluated included patient age, clinical T-stage, Gleason score, pretreatment prostate specific antigen (PSA), risk group, and prostate volume. Low-risk patients were staged as clinical T1c/T2a, Gleason score ≤6, and pretreatment PSA ≤10 ng/mL, intermediate-risk patients presented with one unfavorable prognostic parameter, and high-risk patients presented with two or more unfavorable prognostic parameters (clinical stage T2b, PSA >10 ng/mL, Gleason score ≥7). Treatment parameters included the use of supplemental external beam radiation and choice of isotope. Biochemical disease-free survival was defined by the American Society of Therapeutic Radiation and Oncology consensus definition. Results : For the 255 evaluated patients, the 5-year actuarial biochemical no evidence of disease survival rate was 92.5%. For patients with low, intermediate, and high-risk disease, 95.8%, 98.1%, and 79.4% of patients were free of biochemical failure, respectively. When each risk group was stratified into the percent positive biopsy categories of <34%, 34–50%, and >50%, no statistical difference was found in biochemical outcome for the biopsy subgroups. In multivariate analysis, none of the clinical or treatment parameters predicted for failure in the low-risk group; only Gleason score was predictive for intermediate-risk patients and only PSA for high-risk patients. In the overall population, PSA and Gleason score were both found to be predictors of biochemical failure, but not risk group, clinical stage, or percentage of positive biopsies. There was no significant dependence between the percent positive biopsy group and the Kaplan-Meier biochemical survival rates for any of the various subgroups of clinical and treatment parameters, except for clinical stage T1c-T2a ( p = 0.006). The median postimplant PSA was 0.2 ng/mL for patients with either low-risk disease or <34% positive biopsies and 0.1 ng/mL for all other risk groups or percent positive biopsy subgroups. Conclusion : Although a significant trend was found for biochemical failure with increasing percent positive biopsies in the overall population, our results suggest that the percentage of positive biopsies is not statistically significant in predicting the 5-year biochemical disease-free outcome for patients with low, intermediate, and high-risk disease undergoing permanent prostate brachytherapy. Only the Gleason score in intermediate-risk patients and the pretreatment PSA level in high-risk patients was predictive of biochemical failure. We believe this relative lack of significance for the percentage of positive biopsies is a result of dose escalation far exceeding other radiotherapy modalities and the ability to aggressively treat the periprostatic region compared with radical prostatectomy by way of the accurate placement of periprostatic seeds.

PREDICTING RISK OF PROSTATE SPECIFIC ANTIGEN RECURRENCE AFTER RADICAL PROSTATECTOMY WITH THE CENTER FOR PROSTATE DISEASE RESEARCH AND CANCER OF THE PROSTATE STRATEGIC UROLOGIC RESEARCH ENDEAVOR DATABASES

Biostatistical models to predict stage or outcome in patients with clinically localized prostate cancer with pretreatment prostate specific antigen (PSA), Gleason sum on biopsy or prostatectomy specimen, clinical or pathological stage and other variables, including ethnicity, have been developed. However, to date models have relied on small subsets from academic centers or military populations that may not be representative. Our study validates and updates a model published previously with the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE, UCSF, Urology Outcomes Research Group and TAP Pharmaceutical Products, Inc.), a large multicenter, community based prostate cancer database and Center for Prostate Disease Research (CPDR), a large military database. We validated a biostatistical model that includes pretreatment PSA, highest Gleason sum on prostatectomy specimen, prostatectomy organ confinement status and ethnicity, including white and black patients. We then revised it with the Cox regression analysis of the combined 503 PSA era surgical cases from the CPDR prospective cancer database and 1,012 from the CaPSURE prostate cancer outcomes database. The original equation with 3 risk groups stratified CaPSURE cases into distinct categories with 7-year disease-free survival rates of 72%, 42.1% and 27.6% for low, intermediate and high risk men, respectively. Parameter estimates obtained from a Cox regression analysis provided a revised model equation that calculated the relative risk of recurrence as: exponent (exp)[(0.54 x Race) + (0.05 x sigmoidal transformation of PSA [PSA(ST)]) + (0.23 x Postop Gleason) + (0.69 x Pathologic stage). The relative risk of recurrence, as calculated by the aforementioned equation, was used to stratify the cases into 4 risk groups. Very low-4.7 or less, low-4.7 to 7.1, high-7.1 to 16.7 and very high-greater than 16.7, and patients at risk had 7-year disease-free survival rates of 85.4%, 66.0%, 50.6% and 21.3%, respectively. With a broad cohort of community based, academic and military cases, we developed an equation that stratifies men into 4 discrete risk groups of recurrence after radical prostatectomy and confirmed use of a prior 3 risk group model. Although the variables of ethnicity, pretreatment PSA, highest Gleason sum on prostatectomy specimen and organ confinement status on surgical pathology upon which the model is based are easily obtained, more refined modeling with additional variables are needed to improve prediction of intermediate risk in individuals.

Prognostic value of neuroendocrine serum markers and PSA in irradiated patients with pN0 localized prostate cancer.

The prognosis of patients with localized prostate cancer depends on clinical stage, histological grade, and pretreatment prostate-specific antigen (PSA). We evaluated the additional prognostic impact of serum levels of neuron-specific enolase (NSE) and chromograninA (CgA) after curative radiotherapy and the importance of serum PSA, analyzed 3 months after irradiation. From 1988 to 1995, 161 patients with localized T1-4, pN0M0, prostate adenocarcinoma were treated with external radiation (66Gy, 2Gy/5 fractions per week). Frozen serum samples were assessed for CgA, NSE, and PSA before and 3 months after radiotherapy. CgA was analyzed in only 100 patients. NSE and CgA were determined by a immunometric assay. Total PSA was measured by a time-resolved fluoro-immunometric assay. Prior to radiotherapy CgA was elevated in 16 of 100 patients, and NSE was elevated in 33 of the 161 patients. There was no association between grade, T category or pretreatment PSA and the levels of neuroendocrine markers. Pretreatment-elevated serum NSE, but not initial CgA, identified patients with an unfavorable prognosis. A < 50% reduction of PSA 3 months after radiotherapy was associated with decreased failure-free 10 years urvival. Multivariate analysis demonstrated an increased risk of failure for patients with elevated pretreatment NSE and PSA values, T3 category, and decline of PSA less than 50% 3 months after radiotherapy. The presence of none or several risk factors (1-4) defined clearly separable groups. Together with T category and pretreatment serum PSA values, serum NSE values before radiotherapy and decrease of serum PSA 3 months after radiotherapy represent easily assessable prognostic parameters in patients undergoing curative radiation treatment for prostate cancer.

Defining the optimal radiation dose with three-dimensional conformal radiation therapy for patients with nonmetastatic prostate carcinoma by using recursive partitioning techniques.

The objective of this study was to determine the effect of dose and its interaction with known prognostic variables, including pretreatment prostate specific antigen (PSA), Gleason score (GS), and T classification, on patients with nonmetastatic prostate carcinoma treated with three-dimensional conformal radiation therapy (3DCRT) alone using recursive partitioning analysis. Between November 1987 and November 1997, 939 patients with nonmetastatic prostate carcinoma were treated with 3DCRT alone at Fox Chase Cancer Center. Biochemical no evidence of disease (bNED) control was defined using the American Society of Therapeutic Radiology and Oncology Consensus definition. Recursive partitioning analysis was used to identify subgroups with similar risks of bNED failure. Prognostic factors used in the model included pretreatment PSA, GS, T classification, and radiation dose. The median follow-up was 47 months (range, 2-133 months). Twelve terminal nodes of the decision tree were merged to form four prognostic groups with similar bNED control rates. The 5-year actuarial rates of bNED control rates for Groups I, II, III, and IV were 84%, 41%, 16%, and 67%, respectively (P < 0.0001). Increasing the dose to greater than 7235 centigray (cGy) improved bNED control rates for patients with PSA levels of 10-19.9 ng/mL and T1/2a classification disease. Increasing the dose to greater than 7629 cGy improved bNED control rates for patients with T2b/3 classification disease with PSA levels less than 20 ng/mL. Patients with PSA levels greater than or equal to 20 ng/mL need high-dose 3DCRT. For those patients with GS 2-6 and T1/2a classification disease, treatment with greater than 7400 cGy resulted in 67% bNED control rate versus 16% at 5 years for treatment with less than 7400 cGy. High radiation dose (> 7700 cGy) improved bNED control rate from 16% to 41% for patients with high-risk disease (PSA > or = 20 ng/mL and GS 7-10) at 5 years. The authors showed that with recursive partitioning techniques radiation dose continues to be an important predictor of bNED control rate and that a radiation dose response for patients with clinically localized prostate carcinoma exists. Patients with one or more prognostic feature (PSA > 10 ng/mL, classification T2b/T3, GS 7-10, or the presence of perineural invasion) achieve similar rates of bNED control compared with those patients with lower volume disease when radiation dose is increased.

External beam radiotherapy dose response characteristics of 1127 men with prostate cancer treated in the PSA era

Purpose: To characterize the relationship of radiotherapy dose to prostate cancer patient outcome, with an emphasis on the influence of pretreatment prognostic variables. Methods and Materials: The 1127 Stage T1–T4 prostate cancer patients examined were treated consecutively with definitive external beam radiotherapy at the University of Texas–M.D. Anderson Cancer Center from 1987 to 1997. All had a pretreatment prostate-specific antigen (PSA) level. Treatment failure was defined as two consecutive PSA elevations on follow-up. There were 994 patients treated with a four-field box throughout to 60–70 Gy after a small reduction at 46 Gy and 161 treated with a six-field conformal boost after 46 Gy to 74–78 Gy. No patient received neoadjuvant or adjuvant androgen ablation. Median follow-up was 51.8 months. Results: Patients were divided into three radiotherapy dose groups consisting of ≤67 Gy ( n = 500), >67–77 Gy ( n = 495), and >77 Gy ( n = 132). Relative to other prognostic factors, there were fewer patients treated to the highest dose level with a pretreatment PSA (PSAB) ≤4 or >20 ng/ml, Stage T3/T4 disease, or a Gleason score of 2–6. Actuarial 4-year freedom from biochemical failure (bNED) rates for the entire cohort were 54%, 71%, and 77% ( p < 0.0001) for the low-, intermediate-, and high-dose groups. PSAB, palpable stage, and Gleason score were also highly significant. In Cox proportional hazards regression, dose ( p < 0.0001 as a continuous or categorical variable) was an independent predictor of bNED, as were the other prognostic factors. Pairwise univariate comparisons showed that an increase in dose from ≤67 Gy to >67–77 Gy was associated with improved bNED rates for all PSAB (≤10 and >10), stage (T1/T2 and T3/T4), and Gleason score (2–6 and 7–10) subgroups tested. In contrast, the only prognostic group that benefited from raising dose from >67–77 Gy to >77 Gy was patients with a PSAB >10 ng/ml; although trends were noted for Stage T1/T2 and Gleason 2–6 patients. Patients with the combined features of a PSAB >10 ng/ml and Stage T1/T2 disease had 4-year bNED rates of 61% and 93% at the intermediate- and high-dose levels. A strongly significant linear association between dose (60–78 Gy) and 4-year actuarial bNED was demonstrated for patients with these intermediate-risk features. Conclusion: Prostate cancer dose response to external beam radiotherapy should be considered in the context of pretreatment prognostic factors. Our data indicate that, for favorable patients with a PSAB of ≤10 ng/ml, intermediate doses of >67–77 Gy provide the same rate of control as higher doses. However, longer follow-up may reveal a benefit to dose escalation >77 Gy, even in this favorable subset. Substantial and clinically relevant enhancements in bNED were seen at all dose levels for moderate-risk patients, such as those having a PSAB >10 ng/ml and Stage T1/T2 disease. Sustained bNED was not realized for high-risk patients, even using 78 Gy; these patients may be best treated with higher doses, whole pelvic irradiation, and/or androgen ablation plus radiation.

Matched-Pair Analysis of Conformal High–Dose-Rate Brachytherapy Boost Versus External-Beam Radiation Therapy Alone for Locally Advanced Prostate Cancer

We performed a matched-pair analysis to compare our institution's experience in treating locally advanced prostate cancer with external-beam radiation therapy (EBRT) alone to EBRT in combination with conformal interstitial high-dose-rate (HDR) brachytherapy boosts (EBRT + HDR). From 1991 to 1998, 161 patients with locally advanced prostate cancer were prospectively treated with EBRT + HDR at William Beaumont Hospital, Royal Oak, Michigan. Patients with any of the following characteristics were eligible for study entry: pretreatment prostate-specific antigen (PSA) level of >/= 10.0 ng/mL, Gleason score >/= 7, or clinical stage T2b to T3c. Pelvic EBRT (46.0 Gy) was supplemented with three (1991 through 1995) or two (1995 through 1998) ultrasound-guided transperineal interstitial iridium-192 HDR implants. The brachytherapy dose was escalated from 5.50 to 10.50 Gy per implant. Each of the 161 EBRT + HDR patients was randomly matched with a unique EBRT-alone patient. Patients were matched according to PSA level, Gleason score, T stage, and follow-up duration. The median PSA follow-up was 2.5 years for both EBRT + HDR and EBRT alone. EBRT + HDR patients demonstrated significantly lower PSA nadir levels (median, 0.4 ng/mL) compared with those receiving EBRT alone (median, 1.1 ng/mL). The 5-year biochemical control rates for EBRT + HDR versus EBRT-alone patients were 67% versus 44%, respectively (P <.001). On multivariate analyses, pretreatment PSA, Gleason score, T stage, and the use of EBRT alone were significantly associated with biochemical failure. Those patients in both treatment groups who experienced biochemical failure had a lower 5-year cause-specific survival rate than patients who were biochemically controlled (84% v 100%; P <.001). Locally advanced prostate cancer patients treated with EBRT + HDR demonstrate improved biochemical control compared with those who are treated with conventional doses of EBRT alone.

External beam radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma

The current study was conducted to evaluate the combination of external beam radiation therapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma. Twenty-six patients were treated on a Phase I/II protocol between June 1990 and April 1993. The median age of the patients was 69 years. Nine patients had well differentiated adenocarcinoma, ten patients had moderately differentiated adenocarcinoma, and six patients had poorly differentiated adenocarcinoma. All patients had American Urologic Society Stage C2-D1 adenocarcinoma. The median pretreatment prostate specific antigen (PSA) level was 29 ng/mL (range, 6-104 ng/mL). All patients received external beam radiation therapy using a four-field technique. The median radiation dose was 6,800 centigrays (cGy) given in 200-cGy fractions. Hyperthermia was administered concurrently with radiation therapy to temperatures of 42.5 degrees C for 30 minutes using a transrectal ultrasound applicator with 3 thermometry probes, given as either a single treatment (9 patients) or as two treatments (17 patients). Overall survival (OS) and biochemical no evidence of disease (bNED) status were calculated using Kaplan-Meier analysis. A consensus conference definition of PSA failure was used. The Cox proportional hazards model was used for multivariate analysis. The median follow-up for all patients was 71 months. The median time to PSA nadir was 15 months with a median PSA nadir value of 1.0 ng/mL. The median and 5-year OS was 88 months and 73%, respectively, and the median and 5-year bNED survival was 36 months and 35%, respectively. Multivariate analysis revealed only the pretreatment PSA level (P = 0.03) and the PSA nadir reached (P < 0.01) to be significant predictors of bNED survival. The duration of hyperthermia therapy showed a trend toward significance for OS (P = 0.06). The current Phase I/II protocol evaluating the combination of prostate hyperthermia and external beam radiation therapy for the treatment of patients with locally advanced prostate carcinoma suggests prostate hyperthermia to be feasible with no apparent significant increased toxicity, although there was no significant improvement in treatment outcome when compared with other studies reported in the literature evaluating external beam radiation therapy with or without androgen suppression. However, further investigation into the duration as well as the temperature of the hyperthermia with a greater number of patients is warranted.

Defining the appropriate radiation dose for pretreatment PSA ≤ 10 ng/mL prostate cancer

Purpose: To investigate whether a dose response exists for biochemical no evidence of disease (bNED) control in prostate cancer patients with pretreatment prostate-specific antigen (PSA) ≤ 10 ng/mL and to identify the patient subgroups affected. Methods and Materials: Between 5/89 and 10/97, 488 T1–T3 NX-0 M0 prostate cancer patients with PSA ≤ 10 ng/mL were treated with three-dimensional conformal radiation therapy (3D-CRT) alone. Median and mean pretreatment PSA values were 6.3 and 6.2, respectively. Gleason scores of 2–6 and 7–10 were noted in 386 and 102 men, respectively. AJCC 1992 palpation T1–T2AB tumors were noted in 415 patients. Perineural invasion (PNI) was noted in 60 men. Mean and median age was 67 and 68 years, respectively. Dose to the center of the prostate ranged from 6260 cGy to 8409 cGy with a mean and median of 7423 cGy and 7278 cGy, respectively. Patients were stratified into three groups according to dose: <7250 cGy, 7250–7599 cGy, and ≥7600 cGy. Median dose in these three groups was 7067 cGy, 7278 cGy, and 7734 cGy, respectively. Univariate analysis was performed to determine differences in bNED control (American Society for Therapeutic Radiology and Oncology [ASTRO] Consensus Guidelines definition of failure) by dose group for the entire cohort, for 310 good prognosis patients (T1–T2A, Gleason score 2–6, absence of PNI), and for 178 poor prognosis patients (T2B–T3 or Gleason score 7–10 or presence of PNI) (1). Multivariate analysis (MVA) was performed to determine if dose was an independent predictor of bNED control. Median follow-up was 36 months. Results: A dose response was not demonstrated for the entire group of patients with pretreatment PSA ≤10 ng/mL. Doses of <7250 cGy, 7250–7599 cGy, and ≥7600 cGy were associated with 5-year bNED control rates of 73%, 86%, and 89%, respectively ( p = 0.12). MVA demonstrated prognosis group ( p = 0.038) to be the only independent predictor of bNED control. Good prognosis patients had a 5-year bNED of 85% and no dose response was seen. The subgroup of poor prognosis patients demonstrated a 5–year bNED control rate of 81% and a dose response was seen for those receiving ≥7600 cGy, compared to the two lower dose groups (94% vs. 75% vs. 70%; p = 0.0062). MVA for the poor prognosis subset demonstrated dose ( p = 0.01) to be the only independent predictor for improved bNED control. Conclusions: The poor prognosis subset of PSA ≤10 ng/mL prostate cancer patients benefit from dose escalation. A dose response is not demonstrated for prostate cancer patients with pretreatment PSA ≤10 ng/mL and other favorable features.

Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont Phase II dose-escalating trial

Purpose: We analyzed our institution’s experience treating patients with unfavorable prostate cancer in a prospective Phase II dose-escalating trial of external beam radiation therapy (EBRT) integrated with conformal high-dose-rate (HDR) brachytherapy boosts. This interim report discusses treatment outcome and prognostic factors using this treatment approach. Methods and Materials: From November 1991 through February 1998, 142 patients with unfavorable prostate cancer were prospectively treated in a dose-escalating trial with pelvic EBRT in combination with outpatient HDR brachytherapy at William Beaumont Hospital. Patients with any of the following characteristics were eligible: pretreatment prostate-specific antigen (PSA) ≥ 10.0 ng/ml, Gleason score ≥ 7, or clinical stage T2b or higher. All patients received pelvic EBRT to a median total dose of 46.0 Gy. Pelvic EBRT was integrated with ultrasound-guided transperineal conformal interstitial iridium-192 HDR implants. From 1991 to 1995, 58 patients underwent three conformal interstitial HDR implants during the first, second, and third weeks of pelvic EBRT. After October 1995, 84 patients received two interstitial implants during the first and third weeks of pelvic EBRT. The dose delivered via interstitial brachytherapy was escalated from 5.50 Gy to 6.50 Gy for each implant in those patients receiving three implants, and subsequently, from 8.25 Gy to 9.50 Gy per fraction in those patients receiving two implants. To improve implant quality and reduce operator dependency, an on-line, image-guided interactive dose optimization program was utilized during each HDR implant. No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 2.1 years (range: 0.2–7.2 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. Results: The pretreatment PSA level was ≥ 10.0 ng/ml in 51% of patients. The biopsy Gleason score was ≥ 7 in 58% of cases, and 75% of cases were clinical stage T2b or higher. Despite the high frequency of these poor prognostic factors, the actuarial biochemical control rate was 89% at 2 years and 63% at 5 years. On multivariate analysis, a higher pretreatment PSA level, higher Gleason score, higher PSA nadir level, and shorter time to nadir were associated with biochemical failure. In the entire population, 14 patients (10%) experienced clinical failure at a median interval of 1.7 years (range: 0.2–4.5 years) after completing RT. The 5-year actuarial clinical failure rate was 22%. The 5-year actuarial rates of local failure and distant metastasis were 16% and 14%, respectively. For all patients, the 5-year disease-free survival, overall survival, and cause-specific survival rates were 89%, 95%, and 96%, respectively. The 5-year actuarial rate of RTOG Grade 3 late complications was 9% with no patient experiencing Grade 4 or 5 acute or late toxicity. Conclusion: Pelvic EBRT in combination with image-guided conformal HDR brachytherapy boosts appears to be an effective treatment for patients with unfavorable prostate cancer with minimal associated morbidity. Our dose-escalating trial will continue.

African American Men with Prostate Cancer Treated by Simultaneous Irradiation

Objectives: Reportedly, African American men (AAM) with prostate cancer present with more advanced disease and have worse outcomes than white men (WM). We evaluate this concept in our series of men with prostate cancer treated with modern simultaneous irradiation in a busy private practice. Materials and Methods: From 1993 to 1998, 1270 men with clinical stage T1T2N0 prostate cancer were treated by ultrasound-guided transperineal implantation of I-125 in the prostate and seminal vesicle (median dose 12,000 cGy) followed by external-beam radiation therapy (4500 cGy) including an additional 750 cGy seminal vesicle boost in men with adverse prognostic factors. None received neoadjuvant or adjuvant hormone therapy. The median pretreatment prostate specific antigen (PSA) level for 141 AAM and 1129 WM was 8.6 ng/ml and 7.1 ng/ml, respectively, a significant difference (p = 0.0001). Disease freedom is defined as achievement and maintenance of a PSA nadir of ≤ 0.2 ng/ml. The median follow-up is 24 months (range 12–66 months). Results: Disease-free survival for the entire group is 89% (± 3%) at 5 years. Overall, or when analyzed by stage, Gleason score, or age, AAM present with higher pretreatment PSA levels than WM. However, according to pretreatment PSA groups of ≤ 4.0 ng/ml, 4.1–10.0 ng/ml, 10.1–20.0 ng/ml, and > 20.0 ng/ml, the 5-year disease-free survival rates for AAM and WM in these groups are 100% and 95%, 85% and 92%, 67% and 80%, 76% and 83%, respectively. No significant difference in disease freedom is observed within the above PSA groups or by analysis of Gleason score or stage. With disease freedom as an end point, race is not a significant factor on multivariate analysis. Conclusions: AAM present with higher pretreatment PSA levels than WM both overall and when stratified by stage, Gleason score, or age. In this series, however, disease-free survival rates of AAM and WM are not significantly different overall or according to pretreatment variables. Thus, race does not appear to be an adverse prognostic factor after simultaneous irradiation.

Defining biochemical cure for prostate carcinoma patients treated with external beam radiation therapy.

The authors retrospectively reviewed their institution's long term experience with conventional external beam radiation therapy (RT) for localized prostate carcinoma to identify criteria associated with long term biochemical cure. Between January 1987 and December 1994, 871 patients were treated with external beam RT alone for clinically localized prostate carcinoma at William Beaumont Hospital, Royal Oak, Michigan. All patients received only external beam RT to a median total dose of 66.6 grays (Gy) (range, 59.4-70.4 Gy). No patient received hormonal therapy unless treatment failure was documented. The median follow-up was 5.0 years (range, 0. 2-11.8 years). Biochemical failure was defined according to the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. In the entire study group, 380 patients experienced biochemical failure at a median interval of 1.5 years after the completion of RT. The 5-year and 7-year actuarial rates of biochemical control were 50% and 48%, respectively. On multivariate analysis, a higher pretreatment prostate specific antigen (PSA) level, higher Gleason score, higher clinical T classification, higher nadir level, and shorter time interval to nadir all were associated significantly with biochemical failure (P < 0.001). The median intervals to biochemical failure for patients with pretreatment PSA levels </= 3.9 ng/mL, 4.0-19.9 ng/mL, and >/= 20.0 ng/mL were 2.2 years, 1.5 years, and 1.2 years, respectively (P < 0. 001). The median intervals to biochemical failure for patients with Gleason scores of 2-4, 5-7, and 8-10 were 1.8 years, 1.5 years, and 1.1 years, respectively (P < 0.001). Only 6 patients failed beyond 5 years after treatment even though 136 patients were at risk for failure beyond this point. When restricting analysis to 643 patients (74%) with >/= 3 years of PSA follow-up, the median nadir level for biochemically controlled patients was 0.6 ng/mL and occurred at a median interval of 1.9 years after RT versus a median nadir level of 1.3 ng/mL (P = 0.002) occurring at a median interval of 1.0 years (P < 0.001) in those patients who experienced biochemical failure. Patients were divided into subgroups based on their PSA nadir level and time to nadir. The 5-year actuarial biochemical control rates for patients with nadir values of </= 0.4 ng/mL, 0.5-0.9 ng/mL, 1. 0-1.9 ng/mL, 2.0-3.9 ng/mL, and >/= 4.0 ng/mL were 78%, 60%, 50%, 20%, and 9%, respectively (P < 0.001). The 5-year actuarial biochemical control rates for patients who reached their nadir at < 1.0 years, 1.0-1.9 years, 2.0-2.9 years, and >/= 3.0 years were 30%, 52%, 64%, and 92%, respectively (P < 0.001). All 52 patients who achieved a nadir of </= 0.4 ng/mL and required >/= 2.0 years to reach this nadir had biochemically controlled disease. These results suggest that a patient has a high likelihood of biochemical cure after treatment for prostate carcinoma with conventional doses of external beam RT if he has not demonstrated biochemical failure within 5 years of treatment. Patients with lower pretreatment PSA levels and lower Gleason scores may require longer follow-up than those with less favorable characteristics to achieve the same certainty of cure. Patients who achieve a PSA nadir </= 0.4 ng/mL and require >/= 2.0 years to reach this nadir have the highest probability of cure.

Update on the treatment of prostate cancer with external beam irradiation

We review the recent changes in the radiotherapeutic management of clinically localized prostate cancer, including the implementation of three-dimensional (3-D) conformal radiation therapy (3DCRT), biochemical disease-free survival (bNED control) using conventional and 3DCRT techniques, and the morbidity of these treatment strategies. The components of 3DCRT are discussed, including patient immobilization, 3-D treatment planning, multileaf collimation, and electronic portal imaging. bNED control rates from institutions using conventional and 3DCRT techniques are compared. The gastrointestinal (GI) and genitourinary (GU) morbidity from prospective trials using conventional doses of radiation are compared to data from 3DCRT series. bNED control rates stratified by pretreatment prostate-specific antigen (PSA) are compared between surgical and radiation series. bNED control rates (3-5 years) for patients treated with conventional and 3DCRT techniques ranged from 44-70% and 30-72% with pretreatment PSA levels 4-10 and 10-20, respectively. Although direct comparisons are difficult between treatment modalities, no difference in bNED control stratified by pretreatment PSA was observed between surgical and radiation patients. Patients with clinically localized prostate cancer treated with 3DCRT demonstrate durable bNED control at 5 years. Conformal radiation techniques, multileaf collimation, electronic portal imaging, and patient immobilization have reduced acute and chronic GI and GU morbidity while allowing safe dose escalation in an effort to further improve local control and overall survival.

Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy.

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). 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). 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). 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.

Age-Related Prostate Cancer Metastases

Objectives. Metastatic prostate cancer results in significant patient morbidity, health care expenditure, and ultimately in mortality. We sought to identify patient and treatment factors predictive of distant metastases in patients completing external beam radiotherapy. Methods. Five hundred sixty-seven patients completing external beam radiotherapy at Fox Chase Cancer Center, Philadelphia, Pennsylvania between March 1987 and November 1994 for Stage T1 to T3 tumors were analyzed. Distant metastases were detected by radionuclide bone scans. Estimates of rates for distant metastases as a first failure were conducted using cumulative incidence methods and predictors of failure were analyzed univariately and multivariately. Results. The median follow-up was 46 months. On univariate analysis, the following were statistically significant predictors of distant metastases at 5 years: patient age greater than 65 years, pretreatment prostate-specific antigen (PSA) level, advanced stage, lower radiation dose, and Gleason score 7 to 10. Multivariate testing confirmed that age greater than 65 years, high pretreatment PSA level, lower radiation dose, and advanced stage were significant independent predictors of distant metastases. Conclusions. Men over the age of 65 years are more likely to experience distant failure than are younger men. The discovery of age-related differences in patterns of failure has significant therapeutic implications with regard to patient selection, trial design, and adjuvant therapy recommendations. Furthermore, age-related differences in failure may influence comparison of outcome data for radiotherapy series, which tend to have older patients, to surgical reports that usually include significantly younger men.