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Objectives: To assess patient-reported prostate cancer-specific quality of life 2 and 3 years after radiotherapy to the prostate in a randomized dose-escalation trial of 70 versus 78 Gy conducted from 1993 to 1998., Methods: Two years after completing radiotherapy, a questionnaire that assessed bladder, rectal, and sexual function was sent to 301 patients in the study. Three years after treatment, a second questionnaire was sent to the 175 patients with adequate follow-up., Results: Three years after radiotherapy, urinary incontinence was reported by 35% of patients, but only 6% required the use of a pad or other protective device. Patients reported increased leakage with a full bladder (urge incontinence) between the 2 and 3-year questionnaires (42% versus 50%; P = 0.03). At 3 years, 33% of patients reported rectal bleeding compared with 47% at 2 years (P = 0.006). Patients in the 78-Gy arm reported more frequent bowel movements at 3 years and less change in bowel function at 2 years than patients in the 70-Gy arm. Before radiotherapy, 84% of patients reported erections adequate for intercourse at least a few times during the previous year. After 2 and 3 years, this had decreased to 49% and 41%, respectively (P <0.02)., Conclusions: By patient-reported questionnaire, 78 Gy produced an increase in bowel movement frequency and no increase in bladder or sexual side effects at 3 years compared with 70 Gy. Comparing the results 2 and 3 years after radiotherapy, the symptoms of rectal bleeding had improved, erectile function had decreased, and urinary urge incontinence had increased.

Background: Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki-67, bcl-2, bax, and bcl-x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone., Methods: Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1-T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki-67 (MIB-1 staining; n = 106 patients), bcl-2 (n = 77 patients), bax (n = 70 patients), and bcl-x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki-67 labeling index (Ki67-LI) was available for all patients and was derived from the percentage of Ki-67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow-up. The median follow-up was 62 months., Results: High Ki67-LI (> 3.5%) expression was observed in 33% of patients, overexpression of bcl-2 was observed in 16% of patients, altered bax expression was observed in 23% of patients, and altered bcl-x expression was observed in 53% of patients. There was no correlation found between the biomarkers. Kaplan-Meier survival estimates of freedom from biochemical failure (bNED) and the log-rank test revealed significantly lower rates in association with high Ki67-LI, positive bcl-2, and altered bax staining. No correlation was observed between bcl-x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl-2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67-LI in predicting bNED., Conclusions: Abnormalities in the expression levels of bcl-2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki-67 staining and conventional clinical prognostic factors., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11230)

Purpose: A positive biopsy after external beam radiotherapy in patients free of any evidence of treatment failure is not synonymous with eventual recurrence. Although biopsy positivity is a predictor of outcome, the utility of biopsy status as a surrogate end point, the effect of radiation dose on biopsy status, and the interrelationships of these associations to prostate-specific antigen (PSA) nadir level are not well-defined. These issues were investigated in a cohort of men with Stage T1-T3 prostate cancer who were randomized to receive between 70 Gy and 78 Gy and were prospectively biopsied at about 2 years after the completion of radiotherapy (RT)., Methods and Materials: Of the 301 assessable patients in the trial, 168 underwent planned sextant or greater prostate post-RT biopsies in the absence of biochemical or clinical failure; this group constituted the study cohort. Of the 168 patients, 87 were in the 70-Gy arm and 81 in the 78-Gy arm. Biopsies were classified into four groups: negative (no tumor), atypical/suspicious cells (not diagnostic of carcinoma), carcinoma with treatment effect (CaTxEffect), and carcinoma without treatment effect (CaNoTxEffect). Any diagnosis of carcinoma in the specimen was classified as biopsy positive. Freedom from failure (FFF) included biochemical failure and/or clinical failure. Kaplan-Meier curves were calculated from the completion of RT. For those alive in the study cohort, the median follow-up was 65 months., Results: The rate of biopsy without tumor was 42%; with atypical cells, it was 28%, with CaTxEffect 21%, and with CaNoTxEffect 9%. The overall biopsy positivity rate (CaTxEffect + CaNoTxEffect) was 30%; 28% in the 70-Gy group and 32% in the 78-Gy group (p = 0.52). The distribution of PSA nadir levels was 73% 0.5-1.0, 5% >1.0-2.0, and 1% >2.0 ng/mL. Significantly more patients randomized to 78 Gy had a PSA nadir of 2.0 ng/mL., Conclusion: For patients free of treatment failure at the time of prostate biopsy 2 years after RT, the prognosis of no tumor cells was the same as that of atypical/suspicious cells and CaTxEffect was the same as CaNoTxEffect. The biopsy positivity rate was not altered by dose, suggesting that most of the outcome differences between the 70-Gy and 78-Gy groups were due to events occurring before prostate biopsy at 2 years and/or were not entirely dependent on biopsy status. Biopsy status is a strong prognostic factor, but, as an early end point, it may be misleading. PSA nadir appears to have little clinical value in patients treated to doses of >/=70 Gy who are failure free 2 years after RT.

A number of retrospective and randomized trials have studied the effect of external-beam radiation therapy (EBRT) plus androgen deprivation therapy (ADT) on locally advanced/high-risk prostate cancer. Of 6 published randomized trials that have compared EBRT plus ADT with EBRT alone, 2 have shown a highly significant overall survival benefit for EBRT plus ADT, and 2 have demonstrated an advantage for the combination in patient subsets based on Gleason score. The results from the positive trials of EBRT plus ADT versus EBRT alone, as well as a recent report of a comparison of short-term (6 months) ADT plus EBRT versus long-term (>6 months) ADT plus EBRT, suggest that short-term ADT plus EBRT preferentially lengthens the survival of patients with Gleason score 2 to 6 disease, whereas for Gleason score 8 to 10 disease, prolongation of survival requires long-term ADT plus EBRT. These data are far from clear-cut because there are factors that confound interpretation of the subgroup analyses. Retrospective data on patients with positive lymph node status support the assertion that EBRT plus ADT prolongs survival to a greater degree than either treatment given individually. The weight of the available investigations on the survival effect of EBRT plus ADT supports its use on a routine basis for patients with high-risk prostate cancer. The results with long-term ADT are much more convincing than short-term ADT, and, as a consequence, 2 to 3 years are recommended.

Purpose: A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer., Methods and Materials: A total of 305 Stage T1-T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis., Results: There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA 10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy., Conclusion: An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives >or=70 Gy to <25% should be used.

Purpose: To determine the significance of Ki-67/MIB1 staining as a marker of patient outcome for prostate cancer patients treated with radiotherapy., Experimental Design: Pretreatment archival prostate biopsy tumor tissue was available from 106 stage T1-T4 prostate cancer patients treated with external beam radiotherapy between 1987 and 1993 at M. D. Anderson Cancer Center. Diagnosis was made from prostate needle biopsy in 64 cases and from transurethral resection of the prostate (TURP) in 42 cases. All patients had a pretreatment prostate-specific antigen (PSA), and no patient had evidence of metastasis. Immunohistochemical staining for MIB1 was used to determine the percentage of Ki-67-positive tumor cells, the Ki-67 labeling index (Ki67-LI). Biochemical failure after radiotherapy was defined as three rises in PSA on follow-up. Median follow-up was 62 months., Results: The mean and median Ki67-LI for the entire cohort was 3.2 and 2.3. The mean and median Ki67-LIs for those diagnosed by needle biopsy were 3.2 and 2.3, and by TURP were 3.1 and 2.4. For all patients, mean Ki67-LI levels were significantly higher with stage T3/T4 disease, Gleason 7-10 disease, and in those that developed treatment failure. Similar relationships were observed when the Ki67-LI was dichotomized into low (< or =3.5%) and high (>3.5%) groups. Actuarial freedom from biochemical failure (bNED) when Ki67-LI was low and high was 76 and 33% at 5 years (P < 0.0001, log rank). Similar statistically significant differences were observed when the TURP and needle biopsy groups were analyzed separately. Cox proportional hazards regression showed that dichotomized Ki67-LI was an independent correlate of bNED, along with pretreatment PSA, Gleason score, and clinical stage., Conclusions: The Ki67-LI obtained from pretreatment prostate cancer tissue is a strong independent predictor of failure after radiotherapy using biochemical criteria. This prognostic factor was equally valuable for patients diagnosed by TURP or needle biopsy.

Objectives: To determine the outcome for node-positive prostate cancer treated by early androgen ablation with or without prostatic radiation., Methods: Two hundred fifty-five men with lymphadenectomy-proven pelvic nodal metastases treated with early androgen ablation alone (n = 183) or with combined ablation and radiation (n = 72) between 1984 and 1998 were retrospectively reviewed for disease outcome and survival. Post-treatment disease status was based on the prostate-specific antigen levels or on the clinical and radiographic status for patients treated before 1987. Univariate and multivariate statistics were used to determine the prognostic factors and assess the influence of radiation treatment., Results: With a median follow-up of 9.4 years, the 5, 10, and 13-year overall survival rate for those treated with early ablation alone was 83%, 46%, and 21%, respectively. The freedom from relapse or rising prostate-specific antigen rate for these patients was 41%, 25%, and 19% at 5, 10, and 13 years, respectively. Distant metastasis and local recurrence occurred with a 10-year actuarial incidence of 44% and 51%, respectively. With a median follow-up of 6.2 years, the 5 and 10-year overall survival rate for those treated with radiation and ablation was 92% and 67%, respectively. The freedom from relapse or rising prostate-specific antigen rate in these men was 91% and 80% at 5 and 10 years, respectively. The superior outcome for combined ablation and radiation was substantial and statistically significant in the univariate and multivariate analyses., Conclusions: Early androgen ablation alone has little curative potential for node-positive prostate cancer. The addition of prostatic radiation to ablation resulted in substantial and significant improvement in disease control and patient survival.

Purpose: To determine the effect of radiotherapy dose on prostate cancer patient outcome and biopsy positivity in a phase III trial., Patients and Methods: A total of 305 stage T1 through T3 patients were randomized to receive 70 Gy or 78 Gy of external-beam radiotherapy between 1993 and 1998. Of these, 301 were assessable; stratification was based on pretreatment prostate-specific antigen level (PSA). Dose was prescribed to the isocenter at 2 Gy per fraction. All patients underwent planning pelvic computed tomography scan to confirm prostate position. Treatment failure was defined as an increasing PSA on three consecutive follow-up visits or the initiation of salvage treatment. Median follow-up was 40 months., Results: One hundred fifty patients were randomized to the 70-Gy arm and 151 to the 78-Gy arm. The difference in freedom from biochemical and/or disease failure (FFF) rates of 69% and 79% for the 70-Gy and 78-Gy groups, respectively, at 5 years was marginally significant (log-rank P: =.058). Multiple-covariate Cox proportional hazards regression showed that the study randomization was an independent correlate of FFF, along with pretreatment PSA, Gleason score, and stage. The patients who benefited most from the 8-Gy dose escalation were those with a pretreatment PSA of more than 10 ng/mL; 5-year FFF rates were 48% and 75% (P: =.011) for the 70-Gy and 78-Gy arms, respectively. There was no difference between the arms ( approximately 80% 5-year FFF) when the pretreatment PSA was < or = 10 ng/mL., Conclusion: A modest dose increase of 8 Gy using conformal radiotherapy resulted in a substantial improvement in prostate cancer FFF rates for patients with a pretreatment PSA of more than 10 ng/mL. These findings document that local persistence of prostate cancer in intermediate- to high-risk patients is a major problem when doses of 70 Gy or less are used.

Purpose: The treatment of R3327-G tumor-bearing rats with androgen ablation (AA) via castration results in a supra-additive increase in apoptosis when 2-8 Gy gamma-irradiation (RT) is given as a single dose 3-14 days afterwards. We report here the dose response and effect of multiple fractions on this supra-additive apoptotic response., Materials and Methods: Dunning R3327-G tumors were grown in the flanks of Copenhagen rats and the experiments were initiated at a tumor volume of 1.0-1.5 cc. Androgen ablation was achieved by castration 3 days prior to gamma-irradiation. Apoptosis was measured with a terminal deoxynucleotidyl transferase dUTP-biotin nick end-labeling assay 6-h after RT, unless otherwise specified., Results: The dose response of the supra-additive apoptotic response was assessed by irradiating castrated animals with single doses of 2, 4, 8, or 16 Gy (n = 5 per group); tumor cell apoptosis at 6-h following irradiation was 2.4%+/-0.7% (+/- SEM), 4.2%+/-0.8%, 6.5%+/-1.4%, and 1.6%+/-0.3%, respectively. The RT only and AA only controls had < 1% apoptosis. The effect of fractionated RT on apoptosis was investigated to determine if the supra-additive apoptotic response was sustained with repeated 2-8 Gy fractions. When tumor-bearing animals were treated with repeated daily 2-Gy fractions, there was a reduction in the level of the supra-additive apoptotic response. After five 2-Gy fractions at 24-h intervals, apoptosis in the combined treated tumors was at levels seen in the AA controls. This raised the possibility that more than 24 h are required for recovery of the high supra-additive apoptotic levels seen after one fraction. When the interfraction interval was extended to 96 h, there was no significant increase in apoptosis over the additive effect of AA and RT. Although there was a decline in supra-additive apoptosis with repeated fractions, a dose response for tumor growth delay was evident for RT alone using 2.5-Gy fractions. Moreover, the combination of AA + fractionated RT resulted in a supra-additive enhancement in tumor growth delay to 5 cc., Conclusion: The early supra-additive apoptotic response from AA and single fraction radiation is not seen at high single fraction doses and is not sustained with repeated fractions. Therefore, the classical apoptotic response that occurs within 24 h of irradiation is not likely to be the main mechanism responsible for any clinical benefit seen with this combination.

Background: Our purpose was to evaluate the relationship of Ki-67 labeling index (Ki67-LI) to deoxyribonucleic acid (DNA) ploidy, S phase fraction (SPF), other clinical prognostic factors, and clinical outcome for patients with prostate cancer treated by external beam radiotherapy., Methods: Tissue was retrieved from 42 patients who underwent transurethral resection of the prostate before treatment with external beam radiotherapy between 1987-1993. DNA histogram profiles were classified as diploid (diploid + near-diploid) and nondiploid (tetraploid + aneuploid). Immunohistochemical staining of Ki-67 by the MIB-1 monoclonal antibody was used to calculate Ki67-LI. Median patient follow-up was 62 months. Treatment failure was defined as two consecutive rises in serum prostate-specific antigen (PSA) or clinical evidence of disease recurrence., Results: The mean and median Ki67-LIs were 3.1 and 2.4, respectively (range, 0-12.4). Mean Ki67-LI values were significantly associated with higher stage, Gleason score, and pretreatment PSA. Nondiploid tumors had significantly higher Ki67-LIs, as did patients who failed radiotherapy over the follow-up period. SPF was not significantly correlated with Ki67-LI. As a categorical variable, the most significant relationships were seen when Ki67-LI was subdivided into thirds around the median (Ki67-LI 1.5-3.5%, and Ki67-LI >3.5%). This trichotomous variable correlated significantly with pretreatment PSA (P = 0.0008), tumor stage (P = 0.016), Gleason score (P = 0.024), and treatment failure (P = 0.0015), but not with DNA-ploidy (P = 0.15). In actuarial univariate analyses, Ki67-LI appeared to be a more significant predictor of patient outcome (P = 0.003) than DNA-ploidy (P = 0.035)., Conclusions: The Ki67-LI correlated with known prognostic factors such as pretreatment PSA, tumor stage, and Gleason score, and was also weakly related to DNA-ploidy. In comparison to DNA-ploidy, Ki67 LI seems to be a better correlate of treatment outcome., (Copyright 1999 Wiley-Liss, Inc.)

Purpose: To evaluate the outcome of clinical Stage III (T3, N0/NX, M0) prostate cancer treated by conventional radiation alone or with adjuvant androgen ablation., Methods and Materials: Three hundred forty-four men with T3, N0/NX, M0 adenocarcinoma of the prostate who received conventional radiation alone (260) or with androgen ablation (84) were analyzed for relapse or rising prostate-specific antigen (PSA), using univariate and multivariate techniques., Results: With a median follow-up of 68 months, the 260 men treated with radiation alone had a 10-year actuarial rate of relapse or rising PSA of 76%. Pretreatment PSA level (< or = 10 ng/ml vs. > 10 < or = 20 ng/ml vs. > 20 ng/ml) and radiation dose (< 68 Gy vs. > or = 68 Gy) were the only independently significant determinants of biochemical failure; Gleason score (2-7 vs. 8-10) was an additional determinant of metastatic relapse. Patients treated to doses < 68 Gy experienced 6-year failure rates exceeding 50% regardless of PSA level. Patients with PSA < or = 10 ng/ml and receiving 68-70 Gy had a 6-year failure of 24%, but those with PSA > 10 ng/ml had relapse rates exceeding 50% even at doses of 70 Gy. At a median follow-up of 44 months, the 84 patients treated with radiation and androgen ablation had a 6-year biochemical failure rate of 22%. The only significant determinant of outcome in this group was pretreatment PSA; patients with PSA < or = 80 ng/ml had a 6-year failure rate of only 12% compared to a failure rate of 53% for those with PSA > 80 ng/ml. The outcome for those treated with combined modalities was significantly better than for those treated with radiation alone in all PSA strata., Conclusion: Conventional radiation alone has little curative potential for Stage III disease. Doses < 68 Gy are particularly ineffective. Patients with PSA < or = 10 ng/ml may be candidates for conventional radiation to a dose of 70 Gy. Other patients are probably best served by combined radiation-androgen ablation or high-dose conformal radiation.

Technological advances in treatment delivery and planning have provided the backdrop for an unprecedented number of options in the treatment of prostate cancer with radiotherapy. The more common choices include classical external-beam radiotherapy, external-beam radiotherapy using three-dimensional treatment planning and conformal radiotherapy (3DCRT), ultrasound-guided transperineal implant monotherapy alone or in combination with external-beam radiotherapy, and intensity-modulated radiotherapy (IMRT) techniques. This chapter reviews the data from these methods with an emphasis on dose escalation, provides comparisons with prostate-specific antigen (PSA)-era radical prostatectomy series where appropriate, and highlights future initiatives designed to further improve outcome.

Background: Despite its subjectivity and inaccuracy, digital rectal examination (DRE) has a long history of well-documented prognostic significance in patients with prostate carcinoma. To the authors' knowledge, very few studies have evaluated the relative prognostic merits of transrectal ultrasound (TRUS) versus DRE. This question is addressed in this study., Methods: The outcome for 558 men with T1-T3, N0, M0 adenocarcinoma of the prostate who underwent both DRE and TRUS and received external beam radiation without androgen ablation was evaluated relative to the prognostic information from DRE, TRUS, or both. The outcome endpoints were no evidence of disease (NED) (no relapse or rising prostate specific antigen level) and freedom from metastases. Prognostic factors were evaluated with univariate and multivariate techniques. The median follow-up was 55 months., Results: Both purely DRE-based and purely TRUS-based T categories correlated significantly with NED status. For DRE T categories, 6-year NED rates for T1/T2 and T3 disease were 64% and 36%, respectively (P < 0.001). For TRUS T categories, the rates for T1/T2 and T3 were 63% and 39%, respectively (P < 0.001). There were significant differences in patient composition between DRE and TRUS T categories. Only 40% of patients were in the same DRE and TRUS category, but the majority of the reclassification based on TRUS was within rather than between major T categories (T1/T2 vs. T3). Changes between the prognostically significant T1/T2 versus T3 categories occurred in < or =25%. This accounted for the similarity in NED outcome for DRE and TRUS T categories. However, TRUS categories did not discriminate significantly for metastatic recurrence between T1/T2 and T3 categories, whereas DRE categories did. Upstaging or downstaging by TRUS relative to DRE did not alter the DRE prognostic groupings substantially., Conclusions: There was no clinically meaningful superiority of TRUS over DRE in the definition of prognostically useful T categories. Moreover, the addition of TRUS to DRE did not enhance the prognostic value of DRE findings in any meaningful way. Despite its subjectivity and inaccuracy, DRE provides prognostic information at least equivalent to TRUS and is preferable because of its low cost.

Purpose: To compare the outcome of familial versus sporadic prostate carcinoma after definitive external radiation., Methods and Materials: Between 1987 and 1996, 1214 men with clinically localized prostate cancer (T1-T4, N0/NX, M0) received definitive radiation therapy in our department. By retrospective review of charts and questioning of patients, a record on the presence or absence of prostate cancer in a first degree relative was obtained in 1164 men. Univariate and multivariate analysis was performed on these cases with relapse or rising prostate-specific antigen (PSA), local recurrence, metastasis, and survival as endpoints., Results: Familiar prostate cancer was present in 148 of 1164 men (13%). Men with familial disease were slightly but significantly younger (mean 66 years) at diagnosis than those with sporadic disease (mean 68 years) (p = 0.02). Apart from this there were no significant differences between the two groups in T-stage, Gleason score, pretreatment PSA levels, DNA ploidy, or serum testosterone levels. There were no significant differences in treatment parameters including radiation dose and the use of adjuvant androgen ablation. With a median follow-up of 42 months, there was no difference in freedom from relapse or rising PSA at 6 years between those with a family history (54%) and those without a family history (58%) (p = 0.171). Likewise there was no difference between the two groups when local recurrence or metastasis was the endpoint. Multiple subgroup analyses (younger and older; T1/T2 and T3; low Gleason and high Gleason; no androgen ablation and androgen ablation; race) failed to reveal any differences in outcome in any category between familial and sporadic disease. Among patients with a rising post-treatment PSA profile, PSA doubling times were similar in those with sporadic and familial disease., Conclusions: This study provides no evidence for any substantial difference between familial and sporadic prostate cancer either in clinicopathological features, in response to treatment, or in ultimate outcome.

Purpose: The purpose of this study was to measure the mobility of the clinical target volume (CTV) in prostate radiotherapy with respect to the pelvic anatomy during a course of therapy. These data are needed to properly design the planning target volume (PTV)., Methods and Materials: Seventeen patients were studied. Each patient underwent computed tomography (CT) scanning for treatment planning purposes. Subsequently, three CT scans were obtained at approximately 2-week intervals during treatment. The prostate, seminal vesicles, bladder, and rectum were outlined on each CT study. The second through the fourth CT studies were aligned with the first study using a rigid body transformation based on the bony anatomy. The transformation was used to compute the center of mass position and bounding box of each organ in the subsequent studies relative to the first study. Differences in the bounding box limits and center of mass positions between the first and subsequent studies were tabulated and correlated with bladder and rectal volume and positional parameters., Results: The mobility of the CTV was characterized by standard deviations of 0.09 cm (left-right), 0.36 cm (cranial-caudal), and 0.41cm (anterior-posterior). Prostate mobility was not significantly correlated with bladder volume. However, the mobility of both the prostate and seminal vesicles was very significantly correlated with rectal volume. Bladder and rectal volumes decreased between the pretreatment CT scan and the first on-treatment CT scan, but were constant for all on-treatment CT scans., Conclusion: Margins between the CTV and PTV based on the simple geometric requirement that a point on the edge of the CTV is enclosed by the PTV 95% of the time are 0.7 cm in the lateral and cranial-caudal directions, and 1.1 cm in the anterior-posterior direction. However, minimum dose to the CTV and avoidance of organs at risk are more important considerations when drawing beam apertures. More consistent methods for reproducing prostate position (e.g., empty rectum) and more sophisticated beam aperture optimization are needed to guarantee consistent coverage of the CTV while avoiding organs at risk.

Purpose: To compare the outcome of irradiated clinically localized prostate cancer in African-American and white patients., Methods and Materials: This was a retrospective review of 1,201 men, 116 African-American and 1,085 white, with T1-T3, N0/NX, M0 prostate cancer receiving external radiation between 1987 and 1996. Pretreatment characteristics, treatment parameters, and outcome (relapse or rising prostate-specific antigen [PSA] levels, local recurrence, metastatic relapse, and survival) were compared between the groups using univariate and multivariate statistical methods., Results: There were no significant differences between African-American and white patients in T-stage, Gleason score, prostatic acid phosphatase (PAP) level, and testosterone level. African-Americans had a significantly lower incidence of abnormal digital rectal findings and a proportionally higher incidence of obstructive urinary symptoms at presentation and tended to be somewhat younger. A major difference between the two groups was in the significantly higher PSA levels among African-Americans (median, 14 ng/ml) than among white patients (median, 9.5 ng/ml). This translated into a higher incidence of unfavorable disease according to our criteria (39% vs. 25%) among African-Americans and, thus, to the more frequent use of adjuvant androgen ablation and to somewhat higher radiation doses in these patients. With a median follow-up of 42 months the overall 6-year freedom from relapse for African-Americans was 63% compared to 61% for whites (p = 0.634). We found no significant differences in biochemical relapse rates between any subgroups of African-Americans and whites. Specifically, even patients who did not have androgen ablation, when stratified by PSA levels, had similar outcomes regardless of race. Likewise, local recurrence and metastasis rates were not significantly different between the two groups., Conclusions: Although African-American patients tend to have higher pretreatment PSA levels than white patients, the outcome for the disease is similar in the two groups when stratified by known pretreatment prognostic factors. Our data provide no evidence for the hypothesis that prostate cancer in African-Americans is intrinsically more virulent than in whites.

Objectives: The strict definition of Stage T1c prostate cancer is that the tumor is not palpable on digital rectal examination (DRE) or seen on imaging studies such as ultrasound. The inclusion of ultrasound imaging was brought about without an understanding of the relationship between ultrasound upstaging and prognosis. We have also noticed that in clinical practice, treatment decisions are made on the basis of the finding of bilateral versus unilateral biopsy positivity. The objectives in this study were to determine the prognostic significance of upstaging by transrectal ultrasound (TRUS) to uT2 or uT3, and unilateral versus bilateral biopsy positivity in patients with Stage T1c cancer as determined by DRE (DRE-Stage T1c patients)., Methods: Between 1987 and 1995 there were 643 patients with DRE-Stage T1-T2 prostate cancer treated with external beam radiotherapy; 24 had T1a, 76 had T1b, 183 had T1c, 133 had T2a, 168 had T2b, and 59 had T2c. Of these, 135 DRE-Stage T1c patients underwent ultrasound staging and 122 underwent bilateral prostate biopsies. All had pretreatment prostate-specific antigen values (PSAs) available and no patient received adjuvant androgen ablation. The median pretreatment PSA was 9.1 ng/mL, median radiotherapy dose was 66.0 Gy, and median follow-up was 41 months. Post-treatment failure was defined as disease recurrence and/or two elevations in PSA on consecutive follow-up visits., Results: The 5-year freedom from failure rate for DRE-Stage T1c patients (71%) was not significantly different from that of DRE-Stage T1b (65%) or DRE-Stage T2a (71%) patients. There was a trend (P = 0.1) toward a worse outcome for DRE-Stage T2b/T2c patients compared with DRE-Stage T1b/T1c/T2a patients. The distribution of DRE-Stage T1c patients by ultrasound staging was 29 with uT1c, 88 with uT2, and 18 with uT3 findings. Twenty percent of patients had bilateral positive biopsy specimens. In univariate and multivariate analyses, the only correlates of patient outcome were pretreatment PSA (P < or = 0.002) and isocenter dose (P = 0.03). TRUS upstaging had no effect on freedom from failure; uT1c patients had about the same risk of relapse or a rising PSA as uT2 or uT3 patients. Patients with bilateral positive prostate biopsy specimens had about the same prognosis as those with unilateral positive biopsy specimens., Conclusions: For patients with DRE-Stage T1c prostate cancer, the data indicate that ultrasound staging and bilateral biopsy positivity are not predictive of outcome for patients treated with external beam radiotherapy and treatment decisions should not be based on these parameters.

Objectives: To evaluate the late effects more than 2 years after radiotherapy using a patient-reported questionnaire in patients with prostate cancer enrolled in a randomized dose-response study comparing 70 Gy (conventional) and 78 Gy (conformal) radiotherapy (RT)., Methods: The first 112 patients in the study were sent questionnaires to evaluate late bladder, rectal, and sexual function. There were 101 evaluable responses, with 50 in the conventional (Conven-RT) arm and 51 in the conformal (3DCRT) arm., Results: The overall rate of persistent incontinence was 29%, with 36% reporting urgency-related and 8% stress-related incontinence at some time after radiation. Use of a urinary protective device was required in 2%. The majority noticed leakage less than once per day (52%). In comparing the Conven-RT group with the 3DCRT group, similar incontinence rates were seen. However, fewer of those who received 3DCRT reported daily leakage of urine (33% versus 63%, P = 0.044). The majority (78%) of patients experienced no or mild change in bowel function after RT. Urgency of bowel movements (BMs) was of concern for 27% of patients; however, 90% reported their BMs were controlled without accidents, and 1% were taking antidiarrheal medications once a week or daily. The Conven-RT group had more moderate or major changes in bowel function than the 3DCRT group (34% versus 10%), more frequent BMs (47% versus 27%), and more urgent BMs (37% versus 18%) (P < or = 0.040 for all three comparisons). Hematochezia was uncommon, occurring once a week in 7% and daily in 4% of patients. Before RT, 80% of patients were potent, with erections adequate for intercourse at least a few times over the prior year. After RT, potency was decreased to 51%, with erections adequate for intercourse at least a few times since the completion of RT., Conclusions: The overall rates of significant complications were extremely low. Although 30% reported incontinence, relatively few patients (2%) required pads. This rate compares favorably with the 31% of patients requiring protection after radical prostatectomy reported previously. Despite the higher treatment doses in the 3DCRT arm, slightly fewer long-term bowel side effects were noted. These data indicate that 78 Gy may safely be delivered using the conformal RT boost treatment technique described.

Prostate cancer patients may now be identified as having a high risk of failing single-modality treatment based on pretreatment prostate specific antigen (PSA), Gleason score, and palpable stage. In particular, a PSA greater than 20 ng/mL portends a biochemical failure rate of 50% to 80% when radiation therapy, surgery, or androgen ablation is administered individually. A number of randomized trials as well as retrospective data show that failure rates are significantly reduced by combining androgen ablation and radiation. The improved results, however, are complicated by the ability to salvage radiation alone-treated patients with androgen ablation and the possibility of less effective salvage (or no effective salvage in the case of permanent androgen ablation) for patients treated with androgen ablation plus radiation. Thus, survival, which is obscured by high rates of intercurrent deaths in this elderly population, is the most important end point in such studies. Two randomized trials, one from the Radiation Therapy Oncology Group (RTOG) and one from the European Organization for Research on Treatment for Cancer (EORTC), of radiation therapy plus adjuvant (as opposed to neoadjuvant) androgen ablation have reported survival gains over radiation therapy alone. In contrast, one neoadjuvant trial from the RTOG failed to show a survival benefit when androgen ablation was added to radiation therapy. In this study, however, androgen ablation was administered for only 4 to 5 months, which may be insufficient. The weight of the evidence to date indicates a true benefit with androgen ablation plus radiation therapy over radiation therapy alone. There are clearly many unanswered questions concerning the optimal timing of androgen ablation and radiation therapy (neoadjuvant versus adjuvant), length of time that androgen ablation should be administered (6 months versus 3 years versus permanent), type of androgen ablation (total androgen ablation or not), and appropriate patient population (definition of high risk). The planned future clinical trials will address many of these issues; however, the full potential of this approach requires an understanding of the fundamental mechanisms involved., (Copyright 1998 W.B. Saunders Company.)

Objectives: To determine the impact of radiation dose on the response of Stage T1/T2 prostate cancer to external beam radiation therapy and to contrast the modern-day clinical and biochemical control rates to those seen after radical prostatectomy or permanent iodine-125 seed implants., Methods: The study cohort consisted of 643 patients with palpable Stage T1/T2, NX/N0, M0 prostate cancer treated with external beam radiotherapy between 1987 and 1995. No patient received neoadjuvant or adjuvant androgen ablation. The radiotherapy isocenter dose ranged from 60 to 78 Gy, with a mean of 67 and a median of 66. Median follow-up was 43 months. The primary end point was freedom from relapse or rising prostate-specific antigen (PSA) level., Results: The patients were divided into two dose groups with the cutpoint based on the mean and median values, and prior analyses. There were 354 patients treated to radiation doses of 67 Gy or less and 289 treated to doses greater than 67 Gy. Those receiving the higher doses had a significantly greater 4-year freedom from failure rate of 87% versus 67% (P <0.0001). Multivariate Cox proportional hazards analyses revealed that isocenter dose was independent of Gleason score and pretreatment PSA level, which were the other significant covariates., Conclusions: Very high freedom from failure rates were achieved when the radiation dose to the prostate was above 67 Gy. These rates are promising when compared to published radical prostatectomy series and most permanent iodine-125 seed implant series in which patients were stratified by pretreatment PSA. Further follow-up is needed to confirm that these promising results are sustained.

Purpose: To determine the external beam radiotherapy dose response of palpable Stage T1-T4, mostly Nx, patients with adenocarcinoma of the prostate., Methods and Materials: There were 938 men consecutively treated between 1987 and 1995 who had pretreatment prostate specific antigen (PSA) levels. Posttreatment failure was defined as disease recurrence and/or two elevations in PSA on consecutive follow-up visits. The radiotherapy technique consisted of a four-field box with a small four-field reduction after 46 Gy in 844 patients (total dose of 60-70 Gy) or with a six-field conformal boost after 46 Gy in 94 patients (total dose of 74-78 Gy). Neoadjuvant or adjuvant androgen ablation was not used in any patient. Median follow-up was 40 months., Results: The mean and median radiotherapy doses for the entire group were 67.8 +/- 13.3 Gy (+/-SEM) and 66 Gy. The mean radiotherapy dose was higher in those who had Stage T3/T4 disease, Gleason scores of 8-10, or pretreatment PSAs of > 4 ng/ml. In general, patients with more aggressive pretreatment prognostic features were treated to higher doses; yet, those that relapsed or had a rising PSA were treated to significantly lower doses. Actuarial analyses were facilitated by dividing patients into three dose groups: < or = 67, > 67-77, and > 77 Gy. The actuarial freedom from failure rates at 3 years were 61, 74, and 96% for the low, intermediate, and high dose groups. Stratification of the patients by pretreatment PSA revealed that dose was a significant correlate of freedom from relapse or a rising PSA for those with PSAs > 4-10, > 10-20, and > 20 ng/ml. The only patients in which an improvement in outcome was not related to higher doses were those with a pretreatment PSA < or = 4 ng/ml. Dose was significantly associated with freedom from failure for Stage T1/T2 and Stage T3/T4 patients, as well as for those stratified by Gleason score. Multivariate analysis using Cox proportional hazards models showed that dose was an independent and highly significant predictor of relapse or a rising PSA., Conclusion: This retrospective review strongly indicates that radiotherapy dose to the prostate is critical to the cure of prostate cancer, even for favorable patients with pretreatment PSAs of > 4-10 ng/ml, Stages T1/T2, or Gleason scores of 2-6. Final confirmation awaits the results of our randomized trial.

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.

Background: This study attempted to define unfavorable locoregional prostate carcinoma and presents the results of treatment with combined radiation and androgen ablation for these patients., Methods: Of a group of 938 men with clinically localized N0/NX disease treated with radiation alone, an unfavorable category included all men with prostate specific antigen (PSA) > 20 ng/mL and all men with 10 < PSA < or = 20 ng/mL but with Gleason's grade > 7. One hundred and eighty-five such men treated with radiation alone and an additional 100 men with similar disease received radiation with early androgen ablation. A second cohort was comprised of 229 men with lymphadenectomy proven pelvic lymph node metastases, with 185 receiving early androgen ablation alone and 44 receiving androgen ablation and local radiation. The outcomes, with recurrence or rising PSA as the endpoint, were compared among these various treatment groups using multivariate techniques., Results: Disease outcome with the combined modality treatment was dramatically improved in both cohorts of men. For those with unfavorable N0/NX disease, the failure rate at 5 years decreased from 82% with only radiation therapy to 15% with combined treatment. Likewise, for patients with lymph node disease, the failure rate at 5 years decreased from 58% with only androgen ablation to 10% with combined treatment. For the whole group with unfavorable disease (unfavorable N0/NX and lymph node positive disease) the 6-year failure decreased from 71% with single modality treatment to 13% with bimodality treatment. There was a close relationship between the incidence of lymph node disease and prognostic categories and patients with otherwise unfavorable disease did not have their poor outlook ameliorated by undergoing a negative lymphadenectomy., Conclusions: Unfavorable locoregional prostate carcinoma can be recognized on the basis of pretreatment PSA level, T category, and Gleason's grade without specific evaluation of pelvic lymph node status. Combined local radiation and androgen ablation for patients with unfavorable disease results in a substantial improvement in disease control compared with that achieved by either modality alone. The authors found no improvement in survival because all groups of men had a normal life expectancy to at least 5 years.

Purpose: To determine whether serum total testosterone levels change after external beam radiation therapy for localized prostate cancer., Methods and Materials: Eighty-five men with clinically localized prostate cancer (T1-T3, N0/NX, M0) who underwent external beam radiation therapy without androgen ablation had pretreatment and 3-month posttreatment total serum testosterone levels determined by radioimmunoassay. Scattered doses to the testicles were measured with thermoluminescent dosimetry in 10 men., Results: Pretreatment serum testosterone levels ranged from 185 to 783 ng/dl, with a mean of 400 ng/dl and a median of 390 ng/dl. The coefficient of variation was 30%. Postradiation 3-month testosterone levels ranged from 163 ng/dl to 796 ng/dl, with mean and median values of 356 ng/dl and 327 ng/ml, respectively. The coefficient of variation was 34%. The 3-month value was significantly lower than the pretreatment value (Wilcoxon paired p = 0.0001). The mean absolute fall was 94 ng/dl and the mean percentage fall was 9%. Although the fall in testosterone level was statistically significant, the difference was very small quantitatively. In contrast, serum prostate-specific antigen levels fell dramatically by 3 months after radiation. Testicular scattered doses ranged from 1.84 to 2.42 Gy, with a mean of 2.07 Gy for a prostatic tumor dose of 68 Gy., Conclusions: Although significant, the fall in serum testosterone level after radiation for localized prostate cancer was small and likely of no pathophysiologic consequence. It is unlikely that scattered testicular radiation plays any significant role in the genesis of this change in testosterone level, which most likely occurs as a nonspecific stress response.

Purpose: Androgen ablation is often combined with radiation in the treatment of patients with prostate cancer, yet, the optimal sequencing and the mechanisms governing the interaction are not understood. The objectives were to determine if cell killing via apoptosis is enhanced when the combined treatment is administered and to define the relationship of changes in this form of cell killing to tumor volume growth delay., Materials and Methods: Dunning R3327-G rat prostate tumors, grown in the flanks of Copenhagen rats, were used at a volume of approximately 1 cc. Androgen ablation was initiated by castration, and androgen restoration was achieved with 0.5 cm silastic tube implants containing testosterone. 60Co was used for irradiation. The terminal deoxynucleotidyl transferase (TUNEL) histochemical assay was used to quantify apoptosis., Results: Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiation of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%. A supraadditive apoptotic response was seen when castration was initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%. When the radiation was administered at increasing times beyond 3 days after castration, the apoptotic response gradually diminished and was back to levels seen in intact rats by 28 days after castration. Tumor volume growth delay studies were consistent with, but not conclusive proof of, a supraadditive effect when the combination was used., Discussion: A supraadditive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors. This supraadditive effect was dependent on the timing of the two treatments. Further studies are required to more fully define the optimal timing and administration of androgen ablation and radiation.

Androgen ablation is frequently used in conjunction with radiotherapy in the treatment of high-risk prostate cancer. Androgen ablation-induced cell kinetic changes could result in sub-additive (increased quiescence) or supra-additive (reduction in repopulation) interactions with radiotherapy. The cell kinetic changes were studied in R3327-G Dunning rat prostate tumors grown in vivo using double thymidine analogue labeling and flow cytometry, the terminal deoxynucleotidyl transferase-mediated nick end labeling assay for apoptosis, and measurements of tumor cell numbers. Tumors grown in intact and castrate male rats were continuously labeled for various periods of time with chlorodeoxyuridine and pulse-labeled with iododeoxyuridine 8 h before tumor removal. Androgen ablation resulted in a maximal reduction in labeling index (10 to 1.6%) and an increase in potential doubling time (Tpot; 6-42 days) within 3 days, which was related to a reduction in growth fraction (65% to <10%). In contrast, the length of S-phase was minimally altered (19 to 23 h). The response to androgen ablation involved little apoptosis and no necrosis, and Tpot was approximately the same as the tumor volume doubling time. Hence, the increase in Tpot was mainly the result of a shift to quiescence, and this shift occurred with minimal cell loss. Because quiescence is usually associated with radioresistance, these cell kinetic changes suggest that a sub-additive interaction may occur for some prostate cancers when androgen ablation and irradiation are given together.

Purpose: Although the pretreatment serum prostate-specific antigen level (PSAL) is the single-most significant predictor of local and biochemical control in prostate cancer patients treated with radiotherapy, it is relatively insensitive for patients with a PSAL in the intermediate range (4-20 ng/ml). PSA density (PSAD) has been shown to be slightly more predictive of outcome than PSAL for this intermediate risk group; however, this improvement is small and of little use clinically. PSA cancer volume (PSACV), an estimate of cancer volume based on PSA, has recently been described and has been purported to be more significant than PSAL in predicting early biochemical failure after radiotherapy. We report a detailed comparison between this new prognostic factor, PSAL, and PSAD., Methods and Materials: The records of 356 patients treated with definitive external beam radiotherapy for regionally localized (T1-4,Nx,M0) adenocarcinoma of the prostate were reviewed. Each patient had a PSAL, biopsy Gleason score, and pretreatment prostate volume by transrectal ultrasonography. The median PSAL was 9.3 ng/ml and 66% had Gleason scores in the 2-6 range. The median radiation dose was 66.0 Gy and the median follow-up for those living was 27 months. PSACV was calculated using a formula which takes into account PSAL, pretreatment prostate ultrasound volume, and Gleason score. The median PSACV was 1.43 cc. Biochemical failure was defined as increases in two consecutive follow-up PSA levels, one increase by a factor > 1.5, or an absolute increase of > 1 ng/ml. Local failure was defined as a cancer-positive prostate biopsy, obtained for evidence of tumor progression., Results: The distributions of PSACV and PSAL were similar and, when normalized by log transformation, were highly correlated (p < 0.0001, linear regression). There was a statistically significant relationship between PSACV and several potential prognostic factors including PSAL, PSAD, stage, Gleason score, and pretreatment prostatic acid phosphatase (PAP). In univariate analyses, PSACV, PSAL, and PSAD proved to be the most significant predictors of both biochemical and local control. In multivariate analyses using Cox proportional hazards models with PSAL, PSAD, PSACV, and PAP as continuous variables, PSAL, PSACV, and Gleason score were significant in predicting biochemical control. Only PSAL was significantly correlated with local control. However, when these analyses were restricted to patients with intermediate PSALs (4-20 ng/ml), only PSACV was significant for predicting both biochemical and local control., Conclusion: PSACV was highly correlated with actuarial local and biochemical control and was superior to both PSAL and PSAD in predicting these outcomes in patients with PSALs between 4 and 20 ng/ml.

Background: Pretreatment serum prostate specific antigen (PSA) level is a powerful prognostic factor for clinically localized prostate carcinoma. The traditional prognostic factors, T classification and Gleason score, appear to have been relegated to a minor position. This study was conducted to evaluate the relative prognostic roles of PSA, T classification, and Gleason score in a large cohort of men irradiated in the PSA era., Methods: The authors analyzed the outcome for a group of 938 men with T1-T4, N0 or NX, M0 prostate carcinoma who received definitive external beam radiation therapy as their only initial treatment during the period 1987-1995. The T classifications were as follows: T1, 283 (30%); T2, 360 (38%); T3/T4, 295 (31%). Gleason scores were as follows: Gleason 2-6, 580 (62%); Gleason 7, 224 (24%); Gleason 8-10, 122 (13%). Pretreatment PSA levels (ng/mL) were as follows: PSA < or = 4, 167 (18%); PSA 4 to < or = 10, 363 (39%); PSA 10 to < or = 20, 259 (28%); PSA > 20, 149 (16%). At a mean follow-up of 43 months (range, 6-106 months), disease outcome specified as relapse/rising PSA, local recurrence, or metastasis was analyzed using univariate and multivariate techniques., Results: The 6-year actuarial incidences of relapse/rising PSA, local recurrence, and metastases were 48%, 27%, and, 6%, respectively. In multivariate regression, pretreatment PSA level, T classification, and Gleason score were each independently highly significantly (P < 0.001) correlated with every endpoint. Pretreatment PSA level was the most significant variable for rising PSA and local recurrence, and T classification was the most significant variable for metastatic relapse. Using relapse/rising PSA as the endpoint, the authors formulated a highly significant 6-tier prognostic grouping based on PSA, T classification, and Gleason score, as follows: Category I: T1/T2, PSA < or = 4, and Gleason 2-6 (relapse rate, 6%); Category II: T1/T2, PSA < or = 4 and Gleason 7-10, or PSA 4 to < or = 10 and Gleason 2-7 (relapse rate, 30%); Category III: T1/T2, PSA 4 to < or = 10 and Gleason 8-10, or PSA 10 to < or = 20 and Gleason < 8 (relapse rate, 40%); Category IV: T3/T4, PSA < 10 (relapse rate, 46%); Category V: T3/T4, PSA 10 to < or = 20, and Gleason < 8 (relapse rate, 57%); Category unfavorable: any T, PSA > 20 and any Gleason, or PSA 10 to < or = 20 and Gleason 8-10 (relapse rate, 88%)., Conclusions: The establishment of T classification and Gleason score as independent prognostic factors bridges an apparent gap between an older era and the current PSA era. PSA has supplemented, rather than supplanted, the utility of the traditionally established prognostic factors for clinically localized prostate carcinoma.

Background: The prognostic significance of primary tumor DNA-ploidy and S-phase fraction (SPF) was evaluated in patients treated with androgen ablation for regionally localized node-positive prostate cancer., Methods: All patients were diagnosed with lymph node involvement by pelvic lymphadenectomy between 1984 and 1992 and were treated only with androgen ablation. Median follow-up was 45 months. Adequate material for DNA/nuclear protein flow cytometric analysis was available in 33 patients., Results: The tumors were classified as diploid in 11, near-diploid in 4, tetraploid in 10, and aneuploid in 8 cases. Grouping the patients by nonaneuploidy (diploid and near-diploid and tetraploid) and aneuploidy revealed actuarial 4-year disease progression rates of 14 and 48% (log-rank, P = 0.04), and overall survival rates of 100 and 61% (P = 0.008); however, biochemical progression (rising prostate-specific antigen profile) rates were similar at around 70%. In contrast, SPF was not significantly related to any of the endpoints tested. Several other potential prognostic factors were examined and none correlated significantly with disease progression or survival., Conclusions: The biochemical progression rates for patients with nonaneuploid and aneuploid tumors were comparable and high, while the disease progression rates were higher and survival rates lower for those with aneuploid tumors. These data indicate that the lead time from biochemical to disease progression and death was shorter with aneuploidy. That these relationships were observed in such a small patient population attest to the strength of DNA-ploidy as a prognostic factor in this cohort.

Objectives: To determine if the serum total testosterone concentration correlates with the outcome for men irradiated for clinically localized prostate cancer., Methods: The outcome-local, nodal, distant metastatic, and biochemical--for 486 men with clinically localized prostate cancer treated by radiation and for whom testosterone levels were available was analyzed. No patient received adjuvant androgen ablation. Patient tumor stages were T1: 129 (27%); T2: 187 (38%); and T3/T4: 170 (35%). Median follow-up was 41 months., Results: Pretreatment testosterone values ranged from 109 to 1121 ng/dL, with a mean of 417 ng/dL and a median of 398 ng/dL. The distribution of patients according to a four-tier testosterone grouping was testosterone level of 300 ng/dL or less, 108 (22%); testosterone level greater than 300 ng/dL but not more than 400 ng/dL, 141 (29%); testosterone level greater than 400 ng/dL but not more than 500 ng/dL, 123 (25%); and testosterone level greater than 500 ng/dL, 114 (23%). There were statistically significant but trivial correlations between testosterone level and age, T-stage, and acid phosphatase level. There was no correlation between testosterone and prostate-specific antigen (PSA) levels. There was a highly significant correlation between testosterone level and metastatic relapse. Patients with testosterone level greater than 500 ng/dL had a markedly higher 6-year metastatic rate (16%) than those with a testosterone level of 500 ng/dL or less (4%) (P = 0.001). In multivariate analysis, testosterone level was an independent determinant of metastatic relapse, second only to PSA level and of about the same power as T-stage. Gleason grade, although significant, was less so than testosterone level. The correlation of testosterone level to outcome appeared to be specific for metastatic relapse having no relation to local outcome. Likewise, high testosterone levels were not associated with acceleration of postradiation serum PSA kinetics., Conclusions: There is a highly significant correlation between pretreatment testosterone level and metastatic relapse in patients with clinically localized prostate cancer treated with radiation. As serum testosterone increases, so too does metastatic relapse. This relationship appears to take a decided turn for the worse at testosterone levels exceeding 500 ng/dL.

Background: The pretreatment serum prostate specific antigen level (PSAL) is the most significant predictor of biochemical and local failure in patients treated with definitive radiotherapy. The role of prostate specific antigen (PSA) density (PSAD) relative to PSAL for such patients is controversial. In this article, we describe a comparative analysis of the prognostic value of PSAL and PSAD., Methods: The study was comprised of 365 patients who were treated with external beam radiotherapy for regionally localized (T1-T4, Nx, M0) adenocarcinoma of the prostate between 1987-1993 and in whom PSAL and pretreatment prostate volume by transrectal ultrasound were available. The mean and median doses were 66.8 Gy and 66 Gy. Median follow-up for those patients living was 27 months. The mean PSAL was 12.7 ng/mL with a median of 9.1 ng/mL. PSAD was calculated by dividing the PSAL by the pretreatment prostate transectal ultrasound volume (in cc). The mean PSAD was 0.44 and the median was 0.31. Biochemical failure was defined as two consecutive increases in follow-up PSAs, one increase by a factor of greater than 1.5 of an absolute increase of greater than 1 ng/mL., Results: The distributions of PSAD and PSAL were similar and were positively skewed. When log-transformed, the distributions of both parameters were normalized and linear regression revealed a high correlation (P < 0.0001). PSAD was significantly associated with several potential prognostic factors, including stage, Gleason score, PSAL, and pretreatment prostatic acid phosphatase. Univariate analyses of PSAD and PSAL revealed that these were the most significant correlates of local and biochemical control. By contrast, stage and Gleason score were the only factors predictive of freedom from distant metastasis. Multivariate analyses using Cox proportional hazards models were then performed to determine if PSAD provided prognostic information independent of PSAL. The manner in which PSAD and PSAL were categorized (four, three, of two groups) dramatically influenced the significance of these covariates. Optimization of these groups for significance showed grouped PSAD to be the stronger predictor of the local control and grouped PSAL to be the stronger predictor of biochemical control. However, when PSAD and PSAL were used as continuous variables, PSAL was the only independently significant prognostic factor for local or biochemical control., Conclusions: PSAD was highly correlated with actuarial patient outcome in the univariate analyses and appeared to provide independent information when PSAL was between 4 and 20 ng/mL. However, the differences based on PSAD were relatively small and, therefore, not clinically useful.

Purpose: To compare conformal radiotherapy using three dimensional treatment planning (3D-CRT) to conventional radiotherapy (Conven-RT) for patients with Stages T2-T4 adenocarcinoma of the prostate., Methods and Materials: A Phase III randomized study was activated in May 1993, to compare treatment toxicity and patient outcome after 78 Gy in 39 fractions using 3D-CRT to that after 70 Gy in 35 fractions using Conven-RT. The first 46 Gy were administered using the same nonconformal field arrangement (four field) in both arms. The boost was given nonconformally using four fields in the Conven-RT arm and conformally using six fields in the 3D-CRT arm. The dose was specific to the isocenter. The first 60 patients, 29 in the 3D-CRT arm and 31 in the Conven-RT arm, are the subject of this preliminary analysis., Results: The two treatment arms were first compared in terms of dosimetry by dose-volume histogram analysis. Using a subgroup of patients in the 3D-CRT arm (n=15), both Conven-RT and 3D-CRT plans were generated and the dose-volume histogram data compared. The mean volumes treated to doses above 60 Gy for the bladder and rectum were 28 and 36% for the 3D-CRT plans, and 43 and 38% for the Conven-RT plans, respectively (p < 0.05 for the bladder volumes). The mean clinical target volume (prostate and seminal vesicles) treated to 95% of the prescribed dose was 97.5% for the 3D-CRT arm, and 95.6% for the Conven-RT arm (p < 0.05). There were no significant differences in the acute reactions between the two arms, with the majority experiencing Grade 2 or less toxicity (92%). Moreover, no relationship was seen between acute toxicity and the volume of bladder and rectum receiving in excess of 60 Gy for those in the 3D-CRT arm. There was also no difference between the groups in terms of early biochemical response. Prostate-specific antigen levels at 3 and 6 months after completion of radiotherapy were similar in the two treatment arms. There was only one biochemical failure in the study population at the time of the analysis., Conclusions: Comparison of the Conven-RT and 3D-RT treatment plans revealed that significantly less bladder was in the high dose volume in the 3D-CRT plans, while the volume of rectum receiving doses over 60 Gy was equivalent. There were no differences between the two treatment arms in terms of acute toxicity or early biochemical response. Longer follow-up is needed to determine the impact of 3D-CRT on long-term patient outcome and late reactions.

Purpose: Patients with regionally localized hormone refractory adenocarcinoma of the prostate are often referred for radiotherapy to relieve local symptoms, prevent further local progression, or prevent impending urinary tract obstruction. However, the merits of radiotherapy for this patient population have not been documented. In this retrospective series, the results of 29 such patients treated at our institution between 1987-1992 are reviewed., Methods and Materials: Prior to androgen ablation, the majority of these patients (79%) had Stage D0 or D1 disease. After androgen ablation, radiotherapy was given to 16 (55%) for progressive symptoms (mostly urinary obstructive), 11 (38%) for palpable local progression in the absence of symptoms, and 2 for a rising prostate specific antigen (PSA) profile without palpable disease. None of the patients had distant metastasis at the time of radiotherapy. The median dose to the prostate was 66 Gy and the median follow-up after radiotherapy was 43 months., Results: Following local-regional radiotherapy, the actuarial rate of local failure at 4 years was only 39%. However, 80% had disease progression or a rising PSA in this time period. The actuarial survival at 4 years following radiotherapy was 39%. Univariate analyses of potential prognostic factors revealed that preandrogen ablation Gleason score, preradiotherapy PSA, and preradiotherapy prostatic acid phosphatase (PAP) were predictive of patient outcome. Most importantly, doses above 60 Gy to the prostate at standard fractionation were associated with symptom-free local control in 90% of patients at 3 years. The majority of the patients were treated using limited fields (n = 20)., Conclusions: The regionally localized hormone refractory prostate cancer patients described benefited from high dose, continuous course, local radiotherapy in that excellent local control rates were obtained for an extended period. Because the majority of these patients fail with distant metastasis within 4 years, this treatment represents an aggressive approach to palliation that is justified by the maintenance of freedom from local symptoms.

Purpose: Prostate-specific antigen (PSA) is a powerful pretreatment prognosticator and a sensitive post-treatment outcome measure for clinically localized prostate cancer treated with radiation therapy. Today, the pretreatment serum PSA level appears to supersede both grade and T-stage as a determinant of outcome. This study was undertaken to attempt a reconciliation between the old (pre-PSA) and the new (PSA) data-in particular to address the question of why stage and grade apparently play so little role in this PSA era., Methods and Materials: We analyzed the outcome of two cohorts of men with T1-T4, NO, or NX, MO prostate cancer, one group (648 patients) treated and followed in the pre-PSA era (1966-1988), another group (707 patients) treated and followed in the PSA era (1987-1993)--who received definitive radiation as their only initial treatment. The patterns of relapse and prognostic factors for these groups were compared and contrasted using univariate and multivariate techniques., Results: At a median follow-up of 6.5 years, the relapse patterns in the pre-PSA series were: local in 109 (17%), nodal in 17 (3%), and distant metastatic in 186 (29%). Actuarial local and metastatic rates at 5 years were 13 and 26%, respectively. Local recurrence was only weakly predictable, Gleason grade being the only significant, albeit weak, covariate. Metastatic failure, however, was highly significantly and meaningfully correlated with Gleason grade and T-stage. Because metastasis was the most common adverse end point in this series, overall freedom from progression also correlated with grade and stage. At a median follow-up of 31 months, the patterns of failure in the PSA series were: local in 77 (11%), nodal in 3 (< 1%), and distant metastatic in 24 (3%). Actuarial local and metastatic rates at 5 years were 30 and 6%, respectively. Local recurrence was highly and meaningfully correlated with pretreatment PSA level, which was the only significant determinant of this end point. Metastatic failure was highly correlated with Gleason grade and T-stage, with PSA playing a much lesser, though significant role. The inversion of failure patterns (local vs. distant) between the two series was striking. The high incidence of local failure in the PSA series was almost entirely related to positive prostatic biopsies pursuant to the investigation of the postradiation rising PSA profile. Of the 77 local recurrences, 69 (90%) were identified in this way. Among 99 men with rising PSA values who underwent investigation (CT scans, bone scans, and biopsies), disease was found in 86, and the patterns of disease in these 86 were: local only in 62 (72%), local and metastatic in 7, and metastatic in 17 (20%). The most common event in the PSA series was the rising PSA profile, and this, too, strongly correlated with the pretreatment PSA level., Conclusion: Based on our earlier finding that the major source of pretreatment serum PSA in patients with clinically localized disease is the primary tumour itself and on the findings in the present report, we conclude that the new major message conveyed by serum PSA relates to the primary tumor and its likely outcome. Gleason grade and T-stage remain major determinants of metastatic relapse. The total and permanent eradication of prostate cancer from the prostate with conventional doses of external beam radiation therapy is harder to achieve than generally appreciated.

Purpose: This study was undertaken to: (a) define the prognostic significance of pretreatment serum prostate-specific antigen (PSA) levels in localized prostate cancer treated with radiation; (b) define the prognostic usefulness of postradiation PSA levels; (c) evaluate the outcome of radiation using PSA as an endpoint., Methods and Materials: Disease outcome in 707 patients with Stages T1 (205 men), T2 (256 men), T3 (239 men), and T4 (7 men), receiving definitive external radiation as sole therapy, was evaluated using univariate and multivariate techniques., Results: At a mean follow-up of 31 months, 157 patients (22%) developed relapse or a rising PSA. Multivariate analysis revealed pretreatment PSA level to be the most significant prognostic factor, with lesser though significant contributions due to Gleason grade (2-6 vs. 7-10) and transurethral resection in T3/T4 disease. The following four prognostic groupings were defined: group I, PSA < or = 4 ng/ml, any grade; group II, 4 < PSA < or = 20, grades 2-6; group III, 4 < PSA < or = 20, grades 7-10; group IV, PSA > 20, any grade. Five-year actuarial relapse rates in these groups were: I, 12%; II, 34%; III, 40%; and IV, 81%. Posttreatment nadir PSA was an independent determinant of outcome and only patients with nadir values < 1 ng/ml fared well (5-year relapse rate 20%). Using rising PSA as an endpoint the 461 patients with T1/T2 disease had an actuarial freedom from disease rate of 70% at 5 years, which appeared to plateau, suggesting that many were cured. No plateau was evident for T3/T4 disease., Conclusion: Pretreatment serum PSA is the single most important predictor of disease outcome after radiation for local prostate cancer. Tumor grade has a lesser though significant prognostic role. Postirradiation nadir PSA value during the first year is a sensitive indicator of response to treatment. Only nadir values < 1 ng/ml are associated with a favorable outlook. A significant fraction of men with T1/T2 disease may be cured with radiation. There was no evidence for a cured fraction among patients with T3/T4 disease.

Purpose: The response of patients with clinical stages T1-4 prostate cancer to radiotherapy is variable. A particularly poor prognostic group has been found to be comprised of those with pretreatment prostate specific antigen (PSA) levels above 30 ng/ml with any tumor grade, or PSA levels > 10 and < or = 30 with tumors grade 3 or 4. These patients have over an 80% actuarial risk of biochemical failure 3 years after definitive external beam radiotherapy. Thus, patients with these high-risk features require more aggressive therapy. During the last 3-4 years, the policy to treat such patients with radiotherapy and androgen ablation (XRT/HORM) was instituted. A retrospective comparison was made between high-risk patients treated with radiotherapy alone (XRT) vs. XRT/HORM., Methods and Materials: Between 1987 and 1991, there were 81 high-risk patients treated with XRT. There were 38 high-risk patients treated with XRT/HORM between 1990 and 1992. The median follow-up was 37 months for the XRT group and 22 months for the XRT/HORM group. No patient had clinical, radiographic, or pathologic evidence of lymph node involvement. The median dose to the prostate was 66 Gy for the XRT group and 68 Gy for the XRT/HORM group., Results: The distributions of several potential prognostic factors were analyzed. Significant differences between the groups were observed for tumor grade, pretreatment prostatic acid phosphatase, and age. The XRT/HORM group was composed of patients with worse features, including a greater proportion of patients with grade 4 tumors, more with abnormal acid phosphatase levels, and more under 60 years of age. The actuarial incidence of a rising PSA at 3 years for the XRT group was 81% vs. 15% for the XRT/HORM group (p < 0.0001). In addition, local relapse at 3 years was 34% for the XRT group and 15% for the XRT/HORM group (p < 0.02). There was no difference between the groups in terms of survival. Cox proportional hazards analyses were performed using several disease end points, including a rising PSA, a rising PSA or disease relapse, any disease relapse, and local relapse, and the only prognostic factor of independent predictive value was treatment group, i.e., XRT vs. XRT/HORM., Conclusions: Based on biochemical and disease relapse end points, definitive radiotherapy is insufficient treatment for high-risk prostate cancer patients. The addition of androgen ablation significantly reduces the recurrence rates, although longer follow-up is needed to determine if the combined treatment impacts significantly on survival.

Purpose: Prostate-specific antigen (PSA) is an important marker for prostate cancer and has been shown to be secreted from the primary tumor and from metastases. However, the relative contribution of the primary and micrometastatic disease to the serum level of PSA in patients with clinically localized disease has not been delineated. This study addresses the source of pretreatment serum PSA in patients with clinically localized disease., Methods and Materials: The fall in serum PSA level following radical prostatectomy (280 patients; 105 T1, 165 T2, 10 T3) or definitive radiotherapy (427 patients; 122 T1, 147 T2, 158 T3/T4) was analyzed with the assumption that any fall in PSA following local treatment reflects the fraction of PSA produced in the prostate and its primary tumor., Results: Serum PSA level became undetectable in 277 of the 280 (99%) patients within 6 months of radical prostatectomy. The three patients who did not achieve undetectable levels had postsurgical values < or = 0.9 ng/ml. Following definitive radiotherapy, nadir serum PSA values were between < or = 0.3 and 20.3 ng/ml, with mean and median values of 1.9 and 1.2 ng/ml, respectively. Nadir PSA was undetectable in 52 patients (12%). Four patients' PSA did not fall, but rose from the start, and each developed metastatic disease within 9 months, and in each metastases appeared to contribute to pretreatment serum PSA. In the remaining patients, the maximal factor by which PSA fell to its nadir was higher the higher the pretreatment PSA level. We present arguments that this is most consistent with the hypothesis that virtually all detectable pretreatment serum PSA derives from the primary tumor. Confirmatory evidence that little of the pretreatment serum PSA came from metastases was obtained by extrapolating the rising PSA profile in 97 patients back to pretreatment time. Back-extrapolated PSA contributed a mean of 7% and a median of 5% to the pretreatment serum value. Because such back-extrapolated values estimate the potentially maximal micrometastatic contribution, metastatic disease at diagnosis contributes little to pretreatment serum PSA., Conclusion: In patients with clinically localized prostate cancer, putative micrometastatic disease contributes negligibly to the pretreatment serum PSA level even when the latter is high. Most likely such patients, when they have metastases, have a very low metastatic burden.

Objectives: To determine the frequency of abnormal p53 expression and to characterize confirmed p53 mutations in tumors from patients with clinically localized adenocarcinoma of the prostate., Methods: p53 protein nuclear accumulation was determined immunohistochemically in the initial diagnostic tumor specimens from 37 patients with clinically localized prostate carcinoma. Two primary antibodies were used on all specimens. Structural analysis of the p53 gene was performed using the methods of polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) and DNA sequencing., Results: In 1 of the 37 (2.7%) tumor specimens, intense p53 nuclear staining was demonstrated using either antibody PAb 1801 or CM-1. The staining in this case was heterogeneous, with approximately 40% of tumor nuclei staining for p53. This tumor specimen was microdissected and DNA was extracted. Following PCR amplification, abnormally migrating bands were noted on SSCP analysis of exon 8. DNA sequencing confirmed the mutation as a C-->A transversion in codon 281 (asp-->glu). PCR/SSCP analysis of exons 5 through 8 was also performed for seven additional tumors that were negative for p53 nuclear accumulation by immunohistochemical (IHC) methods. All of these specimens demonstrated wild-type p53., Conclusions: The results of this study confirm and extend our previous findings that p53 mutations are rare in clinically localized adenocarcinoma of the prostate. In detecting clonal p53 mutations, standard immunohistochemical technique correlates reliably with structural p53 gene analysis of the evolutionary conserved domains encompassing exons 5-8. Importantly, most reports have demonstrated that p53 mutations detected by IHC are a late step in the progression of prostate cancer and are associated with advanced disease, dedifferentiation, and the acquisition of androgen independence.

Objectives: To evaluate disease outcome using serum prostate-specific antigen (PSA) as an outcome measure in patients with T1 or T2 prostate cancer treated with radiation therapy in the PSA era., Methods: We reviewed the outcome for 461 patients with T1 (n = 205) or T2 (n = 256) prostate cancer followed for a median of 31 months after radiation therapy as the sole initial treatment. Univariate and multivariate analyses were used to delineate significant prognostic factors., Results: The freedom from relapse or rising PSA rate was 70% at 6 years and the survival rate was 83%. Although T stage, Gleason grade, serum prostatic acid phosphatase level, and serum PSA level were each significant determinants of outcome in univariate analysis, pretreatment PSA level was the only clearly independent covariate (P < 0.0001) in multivariate analysis. The 5-year actuarial freedom from relapse or from rising PSA levels is shown according to the pretreatment PSA level: 4 ng/mL or less (117 patients), 91%; more than 4 but 10 ng/mL or less (169 patients), 69%; more than 10 but 20 ng/mL or less (118 patients), 62%; and more than 20 ng/mL (57 patients), 38%. PSA doubling times in 75 patients with rising post-treatment profiles ranged from 1.3 to 78.2 months (mean, 14.4; median 11.3). Faster doubling times correlated significantly with adverse pretreatment prognostic factors (high-grade, high pretreatment PSA, and aneuploidy). To date, the survival rate of patients with rising PSA profiles was not depressed below the expected., Conclusions: Radiation therapy is an acceptable modality for treating T1 or T2 disease and produces results comparable to those following radical prostatectomy when patients are stratified according to their pretreatment PSA value. The rapid PSA doubling times observed in patients with relapsing disease are more consistent with a "selective" rather than an "aggravation" mechanism.

Purpose: It is common practice to histologically grade adenocarcinoma of the prostate using the Gleason system. Whereas the prognostic utility of this grading is well known, few studies have comprehensively evaluated it for patients undergoing definitive radiation therapy and generally accepted guidelines as to which Gleason grades should be "lumped" have not been established. This study reports the results of univariate and multivariate evaluation of the prognostic significance of Gleason grade in 648 patients followed for a median of 6.5 years after radiation therapy for T1 to T4, N0, or NX, MO prostate cancer., Methods and Materials: The correlation between Gleason grade and local recurrence, metastatic relapse, any disease relapse, and patient survival was evaluated using univariate and multivariate methods. Analysis was also stratified according to whether the grading was assigned on a needle biopsy or on a transurethral resection specimen., Results: The large number of Gleason grades required grouping of grades for meaningful analysis and we found that a four-tier system (grades 2 and 3, 155 patients; grades 4-6, 290 patients; grade 7, 92 patients; and grades 8-10, 111 patients) correlated best with outcome. In univariate analysis, this four-tier grouping correlated significantly with local recurrence, distant metastases, any relapse, and survival. The incidences of distant metastasis at 10 years were: grades 2 and 3, 13%; grades 4-6, 34%; grade 7, 52%; and, grades 8-10, 63%. The survival rates at 10 years were: grades 2 and 3, 64%; grades 4-6, 60%; grade 7, 46%; and grades 8-10, 24%. In multivariate analysis, Gleason grade was the single most important determinant of outcome for each endpoint. These results applied equally to needle biopsy and transurethral resection specimens., Conclusion: Tumor grade is the single most significant determinant of outcome following radiotherapy for clinically localized prostate cancer. The Gleason system is a valid method for grading tumors to be irradiated. A four-tier grouping into grades 2 and 3, grades 4-6, grade 7, and grades 8-10 appears to be adequate and simple.

Purpose: Patients with node-positive prostate cancer that is regionally localized (T1-4, N1-3, M0) have a relatively poor prognosis when a single-treatment modality such as radical surgery, definitive radiotherapy, or androgen ablation is used. While promising results using radical surgery and androgen ablation have been reported, there are no data to support an analogous approach using local radiotherapy and androgen ablation. In this retrospective review, the outcome after local radiotherapy and early androgen ablation (XRT/HORM) was compared to early androgen ablation alone (HORM)., Methods and Materials: Between 1984 and 1992 there were 181 patients treated with HORM and 27 patients treated with XRT/HORM at the University of Texas M. D. Anderson Cancer Center. The nodal status of all patients was established pathologically by lymph node dissection, which was terminated after frozen section confirmation of involvement. In the majority of cases androgen ablation was by orchiectomy. The median dose to the prostate in XRT/HORM group was 66 Gy. The median follow-up was 45 months; 49 months for the HORM group and 25 months for the XRT/HORM group., Results: The distribution of prognostic factors between the HORM and XRT/HORM groups was similar, with the exception of tumor grade. There was a significantly larger proportion of high grade tumors in the HORM group. In terms of actuarial disease outcome, at 4 years the results of patients in the HORM group were significantly worse, including a rising prostate specific antigen (PSA) of 53%, any disease progression of 32%, a rising PSA or disease progression of 55%, and local progression of 22%. None of the patients in the XRT/HORM group failed biochemically or clinically. To determine the impact of grade on these findings, the analyses were repeated, using only those with grade 2 tumors. A similar pattern was evidenced with significantly worse actuarial outcome at 4 years for the HORM group using the endpoints of a rising PSA (46%), any disease progression (24%), and a rising PSA or disease progression (47%)., Conclusion: Node-positive prostate cancer patients with regionally localized disease fared significantly better when combined local radiotherapy and early androgen ablation were used, as compared to early androgen ablation alone. Although the number of patients in the XRT/HORM group was small and follow-up was short, the combined treatment had a dramatic effect on disease outcome and, therefore, a larger prospective randomized trial is warranted.

Objectives: To determine the prognostic significance of microvessel density (a measure of tumor angiogenesis) in comparison with other prognostic factors for patients with clinically localized prostatic carcinoma treated with external beam radiotherapy., Methods: Microvessel density was quantified within the initial invasive carcinoma from the diagnostic transurethral resection specimen of 25 patients with a mean follow-up of 44 months. Microvessels were identified by immunohistochemical staining of endothelial cells for factor VIII-related antigen in formalin-fixed, paraffin-embedded tissue. Microvessels were counted in a x200 field (0.754 mm2) in the area of maximal angiogenesis., Results: Microvessel density correlated with several pretreatment prognostic factors, including prostate-specific antigen (PSA) (p < 0.0001), tumor grade (p = 0.006), and ploidy (p = 0.016). The degree of tumor angiogenesis also correlated with outcome following external beam radiotherapy. The mean microvessel count in the nine tumors from patients who failed radiotherapy (ie, had rising PSA and/or clinical relapse) was 97.0 +/- 33.6 (+/- SD) per x200 field compared with 46.1 +/- 17.1 for the 16 patients with no evidence of failure (p < 0.0001). Increased microvessel density was also associated with a significantly worse actuarial outcome at 4 years using either biochemical relapse (rising PSA) or a composite endpoint of rising PSA or clinical relapse (p = 0.0003)., Conclusions: The intratumoral quantification of tumor angiogenesis may prove valuable as a prognostic indicator in patients with clinically localized prostate cancer treated with radiotherapy.

Between 1987 and 1991, 269 patients with clinical stage T1 or T2, N0 or Nx adenocarcinoma of the prostate underwent external beam radiation therapy as the sole initial treatment and were followed with serial prostate specific antigen (PSA) levels for 9 to 73 months (mean 33, median 30). Of the patients 26 had clinical evidence of disease relapse, 58 had an increasing PSA profile and 62 had either relapse or an increasing PSA. The actuarial incidence of increasing PSA was 30% at 5 years and the incidence of relapse or increasing PSA was 36% at the same time. With relapse or increasing PSA level as an end point, pretreatment PSA level, Gleason grade and serum prostatic acid phosphatase level were individually significant covariates. However, in multivariate analysis only pretreatment PSA level was significant. The 5-year actuarial rates of relapse or increasing PSA according to pretreatment PSA level were 4 ng./ml. or less-14%, greater than 4 to 10 ng./ml.-33%, greater than 10 to 30 ng./ml.-55% and greater than 30 ng./ml.-greater than 80%. Post-irradiation PSA levels at 3 and 6 months provided prognostic information additional to that inherent before treatment. However, the nadir PSA value, achieved typically at 6 to 12 months, was the most significant aspect of posttreatment PSA. Patients with a nadir PSA level of less than 1 ng./ml. fared well, with a 12% incidence of relapse or increasing PSA at 5 years. Nadir values exceeding 1 ng./ml. were associated with an increasing relapse rate as the nadir value increased, and nearly two-thirds of the cases in which the nadir exceeded 4 ng./ml. failed by 2 years. When increasing PSA was used as an end point additional to relapse, the outcome in this series was significantly worse than in an earlier series evaluated without PSA. Comparing these 2 series resulted in an estimate that PSA begins to increase approximately 4 to 5 years before the appearance of clinically overt disease. These results reveal the high significance of pretreatment PSA levels, significance of nadir PSA values after treatment, earlier detection of persistent disease by the increasing PSA profile, and the fact that total and permanent eradication of localized prostate cancer is considerably more difficult than traditionally believed. The therapeutic implications of this series, and the implications on the quantity and quality of patient lives await prospective study.

Objectives: DNA-ploidy is a strong prognostic factor for prostate cancer patients treated with definitive external beam radiotherapy. Using DNA/nuclear protein flow cytometry, three prognostic groups based on DNA-ploidy were identified: from good to poor, these are diploid, near-diploid, and nondiploid tumors. Since recent evidence indicates that the rate at which prostate-specific antigen (PSA) increases in the presence of biochemical failure is predictive of the time to clinical relapse, we examined the relationship between DNA-ploidy and PSA doubling time (PSA-DT)., Methods: Formalin-fixed paraffin-embedded tissues from 76 patients treated at M.D. Anderson Cancer Center with definitive radiotherapy alone were analyzed for ploidy using DNA/nuclear protein flow cytometry. Of these, 24 of the 27 patients with a rising PSA profile had three or more post-treatment PSA values from which the PSA-DTs were calculated. PSA-DTs were estimated using nonlinear regression techniques., Results: The average PSA-DT for the 24 patients in this cohort was 11.3 +/- 10.5 months (+/- SD) with a median of 8.4 months. Diploidy (n = 3) was associated with a PSA-DT of 27.0 +/- 22.8 months, near-diploidy (n = 7) with a PSA-DT of 12.2 +/- 5.7 months, and non-diploidy (n = 14) with a PSA-DT of 7.5 +/- 5.7 months (p = 0.004, Spearman rank test). Stage, grade, and pretreatment PSA, as well as the endpoints of local control, freedom from metastases, and freedom from any relapse, did not correlate significantly with PSA-DT values. However, when patients were subdivided by PSA-DT into those with values 10 months or less (n = 14) and those more than 10 months (n = 10), there was a correlation with 3-year actuarial freedom from relapse: 28% and 74%, respectively (p < 0.01, log-rank). This subdivision of PSA-DT also correlated with DNA-ploidy (p = 0.03, chi-square) and stage (p = 0.04)., Conclusions: The results show that there is a significant correlation of DNA-ploidy with PSA-DT. Diploidy was associated with the longest PSA-DTs, near-diploidy with intermediate PSA-DTs, and nondiploidy with short PSA-DTs. Patients with short PSA-DTs also had significantly higher actuarial rates of disease relapse at 3 years. These data confirm that PSA-DT is a strong predictor of tumor behavior and that patients who have nondiploid tumors probably require more aggressive, combined modality, treatment.

The primary goal of radical radiation therapy in men with localized prostate carcinoma is cure and a secondary but important goal is to achieve cure without treatment related sequelae, such as loss of continence, rectal injury, loss of potency and the need for castration. A literature review of 2,611 men undergoing irradiation for all stages of localized prostatic carcinoma documented a 0.2% incidence of treatment related mortality, 1.9% severe complications, 0.9% incontinence and 33 to 60% maintenance of full potency 5 or more years after treatment. A separate analysis was made of 331 patients with only early tumors (stages T1 and T2) treated with conventional external beam radiation therapy to doses of 63 to 74 Gy. from 2 individual centers (Massachusetts General Hospital and M.D. Anderson Hospital) and 1 multi-institutional group (Radiation Therapy Oncology Group). Median followup was 6.1 years; however, in 2 series followup ranged to 14 years. This analysis revealed frequencies of treatment associated sequelae of 0% for mortality, 0% severe complications, 0.4% urinary incontinence, 5.4% genitourinary structures (1.2% persisting), 5.1% hematuria (0.9% persisting) and 5.4% rectal bleeding (0.6% persisting). This composite analysis of men undergoing irradiation for stages T1 and T2 tumors with conventional fractionation and doses indicates that acute morbidity is minor and usually transient, severe injury is rare, most late gastrointestinal and genitourinary symptoms of radiation injury are neither permanent nor debilitating, and few symptoms of radiation injury develop beyond 5 years from treatment. These data, combined with the low progression rates (using prostate specific antigen criteria) following irradiation of men with early tumors, further substantiate the primary role of radical radiotherapy in the treatment of surgical risk adversive patients.

Purpose: The increasing proportion of early stage prostate cancer diagnosed by various early detection methods together with reports espousing watchful waiting as a management option raise the possibility that patients may be selected for surveillance according to their initial presentation., Methods and Materials: The outcome for 427 men with clinical stages T1 to T4 localized prostate cancer treated with radiation therapy was evaluated according to their presentation: elevated prostate-specific antigen (PSA) level; abnormal digital rectal examination; or, urologic symptomatology., Results: With a median follow-up of 30 months, there were no significant differences in disease outcome according to initial presentation. The actuarial incidence of relapse at 5 years was: PSA-detected (54 patients), 24%; digital rectal-detected (173 patients) 29%; and, symptom-detected (200 patients) 31% (p = 0.79). Likewise, there were no significant differences in the incidence of postradiation rising PSA profiles among the three groups. The actuarial incidence of relapse and/or rising PSA at 5 years was: PSA-detected 35%; digital rectal-detected 42%; symptom-detected, 48% (p = 0.72). On the other hand, T-stage, Gleason grade, pretreatment PSA, pretreatment acid phosphatase, and transurethral resection in T3/T4 disease were each highly correlated with outcome. In multivariate proportional hazards regression pretreatment PSA (p = 0.0003), Gleason grade (p = 0.045), and transurethral resection in T3/T4 disease (p = 0.0562) correlated with outcome, but initial presentation did not (p = 0.25)., Conclusion: The absence of a prognostic gradient, good to bad, from PSA-detected through digital rectal-detected to symptom-detected cancer suggests that the initial presentation of patients with localized prostate cancer is not a valid basis for selecting watchful waiting vs. initial treatment.