Evaluation of nuclear factor κB and chemokine receptor CXCR4 co-expression in patients with prostate cancer in the Radiation Therapy Oncology Group (RTOG) 8610.

OBJECTIVE: To determine the frequency of nuclear factor κB (NFκB) and the chemokine receptor CXCR4 co-expression in prostate cancer specimens from men with locally advanced disease. PATIENTS AND METHODS: Paraffin-embedded samples from patients enrolled on the Radiation Therapy Oncology Group (RTOG) 8610 trial underwent immunohistochemical staining for NFκB and CXCR4. The amount of NFκB and CXCR4 was scored by a 'blinded' pathologist for the percentage of cells stained (0-100%) and staining intensity (0-3 +). Cox proportional hazard models were used for overall survival and disease-free survival to examine if NFκB and/or CXCR4 expression were associated with patient outcomes with and without adjustment for covariates. RESULTS: Available material and successful staining allowed NFκB and CXCR4 status to be determined for 55 and 63 patients, respectively. Both NFκB and CXCR4 status were available for 51 patients. Of these, 53% were 2/3 + for cytoplasmic NFκB staining and 56% were 2/3 + for CXCR4. In all, 18 of the 51 patients were 2/3 + for both NFκB and CXCR4 (P = 0.129). Ten of 11 patients with 3 + NFκB had 2/3 + CXCR4 (P= 0.004). In this small study, neither NFκB nor CXCR4 were associated with prostate cancer outcomes. CONCLUSIONS: High NFκB expression is associated with CXCR4 expression and they are co-expressed in about one third of patients with clinically localized prostate cancer. Larger studies to accurately determine the frequency of co-expression and prognostic utility of NFκB and CXCR4 alone and in combination are warranted.

Racial differences in CYP3A4 genotype and survival among men treated on Radiation Therapy Oncology Group (RTOG) 9202: a phase III randomized trial.

PURPOSE: Inherited genotypes may explain the inferior outcomes of African American (AA) men with prostate cancer. To understand how variation in CYP3A4 correlated with outcomes, a retrospective examination of the CYP3A4 *1B genotype was performed on men treated with Radiation Therapy Oncology Group (RTOG) 92-02. METHODS AND MATERIALS: From 1,514 cases, we evaluated 56 (28.4%) of 197 AA and 54 (4.3%) of 1,274 European American (EA) patients. All patients received goserelin and flutamide for 2 months before and during RT (STAD-RT) +/- 24 months of goserelin (long-term androgen deprivation plus radiation [LTAD-RT]). Events studied included overall survival and biochemical progression using American Society for Therapeutic Radiology and Oncology consensus guidelines. RESULTS: There were no differences in outcome in patients in with or without CYP3A4 data. There was an association between race and CYP3A4 polymorphisms with 75% of EAs having the Wild Type compared to only 25% of AA men (p <0.0001). There was no association between CYP3A4 classification or race and survival or progression. CONCLUSIONS: The samples analyzed support previously reported observations about the distribution of CYP3A4 *1B genotype by race, but race was not associated with poorer outcome. However, patient numbers were limited, and selection bias cannot be completely ruled out.

Early initiation of salvage hormone therapy influences survival in patients who failed initial radiation for locally advanced prostate cancer: A secondary analysis of RTOG protocol 86-10.

PURPOSE: We examined overall and disease-specific survival outcomes both from the time of initial treatment and from the start of salvage hormone therapy (HT), by the extent of disease progression at the time salvage HT was started in patients treated on RTOG Protocol 86-10. METHODS: [corrected] With a median follow-up of 9.0 years, 247 patients (54%) had received subsequent salvage HT. The overall survival (OVS) and disease-specific survival (DSS) were compared by the extent of disease progression at the time salvage HT was started. RESULTS: For those patients with distant metastases (DM) present at the start of salvage HT, the OVS and DSS were significantly reduced when compared to [corrected] those with DM absent at the time salvage HT was started (OVS at 8 years, 31% vs. 58%; DSS at 8 years, 38% vs. 65%). A statistically significant increase in DSS was observed among the 143 patients with DM absent when patients with prostate-specific antigen (PSA) less than 20 were compared with those with PSA greater than 20 at the time salvage HT was started. CONCLUSION: [corrected] The DSS and the OVS of the relapsed patient are decreased in those with more extensive disease at the time of salvage HT. However, because this protocol could not evaluate the effect of posttreatment PSA velocity on outcomes, which is likely a better predictor of long-term success with salvage HT, these results cannot be taken to demonstrate that early salvage HT in patients with long posttreatment PSA doubling times is necessary for longer survival.

Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31.

PURPOSE: Radiation Therapy Oncology Group protocol 85-31 was designed to evaluate the effectiveness of adjuvant androgen suppression, using goserelin, in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy (RT). METHODS AND MATERIALS: Eligible patients were those with palpable primary tumor extending beyond the prostate (clinical Stage T3) or those with regional lymphatic involvement. Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement was documented histologically. Stratification was based on histologic differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either RT and adjuvant goserelin (Arm I) or RT alone followed by observation and application of goserelin at relapse (Arm II). In Arm I, the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression. RESULTS: Between 1987 and 1992, when the study was closed, 977 patients were entered: 488 to Arm I and 489 to Arm II. As of July 2003, the median follow-up for all patients was 7.6 years and for living patients was 11 years. At 10 years, the absolute survival rate was significantly greater for the adjuvant arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year local failure rate for the adjuvant arm was 23% vs. 38% for the control arm (p <0.0001). The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24% vs. 39% (p <0.001) and 16% vs. 22% (p = 0.0052), respectively, both in favor of the adjuvant arm. CONCLUSION: In a population of patients with unfavorable prognosis carcinoma of the prostate, androgen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival. The improvement in survival appeared preferentially in patients with a Gleason score of 7-10.

Ki-67 staining index predicts distant metastasis and survival in locally advanced prostate cancer treated with radiotherapy: an analysis of patients in radiation therapy oncology group protocol 86-10.

PURPOSE: Proliferative activity defined by Ki-67 staining index (SI) has been correlated with progression and prognosis in a number of malignant tumors including prostate cancer. However, few studies have examined Ki-67 SI in pretreatment diagnostic material from patients treated with definitive radiotherapy. In a prior study, we found that a Ki-67 SI of >3.5% was associated with poorer patient outcome. The goals of this analysis were to validate the prognostic value of Ki-67 SI and this cut point. EXPERIMENTAL DESIGN: Of 456 assessable patients in Radiation Therapy Oncology Group Protocol 86-10, diagnostic material from 108 patients was available for Ki-67 analysis using MIB-1 antibody. Sixty patients were treated with external beam radiotherapy (EBRT) alone, and 48 patients were treated with short-term androgen deprivation + EBRT. Median follow-up was 9 years for those living. The relationship of Ki-67 with distant metastasis (DM), disease-specific survival (DSS), and overall survival (OS) was examined. RESULTS: The median Ki-67 SI was 7.1% (range, 0.2-45.5%). The 7.1% cut point was associated with DM and DSS; however, the 3.5% cut point was as strong a determinant and was the focus of this analysis. In Cox proportional hazards regression, Ki-67 SI was independently associated with DM and DSS. When the Ki-67 SI was 3.5%, the 5-year risk of DM was 13.5% and 50.8% (P = 0.0005), respectively, and the 5-year risk of DSS was 97.3% and 67.7% (P = 0.0039), respectively. No association of Ki-67 SI with OS was observed. CONCLUSIONS: Higher Ki-67 SI was significantly associated with a greater risk of DM and DSS in locally advanced prostate cancer after definitive EBRT or AD + EBRT.

Effect of a short course of neoadjuvant hormonal therapy on the response to subsequent androgen suppression in prostate cancer patients with relapse after radiotherapy: a secondary analysis of the randomized protocol RTOG 86-10.

PURPOSE: To compare, by a secondary analysis, the therapeutic benefits of androgen suppression in protocol prostate cancer patients with relapse after radiotherapy (RT) for locally advanced disease who, in the Phase III trial beginning in 1987, were assigned to receive or not receive a short course of neoadjuvant maximal androgen suppression before definitive RT. METHODS AND MATERIALS: Between 1987 and 1991, 456 patients were entered in the Radiation Therapy Oncology Group trail 86-10 and randomized to receive (Arm I) or not to receive (Arm II) neoadjuvant hormonal therapy (HT), which was 4 months of goserelin (3.6 mg every 4 weeks) and flutamide (250 mg t.i.d.) before and during RT for bulky T2-T4 tumors. The overall and disease-specific survival after both randomization and salvage HT for patients with relapse was evaluated, as well as the duration of response in those patients undergoing salvage HT. The outcomes in patients who had received neoadjuvant HT vs. those who had not were compared. The median follow-up after randomization for all alive patients was 9.0 years and was 5.5 years for alive patients after beginning salvage HT. RESULTS: Fewer patients received salvage HT on Arm I than on Arm II (45% vs. 63%, p <0.001). The outcomes by randomized treatment arm (I vs. II) from the time of beginning salvage HT were similar. At 5 years after salvage HT, the overall survival rates were 41% and 41% and the disease-specific survival rates were 50% and 50%. At 8 years after randomization, the overall survival rates were 47% and 44% and the disease-specific survival rates were 55% and 56%. CONCLUSION: Although a 4-month course of neoadjuvant and concurrent maximum androgen suppression and RT (compared with RT alone) significantly increases the freedom from relapse rate and freedom from receiving salvage HT, it does not compromise the long-term beneficial effect of subsequent salvage HT, if needed for relapse. These findings with long follow-up in patients treated for locally advanced disease diagnosed 9-14 years previously should help allay concerns of the possible development of "resistance" to androgen suppression when 4-month courses of neoadjuvant HT are used before primary treatment.

Vascular endothelial growth factor (VEGF) expression in locally advanced prostate cancer: secondary analysis of radiation therapy oncology group (RTOG) 8610.

BACKGROUND: Angiogenesis is a key element in solid-tumor growth, invasion, and metastasis. VEGF is among the most potent angiogenic factor thus far detected. The aim of the present study is to explore the potential of VEGF (also known as VEGF-A) as a prognostic and predictive biomarker among men with locally advanced prostate cancer. METHODS: The analysis was performed using patients enrolled on RTOG 8610, a phase III randomized control trial of radiation therapy alone (Arm 1) versus short-term neoadjuvant and concurrent androgen deprivation and radiation therapy (Arm 2) in men with locally advanced prostate carcinoma. Tissue samples were obtained from the RTOG tissue repository. Hematoxylin and eosin slides were reviewed, and paraffin blocks were immunohistochemically stained for VEGF expression and graded by Intensity score (0-3). Cox or Fine and Gray's proportional hazards models were used. RESULTS: Sufficient pathologic material was available from 103 (23%) of the 456 analyzable patients enrolled in the RTOG 8610 study. There were no statistically significant differences in the pre-treatment characteristics between the patient groups with and without VEGF intensity data. Median follow-up for all surviving patients with VEGF intensity data is 12.2 years. Univariate and multivariate analyses demonstrated no statistically significant correlation between the intensity of VEGF expression and overall survival, distant metastasis, local progression, disease-free survival, or biochemical failure. VEGF expression was also not statistically significantly associated with any of the endpoints when analyzed by treatment arm. CONCLUSIONS: This study revealed no statistically significant prognostic or predictive value of VEGF expression for locally advanced prostate cancer. This analysis is among one of the largest sample bases with long-term follow-up in a well-characterized patient population. There is an urgent need to establish multidisciplinary initiatives for coordinating further research in the area of human prostate cancer biomarkers.

Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.

PURPOSE: Radiation Therapy Oncology Group (RTOG) 8610 was the first phase III randomized trial to evaluate neoadjuvant androgen deprivation therapy (ADT) in combination with external-beam radiotherapy (EBRT) in men with locally advanced prostate cancer. This report summarizes long-term follow-up results. MATERIALS AND METHODS: Between 1987 and 1991, 456 assessable patients (median age, 70 years) were enrolled. Eligible patients had bulky (5 x 5 cm) tumors (T2-4) with or without pelvic lymph node involvement according to the 1988 American Joint Committee on Cancer TNM staging system. Patients received combined ADT that consisted of goserelin 3.6 mg every 4 weeks and flutamide 250 mg tid for 2 months before and concurrent with EBRT, or they received EBRT alone. Study end points included overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), disease-free survival (DFS), and biochemical failure (BF). RESULTS: Ten-year OS estimates (43% v 34%) and median survival times (8.7 v 7.3 years) favored ADT and EBRT, respectively; however, these differences did not reach statistical significance (P = .12). There was a statistically significant improvement in 10-year DSM (23% v 36%; P = .01), DM (35% v 47%; P = .006), DFS (11% v 3%; P < .0001), and BF (65% v 80%; P < .0001) with the addition of ADT, but no differences were observed in the risk of fatal cardiac events. CONCLUSION: The addition of 4 months of ADT to EBRT appears to have a dramatic impact on clinically meaningful end points in men with locally advanced disease with no statistically significant impact on the risk of fatal cardiac events.