Pretreatment Prostate-specific Antigen Level Research Articles

Efficacy and toxicity of intensity-modulated radiation therapy for prostate cancer in Chinese patients

To report the treatment efficacy and toxicity profile of intensitymodulated radiation therapy in Chinese patients with clinically localised prostate cancer. Historical cohort study. Oncology unit in a university teaching hospital in Hong Kong. Patients with clinically localised prostate cancer undergoing intensity-modulated radiation therapy in our institution between May 2001 and November 2009 were reviewed. The 5-year biochemical failure–free survival, 5-year overall survival, as well as acute/late gastro-intestinal toxicities and genito-urinary toxicities. A total of 182 patients were treated with prostate intensitymodulated radiation therapy with or without whole-pelvic radiotherapy. The median follow-up was 44 months. The median patient age was 72 years. Overall survival of the cohort was 92% after 5 years. The favourable, intermediate, and unfavourable risk category distributions of the National Comprehensive Cancer Network were 21 (12%), 42 (23%), and 119 (65%), respectively. The 5-year actuarial biochemical failure–free survival rates for patients in these categories were 95%, 82%, and 80%, respectively. Multivariate analysis identified early tumour stage, low pre-treatment prostate-specific antigen levels, and the use of adjuvant androgen deprivation as independent prognostic factors for better biochemical failure–free survival. Grade 2 and 3 late gastro-intestinal/genito-urinary toxicities occurred in 8%/3% and 4%/3% of the patients, respectively. Intensity-modulated radiation therapy for prostate cancer is feasible and safe in the Chinese population. These data are consistent with the results of other series in Caucasian populations.

Expression of MMP-1, MMP-9 and TIMP-2 in prostate carcinoma and their influence on prognosis and survival

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) participate in tumorigenesis, and their association with disease outcome is highly controversial. The present study investigates the influence of MMP-1, MMP-9 and TIMP-2 on different clinicopathologic variables and disease-free survival (DFS) of patients with prostate carcinoma. Hundred and forty-five cases are included in the study, and levels of MMP/TIMP expressions are assessed in three tissue compartments (i.e., tumor, stroma and normal glands) with immunohistochemistry. Matrix metalloproteinase-1 expression in tumor cells was associated with lower Gleason scores, pretreatment prostate-specific antigen levels and lower incidence of vascular, perineural and extracapsular invasions. Moreover, MMP-9 positivity and TIMP-2 expression in normal glands were correlated with lower Gleason patterns and early stage at presentation. Expression of MMP in tumor cells and the presence of TIMP-2 in normal glands were associated with better DFS. Variability of MMP/TIMP expressions from case to case makes it difficult to evaluate their impact on clinical outcome. However, these proteins might be new and promising targets for prostate cancer therapy in the future.

Salvage CT-guided Transgluteal Cryoablation for Locally Recurrent Prostate Cancer: Initial Experiences

Technical feasibility of a computed tomography (CT)-guided transgluteal approach for salvage cryoablation of inoperable locally recurrent prostate cancer was evaluated retrospectively. Five procedures were performed under general anesthesia in five patients previously treated with radiation therapy. Median age was 64 years, and average pretreatment prostate-specific antigen (PSA) level was 2.77 ng/dL (range, 0.56–4.23 ng/dL). Each cryoablation procedure was completed in one session. No complications were reported. Mean 3-month and 6-month PSA levels were 0.35 ng/dL (range, 0.16–0.54 ng/dL) and 0.51 ng/dL (range, 0.09–0.94 ng/dL), respectively, representing mean decreases of 84% (range, 71%–92%) and 81% (range, 78%–84%), respectively. Salvage CT-guided transgluteal cryoablation of the prostate therefore appears technically feasible.

Outcomes of salvage prostate cryotherapy stratified by pre-treatment PSA: update from the COLD registry

In this study, we evaluate the outcomes of salvage cryotherapy for locally recurrent prostate cancer within the COLD (cryo online data) Registry. Furthermore, we assess the results of salvage cryotherapy (with intermediate follow-up) stratified by pre-treatment prostate-specific antigen (PSA) levels to determine which patients may best be suited for treatment. The COLD registry was developed as a prospective, centrally collected database among patients undergoing salvage cryoablation for locally recurrent prostate cancer following primary prostate radiotherapy with curative intent. Of the patients undergoing salvage cryotherapy (without neoadjuvant hormonal ablative therapy), complete medical records were available in 156 patients, with their mean follow-up being 3.8 years (0.9-12.7 years). The treatment outcomes of salvage cryotherapy were assessed using the Phoenix definition (nadir PSA + 2 ng/ml) of biochemical failure. Of our entire study population, the biochemical disease-free survival (bDFS) rates at 1, 2, and 3 years were 89.0, 73.7, and 66.7%, respectively. Stratification of our patients into two subgroups is based on their pre-treatment total serum PSA values <5 and ≥5 ng/ml, and bDFS rates at 3 years for these two subgroups were 78.3 and 52.9%, respectively. A Kaplan-Meier analysis of bDFS stratified by these same pre-treatment PSA values revealed that the subset of patients with a PSA ≥ 5 ng/ml had statistically significant poorer bDFS rates (P = 0.01). Salvage prostate cryotherapy is a potentially curative local salvage therapy. The importance of early referral when patients have a pre-treatment PSA < 5 ng/ml is essential to optimize treatment outcomes.

Diethylstilbestrol in castration‐resistant prostate cancer

What's known on the subject? and What does the study add? Diethylstilbestrol (DES) was the first hormone treatment used for prostate cancer and has also shown effectiveness in castration-resistant disease in small studies; however, concerns over thromboembolic toxicity have restricted its use in the past. Over 200 elderly men with castration-resistant prostate cancer were treated with 1-3 mg of DES, given with 75 mg aspirin and breast bud irradiation. Almost 30% of men showed a significant PSA response and the median time to PSA progression was 4.6 months. Almost 20% of patients with pain had a significant analgesic benefit. The most important toxicity was thromboembolism in 10% of men. Overall the drug has an acceptable toxicity profile and offers a palliative benefit in frail elderly men who may not be fit for chemotherapy. • To assess the efficacy and toxicity of diethylstilbestrol (DES) in the management of castration-resistant prostate cancer (CRPC). • A total of 231 patients with CRPC received treatment with DES at the Royal Marsden Hospital between August 1992 and August 2000. • The median pre-treatment prostate-specific antigen (PSA) level was 221 ng/mL. • DES was used at a dose of 1-3 mg daily, with aspirin 75 mg. • The primary endpoint was PSA response rate. • The PSA response rate (using PSA Working Group criteria) was 28.9%. • The median time to PSA progression was 4.6 months. • Of patients with bone pain, 18% had an improvement in their European Organisation for the Research and Treatment of Cancer pain score. • Thromboembolic complications were seen in 9.9% of all patients. • DES has significant activity in CRPC and can be of palliative benefit. • DES has an acceptable toxicity profile in the management of patients with symptomatic CRPC when used at a dose of 1-3 mg, combined with aspirin and prophylactic breast bud radiotherapy.

The impact of dose‐escalated radiotherapy plus androgen deprivation for prostate cancer using 2 linked nomograms

Randomized trials have demonstrated that escalated-dose external-beam radiotherapy (EDRT) is better than standard-dose radiotherapy (SDRT) for patients with prostate cancer and that adding androgen-deprivation therapy (ADT) to SDRT is better than SDRT alone; however, no trials have compared EDRT versus SDRT plus ADT or EDRT versus EDRT plus ADT. The authors designed a model to estimate the results of various doses of radiotherapy (RT) combined with various durations of ADT. From 1989 to 2007, 3215 men consecutively received definitive EDRT with or without ADT. In total, 2012 patients had complete records available for creating the nomogram. The duration of ADT varied for patients who received no RT (n = 1562), ≤6 months of RT (n = 145), from >6 months to <24 months of RT (n = 140), and ≥24 months of RT (n = 165) with a median follow-up of 65.7 months, 66.2 months, 60.1 months, and 63 months, respectively. The model included the following covariates: palpation T-category, biopsy Gleason score, the percentage of tumor cells with a Gleason pattern of 4 or 5, the percentage of tumor tissue, initial pretreatment prostate-specific antigen (PSA) level, ADT duration, and RT dose. Two nomograms, for outcomes with and without ADT, were created from a single competing-risks model. Biochemical failure was defined as a rise in serum PSA of 2 ng/mL over the post-treatment PSA nadir. According to the results from analyzing representative intermediate-risk to high-risk patient parameters, the gains from increasing the RT dose from 70 Gray (Gy) to 80 Gy were far less than the gains from adding ≥3 months of ADT. The nomograms provided unique patient-specific estimates of the effects of various doses and durations of RT and ADT. The results indicated that adding ADT to treatment for intermediate-risk and high-risk prostate cancer is far more beneficial than a modest RT dose escalation.

Role of Isotope Selection in Long-term Outcomes in Patients With Intermediate-risk Prostate Cancer Treated With a Combination of External Beam Radiotherapy and Low-dose-rate Interstitial Brachytherapy

To examine the rates of long-term biochemical recurrence-free survival (BRFS) with respect to isotope in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) and brachytherapy. A total of 242 consecutive patients with intermediate-risk prostate cancer were treated with iodine-125 ((125)I) or palladium-103 ((103)Pd) implants after EBRT (range 45.0-50.4 Gy) from 1996 to 2002. Of the 242 patients, 119 (49.2%) were treated with (125)I and 123 (50.8%) with (103)Pd. Multivariate Cox regression analysis was used to analyze BRFS, defined according to the Phoenix definition (prostate-specific antigen nadir plus 2 ng/mL) with respect to Gleason score, stage, pretreatment prostate-specific antigen level, and source selection. Late genitourinary/gastrointestinal toxicities were assessed using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. At a median follow-up of 10 years, the BRFS rate was 77.3%. A statistically significant difference was found in the 10-year BRFS rate between the (125)I- and (103)Pd-treated groups (82.7% and 70.6%, respectively; P = .001). The addition of hormonal therapy did not improve the 10-year BRFS rate (77.6%) compared with RT alone (77.1%; P = .22). However, a statistically significant difference in the BRFS rate was found with the addition of hormonal therapy to (103)Pd, improving the 10-year BRFS rate for (73.8%) compared with (103)Pd alone (69.1%; P = .008). On multivariate analysis, isotope type ((103)Pd vs (125)I), pretreatment prostate-specific antigen level >10 ng/mL, and greater tumor stage increased the risk of recurrence by 2.6-fold (P = .007), 5.9-fold (P < .0001), and 1.7-fold (P = .14), respectively. (125)I renders a superior rate of BRFS compared with (103)Pd when used with EBRT. Hormonal therapy does not provide additional benefit in patients with intermediate-risk prostate cancer treated with a combination of EBRT and brachytherapy, except for the addition of hormonal therapy to (103)Pd.

Updated Results and Patterns of Failure in a Randomized Hypofractionation Trial for High-risk Prostate Cancer

To report long-term results and patterns of failure after conventional and hypofractionated radiation therapy in high-risk prostate cancer. This randomized phase III trial compared conventional fractionation (80 Gy at 2 Gy per fraction in 8 weeks) vs hypofractionation (62 Gy at 3.1 Gy per fraction in 5 weeks) in combination with 9-month androgen deprivation therapy in 168 patients with high-risk prostate cancer. Freedom from biochemical failure (FFBF), freedom from local failure (FFLF), and freedom from distant failure (FFDF) were analyzed. In a median follow-up of 70 months, biochemical failure (BF) occurred in 35 of the 168 patients (21%) in the study. Among these 35 patients, local failure (LF) only was detected in 11 (31%), distant failure (DF) only in 16 (46%), and both LF and DF in 6 (17%). In 2 patients (6%) BF has not yet been clinically detected. The risk reduction by hypofractionation was significant in BF (10.3%) but not in LF and DF. We found that hypofractionation, with respect to conventional fractionation, determined only an insignificant increase in the actuarial FFBF but no difference in FFLF and FFDF, when considering the entire group of patients. However, an increase in the 5-year rates in all 3 endpoints-FFBF, FFLF, and FFDF-was observed in the subgroup of patients with a pretreatment prostate-specific antigen (iPSA) level of 20 ng/mL or less. On multivariate analysis, the type of fractionation, iPSA level, Gleason score of 4+3 or higher, and T stage of 2c or higher have been confirmed as independent prognostic factors for BF. High iPSA levels and Gleason score of 4+3 or higher were also significantly associated with an increased risk of DF, whereas T stage of 2c or higher was the only independent variable for LF. Our results confirm the isoeffectiveness of the 2 fractionation schedules used in this study, although a benefit in favor of hypofractionation cannot be excluded in the subgroup of patients with an iPSA level of 20 ng/mL or less. The α/β ratio might be more appropriately evaluated by FFLF than FFBF results, at least in high-risk disease.

Posttreatment Prostate Specific Antigen Nadir Predicts Prostate Cancer Specific and All Cause Mortality

We investigated whether the prostate specific antigen nadir predicts prostate cancer specific and all cause mortality in men treated in a randomized trial of radiation with or without 6 months of androgen deprivation therapy. The study included 204 men with cT1b-T2bN0M0 prostate adenocarcinoma and at least 1 unfavorable factor, including prostate specific antigen less than 10 to 40 ng/ml, Gleason 7 or greater, or T3 on magnetic resonance imaging. We performed Fine and Gray regression, and Cox multivariable analysis to determine whether an increasing prostate specific antigen nadir was associated with prostate cancer specific and all cause mortality, adjusting for treatment, age, Adult Comorbidity Evaluation 27 score and cancer prognostic factors. At a 6.9-year median followup median prostate specific antigen nadir was 0.7 ng/ml for radiation alone and 0.1 ng/ml for radiation plus androgen deprivation therapy. The prostate specific antigen nadir (adjusted HR 1.18/ng/ml increase, 95% CI 1.07-1.31, p=0.001) and Gleason 8 or greater (adjusted HR 8.05, 95% CI 1.01-64.05, p=0.049) significantly predicted increased prostate cancer specific mortality. Moderate/severe comorbidity carried a decreased risk (adjusted HR 0.13, 95% CI 0.02-0.96, p=0.045). Higher prostate specific antigen nadir (adjusted HR 1.10/ng/ml increase, 95% CI 1.04-1.17), older age (adjusted HR 1.10/year, 95% CI 1.04-1.15) and interaction between comorbidity score and randomization arm (each p<0.001) increased the all cause mortality risk. Men who achieved a prostate specific antigen nadir of the median value or less had lower estimated prostate cancer specific and all cause mortality at 7 years (3.7% vs 18.3%, p=0.0005 and 31.5% vs 55.0%, p=0.002). Posttreatment prostate specific antigen nadir is significantly associated with the risk of prostate cancer specific and all cause mortality after radiation with or without androgen deprivation therapy. A suboptimal prostate specific antigen nadir may identify candidates for earlier intervention to prolong survival.

DNA-PKcs Expression Predicts Response to Radiotherapy in Prostate Cancer

Double-strand breaks, the most lethal DNA lesions induced by ionizing radiation, are mainly repaired by the nonhomologous end-joining system. The expression of the nonhomologous end-joining pathway has never been studied in prostate cancer, and its prognostic value for patients undergoing radiotherapy remains unknown. Pretreatment biopsies from 238 patients treated with exclusive external beam radiotherapy for localized prostate cancer with ≥ 2 years of follow-up were reviewed to reassess the Gleason score. Of these 238 cases, 179 were suitable for in situ analysis and were included in the tissue microarrays. Expression of the nonhomologous end-joining proteins Ku70, Ku80, DNA-dependent protein kinase, catalytic subunits (DNA-PKcs), and X-ray repair cross complementing 4-like factor was studied by immunohistochemistry, together with the proliferation marker Ki67. The predictive value of the Gleason score for biochemical relapse (using the Phoenix criteria) was markedly improved after review (P<.0001) compared with the initial score (P=.003). The clinical stage, pretreatment prostate-specific antigen level, and perineural invasion status were also associated with progression-free survival (P=.005, P<.0001, and P=.03, respectively). High proliferation (>4%) tends to be associated with biochemical recurrence; however, the difference did not reach statistical significance (P=.06). Although the expression of Ku70, Ku80, and X-ray repair cross complementing 4-like factor was not predictive of relapse, positive DNA-PKcs nuclear staining was closely associated with biochemical recurrence (P=.0002). On multivariate analysis, only the Gleason score, prostate-specific antigen level, and DNA-PKcs status remained predictive of recurrence (P=.003, P=.002, and P=.01, respectively). The results of the present study highly suggest that DNA-PKcs could be a predictive marker of recurrence after radiotherapy, independently of the classic prognostic markers, including the Gleason score modified after review.

The Long-term Results with Delayed-combined Androgen Blockade Therapy in Local or Locally Advanced Prostate Cancer

To evaluate long-term clinical outcomes in cT1c-T3a prostate cancer patients following delayed-combined androgen blockade therapy. From January 2001 to December 2004, 92 cT1c-T3a prostate cancer cases were enrolled. Medical castration and anti-androgen treatment were used sequentially as delayed-combined androgen blockade therapy. Time to prostate-specific antigen biochemical failure was estimated, and risk factors for prostate-specific antigen biochemical failure were evaluated. The average patient age was 76.4 years (range, 59-91 years), the median observation period was 52.8 months (range, 26-106.6 months) and the median pre-treatment prostate-specific antigen level was 14 ng/ml (range, 3.68-492 ng/ml). The TNM classification distribution was as follows: T1c, n= 27; T2a, n = 39; T2b, n = 20; and T3a, n = 6. In the multivariate analysis, Gleason's score ≥8 (P < 0.05; hazard ratio, 3.02), prostate-specific antigen nadir >1.4 ng/ml (P = 0.001; hazard ratio, 8.76) and a half-life of the prostate-specific antigen level >1.2 months (P < 0.005; hazard ratio, 6.3) during the initial 6 months of luteinizing hormone-releasing hormone agonist monotherapy were significant independent risk factors for prostate-specific antigen biochemical failure with luteinizing hormone-releasing hormone agonist monotherapy. The high-risk group, which had at least one of these three risk factors, had a shorter time to prostate-specific antigen biochemical failure than the low-risk group, during luteinizing hormone-releasing hormone agonist monotherapy (P < 0.0001). For the total delayed-combined androgen blockade therapy observation period, the free-prostate-specific antigen biochemical failure rate was 88.3% at 5 years. Only a maintenance period following luteinizing hormone-releasing hormone agonist monotherapy (P < 0.005; hazard ratio, 16.8) was revealed to be a significant independent risk factor for prostate-specific antigen biochemical failure with total delayed-combined androgen blockade. The free-prostate-specific antigen biochemical failure rate of delayed-combined androgen blockade therapy in our study was as valuable as those in other androgen deprivation therapy of previous reports.

Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be performed cautiously.

20 Gy Versus 44 Gy of Supplemental External Beam Radiotherapy With Palladium-103 for Patients With Greater Risk Disease: Results of a Prospective Randomized Trial

The necessity of external beam radiotherapy (EBRT) as a supplement to prostate brachytherapy remains unknown. We report brachytherapy outcomes for patients with higher risk features randomized to substantially different supplemental EBRT regimens. Between December 1999 and June 2004, 247 patients were randomized to 20 Gy vs. 44 Gy EBRT followed by a palladium-103 boost (115 Gy vs. 90 Gy). The eligibility criteria included clinically organ-confined disease with Gleason score 7-10 and/or pretreatment prostate-specific antigen (PSA) level 10-20 ng/mL. The median follow-up period was 9.0 years. Biochemical progression-free survival (bPFS) was defined as a PSA level of ≤0.40 ng/mL after nadir. The median day 0 prescribed dose covering 90% of the target volume was 125.7%; 80 men received androgen deprivation therapy (median, 4 months). Multiple parameters were evaluated for their effect on bPFS. For the entire cohort, the cause-specific survival, bPFS, and overall survival rates were 97.7%, 93.2%, and 80.8% at 8 years and 96.9%, 93.2%, and 75.4% at 10 years, respectively. The bPFS rate was 93.1% and 93.4% for the 20-Gy and 44-Gy arms, respectively (p = .994). However, no statistically significant differences were found in cause-specific survival or overall survival were identified. When stratified by PSA level of ≤10 ng/mL vs. >10 ng/mL, Gleason score, or androgen deprivation therapy, no statistically significant differences in bPFS were discerned between the two EBRT regimens. On multivariate analysis, bPFS was most closely related to the preimplant PSA and clinical stage. For patients with biochemically controlled disease, the median PSA level was <0.02 ng/mL. The results of the present trial strongly suggest that two markedly different supplemental EBRT regimens result in equivalent cause-specific survival, bPFS, and overall survival. It is probable that the lack of benefit for a higher supplemental EBRT dose is the result of the high-quality brachytherapy dose distributions.

Predictors of Metastatic Disease After Prostate Brachytherapy

To identify predictors of metastatic disease after brachytherapy treatment for prostate cancer. All patients who received either brachytherapy alone (implant) or brachytherapy in combination with external beam radiation therapy for treatment of localized prostate cancer at The Mount Sinai Hospital between June 1990 and March 2007 with a minimum follow-up of 2 years were included. Univariate and multivariable analyses were performed on the following variables: risk group, Gleason score (GS), clinical T stage, pretreatment prostate-specific antigen level, post-treatment prostate-specific antigen doubling time (PSA-DT), treatment type (implant vs. implant plus external beam radiation therapy), treatment era, total biological effective dose, use of androgen deprivation therapy, age at diagnosis, and race. PSA-DT was analyzed in the following ordinate groups: 0 to 90 days, 91 to 180 days, 180 to 360 days, and greater than 360 days. We included 1,887 patients in this study. Metastases developed in 47 of these patients. The 10-year freedom from distant metastasis (FFDM) rate for the entire population was 95.1%. Median follow-up was 6 years (range, 2-15 years). The only two significant predictors of metastatic disease by multivariable analyses were GS and PSA-DT (p < 0.001 for both variables). Estimated 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001). Estimated FFDM rates for PSA-DT of 0 to 90 days, 91 to 180 days, 181 to 360 days, and greater than 360 days were 17.5%, 67.9%, 74%, and 94.8%, respectively (p < 0.001). Estimated 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively. A demographic shift to patients presenting with higher-grade disease in more recent years was observed. GS and post-treatment PSA-DT are both statistically significant independent predictors of metastatic disease. Patients with a high GS and/or short PSA-DT have a higher likelihood of developing metastatic disease and should be considered for systemic therapy.

Dose Escalation for Prostate Cancer Radiotherapy: Predictors of Long-Term Biochemical Tumor Control and Distant Metastases–Free Survival Outcomes

BackgroundHigher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients. ObjectiveIdentify predictors of biochemical tumor control and distant metastases–free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT. Design, setting, and participantsThis retrospective analysis comprised 2551 patients with clinical stages T1–T3 PCa. Median follow-up was 8 yr, extending >20 yr. InterventionPrescription doses ranged from 64.8 to 86.4Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo. MeasurementsA proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed. Results and limitationsRadiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels <70.2Gy and 70.2–79.2Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse–free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes. ConclusionsHigher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.

Black Men Have Lower Rates Than White Men of Biochemical Failure with Primary Androgen-Deprivation Therapy

Black men have a higher incidence of advanced stage at diagnosis and mortality from prostate cancer than do men in other racial groups. Given that androgen-deprivation therapy (ADT) is one of the mainstays of treatment for advanced prostate cancer, we investigated the development of biochemical failure, or recurrence of elevated prostate-specific antigen (PSA) levels, among different races in men receiving ADT. Patients with prostate cancer who received ADT in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006 were eligible for inclusion in our study. Patients who had prior treatment for their cancer with surgery or radiation were excluded. Treatment failure was defined as an increase in PSA of >2 ng/mL from PSA nadir, with no subsequent decrease in PSA. We compared the biochemical failure rate in white patients to those in black, Hispanic, and Asian/other patients. The Cox proportional hazards regression model was used to estimate hazards ratios. Our study population consisted of 681 patients: 416 (61%) were white; 107 (16%) were black; 107 (16%) were Hispanic; and 51 (7%) were Asian or another race. After we controlled for all demographic variables and for variables related to prostate cancer, blacks were the only group with a lower risk of treatment failure compared with whites. The hazard ratios for treatment failure were as follows: black versus white, 0.66 (p = 0.03); Hispanic versus white, 1.00 (p = 0.8); Asian/other race versus white, 1.5 (p = 0.1). In this multivariate analysis, pretreatment PSA level and cancer stage were the only other variables associated with a higher risk of treatment failure. Among patients receiving ADT as primary monotherapy for prostate cancer, blacks may have a lower rate of biochemical failure compared with whites. Although the etiology of this finding is unclear, it suggests the possibility that prostate cancer in black men may be more androgen sensitive than it is in white men.

Race and Survival Following Brachytherapy-Based Treatment for Men With Localized or Locally Advanced Adenocarcinoma of the Prostate

We investigated whether race was associated with risk of death following brachytherapy-based treatment for localized prostate cancer, adjusting for age, cardiovascular comorbidity, treatment, and established prostate cancer prognostic factors. The study cohort was composed of 5,360 men with clinical stage T1-3N0M0 prostate cancer who underwent brachytherapy-based treatment at 20 centers within the 21st Century Oncology consortium. Cox regression multivariable analysis was used to evaluate the risk of death in African-American and Hispanic men compared to that in Caucasian men, adjusting for age, pretreatment prostate-specific antigen (PSA) level, Gleason score, clinical T stage, year and type of treatment, median income, and cardiovascular comorbidities. After a median follow-up of 3 years, there were 673 deaths. African-American and Hispanic races were significantly associated with an increased risk of all-cause mortality (ACM) (adjusted hazard ratio, 1.77 and 1.79; 95% confidence intervals, 1.3-2.5 and 1.2-2.7; p < 0.001 and p = 0.005, respectively). Other factors significantly associated with an increased risk of death included age (p < 0.001), Gleason score of 8 to 10 (p = 0.04), year of brachytherapy (p < 0.001), and history of myocardial infarction treated with stent or coronary artery bypass graft (p < 0.001). After adjustment for prostate cancer prognostic factors, age, income level, and revascularized cardiovascular comorbidities, African-American and Hispanic races were associated with higher ACM in men with prostate cancer. Additional causative factors need to be identified.

Lactate dehydrogenase, Gleason score and HER-2 overexpression are significant prognostic factors for M1b prostate cancer

It has not been elucidated whether certain types of M1b prostate cancer (M1b PC) are associated with a poor outcome. The present study retrospectively identified predictive factors related to the outcome of M1b PC. The subjects were 104 patients who attended our hospital and received a diagnosis of M1b PC. The observation period ranged from 4 to 122 months (median, 43 months). The parameters investigated were: T classification, N classification, Gleason score (GS), pretreatment prostate-specific antigen (PSA) level, extent of disease (EOD) grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium, and hemoglobin (Hb) levels, platelet count, and the status of HER-2 overexpression as determined with a Hercep Test(TM) Kit using initial needle biopsy specimens for diagnosis. Log-rank test and Cox univariate analysis identified the following factors with statistically significant differences: pretreatment PSA ≥ 192, N1, GS ≥ 8, EOD grade 3+4, high LDH, high ALP, low Hb, and HER-2 overexpression. Multivariate Cox proportional hazard analysis identified the factors GS ≥ 8, high LDH, and HER-2 overexpression with significant differences. The hazard ratio was 5.962, 2.465, and 2.907, respectively, and the probability value was P=0.0218, P=0.0207 and P=0.0090, respectively. When the subjects with GS ≥ 8, high LDH, and HER-2 over-expression were classified as the high-risk group, the 5-year cause-specific survival rate was 51.2, 29.6, and 20.0%, respectively. The present study showed that M1b PC patients with GS ≥ 8, high LDH, and HER-2 overexpression have a very poor outcome and thus, should be treated as a high-risk group requiring close follow-up.

Long‐term survival after radical prostatectomy versus external‐beam radiotherapy for patients with high‐risk prostate cancer

The long-term survival of patients with high-risk prostate cancer was compared after radical prostatectomy (RRP) and after external beam radiation therapy (EBRT) with or without adjuvant androgen-deprivation therapy (ADT). In total, 1238 patients underwent RRP, and 609 patients received with EBRT (344 received EBRT plus ADT, and 265 received EBRT alone) between 1988 and 2004 who had a pretreatment prostate-specific antigen (PSA) level ≥ 20 ng/mL, a biopsy Gleason score between 8 and 10, or clinical tumor classification ≥ T3. The median follow-up was 10.2 years, 6.0 years, and 7.2 years after RRP, EBRT plus ADT, and EBRT alone, respectively. The impact of treatment modality on systemic progression, cancer-specific survival, and overall survival was evaluated using multivariate Cox proportional hazard regression analysis and a competing risk-regression model. The 10-year cancer-specific survival rate was 92%, 92%, and 88% after RRP, EBRT plus ADT, and EBRT alone, respectively (P = .06). After adjustment for case mix, no significant differences in the risks of systemic progression (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.51-1.18; P = .23) or prostate cancer death (HR, 1.14; 95% CI, 0.68-1.91; P = .61) were observed between patients who received EBRT plus ADT and patients who underwent RRP. The risk of all-cause mortality, however, was greater after EBRT plus ADT than after RRP (HR, 1.60; 95% CI, 1.25-2.05; P = .0002). RRP alone and EBRT plus ADT provided similar long-term cancer control for patients with high-risk prostate cancer. The authors concluded that continued investigation into the differing impact of treatments on quality-of-life and noncancer mortality will be necessary to determine the optimal management approach for these patients.

Correlation between Chemokine Receptor CXCR4 Expression and Prognostic Factors in Patients with Prostate Cancer

PurposeWe evaluated the correlation between the expression of CXCR4 and prognostic factors in patients with prostate cancer.Materials and MethodsA total of 57 patients who had undergone surgery for prostate cancer were enrolled. Specimens were obtained before any treatment and were stained with antihuman CXCR4 antibody. The intensity of staining was graded as low or high. The age, pretreatment prostate-specific antigen (PSA) level, Gleason score, T stage, biochemical recurrence, local recurrence, and distant metastasis were compared according to the expression of CXCR4 in patients with prostate cancer.ResultsLocal recurrence was higher in the group with high expression, in 11 of 36 cases (30.6%), than in the group with low expression, in 1 of 21 cases (4.8%), with statistical significance (p=0.040). Distant metastasis was also associated with expression, occurring in 10 of 36 cases (27.8%) in the group with high expression and in 1 of 21 cases (4.8%) in the group with low expression (p=0.041). In the logistic regression test, CXCR4 expression was the only factor in determining local recurrence (p=0.016) and distant metastasis (0.022). Furthermore, the group with high CXCR4 expression showed significantly longer cancer-specific survival than did the low expression group (p=0.041). CXCR4 showed no association with age (p=0.881), pretreatment PSA level (p=0.584), Gleason score (p=0.640), T stage (p=0.967), or biochemical recurrence (p=0.081).ConclusionsThe high expression of CXCR4 was associated with local recurrence and distant metastasis. CXCR4 expression was shown to be a useful prognostic factor for patients with prostate cancer.