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At least 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Syndecan-1 responsive microRNA-126 and 149 regulate cell proliferation in prostate cancer

Highlights: • Syndecan-1 is highly expressed in androgen independent prostate cancer cells, PC3. • Syndecan-1 regulates the expression of miR-126 and -149 in prostate cancer cells. • MiR-126 and 149 control cell growth via p21 induction and senescence mechanism. • MiR-126 and 149 promote cell proliferation by suppressing SOX2, NANOG, and Oct4. - Abstract: MicroRNAs (miRNAs) are short (19–24 nt), low molecular weight RNAs that play important roles in the regulation of target genes associated with cell proliferation, differentiation, and development, by binding to the 3′-untranslated region of the target mRNAs. In this study, we examined the expression of miRNA-126 (miR-126) and miR-149 in prostate cancer, and investigated the molecular mechanisms by which they affect syndecan-1 in prostate cancer. Functional analysis of miR-126 and miR-149 was conducted in the prostate cancer cell lines, PC3, Du145, and LNCaP. The expression levels of SOX2, NANOG, Oct4, miR-126 and miR-149 were evaluated by quantitative RT-PCR. After silencing syndecan-1, miR-126, and/or miR-149 in the PC3 cells, cell proliferation, senescence, and p21 induction were assessed using the MTS assay, senescence-associated β-galactosidase (SA-β-Gal) assay, and immunocytochemistry, respectively. Compared to the Du145 and LNCaP cells, PC3 cells exhibited higher expression of syndecan-1. When syndecan-1 was silenced, the PC3 cells showed reduced expression of miR-126 and miR-149 most effectively. Suppression of miR-126 and/or miR-149 significantly inhibited cell growth via p21 induction and subsequently, induced senescence. The mRNA expression levels of SOX2, NANOG, and Oct4 were significantly increased in response to the silencing of miR-126 and/or miR-149. Our results suggest that miR-126 and miR-149 are associated with the expression of syndecan-1 in prostate cancer cells. These miRNAs promote cell proliferation by suppressing SOX2, NANOG, and Oct4. The regulation of these factors by miR-126 and miR-149 is essential for syndecan-1-mediated development of androgen-refractory prostate cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

ID4 promotes AR expression and blocks tumorigenicity of PC3 prostate cancer cells

Deregulation of tumor suppressor genes is associated with tumorigenesis and the development of cancer. In prostate cancer, ID4 is epigenetically silenced and acts as a tumor suppressor. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. Previous study from our lab showed that ectopic ID4 expression in DU145 attenuates proliferation and promotes AR expression suggesting that ID4 dependent AR activity is tumor suppressive. In this study, we examined the effect of ectopic expression of ID4 on highly malignant prostate cancer cell, PC3. Here we show that stable overexpression of ID4 in PC3 cells leads to increased apoptosis and decreased cell proliferation and migration. In addition, in vivo studies showed a decrease in tumor size and volume of ID4 overexpressing PC3 cells, in nude mice. At the molecular level, these changes were associated with increased androgen receptor (AR), p21, and AR dependent FKBP51 expression. At the mechanistic level, ID4 may regulate the expression or function of AR through specific but yet unknown AR co-regulators that may determine the final outcome of AR function. - Highlights: • ID4 expression induces AR expression in PC3 cells, which generally lack AR. • ID4 expression increased apoptosis and decreased cell proliferation and invasion. • Overexpression of ID4 reduces tumor growth of subcutaneous xenografts in vivo. • ID4 induces p21 and FKBP51 expression- co-factors of AR tumor suppressor activity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

PART-1 functions as a competitive endogenous RNA for promoting tumor progression by sponging miR-143 in colorectal cancer

LncRNAs were altered in several cancers and played a crucial role in various biological activities and progressions of different diseases, including proliferation, chemical resistance, and metastasis. In the present study, we revealed that prostrate androgen-regulated transcript-1 (PART-1) was highly expressed in colorectal cancer cells and tissues, and knockdown of PART-1 suppressed cell proliferation and metastasis, both in vitro and in vivo. In addition, PART-1 functioned as a ceRNA of DNMT3A, by sponging miR-143. Finally,PART-1 induced tumor progression by regulating DNMT3A. - Highlights: • Prostrate androgen-regulated transcript-1 (PART-1) was highly expressed in colorectal cancer cells and tissues. • Knockdown of PART-1 suppressed cell proliferation and metastasis, both in vitro and in vivo. • PART-1 functioned as a ceRNA of DNMT3A, by sponging miR-143. • PART-1 induced tumor progression by regulating DNMT3A.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo

Highlights: • SF2523 inhibits human prostate cancer cell survival and proliferation. • SF2523 induces apoptosis activation in human prostate cancer cells. • SF2523 inhibits BRD4-regulated proteins and AKT-S6K1 activation in prostate cancer cells. • SF2523 administration inhibits prostate cancer xenograft growth in SCID mice. Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non-cytotoxic to the prostate epithelial cells. At the molecular level, SF2523 downregulated BRD4-regulated genes (cyclin D1, c-Myc and androgen receptor) and almost blocked AKT-S6K1 activation in prostate cancer cells. In vivo, SF2523 intraperitoneal administration at the well-tolerated dose inhibited human prostate cancer xenograft growth in severe combined immunodeficient (SCID) mice. BRD4-regulated genes (cyclin D1, c-Myc and androgen receptor) and AKT-S6K1 activation were inhibited in SF2523-treated tumors. Together, dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Establishment and characterization of five immortalized human scalp dermal papilla cell lines

Highlights: • Five immortalized human dermal papilla cell lines are established and characterized. • Cell lines are named KNU-101, KNU-102, KNU-103, KNU-201 and KNU-202. • These cell lines maintain in vivo characteristics of dermal papilla cells. Dermal papilla (DP) regulates the growth and cycling of hair follicles. Cultured DP cells are useful for the study of their role in relation to hair growth and regeneration. However, cultivation of human DP cells is tedious and difficult. In addition, cultured DP cells possess a relatively short replicative life span, requiring immortalized human DP cell lines. We previously established an immortalized human DP cell line, SV40T-hTERT-DPC, by introducing human telomerase reverse transcriptase (hTERT) gene into the transformed cell line, SV40T-DPC. In this study, we co-transfected the simian virus 40 large T antigen (SV40T-Ag) and hTERT into DP cells from scalp hair follicles from a male with androgenetic alopecia and established five immortalized DP cell lines and named KNU-101, KNU-102, KNU-103, KNU-201 and KNU-202. We then evaluated tumorigenicity, expression of DP markers, responses to androgen, Wnt3a and BMP4, and expression of DP signature genes. These cell lines displayed early passage morphology and maintained responses to androgen, Wnt and BMP. Furthermore, these cell lines expressed DP markers and DP signature genes. KNU cell lines established in this study are potentially useful sources for hair research.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Association between fetal exposure to phthalate endocrine disruptor and genome-wide DNA methylation at birth

Highlights: • Humans are ubiquitously exposed to phthalates through digestion, inhalation, or dermal absorption. • DNA methylation has been hypothesized to be an important mechanism in in utero phthalate exposure. • DNA methylation changes are involved in androgen response, estrogen response, protein secretion, and spermatogenesis. • Three CpG sites (cg00935782, cg07732421, and cg00764560) are involved in genes of response to androgen. Phthalic acid esters are ubiquitous and antiandrogenic, and may cause systemic effects in humans, particularly with in utero exposure. Epigenetic modification, such as DNA methylation, has been hypothesized to be an important mechanism that mediates certain biological processes and pathogenic effects of in utero phthalate exposure.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2010

Expression of Bcl-2, p53, and MDM2 in Localized Prostate Cancer With Respect to the Outcome of Radical Radiotherapy Dose Escalation

Purpose: Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation. Methods and Materials: Between 1995 and 2001, 308 patients with localized prostate cancer received neoadjuvant androgen deprivation and radical radiotherapy at our institution in one of two dose-escalation trials. The biopsy specimens in 201 cases were used to make a biopsy tissue microarray. We evaluated tumor expression of Bcl-2, p53, and MDM2 by immunohistochemistry with respect to outcome. Results: Median follow-up was 7 years, and 5-year freedom from biochemical failure (FFBF) was 70.4% (95% CI, 63.5-76.3%). On univariate analysis, expression of Bcl-2 (p < 0.001) and p53 (p = 0.017), but not MDM2 (p = 0.224), was significantly associated with FFBF. Expression of Bcl-2 remained significantly associated with FFBF (p = 0.001) on multivariate analysis, independently of T stage, Gleason score, initial prostate-specific antigen level, and radiotherapy dose. Seven-year biochemical control was 61% vs. 41% (p = 0.0122) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-positive tumors and 87% vs. 81% (p = 0.423) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2-negative tumors. There was no statistically significant interaction between dose and Bcl-2 expression. Conclusions: Bcl-2 expression was a significant, independent determinant of biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for prostate cancer. These data generate the hypothesis that Bcl-2 expression could be used to inform the choice of radiotherapy dose in individual patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Acute and Late Toxicity in a Randomized Trial of Conventional Versus Hypofractionated Three-Dimensional Conformal Radiotherapy for Prostate Cancer

Purpose: To compare the toxicity between hypofractionation vs. conventional fractionation schedules in patients with high-risk prostate cancer. Methods and Materials: Between January 2003 and December 2007, 168 patients were randomized to receive either hypofractionated (62 Gy in 20 fractions within 5 weeks, 4 fractions/wk) or conventionally fractionated (80 Gy in 40 fractions within 8 weeks) three-dimensional conformal radiotherapy to the prostate and seminal vesicles. All patients had undergone a 9-month course of total androgen deprivation, with radiotherapy starting 2 months after initiation of the total androgen deprivation. Results: The median follow-up was 32 and 35 months in the hypofractionation and conventional fractionation arms, respectively. For the patients developing acute toxicity, no difference between the two fractionation groups was found in either severity or duration of gastrointestinal or genitourinary toxicity. Also, no difference was found in the incidence and severity of late gastrointestinal and genitourinary toxicity between the two treatment schedules, with a 3-year rate of Grade 2 or greater toxicity of 17% and 16% for the hypofractionation arm and 14% and 11% for the conventional fractionation arm, respectively. A statistically significant correlation between acute and late gastrointestinal toxicity was found only in the conventional fractionation group. Conclusion: Our findings suggest that the hypofractionation regimen used in our study is safe, with only a slight, nonsignificant increase in tolerable and temporary acute toxicity compared with the conventional fractionation schedule. The severity and frequency of late complications was equivalent between the two treatment groups.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Dose-Fractionation Sensitivity of Prostate Cancer Deduced From Radiotherapy Outcomes of 5,969 Patients in Seven International Institutional Datasets: {alpha}/{beta} = 1.4 (0.9-2.2) Gy

Purpose: There are reports of a high sensitivity of prostate cancer to radiotherapy dose fractionation, and this has prompted several trials of hypofractionation schedules. It remains unclear whether hypofractionation will provide a significant therapeutic benefit in the treatment of prostate cancer, and whether there are different fractionation sensitivities for different stages of disease. In order to address this, multiple primary datasets have been collected for analysis. Methods and Materials: Seven datasets were assembled from institutions worldwide. A total of 5969 patients were treated using external beams with or without androgen deprivation (AD). Standard fractionation (1.8-2.0 Gy per fraction) was used for 40% of the patients, and hypofractionation (2.5-6.7 Gy per fraction) for the remainder. The overall treatment time ranged from 1 to 8 weeks. Low-risk patients comprised 23% of the total, intermediate-risk 44%, and high-risk 33%. Direct analysis of the primary data for tumor control at 5 years was undertaken, using the Phoenix criterion of biochemical relapse-free survival, in order to calculate values in the linear-quadratic equation of k (natural log of the effective target cell number), {alpha} (dose-response slope using very low doses per fraction), and the ratio {alpha}/{beta} that characterizes dose-fractionation sensitivity. Results: There was no significant difference between the {alpha}/{beta} value for the three risk groups, and the value of {alpha}/{beta} for the pooled data was 1.4 (95% CI = 0.9-2.2) Gy. Androgen deprivation improved the bNED outcome index by about 5% for all risk groups, but did not affect the {alpha}/{beta} value. Conclusions: The overall {alpha}/{beta} value was consistently low, unaffected by AD deprivation, and lower than the appropriate values for late normal-tissue morbidity. Hence the fractionation sensitivity differential (tumor/normal tissue) favors the use of hypofractionated radiotherapy schedules for all risk groups, which is also very beneficial logistically in limited-resource settings.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Hypofractionated Concomitant Intensity-Modulated Radiotherapy Boost for High-Risk Prostate Cancer: Late Toxicity

Purpose: To report the acute and late toxicities of patients with high-risk localized prostate cancer treated using a concomitant hypofractionated, intensity-modulated radiotherapy boost combined with long-term androgen deprivation therapy. Methods and Materials: A prospective Phase I-II study of patients with any of the following: clinical Stage T3 disease, prostate-specific antigen level {>=}20 ng/mL, or Gleason score 8-10. A dose of 45 Gy (1.8 Gy/fraction) was delivered to the pelvic lymph nodes with a concomitant 22.5 Gy prostate intensity-modulated radiotherapy boost, to a total of 67.5 Gy (2.7 Gy/fraction) in 25 fractions within 5 weeks. Image guidance was performed using three gold seed fiducials. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, and Radiation Therapy Oncology Group late morbidity scores were used to assess the acute and late toxicities, respectively. Biochemical failure was determined using the Phoenix definition. Results: A total of 97 patients were treated and followed up for a median of 39 months, with 88% having a minimum of 24 months of follow-up. The maximal toxicity scores were recorded. The grade of acute gastrointestinal toxicity was Grade 0 in 4%, 1 in 59%, and 2 in 37%. The grade of acute urinary toxicity was Grade 0 in 8%, 1 in 50%, 2 in 39%, and 3 in 4%. The grade of late gastrointestinal toxicity was Grade 0 in 54%, 1 in 40%, and 2 in 7%. No Grade 3 or greater late gastrointestinal toxicities developed. The grade of late urinary toxicity was Grade 0 in 82%, 1 in 9%, 2 in 5%, 3 in 3%, and 4 in 1% (1 patient). All severe toxicities (Grade 3 or greater) had resolved at the last follow-up visit. The 4-year biochemical disease-free survival rate was 90.5%. Conclusions: A hypofractionated intensity-modulated radiotherapy boost delivering 67.5 Gy in 25 fractions within 5 weeks combined with pelvic nodal radiotherapy and long-term androgen deprivation therapy was well tolerated, with low rates of severe toxicity. The biochemical control rate at early follow-up has been promising. Additional follow-up is needed to determine the long-term biochemical control and prostate biopsy results.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Robotic Image-Guided Stereotactic Radiotherapy, for Isolated Recurrent Primary, Lymph Node or Metastatic Prostate Cancer

Purpose: To evaluate the outcome of robotic CyberKnife (Accuray, Sunnyvale, CA)-based stereotactic radiotherapy (CBK-SRT) for isolated recurrent primary, lymph node, or metastatic prostate cancer. Methods and Materials: Between May 2007 and December 2009, 34 consecutive patients/38 lesions were treated (15 patients reirradiated for local recurrence [P], 4 patients reirradiated for anastomosis recurrence [A], 16 patients treated for single lymph node recurrence [LN], and 3 patients treated for single metastasis [M]). In all but 4 patients, [{sup 11}C]choline positron emission tomography/computed tomography was performed. CBK-SRT consisted of reirradiation and first radiotherapy in 27 and 11 lesions, respectively. The median CBK-SRT dose was 30 Gy in 4.5 fractions (P, 30 Gy in 5 fractions; A, 30 Gy in 5 fractions; LN, 33 Gy in 3 fractions; and M, 36 Gy in 3 fractions). In 18 patients (21 lesions) androgen deprivation was added to CBK-SRT (median duration, 16.6 months). Results: The median follow-up was 16.9 months. Acute toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event). Late toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event and 1 Grade 2 event). Biochemical response was observed in 32 of 38 evaluable lesions. Prostate-specific antigen stabilization was seen for 4 lesions, and in 2 cases prostate-specific antigen progression was reported. The 30-month progression-free survival rate was 42.6%. Disease progression was observed for 14 lesions (5, 2, 5, and 2 in Groups P, A, LN, and M respectively). In only 3 cases, in-field progression was seen. At the time of analysis (May 2010), 19 patients are alive with no evidence of disease and 15 are alive with disease. Conclusions: CyberKnife-based stereotactic radiotherapy is a feasible approach for isolated recurrent primary, lymph node, or metastatic prostate cancer, offering excellent in-field tumor control and a low toxicity profile. Further investigation is warranted to identify the patients who benefit most from this treatment modality. The optimal combination with androgen deprivation should also be defined.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Benchmarking Dosimetric Quality Assessment of Prostate Intensity-Modulated Radiotherapy

Purpose: To benchmark the dosimetric quality assessment of prostate intensity-modulated radiotherapy and determine whether the quality is influenced by disease or treatment factors. Patients and Methods: We retrospectively analyzed the data from 155 consecutive men treated radically for prostate cancer using intensity-modulated radiotherapy to 78 Gy between January 2007 and March 2009 across six radiotherapy treatment centers. The plan quality was determined by the measures of coverage, homogeneity, and conformity. Tumor coverage was measured using the planning target volume (PTV) receiving 95% and 100% of the prescribed dose (V{sub 95%} and V{sub 100%}, respectively) and the clinical target volume (CTV) receiving 95% and 100% of the prescribed dose. Homogeneity was measured using the sigma index of the PTV and CTV. Conformity was measured using the lesion coverage factor, healthy tissue conformity index, and the conformity number. Multivariate regression models were created to determine the relationship between these and T stage, risk status, androgen deprivation therapy use, treatment center, planning system, and treatment date. Results: The largest discriminatory measurements of coverage, homogeneity, and conformity were the PTV V{sub 95%}, PTV sigma index, and conformity number. The mean PTV V{sub 95%} was 92.5% (95% confidence interval, 91.3-93.7%). The mean PTV sigma index was 2.10 Gy (95% confidence interval, 1.90-2.20). The mean conformity number was 0.78 (95% confidence interval, 0.76-0.79). The treatment center independently influenced the coverage, homogeneity, and conformity (all p < .0001). The planning system independently influenced homogeneity (p = .038) and conformity (p = .021). The treatment date independently influenced the PTV V{sub 95%} only, with it being better at the start (p = .013). Risk status, T stage, and the use of androgen deprivation therapy did not influence any aspect of plan quality. Conclusion: Our study has benchmarked measures of coverage, homogeneity, and conformity for the treatment of prostate cancer using IMRT. The differences seen between centers and planning systems and the coverage deterioration over time highlight the need for every center to determine their own benchmarks and apply clinical vigilance with respect to maintaining these through quality assurance.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

The Percent of Positive Biopsy Cores Improves Prediction of Prostate Cancer-Specific Death in Patients Treated With Dose-Escalated Radiotherapy

Purpose: To examine the prognostic utility of the percentage of positive cores (PPC) at the time of prostate biopsy for patients treated with dose-escalated external beam radiation therapy. Methods and Materials: We performed a retrospective analysis of patients treated at University of Michigan Medical Center to at least 75 Gy. Patients were stratified according to PPC by quartile, and freedom from biochemical failure (nadir + 2 ng/mL), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) were assessed by log-rank test. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cut point for PPC stratification. Finally, Cox proportional hazards multivariate regression was used to assess the impact of PPC on clinical outcome when adjusting for National Comprehensive Cancer Network (NCCN) risk group and androgen deprivation therapy. Results: PPC information was available for 651 patients. Increasing-risk features including T stage, prostate-specific antigen, Gleason score, and NCCN risk group were all directly correlated with increasing PPC. On log-rank evaluation, all clinical endpoints, except for OS, were associated with PPC by quartile, with worse clinical outcomes as PPC increased, with the greatest impact seen in the highest quartile (>66.7% of cores positive). ROC curve analysis confirmed that a cut point using two-thirds positive cores was most closely associated with CSS (p = 0.002; area under ROC curve, 0.71). On univariate analysis, stratifying patients according to PPC less than or equal to 66.7% vs. PPC greater than 66.7% was prognostic for freedom from biochemical failure (p = 0.0001), FFM (p = 0.0002), and CSS (p = 0.0003) and marginally prognostic for OS (p = 0.055). On multivariate analysis, after adjustment for NCCN risk group and androgen deprivation therapy use, PPC greater than 66.7% increased the risk for biochemical failure (p = 0.0001; hazard ratio [HR], 2.1 [95% confidence interval (CI), 1.4-3.0]) and FFM (p = 0.05; HR, 1.7 [95% CI, 1.1-2.9]) and marginally increased the risk for CSS (p = 0.057; HR, 2.1 [95% CI, 1.0-4.6]). Conclusion: PPC at the time of biopsy adds prognostic value for clinically meaningful endpoints for patients treated with dose-escalated radiation therapy. This was particularly true for NCCN-defined intermediate- and high-risk patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Image-Guided Radiotherapy for Prostate Cancer: A Prospective Trial of Concomitant Boost Using Indium-111-Capromab Pendetide (ProstaScint) Imaging

Purpose: To evaluate, in a prospective study, the use of {sup 111}In-capromab pendetide (ProstaScint) scan to guide the delivery of a concomitant boost to intraprostatic region showing increased uptake while treating the entire gland with intensity-modulated radiotherapy for localized prostate cancer. Methods and Materials: From September 2002 to November 2005, 71 patients were enrolled. Planning pelvic CT and {sup 111}In-capromab pendetide scan images were coregistered. The entire prostate gland received 75.6 Gy/42 fractions, whereas areas of increased uptake in {sup 111}In-capromab pendetide scan received 82 Gy. For patients with T3/T4 disease, or Gleason score {>=}8, or prostate-specific antigen level >20 ng/mL, 12 months of adjuvant androgen deprivation therapy was given. In January 2005 the protocol was modified to give 6 months of androgen deprivation therapy to patients with a prostate-specific antigen level of 10-20 ng/mL or Gleason 7 disease. Results: Thirty-one patients had low-risk, 30 had intermediate-risk, and 10 had high-risk disease. With a median follow-up of 66 months, the 5-year biochemical control rates were 94% for the entire cohort and 97%, 93%, and 90% for low-, intermediate-, and high-risk groups, respectively. Maximum acute and late urinary toxicities were Grade 2 for 38 patients (54%) and 28 patients (39%) and Grade 3 for 1 and 3 patients (4%), respectively. One patient had Grade 4 hematuria. Maximum acute and late gastrointestinal toxicities were Grade 2 for 32 patients (45%) and 15 patients (21%), respectively. Most of the side effects improved with longer follow-up. Conclusion: Concomitant boost to areas showing increased uptake in {sup 111}In-capromab pendetide scan to 82 Gy using intensity-modulated radiotherapy while the entire prostate received 75.6 Gy was feasible and tolerable, with 94% biochemical control rate at 5 years.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2011

Gleason Pattern 5 Is the Greatest Risk Factor for Clinical Failure and Death From Prostate Cancer After Dose-Escalated Radiation Therapy and Hormonal Ablation

Purpose: The division of Gleason score (GS) into three categories (2-6, 7, 8-10) may not fully use its prognostic power, as revealed by recent reports demonstrating the presence of Gleason Pattern 5 (GP5) as a strong predictor for biochemical recurrence. Therefore, we analyzed the clinical outcomes in patients treated with dose-escalated radiation therapy (RT) based on the presence or absence of GP5. Methods and Materials: Outcomes were analyzed for 718 men treated for localized prostate cancer with external-beam RT to a minimum planning target volume dose of at least 75 Gy. We assessed the impact of GP5 and that of pretreatment- and treatment-related factors on freedom from biochemical failure, freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS). Results: At biopsy, 89% of patients had no GP5, and 11% (76/718) had GP5. There were no differences in age, comorbid illness, T stage, prostate-specific antigen, or the use or duration of androgen deprivation therapy between GS8 without GP5 and GS8-10 with GP5. The presence of GP5 predicted lower FFM (p < 0.002; hazard ratio [HR] 3.4 [1.7-7.1]); CSS (p < 0.0001; HR 12.9 [5.4-31]); and OS (p < 0.0001; HR 3.6 [2.0-6.5]) in comparison with GS8 (without GP5). The 8-year FFM, CSS, and OS were 89%, 98%, and 57%, respectively, for those with Gleason 8 prostate cancer without GP5 in comparison with 61%, 55%, and 31%, respectively, for those with GP5. In addition, both FFM and CSS were strongly influenced by androgen deprivation therapy given concurrently with RT. On multivariate analysis, GP5 was the strongest prognostic factor for all clinical endpoints, including OS. Conclusion: The presence of GP5 predicts for worse clinical behavior, which therefore needs to be accounted for by risk stratification schemes. Further intensification of local and/or systemic therapy may be appropriate for such patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Radiotherapy Doses of 80 Gy and Higher Are Associated With Lower Mortality in Men With Gleason Score 8 to 10 Prostate Cancer

Purpose: Men with Gleason score (GS) 8-10 prostate cancer (PCa) are assumed to have a high risk of micrometastatic disease at presentation. However, local failure is also a major problem. We sought to establish the importance of more aggressive local radiotherapy (RT) to {>=}80 Gy. Methods and Materials: There were 226 men treated consecutively with RT {+-} ADT from 1988 to 2002 for GS 8-10 PCa. Conventional, three-dimensional conformal or intensity-modulated (IM) RT was used. Radiation dose was divided into three groups: (1) <75 Gy (n = 50); (2) 75-79.9 Gy (n = 60); or (3) {>=}80 Gy (n = 116). The endpoints examined included biochemical failure (BF; nadir + 2 definition), distant metastasis (DM), cause-specific mortality, and overall mortality (OM). Results: Median follow-up was 66, 71, and 58 months for Groups 1, 2, and 3. On Fine and Gray's competing risk regression analysis, significant predictors of reduced BF were RT dose {>=}80 Gy (p = 0.011) and androgen deprivation therapy duration {>=}24 months (p = 0.033). In a similar model of DM, only RT dose {>=}80 Gy was significant (p = 0.007). On Cox regression analysis, significant predictors of reduced OM were RT dose {>=}80 Gy (p = 0.035) and T category (T3/4 vs. T1, p = 0.041). Dose was not a significant determinant of cause-specific mortality. Results for RT dose were similar in a model with RT dose and ADT duration as continuous variables. Conclusion: The results indicate that RT dose escalation to {>=}80 Gy is associated with lower risks of BF, DM, and OM in men with GS 8-10 PCa, independently of androgen deprivation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

Quality of Life After Hypofractionated Concomitant Intensity-Modulated Radiotherapy Boost for High-Risk Prostate Cancer

Purpose: To evaluate the change in health-related quality of life (QOL) of patients with high-risk prostate cancer treated using hypofractionated radiotherapy combined with long-term androgen deprivation therapy. Methods and Materials: A prospective Phase I-II study enrolled patients with any of the following: clinical Stage T3 disease, prostate-specific antigen level {>=}20 ng/mL, or Gleason score 8-10. Radiotherapy consisted of 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes with a concomitant 22.5 Gy intensity-modulated radiotherapy boost to the prostate, for a total of 67.5 Gy (2.7 Gy per fraction) in 25 fractions over 5 weeks. Daily image guidance was performed using three gold seed fiducials. Quality of life was measured using the Expanded Prostate Cancer Index Composite (EPIC), a validated tool that assesses four primary domains (urinary, bowel, sexual, and hormonal). Results: From 2004 to 2007, 97 patients were treated. Median follow-up was 39 months. Compared with baseline, at 24 months there was no statistically significant change in the mean urinary domain score (p = 0.99), whereas there were decreases in the bowel (p < 0.01), sexual (p < 0.01), and hormonal (p < 0.01) domains. The proportion of patients reporting a clinically significant difference in EPIC urinary, bowel, sexual, and hormonal scores at 24 months was 27%, 31%, 55%, and 60%, respectively. However, moderate and severe distress related to these symptoms was minimal, with increases of only 3% and 5% in the urinary and bowel domains, respectively. Conclusions: Hypofractionated radiotherapy combined with long-term androgen deprivation therapy was well tolerated. Although there were modest rates of clinically significant patient-reported urinary and bowel toxicity, most of this caused only mild distress, and moderate and severe effects on QOL were limited. Additional follow-up is ongoing to characterize long-term QOL.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2012

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

Purpose: 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. Methods and Materials: 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. Results: 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. Conclusion: 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.

62 RADIOLOGY AND NUCLEAR MEDICINE↗