High-risk Prostate Adenocarcinoma Research Articles

Association Between T-Stage and Cancer-Specific Mortality among Men with High-Risk Prostate Adenocarcinoma

Risk group stratification identifies men with high-risk prostate adenocarcinoma (Gleason 8-10, PSA > 20 ng/mL, or cT3-T4) who benefit from more intense treatment. However, many patients are classified as high-risk with only one high-risk feature. Although many trials that are the basis for 2-3 years of androgen deprivation therapy (ADT) studied patients with mostly cT3/T4 disease, PSA-detected, non-palpable T1c disease is currently the most commonly detected. We assessed whether within localized high-risk prostate cancer, survival differences existed based on T-stage. Data from men with high-risk N0M0 prostate adenocarcinoma from the 2004 to 2015 Surveillance, Epidemiology, and End Results database were used. Ten-year PCSM was estimated using Fine-Gray competing-risk regression. The independent variable of interest was clinical T-stage (cT1/2 vs. cT3/4); adjustments were made for PSA, Gleason score, treatment with radical prostatectomy (RP) and radiation (RT), and relevant demographic factors. A second analysis assessed PCSM only among men who received RP, with pathologic T-stage as co-variate (pT2 vs. pT3/4). The average of 12 prostate cancer prognostic signatures, including Decipher prostate cancer signature, compared genomic risk score by pT-stage. For 63,319 men included (median follow-up 6.4 years, median age 68 years), 56,322 (89.0%) had cT1/2, and 6,997 (11.1%) had cT3/4 disease. Ten-year PCSM for men with cT1/2 disease was 12.5%, and for men with cT3/4 disease was 17.5% (competing risk regression HR 0.55, 95CI 0.51—0.60, P<0.001). Greater PSA and greater Gleason score were associated with greater PCSM; receipt of RP, RT, being married, greater income, and later year of diagnosis were associated with lower PCSM. African American and Other race were also associated with lower PCSM. Of the 20,409 men who received radical prostatectomy, 9,953 (48.8%) had pT2 disease and 10,456 (51.2%) had pT3/4 disease. Ten-year PCSM for post-RP men with pT2 disease was 3.5%, and for men with pT3/4 disease was 11.9% (competing risk regression HR 0.29, 95CI 0.24—0.35, P<0.001). Greater PSA, Gleason score, receipt of radiation, and earlier year of diagnosis were associated with worse PCSM. Within a high-risk prospective RP cohort (n = 10,419) from the Decipher GRID registry (NCT02609269), patients with pT3/4 had significantly higher genomic risk scores than patients with pT2 (p<0.001). Men with cT1/2 disease had improved cancer-specific outcomes compared to men with cT3/4. Among men treated with RP, pT2 disease was associated with lower PCSM compared to pT3/4. Genomic risk scores validated these findings. Therefore, treatment paradigms given clinically relevant sub-classification of high-risk tumors based on size merit further study, with a focus on shorter-duration ADT among men with high-risk but T1/2 disease. As cT1c disease is most commonly diagnosed, more men with smaller tumors should be included in trials.

Incidencia de adenocarcinoma en zona transicional de próstata en institución pública. Cochabamba, Bolivia

El cáncer en la zona de transición representa el 20-25% de los casos (en piezas de prostatectomías radicales), su diagnóstico con frecuencia es de manera incidental, siendo identificados clínicamente como supuestos adenomas. Objetivo: determinar la incidencia de Adenocarcinoma en la Zona transicional de Próstata e identificar etapas precancerosas en pacientes con clínica de HPB. Métodos: estudio longitudinal de tipo retrospectivo desde el 2013-2018 en la ciudad de Cochabamba-Bolivia; población de estudio: pacientes sometidos a prostatectomía simple, retropúbica y/o transvesical. Recolección de datos: a partir de historias clínicas, en pacientes con clínica de hiperplasia benigna de próstata y PSA total &lt; 4 ng/ml. Resultados: se identificó 76 pacientes, de los cuales; 5 pacientes resultaron con Adenocarcinoma y 9 pacientes con: Neoplasia Intraepitelial Prostática de Alto Grado 2,6 %, Proliferación acinar pequeña atípica 7,9%, representando así un 10,5%. En cuanto a la invasión representaron un 5,3% con invasión perineal, 2,6% invasión linfovascular y ninguno con invasión extravascular. Discusión: pacientes con cáncer de próstata zona transicional, presentan un Antígeno prostático específico alto susceptibles a Adenocarcinoma. Sin embargo, en esta investigación se encontró Adenocarcinoma de próstata de alto riesgo con Antígeno prostático específico total menor a 4 ng/ml. A pesar de los instrumentos clínicos e indicaciones para la decisión de terapia quirúrgica de una supuesta hiperplasia prostática benigna, existe en el estudio una incidencia del 6,5% de Adenocarcinoma en Zona Transicional, con un 10,5 % de incidencia de presentación de formas precancerosas y el 17,1% de los pacientes del estudio se encuentran en riesgo de letalidad de la enfermedad.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer.

Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.

Ten-Year Update of a Randomized, Prospective Trial of Conventional Fractionated Versus Moderate Hypofractionated Radiation Therapy for Localized Prostate Cancer.

The previously published single institution randomized prospective trial failed to show superiority in the 5-year biochemical and/or clinical disease failure (BCDF) rate with moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) versus conventionally fractionated IMRT (C-IMRT). We now present 10-year disease outcomes using updated risk groups and definitions of biochemical failure. Men with protocol-defined intermediate- and high-risk prostate adenocarcinoma were randomly assigned to receive C-IMRT (76 Gy in 38 fractions) or H-IMRT (70.2 Gy in 26 fractions). Men with high-risk disease were all prescribed 24 months of androgen deprivation therapy (ADT) and had lymph node irradiation. Men with intermediate risk were prescribed 4 months of ADT at the discretion of the treating physician. The primary endpoint was cumulative incidence of BCDF. We compared disease outcomes and overall mortality by treatment arm, with sensitivity analyses for National Comprehensive Cancer Network (NCCN) risk group adjustment. Overall, 303 assessable men were randomly assigned to C-IMRT or H-IMRT. The median follow-up was 122.9 months. Per updated NCCN risk classification, there were 28 patients (9.2%) with low-risk, 189 (62.4%) with intermediate-risk, and 86 (28.4%) with high-risk prostate cancer. The arms were equally balanced for clinicopathologic factors, except that there were more black patients in the C-IMRT arm (17.8% v 7.3%; P = .02). There was no difference in ADT use (P = .56). The 10-year cumulative incidence of BCDF was 25.9% in the C-IMRT arm and was 30.6% in the H-IMRT arm (hazard ratio, 1.31; 95% CI, 0.82 to 2.11). The two arms also had similar cumulative 10-year rates of biochemical failure, prostate cancer-specific mortality, and overall mortality; however, the 10-year cumulative incidence of distant metastases was higher in the H-IMRT arm (rate difference, 7.8%; 95% CI, 0.7% to 15.1%). H-IMRT failed to demonstrate superiority compared with C-IMRT in long-term disease outcomes.

A phase Ib/II trial of perioperative intratumoral MVA-BN-brachyury (MVA) plus systemic PROSTVAC and atezolizumab (Atezo) for intermediate-risk and high-risk localized prostate cancer (AtezoVax).

TPS382 Background: Many patients with intermediate or high-risk localized prostate cancer relapse after prostatectomy, identifying an unmet need. Cancer vaccines increase the infiltrating lymphocyte concentration in localized and metastatic prostate cancer (PMID 25255802, 29858218). We hypothesize that treatment with a combination of two vaccines plus PD-L1 inhibition will be safe and significantly stimulate immune infiltration within the tumor microenvironment. MVA is a modified vaccinia virus that is replication-deficient, inducing the generation of tumor antigen-specific killer T-cells. PROSTVAC is a poxviral based cancer vaccine using a vaccinia virus prime and fowlpox based boost along with co-stimulatory molecules B7.1, leukocyte function-associated antigen-3, and intercellular adhesion molecule-1. Methods: This study is a single-arm,, phase I/II investigator initiated trial (NCT04020094). Primary objectives: 1) Safety, 2) Quantitative change in infiltrating CD8+ lymphocytes between the biopsy and prostatectomy as measured by immunofluorescence. Secondary endpoints: 1) 6- and 12-month undetectable PSA rate; 2) PSA-PFS compared to institutional historic control. Inclusion criteria: unfavorable intermediate to very high-risk prostate adenocarcinoma (per NCCN). Exclusion criteria: non-adenocarcinoma histology and metastatic disease (including regional nodal metastasis). A total of 22 patients will be enrolled starting with a 6 patient safety lead in. Prostate MRI will be obtained prior to treatment. Treatment schema: 2 neoadjuvant cycles (Atezo + MVA + PROSTVAC), followed by prostatectomy then 6 additional adjuvant cycles (Atezo + PROSTVAC). Neoadjuvant cycle 1: atezolizumab (1200mg IV Q3wks), PROSTVAC-V (Prime, 2x108 Inf.U subcutaneous), MVA (2 x 108 Inf.U/0.5 ml, intra-tumoral injection, volume determined by MRI). Neoadjuvant cycle 2: atezolizumab, PROSTVAC-F (Boost, 1x109 Inf.U, subcutaneous), MVA. Adjuvant: atezolizumab and PROSTVAC-F. Clinical trial information: NCT04020094.

Performance of Diffusion Kurtosis Imaging Versus Diffusion Tensor Imaging in Discriminating Between Benign Tissue, Low and High Gleason Grade Prostate Cancer

To investigate the performance of diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in discriminating benign tissue, low- and high-grade prostate adenocarcinoma (PCa). Forty-eight patients with biopsy-proven PCa of different Gleason grade (GG), who provided written informed consent, were enrolled. All subjects underwent 3T DWI examinations by using b values 0, 500, 1000, 1500, 2000, and 2500 s/mm2 and six gradient directions. Mean diffusivity, fractional anisotropy (FA), apparent kurtosis (K), apparent kurtosis-derived diffusivity (D), and proxy fractional kurtosis anisotropy (KFA) maps were obtained. Regions of interest were selected in PCa, in the contralateral benign zone, and in the peritumoral area. Histogram analysis was performed by measuring mean, 10th, 25th, and 90th (p90) percentile of the whole-lesion volume. Kruskal-Wallis test with Bonferroni correction was used to assess significant differences between different regions of interest. The correlation between diffusion metrics and GG and between DKI and DTI parameters was evaluated with Pearson's test. ROC curve analysis was carried out to analyze the ability of histogram variables to differentiate low- and high-GG PCa. All metrics significantly discriminated PCa from benign and from peritumoral tissue (except for K, KFAp90, and FA). Kp90 showed the highest correlation with GG and the best diagnostic ability (area under the curve = 0.84) in discriminating low- from high-risk PCa. Compared to DTI, DKI provides complementary and additional information about prostate cancer tissue, resulting more sensitive to PCa-derived modifications and more accurate in discriminating low- and high-risk PCa.

Long-term outcomes analysis of low-dose-rate brachytherapy in clinically T3 high-risk prostate cancer

PurposeThe available data demonstrating that superiority of LDR brachytherapy (LDR-BT) boost in high-risk prostate cancer patients under represents patients with extracapsular extension (T3a) and/or seminal vesicle invasion (T3b) have been limited. We report long-term clinical outcomes data for patients with cT3a/b disease receiving LDR-BT. Methods and MaterialsNinety-nine men (median age: 69.4 years) with cT3a/bN0M0 high-risk prostate adenocarcinoma received definitive LDR-BT or LDR-BT boost after external beam radiation therapy (EBRT) at a single institution between 1998 and 2007. About 86% of patients received androgen deprivation therapy. Freedom from biochemical failure (FFBF), prostate cancer–specific survival (PCSS), and overall survival (OS) was calculated using the Kaplan–Meier method with the Phoenix definition used as definition of failure. Cox regression analysis was used to compare outcomes between clinical stage, initial PSA, Gleason Score, and percent core positive rate. ResultsWith a median followup of 7 years, 7-year rate of FFBF, PCSS, and OS for the entire cohort was 65.2% (±5.6%), 90.1% (±3.6%), and 77.9% (±4.7%), respectively. LDR-BT boost patients achieved a 7-year FFBF rate of 73.5 (±6.5%). No significant difference in outcomes was present between T3a or T3b disease, Gleason score, iPSA stratification and percent core positive rates. ConclusionsLDR-BT, primarily as a boost in conjunction with ADT and EBRT, is not only feasible, but also highly effective in men with cT3a and cT3b high-risk prostate cancer resulting in excellent biochemical control and survival outcomes. LDR-BT boost implantation of patients should be strongly considered for cT3 patients given the merits of trimodality care.

Testosterone nadir and PSA recurrence-free survival in men with intermediate and high-risk localized prostate cancer undergoing definitive radiotherapy and androgen deprivation therapy.

100 Background: There is limited data on the relationship between testosterone level during androgen deprivation and clinical outcomes of localized prostate cancer treated with hormone therapy and radiation therapy (RT). Here we investigate the association between testosterone nadir during androgen deprivation therapy and prostate-specific antigen (PSA) response and survival. Methods: Using a nationwide Veterans Affairs database, we identified 899 patients with intermediate- or high-risk localized prostate adenocarcinoma diagnosed between 2000 and 2015 and treated with gonadotropin-releasing hormone agonists and RT. All patients had total testosterone measurements while receiving hormone therapy and between 6 weeks and 6 months after the start of hormone therapy. Using univariable and multivariable models we examined the effect of testosterone nadir on 3-month post-treatment PSA, PSA recurrence-free survival, and prostate cancer-specific survival. Multivariable models included age at diagnosis, Gleason score, tumor stage, anti-androgen therapy, hormone therapy duration, comorbidity, BMI, and pre-treatment PSA. Results: Of the 899 patients with testosterone data, 481 patients had a testosterone nadir of &lt; 20 ng/dL, 305 had a nadir between 20 and 49 ng/dL, and 113 had a nadir ≥50 ng/dL. Higher testosterone nadir was associated with higher 3-month post-treatment PSA on univariable (Spearman rho = 0.22, p &lt; 0.001, n = 651) and multivariable (ß = 0.03, 95% CI 0.01-0.05, p = 0.004) analysis. In multivariable Cox regression, higher testosterone nadir was associated with an increased risk of PSA recurrence (hazard ratio [HR] 1.43 per 10-fold increase in testosterone nadir, 95% CI 1.07-1.90, p = 0.01, n = 715) but not prostate cancer-specific mortality (HR 1.45, 95% CI 0.87-2.42, p = 0.16, n = 891). Conclusions: Higher nadir testosterone levels in intermediate- or high-risk localized prostate cancer patients undergoing hormone therapy is associated with higher 3-month post-treatment PSA and inferior PSA recurrence-free survival, though there was no significant effect on prostate cancer-specific mortality.

Long-Term Outcomes Analysis of Low Dose Rate Brachytherapy (LDR-BT) in Clinically T3 High-Risk Prostate Carcinoma

Prior utilization and reporting of outcomes with Low Dose Rate Prostate Brachytherapy (LDR-BT) in patients with prostatic extracapsular extension (T3a) and/or seminal vesicle invasion (T3b) has been limited. Herein, we report the long term clinical outcomes data for patients with cT3a/b disease receiving LDR-BT based treatment approaches and hypothesize that these approaches will achieve acceptable long term biochemical control rates. 99 men (median age: 69.4 years) with cT3a (75%) or cT3b (25%) high-risk prostate adenocarcinoma received definitive LDR-BT (29%) or LDR-BT boost following external beam (EBRT) with I-125 or Pd-103 at a single institution between 1998 and 2007. Median PSA at diagnosis was 11.4 ng/ml with 51% and 49% of men having initial gleason scores of <7 and 8-10, respectively. All patients receiving definitive LDR-BT refused receipt of EBRT. 86% of patients received Androgen Deprivation Therapy. Sources were delivered via a pre-planned, template-based, pre-loaded needle technique. Biochemical relapse free survival (BRFS), Prostate Cancer Specific Mortality (PCSM), and Overall Survival (OS) were calculated using the Kaplan-Meier method with the Phoenix definition (nadir plus 2ng/ml) as definition of failure. Outcomes are reported as estimates (+/- standard error). Cox-Regression analysis was used to compare outcomes between T3a & T3b disease, initial Gleason Scores (6-10) as well as among stratification of initial PSA (iPSA: <10ng/ml, 10-20, >20), and Percent Core Positive rates (<25%, 25-50%, 50-75%, >75%). With a median follow up time of 6.9 years, 7 year BRFS was 65.2% (+/- 5.6%), 7 year PCSM was 9.9% (+/- 3.6%), and 7 year OS was 77.9% (+/- 4.7%) for all patients. No significant difference in BRFS, PCSM or OS rates was present between T3a or T3b disease, initial gleason score, iPSA stratification or percent core positive rates. Men with cT3 high-risk disease achieve excellent biochemical control and survival outcomes with use of LDR-BT based treatment techniques, suggesting that the presence of T3 disease should not be a contraindication to use of LDR-BT. No significant difference in outcomes is present based on initial tumor related characteristics at this follow up period.

Comparison of neoadjuvant vs concurrent/adjuvant androgen deprivation in men with high-risk prostate cancer receiving definitive radiation therapy.

It is unknown whether there is a benefit to starting androgen deprivation therapy (ADT) prior to rather than concurrently with definitive radiation therapy in men with high-risk prostate cancer. We studied the National Cancer Data Base to determine whether the timing of ADT impacts survival. Men diagnosed with high-risk prostate adenocarcinoma who received external beam radiation therapy (EBRT) to a dose of 70-81 Gy along with ADT from 2004-2011 were included. Those who started ADT 42-90 days before EBRT were identified as having received neoadjuvant hormonal therapy (N-HT) and those who received ADT from 14 days before their radiation until 84 days after the start of EBRT were categorized as receiving concurrent/adjuvant treatment (C-HT). We used the log-rank test to compare Kaplan-Meier survival curves and multivariable Cox regression to assess the impact of covariables on overall survival (OS). Among 11,491 included patients, those receiving N-HT were 1 year older (p<0.001) and more likely to have Gleason 8-10 disease (p = 0.01) and cT3-4 disease (p = 0.002). Men receiving N-HT had a 5-year and median OS of 80.6% and 111.4 months, respectively, compared to 78.3% and 108.9 months, respectively, in those receiving C-HT (p = 0.03). This benefit remained significant on multivariable analysis (hazard ratio 0.86, 95% confidence interval 0.77-0.96, p = 0.008). Duration of ADT was not available to report. External beam radiation therapy with N-HT was associated with improved overall survival compared to C-HT. This study is hypothesis-generating and further studies are needed to best qualify the sequencing of hormone therapy with the duration of treatment.

Definition and Validation of “Favorable High-Risk Prostate Cancer”: Implications for Personalizing Treatment of Radiation-Managed Patients

To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease. We studied 3618 patients with cT1-T3aN0M0 high-risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer-specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate-risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268). Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease.

Oncologic and quality-of-life outcomes with wide resection in robot-assisted laparoscopic radical prostatectomy

ObjectivesTo assess urinary quality-of-life (QoL) and oncologic outcomes between wide resection (WR) robot-assisted laparoscopic radical prostatectomy (RALP) and non-WR (NWR) RALP in men with intermediate- or high-risk (Cancer of the Prostate Risk Assessment [CAPRA]-9 >2) prostate adenocarcinoma. MethodsPatients undergoing RALP (2004–2013) for intermediate- or high-risk prostate adenocarcinoma were analyzed. Kaplan-Meier methodology with Cox proportional hazards regression evaluated biochemical recurrence–free survival (BCR-FS). Multiple logistic regression was used to determine the relationship between (1) WR with positive surgical margins (+SM) and (2) WR with posterolateral+SM after adjusting for demographics and CAPRA-9 score. University of California, Los Angeles-Prostate Cancer Index and Extended Prostate Cancer Index Composite questionnaires assessed urinary QoL. Multiple mixed-effects linear regression adjusting for demographics and CAPRA-9 evaluated differences in QoL between WR and NWR. ResultsA total of 483 RALP cases met inclusion criteria—129 (26.7%) underwent WR and 354 (73.3%) underwent NWR-RALP. There were no demographic differences between groups. Burden of disease was greater in patients undergoing WR (P<0.001). There was no difference in+SM rates between WR and NWR (P = 0.505). Adjusting for demographics and CAPRA-9 score, WR patients had a clinically relevant 27% decrease in posterolateral+SM (odds ratio = 0.73; 95% CI: 0.38–1.41; P = 0.351). WR was not associated with worse BCR-FS (hazard ratio = 1.24; 95% CI: 0.83–1.86, P = 0.30). Adjusting for pathology, University of California, Los Angeles and Extended Prostate Cancer Index Composite urinary domain scores were similar between WR and NWR groups. ConclusionDespite WR patients having worse clinical disease, WR-RALP can be performed with minimal detriment to BCR-FS and urinary QoL. The greater incidence of occult metastasis in higher risk patients may make surgical technique a nonsignificant factor. Nevertheless, WR remains a reasonable option for complete surgical excision.

Phase I Trial of Weekly Docetaxel, Total Androgen Blockade, and Image-Guided Intensity-Modulated Radiotherapy for Localized High-Risk Prostate Adenocarcinoma

BackgroundThis was a phase I study to find the maximum tolerable dose (MTD) of weekly docetaxel combined with high-dose intensity-modulated radiotherapy (IMRT) and androgen deprivation therapy (ADT). Patients and MethodsMen with localized high-risk prostate cancer (HRPC) were treated with weekly docetaxel at 10 to 30 mg/m2 concurrent with IMRT of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles. ADT consisted of a gonadotropin-releasing hormone agonist (GnRHa) and bicalutamide beginning 2 months before and during chemoradiation. GnRHa was continued for 24 months. ResultsNineteen patients were enrolled. No dose-limiting toxicity (DLT) was seen with docetaxel doses up to 25 mg/m2. At the 30 mg/m2 level, 2 of 4 patients experienced DLTs of both grade 3 fatigue and dyspepsia. At 41 months' median follow-up, 2 patients had died—1 from metastatic prostate cancer and the other from heart failure. Two other patients experienced biochemical failure. One patient with bladder invasion at diagnosis experienced late grade 2 urinary hesitancy 9 months after completion of radiotherapy, requiring short-term intermittent catheterization. All patients had erectile dysfunction, but no late toxicities worse than grade 2 were identified. ConclusionWeekly docetaxel may be combined with high-dose IMRT and long-term ADT up to a MTD of 25 mg/m2. Acute toxicities and long-term side effects of this regimen were acceptable. Future studies evaluating the efficacy of docetaxel, ADT, and IMRT for localized HRPC should use a weekly dose of 25 mg/m2 when limiting the irradiated volume to the prostate and seminal vesicles.

IMRT (SIB) in high risk prostate adenocarcinoma: Institutional experience

IMRT (SIB) in high risk prostate adenocarcinoma: Institutional experience

Hypofractionated concomitant boost in intermediate and high risk prostate adenocarcinoma

Hypofractionated concomitant boost in intermediate and high risk prostate adenocarcinoma

Response of the Insulin-Like Growth Factor (IGF) System to IGF-IR Inhibition and Androgen Deprivation in a Neoadjuvant Prostate Cancer Trial: Effects of Obesity and Androgen Deprivation

Prostate cancer patients at increased risk for relapse after prostatectomy were treated in a neoadjuvant study with androgen deprivation therapy (ADT) in combination with cixutumumab, an inhibitory fully human monoclonal antibody against IGF receptor 1 (IGF-IR). A clinical trial with prospective collection of serum and tissue was designed to test the potential clinical efficacy of neoadjuvant IGF-IR blockade combined with ADT in these patients. The effect of body mass index (BMI) on response of IGF-IR/insulin components to IGF-IR blockade was also examined. Eligibility for the trial required the presence of high-risk prostate adenocarcinoma. Treatment consisted of bicalutamide, goserelin, and cixutumumab for 13 weeks before prostatectomy. Here we report on an analysis of serum samples from 29 enrolled patients. Changes in IGF and glucose homeostasis pathways were compared to control samples from patients in a concurrent clinical trial of neoadjuvant ADT alone. Significant increases were seen in GH (P = .001), IGF-I (P < .0001), IGF-II (P = .003), IGF binding protein (IGFBP)-3 (P < .0001), C-peptide (P = .0038), and insulin (P = .05) compared to patients treated with ADT alone. IGFBP-1 levels were significantly lower in the cixutumumab plus ADT cohort (P = .001). No significant changes in blood glucose were evident. Patients with BMIs in the normal range had significantly higher GH (P < .05) and IGFBP-1 (P < 0.5) levels compared to overweight and obese patients. Patients with IGF-IR blockade in combination with ADT demonstrated significant changes in IGF and glucose homeostasis pathway factors compared to patients receiving ADT alone. In the patients receiving combination therapy, patients with normal BMI had serum levels of glucose homeostasis components similar to individuals in the ADT-alone cohort, whereas patients with overweight and obese BMIs had serum levels that differed from the ADT cohort.

A Pilot 11C-Choline PET/CT Imaging Study Investigating the Ability to Detect Occult Metastatic Osseous Disease in Newly Diagnosed High-Risk Prostate Adenocarcinoma

A Pilot 11C-Choline PET/CT Imaging Study Investigating the Ability to Detect Occult Metastatic Osseous Disease in Newly Diagnosed High-Risk Prostate Adenocarcinoma

Phase I trial of total androgen blockade, weekly docetaxel, and image-guided intensity-modulated radiotherapy for localized high-risk prostate adenocarcinoma.

96 Background: High-risk prostate cancer patients have high rates of treatment failure and improved outcomes are needed. Docetaxel has shown efficacy in hormone-resistant prostate cancer and can act as a radiosensitizer. Dose escalation studies with radiation therapy have found improved freedom from failure rates. The addition of androgen deprivation therapy (ADT) improves overall survival. Therefore, this phase I study was designed to find the maximum tolerable dose (MTD) of weekly docetaxel when combined with high-dose image-guided intensity-modulated radiotherapy (IGRT) and ADT in patients with high-risk prostate cancer. Methods: Men with high-risk adenocarcinoma of the prostate (≥T2c, or PSA ≥20ng/ml, or Gleason ≥8) were treated with weekly docetaxel (given at 10-30 mg/m2, increasing by 5 mg/m2until the MTD was reached) concurrently with IGRT of 77.4 Gy in 43 fractions to the prostate and 45 Gy in 25 fractions to the proximal seminal vesicles. ADT consisted of a gonadotropin-releasing hormone agonist (GnRHa) and bicalutamide beginning 2 months before chemoradiation and continuing 2 months concurrently. The GnRHa was then continued for an additional 24 months. Results: 19 patients began combined chemoradiation between April 2006 and December 2010. Median follow-up is 32 months. No dose-limiting toxicities (DLTs) were seen in patients treated with docetaxel doses up to 25 mg/m2. However, at the 30 mg/m2level, 2 of 4 patients experienced DLTs of both grade 3 fatigue and grade 3 upper GI toxicity, indicating the MTD had been exceeded. At last follow-up, 2 patients had died, one from metastatic prostate cancer and the other from heart failure. A second patient demonstrated biochemical failure by the Phoenix criteria at 46 months, giving an actuarial biochemical disease-free survival (bDFS) at 3 years of 94.7%. All patients had ≥grade 2 erectile dysfunction but no other ≥grade 2 long-term toxicities were identified. Conclusions: Weekly docetaxel may be combined with high-dose IGRT and long-term ADT up to a MTD of 25 mg/m2. Long-term side effects with this regimen were minimal, and bDFS rate is encouraging. Clinical trial information: NCT00099086.

11C-Choline PET-CT Detection of Osseous Metastases versus Bone Scan in Newly Diagnosed High Risk Prostate Cancer Patients-A Pilot Study

Purpose: Identification of osseous metastatic prostate adenocarcinoma (PCa) is traditionally based on bone scan and computerized tomography (CT) imaging. Positron emission tomography (PET) has been investigated to improve detection of metastatic disease. Given the high number of false positive and false negative results with 18-fluorodeoxyglucose (18F-FDG) PET, novel tracers including 11C-Choline have been investigated for earlier identification metastatic disease. We present a prospective pilot study comparing 11C-Choline PET/CT against traditional bone scan in detecting osseous metastases in newly diagnosed high risk PCa. Methods: High-risk PCa patients underwent a standard initial workup: H&P, transrectal US-guided biopsy, PSA evaluation, CT scan, and bone scan. An experimental 11C-Choline PET/CT scan served to evaluate the extent of disease and predict for occult metastases. Pre-treatment bone scan and 11C-Choline PET/CT interpretations were compared with follow-up imaging, PSA, and clinical assessments to determine the predictive value of pre-treatment 11C-Choline imaging and overall outcomes. Results: Nine patients were successfully enrolled with 11C-Choline PET imaging during the initial workup. Three patients had evidence of osseous metastases on both CT and bone scans. Two of three patients had clinical findings consistent with their imaging, with all three patients exhibiting baseline PSA levels >50. Of the three patients deemed metastatic by conventional radiography, only two of the three corresponding 11C-Choline PET/CT images were in agreement with conventional imaging. The final patient had a negative 11C-Choline study with a T10 sclerotic focus on conventional imaging that was unchanged in follow-up scans despite post-treatment biochemical failure. A fourth patient without evidence of osseous metastatic disease on conventional scans demonstrated a positive 11C-Choline PET/CT scan on initial workup. In follow-up, the patient had evidence of diffuse osseous metastatic disease visualized on conventional imaging. Conclusion: In this limited prospective series, our results suggest an increased sensitivity of 11C-Choline PET/ CT in identifying active lytic lesions and true bony metastasis.

The Number of High-Risk Factors and the Risk of Prostate Cancer–Specific Mortality After Brachytherapy: Implications for Treatment Selection

To determine whether an increasing number of high-risk factors is associated with higher prostate cancer-specific mortality (PCSM) among men treated with brachytherapy (BT)-based treatment, and whether supplemental therapy has an impact on this risk. We analyzed the cases of 2234 men with localized prostate cancer treated between 1991 and 2007 with low-dose rate BT monotherapy (n = 457) or BT with supplemental external-beam radiotherapy (EBRT, n = 229), androgen suppression therapy (AST, n = 424), or both (n = 1124). All men had at least one high-risk factor (prostate-specific antigen >20 ng/mL, biopsy Gleason score 8-10, or clinical stage ≥T2c). Competing-risks multivariable regressions were performed to determine whether the presence of at least two high-risk factors was associated with an increased risk of PCSM, with adjustment for age, comorbidity, and the type of supplemental treatment. The median follow-up time was 4.3 years. The number of men with at least two high-risk factors was highest in the group treated with BT, EBRT, and AST (21%), followed by BT plus EBRT or AST (13%), and BT alone (8%) (p(trend) < 0.001). The adjusted hazard ratio (AHR) for PCSM for those with at least two high-risk factors (as compared with one) was 4.8(95% confidence interval [CI], 2.8-8.0; p < 0.001). The use of both supplemental EBRTand AST was associated with a decreased risk of PCSM (AHR 0.5; 95% CI, 0.2-0.9; p = 0.03) compared with BT alone. When the high-risk factors were analyzed separately, Gleason score 8-10 was most significantly associated with increased PCSM (AHR 6.2; 95% CI, 3.5-11.2; p < 0.001). Men with high-risk prostate adenocarcinoma treated with BT have decreased PCSM if they receive trimodailty therapy that includes EBRT and AST. This benefit is likely most important in men with multiple determinants of high risk.