scholarly journals Radiation and Androgen Deprivation Therapy With or Without Docetaxel in the Management of Nonmetastatic Unfavorable-Risk Prostate Cancer: A Prospective Randomized Trial

2021 ◽  
pp. JCO.21.00596
Author(s):  
Anthony V. D'Amico ◽  
Wanling Xie ◽  
Elizabeth McMahon ◽  
Marian Loffredo ◽  
Shana Medeiros ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Treatment Effect ◽  
Specific Antigen ◽  
Androgen Deprivation ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Specific Mortality ◽  
Risk Prostate Cancer ◽  
The Impact

PURPOSE Although docetaxel is not recommended when managing men with unfavorable-risk prostate cancer (PC) given negative or inconclusive results from previous randomized trials, unstudied benefits may exist. METHODS Between September 21, 2005, and January 13, 2015, we randomly assigned 350 men 1:1 with T1c-4N0M0 unfavorable-risk PC to receive radiation therapy (RT) and androgen deprivation therapy (ADT) plus docetaxel (60 mg/m2 once every 3 weeks for three cycles before RT and 20 mg/m2 once weekly during RT) versus ADT + RT. We evaluated the treatment effect of adding docetaxel to ADT + RT on the primary end point of overall survival (OS) and the incidence of RT-induced cancers and explored whether the impact of the treatment effect on OS differed within prostate-specific antigen (PSA) subgroups (< 4, > 20 v 4-20 ng/mL) using the interaction test for heterogeneity adjusted for age and PC prognostic factors. RESULTS After a median follow-up of 10.2 years, 89 men died (25.43%); of these, 42 from PC (47.19%). Although OS was not significantly increased in the docetaxel arm (the restricted mean survival time over 10 years was 9.11 v 8.82 years; P = .22), significantly fewer RT-induced cancers were observed (10-year estimates: 0.61% v 4.90%; age-adjusted hazard ratio of 0.13; 95% CI, 0.02 to 0.97; P = .046). The treatment effect of adding docetaxel to ADT + RT on OS significantly differed in men with a PSA < 4 ng/mL versus 4-20 ng/mL (adjusted hazard ratio: 0.27 and 1.51, respectively) because of less PC-specific mortality on the docetaxel arm (0.00% v 28.57%) among men with PSA < 4 ng/mL. CONCLUSION Adding docetaxel to ADT + RT did not prolong OS in men with unfavorable-risk PC, but decreased RT-induced cancer incidence, and may prolong OS in the subgroup of men with a PSA < 4 ng/mL by reducing PC-specific mortality.

scholarly journals Association of SLCO2B1 Genotypes With Time to Progression and Overall Survival in Patients Receiving Androgen-Deprivation Therapy for Prostate Cancer

2016 ◽  
Vol 34 (4) ◽  
pp. 352-359 ◽  
Author(s):  
Xiaodong Wang ◽  
Lauren C. Harshman ◽  
Wanling Xie ◽  
Mari Nakabayashi ◽  
Fangfang Qu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Androgen Deprivation Therapy ◽  
Genetic Variants ◽  
Androgen Deprivation ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Time To Progression ◽  
Multivariable Analyses ◽  
The Impact

Purpose To validate the association of three previously demonstrated SLCO2B1 germline variants with time to progression (TTP) in patients receiving androgen-deprivation therapy (ADT), and to evaluate if the SLCO2B1 genetic variants impacted overall survival (OS) for prostate cancer (PC). Patients and Methods Three single nucleotide polymorphisms (SNPs), exonic SNP rs12422149 and intronic SNPs rs1789693 and rs1077858, were genotyped in an independent validation cohort of 616 patients with PC who were treated with ADT at the Dana-Farber Cancer Institute from 1996 to 2013. Multivariable Cox proportional hazards regression adjusting for known prognostic factors estimated the association of these genetic variants with TTP and OS in patients receiving ADT. The expression of SLCO2B1 was examined in prostatectomy samples, and the impact of SLCO2B1 expression level on DHEAS (dehydroepiandrosterone sulfate) uptake was evaluated in cell lines. Results The association between exonic SNP rs12422149 and TTP in patients treated with ADT was confirmed in univariable (P = .019) and multivariable analyses (adjusted hazard ratio, 1.31; 95% CI, 1.00 to 1.72 for GG v AA/AG; P = .049). Because OS had not been previously evaluated, we examined the association in the combined initial and validation cohorts (N = 1,094). The intronic SNP rs1077858 was associated with OS in both univariable (P = .009; Bonferroni’s method adjusted P = .027) and multivariable analyses (adjusted hazard ratio, 1.35; 95% CI, 1.07 to 1.71 for GG v AA/AG; P = .012). SLCO2B1 expression in normal prostate tissue and in 22RV1 cells carrying the major allele of SNP rs1077858 was significantly lower than in cells carrying the risk allele. We show in vitro that SLCO2B1 expression levels correlated with DHEAS uptake by PC cells. Conclusion The association of SNP rs1077858 with OS may be a result of differential SLCO2B1 expression and the consequent increased uptake of DHEAS and subsequent resistance to ADT, which, in turn, may contribute to decreased OS.

Radiation and androgen deprivation therapy with or without docetaxel in the management of non-metastatic unfavorable-risk prostate cancer: A prospective randomized trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5011-5011
Author(s):  
Anthony Victor D'Amico ◽  
Wanling Xie ◽  
Elizabeth McMahon ◽  
Marian Loffredo ◽  
Shana Medeiros ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Androgen Deprivation Therapy ◽  
Cancer Incidence ◽  
Treatment Effect ◽  
Specific Antigen ◽  
Androgen Deprivation ◽  
High Grade ◽  
Risk Prostate Cancer

5011 Background: For men with unfavorable-risk non-metastatic (M0) prostate cancer (PC) the addition of docetaxel to radical prostatectomy (RP) or radiation therapy (RT) and androgen deprivation therapy (ADT) has been studied in 6 randomized controlled trials with negative or inconclusive results. Specifically, an overall survival (OS) benefit with a non-significant reduction in PC-specific mortality (PCSM) has been observed in two of the 6 studieswhere > 80% of the patients had high-grade PC. A plausible hypothesis for the OS benefit and a non-significant reduction in PCSM is that docetaxel reduces PCSM in the small subset of men with low prostate-specific antigen (PSA)-producing, high-grade PC that may be resistant to conventional ADT while also reducing non-PCSM by reducing death from RT-induced cancers. Given that docetaxel even at low doses (i.e. 20 mg/m2) is a potent radiosensitizer,it is plausible that it can sterilize cells that survive RT-induced damage and later develop into RT-induced cancers. Therefore, while docetaxel is not recommended when managing men with unfavorable-risk prostate cancer given inconclusive results from prior randomized trials, unstudied benefits may exist. Methods: This multicenter international randomized phase 3 trial (National Clinical Trial # 00116142) assigned 350 men with T1c-4N0M0 unfavorable-risk PC to receive ADT+RT and Docetaxel (60 mg/m2 q3 weeks for 3 cycles before RT and 20 mg/m2 weekly during RT) versus ADT+RT (1:1 ratio). Collection of data at each follow-up visit on second cancer incidence and survival status was recorded. We evaluated the treatment effect of adding docetaxel to ADT+RT on the primary endpoint of OS and the incidence of RT-induced cancers and explored whether the treatment effect impacted OS differed differently within PSA subgroups ( < 4, > 20 versus 4-20 ng/mL) using the interaction test for heterogeneity adjusted for age and known PC prognostic factors. Results: After a median follow-up of 10.2 years, 89 men died (25.43%); of these 42 from PC (47.19%). While OS was not significantly increased on the docetaxel arm [restricted mean survival time over 10-years was 9.11 versus 8.82 years with a difference of 0.29 (95% CI: -0.19, 0.76) years (p = 0.22)], significantly fewer RT-induced cancers were observed [10-year estimates: 0.61% versus 4.90%: age-adjusted HR of 0.13: 95% CI: 0.02, 0.97; p = 0.046]. For men with a PSA < 4 ng/mL versus 4-20 ng/mL the treatment effect of adding docetaxel to ADT+RT on OS differed significantly [Adjusted HR: 0.27, 1.51; pinteraction = 0.047] due to less PCSM on the docetaxel arm [0/13 (0.00%) versus 4/14 (28.57%)] among men with PSA < 4 ng/mL. Conclusions: Adding docetaxel to ADT+RT did not prolong OS in men with unfavorable-risk PC, but decreased RT-induced cancer incidence, and may prolong OS in the subgroup of men with a PSA < 4 ng/mL by reducing PCSM. Clinical trial information: NCT00116142.

scholarly journals Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921

2018 ◽  
Vol 36 (15) ◽  
pp. 1498-1504 ◽  
Author(s):  
Maha Hussain ◽  
Catherine M. Tangen ◽  
Ian M. Thompson ◽  
Gregory P. Swanson ◽  
David P. Wood ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Radical Prostatectomy ◽  
Specific Antigen ◽  
Androgen Deprivation ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Adjuvant Radiation ◽  
High Risk Prostate Cancer ◽  
Risk Prostate Cancer

Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] ≥ 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6. Patients with PSA ≤ 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided α = .05. Results Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.

scholarly journals Role of Androgen Deprivation Therapy for Node-Positive Prostate Cancer

2009 ◽  
Vol 27 (1) ◽  
pp. 100-105 ◽  
Author(s):  
Yu-Ning Wong ◽  
Stephen Freedland ◽  
Brian Egleston ◽  
Gary Hudes ◽  
J. Sanford Schwartz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lymph Nodes ◽  
Androgen Deprivation Therapy ◽  
Specific Antigen ◽  
Androgen Deprivation ◽  
Regional Lymph Nodes ◽  
Node Positive ◽  
Survival Difference ◽  
Significant Difference ◽  
The Impact

Purpose To determine the impact of adjuvant androgen deprivation therapy (ADT) for patients who have node-positive prostate cancer in the prostate-specific antigen (PSA) era. Patients and Methods We used linked Surveillance, Epidemiology and End Results-Medicare data to construct a cohort of men who underwent radical prostatectomy (RP) between 1991 and 1999 and who had positive regional lymph nodes. We classified men as receiving adjuvant ADT if they received ADT within 120 days of RP, and we compared them to the men who had not received adjuvant ADT. We used propensity scores to balance potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of nodal disease, demographics, receipt of radiation therapy) and Cox proportional hazard methods to measure the impact of adjuvant ADT on overall survival (OS), stratified by propensity score quintile. We conducted a sensitivity analysis that used 90, 150, 180, and 365 days as the definition for adjuvant ADT. Results A total of 731 men were identified, 209 of whom received ADT within 120 days of RP. There was no statistically significant difference in OS between the adjuvant ADT and non-ADT group (HR, 0.97; 95% CI, 0.71 to 1.27). There was no statistically significant survival difference with 90, 150, 180, and 365 days as the adjuvant ADT definition. Conclusion Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival. Because observational studies should be considered hypothesis-generating studies, these results should be validated in a prospective fashion in a similar patient population.

scholarly journals The castration level of testosterone and hormonal resistance of prostate cancer in androgen deprivation therapy

2020 ◽  
pp. 100-108
Author(s):  
I. G. Rusakov ◽  
A. A. Gritskevich ◽  
T. P. Baitman ◽  
S. V. Mishugin
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Androgen Deprivation Therapy ◽  
Specific Antigen ◽  
Treatment Strategies ◽  
Significant Risk ◽  
Androgen Deprivation ◽  
Early Detection Of Disease ◽  
Biomarker Analysis ◽  
The Impact

This review is dedicated to the impact of modern achievements on the definition and diagnostics of castration-resistant prostate cancer (PCa) (CRPC), prognostic factors for its progression, and treatment strategies.It was proven with new sensitive methods of diagnostics that surgical castration (CS) decreases serum testosterone (T) levels to < 20 ng/dL, while achieving T < 20 ng/dL improves outcomes and delays the development of CRPC. Regular assessment of the T level makes it possible to understand whether this androgen is adequately suppressed in the setting of potential progression of CRPC, given that late dosing may lead to an increase in T level. Improved imaging techniques and biomarker analysis enable early detection of disease progression. Prognostically significant risk factors for CRPC progression include Gleason score, the extent of metastatic spread, hereditary characteristics such as gene mutations affecting androgen receptor (AR) amplification or DNA repair deficiency mutations, prostate-specific antigen (PSA) kinetics, and biomarker levels. Today, treatment options for CRPC have gone beyond androgen deprivation therapy (ADT) to include therapy that blocks T-synthesis and/or suppresses its activity through various mechanisms. Future directions include therapies using new biological targets, drug combinations and personalized therapies. It is necessary to assess the possible reasons for the difference in the pharmacodynamics and pharmacokinetics of androgendeprivation drugs, to study the features of the processes of destruction of drugs under the action of endogenous enzymes and resorption in the subcutaneous or muscle depot, which may cause the resistance to therapy.The aim of improved treatment and diagnostic options for PCa is to delay its progression to CRPC and to prolong patient survival. Rethinking of the castration concept and advances in understanding the biology of disease progression make it necessary to revise diagnostic and treatment strategies. ADT is a fundamental vector of treatment, and it should be continued even if some new ways of treatment for CRPC are introduced.

The impact of multifocal perineural invasion on biochemical recurrence and timing of adjuvant androgen-deprivation therapy in high-risk prostate cancer following radical prostatectomy.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e595-e595
Author(s):  
Pengfei Shen ◽  
Guangxi Sun ◽  
Hao Zeng ◽  
Xingming Zhang
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Radical Prostatectomy ◽  
Androgen Deprivation Therapy ◽  
Biochemical Recurrence ◽  
Perineural Invasion ◽  
Androgen Deprivation ◽  
High Risk Prostate Cancer ◽  
Risk Prostate Cancer ◽  
The Impact

e595 Background: Perineural invasion (PNI) is a distinct pathologic entity and a recognized source of tumor spread. However, the role of PNI in high-risk prostate cancer (PCa) has not been explored. We investigated the impact of the severity of PNI on biochemical recurrence (BCR) and optimal timing of adjuvant androgen deprivation therapy (ADT) post radical prostatectomy (RP). Methods: Of 265 prostatectomies, median follow-up 45 months, were assessed for the presence of PNI and its intensity (unifocal PNI and multifocal PNI) in RP specimen. Kaplan-Merier curves were used to estimate BCR probabilities. Cox proportional hazard models were used to address predictors of BCR. Harrell’s C-index was conducted to further validate prognostic value of multi-PNI. Results: A total of 123 patients (46.4%) were PNI positive, among which, 91 (74%) and 32 (26%) had unifocal PNI (uni-PNI) and multifocal PNI (multi-PNI), respectively. Other than uni-PNI, the presence of multi-PNI was strongly associated with increasing incidence of BCR (HR = 3.87, 95% CI: 1.66-9.01, p = 0.002). Patients with uni-PNI seemed to have a similar BCR rate to those without PNI after adjuvant ADT. For men with multi-PNI, immediate ADT obviously appeared to be superior to delayed ADT in decreasing biochemical failure. Conclusions: Multi-PNI detected in high-risk RP specimens could be a prognosticator for early biochemical relapse post-surgery. Our findings suggest that patients with multi-PNI appear appropriate to choose adjuvant therapy as soon as possible after surgery.

Optimizing the use of androgen deprivation therapy in men with localized intermediate-risk prostate cancer in the era of modern dose-escalated radiation therapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 109-109
Author(s):  
Sagar Anil Patel ◽  
Kevin H. Nguyen ◽  
Alan K. Lee ◽  
David Jeffrey Demanes ◽  
Albert Chang
Keyword(s):  
Prostate Cancer ◽  
Androgen Deprivation Therapy ◽  
Dose Escalation ◽  
Clinical Stage ◽  
Androgen Deprivation ◽  
High Dose ◽  
Intermediate Risk ◽  
Risk Prostate Cancer ◽  
The Impact ◽  
Group D

109 Background: While level one evidence has shown an overall survival (OS) advantage with the addition of androgen deprivation therapy (ADT) to radiotherapy (RT) for intermediate risk prostate cancer (PCa), the benefit in the era of modern dose escalation is controversial, especially given the heterogeneity within this risk group. We assessed the impact of adding ADT to high dose RT on OS for intermediate risk PCa stratified by number of intermediate risk factors (IRF). Methods: We identified 114,339 men with intermediate risk PCa (Gleason 7, clinical stage T1-2, PSA < 20 ng/mL) using the National Cancer Database. Men were stratified into the following subgroups based on the number of IRFs (Gleason 7, cT2b-c, PSA > 10-20 ng/mL): A) Gleason 3+4 and no other IRF, B) Gleason 4+3 and no other IRF, C) two IRFs, and D) three IRFs. The addition of ADT to dose-escalated external beam RT (DE-EBRT, ≥ 75.6 Gy), brachytherapy (BT), or combination EBRT+BT on OS was assessed within each subgroup using Kaplan-Meier and log-rank tests in propensity score-matched cohorts in all men and subsequently only in those with Charlson-Deyo comorbidity index (CDI) of zero. Results: There was no OS benefit with the addition of ADT to DE-EBRT, BT, or EBRT+BT in groups A, B, and C, even after limiting the cohort to men with CDI = 0. However, in group D, the addition of ADT to DE-EBRT was associated with a trend for OS improvement in patients with CDI = 0 only (8-year OS with and without ADT 68.3% and 62.4%, respectively, log-rank P= .07). Conversely, there was a trend for OS decrement with the addition of ADT to DE-EBRT in men with CDI ≥ 1 (8-year OS with and without ADT 61.8% and 67.5%, respectively, log-rank P= .06). There was no OS benefit of ADT in group D treated with BT or EBRT+BT, regardless of comorbidity status. Conclusions: The OS benefit of ADT in men with intermediate risk PCa may be limited to those with 3 IRFs and minimal comorbidities treated with DE-EBRT. If prospectively validated, extreme dose escalation achieved with BT (alone or in combination with EBRT) may obviate the addition of ADT in all men with intermediate risk disease, especially in an era of advanced molecular imaging.

Treatment timing in localized high-risk prostate cancer treated with radiation and androgen deprivation therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 359-359
Author(s):  
Shaakir Hasan ◽  
Stanislav Lazarev ◽  
Daniel Gorovets ◽  
Madhur Garg ◽  
Robert H. Press ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Androgen Deprivation Therapy ◽  
Treatment Time ◽  
Androgen Deprivation ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer ◽  
Multivariable Regression ◽  
The Impact

359 Background: Data regarding the impact of overall treatment time in prostate radiotherapy predate the dose escalation era and is absent in high risk disease. We hypothesize that delays in initiating androgen deprivation therapy (ADT) and in completing fractionated radiotherapy (XRT) correlate with worse outcomes in high risk prostate cancer. Methods: Using the National Cancer Database, we identified 9,611 cases of localized high risk prostate cancer, defined as Grade groups 4 and 5 (Gleason 8-10), PSA < 40, and T1-T3N0M0, treated with conventionally fractionated XRT (74-81 Gy, median 78 Gy) and ADT between 2010-2014 with at least 12 months follow-up (median 40). Receiver operating characteristic (ROC) analyses determined a-priori values for days to initiation of treatment (ADT or XRT) and number of “missed” treatment days (number of days beyond the minimum required to complete XRT). Multivariable regression models with propensity matching conveyed the relative impact of these timing parameters on survival. Results: The median time from diagnosis to treatment intervention was 63 days and median missed XRT treatment days was 2.2. The greatest difference in survival was seen when intervention was initiated beyond 74 days from diagnosis (HR=1.21, P=0.045) and when more than 3 XRT treatment days were missed (HR=1.27, P=0.006). Only missed treatment days correlated with survival as a continuous variable (HR=1.028, P<0.001) on multivariable analysis. On a multivariable regression model propensity-matched for missed treatment days, independent predictors for worse survival include older age, higher comorbidity score, dose below 78 Gy, grade group 5, and PSA > 20. Greater than 3 missed treatment days remained an independent predictor; adjusted HR = 1.23 (P=0.002). The lone predictors of missed treatments was African American race (OR=1.21). Conclusions: Although outcomes in prostate cancer are not typically thought to be associated with treatment time, our study, the largest such analysis to date, revealed a strong independent correlation between timely completion of XRT and survival in high risk disease. The association between survival and time to initiating ADT was not nearly as strong.

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