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Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation.

ABSTRACT: This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer (CRPC) and death.Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT was stopped, and monthly prostate-specific antigen (PSA) levels were observed during the off-treatment interval. When the PSA reached a threshold value (1 ng/mL for RP, 4 ng/mL for RT), ADT was resumed in a new cycle. Patients were treated intermittently in this manner until CRPC, which was defined as > or = two consecutive increasing PSA values while on ADT with castrate testosterone levels.Seventy-two of 100 patients enrolled onto the study met criteria for this analysis. The duration of the first off-treatment interval (< or = v > 40 weeks) was associated with shorter time to CRPC (hazard ratio = 2.9; 95% CI, 1.1 to 7.7; P = .03) and death (hazard ratio = 3.8; 95% CI, 1.1 to 13.6; P = .04) after adjusting for age, stage, grade, and PSA at diagnosis.In patients who completed the first cycle of IAD, a duration of the first off-treatment interval of < or = 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis.

SUBMITTER: Yu EY

PROVIDER: S-EPMC2881848 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation.

Yu Evan Y EY Gulati Roman R Telesca Donatello D Jiang Peter P Tam Stephen S Russell Kenneth J KJ Nelson Peter S PS Etzioni Ruth D RD Higano Celestia S CS

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100426 16

<h4>Purpose</h4>This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer (CRPC) and death.<h4>Patients and methods</h4>Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT ...[more]

PMID: 20421544

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Project description:ObjectivesTo investigate the associations of host metabolic factors and metabolic syndrome on prostate cancer-specific death (PCSD) and overall survival (OS) in patients treated with androgen deprivation therapy (ADT) for biochemically recurrent disease.Patients and methodsThe analysis included 273 patients with prostate cancer treated with ADT for rising prostate-specific antigen level after surgery or radiotherapy. Patients were assessed for the presence of diabetes, hypertension, dyslipidaemia and obesity before commencing ADT, and Adult Treatment Panel III criteria were used to assess the presence of the composite diagnosis of metabolic syndrome. A competing risks regression model was used to assess associations of time to PCSD with the metabolic conditions, while a multivariable Cox regression model was used to assess associations of OS with metabolic syndrome and metabolic conditions.ResultsDuring a median follow-up of 11.6 years, 157 patients (58%) died, of whom 58 (21%) died from prostate cancer. At the start of ADT the median (range) patient age was 74 (46-92) years and the median PSA level was 3.0 ng/mL. Metabolic syndrome was observed in 31% of patients; hypertension (68%) and dyslipidaemia (47%) were the most common metabolic conditions. No association of PCSD and metabolic syndrome status was observed. Patients with hypertension tended to have a higher cumulative incidence of PCSD than those without hypertension (sub-distribution hazard ratio [HR] 1.59, 95% confidence interval [CI] 0.89, 2.84; P = 0.11) although the difference was not statistically significant. Patients with metabolic syndrome had an increased risk of death from all causes (HR 1.56, 95% CI 1.07, 2.29; P = 0.02) when compared with patients without metabolic syndrome, as did patients with hypertension (HR 1.72, 95% CI 1.18, 2.49; P = 0.004).ConclusionsNo association of PCSD and metabolic syndrome was observed in this cohort of men receiving ADT for biochemically recurrent prostate cancer. Metabolic syndrome was associated with an increased risk of death from all causes and a similar effect was also observed for patients with prostate cancer with hypertension alone.

Project description:BackgroundCastration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.MethodsMen with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.ResultsA total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.ConclusionsOur findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).

Project description:ObjectivesThe objective of the study is to compare the efficacy and safety of alternative androgen therapy (AAT) with enzalutamide + androgen deprivation therapy (ADT) and flutamide + ADT in the treatment of Japanese men with metastatic or nonmetastatic castration-resistant prostate cancer (CRPC) who progressed despite combined androgen blockade (CAB) with bicalutamide + ADT. AAT treatment sequence was also investigated.Materials and methodsThe open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016 to March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375mg/day [125mg three times daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety.ResultsOverall, 206 men were randomized (enzalutamide first, n = 102; flutamide first, n = 104) and stratified by study site and disease stage; 133 patients transitioned to second-line therapy (enzalutamide first, n = 48; flutamide first, n = 85). TTPP1 was significantly improved with enzalutamide first versus flutamide first (median 21.4 months vs. 5.8 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] [0.29, 0.61]). TTPP2 was numerically improved with enzalutamide first versus flutamide first (median not reached vs. 21.2 months; HR 0.76; 95% CI [0.48, 1.19]). Both treatments were generally well tolerated, with AEs consistent with their known safety profiles.ConclusionFirst-line AAT with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT. Enzalutamide + ADT may therefore be the preferred first-line AAT option in Japanese men with metastatic or nonmetastatic CRPC who progress despite CAB with bicalutamide + ADT.

Dataset Information

Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation.

Publications

Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation.

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