Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer

A B S T R A C T Purpose Mitoxantrone-corticosteroid is currently the standard palliative treatment in hormone-refractory prostate cancer (HRPC) patients. Recent clinical trials documented the high activity of the docetaxel-estramustine combination. We conducted a randomized phase II study to evaluate prostate-specific antigen (PSA) response (primary end point) and safety of two docetaxelestramustine-prednisone (DEP) regimens and mitoxantrone-prednisone (MP). Patients and Methods One hundred thirty metastatic HRPC patients were randomly assigned to receive docetaxel (70 mg/m 2 on day 2 or 35 mg/m 2 on days 2 and 9 of each 21-day cycle) and estramustine (280 mg PO tid on days 1 through 5 and 8 through 12) or mitoxantrone 12 mg/m 2 every 3 weeks; all patients received prednisone (10 mg daily). Results One hundred twenty-seven patients were assessable for PSA response and safety. A Ն 50% PSA decline was found in a greater percentage of patients in the docetaxel arms (67% and 63%) compared with MP (18%; P ϭ .0001). Median time to PSA progression was five times longer with DEP than with MP (8.8 and 9.3 v 1.7 months, respectively; P ϭ .000001). Overall survival was better in the docetaxel arms (18.6 and 18.4 months) compared with the MP arm (13.4 months), but not significantly so (P ϭ .3). Crossover rates differed significantly among treatment arms (16%, 10%, and 48% in arms A, B, and C, respectively; P ϭ .00001). Treatment-related toxicities were mild and mainly hematologic. Conclusion The results of this randomized phase II study showed significantly higher PSA decline Յ 50% and longer times to progression in HRPC patients receiving DEP-based chemotherapy than MP, and that DEP could be proposed in this setting

Prostate-specific antigen doubling-time (PSA DT) before onset of chemotherapy as survival predictor for hormone refractory prostate cancer (HRPC) patients

International audienceBackground: PSA DT has been reported as a prognostic factor in prostate cancer patients (pts) who relapse after radical prostatectomy, radiation or hormonal therapy. The rate at which the PSA is rising is known to correlate with cancer aggressiveness. We evaluated the interest of the initial PSA DT value, before start of chemotherapy (CT), as a surrogate end point for survival of metastatic HRPC pts. Methods: PSA DT was calculated as log x 2 divided by the slope of the log PSA line (the difference in the 2 log PSA values divided by the time between). A minimum of three PSA measurements were required, maximum three months before start of CT. The primary outcome measure was overall survival. Differences in survival rates and PSA DT were calculated using the log-rank and Cox hazard regression methods, stratified according to CT regimen. All statistical tests were two-sided. Hazard ratio (HR) and relative risk reduction were also estimated with 95% confidence interval (CI). Results: A retrospective analysis was performed on 202 metastatic HRPC pts, registered from June 1999 to July 2004 in a single institution. Pts received as first-line CT: docetaxel- (77%) or mitoxantrone (23%) based regimen. The median PSA DT value was 44 days (range 5-1028 days) and median interval between two consecutive PSA determinations before CT (used tu estimate the PSA DT) was 21 days. Overall, there were 124 deaths (61%). Median survival was 14.3 months (95% CI, 10.5 to 18 months) for pts with PSA DT 44 days. There were significant differences between survival distributions of PSA DT categories (log-rank, p=0.006), independently of CT regimen. The stratified HR was 0.61 (95% CI, 0.43 to 0.87) with a relative risk reduction of 39% (95% CI, 13% to 57%). Conclusions: A low PSA DT before onset of CT in HRPC pts was associated with an increased risk of death. This parameter could be a potential auxiliary end point in the evaluation of new cytotoxic drugs in metastatic HRPC setting. These data may be also useful in the design of clinical trials and the identification of men for enrolment into experimental protocols

Docetaxel versus mitoxantrone as first-line chemotherapy for hormone-refractory prostate cancer (HRPC) patients. A meta-analysis of 3-year overall survival results. Journal of Clinical Oncology

International audienceBackground: Docetaxel (DTX) based chemotherapy is considered the standard treatment for metastatic HRPC patients (pts), with a median survival advantage of 2 months, compared to mitoxantrone (MT). DTX advantage at long term is not defined and further evaluations are needed. Methods: We conducted a meta-analysis to assess the effect of DTX chemotherapy (CT) on overall survival (OS) compared to MT for metastatic HRPC pts. OS probabilities at 12, 18, 24, 30 and 36 months, were considered as the endpoints of interest. Subgroups analysis were performed to evaluate the impact on OS of DTX dose intensity (DI), between dose-dense (q1w) and dose-intense (q3w) schedules. Estimates of the effectiveness of CT were expressed as relative risk reduction (RRR), using a fixed effects model. Associated statistics with 95% confidence interval (CI) were calculated based on adjusted number of pts at risk and events (according to the extent of follow-up) using EasyMA software. Results: Three randomized controlled trials comparing DTX with MT-based CT in HRPC pts were selected (Tannock, Petrylak, NEJM 2004; Oudard, JCO 2005). A total of 1807 pts were included, 1092 allocated to DTX and 715 allocated to MT. The follow-up range was 13.9-58.5 months. No differences were found according to Gleason score, performance status and sites of metastasis. Overall analysis demonstrates a significant OS benefit for DTX at any time points, without any significant heterogeneity (Table). There was a significant difference in OS in favor of DTX dose-intense arm comparing to MT, with no OS benefit for DTX dose-dense schedule. The rank test for publication bias were not significant. Conclusions: This meta-analysis shows on a large data set that DTX-based CT significantly reduced the risk of death by 8-21%, a benefit persisting 3 years later after the start of CT. The benefit of DTX over MT was related to DTX schedule and dose-intense model

Prostate-specific antigen doubling-time (PSA DT) before onset of chemotherapy as survival predictor for hormone refractory prostate cancer (HRPC) patients

International audienceBackground: PSA DT has been reported as a prognostic factor in prostate cancer patients (pts) who relapse after radical prostatectomy, radiation or hormonal therapy. The rate at which the PSA is rising is known to correlate with cancer aggressiveness. We evaluated the interest of the initial PSA DT value, before start of chemotherapy (CT), as a surrogate end point for survival of metastatic HRPC pts. Methods: PSA DT was calculated as log x 2 divided by the slope of the log PSA line (the difference in the 2 log PSA values divided by the time between). A minimum of three PSA measurements were required, maximum three months before start of CT. The primary outcome measure was overall survival. Differences in survival rates and PSA DT were calculated using the log-rank and Cox hazard regression methods, stratified according to CT regimen. All statistical tests were two-sided. Hazard ratio (HR) and relative risk reduction were also estimated with 95% confidence interval (CI). Results: A retrospective analysis was performed on 202 metastatic HRPC pts, registered from June 1999 to July 2004 in a single institution. Pts received as first-line CT: docetaxel- (77%) or mitoxantrone (23%) based regimen. The median PSA DT value was 44 days (range 5-1028 days) and median interval between two consecutive PSA determinations before CT (used tu estimate the PSA DT) was 21 days. Overall, there were 124 deaths (61%). Median survival was 14.3 months (95% CI, 10.5 to 18 months) for pts with PSA DT 44 days. There were significant differences between survival distributions of PSA DT categories (log-rank, p=0.006), independently of CT regimen. The stratified HR was 0.61 (95% CI, 0.43 to 0.87) with a relative risk reduction of 39% (95% CI, 13% to 57%). Conclusions: A low PSA DT before onset of CT in HRPC pts was associated with an increased risk of death. This parameter could be a potential auxiliary end point in the evaluation of new cytotoxic drugs in metastatic HRPC setting. These data may be also useful in the design of clinical trials and the identification of men for enrolment into experimental protocols

Temporal dynamics of MOG antibodies in children with acquired demyelinating syndrome

BACKGROUND AND OBJECTIVE: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody–associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG‐IgG titers in children with MOGAD in correlation with clinical presentation and disease course. METHODS: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG–positive. RESULTS: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG–negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG–negative. DISCUSSION: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG–negative, are shown to have a significantly reduced relapse risk

Treatment patterns and use of resources in patients with tuberous sclerosis complex : insights from the TOSCA registry

Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by <15% of the patients, regardless of age. The long-term nature, together with the variability in its clinical manifestations, makes TSC a complex and resource-demanding disease. The present study shows a comprehensive picture of the resource use implications of TSC