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

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

What is the place of clinical variables in advanced non-small cell lung cancer (NSCLC) patients treated with chemotherapy ?

International audienceBackground: Chemotherapy (CT) has shown its effectiveness in symptom control and quality of life improvement in advanced NSCLC patients. The therapeutic strategy and some clinical variables could have a major impact on outcome. Methods: Our retrospective analysis evaluated the impact on overall survival (OS) of the clinical benefit (CB), ECOG performance status (PS) and toxicity, function of treatment. CB was defined as disease-related symptoms improvement according to hospitalization report. Only grade III-IV CTC-NCI version 2 toxicities have been considered. OS was calculated between start of CT and death or last follow-up. Multivariate Cox regression analysis including CB, PS, toxicity and age, stratified by AJCC initial stage was used. Results: Data of 68 consecutive stage IIIB-IV patients treated in a single French centre were analyzed. Chemotherapy was platinum-salt based in 88, 45 and 25% of pts for the first, second and third-line, respectively. Median age was 61 years, 37% were women. More than half (66%) were metastatic and 14% were previously irradiated. Median survival was 14 months (95% CI, 6.1-21.8), 53 % of patients are dead. The risk of death PS-related was multiplied by 2.3, 2.4 and 5.3 for the first, second and third-line of CT, respectively. PS and CB were initially associated with OS (first and second-line CT), but after the third-line of CT only PS was significantly related with OS. The risk of death reduction induced by a CB was 59, 82 and 29%, respectively. Less toxicities during CT were associated with a better OS (an unsignificant 20- 30% risk of death reduction), independently of the chronology of CT. Older pts >70 years have a higher risk of death (HR=1.87), independently of the CB and treatment-related toxicities in the multivariate analysis (P=0.18), sex-adjusted. Conclusions: No matter how many lines of CT are used for a specified patient, the ECOG PS was a patient-related variable with a dominant impact on the outcome. CT must be less toxic in order to achieve a CB and ameliorate the PS

Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand

International audiencePURPOSE: Onycholysis and skin toxicity occur in approximately 30% of patients treated with docetaxel. We investigated the efficacy and safety of an Elasto-Gel (84400 APT Cedex, Akromed, France) frozen glove (FG) for the prevention of docetaxel-induced onycholysis and skin toxicity. PATIENTS AND METHODS: Patients receiving docetaxel 75 mg/m2 alone or in combination chemotherapy were eligible for this case-control study. Each patient wore an FG for a total of 90 minutes on the right hand. The left hand was not protected and acted as the control. Onycholysis and skin toxicity were assessed at each cycle by National Cancer Institute Common Toxicity Criteria and documented by photography. Wilcoxon matched-pairs rank test was used. RESULTS: Between August 2002 and September 2003, 45 patients were evaluated. Onycholysis and skin toxicity were significantly lower in the FG-protected hand compared with the control hand (P = .0001). Onycholysis was grade (G) 0 in 89% v 49% and G1 to 2 in 11% v 51% for the FG-protected hand and the control hand, respectively. Skin toxicity was G0 in 73% v 41% and G1 to 2 in 27% v 59% for the FG-protected and the control hand, respectively. Median time to nail and skin toxicity occurrence was not significantly different between the FG-protected and the control hand, respectively (106 v 58 days for nail toxicity; 57 v 58 days for skin toxicity). Five patients (11%) experienced discomfort due to cold intolerance. CONCLUSION: FG significantly reduces the nail and skin toxicity associated with docetaxel and provides a new tool in supportive care management to improve a patient's quality of life

Optimum timing of Gefinitib therapy in metatastic non-small cell lung cancer (NSCLC) patients

International audienceBackground: Gefitinib (IressaTM) is approved in for use as monotherapy for the treatment of patients (pts) with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapy (CT). CT that include a taxane, vinorelbine or gemcitabine remains the alternative for the second- and third-line CT. The modality of combining these CT in a sequential manner and the place of target therapies could have a major impact on survival. Methods: The present analysis evaluates the efficacy of Gefitinib for metastatic NSCLC pts. The primary outcome measure was the impact of the moment of gefitinib initiation on Time from Primary Diagnosis (TPD). TPD was calculated from primary diagnosis until death or last follow-up. Cox hazard regression analysis was performed, stratified according the initial stage of disease (AJCC 1997) and baseline ECOG performance status (PS). Progression-free survival (PFS), overall survival (OS) and TPD were estimated by Kaplan-Meier method. Gefitinib was given at a dose of 250 mg daily until disease progression in an expanded access program. Results: A retrospective analysis was performed on 71 pts, treated with gefitinib from August 2001 to October 2004 in a single institution. Median age was 59 year (range 44-85), sex M/F: 52/19 pts, ECOG PS: 0-1/2-3: 20/44 pts. Pts distribution according to treatment line was:17 pts (24%) receiving gefitinib as second-line, 16 pts (23%) as third-line, 23 pts (32%) as fourth-line CT. There were 4 pts (6%) with partial response, and 15 pts (21%) with stable disease. The median PFS and OS were 2.6 months (95% CI,1.8-3.4 months) and 5 months (95% CI,3-7 months), respectively, independently of CT line number. The median TPD for our cohort was 18.5 months (95% CI, 15.7-21.2 months). A negative and strong association (Cox coefficient = -0.6) between TPD and the moment of gefitinib initiation was observed (P=0.006, two-sided), demonstrating a major impact of precocity of treatment initiation. Conclusions: Our analysis demonstrates that the prognosis in these patients depends on the precocity of gefitinib initiation. These data may be useful in the design of clinical trials to earlier introduce target therapy, combined with chemotherapy