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. Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analy Treatment of Hormone-Refractory Prostate Cancer with Docetaxel or Mitoxantrone: Relationships between Prostate-Specific Antigen, Pain, and Quality of Life Response and Survival in the TAX-327 Study Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial Adjuvant leuprolide with or without docetaxel in patients with high‐risk prostate cancer after radical prostatectomy (TAX‐3501) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered: A Post Hoc Analysis of the Mainsail Study Long-term followup of a randomized study of locally advanced prostate cancer treated with combined orchiectomy and external radiotherapy versus radiotherapy alone. Prospective randomized trial comparing flutamide as adjuvant treatment versus observation after radical prostatectomy for locally advanced, lymph node-negative prostate cancer. A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. A phase III trial of docetaxel-estramustine in high-risk localised prostate cancer: a planned analysis of response, toxicity and quality of life in the GETUG 12 trial. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer.
Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death . Adjuvant and rogen-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 r and omly 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 r and omly 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 PURPOSE Long-term and rogen suppression plus radiotherapy ( AS+RT ) is st and ard treatment of high-risk prostate cancer . A r and omized trial , Radiation Therapy Oncology Group trial 9902 , was undertaken to determine whether adjuvant chemotherapy with paclitaxel , estramustine , and etoposide ( TEE ) plus AS+RT would improve disease outcomes with acceptable toxicity . METHODS AND MATERIAL S High-risk ( prostate-specific antigen 20 - 100 ng/mL and Gleason score > or=7 ; or Stage T2 or greater , Gleason score 8 , prostate-specific antigen level < 100 ng/mL ) nonmetastatic prostate cancer patients were r and omized to AS+RT ( Arm 1 ) vs. AS+RT plus four cycles of TEE ( Arm 2 ) . TEE was delivered 4 weeks after RT . AS continued for 2 years for both treatment arms . RT began after 8 weeks of AS began . RESULTS The Radiation Therapy Oncology Group 9902 trial opened January 11 , 2000 . Excess thromboembolic toxicity was noted , leading to study closure October 4 , 2004 . A total of 397 patients were accrued , and the data for 381 were analyzable . An acute and long-term toxicity analysis was performed . The worst overall toxicities during treatment were increased for Arm 2 . Of the 192 patients , 136 ( 71 % ) on Arm 2 had RTOG Grade 3 or greater toxicity compared with 70 ( 37 % ) of 189 patients on Arm 1 . Statistically significant increases in hematologic toxicity ( p < 0.0001 ) and gastrointestinal toxicity ( p = 0.017 ) but not genitourinary toxicity ( p = 0.07 ) were noted during treatment . Two Grade 5 complications related to neutropenic infection occurred in Arm 2 . Three cases of myelodysplasia/acute myelogenous leukemia were noted in Arm 2 . At 2 and 3 years after therapy completion , excess long-term toxicity was not observed in Arm 2 . CONCLUSION TEE was associated with significantly increased toxicity during treatment . The toxicity profiles did not differ at 2 and 3 years after therapy . Toxicity is an important consideration in the design of trials using adjuvant chemotherapy for prostate cancer Purpose : The TAX-327 study r and omized 1,006 men with metastatic hormone-refractory prostate cancer to receive 3-weekly docetaxel , weekly docetaxel , or mitoxantrone , each with prednisone . Experimental Design : We used the TAX-327 data base to address ( a ) the relationship between quality of life ( QoL ) and pain ; ( b ) whether minimally symptomatic patients benefit from treatment or have treatment-related decline in QoL ; ( c ) the relationships between prostate-specific antigen ( PSA ) response , pain response , and QoL response ; ( d ) the times at which these responses are first observed ; and ( e ) whether PSA , pain , and /or QoL response predict for overall survival . Results : At baseline , 374 of 815 men assessed for QoL had major pain ; of these , 92 % had substantial impairment of QoL compared with 75 % without major pain ( P < 0.001 ) . Men with minimal symptoms had prolonged survival ( median , 25.6 months ) compared with symptomatic patients ( median , 17.1 months ; P = 0.009 ) ; they were more likely to have initial deterioration of QoL if treated with weekly docetaxel .  PSA response and pain response , but not QoL response , were independently associated with survival in l and mark analysis . Median times to PSA and pain response were 44 and 27 days , respectively ; some men had initial increase in serum PSA before subsequent decline . Conclusions : Symptoms other than pain contribute to impaired QoL in men with hormone-refractory prostate cancer . Those with minimal symptoms have prolonged survival . Both pain and PSA response are associated with survival but are not adequate to use as surrogate end points in phase 3 studies . Early increases in serum PSA ( up to 12 weeks ) should be ignored when determining response or progression CONTEXT Interstitial radiation ( implant ) therapy is used to treat clinical ly localized adenocarcinoma of the prostate , but how it compares with other treatments is not known . OBJECTIVE To estimate control of prostate-specific antigen ( PSA ) after radical prostatectomy ( RP ) , external beam radiation ( RT ) , or implant with or without neoadjuvant and rogen deprivation therapy in patients with clinical ly localized prostate cancer . DESIGN Retrospective cohort study of outcome data compared using Cox regression multivariable analyses . SETTING AND PATIENTS A total of 1872 men treated between January 1989 and October 1997 with an RP ( n = 888 ) or implant with or without neoadjuvant and rogen deprivation therapy ( n = 218 ) at the Hospital of the University of Pennsylvania , Philadelphia , or RT ( n = 766 ) at the Joint Center for Radiation Therapy , Boston , Mass , were enrolled . MAIN OUTCOME MEASURE Actuarial freedom from PSA failure ( defined as PSA outcome ) . RESULTS The relative risk ( RR ) of PSA failure in low-risk patients ( stage T1c , T2a and PSA level < or = 10 ng/mL and Gleason score < or = 6 ) treated using RT , implant plus and rogen deprivation therapy , or implant therapy was 1.1 ( 95 % confidence interval [ CI ] , 0.5 - 2.7 ) , 0.5 ( 95 % CI , 0.1 - 1.9 ) , and 1.1 ( 95 % CI , 0.3 - 3.6 ) , respectively , compared with those patients treated with RP . The RRs of PSA failure in the intermediate-risk patients ( stage T2b or Gleason score of 7 or PSA level > 10 and < or = 20 ng/mL ) and high-risk patients ( stage T2c or PSA level > 20 ng/mL or Gleason score > or = 8) treated with implant compared with RP were 3.1 ( 95 % CI , 1.5 - 6.1 ) and 3.0 ( 95 % CI , 1.8 - 5.0 ) , respectively . The addition of and rogen deprivation to implant therapy did not improve PSA outcome in high-risk patients but result ed in a PSA outcome that was not statistically different compared with the results obtained using RP or RT in intermediate-risk patients . These results were unchanged when patients were stratified using the traditional rankings of biopsy Gleason scores of 2 through 4 vs 5 through 6 vs 7 vs 8 through 10 . CONCLUSIONS Low-risk patients had estimates of 5-year PSA outcome after treatment with RP , RT , or implant with or without neoadjuvant and rogen deprivation that were not statistically different , whereas intermediate- and high-risk patients treated with RP or RT did better then those treated by implant . Prospect i ve r and omized trials are needed to verify these findings Summary Background Long-term hormone therapy has been the st and ard of care for advanced prostate cancer since the 1940s . STAMPEDE is a r and omised controlled trial using a multiarm , multistage platform design . It recruits men with high-risk , locally advanced , metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy .  We report primary survival results for three research comparisons testing the addition of zoledronic acid , docetaxel , or their combination to st and ard of care versus st and ard of care alone . Methods St and ard of care was hormone therapy for at least 2 years ; radiotherapy was encouraged for men with N0M0 disease to November , 2011 , then m and ated ; radiotherapy was optional for men with node-positive non-metastatic ( N+M0 ) disease . Stratified r and omisation ( via minimisation ) allocated men 2:1:1:1 to st and ard of care only ( SOC-only ; control ) , st and ard of care plus zoledronic acid ( SOC + ZA ) , st and ard of care plus docetaxel ( SOC + Doc ) , or st and ard of care with both zoledronic acid and docetaxel ( SOC + ZA + Doc ) . Zoledronic acid ( 4 mg ) was given for six 3-weekly cycles , then 4-weekly until 2 years , and docetaxel ( 75 mg/m2 ) for six 3-weekly cycles with prednisolone 10 mg daily . There was no blinding to treatment allocation . The primary outcome measure was overall survival . Pairwise comparisons of research versus control had 90 % power at 2·5 % one-sided α for hazard ratio ( HR ) 0·75 , requiring roughly 400 control arm deaths . Statistical analyses were undertaken with st and ard log-rank-type methods for time-to-event data , with hazard ratios ( HRs ) and 95 % CIs derived from adjusted Cox models . This trial is registered at Clinical Trials.gov ( NCT00268476 ) and ControlledTrials.com ( IS RCT N78818544 ) . Findings 2962 men were r and omly assigned to four groups between Oct 5 , 2005 , and March 31 , 2013 . Median age was 65 years ( IQR 60–71 ) . 1817 ( 61 % ) men had M+ disease , 448 ( 15 % ) had N+/X M0 , and 697 ( 24 % ) had N0M0 . 165 ( 6 % ) men were previously treated with local therapy  , and median prostate-specific antigen was 65 ng/mL ( IQR 23–184 ) . Median follow-up was 43 months ( IQR 30–60 ) . There were 415 deaths in the control group ( 347 [ 84 % ] prostate cancer ) . Median overall survival was 71 months ( IQR 32 to not reached ) for SOC-only , not reached ( 32 to not reached ) for SOC + ZA ( HR 0·94 , 95 % CI 0·79–1·11 ; p=0·450 ) , 81 months ( 41 to not reached ) for SOC + Doc ( 0·78 , 0·66–0·93 ; p=0·006 ) , and 76 months ( 39 to not reached ) for SOC + ZA + Doc ( 0·82 , 0·69–0·97 ; p=0·022 ) . There was no evidence of heterogeneity in treatment effect ( for any of the treatments ) across prespecified subsets . Grade 3–5 adverse events were reported for 399 ( 32 % ) patients receiving SOC , 197 ( 32 % ) receiving SOC + ZA , 288 ( 52 % ) receiving SOC + Doc , and 269 ( 52 % ) receiving SOC + ZA + Doc . Interpretation Zoledronic acid showed no evidence of survival improvement and should not be part of st and ard of care for this population . Docetaxel chemotherapy , given at the time of long-term hormone therapy initiation , showed evidence of improved survival accompanied by an increase in adverse events . Docetaxel treatment should become part of st and ard of care for adequately fit men commencing  long-term hormone  therapy . Funding Cancer Research UK , Medical Research Council , Novartis , Sanofi-Aventis , Pfizer , Janssen , Astellas , NIHR Clinical Research Network , Swiss Group for Clinical Cancer Research The current trial evaluated 2 common therapies for patients with advanced prostate cancer , docetaxel and hormonal therapy ( HT ) , in the surgical adjuvant setting BACKGROUND Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced , hormone-refractory prostate cancer , but it does not improve survival . We compared such treatment with docetaxel plus prednisone in men with this disease . METHODS From March 2000 through June 2002 , 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily  and were r and omly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks , 75 mg of docetaxel per square meter every three weeks , or 30 mg of docetaxel per square meter weekly for five of every six weeks . The primary end point was overall survival . Secondary end points were pain , prostate-specific antigen ( PSA ) levels , and the quality of life . All statistical comparisons were against mitoxantrone . RESULTS As compared with the men in the mitoxantrone group , men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 ( 95 percent confidence interval , 0.62 to 0.94 ; P=0.009 by the stratified log-rank test ) and those given weekly docetaxel had a hazard ratio for death of 0.91 ( 95 percent confidence interval , 0.75 to 1.11 ; P=0.36 ) . The median survival was 16.5 months in the mitoxantrone group , 18.9 months in the group given docetaxel every 3 weeks , and 17.4 months in the group given weekly docetaxel . Among these three groups , 32 percent , 45 percent , and 48 percent of men , respectively , had at least a 50 percent decrease in the serum PSA level ( P<0.001 for both comparisons with mitoxantrone ) ; 22 percent , 35 percent ( P=0.01 ) , and 31 percent ( P=0.08 ) had predefined reductions in pain ; and 13 percent , 22 percent ( P=0.009 ) , and 23 percent ( P=0.005 ) had improvements in the quality of life . Adverse events were also more common in the groups that received docetaxel . CONCLUSIONS When given with prednisone , treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain , serum PSA level , and quality of life , as compared with mitoxantrone plus prednisone PURPOSE Radiation Therapy Oncology Group protocol 85 - 31 was design ed to evaluate the effectiveness of adjuvant and rogen suppression , using goserelin , in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy ( RT ) . METHODS AND MATERIAL S Eligible patients were those with palpable primary tumor extending beyond the prostate ( clinical Stage T3 ) or those with regional lymphatic involvement . Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and /or seminal vesicle involvement was documented histologically . Stratification was based on histologic differentiation , nodal status , acid phosphatase status , and prior prostatectomy . The patients were r and omized to either RT and adjuvant goserelin ( Arm I ) or RT alone followed by observation and application of goserelin at relapse ( Arm II ) . In Arm I , the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression . RESULTS Between 1987 and 1992 , when the study was closed , 977 patients were entered : 488 to Arm I and 489 to Arm II . As of July 2003 , the median follow-up for all patients was 7.6 years and for living patients was 11 years . At 10 years , the absolute survival rate was significantly greater for the adjuvant arm than for the control arm : 49 % vs. 39 % , respectively ( p = 0.002 ) . The 10-year local failure rate for the adjuvant arm was 23 % vs. 38 % for the control arm ( p < 0.0001 ) . The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24 % vs. 39 % ( p < 0.001 ) and 16 % vs. 22 % ( p = 0.0052 ) , respectively , both in favor of the adjuvant arm . CONCLUSION In a population of patients with unfavorable prognosis carcinoma of the prostate , and rogen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival . The improvement in survival appeared preferentially in patients with a Gleason score of 7 - 10 Importance The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer ( mCPRC ) has not been investigated yet . It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles . Objective To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival ( OS ) in a post hoc analysis of the Mainsail trial . Design , Setting , and Participants The Mainsail trial was a multinational r and omized phase 3 study of 1059 patients with mCRPC receiving docetaxel , prednisone , and lenalidomide ( DPL ) or docetaxel , prednisone , and a placebo ( DP ) .  Study patients were treated until progressive disease or unacceptable adverse effects occurred . Median OS was found to be inferior in the DPL arm compared with the DP arm . As a result of increased toxic effects with the DPL combination , patients on DPL received fewer  docetaxel cycles ( median , 6 ) vs 8 cycles in the control group . As the dose intensity was comparable in both treatment arms , we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS . We conducted primary univariate and multivariate analyses for the intention-to-treat population . Additional sensitivity analyses were done , excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons , minimizing the effect of confounding factors . Main Outcomes and Measures Total number of docetaxel cycles delivered as an independent factor for OS . Results Overall , all 1059 patients from the Mainsail trial were included ( mean [ SD ] age , 68.7 [ 7.89 ] years ) . Treatment with 8 or more cycles of docetaxel was associated with superior OS ( hazard ratio [ HR ] , 1.909 ; 95 % CI , 1.660 - 2.194 ; P < .001 ) , irrespective of lenalidomide treatment ( HR , 1.060 ; 95 % CI , 0.924 - 1.215 ; P = .41 ) . Likewise , in the sensitivity analysis , patients who received a greater number of docetaxel cycles had superior OS ; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles ; and patients who received 5 to 7 cycles had a median OS of 22.8 months ( P < .001 ) . Conclusions and Relevance These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit . Prospect i ve validation is warranted PURPOSE In a r and omized study we compared the combination of orchiectomy and radiotherapy to radiotherapy alone as treatment for locally advanced prostate cancer . Patients who were treated only with radiotherapy  initially underwent castration therapy at clinical progression , providing the opportunity to compare immediate vs deferred endocrine intervention . MATERIAL S AND METHODS In this prospect i ve study 91 patients with locally advanced prostate cancer were r and omized to receive external beam radiotherapy ( 46 ) or combined orchiectomy and radiotherapy ( 45 )  after surgical lymph node staging .  Survival rates were calculated . RESULTS During 14 to 19 years of followup 87 % of the patients in the radiotherapy group and 76 % in the combined orchiectomy and radiotherapy group died ( log rank p = 0.03 ) . Prostate cancer mortality was 57 % and 36 % , respectively ( log rank p = 0.02 ) . The difference in favor of combined treatment was mainly caused by lymph node positive tumors . For node negative tumors there was no significant difference in the survival rates . CONCLUSIONS Immediate and rogen deprivation should be considered instead of deferred endocrine treatment started at clinical progression for prostate cancer with spread to regional lymph nodes . While awaiting evidence from r and omized trials , one should consider full dose radiotherapy for local control of locally advanced prostate cancer even when it is lymph node positive OBJECTIVE To assess the efficacy and the tolerability of flutamide as adjuvant treatment after radical prostatectomy for locally advanced , lymph node-negative prostate cancer . METHODS Men with locally advanced , lymph node-negative prostate cancer were r and omized after radical prostatectomy  to receive either flutamide 750 mg daily or no adjuvant treatment .  Recurrence-free and overall survival were the study end points . Recurrence was defined as a PSA value greater than 5ng/ml or two values greater than 2ng/ml more than three months apart with increasing tendency or three values greater than 1ng/ml more than three months apart with increasing tendency or any clinical recurrence . RESULTS 309 patients ( 157 in the control arm and 152 in the flutamide arm ) were eligible for efficacy analysis . The median follow-up was 6.1 years . Recurrence-free survival was better in the flutamide group ( P=0.0041 ) , there was , however , no detectable difference in overall survival ( p=0.92 ) . Moreover , there was a considerable toxicity reported in the flutamide group . CONCLUSION Although having some effect on disease recurrence , adjuvant flutamide treatment does not improve median-term overall survival after radical prostatectomy for locally advanced , lymph node-negative prostate cancer PURPOSE Long-term ( LT ) and rogen suppression ( AS ) with radiation therapy ( RT ) is a st and ard treatment of high-risk , localized prostate cancer ( PCa ) . Radiation Therapy Oncology Group 9902 was a r and omized trial testing the hypothesis that adjuvant combination chemotherapy ( CT ) with paclitaxel , estramustine , and oral etoposide plus LT AS plus RT would improve overall survival ( OS ) . METHODS AND MATERIAL S Patients with high-risk PCa ( prostate-specific antigen 20 - 100 ng/mL and Gleason score [ GS ] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were r and omized to RT and AS ( AS + RT ) alone or with adjuvant CT ( AS + RT + CT ) . CT was given as four 21-day cycles , delivered beginning 28 days after 70.2 Gy of RT . AS was given as luteinizing hormone-releasing hormone for 24 months , beginning 2 months before RT plus an oral anti and rogen for 4 months before and during RT . The study was design ed based on a 6 % improvement in OS from 79 % to 85 % at 5 years , with 90 % power and a 2-sided alpha of 0.05 . RESULTS A total of 397 patients ( 380 eligible ) were r and omized . The patients had high-risk PCa , 68 % with GS 8 to 10 and 34 % T3 to T4 tumors , and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years . The trial closed early because of excess thromboembolic toxicity in the CT arm . The 10-year results for all r and omized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS ( 65 % vs 63 % ; P=.81 ) , biochemical failure ( 58 % vs 54 % ; P=.82 ) , local progression ( 11 % vs 7 % ; P=.09 ) , distant metastases ( 16 % vs 14 % ; P=.42 ) , or disease-free survival ( 22 % vs 26 % ; P=.61 ) . CONCLUSIONS NRG Oncology RTOG 9902 showed no significant differences in OS , biochemical failure , local progression , distant metastases , or disease-free survival with the addition of adjuvant CT to LT AS + RT . The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implication s for the feasibility of clinical trial accrual and tolerability using CT for PCa BACKGROUND Early risk-stratified chemotherapy is a st and ard treatment for breast , colorectal , and lung cancers , but not for high-risk localised prostate cancer . Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer . We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer . METHODS We did this r and omised phase 3 trial at 26 hospitals in France . We enrolled patients with treatment-naive prostate cancer and at least one risk factor ( ie , stage T3-T4 disease , Gleason score of ≥8 , prostate-specific antigen concentration > 20 ng/mL , or pathological node-positive ) . All patients underwent a staging pelvic lymph node dissection . Patients were r and omly assigned ( 1:1 ) to either and rogen deprivation therapy ( ADT ; goserelin 10·8 mg every 3 months for 3 years ) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2 ) and estramustine 10 mg/kg per day on days 1 - 5 , every 3 weeks , or ADT only . The r and omisation was done central ly by computer , stratified by risk factor . Local treatment was administered at 3 months . Neither patients nor investigators were masked to treatment allocation . The primary endpoint was relapse-free survival in the intention-to-treat population . Follow-up for other endpoints is ongoing . This study is registered with Clinical Trials.gov , number NCT00055731 . FINDINGS We r and omly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group . Median follow-up was 8·8 years ( IQR 8·1 - 9·7 ) . 88 ( 43 % ) of 207 patients in the ADT plus docetaxel and estramustine group had an event ( relapse or death ) versus 111 ( 54 % ) of 206 in the ADT only group . 8-year relapse-free survival was 62 % ( 95 % CI 55 - 69 ) in the ADT plus docetaxel and estramustine group versus 50 % ( 44 - 57 ) in the ADT only group ( adjusted hazard ratio [ HR ] 0·71 , 95 % CI 0·54 - 0·94 , p=0·017 ) . Of patients who were treated with radiotherapy and had data available , 31 ( 21 % ) of 151 in the ADT plus docetaxel and estramustine group versus 26 ( 18 % ) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect ( p=0·61 ) . We recorded no excess second cancers ( 26 [ 13 % ] of 207 vs 22 [ 11 % ] of 206 ; p=0·57 ) , and there were no treatment-related deaths . INTERPRETATION Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer . Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival . FUNDING Ligue Contre le Cancer , Sanofi-Aventis , AstraZeneca , Institut National du Cancer CONTEXT Comorbidities may increase the negative effects of specific anticancer treatments such as and rogen suppression therapy ( AST ) . OBJECTIVES To compare 6 months of AST and radiation therapy ( RT ) to RT alone and to assess the interaction between level of comorbidity and all-cause mortality . DESIGN , SETTING , AND PATIENTS At academic and community-based medical centers in Massachusetts , between December 1 , 1995 , and April 15 , 2001 , 206 men with localized but unfavorable-risk prostate cancer were r and omized to receive RT alone or RT and AST combined .  All-cause mortality estimates stratified by r and omized treatment group and further stratified in a postr and omization analysis by the Adult Comorbidity Evaluation 27 comorbidity score were compared using a log-rank test . MAIN OUTCOME MEASURE Time to all-cause mortality . RESULTS As of January 15 , 2007 , with a median follow-up of 7.6 ( range , 0.5 - 11.0 ) years , 74 deaths have occurred . A significant increase in the risk of all-cause mortality ( 44 vs 30 deaths ; hazard ratio [ HR ] , 1.8 ; 95 % confidence interval [ CI ] , 1.1 - 2.9 ; P = .01 ) was observed in men r and omized to RT compared with RT and AST . However , the increased risk in all-cause mortality appeared to apply only to men r and omized to RT with no or minimal comorbidity ( 31 vs 11 deaths ; HR , 4.2 ; 95 % CI , 2.1 - 8.5 ; P < .001 ) . Among men with moderate or severe comorbidity , those r and omized to RT alone vs RT and AST did not have an increased risk of all-cause mortality ( 13 vs 19 deaths ; HR , 0.54 ; 95 % CI , 0.27 - 1.10 ; P = .08 ) . CONCLUSIONS The addition of 6 months of AST to RT result ed in increased overall survival in men with localized but unfavorable-risk prostate cancer . This result may pertain only to men without moderate or severe comorbidity , but this requires further assessment in a clinical trial specifically design ed to assess this interaction . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00116220 AIM To assess docetaxel-estramustine in patients with localised high-risk prostate cancer . PATIENTS AND METHODS After staging pelvic lymph node dissection , patients with high-risk prostate cancer r and omly received and rogen deprivation therapy ( ADT )  ( 3 years)+DE ( 4 cycles of docetaxel 70 mg/m(2)/3 weeks+estramustine 10mg/kg/dd1 - 5 ) or ADT alone . Local therapy was administered at 3 months . RESULTS Four hundred and thirteen patients were accrued : T3-T4 ( 67 % ) , Gleason score ~8 ( 42 % ) , PSA > 20 ng/mL ( 59 % ) , pN+ ( 29 % ) . In the chemotherapy arm , 94 % of patients received the planned four cycles of docetaxel . Local treatment consisted of radiotherapy in 358 patients ( 87 % ) ( median dose 74 Gy in both arms ) . ADT was given for 36 months in both arms . A PSA response ( PSA ~0.2 ng/mL after 3 months of treatment ) was obtained in 34 % and 15 % in the ADT+DE arm and in the ADT arm , respectively ( p<0.0001 ) . Febrile neutropenia occurred in only 2 % . Moderate to severe hot flashes occurred less often in the ADT+DE arm ( 2 % versus 22 % ; p<0.001 ) . There was no toxicity-related death , no secondary leukaemia , and no excess second cancers . Chemotherapy had a negative impact on quality of life ( global health status , p = 0.01 ; fatigue , p = 0.003 ; role functioning , p = 0.003 ; social functioning , p = 0.006 ) at 3 months but this effect disappeared at 1 year . CONCLUSION Docetaxel-estramustine can be combined safely with st and ard therapy in high-risk prostate cancer , with a promising PSA response rate and no negative impact on quality of life after 1 year . Long-term follow-up is required to assess the impact on relapse and survival Recent insights into the regulation of the and rogen receptor ( AR ) activity led to novel therapeutic targeting of AR function in prostate cancer patients .  Docetaxel is an approved chemotherapy for treatment of castration-resistant prostate cancer ; however , the mechanism underlying the action of this tubulin-targeting drug is not fully understood . This study investigates the contribution of microtubules and the cytoskeleton to and rogen-mediated signaling and the consequences of their inhibition on AR activity in human prostate cancer . Tissue microarrays from  docetaxel-treated and untreated prostate cancer patients were comparatively analyzed for prostate-specific antigen ( PSA ) and AR immunoreactivity . The AR transcriptional activity was determined in prostate cancer cells in vitro , based on PSA mRNA expression and the and rogen response element reporter activity . The interaction of AR with tubulin was examined by immunoprecipitation and immunofluorescence . Treatment of prostate cancer patients  with docetaxel led to a significant translocation of AR . In untreated specimens , 50 % prostate tumor cells exhibited nuclear accumulation of AR , compared with docetaxel-treated tumors that had significantly depleted nuclear AR ( 38 % ) , paralleled by an increase in cytosolic AR . AR nuclear localization correlated with PSA expression . In vitro , exposure of prostate cancer cells to paclitaxel ( 1 μmol/L ) or nocodazole ( 5 μg/mL ) inhibited and rogen-dependent AR nuclear translocation by targeting AR association with tubulin . Introduction of a truncated AR indicated the requirement of the NH(2)-terminal domain for AR-tubulin interaction . Our findings show that in addition to blocking cell division , docetaxel impairs AR signaling , evidence that enables new insights into the therapeutic efficacy of microtubule-targeting drugs in prostate cancer
Objective The role of additional chemotherapy in the treatment of high-risk prostate cancer ( PCa ) remains a controversy .
This meta- analysis aim ed to investigate the effect of additional chemotherapy on high-risk PCa .