***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive and rogen-independent prostate cancer . We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic , hormone-independent prostate cancer . METHODS We r and omly assigned 770 men to one of two treatments , each given in 21-day cycles : 280 mg of estramustine three times daily on days 1 through 5 , 60 mg of docetaxel per square meter of body-surface area on day 2 , and 60 mg of dexamethasone in three divided doses before docetaxel , or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily . The primary end point was overall survival ; secondary end points were progression-free survival , objective response rates , and post-treatment declines of at least 50 percent in serum prostate-specific antigen ( PSA ) levels . RESULTS Of 674 eligible patients , 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone . In an intention-to-treat analysis , the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone ( 17.5 months vs. 15.6 months , P=0.02 by the log-rank test ) , and the corresponding hazard ratio for death was 0.80 ( 95 percent confidence interval , 0.67 to 0.97 ) . The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone ( P<0.001 by the log-rank test ) . PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients , respectively ( P<0.001 ) , and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease , respectively ( P=0.30 ) . Grade 3 or 4 neutropenic fevers ( P=0.01 ) , nausea and vomiting ( P<0.001 ) , and cardiovascular events ( P=0.001 ) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone .  Pain relief was similar in both groups . CONCLUSIONS The improvement in median survival of nearly two months with docetaxel and estramustine , as compared with mitoxantrone and prednisone , provides support for this approach in men with metastatic , and rogen-independent prostate cancer This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence PURPOSE Abiraterone acetate is a prodrug of abiraterone , a selective inhibitor of CYP17 , the enzyme catalyst for two essential steps in and rogen bio synthesis . In castration-resistant prostate cancers ( CRPCs ) , extragonadal and rogen sources may sustain tumor growth despite a castrate environment . This phase I dose-escalation study of abiraterone acetate evaluated safety , pharmacokinetics , and effects on steroidogenesis and prostate-specific antigen ( PSA ) levels in men with CPRC with or without prior ketoconazole therapy . PATIENTS AND METHODS Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled . Nineteen patients ( 58 % ) had previously received ketoconazole for CRPC . Bone metastases were present in 70 % of patients , and visceral involvement was present in 18 % . Three patients ( 9 % ) had locally advanced disease without distant metastases . Fasted or fed cohorts received abiraterone acetate doses of 250 , 500 , 750 , or 1,000 mg daily . Single-dose pharmacokinetic analyses were performed before continuous daily dosing . RESULTS Adverse events were predominantly grade 1 or 2 . No dose-limiting toxicities were observed . Hypertension ( grade 3 , 12 % ) and hypokalemia ( grade 3 , 6 % ; grade 4 , 3 % ) were the most frequent serious toxicities and responded to medical management . Confirmed > or = 50 % PSA declines at week 12 were seen in 18 ( 55 % ) of 33 patients , including nine ( 47 % ) of 19 patients with prior ketoconazole therapy and nine ( 64 % ) of 14 patients without prior ketoconazole therapy . Substantial declines in circulating and rogens and increases in mineralocorticoids were seen with all doses . CONCLUSION Abiraterone acetate was well tolerated and demonstrated activity in CRPC , including in patients previously treated with ketoconazole . Continued clinical study is warranted PURPOSE It has been postulated that castration-resistant prostate cancer ( CRPC ) commonly remains hormone dependent . Abiraterone acetate is a potent , selective , and orally available inhibitor of CYP17 , the key enzyme in and rogen and estrogen bio synthesis . PATIENTS AND METHODS This was a phase I/II study of abiraterone acetate in castrate , chemotherapy-naive CRPC patients ( n = 54 ) with phase II expansion at 1,000 mg ( n = 42 ) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen ( PSA ) decline of > or = 50 % ( null hypothesis = 0.1 ; alternative hypothesis = 0.3 ; alpha = .05 ; beta = .14 ) . Computed tomography scans every 12 weeks and circulating tumor cell ( CTC ) enumeration were performed . Prospect i ve reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued . RESULTS A decline in PSA of > or = 50 % was observed in 28 ( 67 % ) of 42 phase II patients , and declines of > or = 90 % were observed in eight ( 19 % ) of 42 patients . Independent radiologic evaluation reported partial responses ( Response Evaluation Criteria in Solid Tumors ) in nine ( 37.5 % ) of 24 phase II patients with measurable disease . Decreases in CTC counts were also documented . The median time to PSA progression ( TTPP ) on abiraterone acetate alone for all phase II patients was 225 days ( 95 % CI , 162 to 287 days ) . Exploratory analyses were performed on all 54 phase I/II patients ; the addition of dexamethasone at disease progression reversed resistance in 33 % of patients regardless of prior treatment with dexamethasone , and pretreatment serum and rogen and estradiol levels were associated with a probability of > or = 50 % PSA decline and TTPP on abiraterone acetate and dexamethasone . CONCLUSION CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses , confirming that CRPC commonly remains hormone driven PURPOSE The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate , an oral , specific , irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer ( CRPC ) . PATIENTS AND METHODS In this multicenter , two-stage , phase II study , abiraterone acetate 1,000 mg was administered once daily continuously . The primary end point was achievement of a prostate-specific antigen ( PSA ) decline of > or = 50 % in at least seven of 35 patients . Per an attained phase II design , more than 35 patients could be enrolled if the primary end point was met . Secondary objectives included : PSA declines of > or = 30 % and > or = 90 % ; rate of RECIST ( Response Evaluation Criteria in Solid Tumors ) responses and duration on study ; time to PSA progression ; safety and tolerability ; and circulating tumor cell ( CTC ) enumeration . RESULTS Docetaxel-treated patients with CRPC ( N = 47 ) were enrolled .  PSA declines of > or = 30 % , > or = 50 % and > or = 90 % were seen in 68 % ( 32 of 47 ) , 51 % ( 24 of 47 ) , and 15 % ( seven of 47 ) of patients , respectively . Partial responses ( by RECIST ) were reported in eight ( 27 % ) of 30 patients with measurable disease . Median time to PSA progression was 169 days ( 95 % CI , 113 to 281 days ) . The median number of weeks on study was 24 , and 12 ( 25.5 % ) of 47 patients remained on study > or = 48 weeks . CTCs were enumerated in 34 patients ; 27 ( 79 % ) of 34 patients had at least five CTCs at baseline . Eleven ( 41 % ) of 27 patients had a decline from at least five to less than 5 CTCs , and 18 ( 67 % ) of 27 had a > or = 30 % decline in CTCs after starting treatment with abiraterone acetate . Abiraterone acetate was well tolerated . CONCLUSION Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC . R and omized , phase III trials of abiraterone acetate are underway to define the future role of this agent PURPOSE Studies indicate that castration-resistant prostate cancer ( CRPC ) remains driven by lig and -dependent and rogen receptor ( AR ) signaling . To evaluate this , a trial of abiraterone acetate-a potent , selective , small-molecule inhibitor of cytochrome P ( CYP ) 17 , a key enzyme in and rogen synthesis -was pursued . PATIENTS AND METHODS Chemotherapy-naïve men ( n = 21 ) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily , continuous abiraterone acetate , which escalated through five doses ( 250 to 2,000 mg ) in three-patient cohorts . RESULTS Abiraterone acetate was well tolerated . The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess-namely hypertension , hypokalemia , and lower-limb edema-were successfully managed with a mineralocorticoid receptor antagonist . Antitumor activity was observed at all doses ; however , because of a plateau in pharmacodynamic effect , 1,000 mg was selected for cohort expansion ( n = 9 ) . Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone , downstream and rogenic steroids , and estradiol in all patients . Declines in prostate-specific antigen > or= 30 % , 50 % , and 90 % were observed in 14 ( 66 % ) , 12 ( 57 % ) , and 6 ( 29 % ) patients , respectively , and lasted between 69 to > or= 578 days . Radiologic regression , normalization of lactate dehydrogenase , and improved symptoms with a reduction in analgesic use were documented . CONCLUSION CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC . These data confirm that CRPC commonly remains dependent on lig and -activated AR signaling To test the hypothesis that maximal and rogen blockade improves the effectiveness of the treatment of prostatic cancer , we conducted a r and omized , double-blind trial in patients with disseminated , previously untreated prostate cancer ( stage D2 ) . All 603 men received leuprolide  , an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins , in combination with either placebo or flutamide , a nonsteroidal anti and rogen that inhibits the binding of and rogens to the cell nucleus . As compared with the 300 patients receiving leuprolide and placebo , the 303 patients r and omly assigned to receive leuprolide and flutamide had a longer progression-free survival ( 16.5 vs. 13.9 months ; 
    Output:
    
This meta- analysis suggested that the adverse events caused by abiraterone are acceptable and can be controlled .
CONCLUTIOS : Abiraterone significantly prolonged OS , RPFS and time to progression  patients with mCRPC , regardless of prior chemotherapy or whether chemotherapy-naive , and no unexpected toxicity was evident .
Abiraterone can serve as a new st and ard therapy for mCRPC