human
***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: Following 2 pilot studies which showed 57 and 61 % response rates to intravenous cisplatin for transitional cell carcinoma of the bladder prior to definitive treatment , the West Midl and s Urological Research Group ( WMURG ) and the Australian Bladder Cancer Study Group ( ABCSG ) independently began r and omised trials to test the survival benefit of neo-adjuvant intravenous cisplatin prior to radiotherapy in T2-T4 M0 transitional cell carcinoma of the bladder . Both trials failed to recruit their target numbers of 250 patients in the West Midl and s and 320 in Australia . Since they had similar treatment protocol s and eligibility criteria , they were combined in an overview analysis , achieving a total number of 255 patients . Each treatment group was compared with its own control group and the differences were pooled to give an overall result . There was no difference in survival between treated and control patients . The odds ratio was 1.13 with the control groups faring marginally better than the chemotherapy groups . Even with 255 patients the 95 % confidence interval of the odds ratio was wide ( 0.80 - 1.57 ) . Although there is no clear evidence of a clinical ly worthwhile benefit from neo-adjuvant cisplatin , this approach must be tested in a larger study using combination treatments with greater activity in metastatic disease BACKGROUND This study aim ed to determine the clinical benefit of neoadjuvant methotrexate , doxorubicin , vinblastine , and cisplatin ( MVAC ) in patients with muscle-invasive bladder cancer ( MIBC ) treated with radical cystectomy . PATIENTS AND METHODS Patients with MIBC ( T2 - 4aN0M0 ) were r and omised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy ( NAC arm ) or radical cystectomy alone ( RC arm ) . The primary end point was overall survival ( OS ) . Secondary end points were progression-free survival , surgery-related complications , adverse events during chemotherapy , proportion with no residual tumour in the cystectomy specimens , and quality of life . To detect an improvement in 5-year OS from 45 % in the RC arm to 57 % in the NAC arm with 80 % power , 176 events were required per arm . RESULTS Patients ( N = 130 ) were r and omly assigned to the RC arm ( N = 66 ) and the NAC arm ( N = 64 ) . The patient registration was terminated before reaching the initially planned number of patients because of slow accrual . At the second interim analysis just after the early stoppage of patient accrual , the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion . OS of the NAC arm was better than that of the RC arm , although the difference was not statistically significant [ hazard ratio 0.65 , multiplicity adjusted 99.99 % confidence interval 0.19 - 2.18 , one-sided P = 0.07 ] . In the NAC arm and the RC arm , 34 % and 9 % of the patients had pT0 , respectively ( P < 0.01 ) . In subgroup analyses , OS in almost all subgroups was in favour of NAC . CONCLUSIONS This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC . NAC with MVAC can still be considered promising as a st and ard treatment . UMIN CLINICAL TRIALS REGISTRY IDENTIFIER C000000093 BACKGROUND Characterising responders to neoadjuvant chemotherapy ( NAC ) is important to minimise overtreatment and the unnecessary delay of definitive treatment of urothelial urinary bladder cancer . OBJECTIVE To assess the effect of NAC on tumour downstaging and overall survival . DESIGN , SETTING , AND PARTICIPANTS A total of 449 patients from the r and omised prospect i ve Nordic Cystectomy Trials 1 and 2 were analysed retrospectively . Eligible patients were defined as T2-T4aNXM0 preoperatively and pT0-pT4aN0-N+M0 postoperatively . The median follow-up time was 5 yr . INTERVENTION The experimental arm consisted of cisplatin-based NAC ; the control arm consisted of cystectomy only . MEASUREMENTS The primary outcome was tumour downstaging defined as pathologic TNM less than clinical TNM . Different downstaging thresholds were applied : complete downstaging ( CD ) ( pT0N0 ) , noninvasive downstaging ( NID ) ( pT0/pTis/pTaN0 ) , and organ confinement ( OC ) ( ≤ pT3aN0 ) . Downstaging rates and nodal status were compared between the study arms using the chi-square test . Secondary outcome was overall survival ( OS ) stratified by treatment arm , downstaging categories , and clinical stages , analysed by the Kaplan-Meier method . The following covariates were tested as prognostic factors in univariate and multivariate analyses using the Cox regression method : age , sex , clinical stage , pN status , NAC , CD , NID , and OC . RESULTS AND LIMITATIONS Downstaging rates increased significantly in the NAC arm independent of the downstaging threshold . The impact was more prominent in clinical T3 tumours , with a near threefold increase in CD tumours . The combination of CD and NAC  showed an absolute risk reduction of 31.1 % in OS at 5 yr compared with CD controls . The combination of NAC and CD revealed a hazard ratio of 0.32 compared with 1.0 for the combination of no NAC and no CD . Limitations were the retrospective approach and uncertain clinical TNM staging . CONCLUSIONS Survival benefits of NAC are reflected in downstaging of the primary tumour . Chemo-induced downstaging might be a potential surrogate marker for OS This prospect i ve , r and omized study based on two associated trials was design ed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b , NX-3 , MO transitional cell carcinoma of the bladder . In the first trial , local treatment consisted of cystectomy ( DAVECA 8901 ) and in the other trial the treatment was radiotherapy ( DAVECA 8902 ) ; 153 eligible patients were r and omized . The majority of the patients ( 89 % ) completed the protocol . The overall time to progression for all 153 patients was 12.9 months . Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy . The actuarial 5-year overall survival rate for all 153 patients was 29 % , and 29 % for both treatment groups . Multivariate analyses showed that T-stage , tumour size and serum creatinine were independent prognostic factors for survival . The cystectomy trial included 33 patients . Median survival was 78.9 months , 82.5 months with chemotherapy and 45.8 months without chemotherapy ( p=0.76 ) . The radiotherapy trial included 120 patients . The median survival was 17.6 months . Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy . The 5-year survival rate was 19 % in the group receiving chemotherapy and 24 % in the groups not receiving chemotherapy ( p=0.98 ) . Late toxicity grade 3 or 4 of the bladder was recorded in 25 % of the patients ( actuarial rate ) . Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 r and omized patients with invasive bladder cancer PURPOSE In advanced urothelial cancer , treatment with dose-dense methotrexate , vinblastine , doxorubicin , and cisplatin ( ddMVAC ) results in a high response rate , less toxicity , and few dosing delays . We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer ( MIUC ) . PATIENTS AND METHODS Patients with cT2-cT4 , N0 - 1 , M0 MIUC were enrolled . Four cycles of ddMVAC were administered , followed by radical cystectomy . The primary end point was pathologic response ( PaR ) defined by pathologic downstaging to ≤ pT1N0M0 . The study used Simon 's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35 % versus 55 % . Secondary end points included toxicity , disease-free survival ( DFS ) , radiologic response ( RaR ) , and biomarker correlates , including ERCC1 . RESULTS Between December 2008 and April 2012 , 39 patients ( cT2N0 , 33 % ; cT3N0 , 18 % ; cT4N0 , 3 % ; cT2 - 4N1 , 43 % ; unspecified , 3 % ) were enrolled . Median follow-up was 2 years . Overall , 49 % ( 80 % CI , 38 to 61 ) achieved PaR of ≤ pT1N0M0 , and we concluded this regimen was effective . High- grade ( grade ≥ 3 ) toxicities were observed in 10 % of patients , with no neutropenic fevers or treatment-related death . One-year DFS was 89 % versus 67 % for patients who achieved PaR compared with those who did not ( hazard ratio [ HR ] , 2.6 ; 95 % CI , 0.8 to 8.1 ; P = .08 ) and 86 % versus 62 % for patients who achieved RaR compared with those who did not ( HR , 4.1 ; 95 % CI , 1.3 to 12.5 ; P = .009 ) . We found no association between serum tumor markers or ERCC1 expression with response or survival . CONCLUSION In patients with MIUC , neoadjuvant ddMVAC was well tolerated and result ed in significant pathologic and radiologic downstaging PURPOSE This phase III trial was de - signed to compare the survival benefit , surgical respectability , and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy ( arm A ) , with those treated by radical cystectomy ( arm B ) in the management of stage II , III urinary bladder cancer . PATIENTS AND METHODS For inclusion , patients should have pathologically proven urothelial carcinoma in urinary bladder , clinical stages from T2N0M0 to T4aN0M0 , patient age less than 65 years , and performance state ≤ 2 . Additionally , patients should have adequate hematological , renal , and liver functions . Arm A patients underwent 3 cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy , while arm B patients underwent radical cystectomy directly . RESULTS Thirty patients had been enrolled in each arm between September 2009 and April 2014 in 3 educational institutes in Egypt .  The 3 year OS ( overall survival ) for arm A , and B were 60 % and 50 % respectively . The median OS for arm A was 36 + months and that for arm B was 32.5 months . The 3 year progression-free survival ( PFS ) for arm A , and B were 57 % and 43 % respectively . The median PFS for arm A was 36 + months and for arm B was 28 months . A subgroup analysis was performed to correlate between 3 year OS and predetermined prognostic factors including age , tumor size , pathological stage , and the response to neoadjuvant chemotherapy . The later was performed only in arm A. Both treatment arms were tolerated well with mild toxicities profiles . CONCLUSION Neoadjuvant chemotherapy achieved better survival , surgical respectability , with nearly equivalent toxicities when compared with radical cystectomy OBJECTIVES We evaluated pathologic and survival outcomes of GC ( gemcitabine/cisplatin ) and methotrexate/vinblastine/doxorubicin/cisplatin ( M-VAC ) neoadjuvant chemotherapy ( NAC )  in patients with muscle-invasive bladder cancer ( MIBC ) . MATERIAL S AND METHODS A retrospective analysis of prospect ively collected data on 116 patients who received NAC ( GC : n = 58 ; M-VAC : n = 58 ) before radical cystectomy and superextended pelvic lymph node dissection for clinical stage T2 - 4N0M0 bladder cancer was performed . The outcomes were complete response rate ( CRR ; pT0N0 ) , partial response rate ( PRR ; pT0N0 , pTaN0 , pT1N0 , or pTisN0 ) , overall mortality ( OM ) , and recurrence . The Kaplan-Meier method and multivariable Cox regression analysis were used to analyze OM . The cumulative incidence method and Fine and Gray 's competing risk regression analysis were used to analyze recurrence . RESULTS The median follow-up duration was 2.1 years for the GC group and 7.4 years for the M-VAC group ( P < 0.001 ) . There were no statistically significant differences between the GC and M-VAC groups with regard to CRR ( 27.3 % vs. 17.1 % , P = 0.4 
    Output:
    
agent
***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: Following 2 pilot studies which showed 57 and 61 % response rates to intravenous cisplatin for transitional cell carcinoma of the bladder prior to definitive treatment , the West Midl and s Urological Research Group ( WMURG ) and the Australian Bladder Cancer Study Group ( ABCSG ) independently began r and omised trials to test the survival benefit of neo-adjuvant intravenous cisplatin prior to radiotherapy in T2-T4 M0 transitional cell carcinoma of the bladder . Both trials failed to recruit their target numbers of 250 patients in the West Midl and s and 320 in Australia . Since they had similar treatment protocol s and eligibility criteria , they were combined in an overview analysis , achieving a total number of 255 patients . Each treatment group was compared with its own control group and the differences were pooled to give an overall result . There was no difference in survival between treated and control patients . The odds ratio was 1.13 with the control groups faring marginally better than the chemotherapy groups . Even with 255 patients the 95 % confidence interval of the odds ratio was wide ( 0.80 - 1.57 ) . Although there is no clear evidence of a clinical ly worthwhile benefit from neo-adjuvant cisplatin , this approach must be tested in a larger study using combination treatments with greater activity in metastatic disease BACKGROUND This study aim ed to determine the clinical benefit of neoadjuvant methotrexate , doxorubicin , vinblastine , and cisplatin ( MVAC ) in patients with muscle-invasive bladder cancer ( MIBC ) treated with radical cystectomy . PATIENTS AND METHODS Patients with MIBC ( T2 - 4aN0M0 ) were r and omised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy ( NAC arm ) or radical cystectomy alone ( RC arm ) . The primary end point was overall survival ( OS ) . Secondary end points were progression-free survival , surgery-related complications , adverse events during chemotherapy , proportion with no residual tumour in the cystectomy specimens , and quality of life . To detect an improvement in 5-year OS from 45 % in the RC arm to 57 % in the NAC arm with 80 % power , 176 events were required per arm . RESULTS Patients ( N = 130 ) were r and omly assigned to the RC arm ( N = 66 ) and the NAC arm ( N = 64 ) . The patient registration was terminated before reaching the initially planned number of patients because of slow accrual . At the second interim analysis just after the early stoppage of patient accrual , the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion . OS of the NAC arm was better than that of the RC arm , although the difference was not statistically significant [ hazard ratio 0.65 , multiplicity adjusted 99.99 % confidence interval 0.19 - 2.18 , one-sided P = 0.07 ] . In the NAC arm and the RC arm , 34 % and 9 % of the patients had pT0 , respectively ( P < 0.01 ) . In subgroup analyses , OS in almost all subgroups was in favour of NAC . CONCLUSIONS This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC . NAC with MVAC can still be considered promising as a st and ard treatment . UMIN CLINICAL TRIALS REGISTRY IDENTIFIER C000000093 BACKGROUND Characterising responders to neoadjuvant chemotherapy ( NAC ) is important to minimise overtreatment and the unnecessary delay of definitive treatment of urothelial urinary bladder cancer . OBJECTIVE To assess the effect of NAC on tumour downstaging and overall survival . DESIGN , SETTING , AND PARTICIPANTS A total of 449 patients from the r and omised prospect i ve Nordic Cystectomy Trials 1 and 2 were analysed retrospectively . Eligible patients were defined as T2-T4aNXM0 preoperatively and pT0-pT4aN0-N+M0 postoperatively . The median follow-up time was 5 yr . INTERVENTION The experimental arm consisted of cisplatin-based NAC ; the control arm consisted of cystectomy only . MEASUREMENTS The primary outcome was tumour downstaging defined as pathologic TNM less than clinical TNM . Different downstaging thresholds were applied : complete downstaging ( CD ) ( pT0N0 ) , noninvasive downstaging ( NID ) ( pT0/pTis/pTaN0 ) , and organ confinement ( OC ) ( ≤ pT3aN0 ) . Downstaging rates and nodal status were compared between the study arms using the chi-square test . Secondary outcome was overall survival ( OS ) stratified by treatment arm , downstaging categories , and clinical stages , analysed by the Kaplan-Meier method . The following covariates were tested as prognostic factors in univariate and multivariate analyses using the Cox regression method : age , sex , clinical stage , pN status , NAC , CD , NID , and OC . RESULTS AND LIMITATIONS Downstaging rates increased significantly in the NAC arm independent of the downstaging threshold . The impact was more prominent in clinical T3 tumours , with a near threefold increase in CD tumours . The combination of CD and NAC  showed an absolute risk reduction of 31.1 % in OS at 5 yr compared with CD controls . The combination of NAC and CD revealed a hazard ratio of 0.32 compared with 1.0 for the combination of no NAC and no CD . Limitations were the retrospective approach and uncertain clinical TNM staging . CONCLUSIONS Survival benefits of NAC are reflected in downstaging of the primary tumour . Chemo-induced downstaging might be a potential surrogate marker for OS This prospect i ve , r and omized study based on two associated trials was design ed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b , NX-3 , MO transitional cell carcinoma of the bladder . In the first trial , local treatment consisted of cystectomy ( DAVECA 8901 ) and in the other trial the treatment was radiotherapy ( DAVECA 8902 ) ; 153 eligible patients were r and omized . The majority of the patients ( 89 % ) completed the protocol . The overall time to progression for all 153 patients was 12.9 months . Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy . The actuarial 5-year overall survival rate for all 153 patients was 29 % , and 29 % for both treatment groups . Multivariate analyses showed that T-stage , tumour size and serum creatinine were independent prognostic factors for survival . The cystectomy trial included 33 patients . Median survival was 78.9 months , 82.5 months with chemotherapy and 45.8 months without chemotherapy ( p=0.76 ) . The radiotherapy trial included 120 patients . The median survival was 17.6 months . Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy . The 5-year survival rate was 19 % in the group receiving chemotherapy and 24 % in the groups not receiving chemotherapy ( p=0.98 ) . Late toxicity grade 3 or 4 of the bladder was recorded in 25 % of the patients ( actuarial rate ) . Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 r and omized patients with invasive bladder cancer PURPOSE In advanced urothelial cancer , treatment with dose-dense methotrexate , vinblastine , doxorubicin , and cisplatin ( ddMVAC ) results in a high response rate , less toxicity , and few dosing delays . We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer ( MIUC ) . PATIENTS AND METHODS Patients with cT2-cT4 , N0 - 1 , M0 MIUC were enrolled . Four cycles of ddMVAC were administered , followed by radical cystectomy . The primary end point was pathologic response ( PaR ) defined by pathologic downstaging to ≤ pT1N0M0 . The study used Simon 's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35 % versus 55 % . Secondary end points included toxicity , disease-free survival ( DFS ) , radiologic response ( RaR ) , and biomarker correlates , including ERCC1 . RESULTS Between December 2008 and April 2012 , 39 patients ( cT2N0 , 33 % ; cT3N0 , 18 % ; cT4N0 , 3 % ; cT2 - 4N1 , 43 % ; unspecified , 3 % ) were enrolled . Median follow-up was 2 years . Overall , 49 % ( 80 % CI , 38 to 61 ) achieved PaR of ≤ pT1N0M0 , and we concluded this regimen was effective . High- grade ( grade ≥ 3 ) toxicities were observed in 10 % of patients , with no neutropenic fevers or treatment-related death . One-year DFS was 89 % versus 67 % for patients who achieved PaR compared with those who did not ( hazard ratio [ HR ] , 2.6 ; 95 % CI , 0.8 to 8.1 ; P = .08 ) and 86 % versus 62 % for patients who achieved RaR compared with those who did not ( HR , 4.1 ; 95 % CI , 1.3 to 12.5 ; P = .009 ) . We found no association between serum tumor markers or ERCC1 expression with response or survival . CONCLUSION In patients with MIUC , neoadjuvant ddMVAC was well tolerated and result ed in significant pathologic and radiologic downstaging PURPOSE This phase III trial was de - signed to compare the survival benefit , surgical respectability , and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy ( arm A ) , with those treated by radical cystectomy ( arm B ) in the management of stage II , III urinary bladder cancer . PATIENTS AND METHODS For inclusion , patients should have pathologically proven urothelial carcinoma in urinary bladder , clinical stages from T2N0M0 to T4aN0M0 , patient age less than 65 years , and performance state ≤ 2 . Additionally , patients should have adequate hematological , renal , and liver functions . Arm A patients underwent 3 cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy , while arm B patients underwent radical cystectomy directly . RESULTS Thirty patients had been enrolled in each arm between September 2009 and April 2014 in 3 educational institutes in Egypt .  The 3 year OS ( overall survival ) for arm A , and B were 60 % and 50 % respectively . The median OS for arm A was 36 + months and that for arm B was 32.5 months . The 3 year progression-free survival ( PFS ) for arm A , and B were 57 % and 43 % respectively . The median PFS for arm A was 36 + months and for arm B was 28 months . A subgroup analysis was performed to correlate between 3 year OS and predetermined prognostic factors including age , tumor size , pathological stage , and the response to neoadjuvant chemotherapy . The later was performed only in arm A. Both treatment arms were tolerated well with mild toxicities profiles . CONCLUSION Neoadjuvant chemotherapy achieved better survival , surgical respectability , with nearly equivalent toxicities when compared with radical cystectomy OBJECTIVES We evaluated pathologic and survival outcomes of GC ( gemcitabine/cisplatin ) and methotrexate/vinblastine/doxorubicin/cisplatin ( M-VAC ) neoadjuvant chemotherapy ( NAC )  in patients with muscle-invasive bladder cancer ( MIBC ) . MATERIAL S AND METHODS A retrospective analysis of prospect ively collected data on 116 patients who received NAC ( GC : n = 58 ; M-VAC : n = 58 ) before radical cystectomy and superextended pelvic lymph node dissection for clinical stage T2 - 4N0M0 bladder cancer was performed . The outcomes were complete response rate ( CRR ; pT0N0 ) , partial response rate ( PRR ; pT0N0 , pTaN0 , pT1N0 , or pTisN0 ) , overall mortality ( OM ) , and recurrence . The Kaplan-Meier method and multivariable Cox regression analysis were used to analyze OM . The cumulative incidence method and Fine and Gray 's competing risk regression analysis were used to analyze recurrence . RESULTS The median follow-up duration was 2.1 years for the GC group and 7.4 years for the M-VAC group ( P < 0.001 ) . There were no statistically significant differences between the GC and M-VAC groups with regard to CRR ( 27.3 % vs. 17.1 % , P = 0.4 
    Output:
    