Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209. Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Neoadjuvant Chemotherapy with Cisplatin and Methotrexate in Patients with Muscle-Invasive Bladder Tumours Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. Neoadjuvant chemotherapy versus cystectomy in management of stages II, and III urinary bladder cancer. Neoadjuvant chemotherapy with gemcitabine/cisplatin vs. methotrexate/vinblastine/doxorubicin/cisplatin for muscle-invasive urothelial carcinoma of the bladder: a retrospective analysis from the University of Southern California. Neoadjuvant Cisplatin-Methotrexate Chemotherapy for Invasive Bladder Cancer - Nordic Cystectomy Trial 2 Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. Gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive transitional and squamous cell carcinoma of the bladder: effect on survival and bladder preservation. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity.
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 = 0.419 ) or PRR ( 45.5 % vs. 37.1 % , P = 0.498 ) . The predicted 5-year freedom from OM rate ( P = 0.634 ) and cumulative incidence of recurrence rate ( P = 0.891 ) did not differ between the GC and M-VAC groups . Multivariable analysis showed that there was no independent association between type of NAC and OM ( P = 0.721 ) or recurrence ( P = 0.065 ) . CONCLUSIONS Pathologic and survival outcomes did not differ in patients who received GC and M-VAC NAC . These data support the use of the GC regimen in the neoadjuvant setting Background : In the first Nordic cystectomy trial ( 1986 - 1989 ) a chemotherapy combination of cisplatin-doxorubicin and external radiation seemed to improve the long-term survival after cystectomy in patients with stage T3-T4a bladder carcinomas . The aim of this study was to investigate if solely neoadjuvant chemotherapy could influence survival in patients with advanced urothelial bladder cancer undergoing cystectomy . Methods : The study ( 1991 - 1997 ) recruited 317 patients with T2-T4aNXM0 urothelial bladder tumours . The patients were r and omly allocated to three courses of cisplatin-methotrexate or no pretreatment before cystectomy , eight were subsequently excluded due to protocol violation . Results : Chemotherapy according to protocol was administered to 74 % ( 115/155 ) of the patients in the experimental arm . No chemotherapy related mortality was observed . Of remaining patients in the experimental arm , 14 did not receive any chemotherapy , nine discontinued after one course and 14 after two courses due to side effects . Median follow-up time among censored patients was 5.3 years . Estimated 5-year overall survival was 53 % in the experimental arm and 46 % in the control arm ( n.s . log-rank test ) . The proportion of patients with pathological stage pT0 was 26.4 % in the experimental arm and 11.5 % in the control arm ( p = 0.001 ) . Risk of locoregional relapse and distant metastases was similar in the study arms . Conclusions : The chemotherapy regimen was well tolerated . Despite substantial downstaging no statistically significant survival benefit with the neoadjuvant therapy could be seen after 5 years of follow-up PURPOSE To assess the efficacy of neoadjuvant methotrexate , cisplatin , and vinblastine ( MCV ) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation . PATIENTS AND METHODS One hundred twenty-three eligible patients with tumor , node , metastasis system clinical stage T2 to T4aNXMO bladder cancer were r and omized to receive ( arm 1 , n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart . Patients assigned to arm 2 ( n=62 ) did not receive MCV before concurrent cisplatin and radiation therapy . Tumor response was scored as a clinical complete response ( CR ) when the cystoscopic tumor-site biopsy and urine cytology results were negative . The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin . Those with less than a CR underwent cystectomy . The median follow-up of all patients who survived is 60 months . RESULTS Seventy-four percent of the patients completed the protocol with , at most , minor deviations ; 67 % on arm 1 and 81 % on arm 2 . The actuarial 5-year overall survival rate was 49 % ; 48 % in arm 1 and 49 % in arm 2 . Thirty-five percent of the patients had evidence of distant metastases at 5 years ; 33 % in arm 1 and 39 % in arm 2 . The 5-year survival rate with a functioning bladder was 38 % , 36 % in arm 1 and 40 % in arm 2 . None of these differences are statistically significant . CONCLUSION Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our st and ard induction therapy or to increase freedom from metastatic disease . There was no impact on 5-year overall survival PURPOSE To compare long-term survival in patients with locally advanced or metastatic transitional cell carcinoma ( TCC ) of the urothelium treated with gemcitabine/cisplatin ( GC ) or methotrexate/vinblastine/doxorubicin/cisplatin ( MVAC ) . PATIENTS AND METHODS Efficacy data from a large r and omized phase III study of GC versus MVAC were up date d. Time-to-event analyses were performed on the observed distributions of overall and progression-free survival . RESULTS A total of 405 patients were r and omly assigned : 203 to the GC arm and 202 to the MVAC arm . At the time of analysis , 347 patients had died ( GC arm , 176 patients ; MVAC arm , 171 patients ) . Overall survival was similar in both arms ( hazard ratio [ HR ] , 1.09 ; 95 % CI , 0.88 to 1.34 ; P = .66 ) with a median survival of 14.0 months for GC and 15.2 months for MVAC . The 5-year overall survival rates were 13.0 % and 15.3 % , respectively ( P = .53 ) . The median progression-free survival was 7.7 months for GC and 8.3 months for MVAC , with an HR of 1.09 . The 5-year progression-free survival rates were 9.8 % and 11.3 % , respectively ( P = .63 ) . Significant prognostic factors favoring overall survival included performance score ( > 70 ) , TNM staging ( M0 v M1 ) , low/normal alkaline phosphatase level , number of disease sites ( < or= three ) , and the absence of visceral metastases . By adjusting for these prognostic factors , the HR was 0.99 for overall survival and 1.01 for progression-free survival . The 5-year overall survival rates for patients with and without visceral metastases were 6.8 % and 20.9 % , respectively . CONCLUSION Long-term overall and progression-free survival after treatment with GC or MVAC are similar . These results strengthen the role of GC as a st and ard of care in patients with locally advanced or metastatic TCC From November 1984 to April 1989 , 122 patients with clinical T2 - 4a Nx-2 M0 transitional cell carcinoma of the bladder were entered in a prospect i ve r and omized trial to compare survival between a control group of 60 patients treated only with radical cystectomy ( arm A ) and a group of 62 patients treated with 3 cycles of 100 mg./m.2 neoadjuvant cisplatin before radical cystectomy ( arm B ) . Secondary objectives of the trial were comparison of the disease-free interval and time to death , significance of response of the primary tumor to  cisplatin  , pattern of relapse and toxicity . As of April 1993 after a median followup of 78.2 months ( range 48 to 101 ) no difference in survival between the control patients and those who received neoadjuvant cisplatin has been observed . The overall direct survival is 37.3 % for arm A and 35.5 % for arm B. The  survival rate of the 109 patients who complied with the protocol is 38.2 % for 55 patients of the control group and 40.7 % for 54 patients of the cisplatin group . Survival rates of patients theoretically rendered free of disease by radical cystectomy ( complete response pT0 - 4a , pN0 - 2 , M0 ) is 43.7 % for 40 control patients and 47.8 % for 41 cisplatin treated patients . The time to relapse in complete response patients was significantly longer ( p = 0.0298 ) for those who received cisplatin ( arm A 13.1 months versus arm B 30.3 months ) . The time to death ( cause specific ) did not differ significantly between both groups overall ( p = 0.1349 ) but it was significantly different between controls and responders ( p = 0.0501 ) . Preoperative cisplatin downstaged the primary tumor in 19 patients ( 33.9 % ) , of whom 11 ( 19.6 % ) had no tumor in the cystectomy specimen ( pT0 ) and 8 ( 14.3 % ) had superficial tumor ( pTis pTa pT1 ) . In 6 patients ( 9.7 % ) disease progressed during chemotherapy . The survival of the responders was significantly better than that of nonresponders ( p = 0.0142 ) , with specific death rate of 26.3 % and 62.5 % , respectively , and a median time to death of 43 months for responders and 30.5 months for nonresponders . Patients without nodal involvement ( pN0 ) or with only 1 micrometastasis ( pN1 ) fared significantly better ( p = 0.0001 ) than those with major node invasion ( pN2 - 4 ) , irrespective of the treatment received . The survival rate is 48.6 % for patients with pN0 disease , 37.5 % for pN1 and 5 % for pN2 - 4 . Toxicity of cisplatin was minimal and there were no differences in perioperative morbidity between the arms . ( ABSTRACT TRUNCATED AT 400 WORDS An analysis by the Nordic Cooperative Bladder Cancer Study Group concerned the possible benefit of neoadjuvant chemotherapy -- given before scheduled low-dose irradiation and cystectomy . In the trial , started in 1985 , 311 patients with locally advanced bladder cancer , T1 grade 3 , T2-T4a NXMO , were r and omly allocated to a ' chemotherapy ' or a ' no chemotherapy ' group .  Chemotherapy consisted of two cycles comprising cisplatin 70 mg/m2 and doxorubicin 30 mg/m2 , with a 3-week interval between cycles 1 and 2 . All patients were locally irradiated with 4 Gy daily for 5 consecutive days . The follow-up included 266 cystectomized patients . In May 1992 the mean observation time was 18 months for all patients and 47 months for those still alive . The results suggest that a significant downstaging in the group r and omized to chemotherapy was found only in T1 , grade 3 tumours ( 56 patients , p = 0.002 ) . The  overall survival rate in all 311 patients was significantly higher in the  chemotherapy group ( p = 0.03 ) and likewise among the 253 patients with T2-T4a tumour ( p = 0.018 ) . For the 210 patients who underwent cystectomy for T2-T4a tumour , there was a trend towards longer survival when chemotherapy was given ( p = 0.057 ) . Patients with initially muscle-invasive tumour who responded to neoadjuvant treatment survived longer than non responders ( p = 0.0005 ) . The results suggest that neoadjuvant chemotherapy improve the outcome of radical surgery for muscle-invasive bladder cancer , though the effect on long-term survival is inconclusive . Further studies on the effect of neoadjuvant chemotherapy is initiated PURPOSE Chemotherapy is widely used in patients with locally advanced bladder cancer but until now there has been no conclusive evidence that this therapy improves survival . The Nordic Cooperative Bladder Cancer Study Group conducted a r and omized phase III study to assess the possible benefit of neoadjuvant chemotherapy in patients with bladder cancer undergoing radical cystectomy after short-term radiotherapy . MATERIAL S AND METHODS Our trial included 325 patients with locally advanced stage T1 grade 3 or stages T2 to T4aNXM0 bladder cancer allocated r and omly into a chemotherapy or no chemotherapy group ( control ) . The chemotherapy schedule consisted of 2 cycles of 70 mg./m.2 cisplatin and 30 mg./m.2 doxorubicin with a 3-week interval between the cycles . RESULTS After 5 years the overall survival rate was 59 % in the chemotherapy group and 51 % in the control group ( p = 0.1 ) . The corresponding cancer specific survival rate was 64 and 54 % , respectively . In regard to treatment , no difference was observed for stages T1 and T2 disease , while there was a 15 % difference in overall survival for patients with stages T3 to T4a disease ( p = 0.03 ) . In a multivariate analysis only chemotherapy and T category emerged as independent prognostic factors . The relative death risk for patients who received chemotherapy was 0.69 ( 95 % confidence interval 0.49 to 0.98 ) compared to the control group after adjustment for the other tested factors . CONCLUSIONS Neoadjuvant chemotherapy seems to improve long-term survival after cystectomy in patients with stages T3 to T4a bladder carcinoma , while no survival benefit was found for stages T1 to T2 disease BACKGROUND Despite aggressive local therapy , patients with locally advanced bladder cancer have a significant risk of distant metastases . This study evaluated the role of neoadjuvant combination chemotherapy with gemcitabine/cisplatin ( GC ) in improving the outcome of this group of patients over radical cystectomy alone .  PATIENTS AND METHODS A total of 114 patients with newly diagnosed bladder cancer ( T3 - 4 , N0 - 2 , M0 ) were r and omized to radical cystectomy alone  or initial 3 cycles of GC , then managed according to response . Patients who achieved complete response completed 6 cycles of GC followed by local radiation therapy ( RT ) only . If tumors were downstaged to T1 , complete transurethral resection was done , followed by 3 cycles of GC and then RT . Patients with partial response underwent radical cystectomy followed by 3 cycles of GC . Patients with stable disease or disease progression underwent radical cystectomy . RESULTS The overall response rate to GC was 55.1 % , and complete response was achieved in 28.6 % . The 3-year overall survival ( OS ) was 51.9 % versus 51.2 % in the chemotherapy and surgery arms , respectively ( P = .399 ) . The 3-year disease-free survival was 31.8 % in the chemotherapy arm and 45.1 % in the surgery arm ( P = .06 ) . Bladder preservation was achieved in 22.5 % of patients in the neoadjuvant arm . OS was 78 % in responding patients and 100 % in patients with complete response . CONCLUSION Neoadjuvant GC did not improve survival in locally advanced bladder cancer over radical cystectomy alone . However , bladder preservation was feasible , and OS in responding patients was impressive . Therefore , predictive models to select patients are needed . This is the largest prospect i ve study of squamous cell carcinoma and transitional cell carcinoma using neoadjuvant GC BACKGROUND Despite aggressive local therapy , patients with locally advanced bladder cancer are at significant risk for metastases . We evaluated the ability of neoadjuvant chemotherapy to improve the outcome in patients with locally advanced bladder cancer who were treated with radical cystectomy .  METHODS Patients were enrolled if they had muscle-invasive bladder cancer ( stage T2 to T4a ) and were to be treated with radical cystectomy .  They were stratified according to age ( less than 65 years vs. 65 years or older ) and stage ( superficial muscle invasion vs. more extensive disease ) and were r and omly assigned to radical cystectomy alone or three cycles of methotrexate , vinblastine , doxorubicin , and cisplatin followed by radical cystectomy . RESULTS We enrolled 317 patients over an 11-year period , 10 of whom were found to be ineligible ; thus , 154 were assigned to receive surgery alone and 153 to receive combination therapy . According to an intention-to-treat analysis , the median survival among patients assigned to surgery alone was 46 months , as compared with 77 months among patients assigned to combination therapy ( P=0.06 by a two-sided stratified log-rank test ) . In both groups , improved survival was associated with the absence of residual cancer in the cystectomy specimen . Significantly more patients in the combination-therapy group had no residual disease than patients in the cystectomy group ( 38 percent vs. 15 percent , P<0.001 ) . CONCLUSIONS As compared with radical cystectomy alone , the use of neoadjuvant methotrexate , vinblastine , doxorubicin , and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer PURPOSE Neoadjuvant cisplatin-based chemotherapy is st and ard of care for muscle-invasive bladder cancer ( MIBC ) ; however , it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy . We hypothesized that three cycles of neoadjuvant accelerated methotrexate , vinblastine , doxorubicin , and cisplatin ( AMVAC ) would be safe , shorten the time to surgery , and yield similar pathologic complete response ( pT0 ) rates compared with historical controls . PATIENTS AND METHODS Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection . The primary end point was pT0 rate . Telomere length ( TL ) and p53 mutation status were correlated with response and toxicity . RESULTS Forty-four patients were accrued ; 60 % had stage III to IV disease ; median age was 64 years . Forty patients were evaluable for response , with 15 ( 38 % ; 95 % CI , 23 % to 53 % ) showing pT0 at cystectomy , meeting the primary end point of the study . Another six patients ( 14 % ) were downstaged to non-muscle invasive disease . Most ( 82 % ) experienced only grade 1 to 2 treatment-related toxicities . There were no grade 3 or 4 renal toxicities and no treatment-related deaths . One patient developed metastases and thus did not undergo cystectomy ; all others ( n = 43 ) proceeded to cystectomy within 8 weeks after last chemotherapy administration . Median time from start of chemotherapy to cystectomy was 9.7 weeks . TL and p53 mutation did not predict response or toxicity . CONCLUSION AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with st and ard 12-week regimens . Further analysis is ongoing to ascertain whether molecular alterations in tumor sample s can predict response to chemotherapy
BACKGROUND Platinum-based neoadjuvant chemotherapy has been shown to improve survival outcomes in muscle-invasive bladder cancer patients .
We performed a systematic review and meta- analysis to provide up date d results of previous findings .
IMPLICATION S FOR PRACTICE Platinum-based neoadjuvant chemotherapy ( NCT ) has been shown to improve survival outcomes in muscle-invasive bladder cancer ( MIBC ) patients , but the optimal neoadjuvant regimen has not been established .
Methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) and gemcitabine and cisplatin/carboplatin ( GC ) are two of the most commonly used chemotherapy regimens in modern oncology .