Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Efficacy and tolerability of concurrent weekly low dose cisplatin during radiation treatment of localised muscle invasive bladder transitional cell carcinoma: a report of two sequential Phase II studies from the Trans Tasman Radiation Oncology Group. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. Effective bladder sparing therapy with intra-arterial cisplatin and radiotherapy for localized bladder cancer. Radical cystectomy for invasive bladder cancer: results of multi-institutional pooled analysis. Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer Bladder-sparing multimodality treatment of muscle-invasive bladder cancer: a five-year follow-up. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Phase II study of radiochemotherapy with vinblastine in invasive bladder cancer. Cystectomy for bladder cancer: a contemporary series. Chemoradiotherapy for muscle invading bladder carcinoma. Final report of a single institutional organ-sparing program. Concomitant Radiotherapy and Carboplatin in Locally Advanced Bladder Cancer Phase I study of gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer. Combined chemotherapy and radiation with selective organ preservation for muscle-invasive bladder carcinoma. A single-institution phase II study. Quality of life assessment after concurrent chemoradiation for invasive bladder cancer: results of a multicenter prospective study (GETUG 97-015). Combined modality treatment with bladder preservation for muscle invasive bladder cancer. Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95). Trimodality bladder preservation therapy for muscle-invasive bladder cancer. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. Whole-pelvis or bladder-only chemoradiation for lymph node-negative invasive bladder cancer: single-institution experience. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Radical cystectomy versus bladder-preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification biasin cancer observational comparative effectiveness research. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients.
BACKGROUND The purpose of the study was to evaluate the benefit of adjuvant chemotherapy ( AC ) versus surgery alone in patients with muscle-invasive bladder cancer ( MIBC ) . PATIENTS AND METHODS One hundred and ninety-four patients with pT2G3 , pT3 - 4 , N0 - 2 transitional cell bladder carcinoma were r and omly allocated to control ( 92 patients ) or to four courses of AC ( 102 patients ) . These latter patients were further r and omly assigned to receive gemcitabine 1000 mg/m(2 ) days 1 , 8 and 15 and cisplatin 70 mg/m(2 ) day 2 or gemcitabine as above plus cisplatin 70 mg/m(2 ) day 15 , every 28 days . RESULTS At a median follow-up of 35 months , the 5-year overall survival ( OS ) was 48.5 % , with no difference between the two arms [ P = 0.24 , hazard ratio ( HR ) 1.29 , 95 % confidence interval ( CI ) 0.84 - 1.99 ] . Mortality hazard was significantly correlated with Nodes ( N ) and Tumor ( T ) stage . The control and AC arms had comparable disease-free survival ( 42.3 % and 37.2 % , respectively ; P = 0.70 , HR 1.08 , 95 % CI 0.73 - 1.59 ) . Only 62 % of patients received the planned cycles . A significant higher incidence of thrombocytopenia was observed in patients receiving cisplatin on day 2 ( P = 0.006 ) . A similar global quality of life was observed in the two arms . CONCLUSION The study was underpowered to demonstrate that AC with cisplatin and gemcitabine improves OS and disease-free survival in patients with MIBC BACKGROUND AND PURPOSE To determine the feasibility , toxicity , and clinical effectiveness of concurrent weekly cisplatin chemotherapy in conjunction with definitive radiation in the treatment of localised muscle invasive bladder cancer . PATIENTS AND METHODS In January 1997 the Trans Tasman Radiation Oncology Group embarked on a Phase II study ( TROG 97.01 ) of weekly cisplatin ( 35 mg/m(2 ) x 7 doses ) plus radiation to a dose of 63 Gy over 7 weeks . Following an interim toxicity analysis , the dose intensity of cisplatin was reduced to 6 cycles and the radiation schedule changed to 64 Gy over 6.5 weeks leading to the second study ( TROG 99.06 ) . A total of 113 patients were enrolled . RESULTS Acute grade 3 urinary toxicity occurred in 23 % of the patients . Acute grade 4 pelvic toxicity was not seen . Thirty-eight patients ( 33 % ) experienced grade 3 or 4 cisplatin related toxicities with 15 patients ( 12 % ) requiring significant dose modification . The reduced dose intensity in Study 99.06 improved tolerability . Incidence of significant late morbidity was low ( 6 % ) . Seventy-nine patients ( 70 % ) achieved complete remission at the 6 month cystoscopic assessment . Local invasive recurrence was seen in 11 of the 79 patients ( 14 % ) . In 18 patients ( 16 % ) isolated superficial TCC/CIS were detected ( 6 months and beyond ) . The local control rate was 45 % with a functional bladder being retained in 69 of the 113 patients ( 61 % ) . RFS and DSS at 5 years were 33 % and 50 % , respectively . CONCLUSION Our two sequential Phase II studies have shown that concurrent chemoradiation using weekly cisplatin in the management of localised invasive bladder TCC is feasible and reasonably well tolerated . This approach is currently being investigated further in a r and omised study PURPOSE St and ard treatment for muscle invasive transitional cell cancer of the bladder is radical cystectomy . Despite careful staging , the majority of cancers with regional lymph node involvement and /or invasion to adjacent organs eventually recur . We investigated the benefit of chemotherapy with cisplatin , methotrexate and vinblastine ( CMV ) after radical cystectomy . MATERIAL S AND METHODS A prospect i ve trial was done in which patients were r and omized after cystectomy to receive either 4 cycles of CMV chemotherapy or observation .  At relapse , patients were treated with st and ard CMV chemotherapy for metastatic disease at our institution . RESULTS Of 55 patients who entered this trial 1 was ineligible and in 4 it is too soon to be evaluated . Of the 50 evaluable patients 25 were r and omized to receive adjuvant CMV chemotherapy and 25 were observed . In the CMV arm 12 ( 48 % ) and in the observation arm 5 ( 25 % ) never had recurrence . With a median followup of 62 months and no patient with less than 2 years of followup , the freedom from progression in the adjuvant chemotherapy group was superior to that in the observation group ( median 37 versus 12 months , respectively , p = 0.01 ) . Median survival in the adjuvant group was 63 months compared to 36 months for the observation group . Surprisingly , some cases with relapse could be salvaged with CMV chemotherapy , perhaps contributing to this lack of difference in overall survival ( p = 0.32 ) . CONCLUSIONS Treatment with CMV chemotherapy after radical cystectomy is an acceptable approach in patients with stages p3b and p4N0 or N1 transitional cell carcinoma of the bladder . Further studies must be performed to determine whether these results can be extrapolated to patients with more limited disease ( stages p2 and p3a ) who are currently treated with radical cystectomy or definitive irradiation PURPOSE We evaluated the feasibility and efficacy of the organ preserving strategy of intra-arterial cisplatin and concurrent radiotherapy for localized bladder cancer . MATERIAL S AND METHODS Bladder preservation has been pursued over the decades in treatment regimens featuring radiotherapy alone or in conjunction with single or multiagent chemotherapy . The chemotherapy has consisted almost exclusively of intravenously administered drugs . There are theoretical and clinical data demonstrating a higher concentration of cisplatin within tumors following intra-arterial as opposed to intravenous delivery . This study was performed to evaluate whether this increased concentration would enhance radiosensitization and thereby increase the success of bladder preservation . RESULTS We report on our prospect ively collected experience during 15 years of treating 200 patients with localized bladder cancer using this regimen of 3 courses of intra-arterial cisplatin integrated with pelvic radiotherapy  and reserving cystectomy for salvage as required . We report on the efficacy in terms of complete response rate , ultimate tumor-free bladder preservation , overall survival and patterns of failure . We detail the acute and chronic toxicity observed to date . CONCLUSIONS This strategy has result ed in a durable high complete response rate and overall tumor-free bladder preservation rate of 75 % while maintaining a survival comparable to that achieved with cystectomy . These results corroborate the hypothesis that intra-arterial administration of cisplatin enhances radiosensitization during pelvic radiotherapy BACKGROUND We report the outcome of radical cystectomy for patients with invasive bladder cancer , who did not have regional lymph node or distant metastases , at 21 hospitals . METHODS Retrospective , non-r and omized , multi-institutional pooled data were analyzed to evaluate outcomes of patients who received radical cystectomy . Between 1991 and 1995 , 518 patients with invasive bladder cancer were treated with radical cystectomy at 21 hospitals . Of these , 250 patients ( 48.3 % ) received some type of neoadjuvant and /or adjuvant therapy depending on the treatment policy of each hospital . RESULTS The median follow-up period was 4.4 years , ranging from 0.1 to 11.4 years . The 5-year overall survival rate was 58 % for all 518 patients . The 5-year overall survival rates for patients with clinical T2N0M0 , T3N0M0 and T4N0M0 were 67 % , 52 % and 38 % , respectively . The patients with pT1 or lower stage , pT2 , pT3 and pT4 disease without lymph node metastasis had 5-year overall survivals of 81 % , 74 % , 47 % and 38 % , respectively . The patients who were node positive had the worst prognosis , with a 30 % overall survival rate at 5 years . Neoadjuvant or adjuvant chemotherapy did not provide a significant survival advantage , although adjuvant chemotherapy improved the 5-year overall survival in patients with pathologically proven lymph node metastasis . CONCLUSIONS The current retrospective study showed that radical cystectomy provided an overall survival equivalent to studies reported previously , but surgery alone had no more potential to prolong survival of patients with invasive cancer . Therefore , a large-scale r and omized study on adjuvant treatment as well as development of new strategies will be needed to improve the outcome for patients with invasive bladder cancer We conducted a phase I/II study investigating synchronous chemoradiotherapy with mitomycin C and infusional 5-fluorouracil ( 5-FU ) in muscle invasive bladder cancer . Early dose escalation results were previously published . We report the long-term toxicity and efficacy results with the optimised regimen . Patients with muscle invasive bladder cancer with glomerular filtration rate > 25 ml min−1 were eligible .  Mitomycin ( 12 mg m−2 on day 1 only ) and infusional 5-FU ( 500 mg m−2 day−1 ) for 5 days were administered during weeks 1 and 4 of radiotherapy of 55 Gy in 20 fractions . A total of 41 patients were enrolled , median age was 68 years , 33 were male and eight female patients . Out of the 41 patients , 20 ( 49 % ) had hydronephrosis at presentation and 25 ( 62 % ) had T3b or T4 disease . Four patients experienced Grade III thrombocytopenia and three patients had Grade III neutropenia . There were no episodes of febrile neutropenia . Four patients experienced Grade III diarrhoea and 1 Grade III urgency and dysuria . Six patients did not undergo cystoscopic evaluation due to early metastatic spread although there was no clinical suggestion of bladder failure . In all , out of 35 evaluable patients , 25 ( 71 % ) had macroscopic complete response at 3-month cystoscopy , and biopsy confirmed in 24 out of 25 . A total of 16 ( 39 % ) patients remain alive with a median follow-up of 50.7 ( range 23.5–68.8 ) months , 14 with a functioning bladder with no reported long-term treatment-related bladder or bowel toxicity . Five out of 41 patients have undergone salvage cystectomy : two for persistent CIS , two T1 and one muscle invasive recurrence . Four patients have received intravesical chemotherapy , of whom two remain alive with a functioning bladder . Overall 12- , 24- and 60-month ( m ) survival rates were 68 , 49 and 36 % . Local and distant progression free rates were 82 and 86 % at 12-m and 79 and 75 % at 24-m . Organ preservation using multimodality therapy is feasible and safe , even in patients with poor renal reserve , and does not compromise salvage therapies . A national phase III trial BC2001 ( www.bc2001.org.uk ) exploring the effects of synchronous chemoradiotherapy with this regimen is currently recruiting OBJECTIVES To determine the long-term results of a bladder-sparing approach in the treatment of muscle-invasive bladder cancer . METHODS Ninety-four patients with invasive transitional cell carcinoma of the bladder were treated by transurethral resection followed by 2 or 3 cycles of cisplatin-based chemotherapy . Patients were then treated with 6480 cGy of radiation in 49 patients , segmental cystectomy in 8 , or surveillance only in 7 . Patients who failed to respond to chemotherapy or radiation therapy , or who developed recurrent muscle-invasive disease in follow-up , underwent salvage cystectomy . Patients were then carefully followed for a median follow-up of more than 5 years . RESULTS After initial therapy , 53 patients ( 56 % ) were alive with their bladder preserved . Thirty of those 53 ( 57 % ) developed a local recurrence in follow-up . After a median follow-up of more than 5 years , the ultimate relapse-free survival is 49 % ( Stage T2 , 84 % ; T3 , 53 % ; and T4 , 11 % ; P < 0.01 ) . Of all patients enrolled , 53 % had bladder preservation ; however , of the currently surviving patients , 16 of 39 ( 41 % ) have their bladders intact ( T2 , 50 % ; T3 , 37 % ; T4 , 0 % ) . Only 18 % of the initially enrolled population is alive with a preserved bladder . The 5-year survival of patients who had cystectomy at some point during the study , compared with those who have had their bladders preserved , was 65 % versus 40 % , respectively ( P < 0.01 ) . CONCLUSIONS Our long-term results with multimodality therapy with attempted bladder preservation showed no definitive improvement in survival compared with modern series of cystectomy alone , and a disappointingly low rate of disease-free bladder preservation . We found a high rate of locally recurrent disease in the preserved bladders . We also noted a decrease in survival in our patients with bladder preservation compared with those without preservation . Bladder preservation , although possible , should be limited to a very select group of patients BACKGROUND Whether organ-conserving treatment by combined-modality therapy ( CMT ) achieves comparable long-term survival to radical cystectomy ( RC ) for muscle-invasive bladder cancer ( BCa ) is largely unknown . OBJECTIVE Report long-term outcomes of patients with muscle-invasive BCa treated by CMT .  DESIGN , SETTING , AND PARTICIPANTS We conducted an analysis of successive prospect i ve protocol s at the Massachusetts General Hospital ( MGH ) treating 348 patients with cT2 - 4a disease between 1986 and 2006 . Median follow-up for surviving patients was 7.7 yr . INTERVENTIONS Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy ( RT ) after maximal transurethral resection of bladder tumor ( TURBT ) plus neoadjuvant or adjuvant chemotherapy . Repeat biopsy was performed after 40 Gy , with initial tumor response guiding subsequent therapy . Those patients showing complete response ( CR ) received boost chemotherapy and RT . One hundred two patients ( 29 % ) underwent RC-60 for less than CR and 42 for recurrent invasive tumors . MEASUREMENTS Disease-specific survival ( DSS ) and overall survival ( OS ) were evaluated using the Kaplan-Meier method . RESULTS AND LIMITATIONS Seventy-two percent of patients ( 78 % with stage T2 ) had CR to induction therapy . Five- , 10- , and 15-yr DSS rates were 64 % , 59 % , and 57 % ( T2=74 % , 67 % , and 63 % ; T3 - 4=53 % , 49 % , and 49 % ) , respectively . Five- , 10- , and 15-yr OS rates were 52 % , 35 % , and 22 % ( T2 : 61 % , 43 % , and 28 % ; T3 - 4=41 % , 27 % , and 16 % ) , respectively . Among patients showing CR , 10-yr rates of noninvasive , invasive , pelvic , and distant recurrences were 29 % , 16 % , 11 % , and 32 % , respectively . Among patients undergoing visibly complete TURBT , only 22 % required cystectomy ( vs 42 % with incomplete TURBT ; log-rank p<0.001 ) . In multivariate analyses , clinical T-stage and CR were significantly associated with improved DSS and OS . Use of neoadjuvant chemotherapy did not improve outcomes . No patient required cystectomy for treatment-related toxicity . CONCLUSIONS CMT achieves a CR and preserves the native bladder in > 70 % of patients while offering long-term survival rates comparable to contemporary cystectomy series . These results support modern bladder-sparing therapy as a proven alternative for selected patients Concurrent vinablastine-based radiochemotherapy was evaluated in 84 bladder-cancer patients . It was effective in more than half : tumour-specific survival ( 51 % 9-year ) , local control rate ( 55 % 9-year ) . The drawback was the impaired function of the bladder ( 9-year prevalence SOMA G3 - 4 symptoms : 66 % ) , indicating the need for treatment aim ed at reducing chronic morbidity PURPOSE To vali date the current TNM staging system , we analyzed our contemporary experience with 300 cystectomies .  MATERIAL S AND METHODS The pathological material and medical records of 300 patients treated with cystectomy  were review ed , and the new TNM classification was adopted . RESULTS The median followup of patients with no evidence of disease was 65 months , and overall survival rate was 45 % with a median survival of 50 months . In a Cox regression analysis only patient age , pT stage and neoadjuvant chemotherapy were significant factors for survival . The disease specific survival was 67 % with a median survival of 94 months . In a multiple proportional hazards analysis only pT stage and previous chemotherapy were significant factors of disease specific survival . A significant difference was seen in the overall and disease specific survival between patients with organ confined and nonorgan confined tumors . We did not observe a difference in the survival rate among patients with pT4a to pT3 tumors . Significant differences were not seen in survival rates between sexes or among patients of different age groups . Transitional cell carcinoma was the predominant histological type , and no significant difference was found in patient outcome among the different histological subtypes . CONCLUSIONS Bladder cancer can be categorized into organ confined and nonorgan confined tumors . This dichotomous grouping is better suited for evaluating adjuvant clinical trials . The pT stage of the bladder and prostate should be prospect ively analyzed together to better define the clinical implication s of prostatic involvement . In our opinion the histological subtypes do not affect outcome PURPOSE Chemoradiotherapy is becoming an alternative to radical cystectomy among patients with muscle invading bladder cancer . We began a prospect i ve study in 1988 to determine the possibilities of conservative treatment and aim ing to improve the results obtained by cystectomy alone in invasive bladder cancer . A combination of methotrexate , vinblastine , adriamycin , and cisplatin ( M-VAC ) , followed by radiotherapy and concomitant cisplatin was used . METHODS Fifty patients with good performance status and with stages T2 to T4 operable untreated invasive bladder cancer were entered in the study . Treatment protocol was as follows : ( i ) cytoreductive transurethral resection ; ( ii ) two cycles of M-VAC chemotherapy ; ( iii ) radiotherapy , 45 Gy on pelvic volume and , at the same time , 20 mg/m(2 ) cisplatin on days 1 to 5 . Cystoscopic evaluation : if there was a complete response , radiotherapy was completed up to 65 Gy ; if there was not a complete response , a cystectomy was performed . Median follow-up of the series was 73 months ( 18 - 180 m ) . RESULTS Tumor response was as follows : 34 complete responses ( 68 % ) , 9 partial responses ( 18 % ) , and 7 nonresponses ( 14 % ) were observed . The 5-year overall survival and local control were 48 % and 47 % , respectively . For the complete responder patient , 5-year survival and local control were 65 % and 70 % , respectively . Severe toxicity was uncommon . The most frequent were leucopenia and cystitis . No treatment-related deaths occurred with either treatment protocol . CONCLUSIONS Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer , although a r and omized clinical trial would be required to produce definitive results Objective : The aim of the study was to assess the efficacy and safety of concomitant radiotherapy ( CRT ) and carboplatin . Patients and Methods : From 1992 until 1997 , 67 patients with T3 invasive bladder cancer ( IBC ) were treated using CRT and carboplatin . X-Ray radiotherapy ( 10 MeV ) was applied using LINAC in a locoregional technique , with a total tumor dose of 65 Gy in 32 fractions . Carboplatin was administered as a bolus infusion once a week , on day 5 , up to a total dose of 900 mg . Results : The most frequent toxicity was hematological . Of the 67 treated patients , 92.5 % achieved a clinical ly complete response , and 7.5 % developed progressive disease during therapy . The 5-year overall survival was 55 % and disease-free survival was 35 % . Conclusion : CRT and carboplatin appear to be safe and extremely active in the treatment of T3 IBC , but the results should be confirmed in a r and omized study PURPOSE Although the use of radical transurethral resection followed by concurrent radiochemotherapy leads to a similar survival rate to that achieved after cystectomy , the number of long-term survivors is low in both cases . An improvement may be obtained by adding a new drug , such as gemcitabine , which is active in bladder cancer and acts as a radiosensitizer . However , because gemcitabine may be very toxic when associated with radiotherapy , we design ed this dose-finding study in an attempt to find the dose that can be safely added to radiotherapy and concurrent cisplatin in patients treated with transurethral resection for infiltrating bladder cancer . PATIENTS AND METHODS After undergoing macroscopically complete transurethral resections for transitional carcinoma of the bladder , patients staged pT2 or higher and without distant metastases concurrently received 54 Gy of fractionated radiotherapy over 6 weeks with cisplatin ( 100 mg/m(2 ) q.3 w ) , starting on Day 1 of radiotherapy . Concomitant gemcitabine was administered on Days 1 , 8 , and 15 q.3 w for 2 cycles at a dose of 200 mg/m(2 ) , escalated to 500 mg/m(2 ) , with a 100 mg/m(2 ) increase at each dose level . The maximum tolerated dose was defined as the dose of gemcitabine associated with dose-limiting toxic effects ( febrile neutropenia , Grade 4 thrombocytopenia , Grade 3 or 4 enteric toxicity , or Grade 4 nonhematologic toxicity ) in 33 % of the patients treated at that dose level . Six to 8 weeks after completing the therapy , the patients underwent cystoscopic reevaluation with multiple biopsies of the initial tumor site . RESULTS Of our consecutive series of 16 patients , 5 received a gemcitabine dose of 200 mg/m(2)/week , 3 a dose of 300 mg/m(2)/week , 3 a dose of 400 mg/m(2)/week , and 5 a dose of 500 mg/m(2)/week for 6 weeks . No dose-limiting toxicity was observed at doses of up to 400 mg/m(2)/week . At the dose 500 mg/m(2)/week , 1 patient experienced an intestinal perforation that recovered after surgery , and another suddenly died after developing Grade 3 untreated diarrhea in the last treatment week . All of the 15 evaluable patients were microscopically disease free at the cystoscopic reevaluation ; furthermore , the posttreatment computed tomography scans did not reveal any distant metastases . CONCLUSIONS After transurethral resection for the conservative treatment of infiltrating bladder cancer , gemcitabine doses of up to 400 mg/m(2)/week seem to be safe in combination with cisplatin and radiotherapy in organ-sparing management . On the basis of the promising results of this Phase I study , we are currently conducting a Phase II trial to verify the possible improvement in local control result ing from the addition of gemcitabine OBJECTIVE To assess in a phase II trial the effectiveness and toxicity of combined chemotherapy and radiation with selective bladder preservation by response in the treatment of muscle-invasive bladder carcinoma . PATIENTS AND METHODS Fifty-six eligible patients with T2 - 4 M0 transitional cell bladder cancer suitable for radical surgery and multi-agent chemotherapy  received two courses of methotrexate , cisplatin and vinblastine , followed by 40 Gy of pelvic radiotherapy in 1.8 Gy fractions with concomitant cisplatin . Tumour response was evaluated by cystoscopy and biopsy . Those responding completely were given a 24 Gy bladder boost plus cisplatin ; patients with residual tumour were assigned to immediate cystectomy . RESULTS After induction therapy , 28 patients ( 50 % ) responded completely ; 22 operable patients with residual tumour underwent immediate cystectomy , while 34 patients were consoli date d with cisplatin and radiation .  Bladder relapses developed in 16 patients ; seven had successful endovesical therapy for superficial disease and salvage cystectomy was possible in four of nine cases with invasive recurrence . Distant metastases occurred in 22 cases ( 39 % ) . After a median follow-up of 46 months , the 5-year actuarial disease-specific survival was 59 % , disease-free survival 54 % and local control without cystectomy ( bladder preservation ) 41 % . There were no treatment-related deaths ; grade 3 late complications occurred in two patients . CONCLUSION This combined chemotherapy-radiotherapy regimen with selective organ preservation should be considered as an option for muscle-invasive bladder carcinoma . The initial results suggest the possibility of retaining a functioning bladder in many patients , without compromising survival , compared with elective cystectomy approaches . A longer follow-up and quality -of-life assessment remain essential for a better definition of selection criteria and long-term results of this combined modality PURPOSE To evaluate bladder preservation and functional quality after concurrent chemoradiotherapy for muscle-invasive cancer in 53 patients included in a Phase II trial . PATIENT AND METHODS Pelvic irradiation delivered 45 Gy , followed by an 18-Gy boost . Concurrent chemotherapy with cisplatin and 5-fluorouracil by continuous infusion was performed at Weeks 1 , 4 , and 7 during radiotherapy .  Patients initially suitable for surgery were evaluated with macroscopically complete transurethral resection after 45 Gy , followed by radical cystectomy in case of incomplete response . The European Organization for Research and Treatment of Cancer quality of life question naire QLQ-C30 , specific items on bladder function , and the Late Effects in Normal Tissues-Subjective , Objective , Management , and Analytic ( LENT-SOMA ) symptoms scale were used to evaluate quality of life before treatment and 6 , 12 , 24 , and 36 months after treatment . RESULTS Median age was 68 years for 51 evaluable patients . Thirty-two percent of patients had T2a tumors , 46 % T2b , 16 % T3 , and 6 % T4 . A visibly complete transurethral resection was possible in 66 % . Median follow-up was 8 years . Bladder was preserved in 67 % ( 95 % confidence interval , 52 - 79 % ) of patients . Overall survival was 36 % ( 95 % confidence interval , 23 - 49 % ) at 8 years for all patients , and 45 % ( 28 - 61 % ) for the 36 patients suitable for surgery . Satisfactory bladder function , according to LENT-SOMA , was reported for 100 % of patients with preserved bladder and locally controlled disease 6 - 36 months after the beginning of treatment . Satisfactory bladder function was reported for 35 % of patients before treatment and for 43 % , 57 % , and 29 % , respectively , at 6 , 18 , and 36 months . CONCLUSIONS Concurrent chemoradiation therapy allowed bladder preservation with tumor control for 67 % patients at 8 years . Quality of life and quality of bladder function were satisfactory for 67 % of patients OBJECTIVE To evaluate the 5-year results of the following trimodal therapy for treatment of some selected cases of muscle invasive bladder cancer . MATERIAL S AND METHODS In this prospect i ve study , we included 104 patients with transitional cell carcinoma ( TCC ) ( T2 and T3a , N0 , M0 ) who were amenable to complete transurethral resection . All patients received adjuvant chemo-radiotherapy ( CRT ) in the form of gemcitabine and cisplatin and conventional radiotherapy after the maximum resection of their tumors . Two weeks later , all cases had radiologic and cystoscopic evaluation . The patients who showed no evidence of the bladder tumors [ complete response ( CR ) ] went on to complete the CRT , while those with recurrent invasive tumors did not receive any more CRT and were assigned to have salvage cystectomy . Thereafter , all patients were subjected to a regular follow-up . RESULTS This trimodal therapy was well tolerated in most of cases with no severe acute toxicities . Complete response was achieved in 78.8 % of cases after the initial CRT , and tumor grade was found to be the most significant risk factor to predict this response ( P = 0.004 ) . With a median follow-up of 71 months for patients with initial CR , 16.2 % of cases showed muscle invasive recurrences , and multifocality was the only significant risk factor for their development ( P = 0.003 ) . Meanwhile , superficial recurrences were detected in 8.1 % of cases with initial CR and were successfully treated with transurethral resection and intravesical bacillus Calmette-Guerin ( BCG ) . On the other h and , we reported distant metastasis in 24.3 % of patients with initial CR , and tumor grade , stage and multifocality were the most significant risk factors for this complication ( P = 0.002 , 0.031 , 0.006 ) . No cases of contracted bladder or late gastrointestinal complications were demonstrated in this series . The 5-year overall survival rate for patients with initial CR was 67.6 % , and for all the patients in this study it was 59.4 % . CONCLUSIONS This trimodal therapy can be considered as a treatment option for patients with localized muscle invasive TCC . The best c and i date s for such therapy are those with solitary T2 , low grade tumors that are amenable to complete transurethral resection PURPOSE Radical cystectomy as st and ard treatment of muscle-invasive urothelial carcinoma of the urinary bladder cures less than 50 % of patients with locally advanced bladder cancer . We compared two adjuvant combination chemotherapies in patients with stage pT3a-4a and /or pathologic node-positive transitional-cell carcinoma of the bladder after radical cystectomy .  PATIENTS AND METHODS A total of 327 patients were r and omly assigned to either adjuvant systemic chemotherapy with three cycles of cisplatin 70 mg/qm(2 ) on day 1 and methotrexate 40 mg/qm(2 ) on days 8 and 15 of a 21-day cycle ( CM ) or three cycles of methotrexate 30 mg/qm(2 ) on days 1 , 15 , and 22 , vinblastine 3 mg/qm(2 ) on days 2 , 15 , and 22 , epirubicin 45 mg/qm(2 ) on day 2 , and cisplatin 70 mg/qm(2 ) on day 2 of a 28-day cycle ( M-VEC ) . RESULTS The hazard ratio for progression-free survival as the primary end point was 1.13 ( 90 % CI , 0.86 to 1.48 ) for 163 CM patients compared with 164 M-VEC patients whose right-h and limit remained below the upper bound compatible with the noninferiority hypothesis ( alpha = .0403 ) . The 5-year progression-free , tumor-specific , and overall survival rates ( point estimates + /- SE ) for CM versus M-VEC were 46.3 % + /- 4.6 % v 48.8 % + /- 4.5 % , 52.0 % + /- 4.6 % v 52.3 % + /- 4.8 % , and 46.1 % + /- 4.3 % v 45.1 % + /- 4.6 % , respectively . WHO grade 3 and 4 leukopenia occurred in 7.0 % of patients treated with CM and 22.2 % of patients treated with M-VEC ( P < .0001 ) . CONCLUSION CM can not be considered inferior to M-VEC with regard to progression-free survival of patients with locally advanced bladder cancer after radical cystectomy . Moreover , patients receiving adjuvant CM combination therapy experienced significantly less grade 3 and 4 leukopenia than patients treated with M-VEC Potentially curative treatments for patients with muscle-invasive bladder cancer ( MIBC ) are underused , especially in the elderly .  Trimodality bladder preservation therapy , which includes a maximally safe transurethral resection of the bladder tumor , followed by concurrent chemoradiation , fulfills this currently unmet need . In multiple prospect i ve clinical trials and large institutional series , trimodality therapy has demonstrated excellent 5-year overall survival rates of 48 % to 65 % , comparable to those reported in cystectomy studies . Approximately 75 % to 80 % of long-term survivors maintain their native bladders , which tend to function well and allow patients to maintain excellent quality of life .  Salvage cystectomy for patients who develop a local invasive recurrence can be performed with acceptable operative complication rates , and results in excellent long-term disease control and survival outcomes . For patients with MIBC who are noncystectomy c and i date s , or select patients who are motivated to keep their native bladders , trimodality bladder preservation therapy is recognized by the International Consultation on Urological Diseases-European Association of Urology and the NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer as an effective alternative to radical cystectomy , and should be considered . In the future , biomarkers may allow improved selection of patients for whom trimodality bladder preservation therapy is most likely to succeed Between April 1984 and May 1989 , 77 eligible patients with invasive , nonmetastatic ( stage M0 ) transitional cell carcinoma of the bladder were stratified after radical cystectomy and pelvic lymph node dissection on the basis of nodal status ( stage pN0 versus pN1 - 2 ) and were r and omly assigned to either observation or postoperative cisplatin chemotherapy ( 3 courses of 90 mg./m.2 cisplatin given for 3 consecutive days at monthly intervals ) . Patient eligibility included a creatinine clearance of greater than 60 ml . per minute . There were 40 eligible patients in the control group ( median age 61 years ) and 37 in the cisplatin group ( median age 64 years ) . In regard to postoperative tumor stage and nodal status , there was no statistical difference between the 2 patient groups . In the cisplatin group 21 patients received the full dose , 9 required dose reduction and 7 refused treatment . Median followup was 5 years 9 months ( range 3 to 8 years ) . Survival analysis showed no significant difference ( log rank p = 0.65 ) between the 40 patients in the control group and the 37 in the cisplatin group . The survival rate at 5 years was 54 % ( 95 % confidence interval 39 to 69 % ) in the control group and 57 % ( 95 % confidence interval 40 to 74 % ) in the treatment group . Patients with cancer confined to the bladder wall ( stage pT3a or less ) had a 5-year overall survival rate of 70 % and those with tumor growth in the perivesical fat or into the prostate ( stages pT3b plus pT4a ) had a 5-year overall survival rate of 40 % . This difference in survival between the low stage subgroup ( stages pT3a or less ) and the high stage subgroup ( pT3b plus pT4a ) is highly significant ( p = 0.0043 ) . However , no difference between the controls and the cisplatin group was found within either the low or high stage subgroups . The reasons for failing to show a survival benefit from adjuvant high dose cisplatin monotherapy after radical cystectomy are discussed 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 The aim of this prospect i ve , phase II trial was to determine the response of muscle-invasive bladder cancer ( MIBC ) to concurrent chemoradiotherapy of weekly gemcitabine with 4 weeks of radiotherapy ( RT ; GemX ) . PATIENTS AND METHODS Fifty patients with transitional cell carcinoma , stage T2 - 3 , N0 , M0 after transurethral resection and magnetic resonance imaging , were recruited .  Gemcitabine was given intravenously at 100 mg/m(2 ) on days 1 , 8 , 15 , and 22 of a 28-day RT schedule that delivered 52.5 Gy in 20 fractions . Chemotherapy was stopped for Radiation Therapy Oncology Group ( RTOG ) grade 3 bladder or bowel toxicity . The primary end points were tumor response , toxicity , and survival . RESULTS All patients completed RT ; 46 tolerated all four cycles of gemcitabine . Two patients stopped after two cycles , and two stopped after three cycles , because of bowel toxicity .  Forty-seven patients had a post-treatment cystoscopy ; 44 ( 88 % ) achieved a complete endoscopic response . At a median follow-up of 36 months ( range , 15 to 62 months ) , 36 patients were alive , and 32 of these had a functional and intact bladder . Fourteen patients died ; seven died as a result of metastatic MIBC , five died as a result of intercurrent disease , and two died as a result of treatment-associated deaths . Four patients underwent cystectomy ; three because of recurrent disease and one because of toxicity . One patient required a bowel resection for late toxicity . By using Kaplan-Meier analyses , 3-year cancer-specific survival was 82 % , and overall survival was 75 % . CONCLUSION Concurrent gemcitabine-based chemoradiotherapy ( ie , GemX ) produces a high response rate in MIBC and has durable local control and acceptable toxicity , which allows patients to preserve their own bladder . This treatment modality warrants additional investigation in a phase III setting BACKGROUND Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer . In other disease sites , synchronous chemoradiotherapy has been associated with increased local control and improved survival , as compared with radiotherapy alone . METHODS In this multicenter , phase 3 trial , we r and omly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy .  The regimen consisted of fluorouracil ( 500 mg per square meter of body-surface area per day ) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C ( 12 mg per square meter ) on day 1 . Patients were also r and omly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy ( in which the volume of bladder receiving full-dose radiotherapy was reduced ) in a partial 2-by-2 factorial design ( results not reported here ) . The primary end point was survival free of locoregional disease . Secondary end points included overall survival and toxic effects . RESULTS At 2 years , rates of locoregional disease-free survival were 67 % ( 95 % confidence interval [ CI ] , 59 to 74 ) in the chemoradiotherapy group and 54 % ( 95 % CI , 46 to 62 ) in the radiotherapy group . With a median follow-up of 69.9 months , the hazard ratio in the chemoradiotherapy group was 0.68 ( 95 % CI , 0.48 to 0.96 ; P=0.03 ) . Five-year rates of overall survival were 48 % ( 95 % CI , 40 to 55 ) in the chemoradiotherapy group and 35 % ( 95 % CI , 28 to 43 ) in the radiotherapy group ( hazard ratio , 0.82 ; 95 % CI , 0.63 to 1.09 ; P=0.16 ) . Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment ( 36.0 % vs. 27.5 % , P=0.07 ) but not during follow-up ( 8.3 % vs. 15.7 % , P=0.07 ) . CONCLUSIONS Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer , as compared with radiotherapy alone , with no significant increase in adverse events . ( Funded by Cancer Research U.K. ; BC2001 Current Controlled Trials number , IS RCT N68324339 . ) PURPOSE Whole-pelvis ( WP ) concurrent chemoradiation ( CCRT ) is the st and ard bladder preserving option for patients with invasive bladder cancer . The st and ard practice is to treat elective pelvic lymph nodes , so our aim was to evaluate whether bladder-only ( BO ) CCRT leads to results similar to those obtained by st and ard WP-CCRT . METHODS AND MATERIAL S Patient eligibility included histopathologically proven muscle-invasive bladder cancer , lymph nodes negative ( T2-T4 , N- ) by radiology , and maximal transurethral resection of bladder tumor with normal hematologic , renal , and liver functions . Between March 2005 and May 2006 , 230 patients were accrued . Patients were r and omly assigned to WP-CCRT ( 120 patients ) and BO-CCRT ( 110 patients ) . Data regarding the toxicity profile , compliance , initial complete response rates at 3 months , and occurrence of locoregional or distant failure were recorded . RESULTS With a median follow-up time of 5 years ( range , 3 - 6 ) , WP-CCRT was associated with a 5-year disease-free survival of 47.1 % compared with 46.9 % in patients treated with BO-CCRT ( p = 0.5 ) . The bladder preservation rates were 58.9 % and 57.1 % in WP-CCRT and BO-CCRT , respectively ( p = 0.8 ) , and the 5-year overall survival rates were 52.9 % for WP-CCRT and 51 % for BO-CCRT ( p = 0.8 ) . CONCLUSION BO-CCRT showed similar rates of bladder preservation , disease-free survival , and overall survival rates as those of WP-CCRT . Smaller field sizes including bladder with 2-cm margins can be used as bladder preservation protocol for patients with muscle-invasive lymph node-negative bladder cancer to minimize the side effects of CCRT OBJECTIVE To report long-term outcomes of selective organ preservation for muscle-invasive bladder cancer ( MIBC ) using 2 bladder-sparing trimodality approaches . MATERIAL S AND METHODS From 1990 to 2010 , 80 patients with T2-T4 bladder cancer were prospect ively enrolled in 2 successive bladder-sparing protocol s. Forty-one patients were treated with neoadjuvant methotrexate , cisplatin , and vinblastine ( MCV ) chemotherapy followed by radiotherapy ( 60 Gy ) in complete responders ( protocol 1 [ P1 ] ) and 39 patients were treated with weekly cisplatin concurrent with radiotherapy ( 64.8 Gy ) ( protocol 2 [ P2 ] ) . RESULTS The median follow-up was 72 months ( range , 9 - 204 months ) . Five and 10-year cumulative overall survival for all series were 73 % and 60 % and the corresponding numbers for cancer-specific survival were 82 % and 80 % , respectively . Of all surviving patients , 83 % maintained their own bladder . Although there were no significant differences in overall survival ( P = .820 ) , cancer-specific survival ( P = .688 ) and distant metastasis ( P = .417 ) between protocol s , complete response rates ( P = .003 ) , and disease-free survival ( P = .031 ) were significantly higher in P2 treatment . CONCLUSION Trimodality therapy with bladder preservation represents a real alternative to radical cystectomy ( RC ) in selected patients .  Overall survival and cancer-specific survival rates are encouraging with more than 80 % of survivors retaining functional bladders OBJECTIVES Radical cystectomy ( RC ) is the st and ard treatment for muscle-invasive urothelial carcinoma of the bladder . Trimodality bladder-preserving therapy ( BPT ) is an alternative to RC , but r and omized comparisons of RC versus BPT have proven infeasible . To compare RC versus BPT , we undertook an observational cohort study using registry and administrative cl aims data from the Surveillance , Epidemiology and End Results -Medicare data base . METHODS We identified patients age 65 years or older diagnosed between 1995 and 2005 who received RC ( n = 1426 ) or BPT ( n = 417 ) . We examined confounding and stage misclassification in the comparison of RC and BPT by using multivariable adjustment , propensity score-based adjustment , instrumental variable ( IV ) analysis , and simulations . RESULTS Patients who received BPT were older and more likely to have comorbid disease . After propensity score adjustment , BPT was associated with an increased hazard of death from any cause ( hazard ratio [ HR ] 1.26 ; 95 % confidence interval [ CI ] 1.05 - 1.53 ) and from bladder cancer ( HR 1.31 ; 95 % CI 0.97 - 1.77 ) . Using the local area cystectomy rate as an instrument , IV analysis demonstrated no differences in survival between BPT and RC ( death from any cause HR 1.06 ; 95 % CI 0.78 - 1.31 ; death from bladder cancer HR 0.94 ; 95 % CI 0.55 - 1.18 ) . Simulation studies for stage misclassification yielded results consistent with the IV analysis . CONCLUSIONS Survival estimates in an observational cohort of patients who underwent  RC  versus  BPT  differ by analytic method . Multivariable and propensity score adjustment revealed greater mortality associated with BPT relative to RC , while IV analysis and simulation studies suggest that the two treatments are associated with similar survival outcomes BACKGROUND The optimal treatment strategy for muscle-invasive bladder cancer ( BCa ) remains controversial . OBJECTIVE Better define the long-term outcomes of radical cystectomy ( RC ) alone for BCa and determine the impact of pathologic downstaging after transurethral resection in a large and homogeneous single-center series . DESIGN , SETTING , AND PARTICIPANTS A cohort of 1100 patients undergoing RC with pelvic lymph node dissection ( PLND ) without neoadjuvant therapy for urothelial carcinoma of the bladder between January 1 , 1986 , and December 2009 was evaluated . Patients with other than metastases to the pelvic lymph nodes were excluded . Median age was 65 yr .  Clinical course , pathologic characteristics , and long-term outcomes were evaluated . Follow-up was obtained until December 2009 with a median of 38 mo and a completeness of 96.5 % . INTERVENTION RC with PLND ; urinary diversion with ileal neobladder whenever possible . MEASUREMENTS Primary end points were disease-specific survival ( DSS ) , recurrence-free survival ( RFS ) , and overall survival ( OS ) according to the tumor stage of the RC specimen versus the maximum tumor stage . The log-rank test was used to compare subgroups . RESULTS AND LIMITATIONS The 30-d ( 90-d ) mortality rate was 3.2 % ( 5.2 % ) . The 10-yr OS , DSS , and RFS rates were 44.3 % , 66.8 % , and 65.5 % , respectively . Based on the tumor stage of the RC specimen , the 10-yr DSS rate was pT0/a/is/1 pN0 : 90.5 % , pT2a/b pN0 : 66.8 % , pT3a/b pN0 : 59.7 % , pT4a/b pN0 : 36.6 % , and pTall pN+ : 16.7 % . Downstaging by transurethral resection of the prostate was observed in 382 patients . Patients with maximum tumor stage pT2a/b pN0 had distinctly better 10-yr DSS rates than those with pT2a/b pN0 in the RC specimen : pT2a pN0 : 92.2 % versus 73.8 % ; pT2b : 75.0 % versus 62.0 % . A total of 49 % female and 80 % male patients received an ileal neobladder . CONCLUSIONS This contemporary and homogeneous single-center series found acceptable OS , DFS , and RFS for patients undergoing RC . Pathologic downstaging had a significant impact on survival
BACKGROUND Radical cystectomy ( RC ) represents the mainstay of treatment in patients with muscle-invasive urinary bladder cancer but how it compares with the best organ preservation approach is not known .
MATERIAL S AND METHODS The objective of our review is to compare the 5-year overall survival ( OS ) rates from retrospective and prospect i ve studies of RC and trimodality treatment ( TMT ) , i.e. concurrent delivery of chemotherapy and radiotherapy after a transurethral resection of bladder tumor ( TURBT ) , involving a total of 10,265 and 3131 patients , respectively .