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. Effective bladder sparing therapy with intra-arterial cisplatin and radiotherapy for localized bladder cancer. 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. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Phase II study of radiochemotherapy with vinblastine in invasive bladder cancer. 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. Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. 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. Trimodality bladder preservation therapy for muscle-invasive bladder cancer. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. 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. Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy.
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 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 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 To examine combination cisplatin and twice-daily accelerated irradiation ( RT ) after aggressive transurethral resection of bladder tumor ( TURBT ) in an attempt to preserve the bladder and to determine the likelihood that patients who complete this regimen could then complete three cycles of methotrexate , cisplatin , vinblastine ( MCV ) chemotherapy .  Between 1998 and 2000 , 52 patients with Stage T2-T4aN0M0 disease , from 17 institutions , were entered into the trial . Forty-seven patients were deemed eligible ; the planned accrual was 40 . Of the 46 patients , 68 % were > 60 years old , 70 % were men , and 96 % had a Karnofsky score > /=90 . The clinical T stage was T2 in 66 % , T3a in 25 % , and T3b in 9 % . The median follow-up at the time of analysis was 26 months . The protocol required TURBT within 6 weeks of the initiation of induction therapy . Induction treatment involved 13 days of concomitant boost RT , 1.8 Gy to the pelvis in the morning followed by 1.6 Gy to the tumor 4 - 6 h later . For sensitization , cisplatin ( 20 mg/m(2 ) ) was given on the first 3 days of each treatment week . Three to four weeks after induction , patients were evaluated cystoscopically for residual disease . Patients whose biopsies and cytologic evaluations showed no disease completed consolidation chemoirradiation . Patients with residual tumor went on to cystectomy . After either consolidation or cystectomy , patients were to complete three cycles of MCV chemotherapy . Of the 47 patients , 45 % completed all phases of the protocol treatment with minor , or no , deviations . Five patients refused either the postinduction evaluation or cystectomy and 6 refused adjuvant chemotherapy . The CR rate after induction therapy was 74 % . For 2 patients , residual disease after induction was limited to positive cytologic findings , and for 8 patients , biopsy of the primary site revealed persistence . Of the 8 cystectomy patients , 2 had no evidence of disease in the bladder at pathologic review of the surgery specimen . Grade 3 toxicity related to chemotherapy was observed in 11 % of patients during both induction and consolidation , and in 41 % during adjuvant chemotherapy . A total of 8 patients ( 36 % of those receiving adjuvant chemotherapy ) went on to develop Grade 4 neutropenia or thrombocytopenia during additional adjuvant chemotherapy .  Grade 3 toxicity due to RT was seen in 4 % and 0 % of patients during induction and consolidation , respectively . One patient developed Grade 4 hydronephrosis during consolidation . The projected 36-month value for locoregional failure , distant metastasis , overall survival , and bladder-intact survival was 27 % , 29 % , 61 % , and 48 % , respectively . After aggressive TURBT , twice-daily accelerated RT initiated in concomitant-boost format is well tolerated and results in a rate of complete response ( 74 % ) similar to that in previous bladder-sparing trials . The projected 2-year values for locoregional control , bladder-intact survival , and overall survival were also consistent with previously reported trials of bladder-sparing treatment . With only 45 % of patients completing three cycles of MCV , this form of adjuvant chemotherapy appears to be poorly tolerated by most patients OBJECTIVES To evaluate the outcomes of patients with muscle-invasive Stage T2 - 4a bladder carcinoma managed by transurethral surgery and concurrent chemoradiation .  METHODS A total of 190 patients were treated on institutional prospect i ve protocol s using concurrent cisplatin-containing chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor . Patients were re-evaluated by repeated biopsy and urine cytologic analysis after 40 Gy , with the initial tumor response guiding subsequent therapy . One hundred twenty-one patients with a complete response by cytologic and histologic examination and those medically unfit for cystectomy received  boost chemoradiation to 64 to 65 Gy . Those patients without a complete response were advised to undergo radical cystectomy . A total of 66 patients ( 35 % ) ultimately underwent radical cystectomy ; 41 for less than a complete response and an additional 25 for recurrent invasive tumors . The median follow-up was 6.7 years for all surviving patients . RESULTS The 5 and 10-year actuarial overall survival rate was 54 % and 36 % , respectively ( Stage T2 , 62 % and 41 % ; Stage T3-T4a , 47 % and 31 % , respectively ) . The 5 and 10-year disease-specific survival rate was 63 % and 59 % ( Stage T2 , 74 % and 66 % ; Stage T3-T4a , 53 % and 52 % ) , respectively . The 5 and 10-year disease-specific survival rate for patients with an intact bladder was 46 % and 45 % ( Stage T2 , 57 % and 50 % ; Stage T3-T4a , 35 % and 34 % ) , respectively . The pelvic failure rate was 8.4 % . No patient required cystectomy because of bladder morbidity . CONCLUSIONS The 10-year overall survival and disease-specific survival rates are comparable with the results reported for contemporary radical cystectomy for patients of similar clinical and pathologic stage . One third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy . A trimodality approach with bladder preservation based on the initial tumor response is , therefore , safe , with most long-term survivors retaining functional bladders 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 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 improve the results obtained by cystectomy alone and to determine the possibilities of conservative treatment in invasive bladder cancer , we design ed a prospect i ve study using a combination of fluorouracil ( 5-FU ) plus cisplatin and concomitant radiation therapy , followed by either cystectomy or additional chemoradiotherapy . PATIENTS AND METHODS Fifty-four patients with stage T2 to T4 operable untreated invasive bladder cancer were entered onto the study . Treatment was begun in all patients by transurethral resection ( TUR ) and followed by the 5-FU-cisplatin combination with concomitant bifractionated split-course radiation therapy . A control cystoscopy was performed 6 weeks after completion of the neoadjuvant program . Patients with persistent tumor underwent cystectomy . Complete responders were treated by either additional chemoradiotherapy ( group A ) or cystectomy ( group B ) . RESULTS At control cystoscopy , 40 of 54 patients ( 74 % ) had a histologically documented complete response . Four responders developed recurrent pelvic disease after a mean follow-up time of 27 + /- 12 months ( three in group A and one in group B ) . Metastatic disease , which developed in 16 patients , occurred more frequently in the nonresponders ( 71 % ) than in responders ( 15 % ) . The disease-free survival rate at 3 years was 62 % ; it was significantly better in responders ( 77 % ) than in nonresponders ( 23 % ) . There was no difference in survival between groups A and B. CONCLUSION This neoadjuvant chemoradiotherapy combination , easy to implement and well tolerated even in elderly patients , provides a high complete response rate . It may prove to be effective in inoperable patients and may be proposed as conservative treatment in patients with a complete response to the initial course of chemoradiation 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 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 PURPOSE This phase II study was design ed to evaluate effectiveness and toxicity of a combined chemoradiotherapy program with selective bladder preservation in the management of patients with invasive bladder cancer . PATIENTS AND METHODS Ninety-one eligible patients with invasive bladder cancer stages T2M0 to T4AM0 suitable for radical cystectomy received two courses of methotrexate , cisplatin , and vinblastine ( MCV regimen ) followed by radiotherapy with 39.6 Gy and concurrent cisplatin . After complete urologic evaluation , operable patients who achieved complete response were selected for bladder preservation and treated with consolidation cisplatin-radiotherapy . RESULTS Of 91 eligible patients , 85 underwent complete urologic evaluation and 68 ( 75 % ; 95 % confidence interval [ CI ] , 59 % to 84 % ) had documented complete responses . Fourteen operable patients with residual tumor underwent immediate cystectomy . Of 70 patients treated with consolidation cisplatin-radiotherapy , 36 subsequently developed bladder recurrences , 23 of which were invasive . Patients with invasive recurrence ( n = 16 ) , extensive noninvasive recurrence ( n = 6 ) , or severe treatment complications ( n = 1 ) underwent salvage cystectomy . Thus , a total of 37 of 91 patients ( 40 % ) required cystectomy . The 4-year cumulative risk of invasive local failure ( which includes induction failures ) was 43 % ( 95 % CI , 33 % to 53 % ) . The 4-year actuarial risk of distant metastasis was 22 % ( 95 % CI , 13 % to 31 % ) . The 4-year actuarial survival rate of the entire group was 62 % ( 95 % CI , 52 % to 72 % ) . The 4-year actuarial rate of survival with bladder intact was 44 % ( 95 % CI , 34 % to 54 % ) . CONCLUSION Initial results of this combined chemoradiotherapy program show that bladder preservation can be achieved in the majority of patients , and that overall survival is similar to that reported with aggressive surgical approaches . Long-term survival and quality -of-life assessment s require longer follow-up study 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 OBJECTIVES To evaluate the safety , tolerance , protocol completion rate , tumor response rate , and patient survival of chemoradiotherapy for patients with muscle-invasive operable bladder cancer . METHODS After transurethral resection of the tumor in patients with Stage T2-T4a bladder cancer , twice-daily radiotherapy with paclitaxel and cisplatin chemotherapy induction ( TCI ) was administered . If repeat biopsy showed less than Stage T1 disease , consolidation with TCI was given . If repeat biopsy showed greater than Stage T1 disease , cystectomy was recommended . Adjuvant gemcitabine and cisplatin were given to all patients . RESULTS A total of 80 patients met protocol eligibility .  TCI result ed in 26 % developing grade 3 - 4 acute toxicity , mainly gastrointestinal ( 25 % ) . During consolidation TCI , grade 3 - 4 acute toxicity , all transient , was reported in 8 % . Four cycles of adjuvant chemotherapy were completed per protocol or with minor deviations in 70 % of the patients . Adjuvant treatment was associated with grade 3 toxicity in 46 % and grade 4 in 26 % . One patient had a fatal hemorrhagic stroke . Late bladder radiation toxicity was evaluated in 53 patients with > or = 2 years of follow-up . Of these 53 patients , 3 experienced self-limited , late grade 3 bladder toxicity . The postinduction complete response rate was 81 % ( 65/80 ) , 36 of the 80 patients died ( 22 of bladder cancer ) . At a median follow-up of 49.4 months , the actuarial 5-year overall and disease-specific survival rate was 56 % and 71 % , respectively . CONCLUSIONS These favorable tumor response rates with possible increased bladder preservation rates suggest that this treatment regimen deserves further study 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
PURPOSE Despite the numerous prospect i ve and retrospective studies published during the last 2 decades aim ing at testing the safety and the efficacy of trimodality therapy ( TMT ) as a conservative treatment , an optimal therapeutic strategy has not yet been identified .
We made a systematic overview of the 5-year outcomes from 31 trials of combined chemotherapy and radiation ( CRT ) after  transurethral resection of muscle-infiltrating bladder tumours ( TURBT ) , the so-called trimodality therapy .