Comparison of outcomes between trimodal therapy and radical cystectomy in muscle-invasive bladder cancer: a propensity score matching analysis. Combined treatment of invasive bladder carcinoma with transurethral resection, induction chemotherapy, and radical radiotherapy plus concomitant protracted infusion of cisplatin and 5‐fluorouracil Combined chemoradiotherapy with gemcitabine in patients with locally advanced inoperable transitional cell carcinoma of the urinary bladder and/or in patients ineligible for surgery: a phase I trial. Clinical and patient‐reported outcomes of SPARE – a randomised feasibility study of selective bladder preservation versus radical cystectomy Comparative Effectiveness of Trimodal Therapy Versus Radical Cystectomy for Localized Muscle-invasive Urothelial Carcinoma of the Bladder. 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. A randomised trial of accelerated radiotherapy for localised invasive bladder cancer. Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic. Radical Cystectomy is the best choice for most patients with muscle-invasive bladder cancer? Opinion: No 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. Radical cystectomy versus bladder-preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification biasin cancer observational comparative effectiveness research. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.
Although radical cystectomy ( RC ) is considered as the st and ard therapy for muscle-invasive bladder cancer ( MIBC ) , trimodal therapy ( TMT ) combining transurethral resection of the tumor with radiotherapy and chemotherapy is increasingly recommended as an alternative approach for bladder preservation . In the absence of r and omized trials , we compared the clinical outcomes between RC and TMT using propensity score matching with 50 patients in the RC arm and 29 patients in the TMT arm . With respective median follow-up periods of 23 and 32 months for the RC and TMT groups , 5-year distant metastasis-free survival ( 58 % vs. 67 % ) , overall survival ( 56 % vs. 57 % ) , and cancer-specific survival ( 69 % vs. 63 % ) rates between the RC and TMT groups , respectively , were similar . However , the 5-year local recurrence-free survival was significantly better in the RC group than in the TMT group ( 74 % vs. 35 % ) . Following TMT , acute grade 3 hematological ( n = 2 ) and late grade 3 genitourinary ( n = 1 ) toxicities were reported . These findings demonstrated that oncological outcomes of TMT were comparable with those of RC , except for poorer local control . Large-scale , r and omized trials are warranted to confirm the findings of the present retrospective comparison and to guide toward best treatment options The aim of this study was to define the maximum tolerated doses ( MTDs ) of cisplatin ( CDDP ) and 5‐fluorouracil ( 5‐FU ) administered as protracted intravenous infusion ( PVI ) during hyperfractionated radiotherapy ( HFRT ) administered with organ‐sparing intent to patients with infiltrating transitional cell carcinoma of the bladder ( TCCB ) BACKGROUND We conducted a phase I trial of gemcitabine ( gem ) with concurrent radiotherapy in patients with muscle-invasive bladder cancer ( BC ) ineligible for surgery or cisplatin or refusing organ loss . PATIENTS AND METHODS Patients with urothelial cancer , cT2-T4 , cN0 - 1 , M0 , ineligible for surgery due to local tumor extension , PS , age or co-morbidities or who refused surgery were included . After maximal transurethral resection , the treatment schedule included : twice-weekly i.v . infusion of gem [ dose levels ( DL ) 1 - 6 : 20 , 27 , 30 , 33 , 50 and 40 mg/m(2 ) , respectively ] for 30 min and concurrent radiotherapy ( RT ) to the bladder with 55.5 Gy . The primary end point was to determine the maximum-tolerated dose ( MTD ) and the dose recommended ( RD ) for further studies of this gem schedule . The secondary end point was late toxicity . The MTD was defined by dose-limiting toxicity ( DLT ) in 2 or more of 6 patients , discontinuation of RT and /or gem for > 1 week in 2 or more of 6 patients due to grade ( G ) 3/4 acute and /or late toxicity in more than 2 of 18 patients . RESULTS Thirty-five of 44 patients were assessable for toxicity and thus the primary end point . DLTs occurred in two of five patients at dose level 5 : one G3 alanine aminotransferase elevation and one G3 fatigue . The MTD , therefore , was 50 mg/m(2 ) gem twice weekly . At DL 6 with 40 mg/m(2 ) , the RD was established : only one of six patients developed G3 fatigue and diarrhea . Late toxicity was rare and of low grade ( only G1 - 2 ) . The 2-year locoregional failure rate was 32 % ( 9/28 ) ; 10 of 28 patients ( 38 % ) were alive with an intact bladder and no evidence of recurrent disease , 9 patients developed distant metastases and 6 died of their disease . CONCLUSIONS Gemcitabine in combination with RT is well tolerated in BC patients ineligible for surgery and /or cisplatin . The RD of gemcitabine for subsequent trials is 40 mg/m(2 ) twice weekly with concurrent radiation To test the feasibility of a r and omised trial in muscle‐invasive bladder cancer ( MIBC ) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy ( RC ) or selective bladder preservation ( SBP )  , where definitive treatment [ RC or radiotherapy ( RT ) ] is determined by response to chemotherapy Given the lack of r and omized evidence comparing trimodal therapy ( TMT ) to radical cystectomy ( RC ) for muscle-invasive urothelial carcinoma of the bladder ( UCB ) , we performed an observational cohort study to examine the comparative effectiveness of these two definitive treatments . Within the National Cancer Data Base (2004 - 2011),we identified 1257 ( 9.8 % ) and 11 586 ( 90.2 % ) patients who received TMT and RC , respectively . Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier analysis showed that median overall survival ( OS ) was similar between the TMT ( 40 mo , 95 % confidence interval [ CI ] 34 - 46 ) and RC groups ( 43 mo 95 % CI 41 - 45 ; p=0.3 ) . In IPTW-adjusted Cox regression analysis with a time-varying covariate , TMT was associated with a significant adverse impact on long-term OS ( hazard ratio 1.37 , 95 % CI 1.16 - 1.59 ; p<0.001 ) . Interaction terms indicated that the adverse treatment effect of TMT versus RC decreased with age ( p=0.004 ) , while there was no significant interaction with gender ( p=0.6 ) , Charlson comorbidity index ( p=0.09 ) or cT stage ( p=0.8 ) . In conclusion , we found that TMT was generally associated with worse long-term OS compared to RC for muscle-invasive UCB . However , the survival benefit of RC should be weighed against the risks of surgery , especially in older patients . These results are preliminary and emphasize the need for a r and omized controlled trial to compare TMT versus RC . PATIENT SUMMARY We examined the comparative effectiveness of trimodal therapy versus radical cystectomy for muscle-invasive urothelial carcinoma of the bladder . We found that trimodal therapy was generally associated with worse long-term overall survival , although there may be no difference with radical cystectomy in older individuals 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 BACKGROUND AND PURPOSE To evaluate the efficacy and toxicity of an accelerated fractionation regimen to treat localised muscle invasive bladder cancer . PATIENTS AND METHODS A prospect i ve r and omised trial was undertaken in 229 patients r and omised between 1988 and 1998 comparing accelerated fractionation ( AF ) to a dose of 60.8 Gy in 32 fractions over 26 days with conventional fractionation ( CF ) treating to 64 Gy in 32 fractions over 45 days . Accelerated fractionation was delivered using two fractions per day with a 6h gap between fractions and with the first daily fraction size being 1.8 Gy and the second daily fraction size being 2.0 Gy . There was a 1 week treatment gap after the first 12 fractions . Conventional fractionation was one fraction per day , 5 days per week . Eligible patients had clinical stage T2 or T3 , N0 or N1 , M0 transitional cell carcinoma . The primary endpoint of the trial was local control and the trial was powered to detect a 20 % difference ( alpha 0.05 , power 90 % ) . Secondary endpoints were toxicity and survival . RESULTS In the initial phase of the trial , r and omisation was unequal such that in total 129 patients were r and omised to accelerated fractionation and 100 to conventional fractionation . Acute toxicity was evaluable in 121 patients treated with AF and 96 patients treated with CF . RTOG grade 2 or 3 bowel toxicity was noted in 44 % of AF patients compared to 26 % of CF patients ( P trend = 0.001 ) . Acute grade 2 or 3 bladder toxicity was seen in 35 % of AF patients compared to 36 % of CF patients ( P=0.99 ) . Late radiation toxicity was evaluated in patients surviving free from local recurrence at 2 years post treatment . Late radiation toxicity equivalent to RTOG grade 2 or more had occurred in 44 % ( 95 % CI 34 - 55 % ) of AF patients and in 38 % ( 95 % CI 26 - 49 % ) of CF patients ( logrank over 5 years follow-up P=0.23 ) . There was no significant difference in analysis of time to loss of local tumour control comparing the two treatment arms ; local recurrence was recorded in 29 of the 100 patients treated with CF and in 41 of 129 patients treated with AF ( logrank P=0.86 ) . There was also no significant difference between the treatment arms comparing disease-free survival and overall survival . The overall survival figures at 3 years were for AF 54 % ( 95 % CI 45 - 63 % ) and for CF 47 % ( 95 % CI 36 - 57 % ) . By 5 years the overall survival was 37 % for AF and 40 % for CF . There were two treatment related deaths , both on the AF arm of the trial . CONCLUSIONS This accelerated fractionation schedule did not improve on the efficacy of conventional fractionation for patients with T2 and T3 bladder cancer and accelerated fractionation was associated with increased acute bowel reactions Purpose Multidisciplinary management improves complex treatment decision making in cancer care , but its impact for bladder cancer ( BC ) has not been documented . Although radical cystectomy ( RC ) currently is viewed as the st and ard of care for muscle-invasive bladder cancer ( MIBC ) , radiotherapy-based , bladder-sparing trimodal therapy ( TMT ) that combines transurethral resection of bladder tumor , chemotherapy for radiation sensitization , and external beam radiotherapy has emerged as a valid treatment option . In the absence of r and omized studies , this study compared the oncologic outcomes between patients treated with RC or TMT  by using a propensity score matched-cohort analysis . Methods Data from patients treated in a multidisciplinary bladder cancer clinic ( MDBCC ) from 2008 to 2013 were review ed retrospectively . Those who received TMT for MIBC were identified and matched ( for sex , cT and cN stage , Eastern Cooperative Oncology Group status , Charlson comorbidity score , treatment date , age , carcinoma in situ status , and hydronephrosis ) with propensity scores to patients who underwent RC .  Overall survival and disease-specific survival ( DSS ) were assessed with Cox proportional hazards modeling and a competing risk analysis , respectively . Results A total of 112 patients with MIBC were included after matching ( 56 who had been treated with TMT , and 56 who underwent RC ) . The median age was 68.0 years , and 29.5 % had stage cT3/cT4 disease . At a median follow-up of 4.51 years , there were 20 deaths ( 35.7 % ) in the RC group ( 13 as a result of BC ) and 22 deaths ( 39.3 % ) in the TMT group ( 13 as a result of BC ) . The 5-year DSS rate was 73.2 % and 76.6 % in the RC and TMT groups , respectively ( P = .49 ) . Salvage cystectomy was performed in 6 ( 10.7 % ) of 56 patients who received TMT . Conclusion In the setting of a MDBCC , TMT yielded survival outcomes similar to those of matched patients who underwent RC . Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options , including organ-sparing TMT Progress is a hallmark of human civilization . Over the past centuries , it became easier , faster and safer to travel from point A to point B , and the choices of transportation are now numerous , making it at times challenging for travelers to make their selection and forcing them to buy guidebooks , research travel websites and sometimes even contact the travel agents . Perhaps sailing was once the only way of crossing the ocean , but with advent of aviation it is no longer the case . Similarly , upfront radical surgeries were once patients ’ only hope for cure radical mastectomy for patients with breast cancer , amputation for patients with extremity sarcoma ,  laryngectomy  for patients with laryngeal cancer , radical prostatectomy for patients with prostate cancer , abdominoperineal resection  for patients with anal carcinoma . However , over the past 40 years the field of oncology has embraced organ preservation , often , but not always , through r and omized clinical trials showing equivalent outcomes with smaller surgeries and adjuvant radiation therapy , or replacement of upfront surgery with definitive chemoradiation therapy , reserving organ extirpation for salvage in case of local recurrences . The management of muscle-invasive bladder cancer ( MIBC ) is no different ( 1 ) . Stating that one treatment – such as radical cystectomy – is the best choice for most patients with a particular disease – such as muscle-invasive bladder cancer – is no different from advertising a particular mode of transportation . One treatment never fits all , and the best choice of treatment modality for an individual patient starts with a multi-disciplinary evaluation and inclusion of patients and their caregivers in the decision process . An open discussion of all issues related to radical cystectomy ( RC ) and reconstruction options on one h and , and tri-modality bladder preservation therapy with chemoradiation ( TMT ) on the other h and allows for the ultimate informed consent and highest patient satisfaction . Most discussion s of bladder preservation for MIBC are centered on two themes – efficacy and toxicity 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 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 PURPOSE Phase II clinical studies suggest that hypoxic modification with carbogen and nicotinamide ( CON ) may increase the efficacy of radiotherapy ( RT ) . PATIENTS AND METHODS Three hundred thirty-three patients with locally advanced bladder carcinoma were r and omly assigned to RT alone versus RT with CON . A schedule of either 55 Gy in 20 fractions in 4 weeks or 64 Gy in 32 fractions in 6.5 weeks was used . The primary end point was cystoscopic control at 6 months ( CC(6 m ) ) and secondary end points were overall survival ( OS ) , local relapse-free survival ( RFS ) , urinary and rectal morbidity . RESULTS CC(6 m ) was 81 % for RT + CON and 76 % for RT alone ( P = .3 ) ; however , just more than half of patients underwent cystoscopy at that time . Three-year estimates of OS were 59 % and 46 % ( P = .04 ) and 3-year estimates of RFS were 54 % and 43 % ( P = .06 ) for RT + CON versus RT alone . Risk of death was 14 % lower with RT + CON ( P = .04 ) . In multivariate comparison , RT + CON significantly reduced the risk of relapse ( P = .05 ) and death ( P = .03 ) . There was no evidence that differences in late urinary or GI morbidity between treatment groups or between fractionation schedules were significant . CONCLUSION RT + CON produced a small nonsignificant improvement in CC(6 m ) . Differences in OS , risk of death , and local relapse were significantly in favor of RT + CON .  Late morbidity was similar in both trial arms . Results indicate a benefit of adding CON to radical RT
Purpose To determine the effectiveness and harms of bladder-preserving trimodal therapy ( TMT ) as a first-line treatment versus radical cystectomy ( RC ) plus radical pelvic lymphadenectomy in the treatment of muscle-invasive bladder cancer in terms of overall survival .