Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. 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. Discrepancy between clinical staging through bimanual palpation and pathological staging after cystectomy. A sequential treatment approach to myoinvasive urothelial cancer: a phase II Southwest Oncology Group trial (S0219). Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients Concordant gene expression signatures predict clinical outcomes of cancer patients undergoing systemic therapy. Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. Neoadjuvant Cisplatin-Methotrexate Chemotherapy for Invasive Bladder Cancer - Nordic Cystectomy Trial 2 Phase II trial of paclitaxel, carboplatin and gemcitabine in patients with locally advanced carcinoma of the bladder. Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. A phase II trial of neoadjuvant erlotinib in patients with muscle‐invasive bladder cancer undergoing radical cystectomy: clinical and pathological results Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the M. D. Anderson Cancer Center. Surgical factors influence bladder cancer outcomes: a cooperative group report. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: Results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. 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). Accelerated MVAC as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder. M-CAVI, a neoadjuvant carboplatin-based regimen for the treatment of T2-4N0M0 carcinoma of the bladder. 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.
INTRODUCTION Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) adjuvant chemotherapy .  PATIENTS AND METHODS Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10 % nuclear reactivity on central ly performed immunohistochemistry for p53 were offered r and om assignment to three cycles of adjuvant MVAC versus observation ; p53-negative patients were observed . By using a log-rank test with one-sided α = .05 and β = .10 , 190 p53-positive patients were planned to be r and omly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30 . RESULTS A total of 521 patients were registered , 499 underwent p53 assessment , 272 ( 55 % ) were positive , and 114 ( 42 % ) were r and omly assigned . Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis . Overall 5-year probability of recurring was 0.20 ( 95 % CI , 0.16 to 0.24 ) with no difference on the basis of p53 status . Only 67 % of patients r and omly assigned to MVAC received all three cycles with 12 patients receiving no treatment . There was no difference in recurrence in the r and omly assigned patients ( hazard ratio , 0.78 ; 95 % CI , 0.29 to 2.08 ; P = .62 ) . CONCLUSION Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed , but the high patient refusal rate , lower than expected event rate , and failures to receive assigned therapy severely compromised study power 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 OBJECTIVES In muscle invasive bladder cancer ( MIBC ) , careful clinical staging is essential for patient counseling and decision-making . Bimanual palpation ( BP ) is an integral part and guideline advice of clinical staging . Until now , however , the value of BP has never been studied . With this study , we aim to determine the accuracy of clinical staging through BP . METHODS Detailed clinical data were collected from a population -based series of 1,409 patients with MIBC , diagnosed between 1989 and 2005 , in the region of the Comprehensive Cancer Centre East in The Netherl and s. Selected were all patients who underwent BP ( n = 738 ) . Preoperative  tumor-stage ( cT-stage ) determined through BP was compared with post-cystectomy pT-stage . Contingency tables were made to determine the correlation between cT-stage and pT-stage . RESULTS In 18 of 142 patients in whom BP showed an organ-confined tumor , the tumor was unresectable ( pT4 ) at the time of surgery . Four out of 9 patients who had a suspected T4 tumor on BP but who underwent cystectomy anyway appeared to have operable tumors at cystectomy . In 87 patients ( 57.6 % ) , accurate staging through  BP  was observed . In 17 patients ( 11.3 % ) , clinical overstaging was found , and in 47 patients , ( 31.1 % ) clinical understaging . CONCLUSIONS Frequently , pT-stage after cystectomy does not correlate with preoperative cT-stage based on BP . Discrepancy was observed in 42 % of the patients : in 11 % , clinical overstaging and in 31 % , clinical understaging . Based on these data , some caution is suggested when interpreting the outcome of BP . Prospect i ve data is needed for a more formal evaluation of the staging accuracy of BP PURPOSE We conducted a phase II trial of neoadjuvant paclitaxel , carboplatin and gemcitabine as well as transurethral resection of bladder tumor to evaluate the clinical T0 ( cT0 ) rate with paclitaxel , carboplatin and gemcitabine , and to study cystoscopic surveillance or immediate cystectomy for patients with cT0 status following chemotherapy .  MATERIAL S AND METHODS Patients with T2-T4a chemotherapy and radiation naive urothelial cancer were eligible . T2 + tumor had to be diagnosed by transurethral bladder tumor resection followed by a second transurethral bladder tumor resection to confirm persistent disease within 16 weeks of the first resection . Three cycles of paclitaxel , carboplatin and gemcitabine were administered within 8 weeks of the second transurethral bladder tumor resection . Patients with cT0 status after paclitaxel , carboplatin and gemcitabine therapy could elect immediate cystectomy or cystoscopic surveillance , and those with greater than cT0 status were to undergo immediate cystectomy . RESULTS Of 77 patients 74 were assessable , and cT0 status after paclitaxel , carboplatin and gemcitabine was achieved in 34 of 74 patients ( 46 % ) . Of the 34 patients with cT0 status 10 underwent immediate cystectomy , 6 of whom had persistent cancer . Persistent tumor at transurethral bladder tumor resection was seen in 28 patients ( 38 % ) and 21 underwent cystectomy . Thus , 35 of 74 patients underwent cystectomy . With a median followup of 22 months 2-year overall survival was 59 % ( 95 % CI 45 , 72 ) and among cT0 cases it was 75 % ( 95 % CI 57 , 93 ) . CONCLUSIONS Although neoadjuvant paclitaxel , carboplatin and gemcitabine had a promising 46 % cT0 rate , the study failed to meet the primary objective as there was an unacceptably high rate ( 60 % ) of persistent cancer at cystectomy in patients presumed to have pT0 status . Patients completing neoadjuvant chemotherapy should strongly consider definitive local therapy rather than cystoscopic surveillance regardless of post-chemotherapy cT0 status BACKGROUND Perioperative cisplatin combination chemotherapy is associated with a survival benefit in patients with invasive bladder cancer ( BCa ) . However , in a recent report from the National Cancer Data base ( NCDB ) , only 11.6 % of stage III BCa patients received perioperative chemotherapy , the majority in the adjuvant setting . OBJECTIVE We explore the impact of postoperative complications on the timing of adjuvant chemotherapy . DESIGN , SETTING , AND PARTICIPANTS An independent review board approved the review of 1142 consecutive radical cystectomies ( RC ) , and data from these cases were entered into a prospect i ve complication data base ( 1995 - 2005 ) which was utilized and retrospectively review ed for accuracy at a single , academic , tertiary cancer center . INTERVENTIONS All patients underwent RC/urinary diversion by high-volume , fellowship-trained , urologic oncologists . MEASUREMENTS All complications within 90 d of surgery were defined and grade d using a five- grade modification of the original Clavien system utilized at Memorial Sloan-Kettering Cancer Center and stratified into 11 categories . Grade 2 - 5 complications typically prohibit starting adjuvant chemotherapy . Univariate and multivariable logistic regression were used to evaluate variables associated with complications . RESULTS AND LIMITATIONS Overall , 64 % ( 735 of 1142 patients ) experienced one or more complications , of which 83 % ( 611 of 735 ) were grade 2 - 5 . Furthermore , 57 % of grade 2 - 5 complications ( 347 of 611 ) occurred between discharge and 90 d , 38 % ( 233 of 611 ) within 6 wk , and 19 % ( 114 of 611 ) between 6 wk and 12 wk , the general time frame for adjuvant chemotherapy . Overall , 26 % ( 298 of 1142 patients ) required readmission . Surgical morbidity at a high-volume tertiary cancer center may not reflect the case mix or surgical experience seen in the community setting . CONCLUSION This series demonstrates that 30 % of patients ( 347 of 1142 ) undergoing RC may not have been able to receive adjuvant chemotherapy due to postoperative complications . This information should be taken into consideration when planning multimodal therapy and further supports the use of perioperative chemotherapy in the neoadjuvant setting Significant anti-tumor responses have been reported in a small subset of cancer patients treated with the immunotherapeutic agent anti-CTLA-4 antibody .  All clinical trials to date , comprising over 3,000 patients , have been conducted in the metastatic disease setting , which allows for correlation of drug administration with clinical outcome but has limited analyses of intermediate biomarkers to indicate whether the drug has impacted human immune responses within the tumor microenvironment . We conducted a pre-surgical clinical trial in six patients with localized bladder cancer , which allowed for correlation of drug administration with biomarkers in both blood and tumor tissues but did not permit correlation with clinical outcome . We found that CD4 T cells from peripheral blood and tumor tissues of all treated patients had markedly increased expression of inducible costimulator ( ICOS ) . These CD4+ICOShi T cells produced IFN-gamma ( IFNγ ) and could recognize the tumor antigen NY-ESO-1 . Increase in CD4+ICOShi cells led to an increase in the ratio of effector to regulatory T cells . To our knowledge , these are the first immunologic changes reported in both tumor tissues and peripheral blood as a result of treatment with anti-CTLA-4 antibody , and they may be used to guide dosing and scheduling of this agent to improve clinical responses Conventional development of multivariate gene expression models  ( GEM ) predicting therapeutic response of cancer patients is based on analysis of patients treated with specific regimens , which limits generalization to different or novel drug combinations . We overcome this limitation by developing GEMs based on in vitro drug sensitivities and microarray analyses of the NCI-60 cancer cell line panel . These GEMs were evaluated in blind fashion as predictors of tumor response and /or patient survival in seven independent cohorts of patients with breast ( n = 275 ) , bladder ( n = 59 ) , and ovarian ( n= 143 ) cancer treated with multiagent chemotherapy , of which 233 patients were from prospect ively enrolled clinical trials . In all studies , GEMs effectively stratified tumor response and patient survival independent of established clinical and pathologic tumor variables . In bladder cancer patients treated with neoadjuvant methotrexate , vinblastine , Adriamycin ( doxorubicin ) , and cisplatin , the 3-year overall survival for those with favorable GEM scores was 81 % versus 33 % for those with less favorable scores ( P = 0.002 ) . GEMs for breast cancer patients treated with 5-fluorouracil , Adriamycin ( doxorubicin ) , and cyclophosphamide and ovarian cancer patients treated with platinum-containing regimens also stratified patient survival [ 5-year overall survival 100 % versus 74 % ( P = 0.05 ) and 3-year overall survival 68 % versus 43 % ( P = 0.008 ) , respectively ] . Importantly , clinical prediction using our in vitro GEM was superior to that of conventionally derived GEMs . We show a facile yet effective approach to GEM derivation that identifies patients most likely to benefit from selected multiagent therapy . Use of such in vitro-based GEMs may provide a robust and generalizable approach to personalized cancer therapy PURPOSE Neoadjuvant chemotherapy for invasive bladder cancer , involving a regimen of methotrexate , vinblastine , doxorubicin , and cisplatin ( M-VAC ) , can improve the resectability of larger neoplasms for some patients and offer a better prognosis . However , some suffer severe adverse drug reactions without any effect , and no method yet exists for predicting the response of an individual patient to chemotherapy . Our purpose in this study is to establish a method for predicting response to the M-VAC therapy . EXPERIMENTAL DESIGN We analyzed gene expression profiles of biopsy material s from 27 invasive bladder cancers using a cDNA microarray consisting of 27,648 genes , after population s of cancer cells had been purified by laser microbeam microdissection .  RESULTS We identified dozens of genes that were expressed differently between nine " responder " and nine " nonresponder " tumors ; from that list we selected the 14 " predictive " genes that showed the most significant differences and devised a numerical prediction scoring system that clearly separated the responder group from the nonresponder group . This system accurately predicted the drug responses of 8 of 9 test cases that were reserved from the original 27 cases . Because real-time reverse transcription-PCR data were highly concordant with the cDNA microarray data for those 14 genes , we developed a quantitative reverse transcription-PCR-based prediction system that could be feasible for routine clinical use . CONCLUSIONS Our results suggest that the sensitivity of an invasive bladder cancer to the M-VAC neoadjuvant chemotherapy can be predicted by expression patterns in this set of genes , a step toward achievement of " personalized therapy " for treatment of this disease 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 BACKGROUND Cisplatin-based chemotherapy is a st and ard treatment of metastatic urothelial carcinoma ( UC ) , though carboplatin-based chemotherapy is frequently substituted due to improved tolerability . Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking , a meta- analysis was carried out . METHODS PubMed was search ed for articles published from 1966 to 2010 . Eligible studies included prospect i ve r and omized trials evaluating  cisplatin- versus carboplatin-based regimens in patients with metastatic UC . Individual patient data were not available and survival data were inconsistently reported . Therefore , the analysis focused on overall response ( OR ) and complete response ( CR ) rates . The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios ( RRs ) . RESULTS A total of 286 patients with metastatic UC from four r and omized trials were included .  Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR [ RR = 3.54 ; 95 % confidence interval ( CI ) 1.48 - 8.49 ; P = 0.005 ] and OR ( RR = 1.34 ; 95 % CI 1.04 - 1.71 ; P = 0.02 ) . Survival end points could not be adequately assessed due to inconsistent reporting among trials . CONCLUSIONS Cisplatin-based , as compared with carboplatin-based , chemotherapy significantly increases the likelihood of both OR and CR in patients with metastatic UC . The impact of improved response proportions on survival end points could not be assessed A total of 83 patients with nonorgan-confined bladder cancer with or without lymph node metastases ( tumor stages pT3b , pT4a and /or pN1 , pN2 ) was evaluated in November 1993 for relapse-free and overall survival .  All patients underwent radical cystectomy between 1987 and 1991 , 38 underwent adjuvant polychemotherapy with methotrexate , vinblastine and cisplatin plus doxorubicin ( M-VAC ) or epirubicin ( M-VEC ) . Of the 83 patients 49 had entered a prospect i ve r and omized trial comparing adjuvant to no adjuvant treatment . The protocol was activated in May 1987 . Patient recruitment was concluded in December 1990 because an interim analysis of the 49 r and omized patients revealed a significant prognostic advantage in favor of the 26 patients r and omized to the chemotherapy group compared to 23 in the control group ( p = 0.0015 , log-rank test for relapse-free survival curves ) . Preliminary data were published in 1992 . Of the 26 patients r and omized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC , 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function . The up date of patient followup obtained in November 1993 continues to demonstrate a significant improvement in progression-free survival in favor of patients r and omized for adjuvant chemotherapy ( p = 0.0005 ) . Followup of patients living free of disease ranged from 38 to 78 months . In a second analysis of actual treatment , the total collective of 83 patients treated from 1987 to 1991 was review ed : 38 who had actually undergone  adjuvant M-VAC/M-VEC  ( 18 during the prospect i ve trial and 20 in 1991 as the routinely recommended therapy ) were compared with 45 without adjuvant M-VAC/M-VEC ( 7 refused to participate in the adjuvant trial , 8 r and omized for but did not undergo adjuvant M-VAC/M-VEC , 23 belonged to the control group of the trial , and 7 underwent cystectomy in 1991 and remained without adjuvant treatment ) . This analysis again revealed a significant prognostic advantage in favor of the patients treated with adjuvant M-VAC/M-VEC . We conclude that adjuvant chemotherapy with M-VAC/M-VEC leads to a significant prolongation of relapse-free survival and to an improvement of the definitive cure rates after radical cystectomy for locally advanced transitional cell carcinoma of the bladder PURPOSE We present the characteristics and outcomes of a large , contemporary , consecutive series of patients treated with radical cystectomy and pelvic lymphadenectomy for transitional cell carcinoma of the bladder . MATERIAL S AND METHODS We developed a multi-institutional data base and collected retrospective and prospect i ve data on 888 consecutive patients with bladder transitional cell carcinoma who were treated with radical cystectomy and pelvic lymphadenectomy at 3 academic centers in the United States between 1984 and 2003 . RESULTS Of the patients 25 % had extravesical tumor extension with negative lymph nodes and 23 % had lymph node metastasis . The rate of lymph node involvement increased with advancing pathological stage . Mean recurrence-free and bladder cancer specific survival + /- SE was 58 % + /- 2 % and 66 % + /- 2 % at 5 years , respectively . On preoperative multivariate analysis clinical tumor stage and neoadjuvant systemic chemotherapy were associated with cancer recurrence , while more advanced age , clinical tumor stage and preoperative carcinoma in situ were associated with bladder cancer specific mortality . On postoperative multivariate analysis pathological tumor stage , lymph node metastasis , lymphovascular invasion , adjuvant radiotherapy and adjuvant chemotherapy were associated with cancer recurrence , while higher pathological tumor stage , more advanced age , lymph node metastasis , lymphovascular invasion and adjuvant radiotherapy were associated with disease specific survival . Patients with metastasis to regional lymph nodes ( pT any N1 - 3 ) were at significantly higher risk for bladder cancer recurrence and death than patients with extravesical tumor extension ( pT3N0 ) , who in turn were at significantly higher risk than patients with organ confined disease ( pT2 N0 or less ) . CONCLUSIONS The results of this large , contemporary , multi-institutional series show that radical cystectomy and pelvic lymphadenectomy provide durable local control and disease specific survival in patients with localized invasive transitional cell carcinoma Background : In the first Nordic cystectomy trial ( 1986 - 1989 ) a chemotherapy combination of cisplatin-doxorubicin and external radiation seemed to improve the long-term survival after cystectomy in patients with stage T3-T4a bladder carcinomas . The aim of this study was to investigate if solely neoadjuvant chemotherapy could influence survival in patients with advanced urothelial bladder cancer undergoing cystectomy . Methods : The study ( 1991 - 1997 ) recruited 317 patients with T2-T4aNXM0 urothelial bladder tumours . The patients were r and omly allocated to three courses of cisplatin-methotrexate or no pretreatment before cystectomy , eight were subsequently excluded due to protocol violation . Results : Chemotherapy according to protocol was administered to 74 % ( 115/155 ) of the patients in the experimental arm . No chemotherapy related mortality was observed . Of remaining patients in the experimental arm , 14 did not receive any chemotherapy , nine discontinued after one course and 14 after two courses due to side effects . Median follow-up time among censored patients was 5.3 years . Estimated 5-year overall survival was 53 % in the experimental arm and 46 % in the control arm ( n.s . log-rank test ) . The proportion of patients with pathological stage pT0 was 26.4 % in the experimental arm and 11.5 % in the control arm ( p = 0.001 ) . Risk of locoregional relapse and distant metastases was similar in the study arms . Conclusions : The chemotherapy regimen was well tolerated . Despite substantial downstaging no statistically significant survival benefit with the neoadjuvant therapy could be seen after 5 years of follow-up PURPOSE This 2-arm phase II multicenter trial was design ed to assess the efficacy and toxicity of neoadjuvant paclitaxel , gemcitabine and carboplatin in patients with invasive bladder cancer . MATERIAL S AND METHODS Patients in arm I had clinical stage T2 with hydronephrosis or T3 bladder cancer . They received 3 cycles of chemotherapy ( 200 mg/m(2 ) paclitaxel on day 1 , AUC 5 carboplatin on day 1 , and 800 mg/m(2 ) gemcitabine on days 1 and 8 of each 21-day cycle ) . Response was defined as achievement of a pathological complete response ( pT0 ) . Patients in arm II with T4 or lymph node positive disease received up to 6 cycles of paclitaxel , carboplatin and gemcitabine . Response was defined as conversion to surgical resectability . RESULTS In arm I , 31 patients were enrolled and 22 were evaluable for response . Seven patients had pT0 disease ( 32 % of evaluable patients , 22 % by intent to treat ) . In arm II , 37 patients were enrolled and 29 were evaluable for response with 24 suitable for surgical resection ( 83 % of evaluable and 65 % by intent to treat ) . The most common toxicity was neutropenia with 39 events in arm I and 68 in arm II . There were 7 deaths on study ( 5 during chemotherapy and 2 after cystectomy ) . CONCLUSIONS Neoadjuvant paclitaxel , carboplatin and gemcitabine result ed in a significant number of responses in both arms but greater than anticipated toxicity . The pT0 rate was modest and overall efficacy was difficult to assess due to the toxicity . More studies of novel agents and combinations are needed to improve the efficacy and reduce the toxicity of neoadjuvant therapy for bladder cancer PURPOSE Novel imaging modalities are needed to detect occult metastatic disease in bladder carcinoma . Patients with regional lymphatic spread could be targeted for neoadjuvant chemotherapy , and patients with distant metastatic disease could be spared the unnecessary morbidity of radical cystectomy . Herein , we report a prospect i ve study of positron emission tomography/computed tomography ( PET/CT ) with [(18)F]fluorodeoxyglucose ( FDG ) in patients undergoing radical cystectomy for cT2 - 3N0M0 urothelial carcinoma of the bladder . METHODS Forty-three chemotherapy-naïve patients underwent FDG-PET/CT before planned cystectomy . All had negative conventional CT and bone scintigraphy before enrollment . Positive FDG-PET/CT was confirmed by percutaneous biopsy or open surgical exploration , whereas negative FDG-PET/CT was confirmed by complete lymphadenectomy . Recurrence-free survival ( RFS ) , disease-specific survival ( DSS ) , and overall survival ( OS ) were described using the Kaplan-Meier method and compared using log-rank test . RESULTS Median follow-up was 14.9 months ( range , 0.4 to 46.1 months ) . One patient who did not undergo lymphadenectomy was excluded from the pathology data analysis ( n = 42 ) , whereas another patient who failed to return for follow-up was excluded from survival analysis ( n = 42 ) . FDG-PET/CT demonstrated a positive predictive value of 78 % ( seven of nine ) , a negative predictive value of 91 % ( 30 of 33 ) , sensitivity of 70 % ( seven of 10 ) , and specificity of 94 % ( 30 of 32 ) . RFS , DSS , and OS were all significantly poorer in the patients with positive FDG-PET/CT than in those with negative FDG-PET/CT . CONCLUSION FDG-PET/CT detected occult metastatic disease in seven of 42 patients with negative conventional preoperative evaluations . PET findings were strongly correlated with survival . As such , FDG-PET/CT may help in making treatment decisions before radical cystectomy PURPOSE Studies of perioperative chemotherapy for muscle invasive bladder cancer have shown a survival benefit with combined modality therapy . We review ed chemotherapy use in patients with stage III transitional cell carcinoma of the bladder from 1998 to 2003 to evaluate perioperative chemotherapy treatment patterns . MATERIAL S AND METHODS The National Cancer Data Base collected data on approximately 60 % of all newly diagnosed bladder cancer cases in the United States from 1998 to 2003 . We queried the National Cancer Data Base for all treatment of male and female patients 18 years old or older with bladder transitional cell carcinoma diagnosed between 1998 and 2003 . A total of 224,060 bladder transitional cell carcinoma records were review ed .  Perioperative chemotherapy was defined as chemotherapy given within 4 months before and 4 months after surgery . Of 11,339 cases of stage III bladder cancer treatment , analysis was possible for 7,161 . RESULTS Treatment patterns were analyzed in 7,161 patients with stage III bladder transitional cell carcinoma .  Perioperative chemotherapy was administered to 11.6 % of patients with stage III bladder transitional cell carcinoma with 10.4 % receiving adjuvant chemotherapy and 1.2 % receiving neoadjuvant chemotherapy . When comparing  perioperative chemotherapy use by diagnosis year in 1998 and 2003 , a small statistically significant increase was observed using the Pearson 's chi-square test with Bonferroni correction ( p < 0.05 ) at 11.3 % of patients in 1998 vs 16.8 % in 2003 . CONCLUSIONS Perioperative chemotherapy is underused in the management of surgically resectable stage III transitional cell carcinoma of the bladder . This finding may reflect a delay in implementing the results of recently reported r and omized trials , a low incidence of referrals by urologists for chemotherapy and /or confidence in salvage chemotherapy as an equivalent alternative . Further followup will determine if this treatment pattern changes in the future Study Type – Therapy ( cohort ) Level of Evidence 2b 261 Background : DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer ; however , there is no prospect i ve data on its use in the neoadjuvant setting . Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients , leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes . METHODS Between 8/07 and 12/10 , 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospect i ve phase II clinical trial . Eligibility requirements included at least one of the following : 3-D mass on EUA ( cT3b disease ) , LVI , hydronephrosis , micropapillary features , tumor in a diverticula , and for upper tract tumors a high grade tumor or radiographically measurable sessile mass . The primary endpoint was pathologic down-staging to < = pT1N0M0 . RESULTS Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled .  Pathologic down-staging to < = pT1N0M0 occurred in 53 % of patients overall ( bladder/urethra 45 % , upper tract 75 % ) , and to < = pT0N0M0 in 38 % overall ( bladder/urethra 39 % , upper tract 38 % ) . At a median follow-up of 21 months , the 2-year OS and DSS was 78 % and 85 % , respectively ( bladder 2-yr OS and DSS 75 % , 82 % ; upper tract 93 % , 93 % ) . The median OS and DSS have not yet been reached . The most common grade 3 or greater toxicity was neutropenia in 27 % of patients , followed by fatigue in 10 % . The following grade 3 toxicities were observed in < 10 % of patients : mucositis , DVT/PE , hypertension , nausea/vomiting , thrombocytopenia . One patient experienced cardiac ischemia . CONCLUSIONS Neoadjuvant chemotherapy leads to pathologic down-staging in 45 % of patients with bladder cancer .  DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting . Although bevacizumab did not impact down-staging based upon historical expectations , determining the effect on recurrence requires longer follow-up PURPOSE A r and omized , cooperative group trial ( Southwest Oncology Group 8710 , Intergroup 0080 ) reported that neoadjuvant chemotherapy improved the survival of patients with locally advanced bladder cancer who were treated with radical cystectomy .  We evaluated whether surgical factors from patients enrolled onto the study predicted bladder cancer outcomes . PATIENTS AND METHODS Surgical and tumor factors were recorded from surgical and pathologic reports from 268 patients with muscle-invasive bladder cancer who received radical cystectomy . Cystectomies were performed by 106 surgeons in 109 institutions . Half of the patients received neoadjuvant methotrexate , vinblastine , doxorubicin , and cisplatin ( MVAC ) chemotherapy . Variables were tested in univariate and multivariate analyses for associations with postcystectomy survival ( PCS ) and local recurrence ( LR ) in all patients receiving cystectomy . RESULTS Five-year PCS and LR rates were 54 % and 15 % , respectively . A multivariate model adjusted for MVAC ( P = .97 ) , age ( P = .03 ) , pathologic stage ( P = .0002 ) , and node status ( P = .04 ) showed that surgical variables associated with longer PCS were negative margins ( v positive ; hazard ratio [ HR ] , 0.37 ; P = .0007 ) , and > or = 10 nodes removed ( v < 10 ; HR , 0.51 ; P = .0001 ) . These associations did not differ by treatment arms ( P > .21 for all tests of interactions between treatment and surgical variables ) . Predictors of LR in a multivariate model adjusted for MVAC ( P = .16 ) , pathologic stage ( P = .02 ) , and node status ( P = .37 ) were positive margins ( v negative ; odds ratio [ OR ] , 11.2 ; P = .0001 ) and fewer than 10 nodes removed ( v > or = 10 ; OR , 5.1 ; P = .002 ) . CONCLUSION Surgical factors influence bladder cancer outcomes after cystectomy , after adjustment for pathologic factors and neoadjuvant chemotherapy usage LBA4518 Background : Approximately half of patients with resected invasive bladder cancer will die within the first three years after surgery due to disease relapse , most of the recurrences being systemic . We have studied in a r and omized phase III trial the role of 4 courses of the PGC triplet as compared to observation in this clinical setting . METHODS Eligibility criteria included : ( 1 ) resected high-risk muscle invasive bladder carcinoma ( pT3 - 4 and /or pN+ ) , ( 2 ) ECOG PS 0 - 1 , ( 3 ) adequate renal function ( CrCl > 50 ml/min ) , ( 4 ) ≤ 8 weeks post-cystectomy , ( 5 ) no relevant co-morbidities , and ( 6 ) signed informed consent . Eligible patients were assigned to observation or 4 courses of PGC ( P 80 mg/m2 d1 and 8 , G 1000 mg/m2 d1 and 8 and C 70 mg/m2 d1 ) q21 days . The primary objective was overall survival ( OS ) . RESULTS The study was open in July 2000 and prematurely closed due to poor recruitment in July 2007 , with 142 patients r and omized ( 74 to observation and to 68 to PGC treatment ) . Baseline characteristics were well balanced among study arms . Median age was 63 yrs , pT3 - 4N0 : 44 % , anyTpN+:56 % , PS 0 : 59 % , median time cystectomy-r and omization : 48 days ( 14 - 91 ) . In the PGC arm 76 % of pts completed all 4 courses of therapy . Main Gr 3 - 4 toxicities were neutropenia 41 % , febrile neutropenia 8 % , thrombocytopenia 14 % , anemia 5 % , fatigue 14 % , alopecia 10 % , vomiting 8 % , renal 5 % . There was one toxic death ( sepsis ) . At a median follow up of 30 months ( range 1 - 95 ) , 69 patients have died ( 45 in control arm and 24 in PGC arm ) . OS ( ITT population ) was significantly prolonged in the PCG arm ( median NR ; 5yr OS : 60 % ) compared to observation ( median 26 m ; 5yr OS : 31 % ) ( p<0.0009 ) . DFS ( p<0.0001 ) , TTP ( p<0.0001 ) and disease specific survival ( p<0.0002 ) were also superior in the PGC arm . CONCLUSIONS The results of this study strongly suggest  that adjuvant PGC  improves OS and DFS following cystectomy in high risk invasive bladder cancer . As the study was prematurely closed , the power for firm conclusions is however limited . [ Table : see text ] We assigned 91 patients with deeply invasive , pathological stage P3 , P4 or N+ and Mo transitional cell carcinoma of the bladder ( with or without squamous or gl and ular differentiation ) to adjuvant chemotherapy or to observation after radical cystectomy and pelvic lymph node dissection .  For most patients chemotherapy was planned as 4 courses at 28-day intervals of 100 mg./M.2 cisplatin , 60 mg./M.2 doxorubicin and 600 mg./M.2 cyclophosphamide . A significant delay was shown in the time to progression ( p = 0.0010 ) with 70 % of the patients assigned to chemotherapy free of disease at 3 years compared to 46 % in the observation group . Median survival time for patients in the chemotherapy group was 4.3 years compared to 2.4 years in the observation group ( p = 0.0062 ) . In addition to treatment groups , important prognostic factors included age , gender and lymph node status . The number of involved lymph nodes was the single most important variable . We recommend adjuvant chemotherapy for patients with invasive transitional cell carcinoma after definitive surgical resection PURPOSE Chemotherapy is widely used in patients with locally advanced bladder cancer but until now there has been no conclusive evidence that this therapy improves survival . The Nordic Cooperative Bladder Cancer Study Group conducted a r and omized phase III study to assess the possible benefit of neoadjuvant chemotherapy in patients with bladder cancer undergoing radical cystectomy after short-term radiotherapy . MATERIAL S AND METHODS Our trial included 325 patients with locally advanced stage T1 grade 3 or stages T2 to T4aNXM0 bladder cancer allocated r and omly into a chemotherapy or no chemotherapy group ( control ) . The chemotherapy schedule consisted of 2 cycles of 70 mg./m.2 cisplatin and 30 mg./m.2 doxorubicin with a 3-week interval between the cycles . RESULTS After 5 years the overall survival rate was 59 % in the chemotherapy group and 51 % in the control group ( p = 0.1 ) . The corresponding cancer specific survival rate was 64 and 54 % , respectively . In regard to treatment , no difference was observed for stages T1 and T2 disease , while there was a 15 % difference in overall survival for patients with stages T3 to T4a disease ( p = 0.03 ) . In a multivariate analysis only chemotherapy and T category emerged as independent prognostic factors . The relative death risk for patients who received chemotherapy was 0.69 ( 95 % confidence interval 0.49 to 0.98 ) compared to the control group after adjustment for the other tested factors . CONCLUSIONS Neoadjuvant chemotherapy seems to improve long-term survival after cystectomy in patients with stages T3 to T4a bladder carcinoma , while no survival benefit was found for stages T1 to T2 disease 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 235 Background : Meta- analysis data demonstrate a 5 % absolute survival benefit for the use of neoadjuvant chemotherapy ( NAC ) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer ( MIBC ) . However , there is currently no r and omized controlled trial data on the optimum regimen for this setting . Accelerated MVAC ( AMVAC ) is effective in advanced disease , and has the potential advantage over other NAC regimens of minimising delays to definitive , potentially curative therapy . We present data regarding its use as NAC in MIBC patients . METHODS Retrospective analysis was performed on all 80 consecutive patients with muscle-invasive transitional cell carcinoma of the bladder , treated during a 50-month period at 2 U.K. centers . Patients received either 3 or 4 cycles of methotrexate 30mg/m2 , vinblastine 3mg/m2 , doxorubicin 30mg/m2 and 4-hour infusion of cisplatin 70mg/m2 at 2-week intervals , with G-CSF support , prior to definitive therapy with either radical surgery ( RS ) or radical radiotherapy ( RT ) . RESULTS All planned cycles of chemotherapy were completed in 84 % of patients . All 80 patients received their planned definitive therapy . Pathological complete response ( pCR ) was seen in 43 % of 60 patients treated with surgery following chemotherapy . There were no chemotherapy-related deaths and grade 3 or 4 toxicities were seen in 11 % of patients . Median duration of chemotherapy was 34 days . Dose reduction or delay was required in 7 % and 9 % of patients , respectively . Objective radiological local response was seen in 75 % of patients . At a median follow-up of 27.5 months , 25 ( 32 % ) patients have relapsed and 11 ( 14 % ) died . Two-year disease-free survival was 65 % overall , and was statistically significantly superior in patients who were radiologically node-negative prior to chemotherapy . CONCLUSIONS AMVAC is a safe , well-tolerated , and easily deliverable regimen with excellent treatment outcomes and minimizes delays to definitive treatment . It is an appropriate comparator for future r and omized trials . No significant financial relationships to disclose Carboplatin , methotrexate , and vinblastine ( M-CAVI ) is an active and well-tolerated regimen for bladder cancer patients ineligible for cisplatin-based regimens . We treated 47 T2 - 4 N0 M0 bladder cancer patients with M-CAVI in a neoadjuvant phase II trial . These 47 patients are evaluable for clinical response and toxicity . Clinical overall response rate was 34 % , for a 95 % confidence interval ( CI95 % ) of 21 - 49 % . Pathological response was seen in 40 % of the patients ( CI95 % , 26 - 56 % ) with a 26.5 % rate of pathological complete response ( CI95 % , 15 - 42 % ) . Factors associated with the achievement of a response to therapy were the initial TNM stage ( pT3a or lower , greater than pT3a , p = 0.001 ) and a Karnofsky score greater or equal than 90 % , which was marginally significant ( p = 0.08 ) . With a median follow-up of 14 months , the disease-specific actuarial survival at 2 years is 42 % . No patient has relapsed beyond 21 months of follow-up in a disease-free status . Toxic effects have been moderate . In conclusion , M-CAVI is an active and well-tolerated regimen that should be compared in terms of response rate and survival with a cisplatin-based regimen for invasive bladder cancer 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
CONTEXT Muscle-invasive bladder cancer ( MIBC ) is a disease with a pattern of predominantly distant and early recurrences .
Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC .
OBJECTIVE To review the data supporting perioperative chemotherapy and emerging regimens for MIBC .