Treatment disparities in muscle-invasive bladder cancer: Evidence from a large statewide cancer registry

ObjectiveTo identify patient-level factors that can lead to treatment disparities for muscle invasive bladder cancer, we examine factors associated with receipt of definitive therapy, type of definitive therapy, and neoadjuvant chemotherapy administration in a statewide cohort of muscle-invasive bladder cancer patients.Materials and methodsWe identified 2,434 patients diagnosed with non-metastatic muscle-invasive bladder cancer between 2010 and 2015 using the Pennsylvania Cancer Registry. We divided the cohort into three subsamples to examine receipt of treatment: definitive therapy among all muscle-invasive bladder cancer patients (n = 1548), cystectomy (n = 1254) vs. trimodal therapy (n = 294), and neoadjuvant chemotherapy among radical cystectomy patients (n = 1156). Multivariable logistic regression models controlling for patient-level covariates, including insurance status, and socioeconomic disadvantage (based on Area Deprivation Index from census tract data) were estimated to examine factors associated with each treatment outcome.ResultsOnly 64% of muscle-invasive bladder cancer patients underwent definitive therapy. Those receiving trimodal therapy were more likely to be covered by Medicare than those undergoing cystectomy. Uninsured patients were less likely to undergo definitive treatment and Medicare-insured patients were less likely to undergo cystectomy as their definitive therapy. Patients with greater socioeconomic disadvantage were less likely to receive definitive treatment, undergo cystectomy, or receive neoadjuvant chemotherapy. Over the course of the study period, there was increased neoadjuvant chemotherapy use, but a persistent gap by neighborhood socioeconomic status.ConclusionsSocioeconomic disadvantage and insurance status are patient-level factors associated with suboptimal treatment for muscle-invasive bladder cancer.     

Current Value of Neoadjuvant Chemotherapy Prior to Cystectomy

ContextRadical cystectomy with a pelvic lymph node dissection is considered the most effective treatment option today for patients with muscle-invasive bladder cancer. Unfortunately, in spite of some progress, disease-specific survival rates after cystectomy have not dramatically changed in the last few decades. The significant risk of distant failure indicates that additional systemic treatment is mandatory.ObjectiveThe primary objective of the review was to summarize the data about the benefit of neoadjuvant systemic chemotherapy before cystectomy for muscle-invasive bladder cancer.Evidence acquisitionThe papers evaluating cystectomy cohorts were analyzed including a thorough analysis of treatment failures. The papers presenting prospective randomized trials and meta-analyses on neoadjuvant chemotherapy in bladder cancer were critically reviewed.Evidence synthesisThe rationale for chemotherapy before cystectomy is to treat micrometastases beyond the margins of local therapy already present at the time of diagnosis of invasive bladder cancer. Results of prospective randomized trials indicate survival benefit after neoadjuvant platinum-based combination chemotherapy. To improve the interpretation of data from prospective randomized trials, several meta-analyses were conducted. The most recent meta-analysis, published in 2005, evaluated the individual data from 3005 patients enrolled in 11 prospective controlled trials that compared neoadjuvant chemotherapy plus local treatment with local treatment alone. The data comprised 98% of all patients from known eligible randomized controlled trials. The analysis found significant survival benefit associated with platinum-based combination chemotherapy. It was equivalent to a 5% absolute improvement in overall survival (p = 0.003) and a 9% improvement in disease-free survival (p < 0.0001) at 5 yr.ConclusionsRadical cystectomy with pelvic lymph node dissection remains the standard treatment for muscle-invasive bladder cancer. The quality of surgery is essential for optimal treatment results. The data from prospective randomized trials and meta-analyses provide support for preoperative application of platinum-based combination chemotherapy in all patients.     

Cisplatin-resistant bladder carcinoma cells: enhanced expression of metallothioneins

Cisplatin is one of the most potent cytotoxic drugs and in chemotherapy has ameliorated numerous tumors. Nevertheless, resistance to cisplatin is a problem that is encountered in the chemotherapy of urologic tumors, especially transitional cell carcinomas. In order to improve definition of the mechanisms of cisplatin-resistance we established a series of cisplatin-resistant sublines from the cell line RT 112 in increasing concentrations of cisplatin. The most resistant subline CP3 is approximately 10 times more resistant than the parental line and shows a 10-fold cross-resistance against methotrexate, whereas vinblastine and doxorubicin are equally effective in the parental and sublines. Combined treatment of CP3 cells with cisplatin and buthionine sulfoximine (BSO) does not result in enhanced cell kill, thereby ruling out glutathione as a resistance mechanism. However, in comparison with parental cells, CP3 cells are about 1.5 times more resistant against cadmium. On the protein level, the cisplatin-resistant cells reveal an enhanced expression of metallothionein II (MTII), but not MTI, suggesting that the cisplatin resistance we observed in these sublines is at least partly mediated by MTII. These sublines will in the future serve as valuable tools for the analysis of cisplatin resistance, especially in view of metallothionein-mediated resistance mechanisms. Received: 25 February 1998 / Accepted: 15 July 1998     

Venous thromboembolism risk in patients receiving neoadjuvant chemotherapy for bladder cancer

IntroductionThere is limited evidence to inform thromboprophylaxis use for patients receiving neoadjuvant chemotherapy prior to surgery in bladder cancer. We sought to determine the incidence of venous thromboembolism (VTE) in patients receiving neoadjuvant chemotherapy and cystectomy. We also assessed if the Khorana score was associated with VTE risk.MethodsA retrospective cohort study was performed on consecutive patients who received a radical cystectomy for bladder cancer at The Ottawa Hospital between January 2016 and August 2020. Demographic information, chemotherapy data, operative characteristics, VTE and bleeding outcomes were collected from the start of treatment to 90 days postoperative. A Khorana score was calculated for each patient who received neoadjuvant chemotherapy. The primary outcome for this study was the incidence of VTE from the time the patient started treatment with neoadjuvant chemotherapy until 90 days post-cystectomy. Secondary outcomes included risk factors for VTE during neoadjuvant chemotherapy.ResultsAmong 181 radical cystectomy cases during the study period, 123 had muscle-invasive disease and 72 (39.8%) received neoadjuvant chemotherapy. Eighteen (25.0%) patients who received neoadjuvant chemotherapy and radical cystectomy developed a VTE from the start of chemotherapy to 90 days postoperative. Thirteen of the 18 VTEs (72%) occurred while the patient was receiving chemotherapy. In multivariable analysis, the only factor associated with a significantly increased risk of VTE was treatment with neoadjuvant chemotherapy (Relative risk (RR) 3.05, 95% confidence interval [CI] 1.16–8.02; P = 0.02). A higher Khorana score was not associated with an increased risk of VTE in patients who received neoadjuvant chemotherapy (RR = 0.33, 95% CI 0.08–1.28, P = 0.11). One (1.4%) patient had a major bleeding event during neoadjuvant chemotherapy.ConclusionsPatients receiving neoadjuvant chemotherapy and radical cystectomy are at very high-risk of VTE. Prospective studies that assess the benefits and harms of pharmacologic thromboprophylaxis in this population are needed.     

D2-40/podoplanin expression in cancer stroma by immunohistochemical staining is associated with poor prognosis in bladder cancer patients after radical cystectomy

ObjectivesWe assessed whether D2-40/podoplanin (PDPN) could be used to identify bladder cancer patients with a higher probability of benefiting from cisplatin-based combination chemotherapy.Patients and methodsWe investigated PDPN expression by immunohistochemical analysis of cystectomy specimens from 96 bladder cancer patients who had undergone radical cystectomy without neoadjuvant or adjuvant cisplatin-based combination chemotherapy until recurrence. We classified the cases into 2 groups according to the achievement of 2-year recurrence-free survival (RFS) and evaluated whether PDPN expression was associated with patient prognosis. We also classified the 96 cases into 3 groups according to the possible need for perioperative chemotherapy based on the response to chemotherapy after recurrence as “unnecessary” (achieving 2-year RFS), “responder” (recurring within 2 years and responding to chemotherapy after recurrence), and “non-responder” (not responding chemotherapy following recurrence) and compared PDPN expression between these groups.ResultsAmong 13 cases diagnosed with clinically <T2 disease, all 13 cases achieved 2-year RFS. Only 6 (8.7%) and 9 cases (13.0%) were classified as “responders” and “non-responders,” respectively, out of 69 cases with clinical T2 or higher disease who received cisplatin-based chemotherapy after recurrence. We identified PDPN expression in cancer stroma cells were morphologically fibroblasts, but not in cancer cells. Cases with <1% PDPN staining positivity ratios showed significantly better prognosis compared to that in cases with ≧1% (log-rank tests). Moreover, the positive predictive value and specificity of a <1% PDPN positive staining ratio were 89.5% and 86.7%, respectively, for “unnecessary” perioperative chemotherapy in the 69 cases.ConclusionOur results confirmed that cisplatin-based perioperative chemotherapy is unnecessary in many cases requiring radical cystectomy. To our knowledge, this is the first report of PDPN expression in bladder cancer stroma cells that are morphologically fibroblasts. Although PDPN expression might be associated with poor prognosis after surgery, we did not find that it helped to predict chemotherapy response. Whether PDPN expression by fibroblasts in high-risk bladder cancer cases is a marker for prognosis after radical cystectomy and response to perioperative cisplatin-based chemotherapy to avoid unnecessary chemotherapy warrants further investigation.     

MiR-486-5p enhances cisplatin sensitivity of human muscle-invasive bladder cancer cells by induction of apoptosis and down-regulation of metastatic genes

ObjectivesCisplatin is one of the common chemotherapy drugs for bladder cancer, and resistance to this drug is one of the major obstacles to effective chemotherapy. MicroRNAs (miRNAs) are a category of small noncoding RNAs that can regulate the expression of numerous genes. Recent studies showed that miRNAs can act as a powerful regulator of chemo-sensitivity in cancer cells. Hence, this study aimed to investigate the effects of miRNA-486-5p on cisplatin-sensitivity of different bladder cancer cells.Material and MethodsThe 5637 and EJ138 cancer cells were treated with miRNA-486-5p and cisplatin, individually or in combination.ResultsAfterward, the cytotoxicity effects of these treatments were determined by MTT assay and the increased cisplatin-sensitivity observed in both cell lines, especially, 5637 cells. Moreover, subG1 phase cell cycle arrest, changes in the expression of caspase-9, caspase-3, P53, SIRT1, OLFM4, SMAD2, and Bcl-2 genes and nuclear fragmentation also revealed the induction of apoptosis in all treatments, which increased in combination groups. Also, the combination of miRNA-486-5p with cisplatin significantly down-regulated the expression of migration associated genes including ROCK, CD44, and MMP-9 as compared with cisplatin alone.ConclusionAltogether, these results indicated that the miRNA-486-5p could induce apoptosis and inhibit cell migration ability of the cells. It seems that pre-electroporation of cells with miRNA-486-5p has useful results in the enhancement of cisplatin sensitivity of 5637 and EJ138 cancer cells and this combination may be a promising treatment strategy for bladder cancer therapy.     

Low ERCC1 expression is associated with prolonged survival in patients with bladder cancer receiving platinum-based neoadjuvant chemotherapy

PurposeExcision repair cross-complementation group 1 enzyme (ERCC1) plays a key role in the removal of platinum induced DNA adducts and cisplatin resistance. Prognostic role of ERCC1 expression in the neoadjuvant setting in bladder cancer has not been reported before. We evaluated the prognostic role of ERCC1 expression in bladder cancer receiving platinum-based neoadjuvant chemotherapy.Materials and methodsThirty-eight patients with muscle invasive bladder cancer who received neoadjuvant platinum-based chemotherapy were included. Clinical and histopathologic parameters along with immunohistochemical ERCC1 staining were examined and correlated with response rates and survival.ResultsPathologic complete response rates were similar between patients with low and high ERCC1 expression. Median disease-free survival (DFS) was 9.3 vs. 20.5 months (P = 0.186) and median overall survival (OS) was 9.3 vs. 26.7 months (P = 0.058) in patients with high ERCC1 expression compared with those with low expression, respectively. In multivariate Cox regression analysis: pathological complete response (pCR) after chemotherapy (hazard ratio (HR) 0.1, 95% CI 0.012–0.842, P = 0.034) and high ERCC1 expression (HR 3.7, 95% CI 1.2–11.2, P = 0.019) were significantly associated with DFS. Patient age (>60 vs. ≤60 years) (HR 3.4, 95% CI 1.2–9.4, P = 0.018), the presence of pCR (HR 0.11, 95% CI 0.014–0.981, P = 0.048) and high ERCC expression (HR 6.1, 95 CI 1.9–19.9, P = 0.002) were significantly associated with OS.ConclusionsOur results showed that high ERCC1 expression was independently associated with shorter disease-free and overall survival in patients with bladder cancer who received neoadjuvant platinum-based chemotherapy. ERCC1 may represent a potential predictive marker for platinum-based treatment in bladder cancer.     

Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder

PurposeTo assess whether Bcl-2, an inhibitor of the apoptotic cascade, can predict response to neoadjuvant chemotherapy in patients with urothelial cancer of the bladder (UCB).MethodsBcl-2 expression was analyzed in 2 different tissue microarrays (TMAs). One TMA was constructed of primary tumors and their corresponding lymph node (LN) metastases from 152 patients with chemotherapy-naive UCB treated by cystectomy and pelvic lymphadenectomy (chemotherapy-naive TMA cohort). The other TMA was constructed of tumor samples obtained from 55 patients with UCB before neoadjuvant chemotherapy (transurethral resection of the bladder cancer) and after cystectomy with pelvic lymphadenectomy (residual primary tumor [ypT+], n = 38); residual LN metastases [ypN+], n = 24) (prechemotherapy/postchemotherapy TMA cohort). Bcl-2 overexpression was defined as 10% or more cancer cells showing cytoplasmic immunoreactivity.ResultsIn both TMA cohorts, Bcl-2 overexpression was significantly (P<0.05) more frequent in LN metastases than in primary tumors (chemotherapy-naive TMA group: 18/148 [12%] in primary tumors vs. 39/143 [27%] in metastases; postchemotherapy TMA: ypT+7/35 [20%] vs. ypN+11/19 [58%]). In the neoadjuvant setting, patients with Bcl-2 overexpression in transurethral resection of the bladder cancer specimens showed significantly (P = 0.04) higher ypT stages and less regression in their cystectomy specimens than did the control group, and only one-eighth (13%) had complete tumor regression (ypT0 ypN0). In survival analyses, only histopathological parameters added significant prognostic information.ConclusionsBcl-2 overexpression in chemotherapy-naive primary bladder cancer is related to poor chemotherapy response and might help to select likely nonresponders.     

Do mixed histological features affect survival benefit from neoadjuvant platinum‐based combination chemotherapy in patients with locally advanced bladder cancer? A secondary analysis of Southwest Oncology Group‐Directed Intergroup Study (S8710)

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? In a meta‐analysis of randomized trials, neoadjuvant platinum‐based combination chemotherapy administered before definitive local treatment improved survival of patients with muscle‐invasive bladder cancer compared with definitive local treatment alone. However, it was not known whether chemotherapy was equally effective for pure urothelial carcinoma versus urothelial carcinoma with mixed histological features, such as squamous or glandular differentiation. To address this question we performed a secondary analysis of the Southwest Oncology Group‐directed intergroup randomized trial S8710 of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone for treatment of locally advanced urothelial cancer of the bladder. Our findings suggest that presence of squamous or glandular differentiation does not confer resistance to combination chemotherapy with MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.

OBJECTIVE

? To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of non‐urothelial components in the tumour.

PATIENTS AND METHODS

? This is a secondary analysis of the Southwest Oncology Group‐directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder. ? For the purpose of these analyses, tumours were classified based on the presence of non‐urothelial components as either pure UC (n= 236) or mixed tumours (n= 59). Non‐urothelial components included squamous and glandular differentiation. ? Cox regression models were used to estimate the effect of neoadjuvant MVAC on all‐cause mortality for patients with pure UC and for patients with mixed tumours, with adjustment for age and clinical stage.

RESULTS

? There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25–0.87; P= 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67–1.21; P= 0.48). ? There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P= 0.09).

CONCLUSION

? Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy.     

Update on chemotherapy for advanced bladder cancer

PURPOSE: Recent years have seen several advances in the treatment of locally advanced and metastatic bladder cancer. We summarize the current state of the art for advanced bladder cancer treatment. MATERIALS AND METHODS: A comprehensive review of published, prospective phase II/III clinical trials and retrospective analyses of patients with advanced bladder cancer was performed. RESULTS: Adjuvant and neoadjuvant chemotherapeutic strategies around the time of radical cystectomy have been used to decrease the risk of subsequent metastatic disease. Although the benefit of adjuvant chemotherapy remains unproven, neoadjuvant chemotherapy is associated with a modest 5% to 6% absolute survival benefit in 2 meta-analyses of the available data. Chemoradiation is feasible and effective in some patients, allowing bladder preservation with an acceptable risk of progression. Randomized, phase III data comparing methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy to gemcitabine/cisplatin showed similar response proportions and overall survival with less toxicity in the gemcitabine/cisplatin arm. This has led to the widespread use of gemcitabine/cisplatin as first line chemotherapy for metastatic bladder cancer. The optimal agents and regimens for second line chemotherapy remain undefined. Similarly biological and targeted therapies for advanced bladder cancer remain investigational. CONCLUSIONS: Combination cisplatin based neoadjuvant chemotherapy may benefit patients with locally advanced bladder cancer. Gemcitabine/cisplatin has replaced methotrexate, vinblastine, doxorubicin and cisplatin as the regimen of choice in patients with good renal function. The optimal regimens for the medically unfit patient and second line chemotherapy remain undefined. The development of targeted therapies, less toxic regimens and improved cytotoxic agents are necessary to improve outcomes.     

Urothelial carcinoma in situ response to cisplatin-based neoadjuvant chemotherapy,or lack thereof: Impact on patient selection for organ preservation in muscle-invasive disease?

IntroductionNeoadjuvant cisplatin-based chemotherapy (NACT) followed by radical cystectomy improves urothelial bladder cancer survival [1]. Complete pathological response on cystectomy pathology (pT0N0) is associated with the best survival outcomes [2]. Rates of complete response have increased with improved adoption of NACT calling into question the need for radical cystectomy or perhaps use of organ preservation protocols. In patients with papillary bladder tumors, carcinoma in situ (CIS) has been shown to influence progression and develop into invasive urothelial carcinoma [3]. Furthermore, in patients with invasive urothelial carcinoma, concurrent CIS has been reported in roughly 45% to 65% of cases [4]. Thus, we sought to determine the response rate of CIS to NACT to determine if the presence of CIS should factor into excluding patients from organ preservation.MethodsA review of our prospectively maintained bladder cancer database was performed among patients undergoing preoperative cisplatin-based chemotherapy followed by cystectomy between 2007 and 2017. Presence of CIS before and after radical cystectomy was assessed. Random bladder biopsies or transurethral resection (TUR) with enhanced imaging for CIS (Cysview) were not routinely utilized in the preoperative setting.ResultsOne-hundred eighty-three patients were identified that underwent preoperative cisplatin chemotherapy. A total of 96 (52.4%) unique patients had documented CIS in the entire cohort. Forty-eight (50%) patients were noted to have CIS on TUR. Of these 48 patients, 26 (54.1%) were noted to have residual CIS on final pathology. An additional 48 patients were found to have CIS on final pathology that was not diagnosed on TUR, making a total of 74 (77.1%) patients with CIS refractory to NACT on cystectomy pathology.ConclusionsCIS seems to respond poorly to cisplatin-based neoadjuvant chemotherapy. If organ preservation protocols are considered, a thorough assessment for CIS with enhanced photodynamic detection cystoscopy or random bladder biopsies should be considered. Residual cisplatin-refractory disease, even if noninvasive CIS, may lead to poor outcomes. Future molecular classifiers may assist in disease signatures to help guide treatment protocols.     

Bcl-2 expression identifies patients with advanced bladder cancer treated by radiotherapy who benefit from neoadjuvant chemotherapy

OBJECTIVE: To assess the prognostic significance of Bcl-2 expression on the clinical outcome after radiotherapy for muscle-invasive bladder cancer, and to determine if it is possible to identify a subgroup of patients to whom neoadjuvant chemotherapy can be targeted to improve survival. PATIENTS AND METHODS: Immunohistochemical staining for Bcl-2 and p53 was performed on the tumours of 51 patients with stage T2-T4a NXM0 transitional cell carcinoma of the bladder who had been included in a randomized clinical trial of radiotherapy with or without neoadjuvant cisplatin. The association between positive staining and salvage cystectomy rate and overall survival was examined, with a median follow-up of 12 years. RESULTS: Bcl-2 and p53 expression was positive in 31 (61%) and 39 (76%) of the tumours, with no association between either, or with tumour stage or grade. There was no difference according to Bcl-2 positivity in the salvage cystectomy rate (P = 0.83) or survival (P = 0.68) for the 51 patients as a whole, but Bcl-2-negative patients receiving neoadjuvant cisplatin had a significantly better prognosis, with a median survival of 72 months compared to 17 months in Bcl-2-positive patients, and a 5-year survival rate of 55% (P = 0.03). CONCLUSIONS: Quantifying Bcl-2 in patients undergoing radiotherapy for advanced bladder cancer identifies those who may benefit from neoadjuvant chemotherapy. Further studies of other members of the Bcl-2 family and other proteins controlling both cell proliferation and apoptosis are warranted, to define the roles and the interactions between them that may contribute to oncogenesis and resistance to standard treatments. This may allow the targeting of specific treatments to patients known to be sensitive to them, and aid the future development of novel therapies for bladder cancer.     

Neoadjuvant chemotherapy with docetaxel and cisplatin in patients with high-risk resectable bladder carcinoma: long term results

OBJECTIVES: Neoadjuvant chemotherapy has been used to improve outcome after cystectomy or for selection for bladder preservation in patients with bladder cancer. We have shown encouraging results using docetaxel and cisplatin in patients with advanced urothelial cancer. We are reporting the results of a phase II study using this combination as neoadjuvant treatment in patients with muscle invasive bladder cancer. METHODS: Fifty patients were treated with docetaxel and cisplatin at 75 mg/m2 every 3 weeks for 3 cycles prior to cystectomy. Median follow-up was 70.2 months. RESULTS: Chemotherapy was well tolerated. 5-year survival and progression-free survival (PFS) were 51.92% (95% confidence intervals [CI]: 37.76-66.08) and 52.47% (95%CI: 37.99-66.95). Multivariate analysis showed that clinical stage (cT) < or = 3a was associated with improved 5-year survival (86.42% vs. 40.81%, p = 0.027). Forty one patients underwent cystectomy. No tumor was found in 15 cases (36.6%). 5-year survival was 60.34% (95%CI: 52.2-68.48) and PFS was 57.11% (95%CI: 41.29-72.93). Absence of residual tumor was associated with improved 5-year survival (93.33% vs. 40.72%, p = 0.031). CONCLUSIONS: Neoadjuvant chemotherapy with docetaxel and cisplatin is feasible and produced high pathological complete remission rate and excellent outcome in patients with no residual tumor.     

Partial cystectomy: Review of a single center experience from 2004 to 2019

PurposePartial cystectomy (PC) is a bladder sparing option to treat bladder cancer in a carefully selected group of patients. We sought to analyze outcomes of partial cystectomy (PC) in a contemporary cohort of patients at a single institution.Material and methodsRecords were reviewed for 43 patients with a primary urothelial carcinoma (UC) who had a partial cystectomy with curative intent at Columbia University Medical Center from 2004 to 2019. Endpoints of interest were noninvasive recurrence (defined as any recurrent nonmuscle invasive disease), advanced recurrence (defined as a muscle invasive recurrence or metastasis), and death. We used unadjusted Cox proportional hazards regressions and log rank tests to estimate the association between clinical characteristics and endpoints of interest.ResultsAmong 43 patients with bladder cancer treated with partial cystectomy, median patient age was 73 years (interquartile range 67–77.5) and 86% were male. Twenty-three percent of patients received preoperative neoadjuvant chemotherapy (NAC) and 49% of patients were given perioperative intravesical chemotherapy at the time of PC. Pathologic stage was <T2 for 23 (53%) patients and ≥T2 for 20 (47%) patients. Pathology showed 14% of patients had lymph node involvement, and 9% had positive surgical margins. Mean follow-up was 51 months (range 1–176). Five-year overall survival was 78%. Of 43 patients, 23 patients (53%) had no recurrence, 9 patients (21%) experienced noninvasive intravesical recurrence, and 11 patients (26%) experienced advanced recurrences. Two patients (5%) required salvage radical cystectomy and 8 patients (19%) died of bladder cancer. On univariate analysis, lymphovascular invasion (hazard ratio [HR] 4.4, confidence interval [CI] 1.3–14.3), pathological stage (HR 5.9, CI 1.3–27.4), and NAC (HR 6.5, CI 1.9–22.7) were associated with advanced recurrence. Noninvasive recurrence was associated with not receiving perioperative intravesical chemotherapy (HR 0.7, CI 0.1–6.0).ConclusionsIn well-selected patients, partial cystectomy offers adequate local control of bladder cancer. The risk of systemic progression is similar to reported case series of RC.     

Neoadjuvant chemotherapy (M-VAC) for locally invasive bladder cancer]

Eight patients with locally invasive bladder cancer (stages T2-T4, N0, M0; 7 men and 1 woman; mean age, 72.0 years; age range, 56 to 80 years) were treated with 2 cycles of neoadjuvant chemotherapy consisting of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC). Seven of them underwent radical cystectomy after chemotherapy, while the bladder was preserved in one patient. Seven patients were free of disease during a mean follow-up period of 26.2 months (range 20-30 months). However, one patient whose pathological stage was pT2, N1 died with disease 27 months after radical cystectomy. The patient whose bladder had been preserved showed no recurrence after a follow-up period of 27 months. Pathological examination of the resected specimen after chemotherapy revealed no tumor tissue in three patients; one with negative cytology and two with positive cytology. Downstages were observed in two patients. Results showed that the toxicity of neoadjuvant M-VAC therapy is acceptable and that M-VAC therapy is effective against locally invasive transitional cell carcinoma of the bladder. The problem remains of how to assess the clinical stage more accurately before chemotherapy and radical cystectomy.     

Tratamiento del cáncer de vejiga con invasión muscular y metastásico: actualización de la Guía Clínica de la EAU

ContextNew data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC.ObjectiveTo review the new EAU guidelines for MiM-BC with a specific focus on treatment.Evidence acquisitionNew literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence.Evidence synthesisCurrent data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available.ConclusionsIn the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.     

Long-term outcome of radiation-based conservation therapy for invasive bladder cancer

PURPOSE: To report the long-term results and examine factors associated with bladder preservation, risk of relapse, and survival in patients treated with radical radiotherapy for invasive bladder cancer. MATERIALS AND METHODS: Between 1986 and 1997, 340 patients with T1-T4 bladder cancer were treated at Princess Margaret Hospital and received radiotherapy alone, radiotherapy and concurrent cisplatin chemotherapy, or neoadjuvant chemotherapy followed by radiotherapy. Patients having complete response were followed with regular cystoscopy. Cystectomy was undertaken in suitable patients with persistent or locally recurrent disease. RESULTS: The median age of patients was 71 years, 13% had evidence of regional lymph node involvement, and 27% were medically unfit for radical cystectomy. A total of 247 patients received radiotherapy alone, 36 radiotherapy and concurrent cisplatin chemotherapy, and 57 neoadjuvant chemotherapy followed by radiotherapy. Complete response was obtained in 63.5% of patients overall, and median follow-up was 7.9 years. The 10-year overall survival, cause-specific survival, and local relapse-free rates were 19%, 35%, and 32%, respectively. In 131 patients with muscle-invasive disease confined to the bladder wall (T2N0M0), 10-year cause-specific survival (P = 0.02) and local relapse-free rates (P = 0.03) were 68% and 60% when carcinoma in situ was absent, and 47% and 28%, respectively, when present. In multivariable analysis, younger age, lower T category, and absence of carcinoma in situ were associated with a statistically significant improvement in survival and local control (P 相似文献   

Updated results of bladder-sparing trimodality approach for invasive bladder cancer

PurposeTo update long-term results with selective organ preservation in invasive bladder cancer using aggressive transurethral resection of bladder tumor (TURBT) and radiochemotherapy (RCT) and to identify treatment factors that may predict overall survival (OS).Materials and methodsBetween 1990 and 2007, a total of 74 patients with T2-T4 bladder cancer were enrolled in 2 sequential bladder-sparing protocols including aggressive TURB and RCT. From 1990 to 1999, 41 patients were included in protocol no. 1 (P1) that consisted of three cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy prior to re-evaluation and followed by radiotherapy (RT) 60 Gy in complete responders. Between 2000 and 2007, 33 patients were entered in protocol no. 2 (P2) that consisted of concurrent RCT 64, 8 Gy with weekly cisplatin. In case of invasive residual tumor or recurrence, salvage cystectomy was recommended. Primary endpoints were OS, overall survival with bladder preservation (OSB), and late toxicity.ResultsThe mean follow-up for the whole series was 54 months (range 9–156), 69 months for patients in P1 and 36 months for patients in P2. The actuarial 5-year OS and OSB for all series were 72% and 60%, respectively. Distant metastases were diagnosed in 11 (15%) patients. Grade 3 late genitourinary (GU) and intestinal (GI) complications were 5% and 1.3%, respectively. There were no significant differences in the incidence of superficial recurrences (P = 0.080), muscle-invasive relapses (P = 0.722), distant metastasis (P = 0.744), grade ≥2 late complications (P = 0.217 for GU and P = 0.400 for GI), and death among the 2 protocols (P value for OS = 0.643; P value for OSB = 0.532).ConclusionThese data confirm that trimodality therapy with bladder preservation represents a real alternative to radical cystectomy in selected patients, resulting in an acceptable rate of the long-term survivors retaining functional bladders.     

Complications of radical cystectomy: Impact of the timing of perioperative chemotherapy

Objectives

To evaluate the impact of timing of perioperative chemotherapy on morbidity of radical cystectomy in patients with bladder cancer.

Methods

We compared the complications in patients randomized to neoadjuvant (n = 53) or adjuvant (n = 49) MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy.

Results

In the 95 patients who underwent cystectomy, there were no significant differences in treatment compliance, surgical parameters, or postoperative recovery between the two groups. In patients who received neoadjuvant chemotherapy, there were more complications, and there was one perioperative death; however, these differences were not significant. The neoadjuvant group took longer to complete therapy (P <0.001). Nine patients (3 neoadjuvant, 6 adjuvant) did not undergo cystectomy on time.

Conclusions

Cystectomy following neoadjuvant MVAC chemotherapy is feasible. We were unable to demonstrate any difference between neoadjuvant and adjuvant chemotherapy in mortality, morbidity, or postoperative clinical course.