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Incremental Utility of Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer: Quantifying the Relapse Risk Associated with Therapeutic Effect.

ABSTRACT: The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2-4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recurrence-free survival (RFS) rates according to AC use. Nomogram-derived probabilities of 1-yr recurrence after RC were plotted against actual recurrence rates according to AC use. Overall, we did not see evidence of an AC effect on the 1-yr RFS rate (p=0.6). Conversely, the 1-yr RFS rate was higher among patients with pT3-4 or pN1 disease who received AC (75% vs 54%; p<0.001). We were unable to demonstrate a difference between AC and no AC among patients who received prior NAC (1-yr RFS 57% vs 76%; p=0.057). As the most important finding, AC was associated with incremental RFS benefits only for patients with a nomogram-derived 1-yr recurrence probability of >40%. Patient summary: Maximizing disease control with adjuvant chemotherapy was beneficial for patients with muscle-invasive bladder cancer who had a calculated recurrence risk of >40% and did not impact cancer recurrence in lower-risk disease. Therefore, patient stratification using the nomogram available for predicting recurrence is advisable pending external validation.

SUBMITTER: Pederzoli F

PROVIDER: S-EPMC6852645 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Incremental Utility of Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer: Quantifying the Relapse Risk Associated with Therapeutic Effect.

Pederzoli Filippo F Bandini Marco M Briganti Alberto A Plimack Elizabeth R ER Niegisch Günter G Yu Evan Y EY Bamias Aristotelis A Agarwal Neeraj N Sridhar Srikala S SS Sternberg Cora N CN Vaishampayan Ulka N UN Théodore Christine C Rosenberg Jonathan E JE Harshman Lauren C LC Bellmunt Joaquim J Galsky Matthew D MD Gallina Andrea A Salonia Andrea A Montorsi Francesco F Necchi Andrea A

European urology 20190711 4

The availability of new potent systemic therapies for urothelial carcinoma may change the way we use standard chemotherapy perioperatively. In particular, identifying which patients with muscle-invasive bladder cancer (MIBC) would benefit from adjuvant chemotherapy (AC) is compelling. From a multicenter database we selected 950 patients with cT2-4N0M0 MIBC treated with radical cystectomy (RC), with or without neoadjuvant chemotherapy (NAC), and AC. We used Kaplan-Meier analyses to test 1-yr recu ...[more]

PMID: 31303258

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Project description:BackgroundThe expression alterations of B4GALT1 have been noted in some types of cancer and they are related to cancer cell proliferation, invasiveness, metastasis, and drug resistance. We aimed to establish the expression of B4GALT1 in bladder cancer and its connection to patient outcomes, as well as forecasting the advantages of adjuvant chemotherapy (ACT) in patients with muscle-invasive bladder cancer (MIBC).MethodsThere were 142 and 112 MIBC patients who were consecutively recruited and treated via radical cystectomy from 2008 to 2012 in Shanghai Zhongshan Hospital and Fudan University Shanghai Cancer Center (FUSCC), respectively. Tissue microarrays (TMAs) were constructed in triplicate from specimens that had been fixed in formalin and embedded in paraffin samples. Immunohistochemistry was conducted to evaluate B4GALT1 expression in tumor cores, the connection between B4GALT1 expression and patients' clinical characteristics, and clinical results.ResultsB4GALT1 expression was not connected to clinical prognosis markers, but it was linked to overall survival (OS) (P = 0.013 and P = 0.010, respectively) in the two groups. Moreover, the high levels of B4GALT1 expression were independent indicators of poor OS (P = 0.026 and P = 0.046, respectively). Inclusion of B4GALT1 in the prognostic model revealed a greater predictive accuracy than the primary models. In addition, no differences were observed between B4GALT1 expression (low vs. high) and CD8+ T cell infiltration density (number/cm2) within tumor cores, but there was a positive Pearson correlation between B4GALT1 expression and expression of inhibitory receptor ligands, such as PD-L1 and CTLA4. Most significantly, the advantage of ACT noted in pT3/4 or N+ bladder cancer patients with low B4GALT1 expression was greater than in patients with a high B4GALT1 expression.ConclusionsOur evaluation indicated that B4GALT1 may be a possible prognosticator of MIBC, and it may be a predictive marker for the choice of ACT in pT3/4 or N+ patients.

Project description:Although adjuvant chemotherapy (ACH) is widely used in clinical practice for the management of muscle-invasive bladder cancer (MIBC), a consensus has yet to be established on which ACH regimen is the most effective for improving postoperative survival. In this study, we aimed to systematically assess the optimal ACH regimen for improving survival outcomes in patients treated with radical cystectomy (RC) for MIBC. A comprehensive literature search was conducted in the PubMed, Embase, and the Cochrane Library databases for all articles published until December 2016 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The study end-points were progression-free survival (PFS) and overall survival (OS). A direct pairwise meta-analysis was conducted by pooling the studies that compared RC with ACH and RC alone, and the results are presented as a pooled hazard ratio (HR) with a 95% confidence interval (CI). A Bayesian network meta-analysis was adopted for indirect comparisons among various ACH regimens, and the outcomes are presented as HRs with 95% credible intervals (CrI). The eleven randomized controlled trials ultimately selected for the current analysis comprised of 1,546 patients with 49 to 327 subjects per study. Based on the pairwise meta-analysis, the use of ACH showed significantly better PFS (HR, 0.64; 95% CI, 0.49-0.85) and OS (HR, 0.79; 95% CI, 0.68-0.92) than RC alone. In the network meta-analysis, the gemcitabine/cisplatin/paclitaxel (GCP) combination was the only ACH regimen associated with significant improvement in both the PFS (HR, 0.38; 95% CrI, 0.25-0.58) and OS (HR, 0.38; 95% CrI 0.22-0.65). ACH following RC for MIBC may therefore contribute to improved PFS and OS. In particular, the GCP combination may be the optimal ACH regimen for improving postoperative survival outcomes. Additional well-designed, large scale, prospective, randomized trials are still required to establish the optimal ACH regimen in MIBC patients.

Project description:Radiotherapy for muscle invasive bladder cancer (MIBC) aims to offer organ preservation without oncological compromise. Neo-adjuvant chemotherapy provides survival advantage; response may guide patient selection for bladder preservation and identify those most likely to have favourable result with radiotherapy.Ninety-four successive patients with T2-T4aN0M0 bladder cancer treated between January 2000 and June 2011 were analysed at the Royal Marsden Hospital. Patients received platinum-based chemotherapy following transurethral resection of bladder tumour; repeat cystoscopy (± biopsy) was performed to guide subsequent management. Responders were treated with radiotherapy. Poor responders were recommended radical cystectomy. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method; univariate and multivariate analyses were performed using the Cox proportional hazard regression model.Response assessment was performed in 89 patients. Seventy-eight (88%) demonstrated response; 53 (60%) achieved complete response (CR); 74 responders had radiotherapy; 4 opted for cystectomy. Eleven (12%) demonstrated poor response, 10 received cystectomy. Median survival for CR was 90 months (95% CI 64.7, 115.9) compared with 16 months (95% CI 5.4, 27.4; P < 0.001) poor responders. On multivariate analysis, only response was associated with significantly improved PFS, OS and DSS. After a median follow-up of 39 months (range 4-127 months), 14 patients (16%) required salvage cystectomy (8 for non-muscle invasive disease, 5 for invasive recurrence, 1 for radiotherapy related toxicity). In all, 82% had an intact bladder at last follow-up after radiotherapy; 67% had an intact bladder at last follow-up or death. Our study is limited by its retrospective nature.Response to neo-adjuvant chemotherapy is a favourable prognostic indicator and can be used to select patients for radiotherapy allowing bladder preservation in >80% of the selected patients.

Project description:Introduction and objectiveIdentifying patients that benefit from cisplatin-based adjuvant chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC). The purpose of this study is to correlate "luminal" and "basal" type protein expression with histological subtypes, to investigate the prognostic impact on survival after adjuvant chemotherapy and to define molecular consensus subtypes of "double negative" patients (i.e., without expression of CK5/6 or GATA3).Materials and methodsWe performed immunohistochemical (IHC) analysis of CK5/6 and GATA3 for surrogate molecular subtyping in 181 MIBC samples. The mRNA expression profiles for molecular consensus classification were determined in CK5/6 and GATA3 (double) negative cases using a transcriptome panel with 19.398 mRNA targets (HTG Molecular Diagnostics). Data of 110 patients undergoing radical cystectomy were available for survival analysis.ResultsThe expression of CK5/6 correlated with squamous histological subtype (96%) and expression of GATA3 was associated with micropapillary histology (100%). In the multivariate Cox-regression model, patients receiving adjuvant chemotherapy had a significant survival benefit (hazard ratio [HR]: 0.19 95% confidence interval [CI]: 0.1-0.4, p < 0.001) and double-negative cases had decreased OS (HR: 4.07; 95% CI: 1.5-10.9, p = 0.005). Double negative cases were classified as NE-like (30%), stroma-rich (30%), and Ba/Sq (40%) consensus molecular subtypes and displaying different histological subtypes.ConclusionImmunohistochemical-based classification was associated with histological subtypes of urothelial MIBC. IHC markers like CK5/6 and GATA3 that are used in pathological routine could help to identify patients with basal and luminal tumor characteristics. However, a two-sided classification system might not sufficiently reflect the heterogeneity of bladder cancer to make treatment decisions. Especially the group of IHC-double negative cases, as further analyzed by mRNA expression profiling, are a heterogeneous group with different implications for therapy.

Dataset Information

Incremental Utility of Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer: Quantifying the Relapse Risk Associated with Therapeutic Effect.

Publications

Incremental Utility of Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer: Quantifying the Relapse Risk Associated with Therapeutic Effect.

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