Neoadjuvant Chemotherapy For Muscle-invasive Bladder Cancer Research Articles

Effects of perioperative chemotherapy on prognosis in muscle invasive bladder cancer treated with radical cystectomy.

592 Background: We aimed to evaluate the effect of the number of neoadjuvant chemotherapy (NAC) cycles and the adding adjuvant chemotherapy (AC) after NAC in muscle-invasive bladder cancer (MIBC) on overall survival (OS). Methods: This multicenter retrospective study included 2674 patients with MIBC who underwent radical cystectomy (RC) from 36 institutions within the Japanese Urological Oncology Group. Among them, we selected 1687 patients with cT2-4NxM0 who were treated with RC alone or RC plus perioperative chemotherapy. We compared the effect of the number of NAC cycles (2 vs. ≥3 cycles) and the addition of AC on OS. Cox proportional-hazards regression was used to assess the association of treatment received with OS. Results: Of 1687 patients, 946 were treated with NAC with a median of 3 cycles. Use of NAC significantly prolonged OS compared to the RC alone. The pathological complete response rate was not significantly different between the 2 cycles (22.9%) and ≥3 cycles (27.5%, P = 0.112) groups. OS was not significantly different between the groups (P = 0.559). Multivariable Cox regression analysis showed that pathological high-risk (ypT2–4, pT3–4, or pN+) or cisplatin ineligibility were significantly associated with poor OS, but not the number of NAC cycles (P = 0.238). We identified 942 pathologically high-risk patients after RC who were eligible for AC. We observed no significant OS improvement with addition of AC after NAC as intensive perioperative chemotherapy. The primary limitation is selection bias from confounding by clinical indication. Conclusions: The impact of 3 or more NAC cycles and the addition of AC on OS in MIBC patients treated with RC may be limited.

Predicting clinical outcomes in the S1314-COXEN trial using a multimodal deep learning model integrating histopathology, cell types, and gene expression.

533 Background: Accurate prediction of response to neoadjuvant chemotherapy (NAC) is essential for optimizing treatment outcomes in muscle-invasive bladder cancer (MIBC). We present a cutting-edge multimodal deep learning model aimed at predicting outcomes of NAC from accessible H & E images and molecular data. Methods: We designed a Graph-based Multi-modal Late Fusion (GMLF) deep learning model that integrates three types of data from the S1314-COXEN clinical trial: 1) Neural embeddings from 182 whole slide images (WSIs), generated via the ResNet50 architecture. 2) Cell types based on morphology, including cancer, necrotic, immune, and stromal cells, and their spatial positions within the tumor microenvironment extracted from WSIs using the HoVer-Net framework, a multiple-branch convolutional neural network for predicting cell types. 3) Patient-level RNA expression data derived from 1,071-dimensional gene expression vectors. The dataset was randomly divided into 80% for model training, using 5-fold cross-validation (5-fold CV), and 20% for internal validation. Results: Our dataset included 182 WSIs of 180 patients who were randomized to receive either gemcitabine-cisplatin or dose-dense methotrexate-vinblastine-adriamycin-doxorubicin-cisplatin. Of all patients, 30.8% demonstrated a complete pathological response (pT0 after radical cystectomy). Our GMLF model achieved an AUROC of 0.7417 ± 0.1021 for predicting whether a patient showed a complete pathologic response to NAC in a 5-fold CV. Using an 80/20 training and validation split, the model yielded an AUROC of 0.7236. Interestingly, our model emphasized the contribution of spatial information collected from WSIs. For selecting the best architecture for the histology branch, the Slidegraph+ framework, a graph neural network-based model, achieved an AUROC of 0.6938 ± 0.0565, significantly outperforming patch-level models as the second-best, which achieved AUROC of 0.5572 ± 0.1793. Shapley Additive Explanation (SHAP) analysis revealed RNA expression branch as the most influential, with a mean SHAP magnitude of 0.13, followed by the neural embeddings at 0.12. SHAP-based interpretation identified the most important expressed genes impacting model predictability, including TP63. Our gene set analysis identified the most influential pathways for predicting response, which included basal differentiation and myo-fibroblast enrichment (p-value < 0.05). Conclusions: Our interpretable GMLF model accurately predicts NAC response in patients with MIBC by integrating standard H&E images and RNA expression data. Our model interpretations not only revealed the importance of each modality but also uncovered histopathological, cellular, and molecular underpinnings of response to NAC in MIBC. These findings open the door to AI-guided development of precision therapies for MIBC. Clinical trial information: NCT02177695 .

The assessment of pathological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer patients with DCE-MRI and DWI: a systematic review and meta-analysis.

The purpose of this meta-analysis was to determine the value of dynamic contrast-enhanced-MRI (DCE-MRI) and diffusion-weighted imaging (DWI) in evaluating the pathological response of muscle invasive bladder cancer (MIBC) to neoadjuvant chemotherapy (NAC), and further indirectly compare the diagnostic performance of DCE-MRI and DWI. Literatures associated to DCE-MRI and DWI in the evaluation of pathological response of MIBC to NAC were searched from PubMed, Cochrane Library, web of science, and EMBASE databases. The quality assessment of diagnostic accuracy studies 2 tool was used to assess the quality of studies. Pooled sensitivity (SE), specificity (SP), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curves (AUC) with their 95% confidence intervals (CIs) were calculated to evaluate the diagnostic performance of DCE-MRI and DWI in predicting the pathological response to NAC in patients with MIBC. There were 11 studies involved, 6 of which only underwent DCE- MRI examination, 4 of which only underwent DWI examination, and 1 of which underwent both DCE- MRI and DWI examination. The pooled SE, SP, PLR, NLR, DOR of DCE-MRI were 0.88 (95% CI: 0.78-0.93), 0.88 (95% CI: 0.67-0.96), 7.4 (95% CI: 2.3-24.2), 0.14 (95% CI: 0.07-0.27), and 53 (95% CI: 10-288), respectively. The pooled SE, SP, PLR, NLR, DOR of DWI were 0.83 (95% CI: 0.75-0.88), 0.88 (95% CI: 0.81-0.93), 7.1 (95% CI: 4.3-11.7), 0.20 (95% CI: 0.14-0.28), and 36 (95% CI:18-73), respectively. The AUCs of SROC curve for DCE-MRI and DWI were 0.93 (95% CI: 0.91-0.95) and 0.92 (95% CI: 0.89-0.94), respectively. There were no significant differences between DWI and DCE-MRI for SE, SP, and AUC. This meta-analysis demonstrated high diagnostic performance of both DCE-MRI and DWI in predicting the pathological response to NAC in MIBC. DWI might be a potential substitute for DCE-MRI, with no significant difference in diagnostic performance between the two. However, caution should be taken when applying our results, as our results were based on indirect comparison. No previous studies have comprehensively analysed the value of DCE-MRI and DWI in evaluating the pathological response to NAC in MIBC. According to the current study, both DCE-MRI and DWI yielded high diagnostic performance, with the AUCs of 0.93 and 0.92, respectively. Indirect comparison no significant difference in the diagnostic performanceof DCE-MRI and DWI.

Assessment of Predictive Genomic Biomarkers for Response to Cisplatin-based Neoadjuvant Chemotherapy in Bladder Cancer

Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). It has been shown that somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and FANCC are correlated with pathological response to NAC in MIBC. The objective of this study was to validate these genomic biomarkers in pretreatment transurethral resection material from an independent retrospective cohort of 165 patients with MIBC who subsequently underwent NAC and radical surgery. Patients with ypT0/Tis/Ta/T1N0 disease after surgery were defined as responders. Somatic deleterious mutations in ERCC2 were found in nine of 68 (13%) evaluable responders and two of 95 (2%) evaluable nonresponders (p = 0.009; FDR = 0.03). No correlation was observed between response and alterations in ERBB2 or in ATM, RB1, or FANCC alone or in combination. In an exploratory analysis, no additional genomic alterations discriminated between responders and nonresponders to NAC. No further associations were identified between the aforementioned biomarkers and pathological complete response (ypT0N0) after surgery. In conclusion, we observed a positive association between deleterious mutations in ERCC2 and pathological response to NAC, but not overall survival or recurrence-free survival. Other previously reported genomic biomarkers were not validated. Patient summaryIt is currently unknown which patients will respond to chemotherapy before definitive surgery for bladder cancer. Previous studies described several gene mutations in bladder cancer that correlated with chemotherapy response. This study confirmed that patients with bladder cancer with a mutation in the ERCC2 gene often respond to chemotherapy.

Adverse events during neoadjuvant chemotherapy for muscle invasive bladder cancer-a Swedish retrospective multicentre study of a clinical database.

BackgroundAdverse events (AEs) during neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) are known but insufficiently reported. Clinical implications include affected cardiac, pulmonary, urinary, vascular and haematological organ systems. The main purpose was to evaluate the incidence and severity of AEs for ascertaining possible clinical significance. Further investigating possible effects of AEs on downstaging outcomes—downstaging is considered a surrogate marker for overall survival (OS).MethodsA retrospective evaluation of AEs during ongoing NAC for MIBC patients analysing individual patient data in a clinical database. We identified 687 cystectomies between 2009–2020 at four Swedish urological centres. Inclusion criteria were cT2–4aN0M0 in 261 NAC patients undergoing radical cystectomy (RC). Medical files were reviewed and AEs were assessed and graded, including detailed measurements by the Common Terminology Criteria for Adverse Events (CTCAE) v.5. Data were retrospectively analysed in SPSS statistics 27.0 with Spearman rank-order correlation coefficient and Mann-Whitney U-test (MWU).ResultsA total of 251/261 patients [95% confidence interval (CI), 93–98%] experienced AEs during NAC pre-RC (mean two AEs/patient). In total, 208 (80%) patients received methotrexate, vinblastine, adriamycin (doxorubicin) and cisplatin (MVAC). In the total cohort, 200 (76.6%) received all pre-planned NAC-cycles. Most common AEs were anaemia (88.9%), thrombocytopenia (44.8%) and acute kidney injury (40.6%). Patients with prematurely terminated cycles had higher AE-grades (P=0.042 MWU). A correlation between higher AE-grades and decrease in downstaging existed, in the entire cohort (−0.133; P=0.033) and in patients undergoing all pre-planned NAC-cycles (−0.148; P=0.038). Anaemia and acute kidney injury were individually associated with decreased downstaging (−0.360, P=0.025 and −0.183, P=0.010, respectively).ConclusionsNAC in MIBC poses a significant risk for AEs before RC with clinical implications. For instance, patients terminating chemotherapy prematurely, have higher AE-grades and decreased downstaging. Further, acute kidney injury and anaemia are individually associated with decreased downstaging. We propose that early detection and prevention of AEs may increase downstaging of the primary tumour.

Association of Medicaid expansion with racial disparities in timely neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC).

472 Background: Timely initiation of NAC is critical to improve outcomes in MIBC. Medicaid expansion through the Affordable Care Act improved racial disparities in healthcare access for patients with advanced cancers. This study aimed to assess the association of Medicaid expansion with racial disparities in time-to-NAC in MIBC. Methods: This case-control study queried the National Cancer Database for 18-64 years old Black and White adults who were diagnosed with stage II&III bladder cancer and treated with NAC from Jan 1, 2008 to Dec 31, 2018. The primary endpoint was the timely receipt of NAC, defined as initiation within 45 days from the diagnosis of resectable MIBC. Racial disparity was defined as percentage-point (PP) difference for Black vs. White patients, adjusted for age, sex, income level, clinical stage, and year of diagnosis. Results: The study included 5053 patients (7.2% Black, n = 391). In states without Medicaid expansion, Black patients became less likely to receive timely NAC than their White counterparts (2008-2013: Black 59.6% vs White 63.8%, p = 0.53; 2014-2018: Black 47.9% vs White 61.2%, p < 0.01). In contrast, the racial disparity was narrowed in states with Medicaid expansion (2008-2013: Black 35.7% vs White 62.9%, p < 0.01; 2014-2018: Black 53.4% vs White 59.5%, adjusted PP difference -2.4; p = 0.20). The adjusted difference-in-differences estimate revealed a 26.0 PP reduction in racial disparity (95% CI, 8.1%-44.0%; p < 0.01). Conclusions: Medicaid expansion was associated with significant reduction in racial disparity between Black and White patients in the timely receipt of NAC for MIBC.

Impact of angiotensin-converting enzyme inhibitors (ACEi) on pathologic complete response with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC).

485 Background: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. Angiotensin pathway inhibitors are postulated to favorably reprogram the stroma in part by inhibition of transforming growth factor-β, a major mechanism of resistance, and have been previously reported to be associated with improved outcomes in the setting of immune checkpoint inhibitors (ICIs) for metastatic urothelial carcinoma (Jain R, Clin Genitourin Cancer 2021). In this analysis, we examined the association of angiotensin inhibitors in the setting of NAC for MIBC preceding radical cystectomy (RC). Methods: Pts with MIBC who received NAC preceding radical cystectomy were assembled from 3 institutions: Dana-Farber Cancer Institute (DFCI), Moffitt Cancer Center (MCC) and McGill University Health Center (MUHC). Pts were retrospectively assessed for the association of concurrent ACEi/angiotensin receptor blockers (ARB) use at initiation of NAC on pathologic complete response (pCR), defined as pT0N0, and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. The Kaplan-Meier method was used to estimate OS. Logistic and Cox regression were used to explore factors potentially prognostic for pCR and OS respectively. Results: 302 MIBC pts who received NAC preceding RC were available from 3 institutions: DFCI (n = 187), MCC (n = 50) and MUHC (n = 65). Overall, 141 pts (46.7%) received Cisplatin/Gemcitabine, 130 (43.1%) received dose dense MVAC and the remaining received other regimens. The overall pCR rate was 26.2%. The 5-year OS was 62%. 63 (20.9%) pts were receiving an ACEi and 41 (13.6%) were receiving an ARB. ACEi prior to NAC approached significance for association with pCR (odds ratio = 1.71 (95% CI = 0.94-3.11) p = 0.077). Pts with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% (8/26) vs 17.7% (14/98), p = 0.056) than those not on ACEi; no difference was observed for pts with cT2N0 tumors (31.1% vs 31.3%, p = 0.99). pCR, ECOG-PS and clinical stage were significantly associated with improved OS. ARB intake was not associated with pCR or OS. Conclusions: ACEi intake appeared potentially associated with increased pCR in pts with MIBC receiving NAC, which was more pronounced in those with higher clinical stages cT3/4N0-1. Given the association of pCR with OS, our data suggest the potential relevance of angiotensin as a therapeutic target in aggressive MIBC. Future prospective validation is warranted to repurpose angiotensin inhibitors in this setting, given their excellent toxicity profile and low costs.

Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

BackgroundFor muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. ObjectiveTo investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. Design, setting, and participantsClassification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. Outcome measurements and statistical analysisComplete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. Results and limitationsPatients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11–0.79) and UroC tumors (HR 0.37, 95% CI: 0.14–0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. ConclusionsUrothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. Patient summaryThis study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Comparison of Oncologic Outcomes of Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (ddMVAC) with Gemcitabine and Cisplatin (GC) as Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: Systematic Review and Meta-Analysis

Simple SummaryCurrently, platinum-based neoadjuvant chemotherapy (NAC) is becoming a standard treatment for use in patients with muscle-invasive bladder cancer. However, comparisons of oncologic outcomes for the two most commonly used NAC regimens, ddMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) and GC (gemcitabine and cisplatin), are controversial. We sought to compare the oncologic outcomes of these two regimens via a systematic review and meta-analysis of all the available studies published to date. Through this, we aimed to provide evidence on the optimal NAC regimen for use in muscle-invasive bladder cancer.Platinum-based neoadjuvant chemotherapy (NAC) is widely used for treating muscle-invasive bladder cancer (MIBC). A systematic review was performed following PRISMA guidelines. PubMed, Embase, and the Cochrane Library were searched up to December 2020. We conducted a meta-analysis to compare the oncologic outcomes of ddMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) and GC (gemcitabine and cisplatin), which are the most widely used NAC regimens. Endpoints included pathologic complete response (pCR), pathologic downstaging (pDS), overall survival (OS), and cancer-specific survival (CSS). Five studies, with a total of 1206 patients, were included for meta-analysis. pCR was observed in 35.2% of the ddMVAC arm and in 25.1% of the GC arm, and pCR was significantly higher in ddMVAC than in GC (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.11–1.89; p = 0.006). There was no significant difference in pDS (OR, 1.37; CI, 0.84–2.21; p = 0.20). OS was significantly higher in ddMVAC than in GC (hazard ratio, 2.16; CI, 1.42–3.29; p = 0.0004). Only one study reported CSS outcomes. The results of this analysis indicate that ddMVAC is superior to GC in terms of pCR and OS, suggesting that ddMVAC is more effective than GC in NAC for MIBC. However, this should be interpreted with caution because of the inherent limitations of retrospective studies.

Development of a radiomic signature for predicting response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.

Neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) improves overall survival, but pathological response rates are low. Predictive biomarkers could select those patients most likely to benefit from NAC. Radiomics technology offers a novel, non-invasive method to identify predictive biomarkers. Our study aimed to develop a predictive radiomics signature for response to NAC in MIBC. An institutional bladder cancer database was used to identify MIBC patients who were treated with NAC followed by radical cystectomy. Patients were classified into responders and non-responders based on pathological response. Bladder lesions on computed tomography images taken prior to NAC were contoured. Extracted radiomics features were used to train a radial basis function support vector machine classifier to learn a prediction rule to distinguish responders from non-responders. The discriminative accuracy of the classifier was then tested using a nested 10-fold cross-validation protocol. Nineteen patients who underwent NAC followed by radical cystectomy were found to be eligible for analysis. Of these, nine (47%) patients were classified as responders and 10 (53%) as non-responders. Nineteen bladder lesions were contoured. The sensitivity, specificity, and discriminative accuracy were 52.9±9.4%, 69.4±8.6%, and 62.1±6.1%, respectively. This corresponded to an area under the curve of 0.63±0.08 (p=0.20). Our developed radiomics signature demonstrated modest discriminative accuracy; however, these results may have been influenced by small sample size and heterogeneity in image acquisition. Future research using novel methods for computer-based image analysis on a larger cohort of patients is warranted.

KRT20, KRT5, ESR1 and ERBB2 Expression Can Predict Pathologic Outcome in Patients Undergoing Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-Invasive Bladder Cancer.

Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival, especially those with pathological complete response (pCR). The response to NAC according to molecular subtypes has been discussed. Molecular targets such as estrogen receptor (ESR1) and human epidermal growth factor receptor 2 (ERBB2) play an important role in breast cancer management and have also been associated with urothelial bladder cancer. Hence, the association of Keratin 20 (KRT20) Keratin 5 (KRT5), ESR1, and ERBB2 mRNA expression in MIBC at transurethral resection (TUR-BT) with pCR after NAC was analyzed retrospectively. Formalin-fixed paraffin-embedded tumour tissue samples from TUR-BT of 54 patients (42 males, 12 females, median age of 64) with MIBC were analyzed for KRT20, KRT5, ESR1, and ERBB2 mRNA expression. After NAC, RC was performed, and the specimens were evaluated for pCR. Statistical analyses comprised nonparametric and chi2 testing, partition models, and Spearman correlation analyses. After NAC, 22 out of 54 patients (40.7%) had pCR. Tumours with an elevated expression of markers associated with luminal differentiation (KRT20, ERBB2, ESR1) were associated with a higher chance of pCR (55% vs. 15.8%, p = 0.009). Elevated ERBB2 expression was positively correlated with luminal expression features such as KRT20, and negatively with basal characteristics such as KRT5. Patients with MIBC showing a high expression of ERBB2, ESR1, or KRT20 have a significantly higher chance of pCR following NAC. These findings might improve patient selection for NAC in MIBC.

Diagnostic performance of contrast-enhanced dynamic and diffusion-weighted MR imaging in the assessment of tumor response to neoadjuvant therapy in muscle-invasive bladder cancer.

To evaluate the diagnostic performance of DCE MRI and DWI in the assessment of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). This prospective study included 90 patients with MIBC who finished NAC. Two radiologists independently assessed MRI for the determination of semi-quantitative parameters (wash-in rate and wash-out rate) and apparent diffusion coefficient (ADC) value. The correlation between pCR and wash-in rate, wash-out rate, ADC value were analyzed. The area under the ROC curve (AUC) was used to evaluate the diagnostic performance for detecting pCR. Inter-reader agreement was assessed using the ICC statistics. On cystectomy specimens, pCR was confirmed in (43.3%, 39/90). pCR is negatively correlated with wash-out rate (r = - 0.701, p = 0.01) and ADC value (r = - 0.621, p = 0.01). ADC value is positively correlated with wash-out rate (r = 0.631, p = 0.001). The diagnostic accuracy of ADC value (cut-off value: 0.911 × 10-3mm2/s) and wash-out rate (cut-off value: 0.677 min-1) in the identification of pCR was (92% for reader 1, 91% for reader 2), and (90% for reader 1, 88% for reader 2), respectively. The sensitivity, specificity for predicting pCR using ADC value + washout rate cut off values were 95.4%, 97.7% for reader 1, and 96%, 97% for reader 2, respectively. AUC was 0.981 for reader 1, 0.971 for reader 2. The overall reproducibility of the mean ADC value and wash out rate was excellent (ICC = 0.83-0.90). The ICC values for the mean ADC value, washout rate was 0.89 (95% CI 0.84-0.89) and 0.87 (95% CI 0.86-0.91), respectively. Semi-quantitative parameter (wash-out) derived from DCE-MRI and ADC has the potential to assess the tumor's complete pathologic response. The two parameters using together can offer the best possibility to identify complete response to NAC in MIBC.

Genome-wide CRISPR screen reveals SLFN11 as a potent mediator of cisplatin sensitivity in muscle-invasive bladder cancer

Bladder cancer is among the top ten most common cancer types in the world, with approximately 550,000 new cases annually. The highest burden of bladder cancer is currently on most developed communities across the world and an estimated 9,000 Canadians are diagnosed with bladder cancer each year. Cisplatin-based Neoadjuvant chemotherapy (NAC) followed by radical cystectomy in patients with muscle-invasive bladder cancer (MIBC) has been shown to improve five-year survival, and is therefore currently the first-line standard of care in patients. However, 60% of patients are inherently resistant to NAC at the time of cystectomy. While several mechanisms of cellular resistance to cisplatin have been proposed, the mechanisms presented thus far still do not offer and effective patient response prediction in the context of MIBC. There is therefore, an urgent and unmet need to determine clinically actionable mechanisms of cisplatin resistance. In order to elucidate mechanisms of resistant to cisplatin, the study presented in this thesis takes advantage of a pooled genome‐wide CRISPR knock‐out library targeting 19,114 protein coding genes with 76,441 synthetic guide RNAs (sgRNAs) which allows for an unbiased screen. Upon completion of the screen the top hit was validated in vitro (CRISPR knockout cell lines), in vivo (mouse models) and in patient tumour tissue samples by immunohistochemistry. A full-scale screen revealed that several genes involved in the pro-apoptotic pathway (such as CASP8, BAX, and TNFSFR10A) and cell cycle regulation have the potential to confer resistance to cisplatin when knocked out. For this study however, we validated the top hit from our screen - Schlafen 11 (SLFN11) - and established that the complete loss of SLFN11 confers a cisplatin resistant phenotype in MIBC. We further established that SLFN11 is involved in the regulation of cell cycle progression upon cisplatin challenge and does so via interactions with Mediator of DNA Damage Checkpoint 1 (MDC1) protein. Overall, the study presented here offers SLFN11 as a potential biomarker to aid in clinical decision making and to anticipate resistance to cisplatin-based NAC in MIBC. Furthermore, targeting SLFN11 associated pathways could allow for the development of combination therapies to be used in conjunction with cisplatin in the future.

Dissecting outcomes of patients (pts) with <ypT2N0 disease after neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC): Results from a large, international, multicenter collaboration.

5043 Background: Pathologic complete response (pCR) after NAC for MIBC is strongly correlated with long-term overall survival. However, there are sparse data on the risk of recurrence based on depth of pathologic response (pT0, pTa, pTis, pT1), and the differential impact of clinicopathologic factors and NAC regimen on recurrence. Methods: Baseline data on all pts with cT2-4N0-1 MIBC receiving NAC and who achieved < ypT2N0 disease at radical cystectomy (RC) from 9 international centers were obtained. The key outcome was time to recurrence (TTR) – defined as the time to any recurrence in the urinary tract or regional/distant metastasis, with death (in the absence of recurrence) considered a competing risk. Cox regression analysis was used to analyze the impact of clinical factors on recurrence. Results: A total of 506 pts were available. Median age was 66 years (range 33-86) and 78% (n = 396) were male; median follow-up after RC was 2.6 years. The majority of patients had pure urothelial histology (n = 371, 73%), and baseline stage was cT2N0 (n = 368, 73%), cT3-4N0 (n = 95, 19%) and TanyN1 (n = 43, 9%). NAC regimens were gemcitabine-cisplatin (GC, n = 296, 59%), dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC, n = 141, 28%), split-dose GC (n = 29, 6%), MVAC (n = 29, 6%) and non-cisplatin based regimens (n = 11, 2%). At RC, 304 patients (60%) had ypT0N0 disease, 32 (6%) had ypTaN0, 107 (21%) had ypTisN0 and 63 (13%) had ypT1N0. Overall, 43 patients (8%) recurred with a median TTR of 56 weeks (range 7-251); 5-year freedom from recurrence was 87% (95% CI 83-91). The majority (n = 38) recurred outside the urinary tract. On multivariable analysis, ypTa (HR = 3.36 [1.24-9.11]) and ypT1 (HR = 2.88 [1.33-6.22], p = 0.013) disease at RC were predictors of shorter TTR, while female sex was associated with longer TTR (HR = 0.52 [0.27-0.98], p = 0.043). The type of NAC was not predictive of TTR (GC vs. other, HR = 1.49 [0.75-2.97], p = 0.26). Conclusions: To our knowledge, this is the largest study to quantify the risk of recurrence in pts achieving pathologic response after NAC and RC for MIBC. 8% of patients undergoing NAC and achieving < ypT2N0 at RC recurred. Residual ypTa and ypT1 disease conferred a significantly higher risk of recurrence, while ypTis did not; female sex was associated with a lower risk of recurrence. Importantly, the type of cisplatin-based NAC regimen used was not an independent predictor of recurrence.

PD60-04 SURVIVAL ANALYSIS AND PREDICTORS OF NON-MUSCLE INVASIVE BLADDER CANCER RECURRENCE IN CLINICAL COMPLETE-RESPONDERS AFTER NEOADJUVANT CHEMOTHERAPY FOR MUSCLE-INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Invasive VI (PD60)1 Apr 2020PD60-04 SURVIVAL ANALYSIS AND PREDICTORS OF NON-MUSCLE INVASIVE BLADDER CANCER RECURRENCE IN CLINICAL COMPLETE-RESPONDERS AFTER NEOADJUVANT CHEMOTHERAPY FOR MUSCLE-INVASIVE BLADDER CANCER Helena Vila-Reyes*, Kevin Lee, G.Joel Decastro, Gen Li, Christopher R. Haas, Jamie S. Pak, Izak Faiena, Christopher B. Anderson, and James M. McKiernan Helena Vila-Reyes*Helena Vila-Reyes* More articles by this author , Kevin LeeKevin Lee More articles by this author , G.Joel DecastroG.Joel Decastro More articles by this author , Gen LiGen Li More articles by this author , Christopher R. HaasChristopher R. Haas More articles by this author , Jamie S. PakJamie S. Pak More articles by this author , Izak FaienaIzak Faiena More articles by this author , Christopher B. AndersonChristopher B. Anderson More articles by this author , and James M. McKiernanJames M. McKiernan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000977.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical cystectomy (RC) with neoadjuvant chemotherapy (NAC) is the gold standard treatment for muscle-invasive bladder cancer (MIBC), but 30-40% of the patients achieve a clinical complete response (cCR) after NAC. In cT0 patients who elect bladder preservation, non-muscle invasive (NMIBC) and MIBC relapses may appear during the follow-up. The outcomes of MIBC relapse have been extensively assessed, while NMIBC have been less studied. We report the outcomes and predictive factors related to NMIBC recurrence in patients with cCR following NAC for MIBC who elected surveillance. METHODS: We retrospectively reviewed our cohort of cCR after NAC for MIBC, and selected patients who chose subsequent bladder preservation. Clinical T0 status was assessed with negative re-TURBT, cytology and imaging after NAC. Patients with immediate partial or RC post-NAC and those with positive lymph nodes or metastases pre-NAC, were excluded. Uni- and multivariate models were used to identify predictive factors of NMIBC recurrence and response rate to BCG-treatment. Kaplan Meier estimator and log-rank test were used for survival analysis. RESULTS: We identified 60 patients with cCR from 2001-2019, with a median follow-up of 51.4 mo (IQR 26.3-79.5). Median age at diagnosis was 70 years (IQR 63-75) and 50 (83%) were men. Nine (15%) patients experienced MIBC relapse and were excluded from the study. 51 patients were finally analyzed. Thirteen (25%) patients had previous NMIBC history and 85% of them had received BCG at some point before NAC. Twenty-five (49%) experienced NMIBC recurrences. Only the presence of CIS before NAC was a predictive factor for NMIBC recurrence (OR 4.28 (95% CI [1.07-17.14], p=0.04). Fifteen (60%) patients received BCG, with stages: cTa - 5 (33%), cT1 - 1 (7%) and cTis - 9 (60%). 7 of them (47%) had complete durable responses (median follow-up of 67.4 months). Patients who had CIS at TURBT pre-NAC had a non-significant trend to lower response to BCG (OR 0.13 (95% CI [0.01-1.33], p=0.086). When comparing the NMIBC group with those who did not recur, no differences were observed in terms of metastases-FS, CSS and OS (p=0.26, 0.70 and 0.50, respectively). CONCLUSIONS: Patients with previous MIBC and cCR to NAC who had NMIBC recurrence don’t seem to have a worse MFS, CSS or OS, when compared to those who did not recur. Only CIS pre-NAC was identified as a factor for NMIBC recurrence. Larger series are necessary to identify if there is any predictive factor for BCG-response in NMIBC recurrences following cCR. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1274-e1274 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Helena Vila-Reyes* More articles by this author Kevin Lee More articles by this author G.Joel Decastro More articles by this author Gen Li More articles by this author Christopher R. Haas More articles by this author Jamie S. Pak More articles by this author Izak Faiena More articles by this author Christopher B. Anderson More articles by this author James M. McKiernan More articles by this author Expand All Advertisement PDF downloadLoading ...

Impact of histology and toxicities on outcomes of patients with muscle invasive bladder cancer receiving neoadjuvant chemotherapy.

540 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) extends survival in muscle invasive bladder cancer (MIBC) patients (pts). Pathologic complete response (pCR) is associated with survival. We conducted a retrospective study to examine the prognostic impact of other variables including histologic subtype, location, multifocality, margins, size of tumor and toxicities. Methods: Pts who underwent RC at Dana-Farber for MIBC stage T2-T4N0-1 were studied. Data were collected for demographics, clinical and pathologic variables. Descriptive stats were reported, and Cox proportional hazards regression analyses were conducted to examine the association with recurrence-free survival (RFS) and overall survival (OS). Results: From 2002 to 2018, 150 patients were available. The median age was 66 (range 36-89) and 102 (68%) were male. MVAC/dose dense MVAC, GC and other non-standard regimens were given in 42 (28%), 85 (56.7%) and 23 (15.3%) pts, respectively. The 2-yr RFS was 63.6%, the 5-yr OS was 68.7% and pCR occurred in 38 pts (25.3%). Multivariable analysis identified pure urothelial carcinoma in the residual tumor and absence of pathologic response to be associated with poor RFS and OS. Positive margins were associated with poor RFS, while grade ≥3 toxicities were associated with poor OS. Conclusions: Pure urothelial carcinoma histology was associated with worse RFS and OS following RC after NAC for MIBC, suggesting molecular studies may be useful in these cases. The association of severe toxicities with poor OS suggests that optimal pt selection for NAC and early recognition of toxicities is important.[Table: see text]

Neoadjuvant chemotherapy for bladder cancer

Background: Muscle invasive bladder cancer (MIBC) is an aggressive malignancy, with 5-year survival rates ranging from 36% to 48% for pT3-4/pN+ tumors. Radical cystectomy (RC) remains the gold-standard treatment for the management of MIBC. Perioperative treatment can improve overall survival (OS), with more robust evidence favoring neoadjuvant chemotherapy (NAC). Objective: This review aims to discuss the historical perspectives, recent advances, experimental therapies, and current evidence for the use of various chemotherapeutic drugs in a neo-adjuvant setting for the treatment of MIBC. Data Sources: We searched and analyzed research articles, reviews, clinical trials, and meta-analyses addressing NAC in the management of MIBC. Results: The advantages of NAC in MIBC include the delivery of chemotherapy at the earliest time point when the micrometastatic burden is presumed to be the lowest. It has improved patient compliance and better tolerability in preoperative period with more number of patients completing the therapy. It reflects in vivo chemosensitivity of urothelial cancer along with favorable pathological outcomes in individual showing response. Delay in RC in nonresponders and overtreatment in low-stage disease are the potential disadvantages. Conclusion: NAC in MIBC is associated with improved OS. Cisplatin-based NAC is the current standard of care in eligible patients.

Trend in the use of neo-adjuvant chemotherapy for the management of muscle invasive bladder cancer at a major tertiary care hospital in Pakistan.

e16033 Background: Although the use of Neoadjuvant Chemotherapy (NAC) has now become the standard of care for Muscle Invasive Bladder Cancer (MIBC) in the world, most patients in lower- middle-income countries (LMIC), like Pakistan, are still undergoing upfront surgery despite being ideal candidates for chemotherapy. Multi-disciplinary tumor boards have been critical in the change of this trend in the developed world. We aimed to assess the trends in the use of NAC for patients with muscle invasive bladder cancer before undergoing definitive surgery. Methods: We included patients who underwent surgery for ≥ cT2 MIBC without distant metastasis between 2011 and 2015 at a tertiary care hospital in Karachi, Pakistan. We retrospectively assessed the trends in NAC compared to upfront surgery in these patients. Results: Among the 171 patients included in our study, only 4 (2.34%) received NAC, whereas the other 167 (97.67%) underwent upfront surgery without NAC. Out of the 90 patients who underwent surgery for MIBC between 2011 and 2013, none of them received NAC and underwent upfront surgery. Among the 81 patients with MIBC in 2014 and 2015, 4 patients received NAC before surgery whereas the other 77 underwent upfront surgery. Conclusions: The adoption of NAC for MIBC remains a challenge in lower- middle-income countries such as Pakistan. Introduction of a multidisciplinary tumor board in our hospital since 2014 has shown a slight change in this trend. Better communication between different departments remains the key in significantly changing the trend of a much desired standard of care.

The impact of neoadjuvant chemotherapy (NAC) on conditional survival (CS) among patients with muscle-invasive bladder cancer (MIBC).

520 Background: Achieving a pathologic complete response (pCR) with NAC for MIBC is associated with a favorable prognosis. Patients with pathologic residual disease (pRD) generally have poor outcomes. However, prognosis after radical cystectomy (RC) improves with ongoing survivorship. Whether the difference in prognosis of patients with pCR and pRD is sustained over time has not been explored. Methods: We queried the National Cancer Database for patients who received NAC and RC for clinically localized MIBC (cT2-T4aN0M0) between 2002-2010. We identified patients with pCR (</= pTis) and pRD. Using Kaplan-Meier analysis, we assessed CS up to 5 years given survivorship of 0-4 years using log-rank test with multiple comparison adjustment. Results: The cohort comprised 1,554 patients (pCR: 314, pRD: 1,240). The median follow up was 2.38 (0.04-9.60) and 2.76 (0.01-9.97) years for pCR and pRD, respectively. Patients with pCR had lower stage (cT2= 79% vs. 72%; cT3= 14% vs. 18%; cT4= 7% vs. 10%), more recent diagnosis (2010: 31% vs. 19%), and were more often treated at a high-volume center (>15 RC/year: 61% vs. 49%). Patients with pCR had improved CS relative to those with pRD with survivorship up to 3 years, but the benefit associated with pCR becomes attenuated from 4 years post-RC (Table). Conclusions: MIBC patients with pRD after NAC have worse CS up to years 3 post-RC, but this difference diminishes after 4 years. These findings may inform patient counseling, surveillance intensity, and novel adjuvant approaches for patients with pRD, and are subject to confirmation with a forthcoming multivariable analysis. Probability of surviving to X years (95% CI). [Table: see text]

Association between the Absolute Baseline Lymphocyte Count and Response to Neoadjuvant Platinum-based Chemotherapy in Muscle-invasive Bladder Cancer

AimsPlatinum-based neoadjuvant chemotherapy (NAC) improves overall survival in muscle-invasive bladder cancer (MIBC). A pathological complete response (pCR) at radical cystectomy after NAC is associated with better overall survival, but there are no established predictive biomarkers of response to NAC in MIBC. The aim of this study was to find laboratory variables associated with pCR following NAC. Materials and methodsWe carried out a retrospective review of MIBC patients treated with NAC followed by radical cystectomy at the Sheba Medical Center between 2005 and 2015. Overall survival was calculated using the Kaplan–Meier product-limit method and compared between patients who achieved or did not achieve pCR using the Log-rank test. Baseline and pre-surgery laboratory values were collected and compared between patients who subsequently achieved pCR and those who did not using logistic regression. ResultsFifty-eight patients underwent radical cystectomy after NAC, with a median follow-up of 32 (range 4.8–111.4) months from diagnosis. Of 55 patients with documented pathological outcome on radical cystectomy, 17 (31%) achieved pCR (complete responders). Of the 15 complete responders with follow-up data, 13 (87%) were still alive at time of last follow-up for this study (July 2015). Patients who did not achieve pCR had a significantly worse overall survival than complete responders (P = 0.0007). The baseline lymphocyte count, neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) were significantly associated with response (P = 0.037, P = 0.045, P = 0.042, respectively) on univariate analysis, whereas baseline albumin, haemoglobin, neutrophils, platelets and the total white blood count were not significantly associated with response. Lymphocyte counts were significantly higher in responders than non-responders throughout three time points (P = 0.003 using a generalised linear mixed model). ConclusionsA high baseline level of lymphocytes is associated with the achievement of pCR at radical cystectomy after NAC, which, in turn, is associated with a significantly longer overall survival. Our results suggest that chemosensitivity in MIBC is associated with lymphocyte count.