Retrospective analysis of multiparametric MRI in Predicting Complete Pathologic Response of Neo-adjuvant Chemotherapy in Bladder Cancer

Retrospective analysis of multiparametric MRI in Predicting Complete Pathologic Response of Neo-adjuvant Chemotherapy in Bladder Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Retrospective analysis of multiparametric MRI in Predicting Complete Pathologic Response of Neo-adjuvant Chemotherapy in Bladder Cancer Daan De Maeseneer, Pieter De Visschere, Mats Van den Broecke, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4497035/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Oct, 2024 Read the published version in BMC Medical Imaging → Version 1 posted 11 You are reading this latest preprint version Abstract Background Muscle invasive bladder cancer (MIBC) treatment combines systemic therapy and radical cystectomy (RC) or local (chemo-)radiotherapy. Response to systemic therapy is an important outcome predictor but is difficult to assess pre-operatively. Methods We analyzed multiparametric MRI (mpMRI) in consecutive MIBC patients receiving cisplatin-based neo-adjuvant chemotherapy at our institution. Two readers, blinded for pathological outcome, independently scored mpMRI before and after 2 and 4 cycles using both a qualitative 3-step method and nacVI-RADS. We analyzed accuracy of mpMRI scores to predict pathologic complete response (pCR) and inter-observer agreement. Results We analyzed 46 patients receiving NAC, 6 patients did not undergo RC after NAC and were excluded. Eleven out of 40 (28%) patients showed a pCR. mpMRI could be assessed in over 90% of patients. Radiographic complete response (rCR) using both methods was significantly associated with pCR, with an overall specificity of 96% and sensitivity of 36% and a high inter-observer agreement. rCR as assessed by the 3-step score was significantly associated with disease free survival (DFS) benefit. Conclusion The use of nacVI-RADS can predict pCR after NAC with high specificity but low sensitivity and a high inter-observer agreement. A 3-step score adds value in determining local residual disease, rCR assessed by this method could correlate with DFS benefit. mpMRI scores should be prospectively assessed in future trials of multimodal management of MIBC and can be a predictive asset in routine clinical management. Bladder cancer Multiparametric MRI Neoadjuvant chemotherapy Pathologic complete response radiographic complete response. Figures Figure 1 Figure 2 Take Home Message mpMRI can be used to evaluate response to neo-adjuvant chemotherapy (NAC) in muscle-invasive Bladder Cancer using nacVI-RADS Radiologic complete response (rCR) on mpMRI can accurately predict complete pathological response Adding a 3-step assessment to nacVI-RADS, improves residual disease assessment and could be included in future versions of nacVI-RADS Patient Summary Not all patients respond to systemic therapy in muscle invasive bladder cancer, using MRI we can better determine which patients did respond before undergoing surgery improving outcome prediction and impacting treatment choice. Background Worldwide, bladder cancer is the 12th most diagnosed cancer. In Western Europe and Northern America age-standardized rate is 20/10000 in men and 5/10000 in women ( 1 ). Age standardized rate of mortality is 5.2 / 100,000 in men (8th of all cancers) and 2.2/100,000 in women (14th of all cancers). Radical cystectomy (RC) with pelvic node dissection is the gold standard in treating muscle invasive bladder cancer (MIBC) ( 2 ). A meta-analysis of neo-adjuvant chemotherapy (NAC) in MIBC showed a 16% reduction in overall death risk compared to locoregional therapy alone, especially in node negative patients ( 3 ). NAC probably reduces the risk of peri-operative spill of tumor cells and lowers the burden of micro-metastatic disease, but in non-responders could also delay curative treatment. Response to NAC regimens depend on the type of cisplatin based regimen, 50–60% of patients with MIBC will have residual invasive disease at RC ( 4 , 5 ). The VESPER trial showed superior pathological response rates of dose dense cisplatin-methotrexate-vinblastin-doxorubicin (ddMVAC) compared to cisplatin-gemcitabine ( 6 ). Radiological assessment of response to NAC in MIBC is difficult. Clinical staging including Computed Tomography (CT) imaging will understage MIBC in a significant number of patients ( 7 ). In contrast, a recent study showed downstaging on CT after completion of NAC is a strong predictor of overall survival ( 8 ). Multiparametric magnetic resonance imaging (mpMRI) of the bladder guidelines have been developed. mpMRI has a high accuracy in local staging of MIBC before treatment ( 9 ) and downstaging on mpMRI performed 24 hours after NAC and before surgery showed promising results in early prediction of pathologic response ( 10 ). A novel categorical staging system was proposed based on sequential Vesical Imaging-Reporting and Data System (VI-RADS) evaluation, the Neo-Adjuvant Chemotherapy VI-RADS (nacVI-RADS) ( 11 ). The objective of this study is to assess the accuracy of mpMRI in predicting complete pathologic response after NAC in MIBC patients using both nacVI-RADS and a 3-step qualitative assessment first proposed by Necchi et al ( 12 ). Methods Design, Setting, and participants We identified consecutive patients treated with ddMVAC for NAC for MIBC from 2013 to 2019 at our institution using an electronic chemotherapy database. Patient characteristics including age, sex, prior treatment for non-MIBC, smoking history and pathological results of TURBT were extracted from the database. Patients with predominantly variant (> 50%) histologies at diagnosis were excluded, squamous differentiation was allowed. All patients included were cisplatin eligible with normal left ventricular function and adequate renal function. In concordance with our institution’s guidelines, mpMRI was scheduled before, after 2 cycles to detect early disease progression, and after 4 cycles of ddMVAC. Patients who ultimately did not undergo RC were excluded from this analysis. mpMRI assessment mpMRI were all performed on a 3.0T MRI system (Magnetom Prisma Fit, Siemens, Erlangen, Germany), with an external phased-array surface coil. In the patient preparation motion and susceptibility artifacts were reduced by intravenous administration of 1 ml Hyoscine butylbromide (Buscopan®). The imaging protocol consisted of 1 mm coronal three-dimensional spin echo (T2-SPACE) with 3 mm orthogonal reconstructions in the sagittal and axial planes, 4 mm sagittal and axial turbo spin echo T2-WI without fat suppression, 4 mm axial turbo spin echo T1-WI, 4 mm axial DWI EP2d with b values 50, 400, 800 and calculated b1200 and corresponding ADC map. 3,5 mm axial T1-WI (VIBE-TWIST) dynamic contrast enhanced series and 4 mm axial turbo spin echo T1-WI after Gadolinium. The entire pelvis was imaged from the aortic bifurcation to the inferior margin of the pubic symphysis, including the whole bladder, proximal urethra, pelvic nodes and in males the prostate. Outcome measurement MRI characteristics All mpMRI were independently reviewed by two radiologists, one with more than 10 years of experience in BC imaging and one fifth-year resident. Both readers were blinded to the final pathology. The readers scored for VI-RADS and nacVI-RADS after 2 and 4 cycles of chemotherapy described elsewhere in detail ( 11 ). Two radiologists independently scored mpMRI images pre-, during and post-treatment on a 5-point scale, after which a consensus scoring was reached. Scores 1 and 2 define radiographic complete response (rCR) in nacVI-RADS. Additionally, the readers used a 3-step score to characterize the following parameters: residual disease at T1-WI and T2-WI, presence of hyperintense spots within the bladder wall on DWI, and presence of pathological contrast enhancement on DCE MRI ( 12 ). For step 1, Yes was considered when there was an intravesical nodule, mass or wall thickening with intermediate signal intensity to urine and muscle on T2-WI with or without soft tissue nodularity along the serosal surface or perivesical fat stranding. No reference tissue for the signal intensity was used. For step 2, image analysis was performed qualitatively by means of visual assessment, whereby high signal on the high- b -value images corresponding to a low signal at ADC was defined as positive, i.e. suspicious for residual tumor tissue (‘yes’). The measurements were performed quantitatively by means of apparent diffusion coefficient (ADC) measurements on the ADC maps. After independent scoring, in a second session both readers reached consensus about the scores of the discordant cases. rCR is defined by ‘No’ on all three questions. When patients had more than one lesion, only the score of the lesion with the highest score was registered. Histopathologic evaluation All the RC procedures were carried out by the same experienced surgical team at our center. The cystectomy specimens were analyzed by an experienced genitourinary pathologist with more than 10 years of experience in bladder cancer. The pathology report served as the reference standard for all study cases and ypT0 was considered as pathologic complete response (pCR). Any tumor rest (including non-invasive carcinoma) on cystectomy was considered non-pCR (> ypT0). Endpoint The main endpoint of this study was the accuracy of rCR on mpMRI to predict pCR. Statistical analysis After anonymization of the database, descriptive statistics were used to describe patient characteristics and main findings in patients with a pCR and non-pCR. For the 3-step score each mpMRI step consisted of a dichotomous variable (yes or no), and the proportions of pCR of each question were calculated. Fisher’s exact test was used to determine statistical significance. A ROC analyses was performed using a multivariable model with output of accuracy results for negative answers on > = 1, >= 2, and 3 questions. The threshold for statistical significance was set at p < 0.05. nacVI-RADS was analyzed in the same manner, using score 1 and 2 for rCR. Inter-observer agreement was assessed using Cohen’s Kappa method. Unadjusted Cox regression was used to calculate equality of survival, patients entered analysis on date of TURBT and were censored on reoccurrence, death or last follow-up staging for DFS and death or last patient contact for OS. Cox regression analysis was performed for pCR and both rCR definitions at different time points. All statistical analysis was performed using STATA/IC 16.1 (StataCorp, Tx, USA). Results Patient and tumor characteristics Fifty-five consecutive patients received at least one cycle of ddMVAC at our institution for MIBC during the study period. In total 15 patients were excluded from this analysis as summarized in Fig. 1 . All included patients were staged with TURBT and mpMRI before start of NAC. Median time between TURBT and initiation of ddMVAC was 31 days (IQR 25–42). Eleven patients out of 40 (27%) showed a pCR after NAC (ypT0). Patient characteristics by pathological response are summarized in Table 1 and are typical for a MIBC population at a tertiary referral center. No significant differences were seen between the two cohorts, except for VI-RADS score before treatment (lower clinical stage in pCR cohort) and rate of hydronephrosis (higher rate in non-pCR). Table 1 Patient characteristics. Variables Non-pCR (ypT > 0) pCR (ypT0) N 29 11 Age at TURBT Median (years, IQR) 64 (55–71) 68 (55–70) Time from TURBT to first mpMRI Median (days, IQR) 18 (-1–27) 24 (-3–59) Time from TURBT to start NAC Median (days, IQR) 29 (21–41) 35 (31–74) Gender Male Female 23 (79%) 6 9 (82%) 2 Smoking History Never smoked Current smoker Former smoker N (%) 9 (31%) 10 (34%) 10 (34%) 3 (27%) 4 (36%) 4 (36%) rT stage (mpMRI) rT0 rT2 rT3-4 missing 0 4 20 5 0 1 7 3 VIRADS * 1 2 3 4 5 0 0 3 2 24 3 0 1 0 7 Hydronephrosis ** Yes 15 (52%) 1 (9.1%) Previous history of NMIBC Yes 7 (24%) 2 (18%) Previous BCG treatment Yes 4 (14%) 1 (9.1%) Histology at TURBT Pure UC 27 (93%) 10 (91%) Number of cycles NAC 1 2 3 4 1 1 2 25 (86%) 0 1 0 10 (91%) Time from last cycle NAC to cystectomy Median (days, IQR) 33 (27–43) 37 (29–43) * p value: 0.04 ** p value: 0.01 Pathological Response prediction with post-therapy mpMRI All mpMRI images were analyzed using nacVI-RADS and the 3-step procedure as described above. Three patients could not be included in the 3-step analysis (7.5%), in 1 patient question 2 could not be assessed (due to artifacts on the diffusion weighted images caused by hip prosthesis), in 2 patients question 3 could not be assessed (dynamic contrast enhanced imaging could not be performed because of chronic kidney disease). Results are summarized in Table 2 . Table 2 summary of results nacVI-RADS (A) and 3-step score (B) A nac-ViRADS score N ypT0 (%) ypT > 0 (%) 1 4 3 (27%) 1 (3.4%) 2 2 1 (9.1%) 1 (3.4%) 3 4 0 (0%) 4 (14%) 4 24 5 (45%) 19 (66%) 5 6 2 (18%) 4 (14%) B Step 1 Step 2 Step 3 N ypT0 (%) ypT > 0 (%) Yes Yes Yes 11 1 (9.1%) 10 (38%) Yes No No 3 2 (18%) 1 (3.8%) Yes No Yes 13 3 (27%) 10 (38%) No No No 5 4 (36%) 1 (3.8%) No No Yes 5 1 (9.1%) 4 (15%) The nacVI-RADS (Table 2 A) scores of 1 or 2 define rCR. Two patients did show residual disease at pathology in rCR group, 7 patients without rCR using this method, did have a pCR at cystectomy. For the 3-step score rCR was defined as ‘No’ on all three questions. This was seen in 4 of pCR patients and only in 1 of non-pCR patients. Seven patients were inaccurately staged as non-rCR but with pCR on cystectomy. Only one patient was inaccurately staged as rCR and not pCR. The one patient with rCR and no pCR did show a very significant response (iT4a lesion to ypT2 lesion). Statistical analysis of mpMRI methods resulted in a significant association between pCR and rCR, using both nacVI-RADS (p 0.04) and the 3-step score (p 0.02) (Table 3 ). Table 3 Predictive value of rCR on pCR, expected frequencies (if H0 = true). A. Radiographic evaluation using nacVì-RADS Radiographic complete response No (N) (exp) Yes (N) (exp) Pathologic Complete Response No 27 ( 25 ) 2 ( 4 ) 29 Yes 7 ( 9 ) 4 ( 2 ) 11 34 6 40 Fisher's exact = 0.04 B. Radiographic evaluation using 3-step score Radiographic complete response No (N) (exp) Yes (N) (exp) Pathologic Complete Response No 25 ( 23 ) 1 ( 4 ) 26 Yes 7 ( 10 ) 4 ( 1 ) 11 32 5 37 Fisher's exact = 0.02 mpMRI predicted accurately pCR in 78% (both methods) of patients with a specificity of 93% (nacVI-RADS) and 96% (3-step score). Sensitivity was low using both rCR definitions (both 36%). Positive predictive value was 80%. Images 1 to 3 show examples of a true positive, a true negative and a false positive mpMRI (supplementary material). Inter-observer agreement Agreement between observers using the 3-step score was substantial (72%, Kappa 0.61). Agreement between the 2 readers on VIRADS was moderate to near perfect after C2 and C4. nacVI-RADS scoring showed agreement in 80–98% of cases, with substantial to near perfect Kappa values (Table 4 ). Table 4: Inter-observer agreement nacVI-RADS Survival analysis We performed an exploratory survival analysis. At time of analysis, median follow-up of survivors was 58 months (IQR 43–71). Disease reoccurred in 13 patients within first 24 months, of whom 8 had a local reoccurrence. Ten patients died during follow-up, only 1 patient without prior disease reoccurrence. Median overall survival (mOS) and disease-free survival (mDFS) was not reached for the whole study group. No disease reoccurrence and only 1 death was noted in the pCR group. Regarding mpMRI defined groups, only in the “yes, yes, yes” group mOS was reached (40 months, 95% CI 14 - NR). Using nacVI-RADS, mOS was only reached in group 5 evaluated after cycle 2 (39 months, 95% CI 14 -NR). DFS in pCR patients is significantly higher compared to non-pCR patients (Cox p 0.01). Analysis of mpMRI defined groups showed a significant DFS benefit for rCR patients using the 3-step score (p 0.02), but not for nacVI-RADS (p 0.2) (Fig. 2 ). Again “yes-yes-yes” on 3-step score reached mDFS of 20 months (8.4 - NR). Using nacVI-RADS both scores 3 and 5 reached mDFS after cycle 2 and 4 (16 months and 27 months, resp), regression analysis however did not show significant differences in DFS according to nacVI-RADS grouping at both time points. Discussion We present the results of a retrospective study in a university hospital focusing on pCR prediction using two mpMRI scoring systems after NAC for MIBC. Our results show that using mpMRI for response evaluation after NAC is feasible, less than 10% could not be evaluated using the three-step method, all included cases could be evaluated by nacVI-RADS. mpMRI could accurately predict pCR in 78% of patients with a specificity of 96% (3-step score) and 93% (nacVI-RADS), but low sensitivity. Inter-observer agreement was very high for both methods. pCR and rCR measured by the 3-step score (but not by nacVI-RADS) was significantly associated with DFS benefit. In our series pCR was achieved in 28% of patients. This is lower than historical SWOG 8710 trial data (38%) and a more recent retrospective analysis (41%) by Peyton et al.( 5 , 13 ) Possible explanations are the strict definition of pCR (excluding ypTis), higher percentage of > = T3 tumors (68%), and high percentage of hydronephrosis (40%) which is a known negative prognostic factor.( 14 ) Only one patient with hydronephrosis at diagnosis showed a pCR. The number of patients receiving > = 3 cycles of ddMVAC was very similar to the data from the large retrospective analysis of Peyton et al. (91%). Using the 3-step score, we found a lower proportion of patients with a rCR on MRI (9.1%), compared to the analysis of data from the PURE-01 study evaluating neo-adjuvant pembrolizumab (31%-44%).( 12 ) The value of interim assessment with mpMRI after 2 cycles is difficult to assess in our study. Significant disease progression on interim mpMRI frequently results in omission of cystectomy in our center and thus exclusion from this study. The question remains if de-escalation of NAC is possible in patients with no residual disease after 2 cycles, in our study with predominantly high-risk patients this was the case in 2 patients (5%). Major limitations to this study are the limited number of patients in this single institution analysis. The retrospective nature of the study is partly mitigated by the blinding of the readers to the pathological results and subsequent treatment decisions. Imaging guidelines propose mpMRI or CT scan before the start of NAC but not after completion of NAC. Historical data show a very poor correlation between clinical staging and definitive pathological staging at RC, with around 40% being upstaged.( 15 ) Assessing tumor response on imaging has been become more prominent, especially in trials investigating bladder sparing strategies (RETAIN trial NCT02710734, ALLIANCE NCT03609216, BLADDERPATH trial). Compared to pathological staging using TURBT, imaging is less invasive, can be more standardized and is able to assess extravesical disease. In a large retrospective analysis of TURBT post-NAC, only one in three patients were accurately staged compared to the final RC specimen.( 16 ) mpMRI in bladder cancer has been standardized using VI-RADS.( 17 ) Prospective validation of the VI-RADS has shown to accurately differentiate between MIBC and non-MIBC.( 18 , 19 ) mpMRI characteristics have also been included in tools to predict response to NAC.( 20 ) Some promising results in this setting have been reported, using DWI the ADC values appeared to be significantly more heterogeneous in non-responders,( 21 ) but they are insufficiently reliable. Post-treatment interpretation of MRI is often challenging because previous TURB and bladder instillations may cause edema, inflammation and fibrosis in the bladder wall and surrounding perivesical tissues, making it difficult to distinguish between residual BC and benign treatment-related effects.( 21 – 23 ) After TURB, DCE and even more DWI seem to improve the differentiation between TURB related effects and residual tumor.( 24 , 25 ) After chemoradiotherapy, Yoshida et al ( 26 ) reported that T2-WI alone had low sensitivity, specificity and accuracy to predict pCR (43%, 45% and 44%, respectively). DWI was significantly superior in specificity (92%) and accuracy (80%) as compared to T2 and DCE (18 and 33% respectively), but all sequences showed poor sensitivity for detecting residual disease (43–57%). Persisting early enhancement on DCE, or no increase in ADC from baseline on DWI are indicative of poor chemotherapy response.( 27 ) RECIST 1.1 criteria fail to assess NAC for MIBC because often only bladder wall thickening is present without measurable nodular lesions.( 28 ) Similarly, the five-point VI-RADS scoring system is mainly developed to suggest the likelihood of detrusor muscle invasion in untreated patients (or patients having received only diagnostic TURB).( 17 ) In our study, many VI-RADS 5 patients at onset remained VI-RADS 5 after NAC although the size of the tumor was clearly reduced, and many VI-RADS 2 or 1 lesions (biopsy proven MIBC but not confirmed on imaging) remained VI-RADS 2 or 1 after NAC. The recently proposed nacVI-RADS more accurately scores for these changes. However, by introducing the 3-step scoring system local response evaluation was more reader-friendly, more accurate in assessing residual disease and turned out to be a better predictor of DFS. We propose to add this 3-step method to the nacVI-RADS evaluation of residual disease. The observation of rCR with high specificity after NAC holds the potential implication of omitting further pathological staging before definitive treatment or de-escalating treatment. Especially in bladder sparing treatment strategies this would be advantageous for patients because risk of residual disease in case of rCR on mpMRI would be very low. A rCR on post-NAC mpMRI would also be a prognostic parameter, as it predicts DFS in our study and is significantly correlated with pCR following NAC which is associated with improved survival.( 29 – 31 ) Conclusions mpMRI can predict pCR after neo-adjuvant cisplatin-based chemotherapy with high specificity but low sensitivity. Adding a 3-step score to nacVI-RADS improves evaluation of residual disease, using this assessment rCR was significantly correlated with DFS. mpMRI should be included in future prospective trials of multimodal management of MIBC and can be an important predictive asset in routine clinical management. Abbreviations mpMRI multiparametric magnetic resonance imaging NAC Neo-Adjuvant Chemotherapy VI-RADS Vesical Imaging-Reporting and Data System rCR radiologic Complete Response MIBC Muscle Invasive Bladder Cancer RC radical cystectomy pCR pathologic Complete Response DFS Disease-free Survival ddMVAC dose-dense Methotrexate-Vinblastin-Doxorubicin-Cisplatin CT Computed Tomography TURBT Trans-Urethral Resection of the Bladder ADC Apparent Diffusion Coefficient DWI Diffusion Weighted Imaging ROC Receiver Operating Characteristic IQR interquartile range OS overall survival Declarations Ethical approval and consent to participate declarations This study was approved by the ethics committee at Ghent University Hospital, Belgium. After reviewing the project application, due to the retrospective nature of this study, the necessity of individual patient informed consent was waived. All methods and procedures in this study were carried out in accordance with relevant guidelines and regulations Consent for publication The use of images and data falls within the institutional consent form at Ghent University Hospital, Belgium. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests that are directly or indirectly related to the work submitted for publication. Funding The authors did not receive support from any organization for the submitted work. Authors’ contributions Daan De Maeseneer: Project development, Data collection and management, Data analysis, Manuscript writing. Pieter De Visschere: Data collection, Data analysis, Manuscript editing. Mats Van den Broecke: Data collection Felix Delbare: Data collection Geert Villeirs: Data collection, Manuscript editing. 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Dynamic contrast-enhanced MRI in patients with muscle-invasive transitional cell carcinoma of the bladder can distinguish between residual tumour and post-chemotherapy effect. Eur J Radiol. 2013;82(12):2161–8. Husband JE, Schwartz LH, Spencer J, Ollivier L, King DM, Johnson R, et al. Evaluation of the response to treatment of solid tumours - a consensus statement of the International Cancer Imaging Society. Br J Cancer. 2004;90(12):2256–60. Meyer A, Ghandour R, Bergman A, Castaneda C, Wosnitzer M, Hruby G, et al. The natural history of clinically complete responders to neoadjuvant chemotherapy for urothelial carcinoma of the bladder. J Urol. 2014;192(3):696–701. Mazza P, Moran GW, Li G, Robins DJ, Matulay JT, Herr HW, et al. Conservative Management Following Complete Clinical Response to Neoadjuvant Chemotherapy of Muscle Invasive Bladder Cancer: Contemporary Outcomes of a Multi-Institutional Cohort Study. J Urol. 2018;200(5):1005–13. Robins D, Matulay J, Lipsky M, Meyer A, Ghandour R, DeCastro G, et al. Outcomes Following Clinical Complete Response to Neoadjuvant Chemotherapy for Muscle-invasive Urothelial Carcinoma of the Bladder in Patients Refusing Radical Cystectomy. Urology. 2018;111:116–21. Additional Declarations No competing interests reported. Supplementary Files Image1truepositive.tif Image2truenegative.tif Image3falsepositive.tif Legendsupplementary.docx Cite Share Download PDF Status: Published Journal Publication published 07 Oct, 2024 Read the published version in BMC Medical Imaging → Version 1 posted Editorial decision: Revision requested 23 Jul, 2024 Reviews received at journal 21 Jul, 2024 Reviewers agreed at journal 30 Jun, 2024 Reviewers agreed at journal 28 Jun, 2024 Reviews received at journal 23 Jun, 2024 Reviewers agreed at journal 03 Jun, 2024 Reviewers invited by journal 03 Jun, 2024 Editor invited by journal 03 Jun, 2024 Editor assigned by journal 03 Jun, 2024 Submission checks completed at journal 03 Jun, 2024 First submitted to journal 29 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4497035","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":314183617,"identity":"4e092a82-8931-4244-b16c-de4fea603374","order_by":0,"name":"Daan De 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12:24:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4497035/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4497035/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12880-024-01441-y","type":"published","date":"2024-10-07T15:57:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58596924,"identity":"bcee1c5a-af16-4aee-8a96-356aa0e4063a","added_by":"auto","created_at":"2024-06-18 16:54:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":84417,"visible":true,"origin":"","legend":"\u003cp\u003eSTARD: Standards for Reporting of Diagnostic Accuracy Studies. rCR: radiographic complete response. mpMRI: multi-parametric magnetic resonance imaging. pCR: pathologic complete response.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4497035/v1/aaac70f2b7123763b7f40eca.png"},{"id":58596922,"identity":"5a8da9a4-01a8-4609-ad7f-e6ae9386f771","added_by":"auto","created_at":"2024-06-18 16:54:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":81362,"visible":true,"origin":"","legend":"\u003cp\u003eDisease Free survival estimates. pCR: pathologic complete response. rCR: radiographic complete response.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4497035/v1/ca763458603ac610e06257f4.png"},{"id":66597097,"identity":"0d7cd2c9-436d-461a-8042-4bdf7ac2d321","added_by":"auto","created_at":"2024-10-14 16:07:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":849700,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4497035/v1/0e7c6783-b6f1-4248-bbfb-c2c4f0fec7fb.pdf"},{"id":58596926,"identity":"44a05919-a187-4437-b4f8-58af25b278af","added_by":"auto","created_at":"2024-06-18 16:54:20","extension":"tif","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":3551996,"visible":true,"origin":"","legend":"","description":"","filename":"Image1truepositive.tif","url":"https://assets-eu.researchsquare.com/files/rs-4497035/v1/7928f77bf9142e4095ea8d87.tif"},{"id":58596928,"identity":"57b8deee-bc4c-49b4-aeca-1ca48e97cb18","added_by":"auto","created_at":"2024-06-18 16:54:20","extension":"tif","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":1790912,"visible":true,"origin":"","legend":"","description":"","filename":"Image2truenegative.tif","url":"https://assets-eu.researchsquare.com/files/rs-4497035/v1/86912194373d1d3de3bb7fc5.tif"},{"id":58597744,"identity":"31c5082f-4b57-4985-b256-ba4f7de81455","added_by":"auto","created_at":"2024-06-18 17:02:20","extension":"tif","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":3434520,"visible":true,"origin":"","legend":"","description":"","filename":"Image3falsepositive.tif","url":"https://assets-eu.researchsquare.com/files/rs-4497035/v1/600a725dc905ffb5e6995ec6.tif"},{"id":58596923,"identity":"92c47809-a227-48ba-85cc-692d148cf7db","added_by":"auto","created_at":"2024-06-18 16:54:20","extension":"docx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":17434,"visible":true,"origin":"","legend":"","description":"","filename":"Legendsupplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-4497035/v1/e8abfd1dbabcf47b063ed17d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Retrospective analysis of multiparametric MRI in Predicting Complete Pathologic Response of Neo-adjuvant Chemotherapy in Bladder Cancer","fulltext":[{"header":"Take Home Message","content":"\u003cul\u003e\n \u003cli\u003empMRI can be used to evaluate response to neo-adjuvant chemotherapy (NAC) in muscle-invasive Bladder Cancer using nacVI-RADS\u003c/li\u003e\n \u003cli\u003eRadiologic complete response (rCR) on mpMRI can accurately predict complete pathological response\u003c/li\u003e\n \u003cli\u003eAdding a 3-step assessment to nacVI-RADS, improves residual disease assessment and could be included in future versions of nacVI-RADS\u003cbr\u003e\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Patient Summary","content":"\u003cp\u003eNot all patients respond to systemic therapy in muscle invasive bladder cancer, using MRI we can better determine which patients did respond before undergoing surgery improving outcome prediction and impacting treatment choice.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eWorldwide, bladder cancer is the 12th most diagnosed cancer. In Western Europe and Northern America age-standardized rate is 20/10000 in men and 5/10000 in women (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Age standardized rate of mortality is 5.2 / 100,000 in men (8th of all cancers) and 2.2/100,000 in women (14th of all cancers). Radical cystectomy (RC) with pelvic node dissection is the gold standard in treating muscle invasive bladder cancer (MIBC) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). A meta-analysis of neo-adjuvant chemotherapy (NAC) in MIBC showed a 16% reduction in overall death risk compared to locoregional therapy alone, especially in node negative patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). NAC probably reduces the risk of peri-operative spill of tumor cells and lowers the burden of micro-metastatic disease, but in non-responders could also delay curative treatment. Response to NAC regimens depend on the type of cisplatin based regimen, 50\u0026ndash;60% of patients with MIBC will have residual invasive disease at RC (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The VESPER trial showed superior pathological response rates of dose dense cisplatin-methotrexate-vinblastin-doxorubicin (ddMVAC) compared to cisplatin-gemcitabine (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRadiological assessment of response to NAC in MIBC is difficult. Clinical staging including Computed Tomography (CT) imaging will understage MIBC in a significant number of patients (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In contrast, a recent study showed downstaging on CT after completion of NAC is a strong predictor of overall survival (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Multiparametric magnetic resonance imaging (mpMRI) of the bladder guidelines have been developed. mpMRI has a high accuracy in local staging of MIBC before treatment (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and downstaging on mpMRI performed 24 hours after NAC and before surgery showed promising results in early prediction of pathologic response (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). A novel categorical staging system was proposed based on sequential Vesical Imaging-Reporting and Data System (VI-RADS) evaluation, the Neo-Adjuvant Chemotherapy VI-RADS (nacVI-RADS) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The objective of this study is to assess the accuracy of mpMRI in predicting complete pathologic response after NAC in MIBC patients using both nacVI-RADS and a 3-step qualitative assessment first proposed by Necchi et al (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign, Setting, and participants\u003c/h2\u003e \u003cp\u003eWe identified consecutive patients treated with ddMVAC for NAC for MIBC from 2013 to 2019 at our institution using an electronic chemotherapy database. Patient characteristics including age, sex, prior treatment for non-MIBC, smoking history and pathological results of TURBT were extracted from the database. Patients with predominantly variant (\u0026gt;\u0026thinsp;50%) histologies at diagnosis were excluded, squamous differentiation was allowed. All patients included were cisplatin eligible with normal left ventricular function and adequate renal function. In concordance with our institution\u0026rsquo;s guidelines, mpMRI was scheduled before, after 2 cycles to detect early disease progression, and after 4 cycles of ddMVAC. Patients who ultimately did not undergo RC were excluded from this analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003empMRI assessment\u003c/h2\u003e \u003cp\u003empMRI were all performed on a 3.0T MRI system (Magnetom Prisma Fit, Siemens, Erlangen, Germany), with an external phased-array surface coil. In the patient preparation motion and susceptibility artifacts were reduced by intravenous administration of 1 ml Hyoscine butylbromide (Buscopan\u0026reg;). The imaging protocol consisted of 1 mm coronal three-dimensional spin echo (T2-SPACE) with 3 mm orthogonal reconstructions in the sagittal and axial planes, 4 mm sagittal and axial turbo spin echo T2-WI without fat suppression, 4 mm axial turbo spin echo T1-WI, 4 mm axial DWI EP2d with b values 50, 400, 800 and calculated b1200 and corresponding ADC map. 3,5 mm axial T1-WI (VIBE-TWIST) dynamic contrast enhanced series and 4 mm axial turbo spin echo T1-WI after Gadolinium. The entire pelvis was imaged from the aortic bifurcation to the inferior margin of the pubic symphysis, including the whole bladder, proximal urethra, pelvic nodes and in males the prostate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measurement\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eMRI characteristics\u003c/h2\u003e \u003cp\u003e All mpMRI were independently reviewed by two radiologists, one with more than 10 years of experience in BC imaging and one fifth-year resident. Both readers were blinded to the final pathology. The readers scored for VI-RADS and nacVI-RADS after 2 and 4 cycles of chemotherapy described elsewhere in detail (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Two radiologists independently scored mpMRI images pre-, during and post-treatment on a 5-point scale, after which a consensus scoring was reached. Scores 1 and 2 define radiographic complete response (rCR) in nacVI-RADS.\u003c/p\u003e \u003cp\u003eAdditionally, the readers used a 3-step score to characterize the following parameters: residual disease at T1-WI and T2-WI, presence of hyperintense spots within the bladder wall on DWI, and presence of pathological contrast enhancement on DCE MRI (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). For step 1, Yes was considered when there was an intravesical nodule, mass or wall thickening with intermediate signal intensity to urine and muscle on T2-WI with or without soft tissue nodularity along the serosal surface or perivesical fat stranding. No reference tissue for the signal intensity was used. For step 2, image analysis was performed qualitatively by means of visual assessment, whereby high signal on the high-\u003cem\u003eb\u003c/em\u003e-value images corresponding to a low signal at ADC was defined as positive, i.e. suspicious for residual tumor tissue (\u0026lsquo;yes\u0026rsquo;). The measurements were performed quantitatively by means of apparent diffusion coefficient (ADC) measurements on the ADC maps. After independent scoring, in a second session both readers reached consensus about the scores of the discordant cases. rCR is defined by \u0026lsquo;No\u0026rsquo; on all three questions.\u003c/p\u003e \u003cp\u003eWhen patients had more than one lesion, only the score of the lesion with the highest score was registered.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eHistopathologic evaluation\u003c/h2\u003e \u003cp\u003eAll the RC procedures were carried out by the same experienced surgical team at our center. The cystectomy specimens were analyzed by an experienced genitourinary pathologist with more than 10 years of experience in bladder cancer. The pathology report served as the reference standard for all study cases and ypT0 was considered as pathologic complete response (pCR). Any tumor rest (including non-invasive carcinoma) on cystectomy was considered non-pCR (\u0026gt;\u0026thinsp;ypT0).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEndpoint\u003c/h2\u003e \u003cp\u003eThe main endpoint of this study was the accuracy of rCR on mpMRI to predict pCR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAfter anonymization of the database, descriptive statistics were used to describe patient characteristics and main findings in patients with a pCR and non-pCR. For the 3-step score each mpMRI step consisted of a dichotomous variable (yes or no), and the proportions of pCR of each question were calculated. Fisher\u0026rsquo;s exact test was used to determine statistical significance. A ROC analyses was performed using a multivariable model with output of accuracy results for negative answers on \u0026gt;\u0026thinsp;=\u0026thinsp;1, \u0026gt;= 2, and 3 questions. The threshold for statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. nacVI-RADS was analyzed in the same manner, using score 1 and 2 for rCR. Inter-observer agreement was assessed using Cohen\u0026rsquo;s Kappa method. Unadjusted Cox regression was used to calculate equality of survival, patients entered analysis on date of TURBT and were censored on reoccurrence, death or last follow-up staging for DFS and death or last patient contact for OS. Cox regression analysis was performed for pCR and both rCR definitions at different time points.\u003c/p\u003e \u003cp\u003eAll statistical analysis was performed using STATA/IC 16.1 (StataCorp, Tx, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient and tumor characteristics\u003c/h2\u003e\n \u003cp\u003eFifty-five consecutive patients received at least one cycle of ddMVAC at our institution for MIBC during the study period. In total 15 patients were excluded from this analysis as summarized in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eAll included patients were staged with TURBT and mpMRI before start of NAC. Median time between TURBT and initiation of ddMVAC was 31 days (IQR 25–42). Eleven patients out of 40 (27%) showed a pCR after NAC (ypT0). Patient characteristics by pathological response are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and are typical for a MIBC population at a tertiary referral center. No significant differences were seen between the two cohorts, except for VI-RADS score before treatment (lower clinical stage in pCR cohort) and rate of hydronephrosis (higher rate in non-pCR).\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient characteristics.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNon-pCR (ypT \u0026gt; 0)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epCR\u003c/p\u003e\n \u003cp\u003e(ypT0)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at TURBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (years, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (55–71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (55–70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTime from TURBT to first mpMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (days, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (-1–27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (-3–59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTime from TURBT to start NAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (days, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (21–41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (31–74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (79%)\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (82%)\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking History\u003c/p\u003e\n \u003cp\u003eNever smoked\u003c/p\u003e\n \u003cp\u003eCurrent smoker\u003c/p\u003e\n \u003cp\u003eFormer smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (31%)\u003c/p\u003e\n \u003cp\u003e10 (34%)\u003c/p\u003e\n \u003cp\u003e10 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (27%)\u003c/p\u003e\n \u003cp\u003e4 (36%)\u003c/p\u003e\n \u003cp\u003e4 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erT stage (mpMRI)\u003c/p\u003e\n \u003cp\u003erT0\u003c/p\u003e\n \u003cp\u003erT2\u003c/p\u003e\n \u003cp\u003erT3-4\u003c/p\u003e\n \u003cp\u003emissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVIRADS *\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHydronephrosis **\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious history of NMIBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious BCG treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistology at TURBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePure UC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (91%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of cycles NAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e25 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e10 (91%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTime from last cycle NAC to cystectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian (days, IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (27–43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (29–43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e* \u003cem\u003ep\u003c/em\u003e value: 0.04 ** \u003cem\u003ep\u003c/em\u003e value: 0.01\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003ePathological Response prediction with post-therapy mpMRI\u003c/h2\u003e\n \u003cp\u003eAll mpMRI images were analyzed using nacVI-RADS and the 3-step procedure as described above. Three patients could not be included in the 3-step analysis (7.5%), in 1 patient question 2 could not be assessed (due to artifacts on the diffusion weighted images caused by hip prosthesis), in 2 patients question 3 could not be assessed (dynamic contrast enhanced imaging could not be performed because of chronic kidney disease). Results are summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003esummary of results nacVI-RADS (A) and 3-step score (B) A\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003enac-ViRADS score\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eypT0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eypT \u0026gt; 0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (66%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eB\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStep 1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStep 2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStep 3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eypT0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eypT \u0026gt; 0 (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eThe nacVI-RADS (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA) scores of 1 or 2 define rCR. Two patients did show residual disease at pathology in rCR group, 7 patients without rCR using this method, did have a pCR at cystectomy. For the 3-step score rCR was defined as ‘No’ on all three questions. This was seen in 4 of pCR patients and only in 1 of non-pCR patients. Seven patients were inaccurately staged as non-rCR but with pCR on cystectomy. Only one patient was inaccurately staged as rCR and not pCR. The one patient with rCR and no pCR did show a very significant response (iT4a lesion to ypT2 lesion).\u003c/p\u003e\n \u003cp\u003eStatistical analysis of mpMRI methods resulted in a significant association between pCR and rCR, using both nacVI-RADS (p 0.04) and the 3-step score (p 0.02) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePredictive value of rCR on pCR, expected frequencies (if H0 = true). A. Radiographic evaluation using nacVì-RADS\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eRadiographic complete response\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo (N) (exp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (N) (exp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003ePathologic Complete Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eFisher's exact = 0.04\u003c/p\u003e\u003cspan\u003e\n \u003cp\u003eB. Radiographic evaluation using 3-step score\u003c/p\u003e\n \u003c/span\u003e\u0026nbsp;\u003ctable id=\"Tabb\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eRadiographic complete response\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo (N) (exp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes (N) (exp)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003ePathologic Complete Response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eFisher's exact = 0.02\u003c/p\u003e\n \u003cp\u003empMRI predicted accurately pCR in 78% (both methods) of patients with a specificity of 93% (nacVI-RADS) and 96% (3-step score). Sensitivity was low using both rCR definitions (both 36%). Positive predictive value was 80%. Images 1 to 3 show examples of a true positive, a true negative and a false positive mpMRI (supplementary material).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eInter-observer agreement\u003c/h2\u003e\n \u003cp\u003eAgreement between observers using the 3-step score was substantial (72%, Kappa 0.61). Agreement between the 2 readers on VIRADS was moderate to near perfect after C2 and C4. nacVI-RADS scoring showed agreement in 80–98% of cases, with substantial to near perfect Kappa values (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eTable 4: Inter-observer agreement nacVI-RADS\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSurvival analysis\u003c/h2\u003e\n \u003cp\u003eWe performed an exploratory survival analysis. At time of analysis, median follow-up of survivors was 58 months (IQR 43–71). Disease reoccurred in 13 patients within first 24 months, of whom 8 had a local reoccurrence. Ten patients died during follow-up, only 1 patient without prior disease reoccurrence. Median overall survival (mOS) and disease-free survival (mDFS) was not reached for the whole study group. No disease reoccurrence and only 1 death was noted in the pCR group. Regarding mpMRI defined groups, only in the “yes, yes, yes” group mOS was reached (40 months, 95% CI 14 - NR). Using nacVI-RADS, mOS was only reached in group 5 evaluated after cycle 2 (39 months, 95% CI 14 -NR).\u003c/p\u003e\n \u003cp\u003eDFS in pCR patients is significantly higher compared to non-pCR patients (Cox p 0.01). Analysis of mpMRI defined groups showed a significant DFS benefit for rCR patients using the 3-step score (p 0.02), but not for nacVI-RADS (p 0.2) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Again “yes-yes-yes” on 3-step score reached mDFS of 20 months (8.4 - NR). Using nacVI-RADS both scores 3 and 5 reached mDFS after cycle 2 and 4 (16 months and 27 months, resp), regression analysis however did not show significant differences in DFS according to nacVI-RADS grouping at both time points.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe present the results of a retrospective study in a university hospital focusing on pCR prediction using two mpMRI scoring systems after NAC for MIBC.\u003c/p\u003e \u003cp\u003eOur results show that using mpMRI for response evaluation after NAC is feasible, less than 10% could not be evaluated using the three-step method, all included cases could be evaluated by nacVI-RADS. mpMRI could accurately predict pCR in 78% of patients with a specificity of 96% (3-step score) and 93% (nacVI-RADS), but low sensitivity. Inter-observer agreement was very high for both methods. pCR and rCR measured by the 3-step score (but not by nacVI-RADS) was significantly associated with DFS benefit.\u003c/p\u003e \u003cp\u003eIn our series pCR was achieved in 28% of patients. This is lower than historical SWOG 8710 trial data (38%) and a more recent retrospective analysis (41%) by Peyton et al.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) Possible explanations are the strict definition of pCR (excluding ypTis), higher percentage of \u0026gt;\u0026thinsp;=\u0026thinsp;T3 tumors (68%), and high percentage of hydronephrosis (40%) which is a known negative prognostic factor.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) Only one patient with hydronephrosis at diagnosis showed a pCR. The number of patients receiving\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;3 cycles of ddMVAC was very similar to the data from the large retrospective analysis of Peyton et al. (91%).\u003c/p\u003e \u003cp\u003eUsing the 3-step score, we found a lower proportion of patients with a rCR on MRI (9.1%), compared to the analysis of data from the PURE-01 study evaluating neo-adjuvant pembrolizumab (31%-44%).(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe value of interim assessment with mpMRI after 2 cycles is difficult to assess in our study. Significant disease progression on interim mpMRI frequently results in omission of cystectomy in our center and thus exclusion from this study. The question remains if de-escalation of NAC is possible in patients with no residual disease after 2 cycles, in our study with predominantly high-risk patients this was the case in 2 patients (5%).\u003c/p\u003e \u003cp\u003eMajor limitations to this study are the limited number of patients in this single institution analysis. The retrospective nature of the study is partly mitigated by the blinding of the readers to the pathological results and subsequent treatment decisions.\u003c/p\u003e \u003cp\u003e Imaging guidelines propose mpMRI or CT scan before the start of NAC but not after completion of NAC. Historical data show a very poor correlation between clinical staging and definitive pathological staging at RC, with around 40% being upstaged.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Assessing tumor response on imaging has been become more prominent, especially in trials investigating bladder sparing strategies (RETAIN trial NCT02710734, ALLIANCE NCT03609216, BLADDERPATH trial). Compared to pathological staging using TURBT, imaging is less invasive, can be more standardized and is able to assess extravesical disease. In a large retrospective analysis of TURBT post-NAC, only one in three patients were accurately staged compared to the final RC specimen.(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003cp\u003empMRI in bladder cancer has been standardized using VI-RADS.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Prospective validation of the VI-RADS has shown to accurately differentiate between MIBC and non-MIBC.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) mpMRI characteristics have also been included in tools to predict response to NAC.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) Some promising results in this setting have been reported, using DWI the ADC values appeared to be significantly more heterogeneous in non-responders,(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) but they are insufficiently reliable.\u003c/p\u003e \u003cp\u003ePost-treatment interpretation of MRI is often challenging because previous TURB and bladder instillations may cause edema, inflammation and fibrosis in the bladder wall and surrounding perivesical tissues, making it difficult to distinguish between residual BC and benign treatment-related effects.(\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAfter TURB, DCE and even more DWI seem to improve the differentiation between TURB related effects and residual tumor.(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) After chemoradiotherapy, Yoshida et al (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) reported that T2-WI alone had low sensitivity, specificity and accuracy to predict pCR (43%, 45% and 44%, respectively). DWI was significantly superior in specificity (92%) and accuracy (80%) as compared to T2 and DCE (18 and 33% respectively), but all sequences showed poor sensitivity for detecting residual disease (43\u0026ndash;57%). Persisting early enhancement on DCE, or no increase in ADC from baseline on DWI are indicative of poor chemotherapy response.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eRECIST 1.1 criteria fail to assess NAC for MIBC because often only bladder wall thickening is present without measurable nodular lesions.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) Similarly, the five-point VI-RADS scoring system is mainly developed to suggest the likelihood of detrusor muscle invasion in untreated patients (or patients having received only diagnostic TURB).(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) In our study, many VI-RADS 5 patients at onset remained VI-RADS 5 after NAC although the size of the tumor was clearly reduced, and many VI-RADS 2 or 1 lesions (biopsy proven MIBC but not confirmed on imaging) remained VI-RADS 2 or 1 after NAC. The recently proposed nacVI-RADS more accurately scores for these changes. However, by introducing the 3-step scoring system local response evaluation was more reader-friendly, more accurate in assessing residual disease and turned out to be a better predictor of DFS. We propose to add this 3-step method to the nacVI-RADS evaluation of residual disease.\u003c/p\u003e \u003cp\u003eThe observation of rCR with high specificity after NAC holds the potential implication of omitting further pathological staging before definitive treatment or de-escalating treatment. Especially in bladder sparing treatment strategies this would be advantageous for patients because risk of residual disease in case of rCR on mpMRI would be very low. A rCR on post-NAC mpMRI would also be a prognostic parameter, as it predicts DFS in our study and is significantly correlated with pCR following NAC which is associated with improved survival.(\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003empMRI can predict pCR after neo-adjuvant cisplatin-based chemotherapy with high specificity but low sensitivity. Adding a 3-step score to nacVI-RADS improves evaluation of residual disease, using this assessment rCR was significantly correlated with DFS. mpMRI should be included in future prospective trials of multimodal management of MIBC and can be an important predictive asset in routine clinical management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003empMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emultiparametric magnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNeo-Adjuvant Chemotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVI-RADS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVesical Imaging-Reporting and Data System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003erCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradiologic Complete Response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMIBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMuscle Invasive Bladder Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradical cystectomy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003epCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epathologic Complete Response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDisease-free Survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eddMVAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edose-dense Methotrexate-Vinblastin-Doxorubicin-Cisplatin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTURBT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrans-Urethral Resection of the Bladder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eADC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eApparent Diffusion Coefficient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDWI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiffusion Weighted Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eReceiver Operating Characteristic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethics committee at Ghent University Hospital, Belgium. After reviewing the project application, due to the retrospective nature of this study, the necessity of individual patient informed consent was waived. \u0026nbsp;All methods and procedures in this study were carried out in accordance with relevant guidelines and regulations\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe use of images and data falls within the institutional consent form at Ghent University Hospital, Belgium.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests that are directly or indirectly related to the work submitted for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDaan De Maeseneer: Project development, Data collection and management, Data analysis, Manuscript writing.\u003c/p\u003e\n\u003cp\u003ePieter De Visschere: Data collection, Data analysis, Manuscript editing.\u003c/p\u003e\n\u003cp\u003eMats Van den Broecke: Data collection\u003c/p\u003e\n\u003cp\u003eFelix Delbare: Data collection\u003c/p\u003e\n\u003cp\u003eGeert Villeirs: Data collection, Manuscript editing.\u003c/p\u003e\n\u003cp\u003eSofie Verbeke: Data collection, Manuscript editing.\u003c/p\u003e\n\u003cp\u003eVal\u0026eacute;rie Fonteyne: Data collection, Manuscript editing.\u003c/p\u003e\n\u003cp\u003eKarel Decaestecker: Data collection, Manuscript editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCharles Van Praet: Data collection, Manuscript editing.\u003c/p\u003e\n\u003cp\u003eAlexander Decruyenaere: Data Analysis.\u003c/p\u003e\n\u003cp\u003eSylvie Rottey: Project development, Manuscript editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitjes JA, Bruins HM, Cathomas R, Comperat EM, Cowan NC, Gakis G, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol. 2021;79(1):82\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin M, Joshi M, Meijer RP, Glantz M, Holder S, Harvey HA, et al. Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis. Oncologist. 2016;21(6):708\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZargar H, Espiritu PN, Fairey AS, Mertens LS, Dinney CP, Mir MC, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015;67(2):241\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeyton CC, Tang D, Reich RR, Azizi M, Chipollini J, Pow-Sang JM, et al. Downstaging and Survival Outcomes Associated With Neoadjuvant Chemotherapy Regimens Among Patients Treated With Cystectomy for Muscle-Invasive Bladder Cancer. JAMA Oncol. 2018;4(11):1535\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePfister C, Gravis G, Flechon A, Soulie M, Guy L, Laguerre B, et al. Randomized Phase III Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin, or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with Muscle-invasive Bladder Cancer. Analysis of the GETUG/AFU V05 VESPER Trial Secondary Endpoints: Chemotherapy Toxicity and Pathological Responses. Eur Urol. 2021;79(2):214\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShariat SF, Palapattu GS, Karakiewicz PI, Rogers CG, Vazina A, Bastian PJ, et al. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol. 2007;51(1):137\u0026ndash;49. discussion 49\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFurrer MA, Papa N, Luetolf S, Roth B, Cumberbatch M, Dorin Vartolomei M, et al. A longitudinal study evaluating interim assessment of neoadjuvant chemotherapy for bladder cancer. BJU Int. 2022;130(3):306\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDel Giudice F, Flammia RS, Pecoraro M, Moschini M, D'Andrea D, Messina E, et al. 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Abdom Radiol (NY). 2022;47(2):763\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNecchi A, Bandini M, Calareso G, Raggi D, Pederzoli F, Fare E, et al. Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study. Eur Urol. 2020;77(5):636\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu Z, Zhao J, Li Y, Pang C, Zhu Z, Zhang X. Prognostic value of preoperative hydronephrosis in patients with bladder cancer undergoing radical cystectomy: A meta-analysis. PLoS ONE. 2019;14(9):e0222223.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGray PJ, Lin CC, Jemal A, Shipley WU, Fedewa SA, Kibel AS, et al. Clinical-pathologic stage discrepancy in bladder cancer patients treated with radical cystectomy: results from the national cancer data base. Int J Radiat Oncol Biol Phys. 2014;88(5):1048\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBecker REN, Meyer AR, Brant A, Reese AC, Biles MJ, Harris KT, et al. Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer. Eur Urol. 2021;79(3):364\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePanebianco V, Narumi Y, Altun E, Bochner BH, Efstathiou JA, Hafeez S, et al. Multiparametric Magnetic Resonance Imaging for Bladder Cancer: Development of VI-RADS (Vesical Imaging-Reporting And Data System). Eur Urol. 2018;74(3):294\u0026ndash;306.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng Z, Xu F, Gu Z, Yan Y, Xu T, Liu S, et al. Combining Multiparametric MRI Radiomics Signature With the Vesical Imaging-Reporting and Data System (VI-RADS) Score to Preoperatively Differentiate Muscle Invasion of Bladder Cancer. Front Oncol. 2021;11:619893.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDel Giudice F, Barchetti G, De Berardinis E, Pecoraro M, Salvo V, Simone G, et al. Prospective Assessment of Vesical Imaging Reporting and Data System (VI-RADS) and Its Clinical Impact on the Management of High-risk Non-muscle-invasive Bladder Cancer Patients Candidate for Repeated Transurethral Resection. Eur Urol. 2020;77(1):101\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotterle G, Andrews JR, Morlacco A, Karnes RJ. Predicting Response to Neoadjuvant Chemotherapy in Bladder Cancer. Eur Urol Focus. 2020;6(4):642\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen HT, Jia G, Shah ZK, Pohar K, Mortazavi A, Zynger DL, et al. Prediction of chemotherapeutic response in bladder cancer using K-means clustering of dynamic contrast-enhanced (DCE)-MRI pharmacokinetic parameters. J Magn Reson Imaging. 2015;41(5):1374\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarentsz JO, Berger-Hartog O, Witjes JA, Hulsbergen-van der Kaa C, Oosterhof GO, VanderLaak JA, et al. Evaluation of chemotherapy in advanced urinary bladder cancer with fast dynamic contrast-enhanced MR imaging. Radiology. 1998;207(3):791\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrier BP, Peters M, Barentsz JO, Witjes JA. Evaluation of chemotherapy with magnetic resonance imaging in patients with regionally metastatic or unresectable bladder cancer. Eur Urol. 2006;49(4):698\u0026ndash;703.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarentsz JO, Jager GJ, van Vierzen PB, Witjes JA, Strijk SP, Peters H, et al. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology. 1996;201(1):185\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang HJ, Pui MH, Guo Y, Yang D, Pan BT, Zhou XH. Diffusion-weighted MRI in bladder carcinoma: the differentiation between tumor recurrence and benign changes after resection. Abdom Imaging. 2014;39(1):135\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida S, Koga F, Kawakami S, Ishii C, Tanaka H, Numao N, et al. Initial experience of diffusion-weighted magnetic resonance imaging to assess therapeutic response to induction chemoradiotherapy against muscle-invasive bladder cancer. Urology. 2010;75(2):387\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonaldson SB, Bonington SC, Kershaw LE, Cowan R, Lyons J, Elliott T, et al. Dynamic contrast-enhanced MRI in patients with muscle-invasive transitional cell carcinoma of the bladder can distinguish between residual tumour and post-chemotherapy effect. Eur J Radiol. 2013;82(12):2161\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHusband JE, Schwartz LH, Spencer J, Ollivier L, King DM, Johnson R, et al. Evaluation of the response to treatment of solid tumours - a consensus statement of the International Cancer Imaging Society. Br J Cancer. 2004;90(12):2256\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeyer A, Ghandour R, Bergman A, Castaneda C, Wosnitzer M, Hruby G, et al. The natural history of clinically complete responders to neoadjuvant chemotherapy for urothelial carcinoma of the bladder. J Urol. 2014;192(3):696\u0026ndash;701.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMazza P, Moran GW, Li G, Robins DJ, Matulay JT, Herr HW, et al. Conservative Management Following Complete Clinical Response to Neoadjuvant Chemotherapy of Muscle Invasive Bladder Cancer: Contemporary Outcomes of a Multi-Institutional Cohort Study. J Urol. 2018;200(5):1005\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobins D, Matulay J, Lipsky M, Meyer A, Ghandour R, DeCastro G, et al. Outcomes Following Clinical Complete Response to Neoadjuvant Chemotherapy for Muscle-invasive Urothelial Carcinoma of the Bladder in Patients Refusing Radical Cystectomy. Urology. 2018;111:116\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmim","sideBox":"Learn more about [BMC Medical Imaging](http://bmcmedimaging.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmim/default.aspx","title":"BMC Medical Imaging","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bladder cancer, Multiparametric MRI, Neoadjuvant chemotherapy, Pathologic complete response, radiographic complete response.","lastPublishedDoi":"10.21203/rs.3.rs-4497035/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4497035/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMuscle invasive bladder cancer (MIBC) treatment combines systemic therapy and radical cystectomy (RC) or local (chemo-)radiotherapy. Response to systemic therapy is an important outcome predictor but is difficult to assess pre-operatively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed multiparametric MRI (mpMRI) in consecutive MIBC patients receiving cisplatin-based neo-adjuvant chemotherapy at our institution. Two readers, blinded for pathological outcome, independently scored mpMRI before and after 2 and 4 cycles using both a qualitative 3-step method and nacVI-RADS. We analyzed accuracy of mpMRI scores to predict pathologic complete response (pCR) and inter-observer agreement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed 46 patients receiving NAC, 6 patients did not undergo RC after NAC and were excluded. Eleven out of 40 (28%) patients showed a pCR. mpMRI could be assessed in over 90% of patients. Radiographic complete response (rCR) using both methods was significantly associated with pCR, with an overall specificity of 96% and sensitivity of 36% and a high inter-observer agreement. rCR as assessed by the 3-step score was significantly associated with disease free survival (DFS) benefit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe use of nacVI-RADS can predict pCR after NAC with high specificity but low sensitivity and a high inter-observer agreement. A 3-step score adds value in determining local residual disease, rCR assessed by this method could correlate with DFS benefit. mpMRI scores should be prospectively assessed in future trials of multimodal management of MIBC and can be a predictive asset in routine clinical management.\u003c/p\u003e","manuscriptTitle":"Retrospective analysis of multiparametric MRI in Predicting Complete Pathologic Response of Neo-adjuvant Chemotherapy in Bladder Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-18 16:54:15","doi":"10.21203/rs.3.rs-4497035/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-23T06:15:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-21T12:22:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"161836485608053355696513371529408009159","date":"2024-06-30T10:52:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247892012763021624737782063070675714140","date":"2024-06-28T11:44:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-23T16:22:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"42299891927410096114075789910251453104","date":"2024-06-03T07:31:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-03T07:29:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-03T05:01:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-03T05:00:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-03T05:00:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medical Imaging","date":"2024-05-29T12:22:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-imaging","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmim","sideBox":"Learn more about [BMC Medical Imaging](http://bmcmedimaging.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmim/default.aspx","title":"BMC Medical Imaging","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a5116a7a-d456-466a-83ea-814ffbc1f242","owner":[],"postedDate":"June 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T16:00:12+00:00","versionOfRecord":{"articleIdentity":"rs-4497035","link":"https://doi.org/10.1186/s12880-024-01441-y","journal":{"identity":"bmc-medical-imaging","isVorOnly":false,"title":"BMC Medical Imaging"},"publishedOn":"2024-10-07 15:57:15","publishedOnDateReadable":"October 7th, 2024"},"versionCreatedAt":"2024-06-18 16:54:15","video":"","vorDoi":"10.1186/s12880-024-01441-y","vorDoiUrl":"https://doi.org/10.1186/s12880-024-01441-y","workflowStages":[]},"version":"v1","identity":"rs-4497035","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4497035","identity":"rs-4497035","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}