Reproducibility and diagnostic performance of ADC for assessing response to neoadjuvant immunotherapy in muscle-invasive bladder cancer: a multi-ROI comparison analysis from the phase-Ib NABUCCO trial
Abstract
Objective: MRI is increasingly used to assess treatment response in muscle-invasive bladder cancer (MIBC), but only qualitatively. This study evaluates the reproducibility and predictive value of quantitative apparent diffusion coefficient (ADC), thought to be a non-invasive surrogate for tumor cell density, in patients with MIBC receiving neoadjuvant immunotherapy.
Materials and methods: MRI data from 35 patients, enrolled in the Phase-Ib NABUCCO trial, were analyzed. ADC maps were derived from pre- and post-treatment MRI scans. Three independent radiologists assessed multiple regions of interest (ROIs) to evaluate inter-observer agreement and predictive performance for pathological complete response (pCR). ADC values were normalized using muscle tissue as a reference. Additionally, we analyzed the correlation between ADC and cell densities, derived from multiplex immunofluorescence (mIF) data.
Results: ADC measurements from the whole-tumor ROI ( n = 25) demonstrated the highest reproducibility (0.98, 95% CI = [0.95–0.99]), but lacked predictive value (AUC = 0.31, 95% CI = [0.12–0.53], p = 0.109). The most hypointense ROI ( n = 22) showed the strongest predictive value for pCR (AUC = 0.80, 95% CI = [0.57–1], p = 0.025), though with limited reproducibility. The difference between baseline and follow-up ADC values in the hypointense region ( n = 20) again showed the highest diagnostic accuracy (AUC = 0.80, 95% CI = [0.58–0.98], p = 0.015). Although muscle normalization is proposed to reduce scanner variability, it did not improve predictive performance in this cohort and occasionally reduced reproducibility. No significant correlation was found between whole-tumor ADC and cell density.
Conclusion: Despite analyzing different measurement techniques for ADC values, none was simultaneously reproducible and predictive, nor provided insights into the biology of the tumor. While ADC shows promise in MIBC, there is an urgent need for more standardized, robust imaging biomarkers.
Key Points: Question Non-invasive biomarkers are urgently needed to guide bladder-preserving strategies in MIBC.
Findings DWI-MRI shows promise, but standardized robust imaging biomarkers are essential for reliable response assessment.
Critical relevance statement Standardized or AI-assisted ROI segmentation could improve ADC reproducibility and diagnostic accuracy in multicenter studies.
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BibTeX
@article{greidanus2026reproducibility,
title = {{Reproducibility and diagnostic performance of ADC for assessing response to neoadjuvant immunotherapy in muscle-invasive bladder cancer: a multi-ROI comparison analysis from the phase-Ib NABUCCO trial}},
author = {Joyce Greidanus and Carlotta Bernabei and Kalina Chupetvloska and Georgios Agrotis and Laura S. Mertens and Bas W. G. van Rhijn and Henk G. van der Poel and Michiel S. van der Heijden and Regina G. H. Beets-Tan and Andrea Delli Pizzi and Thierry N. Boellaard and Stefano Trebeschi},
journal = {Insights into imaging},
year = {2026},
month = oct,
doi = {10.1186/s13244-026-02397-z},
url = {https://europepmc.org/article/PMC/PMC13661850},
note = {CC BY},
}
RIS
TY - JOUR
TI - Reproducibility and diagnostic performance of ADC for assessing response to neoadjuvant immunotherapy in muscle-invasive bladder cancer: a multi-ROI comparison analysis from the phase-Ib NABUCCO trial
AU - Joyce Greidanus
AU - Carlotta Bernabei
AU - Kalina Chupetvloska
AU - Georgios Agrotis
AU - Laura S. Mertens
AU - Bas W. G. van Rhijn
AU - Henk G. van der Poel
AU - Michiel S. van der Heijden
AU - Regina G. H. Beets-Tan
AU - Andrea Delli Pizzi
AU - Thierry N. Boellaard
AU - Stefano Trebeschi
PY - 2026
DA - 2026/10/13
JO - Insights into imaging
DO - 10.1186/s13244-026-02397-z
UR - https://europepmc.org/article/PMC/PMC13661850
AB - Objective: MRI is increasingly used to assess treatment response in muscle-invasive bladder cancer (MIBC), but only qualitatively. This study evaluates the reproducibility and predictive value of quantitative apparent diffusion coefficient (ADC), thought to be a non-invasive surrogate for tumor cell density, in patients with MIBC receiving neoadjuvant immunotherapy. Materials and methods: MRI data from 35 patients, enrolled in the Phase-Ib NABUCCO trial, were analyzed. ADC maps were derived from pre- and post-treatment MRI scans. Three independent radiologists assessed multiple regions of interest (ROIs) to evaluate inter-observer agreement and predictive performance for pathological complete response (pCR). ADC values were normalized using muscle tissue as a reference. Additionally, we analyzed the correlation between ADC and cell densities, derived from multiplex immunofluorescence (mIF) data. Results: ADC measurements from the whole-tumor ROI ( n = 25) demonstrated the highest reproducibility (0.98, 95% CI = [0.95–0.99]), but lacked predictive value (AUC = 0.31, 95% CI = [0.12–0.53], p = 0.109). The most hypointense ROI ( n = 22) showed the strongest predictive value for pCR (AUC = 0.80, 95% CI = [0.57–1], p = 0.025), though with limited reproducibility. The difference between baseline and follow-up ADC values in the hypointense region ( n = 20) again showed the highest diagnostic accuracy (AUC = 0.80, 95% CI = [0.58–0.98], p = 0.015). Although muscle normalization is proposed to reduce scanner variability, it did not improve predictive performance in this cohort and occasionally reduced reproducibility. No significant correlation was found between whole-tumor ADC and cell density. Conclusion: Despite analyzing different measurement techniques for ADC values, none was simultaneously reproducible and predictive, nor provided insights into the biology of the tumor. While ADC shows promise in MIBC, there is an urgent need for more standardized, robust imaging biomarkers. Key Points: Question Non-invasive biomarkers are urgently needed to guide bladder-preserving strategies in MIBC. Findings DWI-MRI shows promise, but standardized robust imaging biomarkers are essential for reliable response assessment. Critical relevance statement Standardized or AI-assisted ROI segmentation could improve ADC reproducibility and diagnostic accuracy in multicenter studies.
SN - 1869-4101
ER -