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Background: Gadolinium-based contrast agents (GBCAs) are widely used to enhance tissue contrast during MRI scans and play a crucial role in the management of patients with cancer. However, studies have shown gadolinium deposition in the brain after repeated GBCA administration with yet unknown clinical significance. We aimed to assess the feasibility and diagnostic value of synthetic post-contrast T1-weighted MRI generated from pre-contrast MRI sequences through deep convolutional neural networks (dCNN) for tumour response assessment in neuro-oncology., Methods: In this multicentre, retrospective cohort study, we used MRI examinations to train and validate a dCNN for synthesising post-contrast T1-weighted sequences from pre-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences. We used MRI scans with availability of these sequences from 775 patients with glioblastoma treated at Heidelberg University Hospital, Heidelberg, Germany (775 MRI examinations); 260 patients who participated in the phase 2 CORE trial (1083 MRI examinations, 59 institutions); and 505 patients who participated in the phase 3 CENTRIC trial (3147 MRI examinations, 149 institutions). Separate training runs to rank the importance of individual sequences and (for a subset) diffusion-weighted imaging were conducted. Independent testing was performed on MRI data from the phase 2 and phase 3 EORTC-26101 trial (521 patients, 1924 MRI examinations, 32 institutions). The similarity between synthetic and true contrast enhancement on post-contrast T1-weighted MRI was quantified using the structural similarity index measure (SSIM). Automated tumour segmentation and volumetric tumour response assessment based on synthetic versus true post-contrast T1-weighted sequences was performed in the EORTC-26101 trial and agreement was assessed with Kaplan-Meier plots., Findings: The median SSIM score for predicting contrast enhancement on synthetic post-contrast T1-weighted sequences in the EORTC-26101 test set was 0·818 (95% CI 0·817-0·820). Segmentation of the contrast-enhancing tumour from synthetic post-contrast T1-weighted sequences yielded a median tumour volume of 6·31 cm 3 (5·60 to 7·14), thereby underestimating the true tumour volume by a median of -0·48 cm 3 (-0·37 to -0·76) with the concordance correlation coefficient suggesting a strong linear association between tumour volumes derived from synthetic versus true post-contrast T1-weighted sequences (0·782, 0·751-0·807, p<0·0001). Volumetric tumour response assessment in the EORTC-26101 trial showed a median time to progression of 4·2 months (95% CI 4·1-5·2) with synthetic post-contrast T1-weighted and 4·3 months (4·1-5·5) with true post-contrast T1-weighted sequences (p=0·33). The strength of the association between the time to progression as a surrogate endpoint for predicting the patients' overall survival in the EORTC-26101 cohort was similar when derived from synthetic post-contrast T1-weighted sequences (hazard ratio of 1·749, 95% CI 1·282-2·387, p=0·0004) and model C-index (0·667, 0·622-0·708) versus true post-contrast T1-weighted MRI (1·799, 95% CI 1·314-2·464, p=0·0003) and model C-index (0·673, 95% CI 0·626-0·711)., Interpretation: Generating synthetic post-contrast T1-weighted MRI from pre-contrast MRI using dCNN is feasible and quantification of the contrast-enhancing tumour burden from synthetic post-contrast T1-weighted MRI allows assessment of the patient's response to treatment with no significant difference by comparison with true post-contrast T1-weighted sequences with administration of GBCAs. This finding could guide the application of dCNN in radiology to potentially reduce the necessity of GBCA administration., Funding: Deutsche Forschungsgemeinschaft., Competing Interests: Declaration of interests SH reports grants from the German Research Council and Dietmar-Hopp Foundation, outside of the submitted work. JD reports grants from ViewRay, the Clinical Research Institute, Accuray, RaySearch Laboratories, Vision RT, Merck, Astellas Pharma, AstraZeneca, Siemens Healthcare, Solution Akademie, Egomed, Quintiles, Pharmaceutical Research Association, Boehringer Ingelheim, PTW-Freiburg, and Nanobiotix, outside of the submitted work. MP reports non-financial support from Pfizer, and grants and personal fees from Bayer, outside of the submitted work. MP also has a licensed patent for IDH1 vaccines, a patent H3 vaccine pending, and a patent AHR inhibitor with royalties paid to Bayer. AI reports grants and travel funding from Carthera; research grants from Transgene, Sanofi, Air Liquide, and Nutritheragene; travel funding from Leo Pharma; and is on the advisory board for Novocure and Leo Pharma, outside the submitted work. MjvdB reports personal fees from Roche, Cellgene, Bristol Myers Squibb, Agios, Merck Sharpe & Dohme, and Boehringer Ingelheim; and grants and personal fees from AbbVie, outside of the submitted work. BN is on the scientific advisory board for Karyopharm and BTG Pharmaceuticals and is on the data safety and monitoring board for the University of Pennsylvania (Philadelphia, PA, USA), outside of the submitted work. J-CT reports personal fees from BrainLab and carThera, outside of the submitted work. WW reports grants from Apogenix, Boehringer Ingelheim, and Pfizer; grants and personal fees from Merck Sharp and Dohme and Roche; and personal fees from Bristol Myers Squibb and Celldex, outside of the submitted work. MB reports personal fees from Boehringer Ingelheim, Merck, Bayer, Teva, B Braun, Springer, and Vascular Dynamics; grants and personal fees from Novartis, Codman, and Guerbet; and grants from Siemens, Hopp Foundation, the German Research Council, the EU, Stryker, and Medtronic, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The Response Assessment in Neuro-Oncology (RANO) criteria and requirements for a uniform protocol have been introduced to standardise assessment of MRI scans in both clinical trials and clinical practice. However, these criteria mainly rely on manual two-dimensional measurements of contrast-enhancing (CE) target lesions and thus restrict both reliability and accurate assessment of tumour burden and treatment response. We aimed to develop a framework relying on artificial neural networks (ANNs) for fully automated quantitative analysis of MRI in neuro-oncology to overcome the inherent limitations of manual assessment of tumour burden., Methods: In this retrospective study, we compiled a single-institution dataset of MRI data from patients with brain tumours being treated at Heidelberg University Hospital (Heidelberg, Germany; Heidelberg training dataset) to develop and train an ANN for automated identification and volumetric segmentation of CE tumours and non-enhancing T2-signal abnormalities (NEs) on MRI. Independent testing and large-scale application of the ANN for tumour segmentation was done in a single-institution longitudinal testing dataset from the Heidelberg University Hospital and in a multi-institutional longitudinal testing dataset from the prospective randomised phase 2 and 3 European Organisation for Research and Treatment of Cancer (EORTC)-26101 trial (NCT01290939), acquired at 38 institutions across Europe. In both longitudinal datasets, spatial and temporal tumour volume dynamics were automatically quantified to calculate time to progression, which was compared with time to progression determined by RANO, both in terms of reliability and as a surrogate endpoint for predicting overall survival. We integrated this approach for fully automated quantitative analysis of MRI in neuro-oncology within an application-ready software infrastructure and applied it in a simulated clinical environment of patients with brain tumours from the Heidelberg University Hospital (Heidelberg simulation dataset)., Findings: For training of the ANN, MRI data were collected from 455 patients with brain tumours (one MRI per patient) being treated at Heidelberg hospital between July 29, 2009, and March 17, 2017 (Heidelberg training dataset). For independent testing of the ANN, an independent longitudinal dataset of 40 patients, with data from 239 MRI scans, was collected at Heidelberg University Hospital in parallel with the training dataset (Heidelberg test dataset), and 2034 MRI scans from 532 patients at 34 institutions collected between Oct 26, 2011, and Dec 3, 2015, in the EORTC-26101 study were of sufficient quality to be included in the EORTC-26101 test dataset. The ANN yielded excellent performance for accurate detection and segmentation of CE tumours and NE volumes in both longitudinal test datasets (median DICE coefficient for CE tumours 0·89 [95% CI 0·86-0·90], and for NEs 0·93 [0·92-0·94] in the Heidelberg test dataset; CE tumours 0·91 [0·90-0·92], NEs 0·93 [0·93-0·94] in the EORTC-26101 test dataset). Time to progression from quantitative ANN-based assessment of tumour response was a significantly better surrogate endpoint than central RANO assessment for predicting overall survival in the EORTC-26101 test dataset (hazard ratios ANN 2·59 [95% CI 1·86-3·60] vs central RANO 2·07 [1·46-2·92]; p<0·0001) and also yielded a 36% margin over RANO (p<0·0001) when comparing reliability values (ie, agreement in the quantitative volumetrically defined time to progression [based on radiologist ground truth vs automated assessment with ANN] of 87% [266 of 306 with sufficient data] compared with 51% [155 of 306] with local vs independent central RANO assessment). In the Heidelberg simulation dataset, which comprised 466 patients with brain tumours, with 595 MRI scans obtained between April 27, and Sept 17, 2018, automated on-demand processing of MRI scans and quantitative tumour response assessment within the simulated clinical environment required 10 min of computation time (average per scan)., Interpretation: Overall, we found that ANN enabled objective and automated assessment of tumour response in neuro-oncology at high throughput and could ultimately serve as a blueprint for the application of ANN in radiology to improve clinical decision making. Future research should focus on prospective validation within clinical trials and application for automated high-throughput imaging biomarker discovery and extension to other diseases., Funding: Medical Faculty Heidelberg Postdoc-Program, Else Kröner-Fresenius Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)