Cancer therapy for both central nervous system (CNS) and non-CNS tumors has been previously associated with transient and long-term cognitive deterioration, commonly referred to as 'chemo fog'. This therapy-related damage to otherwise normal-appearing brain tissue is reported using post-mortem neuropathological analysis. Although the literature on monitoring therapy effects on structural magnetic resonance imaging (MRI) is well established, such macroscopic structural changes appear relatively late and irreversible. Early quantitative MRI biomarkers of therapy-induced damage would potentially permit taking these treatment side effects into account, paving the way towards a more personalized treatment planning.This systematic review (PROSPERO number 224196) provides an overview of quantitative tomographic imaging methods, potentially identifying the adverse side effects of cancer therapy in normal-appearing brain tissue. Seventy studies were obtained from the MEDLINE and Web of Science databases. Studies reporting changes in normal-appearing brain tissue using MRI, PET, or SPECT quantitative biomarkers, related to radio-, chemo-, immuno-, or hormone therapy for any kind of solid, cystic, or liquid tumor were included. The main findings of the reviewed studies were summarized, providing also the risk of bias of each study assessed using a modified QUADAS-2 tool. For each imaging method, this review provides the methodological background, and the benefits and shortcomings of each method from the imaging perspective. Finally, a set of recommendations is proposed to support future research.

Danish Center for Particle Therapy Aarhus University Hospital Aarhus Denmark

Department of Diagnostic Physics Division of Radiology and Nuclear Medicine Oslo University Hospital Oslo Norway

Department of Imaging and Pathology KU Leuven Leuven Belgium

Department of Neurosurgery Amsterdam UMC Amsterdam Neuroscience Amsterdam The Netherlands

Department of Radiology and Nuclear Medicine Amsterdam UMC Amsterdam Neuroscience Amsterdam The Netherlands

Department of Radiology University Medical Center Utrecht Utrecht The Netherlands

Department of Technical Disciplines in Medicine Faculty of Health Care University of Prešov Prešov Slovakia

Ghent Institute for Functional and Metabolic Imaging Ghent University Ghent Belgium

Helmholtz Zentrum Dresden Rossendorf Institute of Radiopharmaceutical Cancer Research Dresden Germany

International Institute for the Advanced Studies of Psychotherapy and Applied Mental Health Department of Clinical Psychology and Psychotherapy Babeș Bolyai University Cluj Napoca Romania

International Institute for the Advanced Studies of Psychotherapy and Applied Mental Health Evidence Based Psychological Assessment and Interventions Doctoral School Babeș Bolyai University Cluj Napoca Romania

Neurobiology Research Unit Copenhagen University Hospital Rigshospitalet Denmark

Radiology Deptartment of Diagnostic and Public Health Verona University Verona Italy

St Anne's University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

UCL Queen Square Institute of Neurology University College London London UK

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Advanced MR Techniques for Preoperative Glioma Characterization: Part 2