Volume 180, December 2022, 103859Abstract

Cancer-related cognitive impairment (CRCI) has increasingly been identified over the last two decades in non-CNS system cancer patients. Across Europe, researchers have contributed to this effort by developing preclinical models, exploring underlying mechanisms and assessing cognitive and quality of life changes. The ultimate goal is to develop interventions to treat patients experiencing CRCI. To do so, new challenges need to be addressed requiring the implementation of multidisciplinary research groups. In this consensus paper, we summarize the state of the art in the field of CRCI combined with the future challenges and action plans in Europe. These challenges include data sharing/pooling, standardization of assessments as well as assessing additional biomarkers and neuroimaging investigations, notably through translational studies. We conclude this position paper with specific actions for Europe based on shared scientific expert opinion and stakeholders involved in the Innovative Partnership for Action Against Cancer, with a particular focus on cognitive intervention programs.

Section snippetsContext

Across Europe, survival rates in non-central nervous system (non-CNS) cancer patients have dramatically increased over the last decades (Crocetti et al., 2017, De Angelis et al., 2014). However, there has also led to a concomitant increase in the number of survivors living with potential late effects of cancer and its treatments. As a result, increased attention has been devoted to psychosocial outcomes associated with cancer and cancer treatments and patient quality of life (Aaronson et al.,

Detection of cognitive complaints

Cognitive complaints are prevalent (40–75%) in non-CNS cancer patients (Lange et al., 2019a) and are important to detect, due to their significant negative impact on quality of life (Bray et al., 2018; Giffard et al., 2020; Hardy-Leger et al., 2021). Currently, cognitive complaints, for the most part, are assessed using cancer-specific quality of life questionnaires that are limited in scope. For instance, the European Organization for Research and Treatment of Cancer (EORTC) created the

Direct and indirect risk factors contributing to CRCI

In addition to the appropriate detection of CRCI, it is also crucial to understand potential risk factors, over and above treatment factors. A few of the potential significant risk factors being investigated are described below.

Neurobiological mechanisms and biomarkers

In order to better understand the underlying mechanisms of CRCI, a number of studies have focused on biological as well as neuroimaging markers associated with cognitive difficulties in cancer patients. We summarize the most well-acknowledged findings.

Moving our understanding of CRCI forward

A European consortium of Cancer and Cognition has recently emerged to integrate multidisciplinary expertize. This consortium has been largely involved in the European guidelines of the iPAAC Joint Action initiative dedicated to public authorities that highlighted guidelines for public actions related to CRCI in Europe (Hernández-García et al., 2022). The iPAAC “Work Package 4 – Integration in National Policies and Sustainability” aimed to collect examples of innovative approaches for

Conclusion

Cognitive impairment is an important side-effect reported by the non-CNS patients during and after treatments. European challenges in the field include the improvement of the integration of this question in practice, as suggested by the iPAAC’s report. If health-care providers nowadays recognize this potential side effect, effort should be done to include its screening in routine and to develop strategies to help the patients. These strategies should be supported by European Health Authorities.

CRediT authorship contribution statement

All authors have equally contributed to this work meaning planned, written and corrected the manuscript. Moreover, both JP and CS led the final version of the manuscript and its submission.

Conflict of interest

None of the authors has conflict of interest related to the content of this paper.

Acknowledgments

This work was supported by the Région Normandie (Réseaux d’Intérêts Normands, RIN) and the Ligue contre le Cancer – Normandie. This work was also supported by the Ligue nationale contre le cancer (Cancer and Cognition platform), and the Fonds Européens du Développement Régional (FEDER, project CancerCOG), Normandy Rouen University and Inserm.

Charlotte Sleurs, PhD, is assistant professor at the Department of Cognitive Neuropsychology, Tilburg University (TIU) in the Netherlands. She investigated chemotherapy-related neurotoxicity in pediatric oncology during her PhD. In her post-doc career, she mainly focused on cranial radiotherapy-induced neurotoxicity in neuro-oncology patients. She continues to coordinate research in both topics at TIU and as visiting professor at KU Leuven, Belgium.

References (124)T. Ahles et al.Candidate mechanisms for chemotherapy-induced cognitive changes

Nat. Rev. Cancer

(2007)

T. Åkerstedt et al.Aging and the change in fatigue and sleep - a longitudinal study across 8 years in three age groups

Front. Psychol.

(2018)

T. Akman et al.Evaluation of sleep disorders in cancer patients based on Pittsburgh sleep quality index

Eur. J. Cancer Care

(2015)

A. Amidi et al.Changes in brain structural networks and cognitive functions in testicular cancer patients receiving cisplatin-based chemotherapy

J. Natl. Cancer Inst.

(2017)

Ali Amidi et al.Changes in cognitive functions and cerebral grey matter and their associations with inflammatory markers, endocrine markers, and APOE genotypes in testicular cancer patients undergoing treatment

Brain Imaging Behav.

(2017)

C.D. Andela et al.Effect of androgen deprivation therapy on cognitive functioning in men with prostate cancer: a systematic review

Int. J. Urol.

(2021)

A. Beck et al.Beck Depression Inventory-II. San Antonio

(1996)

L.J. Bernstein et al.Cognitive impairment in breast cancer survivors treated with chemotherapy depends on control group type and cognitive domains assessed: a multilevel meta-analysis

Neurosci. Biobehav. Rev.

(2017)

G. Binarelli et al.Multimodal web‐based intervention for cancer‐related cognitive impairment in breast cancer patients: Cog‐stim feasibility study protocol

Cancers

(2021)

C. Boscher et al.Perceived cognitive impairment in breast cancer survivors and its relationships with psychological factors

Cancers

(2020)

V.J. Bray et al.Systematic review of self-reported cognitive function in cancer patients following chemotherapy treatment

J. Cancer Surviv.

(2018)

C.D.R. Buskbjerg et al.Genetic risk factors for cancer-related cognitive impairment: a systematic review

Acta Oncol.

(2019)

C.R. Buskbjerg et al.Cognitive impairment and associations with structural brain networks, endocrine status, and risk genotypes in newly orchiectomized testicular cancer patients

Brain Imaging Behav.

(2021)

H. Castel et al.Biomarkers associated with cognitive impairment in treated cancer patients: potential predisposition and risk factors

Front, Pharmacol.

(2017)

L. Castelli et al.Fast screening of depression in cancer patients: the effectiveness of the HADS

Eur. J. Cancer Care

(2011)

L. Castelli et al.Sleep problems and their interaction with physical activity and fatigue in hematological cancer patients during onset of high dose chemotherapy

Support. Care Cancer

(2022)

E. Crocetti et al.Trends in net survival from 15 cancers in six European Latin countries: The SUDCAN population-based study material

Eur. J. Cancer Prev.

(2017)

R. De Angelis et al.Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE-5-a population-based study

Lancet Oncol.

(2014)

M.B. De Ruiter et al.Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging

Hum. Brain Mapp.

(2012)

S. Deprez et al.Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients

Hum. Brain Mapp.

(2011)

M.B. de Ruiter et al.Brain white matter microstructure as a risk factor for cognitive decline after chemotherapy for breast cancer

J. Clin. Oncol.

(2021)

S. Deprez et al.Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning

J. Clin. Oncol.

(2012)

A. Dias-Carvalho et al.Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events

Arch. Toxicol.

(2021)

M. Duivon et al.Are sleep complaints related to cognitive functioning in non-central nervous system cancer? A systematic review

Neuropsychol. Rev.

(2021)

J.W.L. Eng et al.A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response

Cancer Immunol. Immunother.

(2014)

K.I. Erickson et al.Physical activity, brain, and cognition

Curr. Opin. Behav. Sci.

(2015)

H.E.M. Feenstra et al.Reliability and validity of a self-administered tool for online neuropsychological testing: the Amsterdam cognition scan

J. Clin. Exp. Neuropsychol.

(2017)

H.A. Fernandes et al.Cognitive rehabilitation for cancer-related cognitive dysfunction: a systematic review

Support. Care Cancer

(2019)

A.C. Furmaniak et al.Exercise for women receiving adjuvant therapy for breast cancer

Cochrane Database Syst. Rev.

(2016)

E.M. Gibson et al.Microglia in cancer therapy-related cognitive impairment

Trends Neurosci.

(2021)

J.M. Giesinger et al.Thresholds for clinical importance were established to improve interpretation of the EORTC QLQ-C30 in clinical practice and research

J. Clin. Epidemiol.

(2020)

B. Giffard et al.The role of metamemory on cognitive complaints in cancer patients

Brain and Behavior

(2020)

G. Godin et al.A simple method to assess exercise behavior in the community

Can. J. Appl. Sport Sci.

(1985)

K. Góra-Kupilas et al.The neuroprotective function of vascular endothelial growth factor (VEGF)

Folia Neuropathol.

(2005)

S. Grayson et al.Factors associated with sleep disturbances in women undergoing treatment for early-stage breast cancer

Support. Care Cancer

(2022)

T.R. Groves et al.5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice

Behav. Brain Res.

(2017)

I. Hardy-Leger et al.Differentiation of groups of patients with cognitive complaints at breast cancer diagnosis: results from a sub-study of the French CANTO cohort

Psychooncology

(2021)

S.C. Hayes et al.The Exercise and Sports Science Australia position statement: exercise medicine in cancer management

J. Sci. Med. Sport

(2019)

M. Hernández-García et al.Contest of best practices tackling social inequalities in cancer prevention: an iPAAC initiative

Eur. J. Public Health

(2022)

S. Het et al.A meta-analytic review of the effects of acute cortisol administration on human memory

Psychoneuroendocrinology

(2005)

Charlotte Sleurs, PhD, is assistant professor at the Department of Cognitive Neuropsychology, Tilburg University (TIU) in the Netherlands. She investigated chemotherapy-related neurotoxicity in pediatric oncology during her PhD. In her post-doc career, she mainly focused on cranial radiotherapy-induced neurotoxicity in neuro-oncology patients. She continues to coordinate research in both topics at TIU and as visiting professor at KU Leuven, Belgium.

Ali Amidi, PhD, is an Associate Professor in Behavioral Neuroscience at the Department of Psychology and Behavioral Sciences, Aarhus University, Aarhus, Denmark and a member of the Unit for Psychooncology & Health Psychology. His research has been dedicated to the investigation of the onset, development, prevention, and treatment of various cancer-related symptoms such as neurocognitive impairment, fatigue, and sleep disturbances in both CNS- and non-CNS cancer populations. He has a particular interest in exploring the neural substrate underlying these symptoms. He is the founder of The Sleep and Circadian Psychology Research Group at Aarhus University.

Lisa M. Wu, PhD, is Associate Professor in the Aarhus Institute of Advanced Studies, Aarhus University in Denmark. She is a clinical psychologist and neuropsychologist who has investigated the nature, severity and mechanistic underpinnings of side- and late-effects of cancer and its treatment, with a particular interest in cognitive impairment, sleep and circadian rhythm dysfunction. She has also undertaken non-pharmacological intervention studies to ameliorate cancer side- and late-effects, including light therapy.

David Kiesl, MD, is a medical Oncologist and Hematologist, at the department for hematology and internal oncology of the Kepler University Hospital in Linz, Austria. He is the head of the institute for sports medicine, the Sportmed-Cardiomed GmbH in Linz In his role as research team leader he coordinates the exercise and cognition study group – Austria and is involved in the oncological care and clinical research in patients with solid and hematooncological cancers.

Philipp Zimmer, PhD, is Full Professor at TU Dortmund University. He is working at the Institute for Sport and Sport Science and chair of the division of Performance and Health. He holds two PhDs, one in exercise science and one in Neuroscience. His main research interest is exercise (neuro-) immunology, with a special focus on persons with cancer and multiple sclerosis. In this context his group is conducting translational clinical trials, combining mechanistic research and patient reported outcomes.

Marie Lange, PhD, is neuropsychologist at the Clinical Research department of Comprehensive Cancer Center of Caen and INSERM U1086 Anticipe, in France. During her PhD, she investigated cancer-related cognitive impairment in elderly breast cancer patients treated by chemotherapy. She coordinates several studies of the French Cancer and Cognition platform mainly focused on the impact of cancer treatments on cognition, including new cancer therapies, and interventional studies to improve cancer-related cognitive impairment.

Anne Rogiers, MD, PhD is a clinical professor at the Faculty of Medicine and Pharmacie of the Vrije Universiteit Brussel (VUB). She obtained her medical degree in 1994 from the VUB and her specialist degree as a psychiatrist in 2001. Since 2018, she has been the head of the Neurocognitive Remediation Clinic at the Department of Psychiatry of the Centre Hospitalier Universitair (CHU) Brugmann, Brussels, Belgium. She works as a scientific collaborator at the Universitair Ziekenhuis Brussel and the Oncology Research Center of the VUB. Prof. Rogiers is also a member of the EORTC Quality of Life Group. During the last 15 years, she has gained clinical and scientific experience in the fields of neuroscience, psycho-oncology, and neuro-oncology. Since 2016, she has focused her research on cancer survivorship, cognition and quality of life in the field of immunotherapy.

Bénédicte Giffard, PhD, is Full Professor of neuropsychology at the University of Caen Normandy in France where she is the head of university educations (master of neuropsychology, continuing education…). She is member of the Executive Committee of the Research Unit 1077 Inserm-EPHE-UNICAEN "Neuropsychology and Imaging of Human Memory", where she funded and leads a research team on the impact of non-CNS cancers on memory functioning. She is co-leader of the Cancer and Cognition clinical research platform within the Cancéropôle Nord-Ouest.

Giulia Binarelli is a psychologist PhD candidate in public health at the University of Caen (research Unit INSERM U-1086) in France. She is investigating the use of digital interventions for cancer-related cognitive impairments in women with breast cancer. She also collaborates in projects aiming to improve patients’ support concerning cancer-related cognitive impairment at Centre François Baclesse.

Cindy Borghgraef is neuropsychologist at the Psycho-Oncology and Geriatric Oncology departments of the Jules Bordet Institute in Brussels, Belgium. During her PhD, she investigated cancer-related cognitive impairment in elderly patients with hematological malignancies treated by chemotherapy. She has also interest in exploring the impact of cognitive impairment on psychological distress and especially sense of being a burden in elderly patients.

Sabine Deprez, PhD, is senior research at the University of KU Leuven, Department of Imaging and Pathology, Translational MRI, KU Leuven in Belgium. Her research focuses on the investigation of the neural correlates of cognitive impairment after cancer treatment in a multidisciplinary set-up, combining multimodal imaging, neuropsychological evaluation and other biomarkers and possible therapeutic interventions.

Mylène Duivon, PhD, is a postdoctoral fellow at the University of Caen (research Unit INSERM U-1086) in France. She investigated the impact of endocrine therapy and sleep on cognitive functioning of breast cancer patients during her Ph.D. Her current research interests focus on the biological predictors of cancer-related cognitive impairment and non-pharmacological interventions to improve cognitive functioning.

Michiel De Ruiter, PhD, worked as an associate staff scientist at the Netherlands Cancer Institute till June 2022. He is trained in cognitive neuroscience. He contributed to neuroimaging and neuropsychological studies focusing on cognitive problems in cancer patients for 15 years. He pursued a career outside academia and now works at the Dutch Federation of Cancer Patient Organizations, where he is involved in a project to improve transparency of oncology care.

Sanne Schagen, PhD, is Group leader and head of the Division of the Psychosocial Research and Epidemiology and coordinator of the Cognition and Cancer research group at the Antoni van Leeuwenhoek (AVL), where she works since 1996. She combines clinical work and research in the fields of cognitive consequences of cancer and cancer treatments. Using neuropsychological research, 'imaging' but also animal experiments, she looks at the presence and causes of cognitive problems (such as memory and concentration problems) in various tumor types and treatments. In addition, we investigate how we can reduce these cognitive complaints and how patients can best deal with them in daily life.

Djihane Ahmed-Lecheheb, PhD Science and health, Project manager of the Platform “Cancer and Cognition”, Research Unit INSERM U1086 ANTICIPE, Center for the fight against cancer, Caen, France. During her postdoctoral fellow, she investigated side effects of chemotherapy in cancer patients and post-cancer follow-up.

Hélène Castel, PhD, is senior researcher at Inserm, University of Rouen Normandie, head of the Team “Genetics, Biology and Plasticity of Brain Tumors” in the researhc Unit 1245 Inserm. She is specialized in Neuro-oncology in i) cancer, biomarkers and cancer treatments on cognition/brain functions in preclinical models and in translational programs, and brain tumor development and remodeling the cerebral microenvironment. The team develops preclinical mouse models of PDX-GBM resection, local treatments and immunotherapy and collaborate with the in a recent sSelected PAIR Tumeurs Cérébrales, the start-up Hippoxis to test a macrophage-regulating compound on GBM (RIN Normandie Neuroncochimie, AMI Oncochimie). The team is an active member of the ERNEST COST action, and GoPa networks of ANOCEF. Recently H. Castel organized and currently coordinates a Working Group on Brain Tumors within the NorthWest Canceropole and has been awarded for a Structuring Program (CNO) on GBM heterogeneity and recurrence, involving at least in part Partner 1 for proteomics of GBM cells during invasion.

Cecilie R. Buskbjerg, PhD, is a postdoctoral fellow at Department of Oncology, Aarhus University Hospital, and Department of Psychology and Behavioral Science, Aarhus University, in Denmark. During her PhD, Cecilie investigated cancer-related cognitive impairment in men undergoing treatment for testicular or prostate cancer with a particular focus on the role of endocrine status, structural brain networks, and risk genotypes. Her current research is mainly concerned with neuropsychological rehabilitation of children and adults treated for CNS tumors and online neuropsychological testing of cancer-related cognitive impairment.

Dr. Mélanie Dos Santos, MD, PhD is a medical Oncologist who also works in the Clinical Research Department in the Comprehensive Cancer Centre Francois Baclesse in Caen, FRANCE. She has recently finished her work on the subject of cognition in oncology as a doctoral student in the research Unit INSERM U-1086, Anticipe (Lower Normandy University). She continues to coordinate research studies on this topic.

Florence Joly, MD, PhD, is a medical Oncologist in the Francois Baclesse Comprehensive Cancer Centre in Caen, Normandy, France. She is at the head of the Clinical Research Department of the François Baclesse Centre. She has coordinated for 6 years the "Symptom Benefit" group of the international intergroup in Onco-gynecology (GCIG). She is a member of the research Unit INSERM U-1086, Anticipe. She developed a large multidisciplinary research program on quality of life with two main topics: long term quality of life among survivors and impact of cancer treatments on cognition. She is at the origin of the French Cancer platform dedicated to Cancer and Cognition and labeled by the French League Against Cancer.

Joy Perrier, PhD, is a post-doctorate working in the field of insomnia, cognition and cancer. Through a multidisciplinary approach, her research aims at studying the modifications of sleep and their consequences on the quality of life, in particular memory, in cancer patients. For this purpose, sleep analyses, physiological measures, but also neuroimaging analyses (fMRI and aMRI) and cognitive performance measures are performed and put into relationship. Thanks to the collaboration with the clinical services of the Centre François Baclesse (Prof. Florence Joly and her team), the results of this research can be taken into account by the clinicians as soon as possible. Joy Perrier is currently holding a Chair of Excellence from the Normandy Region for the ICANSLEEP project (Cancer, Sleep and Memory - 2021–2024).

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