Prevalence of cerebral small-vessel disease in long-term breast cancer survivors exposed to both adjuvant radiotherapy and chemotherapy.

PURPOSE Adjuvant radiotherapy and chemotherapy for breast cancer have been related to transient ischemic attacks and stroke. To date, no studies have investigated the relationship between these adjuvant therapies and subclinical cerebral small-vessel disease in survivors of breast cancer. We compared white matter lesion (WML) volume and prevalence of brain infarctions and cerebral microbleeds (CMBs) between breast cancer survivors exposed to adjuvant radiotherapy and chemotherapy (aRCeBCSs) for primary disease and a population-based reference group. PATIENTS AND METHODS Multimodal magnetic resonance imaging (1.5 T) was performed in 187 aRCeBCSs who received primary breast cancer treatment on average more than 20 years before this study and 374 age-matched reference women without a history of cancer. WML volume was segmented using fully automated software. Experienced raters reviewed all scans for cortical infarctions, lacunar infarctions, strictly lobar CMBs, and deep/infratentorial CMBs with or without lobar CMBs. Within the aRCeBCS group, we also analyzed the association between relative radiotherapy exposure to the carotid artery and prevalence of WML volume and CMBs. RESULTS The aRCeBCS group had a higher prevalence of both total CMBs and CMBs in a deep/infratentorial region than the reference group. No between-group differences were observed in the prevalence of infarctions or WML volume. Exposure of the carotid artery to radiation was not associated with WML volume or CMBs. CONCLUSION More CMBs were found in the aRCeBCS group than in the population-based controls. These vascular lesions potentially mark cerebrovascular frailty that could partially explain the well-documented association between chemotherapy and cognitive dysfunction. No support was found for a radiotherapy-related origin of CMBs.

[1]  Wiro J Niessen,et al.  Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy , 2014, Human brain mapping.

[2]  K. Harrington,et al.  Clinical features of radiation-induced carotid atherosclerosis. , 2014, Clinical oncology (Royal College of Radiologists (Great Britain)).

[3]  Patricia M. Desmond,et al.  Cerebral Microbleeds: A Review of Clinical, Genetic, and Neuroimaging Associations , 2013, Front. Neurol..

[4]  M. Breteler,et al.  Late effects of adjuvant chemotherapy for adult onset non-CNS cancer; cognitive impairment, brain structure and risk of dementia. , 2013, Critical reviews in oncology/hematology.

[5]  Jordi Bruna,et al.  Chemobrain: A systematic review of structural and functional neuroimaging studies , 2013, Neuroscience & Biobehavioral Reviews.

[6]  Michiel B. de Ruiter,et al.  Functional MRI studies in non-CNS cancers , 2013, Brain Imaging and Behavior.

[7]  H. Kooy,et al.  Intensity modulated proton therapy for postmastectomy radiation of bilateral implant reconstructed breasts: a treatment planning study. , 2013, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[8]  R. Bonita,et al.  Cardiovascular toxicities of cancer chemotherapy. , 2013, Seminars in oncology.

[9]  A. Leemans,et al.  Diffusion tensor MRI of chemotherapy-induced cognitive impairment in non-CNS cancer patients: a review , 2013, Brain Imaging and Behavior.

[10]  J. Suri,et al.  Association between Carotid Artery Plaque Type and Cerebral Microbleeds , 2012, American Journal of Neuroradiology.

[11]  Willem Boogerd,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 , 2012, Human brain mapping.

[12]  Ming Liu,et al.  Association between cerebral microbleeds and cognitive function: a systematic review , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[13]  M. Dimopoulos,et al.  Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications. , 2012, Cancer treatment reviews.

[14]  C. Gundy,et al.  Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Sanne B. Schagen,et al.  Chemotherapy-Related Cognitive Dysfunction , 2012, Current Neurology and Neuroscience Reports.

[16]  Wiro J. Niessen,et al.  Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy , 2012, Breast Cancer Research and Treatment.

[17]  B. Melichar,et al.  Intima-media thickness, myocardial perfusion and laboratory risk factors of atherosclerosis in patients with breast cancer treated with anthracycline-based chemotherapy , 2011, Medical oncology.

[18]  M. Breteler,et al.  Incidental findings on brain Magnetic Resonance Imaging in long-term survivors of breast cancer treated with adjuvant chemotherapy. , 2011, European journal of cancer.

[19]  Wiro J. Niessen,et al.  The Rotterdam Scan Study: design and update up to 2012 , 2011, European Journal of Epidemiology.

[20]  M. Arfan Ikram,et al.  The Rotterdam Study: 2012 objectives and design update , 2011, European journal of epidemiology.

[21]  A. Hofman,et al.  Cerebral microbleeds are associated with worse cognitive function: The Rotterdam Scan Study , 2011, Alzheimer's & Dementia.

[22]  T. Ahles,et al.  International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. , 2011, The Lancet. Oncology.

[23]  D. Norris,et al.  Causes and consequences of cerebral small vessel disease. The RUN DMC study: a prospective cohort study. Study rationale and protocol , 2011, BMC neurology.

[24]  J. Fardell,et al.  Neurobiological basis of chemotherapy-induced cognitive impairment: A review of rodent research , 2011, Neuroscience & Biobehavioral Reviews.

[25]  S. Fosså,et al.  Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  Aad van der Lugt,et al.  Prevalence and Risk Factors of Cerebral Microbleeds: An Update of the Rotterdam Scan Study , 2010, Stroke.

[27]  L. Pantoni Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges , 2010, The Lancet Neurology.

[28]  Wiro J. Niessen,et al.  Accuracy and reproducibility study of automatic MRI brain tissue segmentation methods , 2010, NeuroImage.

[29]  N. Miyamatsu,et al.  Cerebral microbleeds predict first-ever symptomatic cerebrovascular events , 2009, Clinical Neurology and Neurosurgery.

[30]  E. Yeh,et al.  Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. , 2009, Journal of the American College of Cardiology.

[31]  Wiro J. Niessen,et al.  White matter lesion extension to automatic brain tissue segmentation on MRI , 2009, NeuroImage.

[32]  L. Holmberg,et al.  Radiation to supraclavicular and internal mammary lymph nodes in breast cancer increases the risk of stroke , 2009, British Journal of Cancer.

[33]  H. Urbach,et al.  Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma. , 2009, Neuro-oncology.

[34]  Monique M. B. Breteler,et al.  The Rotterdam Study: 2016 objectives and design update , 2015, European Journal of Epidemiology.

[35]  Aad van der Lugt,et al.  Cerebral microbleeds: accelerated 3D T2*-weighted GRE MR imaging versus conventional 2D T2*-weighted GRE MR imaging for detection. , 2008, Radiology.

[36]  W. Woodward,et al.  Prospective analysis of carotid artery flow in breast cancer patients treated with supraclavicular irradiation 8 or more years previously , 2008, Cancer.

[37]  A. Saykin,et al.  Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  R. Townsend,et al.  Chemotherapy agents and hypertension: A focus on angiogenesis blockade , 2007, Current hypertension reports.

[39]  M. Muiesan,et al.  Carotid atherosclerosis, arterial stiffness and stroke events. , 2007, Advances in cardiology.

[40]  Michael E. Phelps,et al.  Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy , 2007, Breast Cancer Research and Treatment.

[41]  J. Klijn,et al.  Decreased risk of stroke among 10-year survivors of breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  Aad van der Lugt,et al.  O3-04-07 Prevalence and risk factors of cerebral microbleeds in the Rotterdam scan study , 2006, Alzheimer's & Dementia.

[43]  R. Jagsi,et al.  Stroke rates and risk factors in patients treated with radiation therapy for early-stage breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  W. Woodward,et al.  Supraclavicular radiation for breast cancer does not increase the 10‐year risk of stroke , 2006, Cancer.

[45]  Alan C. Evans,et al.  A fully automatic and robust brain MRI tissue classification method , 2003, Medical Image Anal..

[46]  Ka Sing Wong,et al.  Cerebral Microbleeds as a Risk Factor for Subsequent Intracerebral Hemorrhages Among Patients With Acute Ischemic Stroke , 2003, Stroke.

[47]  J C Froment,et al.  Old Microbleeds Are a Potential Risk Factor for Cerebral Bleeding After Ischemic Stroke: A Gradient-Echo T2*-Weighted Brain MRI Study , 2002, Stroke.

[48]  M. Kim,et al.  5-fluorouracil-induced leukoencephalopathy in patients with breast cancer. , 2001, Journal of Korean medical science.

[49]  J M Wardlaw,et al.  Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study: the Rotterdam Scan Study , 2001, Journal of neurology, neurosurgery, and psychiatry.

[50]  C Caltagirone,et al.  Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. , 2000, JAMA.

[51]  J. Simon,et al.  White matter disease induced by high-dose chemotherapy: longitudinal study with MR imaging and proton spectroscopy. , 1998, AJNR. American journal of neuroradiology.

[52]  P. Lewinsohn,et al.  Center for Epidemiologic Studies Depression Scale (CES-D) as a screening instrument for depression among community-residing older adults. , 1997, Psychology and aging.

[53]  M. Matsumoto,et al.  Ischemic stroke events and carotid atherosclerosis. Results of the Osaka Follow-up Study for Ultrasonographic Assessment of Carotid Atherosclerosis (the OSACA Study). , 1995, Stroke.