Changes in brain white matter integrity after systemic treatment for breast cancer: a prospective longitudinal study
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An increasing number of studies suggest chemotherapy for breast cancer may be neurotoxic. Cross-sectional MRI diffusion tensor imaging (DTI) studies suggest a vulnerability of brain white matter to various chemotherapeutic regimens. Up till now, this was confirmed in one prospective DTI study: Deprez et al. (2012) showed a widespread decline in fractional anisotropy (FA) of breast cancer patients after chemotherapy consisting of 5-fluorouracil (5-FU), epirubicin and cyclophosphamide (FEC) +/− taxanes +/− endocrine treatment. Our aim was to evaluate whether similar detrimental effects on white matter integrity would be observed with the currently widely prescribed anthracycline-based chemotherapy for breast cancer (predominantly doxorubicin and cyclophosphamide +/− taxanes +/− endocrine treatment (=BC + SYST; n = 26) compared to no systemic treatment (BC; n = 23) and no-cancer controls (NC; n = 30). Assessment took place before and six months after chemotherapy, and matched intervals for the unexposed groups. DTI data were analyzed using voxel-based tract-based spatial statistics and region of interest (ROI) analysis. Voxel-based analysis did not show an effect of chemotherapy +/− endocrine treatment on white matter integrity. ROI analysis however indicated subtle detrimental effects of chemotherapy +/− endocrine treatment by showing a larger decline in WM integrity in the superior longitudinal fasciculus and corticospinal tract in BC + SYST than BC. Indications for relatively mild neurotoxicity in our study might be explained by patient characteristics and specific aspects of data analysis. The omission of 5-FU in current treatment regimens or the administration of doxorubicin instead of epirubicin is also discussed as an explanation for the observed effects.
KeywordsBreast cancer Chemotherapy Cognition Neurotoxicity Diffusion tensor imaging (DTI) White matter Side effects CRCI Cancer related cognitive impairment
This study was funded by the Dutch Cancer Society (KWF 2009-4284). We thank Epie Boven, MD, PhD, Suzan van der Meij, MD, Vera Lustig, MD, and Monique Bos, MD, PhD, for their contributions to the patient recruitment. We are indebted to all patients and controls, as well as physicians and nurses of the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, VU University Medical Center, Flevoziekenhuis, Reinier de Graaf Gasthuis and Academic Medical Center, for providing patients for this study and the research assistants for helping collecting the data.
Compliance with ethical standards
This study was funded by the Dutch Cancer Society (grant number KWF 2009–4284).
Conflict of interest
Author Menning declares that she has no conflict of interest. Author de Ruiter declares that he has no conflict of interest. Author Veltman declares that he has no conflict of interest. Author Boogerd declares that he has no conflict of interest. Author Oldenburg declares that she has no conflict of interest. Author Reneman declares that she has no conflict of interest. Author Schagen declares that she has no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., et al. (1993). The European Organization for Research and Treatment of cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute, 85, 365–376. doi: 10.1093/jnci/85.5.365.CrossRefPubMedGoogle Scholar
- Alpherts, W., Aldenkamp, A. P. (1994). FePsy: The iron psyche. Heemstede.Google Scholar
- Cheung, Y. T., Lim, S. R., Ho, H. K., & Chan, A. (2013). Cytokines as mediators of chemotherapy-associated cognitive changes: Current evidence, limitations and directions for future research. PloS One, 8(12). doi: 10.1371/journal.pone.0081234.
- De Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., Caan, M., Douaud, G., et al. (2012). Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: Converging results from multimodal magnetic resonance imaging. Human Brain Mapping, 33(12), 2971–2983. doi: 10.1002/hbm.21422.CrossRefPubMedGoogle Scholar
- Deprez, S., Amant, F., Yigit, R., Porke, K., Verhoeven, J., Van den Stock, J., et al. (2011). Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Human Brain Mapping, 32(3), 480–493. doi: 10.1002/hbm.21033.CrossRefPubMedGoogle Scholar
- Deprez, S., Amant, F., Smeets, A., Peeters, R., Leemans, A., Van Hecke, W., et al. (2012). Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. Journal of Clinical Oncology, 30(3), 274–281. doi: 10.1200/JCO.2011.36.8571.
- Israel, Z. H., Lossos, A., Barak, V., Soffer, D., & Siegal, T. (2000). Multifocal demyelinative leukoencephalopathy associated with 5-fluorouracil and levamisole. Acta Oncologica, 39(1), 117–120.Google Scholar
- Koppelmans, V., de Groot, M., de Ruiter, M. B., Boogerd, W., Seynaeve, C., Vernooij, M. W., et al. (2014). Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy. Human Brain Mapping, 35(3), 889–899. doi: 10.1002/hbm.22221.CrossRefPubMedGoogle Scholar
- McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D., & Saykin, A. J. (2010). Gray matter reduction associated with systemic chemotherapy for breast cancer: A prospective MRI study. Breast Cancer Research and Treatment, 123(3), 819–828. doi: 10.1007/s10549-010-1088-4.CrossRefPubMedPubMedCentralGoogle Scholar
- Menning, S., de Ruiter, M. B., & Kieffer, J. M. Agelink van Rentergem, J., Veltman, D. J., Fruijtier, A., et al. (2016). Cognitive Impairment in a Subset of Breast Cancer Patients After Systemic Therapy - Results From a Longitudinal Study. Journal of Pain and Symptom Management, 52(4), 560–569.e1. doi: 10.1016/j.jpainsymman.2016.04.012.
- Pfefferbaum, A., Rosenbloom, M. J., Chu, W., Sassoon, S. A., Rohlfing, T., Pohl, K. M., et al. (2014). White matter microstructural recovery with abstinence and decline with relapse in alcohol dependence interacts with normal ageing: A controlled longitudinal DTI study. The Lancet. Psychiatry, 1(3), 202–212. doi: 10.1016/S2215-0366(14)70301-3.CrossRefPubMedPubMedCentralGoogle Scholar
- Schilder, C. M., Seynaeve, C., Beex, L. V., Boogerd, W., Linn, S. C., Gundy, C. M., et al. (2010a). Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: Results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. Journal of Clinical Oncology, 28(8), 1294–1300. doi: 10.1200/JCO.2008.21.3553.CrossRefPubMedGoogle Scholar
- Schilder, C. M. T., Seynaeve, C., Linn, S. C., Boogerd, W., Beex, LVAM., Gundy, C. M., et al. (2010b). Cognitive functioning of postmenopausal breast cancer patients before adjuvant systemic therapy, and its association with medical and psychological factors. Critical Reviews in Oncology/Hematology, 76(2), 133–141. doi: 10.1016/j.critrevonc.2009.11.001
- Schmand, B., Lindeboom, J., & van Harskamp, F. (1992). De Nederlandse Leestest Voor Volwassenen. Lisse: Swets & Zeitlinger.Google Scholar
- Schwarz, C. G., Reid, R. I., Gunter, J. L., Senjem, M. L., Przybelski, S. A., Zuk, S. M., et al. (2014). Improved DTI registration allows voxel-based analysis that outperforms tract-based spatial statistics. NeuroImage, 94, 65–78. doi: 10.1016/j.neuroimage.2014.03.026.CrossRefPubMedPubMedCentralGoogle Scholar
- Stewart, A. L., Ware, J. E., Sherbourne, C. D., & Wells, K. B. (1992). Psychological distress/well-being and cognitive functioning measures. In A. L. Stewart & J. E. Ware (Eds.), Measuring functioning and well-being: The medical outcomes study approach (pp. 102–142). Durham, NC: Duke University Press.CrossRefGoogle Scholar
- Stouten-Kemperman, M. M., de Ruiter, M. B., Koppelmans, V., Boogerd, W., Reneman, L., & Schagen, S. B. (2014). Neurotoxicity in breast cancer survivors ≥10 years post-treatment is dependent on treatment type. Brain Imaging and Behavior, 275–284. doi: 10.1007/s11682-014-9305-0.
- Wald, F. D. M., & Mellenbergh, G. J. (1990). De verkorte versie van de Nederlandse vertaling van de Profile of Mood States (POMS). Nederlands Tijdschrift voor de Psychologie, 45, 86–90.Google Scholar
- Wechsler, D. (2000). WAIS-III Nederlandstalige bewerking. Technische Handleiding. Lisse: Swets & Zeitlinger.Google Scholar
- Weiss, D., & Marmar, C. (1997). The impact of event scale - revised. In J. Wilson & T. Keane (Eds.), Assessing psychological trauma and PTSD (pp. 399–411). New York: Guilford Press.Google Scholar