Skip to main content

Advertisement

SpringerLink
Log in

Chemotherapy-induced grey matter abnormalities in cancer survivors: a voxel-wise neuroimaging meta-analysis

  • Review Article
  • Published:
Brain Imaging and Behavior Aims and scope Submit manuscript

Abstract

Background

Findings regarding chemotherapy-induced grey matter abnormalities are heterogeneous, and no meta-analysis has quantitatively assessed brain structural alterations in cancer survivors treated with chemotherapy.

Purpose

To investigate the grey matter abnormalities in non-CNS (central nervous system) cancer survivors treated with chemotherapy using Anisotropic Effect Size Signed Differential Mapping (AES-SDM) software.

Method

We identified studies published up to Sep 2018 that compared grey matter in non-CNS cancer survivors treated with chemotherapy (CT+, 10 data sets including 433 individuals) and cancer survivors not treated with chemotherapy (CT-, 7 data sets including 210 individuals) or healthy controls (HC, 3 data sets including 407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise.

Results

Compared with both CT- and HC, the CT + groups exhibited a reduced grey matter volume (GMV), mainly in the prefrontal and anterior cingulate cortex (ACC) and right fusiform gyrus (FG). A smaller GMV in the FG and prefrontal cortex were found in the CT + compared with the CT-groups and in the CT + groups with impaired cognition. GMV in two areas was positively associated with the time since chemotherapy.

Conclusions

The present results suggest that non-CNS cancer survivors treated with chemotherapy exhibit grey matter abnormalities in the brain, especially in the prefrontal and ACC cortex. Grey matter volume changes after chemotherapy may contribute to cognitive impairments in cancer survivors that can be observed after chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ahles, T. A., & Saykin, A. J. (2007). Candidate mechanisms for chemotherapy-induced cognitive changes. Nature Reviews Cancer, 7, 192–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Amidi, A., Agerbaek, M., Wu, L. M., Pedersen, A. D., Mehlsen, M., Clausen, C. R., et al. (2017). ’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 and Behavior, 11, 769–783.

    PubMed  Google Scholar 

  • Amidi, A., Agerbæk, M., Wu, L. M., Pedersen, A. D., Mehlsen, M., Clausen, C. R., Demontis, D., Børglum, A. D., Harbøll, A., & Zachariae, R. (2016). 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 & Behavior: 1–15.

  • Ashburner, J., & Friston, K. J. (2000). Voxel-based morphometry–the methods. Neuroimage, 11: 805–21.

  • Bas-Hoogendam, J. M., van Steenbergen, H., Nienke Pannekoek, J., Fouche, J. P., Lochner, C., Hattingh, C. J., Cremers, H. R., Furmark, T., Mansson, K. N. T., Frick, A., Engman, J., Boraxbekk, C. J., Carlbring, P., Andersson, G., Fredrikson, M., Straube, T., Peterburs, J., Klumpp, H., Phan, K. L., Roelofs, K., Veltman, D. J., van Tol, M. J., Stein, D. J., & van der Wee, N. J. A. (2017). Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder. NeuroImage: Clinical, 16:678–88.

  • Boedhoe, P. S., Schmaal, L., Abe, Y., Ameis, S. H., Arnold, P. D., Batistuzzo, M. C., et al. (2017). Distinct subcortical alterations in pediatric and adult OCD: A worldwide meta- and mega-analysis . The American Journal of Psychiatry, 174, 60–69.

    PubMed  Google Scholar 

  • Bookstein, F. L. (2001). "Voxel-based morphometry” should not be used with imperfectly registered images. Neuroimage, 14, 1454–1462.

    CAS  PubMed  Google Scholar 

  • Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Sciences, 4, 215–222.

    CAS  PubMed  Google Scholar 

  • Conroy, S. K., McDonald, B. C., Smith, D. J., Moser, L. R., West, J. D., Kamendulis, L. M., et al. (2013). Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage. Breast Cancer Research and Treatment, 137, 493–502.

    CAS  PubMed  Google Scholar 

  • Correa, D. D., Root, J. C., Kryza-Lacombe, M., Mehta, M., Karimi, S., Hensley, M. L., & Relkin, N. (2017). Brain structure and function in patients with ovarian cancer treated with first-line chemotherapy: a pilot study. Brain Imaging & Behavior, 11, 1–12.

    Google Scholar 

  • Davies, R. R., Scahill, V. L., Graham, A., Williams, G. B., Graham, K. S., & Hodges, J. R. (2009). Development of an MRI rating scale for multiple brain regions: comparison with volumetrics and with voxel-based morphometry. Neuroradiology, 51, 491–503.

    PubMed  Google Scholar 

  • de Ruiter, M. B., Reneman, L., Boogerd, W., Veltman, D. J., van Dam, F. S., Nederveen, A. J., et al. (2011). Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Human Brain Mapping, 32, 1206–1219.

    PubMed  Google Scholar 

  • De Ruiter, Michiel, B., Liesbeth Reneman, W., Boogerd, D. J., Veltman, M., Caan, G., Douaud, C., Lavini, S. C., Linn, E., Boven, Frits, S. A. M., & Van Dam (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, 2971–2983.

    PubMed  Google Scholar 

  • de Wit, S. J., Alonso, P., Schweren, L., Mataix-Cols, D., Lochner, C., Menchon, J. M., Stein, D. J., Fouche, J. P., Soriano-Mas, C., Sato, J. R., Hoexter, M. Q., Denys, D., Nakamae, T., Nishida, S., Kwon, J. S., Jang, J. H., Busatto, G. F., Cardoner, N., Cath, D. C., Fukui, K., Jung, W. H., Kim, S. N., Miguel, E. C., Narumoto, J., Phillips, M. L., Pujol, J., Remijnse, P. L., Sakai, Y., Shin, N. Y., Yamada, K., Veltman, D. J., & O. A. van den Heuvel. (2014). Multicenter voxel-based morphometry mega-analysis of structural brain scans in obsessive-compulsive disorder. The American Journal of Psychiatry, 171:340-9.

  • Dietrich, J., Han, R., Yang, Y., Mayer-Proschel, M., & Noble, M. (2006). CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. Journal of Biology, 5, 22.

    PubMed  PubMed Central  Google Scholar 

  • Du, M., Liu, J., Chen, Z., Huang, X., Li, J., Kuang, W., et al. (2014). Brain grey matter volume alterations in late-life depression. Journal of Psychiatry & Neuroscience, 39, 397–406.

    Google Scholar 

  • Egger, M., Davey Smith, G., Schneider, M., & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test, BMJ, 315: 629–34.

  • Feng, Y., Zhang, X. D., Zheng, G., & Zhang, L. J. (2019). Chemotherapy-induced brain changes in breast cancer survivors: evaluation with multimodality magnetic resonance imaging. Brain Imaging and Behavior, 13, 1799–1814.

    PubMed  Google Scholar 

  • Ferguson, R. J., McDonald, B. C., Saykin, A. J., & Ahles, T. A. (2007). Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. Journal of Clinical Oncology, 25, 3866–3870.

    PubMed  Google Scholar 

  • Ferreira, L. K., & Busatto, G. F. (2010). Heterogeneity of coordinate-based meta-analyses of neuroimaging data: an example from studies in OCD, British Journal of Psychiatry, 197:76–7; author reply 77.

  • Fornito, A., Yucel, M., Patti, J., Wood, S. J., & Pantelis, C. (2009). Mapping grey matter reductions in schizophrenia: an anatomical likelihood estimation analysis of voxel-based morphometry studies. Schizophrenia Research, 108, 104–113.

    CAS  PubMed  Google Scholar 

  • Fouche, J. P., du Plessis, S., Hattingh, C., Roos, A., Lochner, C., Soriano-Mas, C., et al. (2017). Cortical thickness in obsessive-compulsive disorder: multisite mega-analysis of 780 brain scans from six centres. British Journal of Psychiatry, 210, 67–74.

    Google Scholar 

  • Fuster, J. (2015). The Prefrontal Cortex (5th Edition).

  • Hu, X., Du, M., Chen, L., Li, L., Zhou, M., Zhang, L., et al. (2017). Meta-analytic investigations of common and distinct grey matter alterations in youths and adults with obsessive-compulsive disorder. Neuroscience & Biobehavioral Reviews, 78, 91–103.

    Google Scholar 

  • Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T., Akechi, T., et al. (2007). Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer, 109, 146–56.

    PubMed  Google Scholar 

  • Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T., Akechi, T., Wada, N., Imoto, S., Murakami, K., & Uchitomi, Y. (2010). Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer, 109:146–56.

  • Jenkins, V., Thwaites, R., Cercignani, M., Sacre, S., Harrison, N., Whiteleyjones, H., Mullen, L., Chamberlain, G., & Davies, K., & Zammit, C. (2016). A feasibility study exploring the role of pre-operative assessment when examining the mechanism of ‘chemo-brain’ in breast cancer patients. Springerplus, 5:390.

  • Kaiser, J., Bledowski, C., & Dietrich, J. (2014). Neural correlates of chemotherapy-related cognitive impairment. Cortex, 54, 33–50.

    PubMed  Google Scholar 

  • Kesler, S. R., Bennett, F. C., Mahaffey, M. L., & Spiegel, D. (2009). Regional brain activation during verbal declarative memory in metastatic breast cancer. Clinical Cancer Research, 15, 6665–6673.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kesler, S. R., Kent, J. S., & O’Hara, R. (2011). Prefrontal cortex and executive function impairments in primary breast cancer. Archives of Neurology, 68, 1447–1453.

    PubMed  PubMed Central  Google Scholar 

  • Koppelmans, V., Breteler, M. M., Boogerd, W., Seynaeve, C., Gundy, C., & Schagen, S. B. (2012). ’Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. Journal of Clinical Oncology, 30, 1080–1086.

    PubMed  Google Scholar 

  • Koppelmans, V., De Ruiter, M. B., Lijn, F. V. D., Boogerd, W., Seynaeve, C., Lugt, A. V. D., Vrooman, H., & Niessen, W. J. & Breteler, M. B. (2012). Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast Cancer Research & Treatment, 132:1099–106.

  • Li, M., & Caeyenberghs, K. (2018). Longitudinal assessment of chemotherapy-induced changes in brain and cognitive functioning: A systematic review. Neuroscience & Biobehavioral Reviews, 92, 304–317.

    Google Scholar 

  • Lim, L., Radua, J., & Rubia, K. (2014). Gray matter abnormalities in childhood maltreatment: a voxel-wise meta-analysis. The American Journal of Psychiatry, 171, 854–863.

    PubMed  Google Scholar 

  • Lui, S., Zhou, X. J., Sweeney, J. A., & Gong, Q. (2016). Psychoradiology: The Frontier of Neuroimaging in Psychiatry. Radiology, 281:357–72.

  • 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, 819–828.

    CAS  PubMed  PubMed Central  Google Scholar 

  • McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D., & Saykin, A. J. (2012). Alterations in brain activation during working memory processing associated with breast cancer and treatment: a prospective functional magnetic resonance imaging study. Journal of Clinical Oncology, 30, 2500–2508.

    PubMed  PubMed Central  Google Scholar 

  • McDonald, B. C., Conroy, S. K., Smith, D. J., West, J. D., & Saykin, A. J. (2013). Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: a replication and extension study. Brain, Behavior, and Immunity, 30(Suppl), S117-25.

    PubMed  Google Scholar 

  • Mcdonald, B. C., & Saykin, A. J. (2013). Alterations in brain structure related to breast cancer and its treatment: chemotherapy and other considerations. Brain Imaging & Behavior, 7, 374–387.

    Google Scholar 

  • Moher, D., Shamseer, L., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., et al. (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews, 4, 1.

    PubMed  PubMed Central  Google Scholar 

  • Myers, J. S. (2012). Chemotherapy-related cognitive impairment: the breast cancer experience. Oncology Nursing Forum, 39, E31–E40.

    PubMed  Google Scholar 

  • Nordin, K., Berglund, G., Glimelius, B., & Sjoden, P. O. (2001). Predicting anxiety and depression among cancer patients: a clinical model. European Journal of Cancer, 37, 376–384.

    CAS  PubMed  Google Scholar 

  • Pomykala, K. L., de Ruiter, M. B., Deprez, S., Mcdonald, B. C., & Silverman, D. H. (2013). Integrating imaging findings in evaluating the post-chemotherapy brain. Brain Imaging & Behavior, 7, 436–452.

    CAS  Google Scholar 

  • Radua, J., Borgwardt, S., Crescini, A., Mataix-Cols, D., Meyer-Lindenberg, A., McGuire, P. K., & Fusar-Poli, P. (2012). Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neuroscience & Biobehavioral Reviews, 36, 2325–2333.

    CAS  Google Scholar 

  • Radua, J., & Mataix-Cols, D. (2009). Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. British Journal of Psychiatry, 195, 393–402.

    Google Scholar 

  • Radua, J., Mataix-Cols, D., Phillips, M. L., El-Hage, W., Kronhaus, D. M., Cardoner, N., & Surguladze, S. (2012). A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. European Psychiatry, 27, 605–611.

    CAS  PubMed  Google Scholar 

  • Radua, J., Rubia, K., Canales-Rodriguez, E. J., Pomarol-Clotet, E., Fusar-Poli, P., & Mataix-Cols, D. (2014). Anisotropic kernels for coordinate-based meta-analyses of neuroimaging studies. Frontiers in Psychiatry, 5, 13.

    PubMed  PubMed Central  Google Scholar 

  • Rust, C., & Davis, C. (2013). Chemobrain in underserved African American breast cancer survivors: a qualitative study. Clinical Journal of Oncology Nursing, 17, E29–E34.

    PubMed  Google Scholar 

  • Saykin, A. J., Ahles, T. A., & McDonald, B. C. (2003). Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives. Seminars in Clinical Neuropsychiatry, 8, 201–216.

    PubMed  Google Scholar 

  • Shackman, A. J., Salomons, T. V., Slagter, H. A., Fox, A. S., Winter, J. J., & Davidson, R. J. (2011). The integration of negative affect, pain and cognitive control in the cingulate cortex. Nature Reviews Neuroscience, 12, 154–167.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shepherd, A. M., Matheson, S. L., Laurens, K. R., Carr, V. J., & Green, M. J. (2012). Systematic meta-analysis of insula volume in schizophrenia. Biological Psychiatry, 72, 775–784.

    PubMed  Google Scholar 

  • Silverman, D. H., Dy, C. J., Castellon, S. A., Lai, J., Pio, B. S., Abraham, L., et al. (2007). Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Research and Treatment, 103, 303–311.

    CAS  PubMed  Google Scholar 

  • Simó, M., Rifà-Ros, X., Rodriguez-Fornells, A., & Bruna, J. (2013). Chemobrain: a systematic review of structural and functional neuroimaging studies. Neuroscience & Biobehavioral Reviews, 37, 1311–1321.

    Google Scholar 

  • Simó, M., Root, J. C., Vaquero, L., Ripolles, P., Jove, J., Ahles, T., et al. (2015). Cognitive and brain structural changes in a lung cancer population. Journal of Thoracic Oncology, 10, 38–45.

    PubMed  PubMed Central  Google Scholar 

  • Simó, M., Vaquero, L., Ripollés, P., Guturbay, A., Jové, J., Navarro, A., et al. (2016). Longitudinal brain changes associated with prophylactic cranial irradiation in lung cancer. Journal of Thoracic Oncology, 11, 475–486.

    PubMed  Google Scholar 

  • Stoutenkemperman, M. M., de Ruiter, M. B., Koppelmans, V., Boogerd, W., Reneman, L., & Schagen, S. B. (2015). Neurotoxicity in breast cancer survivors ≥ 10 years post-treatment is dependent on treatment type. Brain Imaging & Behavior, 9, 275–284.

    Google Scholar 

  • Szczepanski, S. M., & Knight, R. T. (2014). Insights into human behavior from lesions to the prefrontal cortex. Neuron, 83, 1002–1018.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tao, L., Lin, H., Yan, Y., Xu, X., Wang, L., Zhang, J., & Yu, Y. (2017). Impairment of the executive function in breast cancer patients receiving chemotherapy treatment: a functional MRI study. European Journal of Cancer Care (Engl), 26.

  • Wefel, J. S., & Schagen, S. B. (2012). Chemotherapy-related cognitive dysfunction. Current Neurology & Neuroscience Reports, 12, 267–275.

    CAS  Google Scholar 

  • Yuan, P., & Raz, N. (2014). Prefrontal cortex and executive functions in healthy adults: a meta-analysis of structural neuroimaging studies. Neuroscience & Biobehavioral Reviews, 42, 180–192.

    Google Scholar 

Download references

Acknowledgements

This study was supported by Sichuan Science and Technology Program (grant numbers 2018SZ0183, 2017JY0080), Chengdu Science and Technology Program (grant number 2018-YF05-01134-SN), Populations Project of Health Commission of Sichuan Province (18PJ127) and Newton International Fellowship from the Royal Society, UK.

Funding

This study was funded by Sichuan Science and Technology Program (grant numbers 2018SZ0183, 2017JY0080), Chengdu Science and Technology Program (grant number 2018-YF05-01134-SN), Populations Project of Health Commission of Sichuan Province (18PJ127) and Newton International Fellowship from the Royal Society, UK.

Author information

Author notes

  1. Running Niu and Mingying Du contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Running Niu, Mingying Du, Jing Ren, Haomiao Qing, Xiaodong Wang, Guohui Xu & Peng Zhou

  2. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 260 Stetson St., Suite 3326, Cincinnati, OH, USA

    Du Lei

Authors
  1. Running Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingying Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haomiao Qing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaodong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guohui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Du Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The study concepts, study design and integrity of the entire study are guaranteed by all authors; NR and DM had the idea for the article. NR, DM, RJ, QH and WX researched the literature, extracted and analyzed the data and prepared the manuscript. XG, LD and ZP supervised the project at all stages and edited and revised the manuscript.

Corresponding authors

Correspondence to Du Lei or Peng Zhou.

Ethics declarations

Conflict of interest

All authors declare that they have no conflicts of interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A meta-analysis of grey matter in chemo-cancer survivors.

Electronic supplementary material

ESM 1

(DOCX 162 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Niu, R., Du, M., Ren, J. et al. Chemotherapy-induced grey matter abnormalities in cancer survivors: a voxel-wise neuroimaging meta-analysis. Brain Imaging and Behavior 15, 2215–2227 (2021). https://doi.org/10.1007/s11682-020-00402-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11682-020-00402-7

Keywords

Search

Navigation