Skip to main content
SpringerLink
Log in

Evolution of neurocognitive function in long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

  • Published:
Journal of Cancer Survivorship Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to determine the evolution of neurocognitive problems from therapy completion to long-term follow-up in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.

Methods

We evaluated whether attention problems observed at therapy completion evolve into long-term executive dysfunction in 158 survivors treated on a single institution protocol. Treatment data (high-dose intravenous methotrexate exposure [serum concentration] and triple intrathecal chemotherapy injections) were collected. Parent report of behavior and direct cognitive testing of survivors was conducted at end of therapy, and survivors completed neurocognitive testing when > 5 years post-diagnosis.

Results

At the end of chemotherapy, survivors (52% female; mean age 9.2 years) demonstrated higher frequency of impairment in sustained attention (38%) and parent-reported inattention (20%) compared to population expectations (10%). At long-term follow-up, survivors (mean age 13.7 years; 7.6 years post-diagnosis) demonstrated higher impairment in executive function (flexibility 24%, fluency 21%), sustained attention (15%), and processing speed (15%). Sustained attention improved from end of therapy to long-term follow-up (p < 0.001). Higher methotrexate AUC and greater number of intrathecal injections were associated with attention problems (p = 0.009, p = 0.002, respectively) at the end of chemotherapy and executive function (p < 0.001, p = 0.02, respectively) problems at long-term follow-up. Attention problems at the end of therapy were not associated with executive function problems at long-term follow-up (p’s > 0.05). The direct effect of chemotherapy exposure predicted outcomes at both time points.

Conclusions and Implications for Cancer Survivors

Survivors should be monitored for neurocognitive problems well into long-term survivorship, regardless of whether they show attention problems at the end of therapy. Treatment exposures are the best predictor of long-term complications.

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

Consort 1
Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Iyer NS, Balsamo LM, Bracken MB, Kadan-Lottick NS. Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis. Blood. 2015;126(3):346–53. https://doi.org/10.1182/blood-2015-02-627414.

    Article  PubMed  CAS  Google Scholar 

  2. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(26):2730–41. https://doi.org/10.1056/NEJMoa0900386.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Cheung YT, Krull KR. Neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on contemporary treatment protocols: a systematic review. Neurosci Biobehav Rev. 2015;53:108–20. https://doi.org/10.1016/j.neubiorev.2015.03.016.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Krull KR, Brinkman TM, Li C, Armstrong GT, Ness KK, Srivastava DK, et al. Neurocognitive outcomes decades after treatment for childhood acute lymphoblastic leukemia: a report from the St Jude lifetime cohort study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(35):4407–15. https://doi.org/10.1200/jco.2012.48.2315.

    Article  Google Scholar 

  5. Krull KR, Hockenberry MJ, Miketova P, Carey M, Moore IM. Chemotherapy-related changes in central nervous system phospholipids and neurocognitive function in childhood acute lymphoblastic leukemia. Leukemia & lymphoma. 2013;54(3):535–40. https://doi.org/10.3109/10428194.2012.717080.

    Article  CAS  Google Scholar 

  6. Conklin HM, Krull KR, Reddick WE, Pei D, Cheng C, Pui CH. Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia. J Natl Cancer Inst. 2012;104(18):1386–95. https://doi.org/10.1093/jnci/djs344.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Jacola LM, Krull KR, Pui CH, Pei D, Cheng C, Reddick WE, et al. Longitudinal assessment of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy protocol. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(11):1239–47. https://doi.org/10.1200/jco.2015.64.3205.

    Article  CAS  Google Scholar 

  8. Krull KR, Cheung YT, Liu W, Fellah S, Reddick WE, Brinkman TM, et al. Chemotherapy pharmacodynamics and neuroimaging and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34(22):2644–53. https://doi.org/10.1200/jco.2015.65.4574.

    Article  CAS  Google Scholar 

  9. Kanellopoulos A, Andersson S, Zeller B, Tamnes CK, Fjell AM, Walhovd KB, et al. Neurocognitive outcome in very long-term survivors of childhood acute lymphoblastic leukemia after treatment with chemotherapy only. Pediatr Blood Cancer. 2016;63(1):133–8. https://doi.org/10.1002/pbc.25690.

    Article  PubMed  Google Scholar 

  10. Anderson P. Assessment and development of executive function (EF) during childhood. Child neuropsychology : a journal on normal and abnormal development in childhood and adolescence. 2002;8(2):71–82. https://doi.org/10.1076/chin.8.2.71.8724.

    Article  Google Scholar 

  11. Diamond A. Executive functions. Annu Rev Psychol. 2013;64:135–68. https://doi.org/10.1146/annurev-psych-113011-143750.

    Article  PubMed  Google Scholar 

  12. Romine CB, Reynolds CR. A model of the development of frontal lobe functioning: findings from a meta-analysis. Appl Neuropsychol. 2005;12(4):190–201. https://doi.org/10.1207/s15324826an1204_2.

    Article  PubMed  Google Scholar 

  13. Bhojwani D, Sabin ND, Pei D, Yang JJ, Khan RB, Panetta JC, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(9):949–59. https://doi.org/10.1200/jco.2013.53.0808.

    Article  CAS  Google Scholar 

  14. Conners CKS, M. Conners’ continuous performance test II (CPT II V. 5). North Tonawanda, NY: Multi-Health Systems Inc; 2000.

  15. Conners C. Conners rating scales-revised: technical manual. New York: Multi-Health Systems. (Inc); 1997.

  16. Delis DC, Kaplan, E. & Kramer, J.H. . Delis-Kaplan executive function system. San Antonio, TX: Psychological Corporation; 2001.

  17. Wechsler D. Wechsler intelligence scale for children—fourth edition. San Antonio, TX: Harcourt Assessment, Inc; 2003.

    Google Scholar 

  18. Wechsler D. Wechsler adult intelligence scale—fourth edition. Pearson: San Antonio; 2008.

    Google Scholar 

  19. Meyers JE. MKR. Rey complex figure test and recognition trial: professional manual. Psychological Assessment Resources: Odessa, FL; 1995.

    Google Scholar 

  20. Lafayette Instrument Grooved Pegboard Test User Instructions. Lafayett IN: Lafatette Instrument@; 2002.

  21. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57(1):289–300.

    Google Scholar 

  22. Best JR, Miller PH. A developmental perspective on executive function. Child Dev. 2010;81(6):1641–60. https://doi.org/10.1111/j.1467-8624.2010.01499.x.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Barkley RA. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull. 1997;121(1):65–94.

    Article  PubMed  Google Scholar 

  24. Ganesalingam K, Sanson A, Anderson V, Yeates KO. Self-regulation as a mediator of the effects of childhood traumatic brain injury on social and behavioral functioning. Journal of the International Neuropsychological Society : JINS. 2007;13(2):298–311. https://doi.org/10.1017/s1355617707070324.

    Article  PubMed  Google Scholar 

  25. Klenberg L, Korkman M, Lahti-Nuuttila P. Differential development of attention and executive functions in 3- to 12-year-old Finnish children. Dev Neuropsychol. 2001;20(1):407–28. https://doi.org/10.1207/s15326942dn2001_6.

    Article  PubMed  CAS  Google Scholar 

  26. Duncan J, Owen AM. Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci. 2000;23(10):475–83.

    Article  PubMed  CAS  Google Scholar 

  27. Blakemore SJ, Choudhury S. Development of the adolescent brain: implications for executive function and social cognition. Journal of child psychology and psychiatry, and allied disciplines. 2006;47(3–4):296–312. https://doi.org/10.1111/j.1469-7610.2006.01611.x.

    Article  PubMed  Google Scholar 

  28. Reddick WE, Taghipour DJ, Glass JO, Ashford J, Xiong X, Wu S, et al. Prognostic factors that increase the risk for reduced white matter volumes and deficits in attention and learning for survivors of childhood cancers. Pediatr Blood Cancer. 2014;61(6):1074–9. https://doi.org/10.1002/pbc.24947.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Noble KG, Houston SM, Brito NH, Bartsch H, Kan E, Kuperman JM, et al. Family income, parental education and brain structure in children and adolescents. Nat Neurosci. 2015;18(5):773–8. https://doi.org/10.1038/nn.3983.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Mary Relling, PharmD, St. Jude Children’s Research Hospital, and her lab that provide pharmacokinetic data, and Pia Banerjee, PhD, Joycelynn Butler, MS, William Lewis, MS, Adrienne Studaway, Med, Adrienne Studaway, Med, Cynthia Jones, MA, and Deborah Stewart, MA, all from Cognitive Neuroscience group, St. Jude Children’s Research Hospital, for providing technical support.

Funding

This study was funded by NIMH (R01-MH085849 to KR Krull), NCI (U01-CA195547 to MM Hudson/LL Robison), and American Lebanese Syrian Associated Charities.

Author information

Authors and Affiliations

  1. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Wei Liu & DeoKumar Srivastava

  2. School of Public Health, University of Memphis, Memphis, TN, USA

    Wei Liu, Vikki G. Nolan, Hongmei Zhang & James G. Gurney

  3. Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS 735, Memphis, TN, 38105, USA

    Yin Ting Cheung, I-Chan Huang, Leslie L. Robison, Melissa M. Hudson & Kevin R. Krull

  4. Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Heather M. Conklin, Lisa M. Jacola & Kevin R. Krull

  5. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Ching-Hon Pui & Melissa M. Hudson

Authors
  1. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yin Ting Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather M. Conklin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lisa M. Jacola
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. DeoKumar Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vikki G. Nolan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongmei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James G. Gurney
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. I-Chan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Leslie L. Robison
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ching-Hon Pui
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Melissa M. Hudson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kevin R. Krull
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The following authors have made substantial contributions to the intellectual content of the paper, including conception/design (WL, YTC, DS, KRK), acquisition, analysis, or interpretation of data (WL, YTC, HMC, LMJ, DS, VGN, HZ, JGG, IH, LLR, CHP, MMH, KRK), drafting of the manuscript (WL, YTC, KRK), and critical revision of the manuscript for important intellectual content (WL, YTC, HMC, LMJ, DS, VGN, HZ, JGG, IH, LLR, CHP, MMH, KRK). Contributions also include statistical analysis (WL, DS) and obtaining funding (KRK, LLR, MMH). All authors have approved the final version of this manuscript. KRK had full access to all data in the study and had final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Kevin R. Krull.

Ethics declarations

Conflict of interest

All authors have no conflict of interest including financial interests, activities, relationships, and affiliations and sources of funding and support.

Ethical approval

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.

Electronic supplementary material

ESM 1

(DOCX 27 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, W., Cheung, Y.T., Conklin, H.M. et al. Evolution of neurocognitive function in long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only. J Cancer Surviv 12, 398–406 (2018). https://doi.org/10.1007/s11764-018-0679-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11764-018-0679-7

Keywords

Search

Navigation