An Oncologist’s Dilemma: How to Effectively Eliminate CNS Cancers in Children with Radiation Therapy Whilst Preserving Cognitive Function?
Keywords:
MedicineAbstract
Cranial irradiation is commonly adopted in the treatment of central nervous system (CNS) tumours, even in younger cancer patients, despite its severe early and late side effects. One of the major consequences of using radiation therapy in the CNS is the inevitable occurrence of normal tissue toxicity and resultant morbidities including cognitive dysfunction, learn- ing impairments and a lower quality of life. These symptoms are in part due to an arrest in the production or survival of neural precursor cells in particular proliferative regions of the brain including the hippocampus. As the population of childhood survivors of CNS or metastatic malignancy grows, more attention must be paid to the debilitating cognitive co-morbidities resulting from radiation therapy in particular. Protective prophylactic pharmaco- logical agents and precise ‘hippocampal-sparing’ radiation techniques should be considered during treatment, while drug or behavioral interventions may be indicated during a patient’s long term follow up period. This brief review overviews radiation therapy uses and mechanisms, investigates some of the currently known cellular and molecular events that lead to functional decline post-irradiation, examines the scarce therapies available to childhood CNS cancer survivors for their long-term cognitive morbidities to date and identifies possible therapeutic niches that could be targeted either during or post-radiation therapy to attenuate its long term consequences in the human brain.
References
Askins, M. A., & Moore, B. D. (2008). Preventing neurocognitive late effects in childhood cancer survivors. Journal of Child Neurology, 23(10), 1160-1171.
Belka, C., Budach, W., Kortmann, R., & Bamberg, M. (2001). Radiation induced CNS toxicity–molecular and cellular mecha- nisms. British journal of cancer, 85(9), 1233.
Brown, P. D., Pugh, S., Laack, N. N., Wefel, J. S., Khuntia, D., Meyers, C., . . . Roberge, D. (2013). Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-oncology, not114.
Delannes, M., Maire, J. P., Sabatier, J., & Thillays, F. (2012). [Ste- reotactic radiotherapy for intracranial meningioma]. Cancer Radiother, 16 Suppl, S79-89. doi: 10.1016/j.canrad.2011.07.249
Dias, G. P., Hollywood, R., do Nascimento Bevilaqua, M. C., Hindges, R., Nardi, A. E., & Thuret, S. (2014). Consequences
of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms. Neuro-oncology, not321.
Dietrich, J., Monje, M., Wefel, J., & Meyers, C. (2008). Clinical pat- terns and biological correlates of cognitive dysfunction associ- ated with cancer therapy. The Oncologist, 13(12), 1285-1295.
Ekdahl, C. T., Claasen, J.-H., Bonde, S., Kokaia, Z., & Lindvall,
O. (2003). Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A, 100(23), 13632-13637. doi: 10.1073/pnas.2234031100.
Ellenberg, L., Liu, Q., Gioia, G., Yasui, Y., Packer, R. J., Mertens, A., . . . Armstrong, G. (2009). Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology, 23(6), 705.
Eriksson, D., & Stigbrand, T. (2010). Radiation-induced cell death mechanisms. Tumor Biology, 31(4), 363-372.
Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.-M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998). Neurogene- sis in the adult human hippocampus. Nature medicine, 4(11), 13131317.
Fukuda, A., Fukuda, H., Swanpalmer, J., Hertzman, S., Lannering, B., Marky, I., . . . Blomgren, K. (2005). Age‐dependent sensitivity of the developing brain to irradiation is correlated with the number and vulnerability of progenitor cells. Journal of neurochemistry, 92(3), 569-584.
Gibson, E., & Monje, M. (2012). Effect of cancer therapy on neural stem cells: implications for cognitive function. Current opinion in oncology, 24(6), 672-678.
Gondi, V., Pugh, S. L., Tome, W. A., Caine, C., Corn, B., Kanner, A., . . . Greenspoon, J. N. (2014). Preservation of memory with conformal avoidance of the hippocampal neural stem-cell com- partment during whole-brain radiotherapy for brain metasta-
ses (RTOG 0933): a phase II multi-institutional trial. Journal of Clinical Oncology, 32(34), 3810-3816.
Gondi, V., Tomé, W. A., & Mehta, M. P. (2010). Why avoid the hippocampus? A comprehensive review. Radiotherapy and Oncology, 97(3), 370-376.
Heath, J. A., Zacharoulis, S., & Kieran, M. W. (2012). Pediatric neuro-oncology: current status and future directions. Asia Pac J Clin Oncol, 8(3), 223-231. doi: 10.1111/j.1743-7563.2012.01558.x
Jena, R., & Coles, C. E. (2015). Survivorship Issues in Radiation Oncology. Clinical Oncology, 27(11), 619-620. doi: http://dx.doi. org/10.1016/j.clon.2015.07.008
Kaatsch, P. (2010). Epidemiology of childhood cancer. Cancer treatment reviews, 36(4), 277-285.
Kalm, M., Karlsson, N., Nilsson, M. K., & Blomgren, K. (2013). Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain. Experimental neurology, 247, 402-409.
Kebudi, R., Ayan, I., Gorgun, O., Agaoglu, F. Y., Vural, S., & Darendeliler, E. (2005). Brain metastasis in pediatric extracranial solid tumors: survey and literature review. J Neurooncol, 71(1), 43-48. doi: 10.1007/s11060-004-4840-y
Lawrence, Y. R., Li, X. A., El Naqa, I., Hahn, C. A., Marks, L. B., Merchant, T. E., & Dicker, A. P. (2010). Radiation dose–volume effects in the brain. International Journal of Radiation Oncology* Biology* Physics, 76(3), S20-S27.
Lee, T. C., Greene-Schloesser, D., Payne, V., Diz, D. I., Hsu, F.-C., Kooshki, M., . . . Chan, M. D. (2012). Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, pre- vents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiation research, 178(1), 46-56.
Madsen, T. M., Kristjansen, P., Bolwig, T. G., & Wörtwein, G. (2003). Arrested neuronal proliferation and impaired hip- pocampal function following fractionated brain irradiation in the adult rat. Neuroscience, 119(3), 635-642.
Martino, E., Omelyanenko, A., Andäng, M., Delle, U., Elmroth, K., & Blomgren, K. (2015). Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradia- tion-induced cell cycle arrest in vitro. Oncotarget.
Meyers, C. A., Weitzner, M. A., Valentine, A. D., & Levin, V. A. (1998). Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. Journal of Clinical Oncol- ogy, 16(7), 2522-2527.
Monje, M. (2008). Cranial radiation therapy and damage to hip- pocampal neurogenesis. Developmental disabilities research reviews, 14(3), 238-242. Monje, M. L., Mizumatsu, S., Fike, J. R., & Palmer, T. D. (2002). Irradiation induces neural precursor-cell dysfunction. Nature medicine, 8(9), 955-962.
Monje, M. L., Toda, H., & Palmer, T. D. (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science, 302(5651), 1760-1765.
Monje, M. L., Vogel, H., Masek, M., Ligon, K. L., Fisher, P. G., & Palmer, T. D. (2007). Impaired human hippocampal neurogen- esis after treatment for central nervous system malignancies. Annals of neurology, 62(5), 515-520.
Moulder, J. E., & Cohen, E. P. (2007). Future Strategies for Mitigation and Treatment of Chronic Radiation-Induced Normal Tissue Injury. Seminars in Radiation Oncology, 17(2), 141-148. doi: http://dx.doi.org/10.1016/j.semradonc.2006.11.010
Mulhern, R. K., Merchant, T. E., Gajjar, A., Reddick, W. E., & Kun, L. E. (2004). Late neurocognitive sequelae in survivors of brain tumours in childhood. The Lancet Oncology, 5(7), 399-408. NCRI. (2015). Cancer Trends: Primary Brain Cancer. from http:// www.ncri.ie/sites/ncri/files/pubs/Cancer Trends - Brain.pdf
NCRI. (July 2014). Cancer Trends: Childhood Cancer Fact Sheet. from http://www.ncri.ie/publications/cancer-trends-and-pro- jections/cancer-trends-childhood-cancerhttp://www. ncri.ie/publications/cancer-trends-and-projections/can- cer-trends-childhood-cancer.
Oeffinger, K. C., Mertens, A. C., Sklar, C. A., Kawashima, T., Hudson, M. M., Meadows, A. T., . . . Kadan-Lottick, N. S. (2006). Chronic health conditions in adult survivors of childhood cancer. New England Journal of Medicine, 355(15), 1572-1582.
Page, B. R., Shaw, E. G., Lu, L., Bryant, D., Grisell, D., Lesser, G. J.,
. . . Savona, S. R. (2015). Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue. Neuro-oncology, 17(10), 1393-1401.
Peiffer, A. M., Leyrer, C. M., Greene-Schloesser, D. M., Shing, E., Kearns, W. T., Hinson, W. H., . . . Robbins, M. E. (2013). Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline. Neurology, 80(8), 747-753.
Pollack, I. F., & Jakacki, R. I. (2011). Childhood brain tumors: epidemiology, current management and future directions. Nature Reviews Neurology, 7(9), 495-506.
Pospisil, P., Kazda, T., Bulik, M., Dobiaskova, M., Burkon, P., Hynkova, L., . . . Jancalek, R. (2015). Hippocampal proton MR spectroscopy as a novel approach in the assessment of radi-
ation injury and the correlation to neurocognitive function impairment: initial experiences. Radiation Oncology (London, England), 10, 211. doi: 10.1186/s13014-015-0518-1
Raber, J., Rola, R., LeFevour, A., Morhardt, D., Curley, J., Miz- umatsu, S., . . . Fike, J. R. (2004). Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiation research, 162(1), 39-47.
Roddy, E., & Mueller, S. (2015). Late Effects of Treatment of Pediatric Central Nervous System Tumors. Journal of Child Neurology, 0883073815587944.
Rooney, J. W., & Laack, N. N. (2013). Pharmacological interven- tions to treat or prevent neurocognitive decline after brain radiation. CNS Oncol, 2(6), 531-541. doi: 10.2217/cns.13.60
Shaw, E. G., Rosdhal, R., D’Agostino, R. B., Lovato, J., Naughton, M. J., Robbins, M. E., & Rapp, S. R. (2006). Phase II study of done- pezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. Journal of Clinical Oncol- ogy, 24(9), 1415-1420.
Yazlovitskaya, E. M., Edwards, E., Thotala, D., Fu, A., Osusky, K. L., Whetsell, W. O., . . . Hallahan, D. E. (2006). Lithium treatment prevents neurocognitive deficit resulting from cranial irradia- tion. Cancer research, 66(23), 11179-11186. Zanni, G., Di
Zhao, W., Payne, V., Tommasi, E., Diz, D. I., Hsu, F.-C., & Robbins, M. E. (2007). Administration of the peroxisomal proliferator-ac- tivated receptor agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. International Journal of Radiation Oncology* Biology* Physics, 67(1), 6-9.
Belka, C., Budach, W., Kortmann, R., & Bamberg, M. (2001). Radiation induced CNS toxicity–molecular and cellular mecha- nisms. British journal of cancer, 85(9), 1233.
Brown, P. D., Pugh, S., Laack, N. N., Wefel, J. S., Khuntia, D., Meyers, C., . . . Roberge, D. (2013). Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-oncology, not114.
Delannes, M., Maire, J. P., Sabatier, J., & Thillays, F. (2012). [Ste- reotactic radiotherapy for intracranial meningioma]. Cancer Radiother, 16 Suppl, S79-89. doi: 10.1016/j.canrad.2011.07.249
Dias, G. P., Hollywood, R., do Nascimento Bevilaqua, M. C., Hindges, R., Nardi, A. E., & Thuret, S. (2014). Consequences
of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms. Neuro-oncology, not321.
Dietrich, J., Monje, M., Wefel, J., & Meyers, C. (2008). Clinical pat- terns and biological correlates of cognitive dysfunction associ- ated with cancer therapy. The Oncologist, 13(12), 1285-1295.
Ekdahl, C. T., Claasen, J.-H., Bonde, S., Kokaia, Z., & Lindvall,
O. (2003). Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A, 100(23), 13632-13637. doi: 10.1073/pnas.2234031100.
Ellenberg, L., Liu, Q., Gioia, G., Yasui, Y., Packer, R. J., Mertens, A., . . . Armstrong, G. (2009). Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology, 23(6), 705.
Eriksson, D., & Stigbrand, T. (2010). Radiation-induced cell death mechanisms. Tumor Biology, 31(4), 363-372.
Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.-M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998). Neurogene- sis in the adult human hippocampus. Nature medicine, 4(11), 13131317.
Fukuda, A., Fukuda, H., Swanpalmer, J., Hertzman, S., Lannering, B., Marky, I., . . . Blomgren, K. (2005). Age‐dependent sensitivity of the developing brain to irradiation is correlated with the number and vulnerability of progenitor cells. Journal of neurochemistry, 92(3), 569-584.
Gibson, E., & Monje, M. (2012). Effect of cancer therapy on neural stem cells: implications for cognitive function. Current opinion in oncology, 24(6), 672-678.
Gondi, V., Pugh, S. L., Tome, W. A., Caine, C., Corn, B., Kanner, A., . . . Greenspoon, J. N. (2014). Preservation of memory with conformal avoidance of the hippocampal neural stem-cell com- partment during whole-brain radiotherapy for brain metasta-
ses (RTOG 0933): a phase II multi-institutional trial. Journal of Clinical Oncology, 32(34), 3810-3816.
Gondi, V., Tomé, W. A., & Mehta, M. P. (2010). Why avoid the hippocampus? A comprehensive review. Radiotherapy and Oncology, 97(3), 370-376.
Heath, J. A., Zacharoulis, S., & Kieran, M. W. (2012). Pediatric neuro-oncology: current status and future directions. Asia Pac J Clin Oncol, 8(3), 223-231. doi: 10.1111/j.1743-7563.2012.01558.x
Jena, R., & Coles, C. E. (2015). Survivorship Issues in Radiation Oncology. Clinical Oncology, 27(11), 619-620. doi: http://dx.doi. org/10.1016/j.clon.2015.07.008
Kaatsch, P. (2010). Epidemiology of childhood cancer. Cancer treatment reviews, 36(4), 277-285.
Kalm, M., Karlsson, N., Nilsson, M. K., & Blomgren, K. (2013). Loss of hippocampal neurogenesis, increased novelty-induced activity, decreased home cage activity, and impaired reversal learning one year after irradiation of the young mouse brain. Experimental neurology, 247, 402-409.
Kebudi, R., Ayan, I., Gorgun, O., Agaoglu, F. Y., Vural, S., & Darendeliler, E. (2005). Brain metastasis in pediatric extracranial solid tumors: survey and literature review. J Neurooncol, 71(1), 43-48. doi: 10.1007/s11060-004-4840-y
Lawrence, Y. R., Li, X. A., El Naqa, I., Hahn, C. A., Marks, L. B., Merchant, T. E., & Dicker, A. P. (2010). Radiation dose–volume effects in the brain. International Journal of Radiation Oncology* Biology* Physics, 76(3), S20-S27.
Lee, T. C., Greene-Schloesser, D., Payne, V., Diz, D. I., Hsu, F.-C., Kooshki, M., . . . Chan, M. D. (2012). Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, pre- vents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiation research, 178(1), 46-56.
Madsen, T. M., Kristjansen, P., Bolwig, T. G., & Wörtwein, G. (2003). Arrested neuronal proliferation and impaired hip- pocampal function following fractionated brain irradiation in the adult rat. Neuroscience, 119(3), 635-642.
Martino, E., Omelyanenko, A., Andäng, M., Delle, U., Elmroth, K., & Blomgren, K. (2015). Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradia- tion-induced cell cycle arrest in vitro. Oncotarget.
Meyers, C. A., Weitzner, M. A., Valentine, A. D., & Levin, V. A. (1998). Methylphenidate therapy improves cognition, mood, and function of brain tumor patients. Journal of Clinical Oncol- ogy, 16(7), 2522-2527.
Monje, M. (2008). Cranial radiation therapy and damage to hip- pocampal neurogenesis. Developmental disabilities research reviews, 14(3), 238-242. Monje, M. L., Mizumatsu, S., Fike, J. R., & Palmer, T. D. (2002). Irradiation induces neural precursor-cell dysfunction. Nature medicine, 8(9), 955-962.
Monje, M. L., Toda, H., & Palmer, T. D. (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science, 302(5651), 1760-1765.
Monje, M. L., Vogel, H., Masek, M., Ligon, K. L., Fisher, P. G., & Palmer, T. D. (2007). Impaired human hippocampal neurogen- esis after treatment for central nervous system malignancies. Annals of neurology, 62(5), 515-520.
Moulder, J. E., & Cohen, E. P. (2007). Future Strategies for Mitigation and Treatment of Chronic Radiation-Induced Normal Tissue Injury. Seminars in Radiation Oncology, 17(2), 141-148. doi: http://dx.doi.org/10.1016/j.semradonc.2006.11.010
Mulhern, R. K., Merchant, T. E., Gajjar, A., Reddick, W. E., & Kun, L. E. (2004). Late neurocognitive sequelae in survivors of brain tumours in childhood. The Lancet Oncology, 5(7), 399-408. NCRI. (2015). Cancer Trends: Primary Brain Cancer. from http:// www.ncri.ie/sites/ncri/files/pubs/Cancer Trends - Brain.pdf
NCRI. (July 2014). Cancer Trends: Childhood Cancer Fact Sheet. from http://www.ncri.ie/publications/cancer-trends-and-pro- jections/cancer-trends-childhood-cancerhttp://www. ncri.ie/publications/cancer-trends-and-projections/can- cer-trends-childhood-cancer.
Oeffinger, K. C., Mertens, A. C., Sklar, C. A., Kawashima, T., Hudson, M. M., Meadows, A. T., . . . Kadan-Lottick, N. S. (2006). Chronic health conditions in adult survivors of childhood cancer. New England Journal of Medicine, 355(15), 1572-1582.
Page, B. R., Shaw, E. G., Lu, L., Bryant, D., Grisell, D., Lesser, G. J.,
. . . Savona, S. R. (2015). Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue. Neuro-oncology, 17(10), 1393-1401.
Peiffer, A. M., Leyrer, C. M., Greene-Schloesser, D. M., Shing, E., Kearns, W. T., Hinson, W. H., . . . Robbins, M. E. (2013). Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline. Neurology, 80(8), 747-753.
Pollack, I. F., & Jakacki, R. I. (2011). Childhood brain tumors: epidemiology, current management and future directions. Nature Reviews Neurology, 7(9), 495-506.
Pospisil, P., Kazda, T., Bulik, M., Dobiaskova, M., Burkon, P., Hynkova, L., . . . Jancalek, R. (2015). Hippocampal proton MR spectroscopy as a novel approach in the assessment of radi-
ation injury and the correlation to neurocognitive function impairment: initial experiences. Radiation Oncology (London, England), 10, 211. doi: 10.1186/s13014-015-0518-1
Raber, J., Rola, R., LeFevour, A., Morhardt, D., Curley, J., Miz- umatsu, S., . . . Fike, J. R. (2004). Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiation research, 162(1), 39-47.
Roddy, E., & Mueller, S. (2015). Late Effects of Treatment of Pediatric Central Nervous System Tumors. Journal of Child Neurology, 0883073815587944.
Rooney, J. W., & Laack, N. N. (2013). Pharmacological interven- tions to treat or prevent neurocognitive decline after brain radiation. CNS Oncol, 2(6), 531-541. doi: 10.2217/cns.13.60
Shaw, E. G., Rosdhal, R., D’Agostino, R. B., Lovato, J., Naughton, M. J., Robbins, M. E., & Rapp, S. R. (2006). Phase II study of done- pezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life. Journal of Clinical Oncol- ogy, 24(9), 1415-1420.
Yazlovitskaya, E. M., Edwards, E., Thotala, D., Fu, A., Osusky, K. L., Whetsell, W. O., . . . Hallahan, D. E. (2006). Lithium treatment prevents neurocognitive deficit resulting from cranial irradia- tion. Cancer research, 66(23), 11179-11186. Zanni, G., Di
Zhao, W., Payne, V., Tommasi, E., Diz, D. I., Hsu, F.-C., & Robbins, M. E. (2007). Administration of the peroxisomal proliferator-ac- tivated receptor agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment. International Journal of Radiation Oncology* Biology* Physics, 67(1), 6-9.
Downloads
Published
2016-01-01
How to Cite
Strickland, T. (2016). An Oncologist’s Dilemma: How to Effectively Eliminate CNS Cancers in Children with Radiation Therapy Whilst Preserving Cognitive Function?. Trinity Student Medical Journal , 17(1), 22–30. Retrieved from https://ojs.tchpc.tcd.ie/index.php/tsmj/article/view/1752
Issue
Section
Reviews
License
Authors retain copyright and grant the journal the right of first publication with the work simultaneously licensed under a Creative Commons Attribution (CC-BY) 4.0 License that allows others to share the work with an acknowledgement of the work’s authorship and initial publication in this journal.
Provided they are the owners of the copyright to their work, authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository, in a journal or publish it in a book), with an acknowledgement of its initial publication in this journal.
