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Neurocognitive long-term impact of two-field conventional radiotherapy in adult patients with operated pituitary adenomas

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Abstract

Purpose

To assess the long-term impact of postoperative two-field-conventional radiotherapy (RT) on neurocognitive functions of adult patients with operated pituitary adenomas (PA).

Methods

We selected 124 adult patients with operated PA—56 of whom had also received RT—recorded their main clinical data and performed a neuropsychological assessment in all of them that included 15 standardized tests, and a cerebral SPECT in eight patients. Comparative analyses were carried out on major clinical and neurocognitive domains between irradiated and not irradiated patients, and on cerebral SPECT source.

Results

Compared with non-irradiated patients, irradiated patients performed significantly worse on Barcelona’s story recall test (P < 0.001) and arithmetic problems (P < 0.03) and on five categories of the Wisconsin card sorting test, especially on perseverative answers and errors (P < 0.001) without differences in other examined functional domains. RT was the only factor associated with worse results in these tests regardless other clinical and treatment-related variables. Kaplan–Meier analysis suggested that the probability of achieving poorer results with time was related to RT total dose and field-size, type of PA and age at the time of RT. Four of the five SPECTS performed in irradiated patients revealed a similar altered perfusion in the left temporal lobe cortical region.

Conclusions

In adult patients with operated PA, RT was independently associated with an impairment on verbal memory and executive function, when compared to non-irradiated patients. Our data suggest that diagnosis of acromegaly or Cushing’s disease, and age at the time of RT were able to modulate this long-term radioinduced neurocognitive sequelae.

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References

  1. Fischer AW, Holfelder H (1930) Lokales amyloid im gehirn. Dtsch Z Chir 227:475–483

    Article  Google Scholar 

  2. Meadows AT, Gordon J, Massari DJ, Littman P, Fergusson J, Moss K (1981) Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet 2:1015–1018

    Article  CAS  PubMed  Google Scholar 

  3. Moore IM, Kramer JH, Wara W, Halberg F, Ablin AR (1991) Cognitive function in children with leukemia. Effect of radiation dose and time since irradiation. Cancer 68:1913–1917

    Article  CAS  PubMed  Google Scholar 

  4. Glosser G, McManus P, Munzenrider J, Austin-Seymour M, Fullerton B, Adams J, Urie MM (1997) Neuropsychological function in adults after high dose fractionated radiation therapy of skull base tumors. Int J Radiat Oncol Biol Phys 38:231–239

    Article  CAS  PubMed  Google Scholar 

  5. Abayomi OK (2002) Pathogenesis of cognitive decline following therapeutic irradiation for head and neck tumors. Acta Oncol 41:346–351

    Article  PubMed  Google Scholar 

  6. Redmond KJ, Mahone EM, Terezakis S, Ishaq O, Ford E, McNutt T, Kleinberg L, Cohen KJ, Wharam M, Horska A (2013) Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study. Neuro-oncology 15:360–369

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Gondi V, Hermann BP, Mehta MP, Tomé WA (2013) Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys 85:348–354

    Article  PubMed  Google Scholar 

  8. Schindler MK, Forbes ME, Robbins ME, Riddle DR (2008) Aging-dependent changes in the radiation response of the adult rat brain. Int J Radiat Oncol Biol Phys 70:826–834

    Article  PubMed Central  PubMed  Google Scholar 

  9. Coderre JA, Morris GM, Micca PL, Hopewell JW, Verhagen I, Kleiboer BJ, van der Kogel AJ (2006) Late effects of radiation on the central nervous system: role of vascular endothelial damage and glial stem cell survival. Radiat Res 166:495–503

    Article  CAS  PubMed  Google Scholar 

  10. Monje ML, Mizumatsu S, Fike JR, Palmer TD (2002) Irradiation induces neural precursor-cell dysfunction. Nat Med 8:955–962

    Article  CAS  PubMed  Google Scholar 

  11. Ben Abdallah NM, Slomianka L, Lipp HP (2007) Reversible effect of X-irradiation on proliferation, neurogenesis, and cell death in the dentate gyrus of adult mice. Hippocampus 17:1230–1240

    Article  PubMed  Google Scholar 

  12. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765

    Article  CAS  PubMed  Google Scholar 

  13. Yazlovitskaya EM, Edwards E, Thotala D, Fu A, Osusky KL, Whetsell WO Jr, Boone B, Shinohara ET, Hallahan DE (2006) Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res 66:11179–11186

    Article  CAS  PubMed  Google Scholar 

  14. Luria AR (1976) The neuropsycology of memory. John Wiley, New York

    Google Scholar 

  15. Lishman WA (1987) Organic psychiatry: the psychological consecuences of cerebral disorders. Blackwell, Oxford

    Google Scholar 

  16. Starkman MN, Schteingart DE (1981) Neuropsychiatric manifestifications of patients with Cushing’s syndrome. Arch Intern Med 141:215–219

    Article  CAS  PubMed  Google Scholar 

  17. Dorn LD, Burgess ES, Dubbert B, Simpson SE, Friedman T, Kling M, Gold PW, Chrousos GP (1995) Psychopathology in patients with endogenous Cushing’s syndrome: atypical or melancholic features. Clin Endocrinol 43:433–442

    Article  CAS  Google Scholar 

  18. Leon-Carrion J, Martin-Rodriguez JF, Madrazo-Atutxa A, Soto-Moreno A, Venegas-Moreno E, Torres-Vela E, Benito-López P, Gálvez MA, Tinahones FJ, Leal-Cerro A (2010) Evidence of cognitive and neurophysiological impairment in patients with untreated naive acromegaly. J Clin Endocrinol Metab 95:4367–4379

    Article  CAS  PubMed  Google Scholar 

  19. Peace KA, Orme SM, Sebastian JP, Thompson AR, Barnes S, Ellis A, Belchetz PE (1997) The effect of treatment variables on mood and social adjustment in adult patients with pituitary disease. Clin Endocrinol 46:445–450

    Article  CAS  Google Scholar 

  20. Page RC, Hammersley MS, Burke CW, Wass JA (1997) An account of the quality of life of patients after treatment for non-functioning pituitary tumours. Clin Endocrinol 46:401–406

    Article  CAS  Google Scholar 

  21. Grattan-Smith PJ, Morris JG, Shores EA, Batchelor J, Sparks RS (1992) Neuropsychological abnormalities in patients with pituitary tumours. Acta Neurol Scand 86:626–631

    Article  CAS  PubMed  Google Scholar 

  22. McCord MW, Buatti JM, Fennell EM, Mendenhall WM, Marcus RB Jr, Rhoton AL, Grant MB, Friedman WA (1997) Radiotherapy for pituitary adenoma: long-term outcome and sequelae. Int J Radiat Oncol Biol Phys 39:437–444

    Article  CAS  PubMed  Google Scholar 

  23. Peace KA, Orme SM, Padayatty SJ, Godfrey HP, Belchetz PE (1998) Cognitive dysfunction in patients with pituitary tumour who have been treated with transfrontal or transsphenoidal surgery or medication. Clin Endocrinol 49:391–396

    Article  CAS  Google Scholar 

  24. Peace KA, Orme SM, Thompson AR, Padayatty S, Ellis AW, Belchetz PE (1997) Cognitive dysfunction in patients treated for pituitary tumours. J Clin Exp Neuropsychol 19:1–6

    Article  CAS  PubMed  Google Scholar 

  25. Guinan EM, Lowy C, Stanhope N, Lewis PD, Kopelman MD (1998) Cognitive effects of pituitary tumours and their treatments: two case studies and an investigation of 90 patients. J Neurol Neurosurg Psychiatry 65:870–876

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Noad R, Narayanan KR, Howlett T, Lincoln NB, Page RC (2004) Evaluation of the effect of radiotherapy for pituitary tumours on cognitive function and quality of life. Clin Oncol 16:233–237

    Article  CAS  Google Scholar 

  27. Tiemensma J, Kokshoorn NE, Biermasz NR, Keijser BJ, Wassenaar MJ, Middelkoop HA, Pereira AM, Romijn JA (2010) Subtle cognitive impairments in patients with long-term cure of Cushing’s disease. J Clin Endocrinol Metab 95:2699–2714

    Article  CAS  PubMed  Google Scholar 

  28. Tiemensma J, Biermasz NR, van der Mast RC, Wassenaar MJ, Middelkoop HA, Pereira AM, Romijn JA (2010) Increased psychopathology and maladaptive personality traits, but normal cognitive functioning, in patients after long-term cure of acromegaly. J Clin Endocrinol Metab 95:E392–E402

    Article  CAS  PubMed  Google Scholar 

  29. van Beek AP, van den Bergh AC, van den Berg LM, van den Berg G, Keers JC, Langendijk JA, Wolffenbuttel BH (2007) Radiotherapy is not associated with reduced quality of life and cognitive function in patients treated for nonfunctioning pituitary adenoma. Int J Radiat Oncol Biol Phys 68:986–991

    Article  PubMed  Google Scholar 

  30. Brummelman P, Sattler MG, Meiners LC, Elderson MF, Dullaart RP, van den Berg G, Koerts J, Tucha O, Wolffenbuttel BH, van den Bergh AC, van Beek AP (2012) Cognitive performance after postoperative pituitary radiotherapy: a dosimetric study of the hippocampus and the prefrontal cortex. Eur J Endocrinol 166:171–179

    Article  CAS  PubMed  Google Scholar 

  31. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  CAS  PubMed  Google Scholar 

  32. Benton AL (1945) A visual retention test for clinical use. Arch Neurol Psychiatry 54:212–216

    Article  CAS  PubMed  Google Scholar 

  33. Nelson HE (1976) A modified card sorting test sensitive to frontal lobe defects. Cortex 12:313–324

    Article  CAS  PubMed  Google Scholar 

  34. Peña-Casanova J, Guardia J, Bertran-Serra I, Manero RM, Jarne A (1997) Shortened version of the Barcelona test (I): subtests and normal profiles. Neurologia 12:99–111

    PubMed  Google Scholar 

  35. Aberg ND, Brywe KG, Isgaard J (2006) Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. Sci World J 6:53–80

    Article  Google Scholar 

  36. Pruessner M, Pruessner JC, Hellhammer DH, Bruce Pike G, Lupien SJ (2007) The associations among hippocampal volume, cortisol reactivity, and memory performance in healthy young men. Psychiatry Res 155:1–10

    Article  PubMed  Google Scholar 

  37. Klement J, Hubold C, Hallschmid M, Loeck C, Oltmanns KM, Lehnert H, Born J, Peters A (2009) Effects of glucose infusion on neuroendocrine and cognitive parameters in Addison disease. Metabolism 58:1825–1831

    Article  CAS  PubMed  Google Scholar 

  38. Tytherleigh MY, Vedhara K, Lightman SL (2004) Mineralocorticoid and glucocorticoid receptors and their differential effects on memory performance in people with Addison’s disease. Psychoneuroendocrinology 29:712–723

    Article  CAS  PubMed  Google Scholar 

  39. Beclere J (1909) The radiotherapeutic treatment of tumours of the hypophysis, gigantism and acromegaly. Arch Roentgen Ray 3:114

    Google Scholar 

  40. Brada M, Rajan B, Traish D, Ashley S, Holmes-Sellors PJ, Nussey S, Uttley D (1993) The long-term efficacy of conservative surgery and radiotherapy in the control of pituitary adenomas. Clin Endocrinol 38:571–578

    Article  CAS  Google Scholar 

  41. Estrada J, Boronat M, Mielgo M, Magallón R, Millan I, Díez S, Lucas T, Barceló B (1997) The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med 336:172–177

    Article  CAS  PubMed  Google Scholar 

  42. Erfurth EM, Bülow B, Mikoczy Z, Svahn-Tapper G, Hagmar L (2001) Is there an increase in second brain tumours after surgery and irradiation for a pituitary tumour? Clin Endocrinol 55:613–616

    Article  CAS  Google Scholar 

  43. Brada M, Ford D, Ashley S, Bliss JM, Crowley S, Mason M, Rajan B, Traish D (1992) Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. BMJ 304:1343–1346

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Millar JL, Spry NA, Lamb DS, Delahunt J (1991) Blindness in patients after external beam irradiation for pituitary adenomas: two cases ocurring after small daily fractional doses. Clin Oncol 3:291–294

    Article  CAS  Google Scholar 

  45. al-Mefty O, Kersh JE, Routh A, Smith RR (1990) The long-term side effects of radiation therapy for benign brain tumours in adults. J Neurosurg 73:502–512

    Article  CAS  PubMed  Google Scholar 

  46. Ayuk J, Stewart PM (2009) Mortality following pituitary radiotherapy. Pituitary 12:35–39

    Article  PubMed  Google Scholar 

  47. Burman P, Mattsson AF, Johannsson G, Höybye C, Holmer H, Dahlqvist P, Berinder K, Engström BE, Ekman B, Erfurth EM, Svensson J, Wahlberg J, Karlsson FA (2013) Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. J Clin Endocrinol Metab 98:1466–1475

    Article  CAS  PubMed  Google Scholar 

  48. Sattler MG, van Beek AP, Wolffenbuttel BH, van den Berg G, Sluiter WJ, Langendijk JA, van den Bergh AC (2012) The incidence of second tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy versus surgery alone. Radiother Oncol 104:125–130

    Article  PubMed  Google Scholar 

  49. Sattler MG, Vroomen PC, Sluiter WJ, Schers HJ, van den Berg G, Langendijk JA, Wolffenbuttel BH, van den Bergh AC, van Beek AP (2013) Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone. Int J Radiat Oncol Biol Phys 87:53–59

    Article  PubMed  Google Scholar 

  50. Armstrong CL, Gyato K, Awadalla AW, Lustig R, Tochner ZA (2004) A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy. Neuropsychol Rev 14:65–86

    Article  PubMed  Google Scholar 

  51. Naylor AS, Bull C, Nilsson MK, Zhu C, Björk-Eriksson T, Eriksson PS, Blomgren K, Kuhn HG (2008) Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain. Proc Natl Acad Sci USA 105:14632–14637

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Ramón YCS (1952) Structure and connections of neurons. Bull Los Angel Neuro Soc 17:5–46

    Google Scholar 

  53. Morris RG, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature 319:774–776

    Article  CAS  PubMed  Google Scholar 

  54. Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

    Article  CAS  PubMed  Google Scholar 

  55. Hallbergson AF, Gnatenco C, Peterson DA (2003) Neurogenesis and brain injury: managing a renewable resource for repair. J Clin Investig 112:1128–1133

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, Flavell RA, Lu B, Ming GL, Song H (2009) Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323:1074–1077

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank all patients for their collaborative participation in this study and Ana Ruiz, José Ortiz Berrocal, and Rosa Magallón for their help in selecting the battery of neurocognitive tests, SPECT performance and interpretation, and radiotherapy data collection, respectively.

Conflict of interest

The authors have nothing to disclose.

Author information

Authors and Affiliations

  1. Endocrinology and Nutrition Department, La Paz University Hospital, Castellana 261, 28046, Madrid, Spain

    Beatriz Lecumberri & Luis Felipe Pallardo

  2. Endocrinology and Nutrition Department, Puerta de Hierro University Hospital, Madrid, Spain

    Beatriz Lecumberri, Javier Estrada & Tomás Lucas

  3. Neurosurgery Department, Puerta de Hierro University Hospital, Madrid, Spain

    José García-Uría

  4. Statistics Department, Puerta de Hierro University Hospital, Madrid, Spain

    Isabel Millán

  5. Psychiatry Department, Puerta de Hierro University Hospital, Madrid, Spain

    Luis Caballero

  6. Sanchinarro University Hospital, Madrid, Spain

    Tomás Lucas

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  1. Beatriz Lecumberri
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  2. Javier Estrada
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  3. José García-Uría
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  4. Isabel Millán
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  7. Tomás Lucas
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Correspondence to Beatriz Lecumberri.

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Lecumberri, B., Estrada, J., García-Uría, J. et al. Neurocognitive long-term impact of two-field conventional radiotherapy in adult patients with operated pituitary adenomas. Pituitary 18, 782–795 (2015). https://doi.org/10.1007/s11102-015-0653-6

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  • DOI: https://doi.org/10.1007/s11102-015-0653-6

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