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BMC Pediatrics
Published in: BMC Pediatrics 1/2021

Open Access 01-12-2021 | Acute Lymphoblastic Leukemia | Study protocol

Study protocol: DexaDays-2, hydrocortisone for treatment of dexamethasone-induced neurobehavioral side effects in pediatric leukemia patients: a double-blind placebo controlled randomized intervention study with cross-over design

Authors: A. M. van Hulst, E. J. Verwaaijen, M. F. Fiocco, S. M. F. Pluijm, M. A. Grootenhuis, R. Pieters, E. L. T. van den Akker, M. M. van den Heuvel-Eibrink

Published in: BMC Pediatrics | Issue 1/2021

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Abstract

Background

Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by patients and parents as detrimental with respect to health related quality of life (HRQoL). Based on previous studies, it has been suggested that neurobehavioral side effects are associated to cortisol depletion of the mineralocorticoid receptor in the brain. Our previously reported randomized controlled trial, the Dexadagen study (NTR3280), suggests that physiological hydrocortisone addition during dexamethasone treatment may overcome clinically relevant neurobehavioral problems in patients who experience these problems during dexamethasone treatment. With our current study, we aim to replicate these results in a targeted larger sample before further implementing this intervention into standard of care.

Methods

In a national center setting, pediatric ALL patients between 3 and 18 years are enrolled in an Identification study, which identifies patients with clinically relevant dexamethasone-induced neurobehavioral side effects using the Strengths and Difficulties Questionnaire (SDQ). Contributing factors, such as genetic susceptibility, dexamethasone pharmacokinetics as well as psychosocial and family factors are studied to determine their influence in the inter-patient variability for developing dexamethasone-induced neurobehavioral side effects.
Patients with clinically relevant problems (i.e. a rise of ≥ 5 points on the SDQ Total Difficulties Score after 5 days of dexamethasone) are subsequently included in a randomized double-blind placebo-controlled trial with a cross-over design. They receive two courses placebo followed by two courses hydrocortisone during dexamethasone treatment, or vice versa, each time at least 16 days without study medication in between. The primary endpoint is change in SDQ score. The secondary endpoints are sleep (measured with actigraphy and the Sleep Disturbance Scale for Children) and HRQoL (Pediatric Quality of Life Questionnaire).

Discussion

The results of our current study may contribute to the management of future ALL patients who experience dexamethasone-induced neuropsychological problems as it may improve HRQoL for patients who suffer most from dexamethasone-induced neurobehavioral side effects. Furthermore, by investigating multiple risk factors that could be related to inter-patient variability in developing these side effects, we might be able to identify and treat patients who are at risk earlier during treatment.

Trial registration

Medical Ethical Committee approval number: NL62388.078.17. Affiliation: Erasmus Medical Centre. Netherlands Trial Register: NL6507 (NTR6695). Registered 5 September 2017
Literature
1.
Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the children’s cancer group. Blood. 2003;101(10):3809–17.
2.
Kaspers GJL, Veerman AJP, PoppSnijders C, Lomecky M, VanZantwijk CH, Swinkels LMJW, et al. Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Med Pediatr Oncol. 1996;27(2):114–21.CrossRef
3.
Veerman AJ, Kamps WA, van den Berg H, van den Berg E, Bokkerink JP, Bruin MC, et al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004). Lancet Oncol. 2009;10(10):957–66.CrossRef
4.
McGrath P, Pitcher L. “Enough is enough”: Qualitative findings on the impact of dexamethasone during reinduction/consolidation for paediatric acute lymphoblastic leukaemia. Supportive Care Cancer. 2002;10(2):146–55.
5.
de Kloet ER. From receptor balance to rational glucocorticoid therapy. Endocrinology. 2014;155(8):2754–69.CrossRef
6.
Kellner M, Wiedemann K. Mineralocorticoid receptors in brain, in health and disease: possibilities for new pharmacotherapy. Eur J Pharmacol. 2008;583(2–3):372–8.CrossRef
7.
Joels M, de Kloet ER. 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes. J Endocrinol. 2017;234(1):T49–66.CrossRef
8.
Klok MD, Alt SR, Irurzun Lafitte AJ, Turner JD, Lakke EA, Huitinga I, et al. Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder. J Psychiatr Res. 2011;45(7):871–8.CrossRef
9.
ter Heegde F, De Rijk RH, Vinkers CH. The brain mineralocorticoid receptor and stress resilience. Psychoneuroendocrinology. 2015;52:92–110.CrossRef
10.
Otte C, Hinkelmann K, Moritz S, Yassouridis A, Jahn H, Wiedemann K, et al. Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res. 2010;44(6):339–46.CrossRef
11.
Klok MD, Giltay EJ, Van der Does AJ, Geleijnse JM, Antypa N, Penninx BW, de Geus EJ, Willemsen G, Boomsma DI, van Leeuwen N, Zitman FG, de Kloet ER, DeRijk RH. A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females. Transl Psychiatry. 2011;1(12):62.
12.
Meijer OC, de Kloet ER. A Refill for the Brain Mineralocorticoid Receptor: The Benefit of Cortisol Add-On to Dexamethasone Therapy. Endocrinology. 2017;158(3):448–54.CrossRef
13.
Grossmann C, Scholz T, Rochel M, Bumke-Vogt C, Oelkers W, Pfeiffer AFH, et al. Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol. 2004;151(3):397–406.CrossRef
14.
Warris LT, van den Heuvel-Eibrink MM, Aarsen FK, Pluijm SM, Bierings MB, van den Bos C, et al. Hydrocortisone as an intervention for dexamethasone-induced adverse effects in pediatric patients with acute lymphoblastic leukemia: results of a double-blind. Randomized Controlled Trial J Clin Oncol. 2016;34(19):2287–93.PubMed
15.
de Ruiter RD, Gordijn MS, Gemke RJBJ, van den Bos C, Bierings MB, Rotteveel J, et al. Adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia is associated with glucocorticoid receptor polymorphisms ER22/23EK and BclI. Haematologica. 2014;99(8):E136–7.CrossRef
16.
Manenschijn L, van den Akker ELT, Lamberts SWJ, van Rossum EFC. Clinical features associated with glucocorticoid receptor polymorphisms an overview. Glucocorticoids and Mood Clinical Manifestations, Risk Factors, and Molecular Mechanisms. 2009;1179:179–98.
17.
Spijker AT, van Rossum EEC. Glucocorticoid receptor polymorphisms in major depression focus on glucocorticoid sensitivity and neurocognitive functioning. Glucocorticoids and Mood Clinical Manifestations, Risk Factors, and Molecular Mechanisms. 2009;1179:199–215.
18.
Kuningas M, Mooijaart SP, Slagboom PE, Westendorp RG, van Heemst D. Genetic variants in the glucocorticoid receptor gene (NR3C1) and cardiovascular disease risk. The Leiden 85-plus Study. Biogerontology. 2006;7(4):231–8.CrossRef
19.
DeRijk RH, de Kloet ER, Zitman FG, van Leeuwen N. Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior. Endocr Dev. 2011;20:137–48.CrossRef
20.
Vallance K, Liu W, Mandrell BN, Panetta JC, Gattuso JS, Hockenberry M, et al. Mechanisms of dexamethasone-induced disturbed sleep and fatigue in paediatric patients receiving treatment for ALL. Eur J Cancer. 2010;46(10):1848–55.CrossRef
21.
Yang L, Panetta JC, Cai XJ, Yang WJ, Pei DQ, Cheng C, et al. Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol. 2008;26(12):1932–9.CrossRef
22.
Caes L, Goubert L, Devos P, Verlooy J, Benoit Y, Vervoort T. The relationship between parental catastrophizing about child pain and distress in response to medical procedures in the context of childhood cancer treatment: a longitudinal analysis. J Pediatr Psychol. 2014;39(7):677–86.CrossRef
23.
Neece CL, Green SA, Baker BL. Parenting stress and child behavior problems: a transactional relationship across time. Am J Intellect Dev Disabil. 2012;117(1):48–66.CrossRef
24.
van der Geest IM, van den Heuvel-Eibrink MM, Passchier J, van den Hoed-Heerschop C, Pieters R, Darlington ASE. Parenting stress as a mediator of parents’ negative mood state and behavior problems in children with newly diagnosed cancer. Psychooncology. 2014;23(7):758–65.
25.
Kazak AE, Abrams AN, Banks J, Christofferson J, DiDonato S, Grootenhuis MA, et al. Psychosocial Assessment as a Standard of Care in Pediatric Cancer. Pediatr Blood Cancer. 2015;62(Suppl 5):S426–59.CrossRef
26.
Varni JW, Katz ER, Colegrove R, Dolgin M. Perceived social support and adjustment of children with newly-diagnosed cancer. J Dev Behav Pediatr. 1994;15(1):20–6.CrossRef
27.
van Widenfelt BM, Goedhart AW, Treffers PD, Goodman R. Dutch version of the Strengths and Difficulties Questionnaire (SDQ). Eur Child Adolesc Psychiatry. 2003;12(6):281–9.CrossRef
28.
Bruni O, Ottaviano S, Guidetti V, Romoli M, Innocenzi M, Cortesi F, et al. The Sleep Disturbance Scale for Children (SDSC). Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence. J Sleep Res. 1996;5(4):251–61.CrossRef
29.
Romeo DM, Bruni O, Brogna C, Ferri R, Galluccio C, De Clemente V, et al. Application of the sleep disturbance scale for children (SDSC) in preschool age. Eur J Paediatr Neurol. 2013;17(4):374–82.CrossRef
30.
Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak CP. The role of actigraphy in the study of sleep and circadian rhythms. Sleep. 2003;26(3):342–92.CrossRef
31.
Acebo C, Sadeh A, Seifer R, Tzischinsky O, Wolfson AR, Hafer A, et al. Estimating sleep patterns with activity monitoring in children and adolescents: how many nights are necessary for reliable measures? Sleep. 1999;22(1):95–103.CrossRef
32.
Varni JW, Burwinkle TM, Katz ER, Meeske K, Dickinson P. The PedsQL in pediatric cancer: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer. 2002;94(7):2090–106.CrossRef
33.
de Brock AJLL, Vermulst AA, Gerris JRM, Abadin RR. Nijmeegse Ouderlijke Stress Index. Meetinstrument voor de vaststelling van stress bij opvoeders. een uitgebreide versie (NOSI) voor psychodiagnostische doeleinden en een verkorte versie (NOSIK) voor signaleringsdoeleinden: Swets & Zeitlinger; 1992.
34.
Abidin RR. Parenting Stress Index. Charlottesville, VA: Pediatric Psychology Press; 1990.
35.
Haverman L, van Oers HA, Limperg PF, Houtzager BA, Huisman J, Darlington AS, et al. Development and validation of the distress thermometer for parents of a chronically ill child. J Pediatr. 2013;163(4):1140-6 e2.CrossRef
36.
van der Geest IMM, van Dorp W, Pluijm SMF, van den Heuvel-Eibrink MM. The distress thermometer provides a simple screening tool for selecting distressed childhood cancer survivors. Acta Paediatr. 2018;107(5):871–4.CrossRef
37.
Schepers SA, Sint Nicolaas SM, Haverman L, Wensing M, Schouten van Meeteren AYN, Veening MA, et al. Real-world implementation of electronic patient-reported outcomes in outpatient pediatric cancer care. Psychooncology. 2017;26(7):951–9.CrossRef
38.
Ismail MF, Lavelle C, Cassidy EM. Steroid-induced mental disorders in cancer patients: a systematic review. Future Oncol. 2017;13(29):2719–31.CrossRef
39.
Stuart FA, Segal TY, Keady S. Adverse psychological effects of corticosteroids in children and adolescents. Arch Dis Child. 2005;90(5):500–6.CrossRef
Metadata
Title
Study protocol: DexaDays-2, hydrocortisone for treatment of dexamethasone-induced neurobehavioral side effects in pediatric leukemia patients: a double-blind placebo controlled randomized intervention study with cross-over design
Authors
A. M. van Hulst
E. J. Verwaaijen
M. F. Fiocco
S. M. F. Pluijm
M. A. Grootenhuis
R. Pieters
E. L. T. van den Akker
M. M. van den Heuvel-Eibrink
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2021
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-021-02896-6

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