Princess Maxima Center, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.
Mathematical Institute Leiden University, Niels Bohrweg 1, 2333 CA, Leiden, The Netherlands.
BMC Pediatr. 2021 Sep 27;21(1):427. doi: 10.1186/s12887-021-02896-6.
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.
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).
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.
Medical Ethical Committee approval number: NL62388.078.17. Affiliation: Erasmus Medical Centre. Netherlands Trial Register: NL6507 ( NTR6695 ). Registered 5 September 2017.
地塞米松是治疗小儿急性淋巴细胞白血病（ALL）的一种非常有效的药物，但会引起严重的神经行为副作用。这些副作用会对患者和家长的健康相关生活质量（HRQoL）造成负面影响。基于之前的研究，已经有人提出，这些副作用与大脑中的盐皮质激素受体的皮质醇耗竭有关。我们之前报道的一项随机对照试验——Dexadagen 研究（NTR3280）表明，在接受地塞米松治疗时添加生理性氢化可的松可能会克服接受地塞米松治疗的患者出现的临床相关神经行为问题。在我们目前的研究中，我们旨在在进一步将这种干预措施纳入标准治疗之前，在更大的靶向样本中复制这些结果。
在国家中心环境中，招募 3 至 18 岁的小儿 ALL 患者参加一项识别研究，该研究使用长处和困难问卷（SDQ）识别出具有临床相关的地塞米松诱导的神经行为副作用的患者。研究了遗传易感性、地塞米松药代动力学以及心理社会和家庭因素等促成因素，以确定它们在患者间发生地塞米松诱导的神经行为副作用的变异性中的影响。具有临床相关问题的患者（即接受地塞米松治疗 5 天后 SDQ 总分增加≥5 分）随后被纳入一项具有交叉设计的随机双盲安慰剂对照试验。他们在接受地塞米松治疗期间接受两剂安慰剂和两剂氢化可的松治疗，或反之亦然，每次之间至少有 16 天没有研究药物。主要终点是 SDQ 评分的变化。次要终点是睡眠（使用活动记录仪和儿童睡眠障碍量表测量）和 HRQoL（儿科生活质量问卷）。
我们目前研究的结果可能有助于管理未来出现地塞米松诱导的神经心理问题的 ALL 患者，因为它可能会提高最受地塞米松诱导的神经行为副作用影响的患者的 HRQoL。此外，通过研究可能与这些副作用发生的患者间变异性相关的多个风险因素，我们可能能够在治疗期间更早地识别和治疗处于风险中的患者。
医学伦理委员会批准文号：NL62388.078.17。隶属：伊拉斯谟医学中心。荷兰试验注册：NL6507（NTR6695）。于 2017 年 9 月 5 日注册。
