Department of Clinical Pharmacy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
Newcastle University Centre for Cancer, Newcastle University, NE2 4HH Newcastle Upon Tyne, UK.
Eur J Cancer. 2022 Mar;164:137-154. doi: 10.1016/j.ejca.2021.11.001. Epub 2021 Dec 2.
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size-based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1-5) and a grade of recommendation (A-D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
新生儿和婴儿癌症是一种罕见但具有挑战性的疾病。由于在生命的第一年存在明显的生理变化、毒性、死亡率和晚期效应过高，治疗变得复杂。化疗药物的剂量优化可能是改善治疗结果的重要步骤。大多数用于婴儿的抗癌药物都采用基于体表面积的剂量方案。然而，剂量方案通常没有基于证据，并且在肿瘤类型和治疗方案之间，剂量策略经常不一致。在这篇综述中，我们汇集了支持婴儿广泛使用的细胞毒性药物剂量方案的现有药理学证据。我们进行了系统评价，并根据证据水平（1-5 级）和推荐等级（A-D 级）对现有数据进行了排名，根据需要提供了共识推荐的剂量方法。对于 29 种药物中的 9 种（白消安、卡铂、环磷酰胺、柔红霉素、依托泊苷、氟达拉滨、异维 A 酸、美法仑和长春新碱），评分达到 A 级，表明有足够的药理学证据推荐婴儿的剂量方案。对于白消安和卡铂，有足够的数据推荐在婴儿中进行治疗药物监测。对于另外 8 种药物（放线菌素 D、blinatumomab、dinutuximab、多柔比星、巯嘌呤、培门冬酶、硫鸟嘌呤和拓扑替康），有一些药理学证据可用于指导剂量（评为 B 级）。对于其余的药物，包括顺铂、阿糖胞苷、异环磷酰胺和甲氨蝶呤等常用药物，在婴儿中进行剂量的药理学证据有限或不存在：分别为 10 种和 2 种药物评分 C 和 D。该综述为新生儿和婴儿的细胞毒性药物提供了基于临床相关的、有证据支持的剂量指导。
