Over a decade of experience with carboplatin therapeutic drug monitoring in a childhood cancer setting in the United Kingdom.

The widely used platinum agent carboplatin represents a good example of an anticancer drug where clear relationships between pharmacological exposure and clinical response and toxicity have previously been shown. Within the setting of childhood cancer, there are defined groups of patients who present a particular challenge when dosing with carboplatin, including neonates and infants, those who are anephric, and poor prognosis patients receiving high-dose chemotherapy. For these groups, nonstandard chemotherapy dosing regimens are currently utilised, often with different approaches between clinical study protocols and between treatment centres. For the treatment of these patient populations in the UK, there is now significant experience in carrying out therapeutic drug monitoring, aiming to consistently achieve target drug exposures, maximise drug efficacy and minimise treatment-related side effects. An ongoing clinical trial is currently providing information on drug exposure for a wide range of anticancer agents in these hard to treat patient populations. In addition to supporting dosing decisions for individual patients, the collection and analysis of these data may allow the development of future dosing regimens. For example, current reduced dosing approaches for neonates and infants based on age or body weight, may well be better replaced by regimens based on a sound pharmacological rationale. The successful use of adaptive carboplatin dosing in childhood cancer should encourage the development of therapeutic drug monitoring approaches more widely in an oncology setting.

A Case of Subacute Degeneration of the Spinal Cord Due to Vitamin B12 Deficiency Triggered by Nitrous Oxide Use.

In this case report, we discuss a young female who presented to the emergency department with a recent onset of weakness, paraesthesia, and gait disturbance suggestive of peripheral neuropathy and gait ataxia. This was attributed to the occasional use of recreational nitrous oxide (N2O) over the past 10 months. Subacute combined degeneration of the spinal cord is a condition affecting the lateral and posterior columns of the spinal cord, mainly caused by demyelination. The use of recreational N2O depletes the levels of vitamin B12 thus leading to this demyelination of the nervous system. Physical examination revealed T6 and T7 and L3 and L4 sensory deficits bilaterally with hyporeflexia in bilateral knee and ankle reflexes with reduced power in the left lower limb as well as a spastic gait. Her vitamin B12 levels were low (98 g/dL). MRI spine showed a high signal in the posterior cord/ dorsal column. The patient made good recovery post-intramuscular B12 administration and physiotherapy with planned outpatient neurology rehabilitation.

Clinical pharmacology of cytotoxic drugs in neonates and infants: Providing evidence-based dosing guidance.

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.