Summary
Chemotherapy treatment of childhood cancers is associated with significant toxicities. A major challenge in this area is that drugs are handled differently by individual patients, resulting in variable drug exposures following standard doses.
The Newcastle group carried out clinical trials over a number of years, generating data that has impacted on dosing regimens now used for important drugs across a wide range of tumour types. The data has led to dosing tables for optimal carboplatin treatment in patients with varying renal function for several tumour types, and the definition of new dosing regimens for 13-cis-retinoic acid in high-risk neuroblastoma.
This approach has been used to maximise efficacy and minimise toxicity in challenging patient subgroups for a number of commonly used therapeutics, providing clinicians with a vital tool.
Challenge
Chemotherapy treatment for childhood cancers is associated with significant toxicities. There has been considerable focus on clinical trials aiming to maintain excellent response rates to treatment, while minimising these often severe and long-term side effects. A major issue is that an individual patient’s response to a standard dose can vary considerably, especially where doses need to be adjusted for reasons such as physiological differences – infants and younger children or those with reduced kidney function – or poor prognosis patients who may need a high dosage.
Currently there can be marked differences in the timing and dose across paediatric protocols because HCPs don’t know the optimal dose to use. It is clear that marked physiological changes potentially affecting anti-tumour drug disposition can occur in newborn infants and young children. It is therefore advantageous to monitor the actual exposures being achieved in individual patients and adjust the dose accordingly. Our service allows this approach to be implemented on an individual basis if the clinician has concerns over the most appropriate dose of a specific drug.
Objectives
Our service aims to provide advice for clinicians who are concerned about the most appropriate dose to be administered to individual patients; often where the patient is treated outside standard chemotherapy regimens. Over a number of years we have carried out drug monitoring for patients treated at different UK centres for various clinical situations. We can therefore often offer advice based on the knowledge we have gained from similar clinical situations. It is often seen as beneficial to monitor individual patient drug exposures, to adjust the dose administered over several days. We provide this service free of charge.
The service runs in parallel with national clinical pharmacology trials led by Dr Gareth Veal in Newcastle. These involve centres across the UK conducting studies to learn more about the relationships between drug exposure and pharmacokinetics and key clinical parameters, including response and toxicity. A number of trials are now focused on these ‘hard to treat’ paediatric patient populations. The overall objectives are to determine appropriate drug exposures in all children with cancer, and for the data generated to provide evidence for change in terms of identifying and implementing more appropriate dosing regimens for particular subgroups of patients.
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