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• W2891514197 abstract "Adolescents and young adults (AYA) with cancer (considered to be 15–25-year olds in Australia) are a population group well known to have emotional and social needs that differ from older adults, best served by specialist AYA oncology services.1 Although strides have been made in setting up such services in Australia, there are several additional issues regarding AYA that need to be addressed to improve cancer outcomes in this population. One of these is a paucity of knowledge around particular physiological and pharmacological differences in children and adults, which may impact their response to oncological treatments – specifically toxicities and survival – and the second is that there are few physicians trained in adolescent medicine. Critically, there are several new clinical issues facing AYA, which are raising additional issues about the safety and efficacy of dosing in this group. As both under and overdosing of chemotherapy affect survival and late toxicity, clinical research into this area to improve guidance is vital. To understand the issue, a general knowledge of changes in the pharmacokinetic processes of absorption, distribution, metabolism and excretion in ageing is helpful. Applying this population knowledge to individual patients is practical as a guide but can still be problematic, particularly if the child is, for example, of a body size, an ethnicity or a disease stage not included in clinical trials. In this setting, therapeutic drug monitoring (TDM) has been used to fine-tune dosing to improve survival. Most cytotoxic agents are characterised by narrow therapeutic index and significant inter-individual variability. Despite this, TDM is not widely used (apart from methotrexate and busulfan) even outside of the complex AYA group.6 TDM is essential to ensure adequate methotrexate levels in acute lymphoblastic leukaemia (ALL)7 and solid tumour protocols and has led to improved outcomes. Busulfan, with its narrow therapeutic window for both effect and toxicity, requires TDM to ensure optimised outcomes in AYA patients, as age has been demonstrated to impact significantly on clearance, and significantly higher clearance is seen in younger patients.8, 9 As TDM is not widely used when dosing other cytotoxic agents, knowledge of the issues mentioned in Table 1 and local experience has traditionally been relied on to titrate the dose of many drugs for AYA in most centres. Although relatively unscientific, these assumptions and dosing on set protocols derived from predominantly adult studies were deemed to have sufficed in the past. However, we believe we could do better for our AYA. Although it is still taught with respect to prescribing that ‘children are not little adults’, there is a tendency to see adolescents as either ‘large children’ or ‘small adults’. This ignores the detailed understanding of the pharmacokinetic parameters that undergo a huge change between birth and adulthood3 as well as a paucity of data on the effects of individual factors, such as gender, stage of puberty and body size on drug disposition needed to optimise dosing. Today’s adolescent group has significantly different body sizes and compositions compared to previous adolescents, including factors that have clinically relevant effects on distribution, metabolism and excretion of cytotoxic drugs. Australian data have shown that obesity is increasing in adolescents. At age 14–17 years, 29.8% of adolescents born in 1998–2001 were overweight or obese, compared with 18.7% of those born in 1978–1981.10, 11 Obesity impacts the volume of distribution of lipophilic drugs throughout adipose tissue and drug clearance and thus provides a dosing challenge for oncologists. There is limited evidence for dosing guidance in the obese adolescent patient – should it be on actual bodyweight, ideal bodyweight, adjusted bodyweight or lean bodyweight? Should adjustments be made only for lipophilic drugs or for all drugs? TDM would appear to have a helpful role in this decision-making process, along with expertise from laboratory and clinical pharmacologists. Mental health issues are on the rise for young people, both in Australia and around the world.12, 13 The Mission Australia Youth Health report demonstrated a rise in the number of 15–19 year olds who met the criteria for a serious mental illness from 18.7% in 2012 to 22.8% in 2016.12 The second Australian Child and Adolescent Survey of Mental Health and Wellbeing survey demonstrated that 14% of children and adolescents had mental health problems, and 16.7% of those young people with a mental health issue were taking medication.13 Weight gain and gastrointestinal side-effects occur commonly with most antidepressant medications, and drug interactions with cytotoxic drugs and newer agents, such as molecular targeted therapy (particularly CYP450 drug interactions), must be taken into consideration when prescribing in this age group. Adolescence is a time of major psychosocial and developmental change. It is a time of increasing independence and autonomy and also a time for experimentation, particularly with tobacco, recreational drugs and alcohol. Of young people aged 15–24 years, 11% are daily smokers, and 39% drink alcohol at levels that put them at risk of harm.13 Smoking induces the CYP450 enzyme system (inducing CYP1A2 and CYP2B6) with a potential for drug interactions with cyclophosphamide and ifosfamide,14 and rapid cessation of smoking with hospitalisation can also affect drug metabolism. A history of concomitant use of cannabis should also be taken into consideration as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are metabolised by the cytochrome P450 enzyme system,15 and CBD has been well documented to inhibit P450, increasing concentrations of commonly used drugs by up to eightfold.16 THC is highly bound to plasma proteins, and cancer patients who are not eating and are using other highly protein-bound drugs with narrow therapeutic indices should be closely monitored if cannabis is consumed, particularly if intermittently used. ‘Precision medicine’ or molecular targeting of cancer cells aims at delivering drugs to specific cancer genes or proteins to increase effectiveness and decrease the toxicity of therapy. However, in the absence of clinical trials, it can be unclear if response to therapy is the same in AYA as in adults and may be worse.17 Furthermore, the relationship of dose to activity at the cancer cell is unknown in AYA, as are the off-target effects. These effects may be particularly problematic for late toxicity, including effects on endocrine, immune and bone organs. Lastly, clinical trial experience in molecular targets and monoclonal antibody therapy has primarily involved research in patients older than 18 years due to historical challenges of new drug development in younger patients.18 Children and adolescents often gain access to newer agents through compassionate use programmes only, with little collection and streamlining of outcome and toxicity data. Regulatory changes in Europe (The European Paediatric Regulation introduced in 2007) and the United States (Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act) and the work of the Zero Childhood Cancer Study group in Australia aim to address some of these challenges.19 It has been demonstrated that AYA do better on paediatric protocols and when enrolled in clinical trials. Multiple international groups have demonstrated higher remission rates, event-free survival and lower relapse risk of paediatric ALL protocols in AYA patients.20-23 It is likely that there are many reasons for this; however, increased exposure to immunosuppressive drugs with longer protocols, increased use of high-dose methotrexate and TDM and age-based risk stratification may all play a role. There may also be a fundamental difference in the treatment approach, with adult protocols having dose modification or stopping rules aiming to reduce toxicity, where paediatric protocols are likely to tolerate higher levels of toxicity to ensure a cure. AYA patients commonly have better functional performance (ECOG/Karnosfsky scores), few comorbidities and are routinely not on multiple medications; thus, they have a lower risk of drug–drug interactions and are more likely to have superior tolerance to intensive treatment regimens.24 There is a complex interplay of growth and sex hormones during puberty – changes in height, weight, muscle and fat distribution and changes in body composition during adolescence, all of which impact drug disposition and activity. An excellent review of these factors in adolescent oncology has been published by Veal et al.25 Analyses of AYA patients with chemo-sensitive malignancies have demonstrated significant differences in outcomes and toxicity profiles compared with adults and children. Outcomes and toxicity profiles observed in AYA patients treated in the UK paediatric ALL trial (UKALL2003) highlighted significant differences in toxicity in AYA patients compared with patients younger than 10 years.26 There was an increased frequency of pancreatitis, bacterial infection, mucositis, methotrexate encephalopathy and hyperglycaemia in patients older than 10 years. Incidence of DVT, PE, infections and steroid-induced psychosis rose with increasing age, and avascular necrosis occurred overwhelmingly in patients aged 15–19 years, with a peak between 13 and 14 years of age. These differences strongly suggest that pharmacokinetic and pharmacodynamic changes in adolescence, as well as the effect of steroids on bones undergoing pubertal growth changes, play a major role. Khamly et al. confirmed outcome differences primarily in chemo-sensitive malignancy (Hodgkin lymphoma, Ewing sarcoma, osteosarcoma), particularly in male AYA patients, irrespective of age, disease stage, treatment intensity or adherence.27 Female AYA had higher rates of toxicity (neutropenia, anaemia and febrile neutropenia episodes) and significantly better tumour response to chemotherapy (% necrosis at surgery), suggesting that using the same formulae for dosing women as men leads to higher drug exposure in women. This has recently been demonstrated in a pharmacokinetic study in doxorubicin clearance in AYA patients28 and suggests that the survival gap between men and women may be explained by the under-dosing of male AYA patients. Cancer is the leading cause of non-accidental death in young Australians, and improving survival in AYA is critical. Due to the huge physiological changes that occur between birth and adulthood, adolescent dosing cannot be decided by linearly extrapolating from either population. Appropriate dosing requires knowledge of the drug and the pharmacokinetics of AYA with cancer, with the same, lower or higher doses in children and young adults than in older adults depending on the pharmacology of the drug involved and the gender of the patient. Progression towards individualised medicine, incorporating TDM and guidance protocols should fully encompass this vulnerable group of patients. AYA oncologists, in conjunction with clinical pharmacologists, with an understanding of these important pharmacokinetic and pharmacodynamic implications should be developing a joint clinical research programme for AYA, with a clear implementation into practice through pathology laboratories. A focus on personalised and/or toxicity-driven therapy appears to be the best approach in caring for this complex patient group (Table 2)." @default.
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• W2891514197 title "Optimal cancer drug dosing in adolescents: new issues and the old unaddressed ones" @default.
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