November Blog: Approach to chemotherapy dosing in the obese child: an ongoing challenge

Jessica Ryan and Jennifer Martin

University of Newcastle and Hunter New England Health
Newcastle, Australia

On behalf of the TDM in Oncology Committee

Rates of obesity in children and adolescents in the developed world have risen significantly within the last two generations, with rates of obesity (defined as Body Mass Index or BMI >95th centile) as high as 18% in the US [1], 12% in the UK [2] and up to 10% in Australia [3]. Despite this epidemic there remains a paucity of data on the pharmacokinetic and pharmacodynamic impact of obesity. This is particularly concerning in the field of paediatric cancer where pharmacological treatments often have both a narrow therapeutic index and significant consequences of sub-therapeutic dosing (relapse, death) or supra-therapeutic dosing (toxicity, morbidity, mortality). The American Society of Clinical Oncologists (ASCO) 2012 Guideline based on systematic review of the literature and expert panel review concluded that in adults, dosing should be based on actual body weight and/or body surface area (BSA) in kg/ m2, due to lack of evidence for efficacy, reliability, and generalisability of any dose adjustment calculation, and also due to concerns about evidence of under-dosing of obese adult patients[4]. It is unknown if this data can be generalised to the paediatric population and further investigation in this group is essential as the number and extent of children with obesity increases.

Large reviews from both American and European studies of paediatric Acute Lymphoblastic Leukaemia (ALL), the commonest malignancy in childhood, have identified inferior event free survival (EFS) and overall survival (OS) in obese children. [5, 6] Further analysis by the Children’s Oncology Group (COG) showed that only those children who remained obese during the intensive, pre- maintenance phase had inferior EFS, OS and treatment related toxicity. [7] Obese children whose weight entered the middle range (BMI 15th-95th centile) throughout treatment had the same EFS and OS as their normal weight peers, i.e. showing that obesity was a modifiable risk factor. Conversely, analysis performed by Hijaya et al demonstrated no impact of BMI on outcomes in ALL patients treated on St Jude’s protocols Total XII, XIIIA/B, and XIV, and PK analysis revealed no difference in clearance in several chemotherapeutic drugs [8]. Obesity has also been shown to impact on EFS, OS and treatment related toxicity in paediatric Acute Myeloid Leukaemia (AML) [9] [10] Murine studies have demonstrated the role of adipose cells as a sanctuary site for leukaemia and have suggested adiposity can impact on chemosensitivity and apoptosis resistance in tumour cells. [11-13] It is likely that the impact of obesity on paediatric cancer outcomes is multifactorial and includes genetic, socio-economic, and pharmacological reasons, as well as interactions between adipose tissue, inflammation, cytokine release and tumour cells. This makes adequate drug exposure and dose intensity in obese children especially important.

Approach:
A robust pharmacological approach should be considered when commencing chemotherapy in the obese child. There is altered body composition in obesity; obese children are taller and heavier, with ~ 75% of increase in weight from fat mass (abdominal and leg fat), with the remainder related to increased muscle mass, and bone mineral content. [14] Obese adults have been shown to have increased blood volume, cardiovascular output, hepatic blood flow and renal blood flow [15]. Obese children have increased hepatic size and are at increased risk of non-alcoholic steato-hepatitis (NASH). [16]

Impact of obesity on drug metabolism:
Brill et al published a comprehensive systematic review of drug metabolism and elimination in obese adults and children. [15] Using existing PK data they reviewed the impact of obesity on Phase I and II enzyme activity, hepatic blood flow, glomerular filtration and tubular secretion and reabsorption. Their review suggested that obesity has an effect on CYP3A4 and CYP2B6 (potentially impacting on metabolism of cyclosporine, tacrolimus, mycophenolate, sirolimus, doxorubicin, docetaxel, and ifosfamide), xanthine oxidase (increased clearance of 6-mercaptopurine), glutathione S-transferase A1-1 (impacting busulfan metabolism), hepatic blood flow (potentially effecting paclitaxel extraction), glomerular filtration (potentially impacting carboplatin levels), and tubular secretion (potentially effecting cisplatin and topotecan). Systematic review of PK studies conducted in obese children by Harskamp-van Ginkel et al found only 6 studies of antineoplastic/ immunosuppressants, and identified altered volume of distribution in doxorubicin and mercaptopurine, and altered clearance in busulfan and mercaptopurine. [17] Both of these systematic reviews identified that results were often limited by small numbers, variation in dosing strategies and methods of PK analysis. Table 1 gives a brief outline of available PK studies of commonly used agents in paediatric cancer therapy, however not all studies are from paediatric populations.

Table 1. Brief overview of PK studies in chemotherapy commonly used in paediatric cancer.

Recommendations:
It is not possible to make definite dosing recommendations based on the limited data on paediatric patients currently available, however prescribing physicians should ensure that they have considered all the current evidence when approaching dosing decisions in their obese patients. Therapeutic drug monitoring and pharmacovigilance is essential. Until evidence based recommendations for dosing adjustments are made, it seems advisable that obese paediatric patients should be treated as per protocol using actual body weight to calculate body surface area and drug doses. Following this the patient should be closely monitored, not only for toxicity, but also for a lack of toxicity. Where possible dosing should be guided by therapeutic drug monitoring in this patient group (particularly for busulfan), with close consultation with clinical pharmacologists and experienced pharmacists. As rates of obesity rise, national or international pharmacokinetic studies in obese paediatric patients should become a priority.

References:

1. Hales CM, C.M., Fryar CD, Ogden CL. , Prevalence of obesity among adults and youth: United States, 2015–2016. NCHS data brief, no 288, N.C.f.H. Statistics., Editor.: Hyattsville, MD.
2. Baker, C., Obesity Statistics, H.o. Commons, Editor. 2018: United Kingdom.
3. AIHW, Overweight and obesity in Australia: a birth cohort, A.I.o.H.a. Welfare, Editor. 2017: Canberra.
4. Griggs, J.J., et al., Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline. 2012. 30(13): p. 1553-1561.
5. Butturini, A.M., et al., Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia. 2007. 25(15): p. 2063-2069.
6. Gelelete, C.B., et al., Overweight as a Prognostic Factor in Children With Acute Lymphoblastic Leukemia. 2011. 19(9): p. 1908-1911.
7. Orgel, E., et al., Impact on Survival and Toxicity by Duration of Weight Extremes During Treatment for Pediatric Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group. 2014. 32(13): p. 1331-1337.
8. Hijiya, N., et al., Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia. 2006. 108(13): p. 3997-4002.
9. Lange, B.J., et al., Mortality in overweight and underweight children with acute myeloid leukemia. JAMA, 2005. 293(2): p. 203-211.
10. Lange, B.J., et al., Outcomes in CCG-2961, a Children’s Oncology Group Phase 3 Trial for untreated pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. 2008. 111(3): p. 1044-1053.
11. Behan, J.W., et al., Diet-induced obesity alters vincristine pharmacokinetics in blood and tissues of mice. Pharmacological Research, 2010. 61(5): p. 385-390.
12. Behan, J.W., et al., Adipocytes Impair Leukemia Treatment in Mice. 2009. 69(19): p. 7867-7874.
13. Sheng, X. and S.D. Mittelman, The Role of Adipose Tissue and Obesity in Causing Treatment Resistance of Acute Lymphoblastic Leukemia. 2014. 2(53).
14. Wells, J.C.K., et al., Body composition in normal weight, overweight and obese children: matched case–control analyses of total and regional tissue masses, and body composition trends in relation to relative weight. International Journal Of Obesity, 2006. 30: p. 1506.
15. Brill, M.J.E., et al., Impact of Obesity on Drug Metabolism and Elimination in Adults and Children. 2012. 51(5): p. 277-304.
16. Schwimmer, J.B., et al., Prevalence of Fatty Liver in Children and Adolescents. 2006. 118(4): p. 1388-1393.
17. Harskamp-van Ginkel, M.W., et al., Drug dosing and pharmacokinetics in children with obesity: A systematic review. JAMA Pediatrics, 2015. 169(7): p. 678-685.