VOLUME
32
䡠
NUMBER
13
䡠
MAY
1
2014
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Nutritional Status As a Prognostic Indicator for Pediatric Malignancies Paul C.J. Rogers,University of British Columbia and British Columbia Children’s Hospital, Vancouver, British Columbia, Canada See accompanying article on page 1331
Although malnutrition is frequently cited as a poor prognostic indicator for pediatric oncology patients,1-4 nutritional status is infrequently evaluated as a component of clinical trials. Malnutrition has been used interchangeably with undernutrition or protein-energy malnutrition. It is now recognized that there is another end of the spectrum—that is, patients who are obese. The majority of pediatric oncology studies that have reported on an impact of nutritional status on outcomes have only evaluated patients at diagnosis. They did not report on the nutritional changes that occur during treatment and that may have an effect on outcomes. Donaldson et al5 and Mauer et al6 brought it to our attention that nutritional status should be considered by treating pediatric oncologists. Their articles have had little impact on standardizing nutritional clinical practice or on prospectively evaluating nutritional status within clinical trial protocols.7 In the article that accompanies this editorial, Orgel et al8 from the Children’s Oncology Group correlated outcomes to the duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia (ALL). They evaluated 2,008 children treated on a Children’s Oncology Group high-risk ALL protocol. Being obese or underweight for 50% of the time between end of induction and start of maintenance resulted in inferior event-free survival for those patients. Obese status correlated with an increase in hepatic and pancreatic toxicity. Underweight status correlated with an increase of fungal infections and hematologic toxicity. This article is original in that it evaluates the prognostic implications of weight extremes during therapy while on a clinical trial for ALL. There have been conflicting reports of the effect of malnutrition on outcomes of patients with ALL. Some conclude that there is a significant relation between these factors whereas others conclude that there is no correlation.1,4,9 The study from St Jude10 evaluating body mass index and its relationship to dosing did not find any difference in outcome for patients with ALL. Maldonado-Alca´zar et al9 and Sala et al11 have made a correlation of poorer survival outcomes and treatment-related toxicity (TRT) for those who are underweight at diagnosis.9,11 They stressed the need for nutritional interventions. A major flaw in the majority of these reports, and possibly why there are conflicting opinions, has been the assessment of nutritional status, which has been predominantly based on weight, weight for height, and the calculation of body mass index. This was acknowledged as a flaw in the report from Orgel et al.8 Weight as an acute parameter of nutritional status is frequently unreliable due to the changes in hydration, fluid shifts and tumor mass. It is recognized that other Journal of Clinical Oncology, Vol 32, No 13 (May 1), 2014: pp 1293-1294
anthropometric measures will give a better assessment of nutritional status and body composition, such as the use of mid upper arm circumference (MUAC) and triceps skin folds (TSF). These measurements have correlated with DEXA scan.12 MUAC & TSF measurements have been used by the Central American group (AHOPCA) showing that these measurements are feasible in low- and middleincome countries, are better parameters of nutritional assessment and correlate with outcomes.11,13 This is not common practice in North America.7 Global assessment tools have been developed both for adult and pediatrics that include dietary, biochemical and anthropometric assessment, but are not commonly used.1,3,7 There is a lack of consensus on the definition of malnutrition and the use of a standardized tool for that assessment.1,3 Why malnutrition has an impact on prognosis is multifactorial. Variance of body composition of lean body mass and adipose tissue will affect the pharmacokinetics of many of the drugs we use (eg, methotrexate, anthracyclines).14-17 That there is a pharmacokinetic variance, both interpatient and intrapatient, especially at the extremes on malnutrition, will impact on the pharmcodynamics of the drugs we use and their potential effectiveness. The appropriate dosing of drugs of patients with extremes of body composition remains controversial.14,15 Malnourished patients frequently have other comorbidities, such as being immunocompromised with concurrent infections in the undernourished patients, or metabolic disorders in obese patients. These comorbidities may affect outcomes. Patients with poor diets are frequently insufficient or depleted in trace elements and vitamins.18 That impact on prognosis is unknown. Other hormonal, inflammatory and/or metabolic changes are described in the malnourished which may have an influence on the biology of cancers (eg, IGF-1).19 There are potential epigenetic influences from long-term diets that are produced by under- or overnutrition.20-22 Nutrient insufficiencies can both upregulate or downregulate various genes.20-22 The glycemic index of foods is being assessed as a biologic factor in the pathogenesis of cancer, predominately in adult carcinomas.19-23 There is evidence that high-caloric diets are associated with carcinogenesis and thus may impact therapy. There are now studies evaluating this perspective in pediatric oncology. The prevalence of undernutrition at diagnosis varies between countries, especially when high-income countries are compared with middle- and low-income countries.3,4 The causes of undernutrition at diagnosis and during treatment are diverse.2 There are dynamic interactions between the cancer, the metabolic processes of the host, other © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
1293
Editorial
comorbidities, the effect of multimodal therapies, and the socioeconomic status of the patient. Thus there are interacting components of increased needs, decreased intake, inadequate supply, and increased inflammation—all leading to protein-energy deficits, cancer cachexia, and the pathologic sequelae of those deficits.1,2 Patients at high risk for undernutrition can be identified (eg, advanced-stage disease and/or intensive chemotherapy regimens).1-3,5,6 Obesity is pandemic in North America and other high-income countries; pediatric oncology patients are not exempt.24 There is a growing prevalence of obesity in lower- and middle-income countries as diets change to more Western patterns. The impact of obesity on prevalence and prognosis has been documented in several adult cancers, such as breast cancer and colon cancer.19-23 There are reports of the detrimental impact of obesity in children at diagnosis of ALL and acute myeloblastic leukemia.25-27 The article by Orgel et al8 reports on the impact of obesity during therapy. How to deal with this obesity prevalence and its impact on pediatric oncology requires more basic research on genetic predispositions, such as leptin variants.28 Interventional research studies to ameliorate the prognostic influence of obesity are required but will probably be difficult to undertake, given that adherence to changes in diet, exercise, and behavior modification while on therapy maybe poor, especially among adolescents.29 Other novel approaches to obesity, both preventative and reactive, are required for our patients, both on treatment and off treatment. Consideration should be given to the study of interventions such as a low glycemic diet or a ketogenic diet. Nutritional status does change with therapy, and the need to evaluate nutritional status during therapy as a prognostic marker is exemplified by the article by Orgel et al.8 Embedding longitudinal nutritional assessment into randomized phase III clinical trials should become routine so as to prospectively evaluate malnutrition as a prognostic factor and its correlation with TRT. It is also necessary to embed nutritional interventions within phase III clinical trials to evaluate the intervention’s effect on cancer treatments, prognosis, and TRT. Nutrition is a fundamental part of the care of pediatric patients. Adequate and appropriate nutrition (not increasing adiposity) is required to maintain optimal growth and development, possibly to enhance survival outcome, diminish toxicity, and improve quality of life. Ignoring this perspective and research challenge is no longer an option. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Bauer J, Ju¨rgens H, Fru¨hwald MC: Important aspects of nutrition in children with cancer. Adv Nutr 2:67-77, 2011 2. Sala A, Pencharz P, Barr RD: Children, cancer, and nutrition: A dynamic triangle in review. Cancer 100:677-687, 2004 3. Brinksma A, Huizinga G, Sulkers E, et al: Malnutrition in childhood cancer patients: A review on its prevalence and possible causes. Crit Rev Oncol Hematol 83:249-275, 2012 4. Barr RD, Gibson BE: Nutrition status and cancer in childhood. J Pediatr Hematol Oncol 22:491-494, 2000 5. Donaldson SS, Wesley MN, DeWys WD, et al: A study of the nutritional status of pediatric cancer patients. Am J Dis Child 135:1107-1112, 1981 6. Mauer AM, Burgess JB, Donaldson SS, et al: Special nutritional need of children with malignancies: A review. JPEN J Parenter Enteral Nutr 14:315-324, 1990
7. Ladas E, Sacks N, Brophy P, et al: Standards of nutritional care in pediatric oncology: Results from a nationwide survey on the standards of practice in pediatric oncology—A Children’s Oncology Group study. Pediatr Blood Cancer 46:339-344, 2006 8. Orgel E, Sposto R, Malvar J, 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. J Clin Oncol 32:13311337, 2014 9. Maldonado-Alca´zar A, Nu´n˜ez-Enrı´quez JC, Garcı´a-Ruiz CA, et al: Alterations of nutritional status in childhood acute leukemia, in Mejia Arangure JM (ed): Clinical Epidemiology of Acute Lymphoblastic Leukemia: From the Molecules to the Clinic. InTech, Rijeka, Croatia, 2013, pp 277-296 10. Hijiya N, Panetta JC, Zhou Y, et al: Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia. Blood 108:3997-4002, 2006 11. Sala A, Rossi E, Antillon F, et al: Nutritional status at diagnosis is related to clinical outcomes in children and adolescents with cancer: A perspective from Central America. Eur J Cancer 48:243-252, 2012 12. Webber C, Halton J, Walker S, et al: The prediction of lean body mass and fat mass from arm anthropometry at diagnosis in children with cancer. J Pediatr Hematol Oncol 35:530-533, 2013 13. Jaime-Pe´rez JC, Gonza´lez-Llano O, Herrera-Garza JL, et al: Assessment of nutritional status in children with acute lymphoblastic leukemia in northern Me´xico: A 5-year experience. Pediatr Blood Cancer 50:506-508; discussion 517, 2008 14. Murry DJ, Riva L, Poplack DG: Impact of nutrition on pharmacokinetics of anti-neoplastic agents. Int J Cancer Suppl 11:48-51, 1998 15. Cheymol G: Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet 39:215-231, 2000 16. Krishnawamy K: Drug metabolism and pharmacokinetics in malnourished children. Clin Pharmacokinet 17:68-88, 1989 (suppl 1) 17. Ladas EJ, Sacks N, Meacham L, et al: A multidisciplinary review of nutrition considerations in the pediatric oncology population: A perspective from Children’s Oncology Group. Nutr Clin Pract 20:377-393, 2005 18. Stevens J, Waters R, Sieniawska C, et al: Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies. Br J Haematol 154:448-456, 2011 19. Calle EE, Kaaks R: Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579-591, 2004 20. Calle EE, Thun MJ: Obesity and cancer. Oncogene 23:6365-6378, 2004 21. Haggarty P: Nutrition and the epigenome. Prog Mol Biol Translat Sci 108:427-446, 2012 22. Michaud DS, Fuchs CS, Liu S, et al: Dietary glycemic load, carbohydrate, sugar, and colorectal cancer risk in men and women. Cancer Epidemiol Biomarkers Prev 14:138-147, 2005 23. Meyerhardt JA: The impact of glycemic levels in patients with colon cancer. Clin Adv Hematol Oncol 11:93-94, 2013 24. Rogers PC, Meacham LR, Oeffinger KC, et al: Obesity in pediatric oncology. Pediatr Blood Cancer 45:881-891, 2005 25. Lange BJ, Gerbing RB, Feusner J, et al: Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 293:203-211, 2005 26. Tan SY, Poh BK, Nadrah MH, et al: Nutritional status and dietary intake of children with acute leukaemia during induction or consolidation chemotherapy. J Hum Nutr Diet 26:23-33, 2013 (suppl 1) 27. Butturini AM, Dorey FJ, Lange BJ, et al: Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 25:2063-2069, 2007 28. Ross JA, Oeffinger KC, Davies SM, et al: Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study. J Clin Oncol 22:35583562, 2004 29. Co-Reyes E, Li R, Huh W, et al: Malnutrition and obesity in pediatric oncology patients: Causes, consequences, and interventions. Pediatr Blood Cancer 59:1160-1167, 2012
DOI: 10.1200/JCO.2014.55.0616; published online ahead of print at www.jco.org on March 31, 2014
■ ■ ■
1294
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
32
䡠
NUMBER
13
䡠
MAY
1
2014
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Nutritional Status As a Prognostic Indicator for Pediatric Malignancies Paul C.J. Rogers,University of British Columbia and British Columbia Children’s Hospital, Vancouver, British Columbia, Canada See accompanying article on page 1331
Although malnutrition is frequently cited as a poor prognostic indicator for pediatric oncology patients,1-4 nutritional status is infrequently evaluated as a component of clinical trials. Malnutrition has been used interchangeably with undernutrition or protein-energy malnutrition. It is now recognized that there is another end of the spectrum—that is, patients who are obese. The majority of pediatric oncology studies that have reported on an impact of nutritional status on outcomes have only evaluated patients at diagnosis. They did not report on the nutritional changes that occur during treatment and that may have an effect on outcomes. Donaldson et al5 and Mauer et al6 brought it to our attention that nutritional status should be considered by treating pediatric oncologists. Their articles have had little impact on standardizing nutritional clinical practice or on prospectively evaluating nutritional status within clinical trial protocols.7 In the article that accompanies this editorial, Orgel et al8 from the Children’s Oncology Group correlated outcomes to the duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia (ALL). They evaluated 2,008 children treated on a Children’s Oncology Group high-risk ALL protocol. Being obese or underweight for 50% of the time between end of induction and start of maintenance resulted in inferior event-free survival for those patients. Obese status correlated with an increase in hepatic and pancreatic toxicity. Underweight status correlated with an increase of fungal infections and hematologic toxicity. This article is original in that it evaluates the prognostic implications of weight extremes during therapy while on a clinical trial for ALL. There have been conflicting reports of the effect of malnutrition on outcomes of patients with ALL. Some conclude that there is a significant relation between these factors whereas others conclude that there is no correlation.1,4,9 The study from St Jude10 evaluating body mass index and its relationship to dosing did not find any difference in outcome for patients with ALL. Maldonado-Alca´zar et al9 and Sala et al11 have made a correlation of poorer survival outcomes and treatment-related toxicity (TRT) for those who are underweight at diagnosis.9,11 They stressed the need for nutritional interventions. A major flaw in the majority of these reports, and possibly why there are conflicting opinions, has been the assessment of nutritional status, which has been predominantly based on weight, weight for height, and the calculation of body mass index. This was acknowledged as a flaw in the report from Orgel et al.8 Weight as an acute parameter of nutritional status is frequently unreliable due to the changes in hydration, fluid shifts and tumor mass. It is recognized that other Journal of Clinical Oncology, Vol 32, No 13 (May 1), 2014: pp 1293-1294
anthropometric measures will give a better assessment of nutritional status and body composition, such as the use of mid upper arm circumference (MUAC) and triceps skin folds (TSF). These measurements have correlated with DEXA scan.12 MUAC & TSF measurements have been used by the Central American group (AHOPCA) showing that these measurements are feasible in low- and middleincome countries, are better parameters of nutritional assessment and correlate with outcomes.11,13 This is not common practice in North America.7 Global assessment tools have been developed both for adult and pediatrics that include dietary, biochemical and anthropometric assessment, but are not commonly used.1,3,7 There is a lack of consensus on the definition of malnutrition and the use of a standardized tool for that assessment.1,3 Why malnutrition has an impact on prognosis is multifactorial. Variance of body composition of lean body mass and adipose tissue will affect the pharmacokinetics of many of the drugs we use (eg, methotrexate, anthracyclines).14-17 That there is a pharmacokinetic variance, both interpatient and intrapatient, especially at the extremes on malnutrition, will impact on the pharmcodynamics of the drugs we use and their potential effectiveness. The appropriate dosing of drugs of patients with extremes of body composition remains controversial.14,15 Malnourished patients frequently have other comorbidities, such as being immunocompromised with concurrent infections in the undernourished patients, or metabolic disorders in obese patients. These comorbidities may affect outcomes. Patients with poor diets are frequently insufficient or depleted in trace elements and vitamins.18 That impact on prognosis is unknown. Other hormonal, inflammatory and/or metabolic changes are described in the malnourished which may have an influence on the biology of cancers (eg, IGF-1).19 There are potential epigenetic influences from long-term diets that are produced by under- or overnutrition.20-22 Nutrient insufficiencies can both upregulate or downregulate various genes.20-22 The glycemic index of foods is being assessed as a biologic factor in the pathogenesis of cancer, predominately in adult carcinomas.19-23 There is evidence that high-caloric diets are associated with carcinogenesis and thus may impact therapy. There are now studies evaluating this perspective in pediatric oncology. The prevalence of undernutrition at diagnosis varies between countries, especially when high-income countries are compared with middle- and low-income countries.3,4 The causes of undernutrition at diagnosis and during treatment are diverse.2 There are dynamic interactions between the cancer, the metabolic processes of the host, other © 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
1293
Editorial
comorbidities, the effect of multimodal therapies, and the socioeconomic status of the patient. Thus there are interacting components of increased needs, decreased intake, inadequate supply, and increased inflammation—all leading to protein-energy deficits, cancer cachexia, and the pathologic sequelae of those deficits.1,2 Patients at high risk for undernutrition can be identified (eg, advanced-stage disease and/or intensive chemotherapy regimens).1-3,5,6 Obesity is pandemic in North America and other high-income countries; pediatric oncology patients are not exempt.24 There is a growing prevalence of obesity in lower- and middle-income countries as diets change to more Western patterns. The impact of obesity on prevalence and prognosis has been documented in several adult cancers, such as breast cancer and colon cancer.19-23 There are reports of the detrimental impact of obesity in children at diagnosis of ALL and acute myeloblastic leukemia.25-27 The article by Orgel et al8 reports on the impact of obesity during therapy. How to deal with this obesity prevalence and its impact on pediatric oncology requires more basic research on genetic predispositions, such as leptin variants.28 Interventional research studies to ameliorate the prognostic influence of obesity are required but will probably be difficult to undertake, given that adherence to changes in diet, exercise, and behavior modification while on therapy maybe poor, especially among adolescents.29 Other novel approaches to obesity, both preventative and reactive, are required for our patients, both on treatment and off treatment. Consideration should be given to the study of interventions such as a low glycemic diet or a ketogenic diet. Nutritional status does change with therapy, and the need to evaluate nutritional status during therapy as a prognostic marker is exemplified by the article by Orgel et al.8 Embedding longitudinal nutritional assessment into randomized phase III clinical trials should become routine so as to prospectively evaluate malnutrition as a prognostic factor and its correlation with TRT. It is also necessary to embed nutritional interventions within phase III clinical trials to evaluate the intervention’s effect on cancer treatments, prognosis, and TRT. Nutrition is a fundamental part of the care of pediatric patients. Adequate and appropriate nutrition (not increasing adiposity) is required to maintain optimal growth and development, possibly to enhance survival outcome, diminish toxicity, and improve quality of life. Ignoring this perspective and research challenge is no longer an option. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Bauer J, Ju¨rgens H, Fru¨hwald MC: Important aspects of nutrition in children with cancer. Adv Nutr 2:67-77, 2011 2. Sala A, Pencharz P, Barr RD: Children, cancer, and nutrition: A dynamic triangle in review. Cancer 100:677-687, 2004 3. Brinksma A, Huizinga G, Sulkers E, et al: Malnutrition in childhood cancer patients: A review on its prevalence and possible causes. Crit Rev Oncol Hematol 83:249-275, 2012 4. Barr RD, Gibson BE: Nutrition status and cancer in childhood. J Pediatr Hematol Oncol 22:491-494, 2000 5. Donaldson SS, Wesley MN, DeWys WD, et al: A study of the nutritional status of pediatric cancer patients. Am J Dis Child 135:1107-1112, 1981 6. Mauer AM, Burgess JB, Donaldson SS, et al: Special nutritional need of children with malignancies: A review. JPEN J Parenter Enteral Nutr 14:315-324, 1990
7. Ladas E, Sacks N, Brophy P, et al: Standards of nutritional care in pediatric oncology: Results from a nationwide survey on the standards of practice in pediatric oncology—A Children’s Oncology Group study. Pediatr Blood Cancer 46:339-344, 2006 8. Orgel E, Sposto R, Malvar J, 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. J Clin Oncol 32:13311337, 2014 9. Maldonado-Alca´zar A, Nu´n˜ez-Enrı´quez JC, Garcı´a-Ruiz CA, et al: Alterations of nutritional status in childhood acute leukemia, in Mejia Arangure JM (ed): Clinical Epidemiology of Acute Lymphoblastic Leukemia: From the Molecules to the Clinic. InTech, Rijeka, Croatia, 2013, pp 277-296 10. Hijiya N, Panetta JC, Zhou Y, et al: Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia. Blood 108:3997-4002, 2006 11. Sala A, Rossi E, Antillon F, et al: Nutritional status at diagnosis is related to clinical outcomes in children and adolescents with cancer: A perspective from Central America. Eur J Cancer 48:243-252, 2012 12. Webber C, Halton J, Walker S, et al: The prediction of lean body mass and fat mass from arm anthropometry at diagnosis in children with cancer. J Pediatr Hematol Oncol 35:530-533, 2013 13. Jaime-Pe´rez JC, Gonza´lez-Llano O, Herrera-Garza JL, et al: Assessment of nutritional status in children with acute lymphoblastic leukemia in northern Me´xico: A 5-year experience. Pediatr Blood Cancer 50:506-508; discussion 517, 2008 14. Murry DJ, Riva L, Poplack DG: Impact of nutrition on pharmacokinetics of anti-neoplastic agents. Int J Cancer Suppl 11:48-51, 1998 15. Cheymol G: Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet 39:215-231, 2000 16. Krishnawamy K: Drug metabolism and pharmacokinetics in malnourished children. Clin Pharmacokinet 17:68-88, 1989 (suppl 1) 17. Ladas EJ, Sacks N, Meacham L, et al: A multidisciplinary review of nutrition considerations in the pediatric oncology population: A perspective from Children’s Oncology Group. Nutr Clin Pract 20:377-393, 2005 18. Stevens J, Waters R, Sieniawska C, et al: Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies. Br J Haematol 154:448-456, 2011 19. Calle EE, Kaaks R: Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579-591, 2004 20. Calle EE, Thun MJ: Obesity and cancer. Oncogene 23:6365-6378, 2004 21. Haggarty P: Nutrition and the epigenome. Prog Mol Biol Translat Sci 108:427-446, 2012 22. Michaud DS, Fuchs CS, Liu S, et al: Dietary glycemic load, carbohydrate, sugar, and colorectal cancer risk in men and women. Cancer Epidemiol Biomarkers Prev 14:138-147, 2005 23. Meyerhardt JA: The impact of glycemic levels in patients with colon cancer. Clin Adv Hematol Oncol 11:93-94, 2013 24. Rogers PC, Meacham LR, Oeffinger KC, et al: Obesity in pediatric oncology. Pediatr Blood Cancer 45:881-891, 2005 25. Lange BJ, Gerbing RB, Feusner J, et al: Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 293:203-211, 2005 26. Tan SY, Poh BK, Nadrah MH, et al: Nutritional status and dietary intake of children with acute leukaemia during induction or consolidation chemotherapy. J Hum Nutr Diet 26:23-33, 2013 (suppl 1) 27. Butturini AM, Dorey FJ, Lange BJ, et al: Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 25:2063-2069, 2007 28. Ross JA, Oeffinger KC, Davies SM, et al: Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study. J Clin Oncol 22:35583562, 2004 29. Co-Reyes E, Li R, Huh W, et al: Malnutrition and obesity in pediatric oncology patients: Causes, consequences, and interventions. Pediatr Blood Cancer 59:1160-1167, 2012
DOI: 10.1200/JCO.2014.55.0616; published online ahead of print at www.jco.org on March 31, 2014
■ ■ ■
1294
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 4, 2014. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
