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An efficient synthesis of novel 2,4-disubstituted tetrahydroquinolines and quinolines
Archives of Medical Research 47 (2016) 585e592
REVIEW ARTICLE
Importance of Nutrition in the Treatment of Leukemia in Children and Adolescents Ronald D. Barr,a David Gomez-Almaguer,b Jose Carlos Jaime-Perez,b and Guillermo J. Ruiz-Arg€uellesc a
Departments of Pediatrics, Pathology and Medicine, McMaster University, Hamilton, Ontario, Canada Departmento de Hematologıa, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico c Centro de Hematologıa y Medicina Interna, Clınica Ruiz, Puebla, Puebla, Mexico
b
Received for publication July 13, 2016; accepted November 23, 2016 (ARCMED-D-16-00409).
Background and Aims. Malnutrition has been identified as a prognostic factor in children and adolescents with leukemia. Methods. A review of the data available on this topic has been carried out. Results and Conclusions. In children and adolescents (0e19 years of age), acute lymphoblastic leukemia (ALL) is the commonest form of cancer worldwide and malnutrition is prevalent in this age group, especially in low- and middle-income countries where most of these young people live. Obesity, measured by body mass index, is associated with poorer survival rates in children and adolescents with ALL and acute myelogenous leukemia in high-income countries. In contrast, undernutrition is linked to poorer survival rates among young people with leukemia in low- and middle-income countries. Ó 2016 IMSS. Published by Elsevier Inc. Key Words: Nutrition, Leukemia, Children, Treatment.
Introduction In common parlance, the term ‘malnutrition’ connotes inadequate nourishment, although in clinical and epidemiological practice it often encompasses both overweight and obesity. Undernutrition has been defined as ‘‘a state of nutrition in which a deficiency of energy, protein and other nutrients causes measurable adverse effects on tissue/body form and function and clinical outcome’’ (1) and is categorized by the World Health Organization (WHO) as acute (wasting) or chronic (stunting). The former is based on measures of weight for height and the latter on heightfor-age. Both wasting and stunting are prevalent in children in low- and middle income countries (LMICs), especially the former, as defined by the World Bank on the basis of Gross National Income (GNI) per capita (2). The corollary prevails in high-income countries (HICs) in which overweight and obesity, defined commonly by the measure of
Address reprint requests to: Dr. Guillermo J. Ruiz-Arg€uelles, DirectorGeneral, Clinica Ruiz, Calle 8B Sur, 3710, Col. Anzures, Puebla, Puebla, 72530 Mexico; Phone: (þ52) (222) 243-8100 ext. 218; FAX: (þ52) (222) 243-8428; E-mail: [email protected].
body mass index (BMI-wt. in kg/ht. in m2) has become a major public health concern, notably in children and adolescents. Both ends of the spectrum of perturbations of nutritional status, under- and over-nutrition, portend adverse consequences for young people with cancer, commanding international attention and resulting in the formation of expert groups focused on the challenges, exemplified by the Committee on Nutrition and Health in the International Society for Paediatric Oncology (SIOP) (3) and reflected in international workshops such as those convened in Puebla, Mexico (4,5). Measurement of Nutritional Status and Body Composition The first challenge is to determine the most appropriate measures to use in children and adolescents with cancer, particularly in LMICs where the great majority (O85%) live, undernutrition and co-morbidities are prevalent and resources often severely limited (6). Limitations of the WHO categorization include underestimation of wasting in children with cancer in whom it has been known for at least 25 years that O10% of the body weight may be tumor (7), and overestimation of stunting
0188-4409/$ - see front matter. Copyright Ó 2016 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2016.11.013
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in populations with genetically determined short stature such as some of the primitive peoples of equatorial southern Africa and, to a lesser extent, the Maya of Guatemala (8). At the other end of the spectrum of the nutritional status, BMI does not distinguish between lean and fat mass, a real problem in patients with cancer who may be affected by the ‘obesity paradox’. This circumstance occurs when fat mass is increased but lean body mass (notably skeletal muscle mass) is reduced (9) as a result of protein-energy malnutrition. An approach to resolving the measurement of nutritional status in the clinical setting that is especially applicable in LMICs is arm anthropometry that owes much to the work of Frisancho (10). Measurement of mid-upper arm circumference (MUAC) and triceps skin fold thickness (TSFT) avoid the problems attendant on the WHO categorization. Moreover, MUAC offers an estimate of lean body mass (LBM) as TSFT does of fat mass (FM). More precise and accurate measures of body composition are available (Table 1), but most are not suitable for clinical practice. Bio-electrical impedance assessment (BIA) and dual energy x-ray absorptiometry (DXA) are used in the clinical setting, BIA offering the advantage of instrumental portability but limitations in the face of aberrations in body water (11). With DXA, FM, fat-free mass/ LBM and whole body bone mineral content add up almost exactly to total body weight measured directly (12). DXA has been used to validate MUAC and TSFT as measures of LBM and FM, respectively, in children with cancer (13) and has been considered as a clinical ‘gold standard’ for measurement of body composition including in this population (14). Assessment of Nutritional Status Along the Cancer Journey Both over- and undernutrition impact clinical outcomes from diagnosis to long-term survivorship. Nutritional Status at Diagnosis Two landmark retrospective studies were performed by Lange and colleagues in the Children’s Cancer Group (CCG). The first involved 768 children and adolescents with acute myeloid leukemia (AML) of whom 84 (10.9%) were underweight and 114 (14.8%) were overweight or obese, defined by BMI (#10th percentile and $95th percentile respectively). Both groups had Table 1. Measures of body composition . . . . .
Total body water (2H or 18O dilution) Estimation of 40K (fat free mass) Neutron activation (not applicable to children) Bio-electrical impedance assessment Dual-energy x-ray absorptiometry
significantly poorer survival than ‘middle-weight’ patients due to greater treatment-related mortality (TRM), the most common cause of which was infections during remission induction therapy (15). In a subsequent report relating to O4000 children and adolescents with ALL, the CCG investigators focused on the effect of obesity, again as defined by BMI. The 5-year event free survival (EFS) was poorer and the relapse rate higher in obese (n 5 343, 8%) compared to non-obese patients, but only in those 10 years of age and older (16). It is of note that O98.5% of the obese patients received doses of chemotherapy calculated on their actual body surface area; however, there was no excess of early toxicity in the obese group. Such experiences in HICs do not translate readily to LMICs where the prevalence of overweight/obesity in young people with cancer is markedly lower. In the most extensive study conducted to date, a group of investigators in Central America and the Dominican Republic enrolled almost 3000 children and adolescents who were newly diagnosed with cancer. More than 60% had a battery of anthropometric measures made including BMI, MUAC and TSFT. Only 2.4% of the cohort were obese (BMI O95th percentile). According to BMI !5th percentile, 17% of the patients were undernourished. However, using MUAC and TSFT !5th percentile, 46% were severely depleted nutritionally, a figure that rose to 59% with the inclusion of hypoalbuminemia (17). The categories of nutritional status based on arm anthropometry are given in Table 2. Undernutrition was associated with a higher rate of abandonment of therapy and a lower 2-year EFS but no difference in TRM or rate of relapse (all diseases combined). A subsequent retrospective study of almost as many children was undertaken at the Tata Memorial Hospital in Mumbai, India using the categories of nutritional status developed in Central America (18). On this basis, O75% of children with cancer were severely nutritionally depleted, the inclusion of serum albumin having minimal additional value. In comparison, !18.5% were severely undernourished according to BMI, which categorized only 0.8% of children as obese. There was no report of the relationship between clinical outcomes and nutritional status in this study. Similar experiences have been reported from other LMICs including Turkey (19), Morocco (20) and Malawi (21), demonstrating greater sensitivity of arm anthropometry compared to measures based on height and weight.
Table 2. Categories of nutritional status based on arm anthropometry Adequately nourished: MUAC and TSFT O10th percentiles and serum albumin O35 g/L inadequately nourished 1.. Severely depleted: MUAC or TSFT !5th percentile or serum albumin !32 g/L. 2.. Moderately depleted: all others
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Nutritional Status During Treatment In addition to its adverse influences at diagnosis, undernutrition results in reduced tolerance of chemotherapy, alterations in drug metabolism, reduced immunity, increased risk of infection and compromised quality of life during treatments, although the quality of the evidence supporting each of these effects is variable. As noted in a recent review (22), there are very few published accounts of longitudinal studies devoted to nutrition in children and adolescents with cancer, including leukemias. However, several groups of investigators in Mexico have made important observations, focusing on children with ALL (23). In 1989 Lobato-Mendizabal and colleagues in Puebla reported that undernourished children, defined by body weight, had much poorer 5-year disease-free survival (26%) than well- nourished children (83%) with standard risk diseases and showed that the former had lower cumulative doses of maintenance chemotherapy and experienced more relapses than the well-nourished patients (24). A decade later a group from Mexico City reported that undernourished children, defined by weight-for-height, had a significantly greater risk of death early in treatment than well-nourished children (25), whereas Gomez-Almaguer and colleagues in Monterrey, Puebla and Mexico City demonstrated that undernourished children were 3.5 times more likely to die during maintenance chemotherapy (26). Another 10 years later the investigators in Monterrey reported on a serial study of nutritional status, measured by BMI, in children undergoing treatment for ALL (27). Although the serial data were not presented, comparison of BMI and body composition assessment by DXA at diagnosis yielded the following proportions: undernourished 11.8 vs. 20.5% and overweight 14.7 vs. 24.5%, attesting to the superiority of DXA. Arm anthropometry was undertaken also but the results of categorizing nutritional status by this means were not included. In a brief report from Porto Alegre, Brazil, adolescents with hematological malignancies were assessed by BMI at diagnosis and at 3, 6 and 12 months into treatment. Mean Z scores were approximately 1.0, 1.25, 2.0 and 1.25, respectively (28). Not all experiences reported from LMICs follow this trajectory. In Cuba, children with ALL did not have regression of nutritional status during therapy, assessed by weight, height and skinfolds (29). Studies in HICs provide further insights. In a serial investigation of BMI in children and adolescents with ALL in Canada, it was clear that a progressive increase occurred during treatment (30). The proportions of patients with a BMI O85th percentile were 14.8, 16.7, 29.6, 37 and 39.5% at diagnosis and 6, 12, 18 and 24 months of therapy. The proportions were higher in patients who received dexamethasone than in those given prednisone. Similar data were reported subsequently from Switzerland in a group of mixed diagnoses (31). It should be noted that BMI
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underestimates obesity because of underestimation of linear growth retardation (the difference between target height based on parental height and final height) (32). An additional factor in this underestimation is the selective loss of skeletal muscle mass, probably due in large measure to corticosteroid therapy and physical inactivity that occurs early in the treatment of ALL (Figure 1) and does not recover fully by the end of therapy (33). As a corollary, investigators in the Netherlands, using BIA, demonstrated that FM increases steadily during treatment in children with cancer, whereas LBM remains low (34). Finally, one must not lose sight of the adverse effect of treatment on bone mineral mass, leading to osteopenia and osteoporosis (35), and of micronutrient deficiencies (36). Nutritional Morbidity in Survivors There is a considerable body of literature relating to the nutritional status of survivors of cancer in childhood and adolescence following completion of therapy in HICs. Much of it relates to obesity and the consequences of being overweight, a process that begins early in treatment for survivors of ALL (37,38). Whereas the Childhood Cancer Survivor Study reported that children with ALL who had received cranial radiotherapy in the first decade of life were at higher risk for obesity based on BMI (39), a later metaanalysis found no association between patient and treatment-related characteristics and the development of obesity in survivors (40). Particular attention has been paid to the development of the metabolic syndrome, a combination of clinical and laboratory abnormalities linked to the risk of cardiovascular disease (41). In the St. Jude Lifetime Cohort Study (SJLCS) it was shown that a heart-healthy lifestyle is associated with a lower risk of metabolic syndrome among childhood cancer survivors (42), whereas others have observed that adherence to a Mediterranean diet in survivors of ALL was accompanied by lower adiposity and risk of metabolic syndrome (43). That lifestyle, including physical activity, is a
Figure 1. Mean values of the skeletal muscle mass Z-score for the arms (continuous line) and legs (hatched line).
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major determinant of such outcomes and is suggested by findings in Utah where young cancer survivors were not at higher risk of being under- or overweight (assessed by BMI) than comparable members of the general population (44), and a report from Finland on survivors of ALL that showed that they had a normal BMI and physical performance not different from that of healthy controls (45). A very different picture emerges from India, a lowmiddle income country with GNI per capita of US $1570. In the After Completion of Treatment Clinic at the Tata Memorial Hospital in Mumbai, 20% of those in follow-up are survivors of ALL (46). Among those !18 years of age, at a median interval from diagnosis of 6 years, 15.4% were moderately undernourished and 10.8% severely undernourished as measured by WHO BMI Z score. In comparison, 10.8% were overweight and only 2.7% were obese. Among the adult survivors, at a median follow-up of 10 years, 28.8% were underweight, 8.5% overweight and none was obese (46). As for adverse outcomes on bone health, the failure to accrue optimal bone mineral mass poses the risk of fractures in long-term survivors (47). Within the SJLCS, in those who had had ALL, biochemical markers of bone turnover (the dynamic relationship between formation and resorption) were unrelated to bone mineral density in the lumbar spine, but BMI was associated inversely with markers of both bone formation and resorption (48). Interventions to Redress Malnutrition in Survivors of Leukemia in Childhood and Adolescence Children and adolescents undergoing active treatment for leukemia often require nutritional supplementation. When clinically possible, which is much of the time (especially in ALL), there is a strong preference for using the gut, either by mouth or with tube feeding. The advantages of enteral over parenteral feeding are well known (14), although the latter may be required (especially in AML). Innovative approaches for which there is some evidence of benefit, particularly in children with leukemia, include supplementation with omega-3-fatty acids such as eicosapentaenoic acid (49). Appetite stimulation, such as with megestrol acetate (50) or cyproheptadine (51), is not used widely in children. As described initially in Guatemala (52) and subsequently in North America (53), correction of undernutrition at diagnosis in children with ALL restores the good prospects for survival that are compromised in those who remain undernourished. In the longer term and taking a broad approach, Ness and colleagues recognized the frailty phenotype in young adult survivors of cancer in early life (54). In so doing this demands attention to lifestyle counseling, correction of hormonal deficits (such as of growth hormone), dietary modification to improve lean body mass, and exercise to promote
cardiovascular fitness and bone health (55e57). Formal testing of such interventions is in its infancy, but there are indications that integrative programs involving multiple elements may produce positive results (58). The SIOP Committee on Nutrition and Health conducted a survey from which it was determined that priorities for improving the nutritional care of children and adolescents with cancer in LMICs are increased availability of educational resources for patients and families, enhanced education and nutritional assessment tools for physicians and nurses, and examining the role of complementary and alternative therapies in symptom management (59). The first of these has been undertaken successfully in Central America (60). As a first step in determining the need for nutritional intervention, a reliable and valid tool should be used for screening. A recently devised instrument (SCAN) has been proposed for this purpose (61). Nutritional assessment may then follow, preferably based on arm anthropometry. In the event that undernutrition is revealed, supplementation is required. What can be offered is dictated by local resources, prompting the design of a framework for nutritional therapy adapted to local realities (62). Parenteral supplementation is seldom an option in LMICs, largely as a consequence of high cost, but enteral supplementation can be highly effective as reported in a study from Recife, Brazil (63) in which gains in protein and calorie intake were recorded and reflected in BMI Z scores. The challenge of providing nutritional supplementation to children with cancer in LMICs has resulted in some imaginative solutions. In Mexico, fortified chocolate bars containing 200 kcal have been used as snacks (64), whereas in Brazil it was found that homemade nutritional formulas were economical, well accepted by children and adolescents with cancer and had adequate nutritional composition (65). Natural resources have been put to good use in Malawi (66) in the form of ‘chiponde’, a peanutbased ready-to-use therapeutic food (RUTF). A comparable experience in Guatemala involves ‘incaparina’, an RUTF based on a mixture of commercialized maize and soy flours (52). In India, there are numerous locally produced RUTFs (67). Special Case of Hematopoietic Stem Cell Transplantation (HSCT) The impact of HSCT on nutritional status can be approached from the standpoint of energy expenditure. Total energy expenditure consists of basal energy expenditure the largest component, estimated by resting energy expenditure (REE) plus energy required for activity, growth, digestion and absorption of food, and obligatory losses in urine and stool. In children undergoing HSCT, REE (measured by indirect calorimetry) falls progressively in the first 4 weeks (68). The major determinant of REE is
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LBM; therefore, it is not surprising that arm muscle area (AMA) declines in concert with REE after HSCT (69). Survivors of ALL after HSCT have lower LBM and higher visceral and intramuscular fat e the phenomenon of sarcopenic obesity e than children treated with chemotherapy only (70). In a curious experience reported from Brazil, survivors of HSCT (conducted in 40% of the children and adolescents for Fanconi anemia) who were nutritionally depleted as defined by AMA and measured by BIA had a poorer survival than those who were adequately nourished (71); yet, in a later report, the same investigators found no change in LBM measured before and after HSCT in the same patients (72). A form of nutritional morbidity of particular concern in children and adolescents who undergo HSCT is loss of bone mineral that risks fractures, which may be asymptomatic (73). Reduced bone mineral density is a common occurrence that has been described in 50% of children by 6 months after HSCT, correlating with a significant drop in serum levels of the active metabolite 1, 25-dihydroxy vitamin D (72). Others have reported similar findings despite vitamin D supplementation (74). With respect to the impact of nutritional morbidity on clinical outcomes after HSCT, it was perhaps predictable that obesity would be associated with lower overall survival and event-free survival (EFS) with higher treatment-related mortality due mainly to infection and graft-versus-host disease (GVHD) (75). As a corollary, children with an AMA !5th percentile before HSCT had lower EFS and higher non-relapse mortality and relapse rate at both 100 days and 3 years after transplant than better nourished children (76). In that large study of 752 patients, no anthropometric measure correlated with acute or chronic GVHD. The influence of body weight on outcomes was examined by the Center for International Blood and Marrow Research (77). The results in 3687 children who had HSCT for leukemia after cyclophosphamide-based conditioning are displayed in Table 3. Using BMI percentiles for categorization, those who were obese had the lowest relapse rate at 3 years and the highest rate of TRM, whereas the most underweight children had the reverse profile, again highlighting the limitations of measures of nutritional status in children with cancer that are based on body weight. Table 3. Relationships of body weight to clinical outcomes in children and adolescents undergoing allogeneic hematopoietic stem cell transplantation for leukemias BMI percentile (weight category) !5th (underweight) 5the24th (risk of underweight) 25the85th (normal) 86the95th (risk of overweight) O95th (obese)
3-year relapse rate (%)
Cumulative TRM rate (%)
33 33 29 25 21
18 19 21 22 28
TRM, treatment-related mortality.Adapted from Reference 77.
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In a provocative finding that demands confirmation, it has been reported that children who were vitamin D depleted had lower survival rates and more frequent graft rejection after HSCT (78). What about the preferred strategies of nutritional support in the context of HSCT? A Cochrane review, not focused on children and adolescents, concluded that ‘‘Where possible, use of intravenous fluids and oral diet should be considered as a preference to parenteral nutrition; however, in the event of a patient suffering severe gastro-intestinal failure even with a trial of enteral feeding, PN with addition of glutamine could be considered’’ (79). Reports from France (80) and Turkey (81) indicate that the majority of children who require nutritional support following HSCT, and not all of them, will be managed successfully by the enteral route. However, most caregivers, in contrast to health care professionals, prefer the parenteral route as do the great majority of teenagers (82), disparities that may be resolved by education. A highly instructive collaborative study was performed in Boston and Los Angeles in the form of a randomized controlled trial (RCT) in which standard TPN, conventionally providing 130e150% of estimated energy expenditure, was compared to TPN titrated to measured REE. There was no difference in the accumulation of body fat or loss of LBM measured by DXA and arm anthropometry in children undergoing allogeneic HSCT (83). Clearly, it is important to emphasize, especially for practice in LMICs, that TPN is expensive and comes with increased risk of infection and thrombosis in central venous lines, liver dysfunction, hyperglycemia and volume overload (84,85). In contrast, enteral nutrition is relatively inexpensive, maintains gut integrity and mucosal barrier function, and can facilitate the delivery of medication (86). The particular matter of glutamine supplementation needs to be addressed, given the early reports that this reduced mucositis, resulting in less need for IV narcotics and TPN in children undergoing HSCT (87). However, a subsequent Cochrane review of 17 RCTs, conducted mainly in adults, provided no conclusive evidence for benefit (88). This outcome was supported by a later RCT in Italy comparing TPN to glutamine-supplemented TPN (89). Whereas 90% of the children experienced mucositis, there were no differences in the type and duration of analgesic therapy, rates of engraftment and GVHD, early morbidity and mortality, and relapse rate. Remarkably, the patients were described as all being well-nourished before and after HSCT, based on body weight and biochemistry. In conclusion, in children and adolescents (0e19 years of age) ALL is the commonest form of cancer worldwide (90) and malnutrition is prevalent in this age group, especially in LMICs where most of these young people live. Obesity, measured by BMI, is associated with poorer survival rates in children and adolescents with ALL and AML in HICs as confirmed in a recent meta-analysis
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(91). In contrast, undernutrition is linked to poorer survival rates among young people with leukemia in LMICs (17). It must also be acknowledged that BMI is an inadequate measure of body composition, obscuring the depletion of lean body mass that characterizes sarcopenic obesity, a common problem in children and adolescents with leukemia in HICs (92). Moreover, BMI is a less-sensitive measure of undernutrition than arm anthropometry, which is a strong predictor of clinical outcomes in children and adolescents with leukemia in HICs (93). The priority for nutritional intervention in HICs is the prevention and amelioration of obesity with its numerous adverse consequences on health in young people with leukemia. This may be a particular challenge in children and adolescents who have undergone HSCT and are inadequately active physically (94,95). Imaginative solutions to enteral nutritional supplementation have been devised in LMICs, notably in the form of RUTFs, and should be tested in formal clinical trials. The use of additional creatine is also worthy of further exploration (96). Marked loss of bone mineral occurs early in the treatment of children and adolescents with ALL (97) and vitamin D deficiency is prevalent in this population. These observations demand investigation of therapeutic interventions to restore bone mineral mass, including welldesigned studies of bisphosphonates (98). It is disappointing that biochemical markers of bone turnover are not associated with bone mineral density in long-term survivors (48), but innovative interventions to restore bone mass have been undertaken, as in the recent description of mechanical stimulation (99). A review of malnutrition in children with cancer in 2012 was limited by the choice of the authors to restrict the scope to industrialized countries (100). A more recent and geographically inclusive review (22) makes note of the need to develop common measures of nutritional status e only 11/46 studies used arm anthropometry e without which associations with clinical outcomes remain difficult to assess. The authors also pointed out the paucity of longitudinal studies. Deficiencies such as these are being addressed by the Working Group on Nutrition in SIOP; therefore, laying the foundation for future studies directed at interventions to redress nutritional imbalances and so contribute to the progressive improvement in clinical outcomes for children and adolescents with cancer worldwide. References 1. Stratton RJ, Green CJ, Elia M. Disease-related malnutrition, an evidence-based approach to treatment. Wallingford Oxon: CAB International; 2003. 2. Available at: http://data.worldbank.org/news/2015-country-classificat ions. Accessed June 17, 2016. 3. Ladas EJ, Mosby TT, Murphy AI, et al. Meeting report: development of an International Committee on Nutrition and Health for Children with Cancer, International Society of Pediatric Oncology (SIOP). Pediatr Blood Cancer 2012;58:1008e1009.
4. International Union Against Cancer. Nutritional morbidity in children with cancer: Mechanisms, measures and management. Int J Cancer 1998;78(Suppl 11):1e92. 5. Nutrition and cancer in children. The Second International Workshop. Barr RD, ed. Pediatr Blood Cancer 2008;50:437e519. 6. Ribeiro RC, Chantada GL, Arora RS, et al. Pediatric oncology in countries with limited resources. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 7th ed.. Philadelphia: Wolters Kluwer; 2016. pp. 1256e1266. 7. Smith DE, Stevens MCG, Booth IW. Malnutrition at diagnosis of malignancy in childhood: common but mostly missed. Eur J Pediatr 1991;150:318e322. 8. Barr R, Antillon F, Agarwal B, et al. Pediatric oncology in countries with limited resources. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 6th ed.. Philadelphia: Lippincott Williams and Wilkins; 2011. pp. 1463e1473. 9. Gonzalez MC, Pastore CA, Orlandi S, et al. Obesity paradox in cancer: new insights provided by body composition. Am J Clin Nutr 2014;99:999e1005. 10. Frisancho AR. New norms of upper limb fat and muscle areas for assessment of nutritional status. Am J Clin Nutr 1981;34: 2540e2543. 11. Heavens KR, Charkoudian N, O’Brien C, et al. Non-invasive assessment of extracellular and intracellular dehydration in healthy humans using the resistance-reactance-score graph method. Am J Clin Nutr 2016;103:724e729. 12. Sala A, Webber CE, Morrison J, et al. Whole-body bone mineral content, lean body mass, and fat mass measured by dual-energy x-ray absorptiometry in a population of normal Canadian children and adolescents. Can Assoc Radiol J 2007;58:46e52. 13. Barr R, Collins L, Nayiager T. Nutritional status at diagnosis of children with cancer. 2. An assessment by arm anthropometry. J Pediatr Hematol Oncol 2011;33:e101ee104. 14. Sala A, Pencharz P, Barr RD. Children, cancer and nutrition a dynamic triangle in review. Cancer 2004;100:677e687. 15. Lange BI, Gerbing RB, Feusner J, et al. Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 2005;293: 203e218. 16. Butturini AM, Dorey FJ, Lange BJ, et al. Obesity and outcome in pediatric acute lymphoblastic leukemia. J Clin Oncol 2007;25: 2063e2069. 17. 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 2012;48: 243e252. 18. Shah P, Jhaveri U, Idhate TB, et al. Nutritional status at presentation, comparison of assessment tools and importance of arm anthropometry in children with cancer in India. Indian J Cancer 2015;52: 210e215. 19. Oguz A, Karadeniz C, Pelit M, et al. Arm anthropometry in evaluation of malnutrition in children with cancer. Pediatr Hematol Oncol 1999;16:35e41. 20. Tazi I, Hidane Z, Zafad S, et al. Nutritional status at diagnosis in children with malignancies in Casablanca. Pediatr Blood Cancer 2008; 51:495e498. 21. Israels T, Chirambo C, Caron HN, et al. Nutritional status at admission of children with cancer in Malawi. Pediatr Blood Cancer 2008; 51:626e628. 22. Iniesta RR, Paciarotti I, Broughan MFH, et al. Effects of pediatric cancer and its treatment on nutritional status: a systematic review. Nutr Rev 2015;73:276e295. 23. Barr RD. Assessing the impact of nutritional status on clinical outcomes in children and adolescents with cancer: A focus on the contributions from Mexico. Rev Hematol 2010;9:25e29. 24. Lobato-Mendizabal E, Ruiz-Arguelles GJ, Marin-Lopez A. Leukaemia and nutrition 1: Malnutrition is an adverse prognostic
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45. Taskinen MH, Kurimo M, Kanerva J, et al. Physical performance of non-transplanted childhood ALL survivors is comparable to healthy controls. J Pediatr Hematol Oncol 2013;35:276e280. 46. Prasad M, Arora B, Chinnaswamy B, et al. Nutritional status in survivors of childhood cancer: Experience from Tata Memorial Hospital, Mumbai. Indian J Cancer 2015;52:219e223. 47. Wilson CL, Ness KK. Bone mineral density deficits and fractures in survivors of childhood cancer. Curr Osteoporos Rep 2013;11: 329e337. 48. Watsky MA, Carbone LD, An Q, et al. Bone turnover in long-term survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2014;61:1451e1456. 49. Bayram I, Erbey F, Celik N, et al. The use of a protein and energy dense eicosapentaenoic acid containing supplement for malignancy-related weight loss in children. Pediatr Blood Cancer 2009;52:571e574. 50. Cuvelier GDE, Baker TJ, Peddie EF, et al. A randomized, doubleblind, placebo-controlled clinical trial of megestrol acetate as an appetite stimulant in children with weight loss due to cancer and/or cancer therapy. Pediatr Blood Cancer 2014;61:672e679. 51. NCT01132547. Cyproheptadine in preventing weight loss in children receiving chemotherapy for cancer. 52. Antillon F, Rossi E, Molina AL, et al. Nutritional status of children during treatment for acute lymphoblastic leukemia in Guatemala. Pediatr Blood Cancer 2013;60:911e915. 53. 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 2014;32:1331e1337. 54. Ness KK, Armstrong GT, Kundu M, et al. Frailty in childhood cancer survivors. Cancer 2015;121:1590e1597. 55. Wilson CL, Chemaitilly VV, Jones KE, et al. Modifiable factors associated with aging phenotypes among adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2016;34:2509e2515. 56. Gibson TM, Ehrhardt MJ, Ness KK. Obesity and metabolic syndrome among adult survivors of childhood leukemia. Curr Treat Options Oncol 2016;17:17. 57. Boland AM, Gibson TM, Kaste SC, et al. Dietary protein intake and lean muscle mass in survivors of childhood acute lymphoblastic leukemia: Report from the St. Jude Lifetime Cohort Study. Phys Ther 2016;96:1029e1038. 58. Li HC, Chung OK, Ho KY, et al. Effectiveness of an integrated adventure-based training and health education program in promoting regular physical activity among childhood cancer survivors. Psychooncology 2013;22:2601e2610. 59. Murphy AJ, Mosby TT, Rogers PC, et al. An international survey of nutritional practices in low and middle income countries: A report from the International Society of Pediatric Oncology (SIOP) PODC Nutrition Working Group. Eur J Clin Nutr 2014;68:1341e1345. 60. Garcia M, Chismark EA, Mosby T, et al. Development and validation of a nutritional education pamphlet for low literacy pediatric oncology caregivers in Central America. J Cancer Educ 2010;25: 512e517. 61. Murphy AJ, White M, Viani K, et al. Evaluation of the nutrition screening tool for childhood cancer (SCAN). Clin Nutr 2016;35: 219e224. 62. Ladas EJ, Arora B, Howard SC, et al. A framework for adapted nutritional therapy for children with cancer in low and middle income countries: A report from the SIOP PODC Nutrition Working Group. Pediatr Blood Cancer 2016;63:1339e1348. 63. Barbosa JM, Pedrosa F, Coelho Cabral P. Nutritional status and adequacy of enteral nutrition in pediatric cancer patients at a reference centre in north eastern Brazil. Nutr Hosp 2012;27:1099e1105. 64. Gomez-Almaguer D, Montemajor I, Gonzalez-Llano O, et al. Leukemia and nutrition. IV. Improvement in the nutritional status of
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REVIEW ARTICLE
Importance of Nutrition in the Treatment of Leukemia in Children and Adolescents Ronald D. Barr,a David Gomez-Almaguer,b Jose Carlos Jaime-Perez,b and Guillermo J. Ruiz-Arg€uellesc a
Departments of Pediatrics, Pathology and Medicine, McMaster University, Hamilton, Ontario, Canada Departmento de Hematologıa, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico c Centro de Hematologıa y Medicina Interna, Clınica Ruiz, Puebla, Puebla, Mexico
b
Received for publication July 13, 2016; accepted November 23, 2016 (ARCMED-D-16-00409).
Background and Aims. Malnutrition has been identified as a prognostic factor in children and adolescents with leukemia. Methods. A review of the data available on this topic has been carried out. Results and Conclusions. In children and adolescents (0e19 years of age), acute lymphoblastic leukemia (ALL) is the commonest form of cancer worldwide and malnutrition is prevalent in this age group, especially in low- and middle-income countries where most of these young people live. Obesity, measured by body mass index, is associated with poorer survival rates in children and adolescents with ALL and acute myelogenous leukemia in high-income countries. In contrast, undernutrition is linked to poorer survival rates among young people with leukemia in low- and middle-income countries. Ó 2016 IMSS. Published by Elsevier Inc. Key Words: Nutrition, Leukemia, Children, Treatment.
Introduction In common parlance, the term ‘malnutrition’ connotes inadequate nourishment, although in clinical and epidemiological practice it often encompasses both overweight and obesity. Undernutrition has been defined as ‘‘a state of nutrition in which a deficiency of energy, protein and other nutrients causes measurable adverse effects on tissue/body form and function and clinical outcome’’ (1) and is categorized by the World Health Organization (WHO) as acute (wasting) or chronic (stunting). The former is based on measures of weight for height and the latter on heightfor-age. Both wasting and stunting are prevalent in children in low- and middle income countries (LMICs), especially the former, as defined by the World Bank on the basis of Gross National Income (GNI) per capita (2). The corollary prevails in high-income countries (HICs) in which overweight and obesity, defined commonly by the measure of
Address reprint requests to: Dr. Guillermo J. Ruiz-Arg€uelles, DirectorGeneral, Clinica Ruiz, Calle 8B Sur, 3710, Col. Anzures, Puebla, Puebla, 72530 Mexico; Phone: (þ52) (222) 243-8100 ext. 218; FAX: (þ52) (222) 243-8428; E-mail: [email protected].
body mass index (BMI-wt. in kg/ht. in m2) has become a major public health concern, notably in children and adolescents. Both ends of the spectrum of perturbations of nutritional status, under- and over-nutrition, portend adverse consequences for young people with cancer, commanding international attention and resulting in the formation of expert groups focused on the challenges, exemplified by the Committee on Nutrition and Health in the International Society for Paediatric Oncology (SIOP) (3) and reflected in international workshops such as those convened in Puebla, Mexico (4,5). Measurement of Nutritional Status and Body Composition The first challenge is to determine the most appropriate measures to use in children and adolescents with cancer, particularly in LMICs where the great majority (O85%) live, undernutrition and co-morbidities are prevalent and resources often severely limited (6). Limitations of the WHO categorization include underestimation of wasting in children with cancer in whom it has been known for at least 25 years that O10% of the body weight may be tumor (7), and overestimation of stunting
0188-4409/$ - see front matter. Copyright Ó 2016 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2016.11.013
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in populations with genetically determined short stature such as some of the primitive peoples of equatorial southern Africa and, to a lesser extent, the Maya of Guatemala (8). At the other end of the spectrum of the nutritional status, BMI does not distinguish between lean and fat mass, a real problem in patients with cancer who may be affected by the ‘obesity paradox’. This circumstance occurs when fat mass is increased but lean body mass (notably skeletal muscle mass) is reduced (9) as a result of protein-energy malnutrition. An approach to resolving the measurement of nutritional status in the clinical setting that is especially applicable in LMICs is arm anthropometry that owes much to the work of Frisancho (10). Measurement of mid-upper arm circumference (MUAC) and triceps skin fold thickness (TSFT) avoid the problems attendant on the WHO categorization. Moreover, MUAC offers an estimate of lean body mass (LBM) as TSFT does of fat mass (FM). More precise and accurate measures of body composition are available (Table 1), but most are not suitable for clinical practice. Bio-electrical impedance assessment (BIA) and dual energy x-ray absorptiometry (DXA) are used in the clinical setting, BIA offering the advantage of instrumental portability but limitations in the face of aberrations in body water (11). With DXA, FM, fat-free mass/ LBM and whole body bone mineral content add up almost exactly to total body weight measured directly (12). DXA has been used to validate MUAC and TSFT as measures of LBM and FM, respectively, in children with cancer (13) and has been considered as a clinical ‘gold standard’ for measurement of body composition including in this population (14). Assessment of Nutritional Status Along the Cancer Journey Both over- and undernutrition impact clinical outcomes from diagnosis to long-term survivorship. Nutritional Status at Diagnosis Two landmark retrospective studies were performed by Lange and colleagues in the Children’s Cancer Group (CCG). The first involved 768 children and adolescents with acute myeloid leukemia (AML) of whom 84 (10.9%) were underweight and 114 (14.8%) were overweight or obese, defined by BMI (#10th percentile and $95th percentile respectively). Both groups had Table 1. Measures of body composition . . . . .
Total body water (2H or 18O dilution) Estimation of 40K (fat free mass) Neutron activation (not applicable to children) Bio-electrical impedance assessment Dual-energy x-ray absorptiometry
significantly poorer survival than ‘middle-weight’ patients due to greater treatment-related mortality (TRM), the most common cause of which was infections during remission induction therapy (15). In a subsequent report relating to O4000 children and adolescents with ALL, the CCG investigators focused on the effect of obesity, again as defined by BMI. The 5-year event free survival (EFS) was poorer and the relapse rate higher in obese (n 5 343, 8%) compared to non-obese patients, but only in those 10 years of age and older (16). It is of note that O98.5% of the obese patients received doses of chemotherapy calculated on their actual body surface area; however, there was no excess of early toxicity in the obese group. Such experiences in HICs do not translate readily to LMICs where the prevalence of overweight/obesity in young people with cancer is markedly lower. In the most extensive study conducted to date, a group of investigators in Central America and the Dominican Republic enrolled almost 3000 children and adolescents who were newly diagnosed with cancer. More than 60% had a battery of anthropometric measures made including BMI, MUAC and TSFT. Only 2.4% of the cohort were obese (BMI O95th percentile). According to BMI !5th percentile, 17% of the patients were undernourished. However, using MUAC and TSFT !5th percentile, 46% were severely depleted nutritionally, a figure that rose to 59% with the inclusion of hypoalbuminemia (17). The categories of nutritional status based on arm anthropometry are given in Table 2. Undernutrition was associated with a higher rate of abandonment of therapy and a lower 2-year EFS but no difference in TRM or rate of relapse (all diseases combined). A subsequent retrospective study of almost as many children was undertaken at the Tata Memorial Hospital in Mumbai, India using the categories of nutritional status developed in Central America (18). On this basis, O75% of children with cancer were severely nutritionally depleted, the inclusion of serum albumin having minimal additional value. In comparison, !18.5% were severely undernourished according to BMI, which categorized only 0.8% of children as obese. There was no report of the relationship between clinical outcomes and nutritional status in this study. Similar experiences have been reported from other LMICs including Turkey (19), Morocco (20) and Malawi (21), demonstrating greater sensitivity of arm anthropometry compared to measures based on height and weight.
Table 2. Categories of nutritional status based on arm anthropometry Adequately nourished: MUAC and TSFT O10th percentiles and serum albumin O35 g/L inadequately nourished 1.. Severely depleted: MUAC or TSFT !5th percentile or serum albumin !32 g/L. 2.. Moderately depleted: all others
Nutrition in Leukemia
Nutritional Status During Treatment In addition to its adverse influences at diagnosis, undernutrition results in reduced tolerance of chemotherapy, alterations in drug metabolism, reduced immunity, increased risk of infection and compromised quality of life during treatments, although the quality of the evidence supporting each of these effects is variable. As noted in a recent review (22), there are very few published accounts of longitudinal studies devoted to nutrition in children and adolescents with cancer, including leukemias. However, several groups of investigators in Mexico have made important observations, focusing on children with ALL (23). In 1989 Lobato-Mendizabal and colleagues in Puebla reported that undernourished children, defined by body weight, had much poorer 5-year disease-free survival (26%) than well- nourished children (83%) with standard risk diseases and showed that the former had lower cumulative doses of maintenance chemotherapy and experienced more relapses than the well-nourished patients (24). A decade later a group from Mexico City reported that undernourished children, defined by weight-for-height, had a significantly greater risk of death early in treatment than well-nourished children (25), whereas Gomez-Almaguer and colleagues in Monterrey, Puebla and Mexico City demonstrated that undernourished children were 3.5 times more likely to die during maintenance chemotherapy (26). Another 10 years later the investigators in Monterrey reported on a serial study of nutritional status, measured by BMI, in children undergoing treatment for ALL (27). Although the serial data were not presented, comparison of BMI and body composition assessment by DXA at diagnosis yielded the following proportions: undernourished 11.8 vs. 20.5% and overweight 14.7 vs. 24.5%, attesting to the superiority of DXA. Arm anthropometry was undertaken also but the results of categorizing nutritional status by this means were not included. In a brief report from Porto Alegre, Brazil, adolescents with hematological malignancies were assessed by BMI at diagnosis and at 3, 6 and 12 months into treatment. Mean Z scores were approximately 1.0, 1.25, 2.0 and 1.25, respectively (28). Not all experiences reported from LMICs follow this trajectory. In Cuba, children with ALL did not have regression of nutritional status during therapy, assessed by weight, height and skinfolds (29). Studies in HICs provide further insights. In a serial investigation of BMI in children and adolescents with ALL in Canada, it was clear that a progressive increase occurred during treatment (30). The proportions of patients with a BMI O85th percentile were 14.8, 16.7, 29.6, 37 and 39.5% at diagnosis and 6, 12, 18 and 24 months of therapy. The proportions were higher in patients who received dexamethasone than in those given prednisone. Similar data were reported subsequently from Switzerland in a group of mixed diagnoses (31). It should be noted that BMI
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underestimates obesity because of underestimation of linear growth retardation (the difference between target height based on parental height and final height) (32). An additional factor in this underestimation is the selective loss of skeletal muscle mass, probably due in large measure to corticosteroid therapy and physical inactivity that occurs early in the treatment of ALL (Figure 1) and does not recover fully by the end of therapy (33). As a corollary, investigators in the Netherlands, using BIA, demonstrated that FM increases steadily during treatment in children with cancer, whereas LBM remains low (34). Finally, one must not lose sight of the adverse effect of treatment on bone mineral mass, leading to osteopenia and osteoporosis (35), and of micronutrient deficiencies (36). Nutritional Morbidity in Survivors There is a considerable body of literature relating to the nutritional status of survivors of cancer in childhood and adolescence following completion of therapy in HICs. Much of it relates to obesity and the consequences of being overweight, a process that begins early in treatment for survivors of ALL (37,38). Whereas the Childhood Cancer Survivor Study reported that children with ALL who had received cranial radiotherapy in the first decade of life were at higher risk for obesity based on BMI (39), a later metaanalysis found no association between patient and treatment-related characteristics and the development of obesity in survivors (40). Particular attention has been paid to the development of the metabolic syndrome, a combination of clinical and laboratory abnormalities linked to the risk of cardiovascular disease (41). In the St. Jude Lifetime Cohort Study (SJLCS) it was shown that a heart-healthy lifestyle is associated with a lower risk of metabolic syndrome among childhood cancer survivors (42), whereas others have observed that adherence to a Mediterranean diet in survivors of ALL was accompanied by lower adiposity and risk of metabolic syndrome (43). That lifestyle, including physical activity, is a
Figure 1. Mean values of the skeletal muscle mass Z-score for the arms (continuous line) and legs (hatched line).
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major determinant of such outcomes and is suggested by findings in Utah where young cancer survivors were not at higher risk of being under- or overweight (assessed by BMI) than comparable members of the general population (44), and a report from Finland on survivors of ALL that showed that they had a normal BMI and physical performance not different from that of healthy controls (45). A very different picture emerges from India, a lowmiddle income country with GNI per capita of US $1570. In the After Completion of Treatment Clinic at the Tata Memorial Hospital in Mumbai, 20% of those in follow-up are survivors of ALL (46). Among those !18 years of age, at a median interval from diagnosis of 6 years, 15.4% were moderately undernourished and 10.8% severely undernourished as measured by WHO BMI Z score. In comparison, 10.8% were overweight and only 2.7% were obese. Among the adult survivors, at a median follow-up of 10 years, 28.8% were underweight, 8.5% overweight and none was obese (46). As for adverse outcomes on bone health, the failure to accrue optimal bone mineral mass poses the risk of fractures in long-term survivors (47). Within the SJLCS, in those who had had ALL, biochemical markers of bone turnover (the dynamic relationship between formation and resorption) were unrelated to bone mineral density in the lumbar spine, but BMI was associated inversely with markers of both bone formation and resorption (48). Interventions to Redress Malnutrition in Survivors of Leukemia in Childhood and Adolescence Children and adolescents undergoing active treatment for leukemia often require nutritional supplementation. When clinically possible, which is much of the time (especially in ALL), there is a strong preference for using the gut, either by mouth or with tube feeding. The advantages of enteral over parenteral feeding are well known (14), although the latter may be required (especially in AML). Innovative approaches for which there is some evidence of benefit, particularly in children with leukemia, include supplementation with omega-3-fatty acids such as eicosapentaenoic acid (49). Appetite stimulation, such as with megestrol acetate (50) or cyproheptadine (51), is not used widely in children. As described initially in Guatemala (52) and subsequently in North America (53), correction of undernutrition at diagnosis in children with ALL restores the good prospects for survival that are compromised in those who remain undernourished. In the longer term and taking a broad approach, Ness and colleagues recognized the frailty phenotype in young adult survivors of cancer in early life (54). In so doing this demands attention to lifestyle counseling, correction of hormonal deficits (such as of growth hormone), dietary modification to improve lean body mass, and exercise to promote
cardiovascular fitness and bone health (55e57). Formal testing of such interventions is in its infancy, but there are indications that integrative programs involving multiple elements may produce positive results (58). The SIOP Committee on Nutrition and Health conducted a survey from which it was determined that priorities for improving the nutritional care of children and adolescents with cancer in LMICs are increased availability of educational resources for patients and families, enhanced education and nutritional assessment tools for physicians and nurses, and examining the role of complementary and alternative therapies in symptom management (59). The first of these has been undertaken successfully in Central America (60). As a first step in determining the need for nutritional intervention, a reliable and valid tool should be used for screening. A recently devised instrument (SCAN) has been proposed for this purpose (61). Nutritional assessment may then follow, preferably based on arm anthropometry. In the event that undernutrition is revealed, supplementation is required. What can be offered is dictated by local resources, prompting the design of a framework for nutritional therapy adapted to local realities (62). Parenteral supplementation is seldom an option in LMICs, largely as a consequence of high cost, but enteral supplementation can be highly effective as reported in a study from Recife, Brazil (63) in which gains in protein and calorie intake were recorded and reflected in BMI Z scores. The challenge of providing nutritional supplementation to children with cancer in LMICs has resulted in some imaginative solutions. In Mexico, fortified chocolate bars containing 200 kcal have been used as snacks (64), whereas in Brazil it was found that homemade nutritional formulas were economical, well accepted by children and adolescents with cancer and had adequate nutritional composition (65). Natural resources have been put to good use in Malawi (66) in the form of ‘chiponde’, a peanutbased ready-to-use therapeutic food (RUTF). A comparable experience in Guatemala involves ‘incaparina’, an RUTF based on a mixture of commercialized maize and soy flours (52). In India, there are numerous locally produced RUTFs (67). Special Case of Hematopoietic Stem Cell Transplantation (HSCT) The impact of HSCT on nutritional status can be approached from the standpoint of energy expenditure. Total energy expenditure consists of basal energy expenditure the largest component, estimated by resting energy expenditure (REE) plus energy required for activity, growth, digestion and absorption of food, and obligatory losses in urine and stool. In children undergoing HSCT, REE (measured by indirect calorimetry) falls progressively in the first 4 weeks (68). The major determinant of REE is
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LBM; therefore, it is not surprising that arm muscle area (AMA) declines in concert with REE after HSCT (69). Survivors of ALL after HSCT have lower LBM and higher visceral and intramuscular fat e the phenomenon of sarcopenic obesity e than children treated with chemotherapy only (70). In a curious experience reported from Brazil, survivors of HSCT (conducted in 40% of the children and adolescents for Fanconi anemia) who were nutritionally depleted as defined by AMA and measured by BIA had a poorer survival than those who were adequately nourished (71); yet, in a later report, the same investigators found no change in LBM measured before and after HSCT in the same patients (72). A form of nutritional morbidity of particular concern in children and adolescents who undergo HSCT is loss of bone mineral that risks fractures, which may be asymptomatic (73). Reduced bone mineral density is a common occurrence that has been described in 50% of children by 6 months after HSCT, correlating with a significant drop in serum levels of the active metabolite 1, 25-dihydroxy vitamin D (72). Others have reported similar findings despite vitamin D supplementation (74). With respect to the impact of nutritional morbidity on clinical outcomes after HSCT, it was perhaps predictable that obesity would be associated with lower overall survival and event-free survival (EFS) with higher treatment-related mortality due mainly to infection and graft-versus-host disease (GVHD) (75). As a corollary, children with an AMA !5th percentile before HSCT had lower EFS and higher non-relapse mortality and relapse rate at both 100 days and 3 years after transplant than better nourished children (76). In that large study of 752 patients, no anthropometric measure correlated with acute or chronic GVHD. The influence of body weight on outcomes was examined by the Center for International Blood and Marrow Research (77). The results in 3687 children who had HSCT for leukemia after cyclophosphamide-based conditioning are displayed in Table 3. Using BMI percentiles for categorization, those who were obese had the lowest relapse rate at 3 years and the highest rate of TRM, whereas the most underweight children had the reverse profile, again highlighting the limitations of measures of nutritional status in children with cancer that are based on body weight. Table 3. Relationships of body weight to clinical outcomes in children and adolescents undergoing allogeneic hematopoietic stem cell transplantation for leukemias BMI percentile (weight category) !5th (underweight) 5the24th (risk of underweight) 25the85th (normal) 86the95th (risk of overweight) O95th (obese)
3-year relapse rate (%)
Cumulative TRM rate (%)
33 33 29 25 21
18 19 21 22 28
TRM, treatment-related mortality.Adapted from Reference 77.
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In a provocative finding that demands confirmation, it has been reported that children who were vitamin D depleted had lower survival rates and more frequent graft rejection after HSCT (78). What about the preferred strategies of nutritional support in the context of HSCT? A Cochrane review, not focused on children and adolescents, concluded that ‘‘Where possible, use of intravenous fluids and oral diet should be considered as a preference to parenteral nutrition; however, in the event of a patient suffering severe gastro-intestinal failure even with a trial of enteral feeding, PN with addition of glutamine could be considered’’ (79). Reports from France (80) and Turkey (81) indicate that the majority of children who require nutritional support following HSCT, and not all of them, will be managed successfully by the enteral route. However, most caregivers, in contrast to health care professionals, prefer the parenteral route as do the great majority of teenagers (82), disparities that may be resolved by education. A highly instructive collaborative study was performed in Boston and Los Angeles in the form of a randomized controlled trial (RCT) in which standard TPN, conventionally providing 130e150% of estimated energy expenditure, was compared to TPN titrated to measured REE. There was no difference in the accumulation of body fat or loss of LBM measured by DXA and arm anthropometry in children undergoing allogeneic HSCT (83). Clearly, it is important to emphasize, especially for practice in LMICs, that TPN is expensive and comes with increased risk of infection and thrombosis in central venous lines, liver dysfunction, hyperglycemia and volume overload (84,85). In contrast, enteral nutrition is relatively inexpensive, maintains gut integrity and mucosal barrier function, and can facilitate the delivery of medication (86). The particular matter of glutamine supplementation needs to be addressed, given the early reports that this reduced mucositis, resulting in less need for IV narcotics and TPN in children undergoing HSCT (87). However, a subsequent Cochrane review of 17 RCTs, conducted mainly in adults, provided no conclusive evidence for benefit (88). This outcome was supported by a later RCT in Italy comparing TPN to glutamine-supplemented TPN (89). Whereas 90% of the children experienced mucositis, there were no differences in the type and duration of analgesic therapy, rates of engraftment and GVHD, early morbidity and mortality, and relapse rate. Remarkably, the patients were described as all being well-nourished before and after HSCT, based on body weight and biochemistry. In conclusion, in children and adolescents (0e19 years of age) ALL is the commonest form of cancer worldwide (90) and malnutrition is prevalent in this age group, especially in LMICs where most of these young people live. Obesity, measured by BMI, is associated with poorer survival rates in children and adolescents with ALL and AML in HICs as confirmed in a recent meta-analysis
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(91). In contrast, undernutrition is linked to poorer survival rates among young people with leukemia in LMICs (17). It must also be acknowledged that BMI is an inadequate measure of body composition, obscuring the depletion of lean body mass that characterizes sarcopenic obesity, a common problem in children and adolescents with leukemia in HICs (92). Moreover, BMI is a less-sensitive measure of undernutrition than arm anthropometry, which is a strong predictor of clinical outcomes in children and adolescents with leukemia in HICs (93). The priority for nutritional intervention in HICs is the prevention and amelioration of obesity with its numerous adverse consequences on health in young people with leukemia. This may be a particular challenge in children and adolescents who have undergone HSCT and are inadequately active physically (94,95). Imaginative solutions to enteral nutritional supplementation have been devised in LMICs, notably in the form of RUTFs, and should be tested in formal clinical trials. The use of additional creatine is also worthy of further exploration (96). Marked loss of bone mineral occurs early in the treatment of children and adolescents with ALL (97) and vitamin D deficiency is prevalent in this population. These observations demand investigation of therapeutic interventions to restore bone mineral mass, including welldesigned studies of bisphosphonates (98). It is disappointing that biochemical markers of bone turnover are not associated with bone mineral density in long-term survivors (48), but innovative interventions to restore bone mass have been undertaken, as in the recent description of mechanical stimulation (99). A review of malnutrition in children with cancer in 2012 was limited by the choice of the authors to restrict the scope to industrialized countries (100). A more recent and geographically inclusive review (22) makes note of the need to develop common measures of nutritional status e only 11/46 studies used arm anthropometry e without which associations with clinical outcomes remain difficult to assess. The authors also pointed out the paucity of longitudinal studies. Deficiencies such as these are being addressed by the Working Group on Nutrition in SIOP; therefore, laying the foundation for future studies directed at interventions to redress nutritional imbalances and so contribute to the progressive improvement in clinical outcomes for children and adolescents with cancer worldwide. References 1. Stratton RJ, Green CJ, Elia M. Disease-related malnutrition, an evidence-based approach to treatment. Wallingford Oxon: CAB International; 2003. 2. Available at: http://data.worldbank.org/news/2015-country-classificat ions. Accessed June 17, 2016. 3. Ladas EJ, Mosby TT, Murphy AI, et al. Meeting report: development of an International Committee on Nutrition and Health for Children with Cancer, International Society of Pediatric Oncology (SIOP). Pediatr Blood Cancer 2012;58:1008e1009.
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