Cancer and nutrition among children and adolescents in low- and middle-income countries

ABSTRACT Objective : The primary purpose of this review is to investigate the relationships between cancer and nutrition in children and adolescents living in resource-poor, low- and middle-income countries (LMICs) in order to explore potential opportunities for interventions which could improve clinical outcomes in this population. Method : The implications of overlapping age groups of children and adolescents with cancer are examined, as are the adverse influences of under-nutrition and socio-economic deprivation on the efficacy of treatment and cancer survival. Evidence suggestive of novel avenues to enhance prospects for cure, based on increased understanding of the dynamic of nutrition and cancer, is evaluated. Result : Cancer adds to the burden of under-nutrition in disadvantaged populations which is reflective, in large measure, on inadequate governmental expenditure on health which demands public-private partnerships and the use of hospital-based foundations. Structured approaches to the measurement of nutritional status and the design of effective programmes of nutritional supplementation are of proven benefit. Initial results from studies of the perturbed gut microbiome hold considerable promise for further gains. Conclusion A large minority of children with cancer in LMICs are never diagnosed and the same may be true of adolescents. Investing in the training of nutritionists will have substantial returns as will increasing access to essential medicines. Recognition of these challenges has stimulated WHO and other entities to devise major strategies for comprehensive changes in the care of children and adolescents with cancer in LMICs, offering realistic prospects for improved clinical outcomes.


Introduction
Childhood has been defined by international consensus as 0-14 years of age for the purpose of cancer registration which uses the long-standing International Classification of Childhood Cancer, now in its third edition [1]. However, a recent update has expanded the age range to 0-19 years and the number of main tumour groups remains at 12; there are 47 sub-categories [2]. This overlaps now with the most recent classification of cancers in adolescents and young adults, defined as 15-39 years of age, in which the adolescents occupy the age range 15-19 years and there are 11 main categories with 65 sub-categories [3].
Seen through the lens of low-and middle-income countries (LMICs), as defined by the World Bank [4], the plight of young people with cancer reveals considerable disadvantages in comparison to their counterparts in more privileged societies. This is most striking in the estimate from a microsimulation model [5] used by a recent Lancet Oncology Commission, of which both of us were members, that almost 45% of children with cancer in the world are undiagnosed; resulting in a total projected to exceed 6 million in 2020-2050 [6]. Comparable data for adolescents are not available. Marked regional variations in the apparent incidence of individual tumours may reflect differences in causal exposures, best exemplified by Burkitt lymphoma [7], or represent limitations in diagnostic capability, as with the seeming paucity of brain tumours in LMICs and the availability of neuroradiology [8]. Modelled estimates [9] in 5 year survival for all cancers combined, among those diagnosed, has produced considerable variation between countries and world regions (Table 1). Again, no such estimates exist for adolescents. Among the main economic influences on the survival rates of children with cancer is the striking association with average government health expenditure per capita [10].
In approaching the complex relationship between cancer and nutrition [11] it is essential to begin with the recognition of the importance of nutrition to normal growth and development. Nutrition has been characterized as the set of integrated processes by which cells, tissues, organs and the whole body acquire the energy and nutrients for normal structure and function, which is achieved at body level through dietary supply, and the capacity of the body to transform the substrates and co-factors necessary for metabolism. All of these domains (diet, metabolic capacity, body composition and level of demand for energy and nutrients) are influenced by levels of physical activity and can vary according to different physiological and pathological or disease states. [12] Defining nutritional status The term malnutrition is often used inter-changeably with under-nutrition, especially in LMICs where the prevalence is high overall. However, overweight and obesity are being recognized more frequently in children in LMICs as their diet and lifestyle become ever more 'westerenised' [13]. The added burden of cancer is associated with even higher frates of malnutrition, reaching 95% at diagnosis in Malawi [14]. Both over-and under-nutrition complicate the treatment of cancer in young people, with higher rates of treatment-related toxicities during therapy and increased burden of longer term morbidity in survivors after completion of active treatment [15]. These adverse effects compromise health-related quality of life [16] and survival [17]. In addition, as demonstrated in a large multinational study in Central America, malnutrition is associated with increased rates of abandonment of therapy in children and adolescents with cancer [18], a phenomenon which is decidedly uncommon in high income countries (HICs). A subsequent study in Guatemala revealed the added contribution of socioeconomic disadvantage to the negative influence of malnutrition [19].
With this now well-established interplay of cancer and nutrition in children and adolescents in LMICs, the Nutrition Network of SIOP (the International Society of Paediatric Oncology) begins its Terms of Reference with the following statement Malnutrition in its broadest sense poses serious challenges in the management of children and adolescents throughout their cancer journey, from prior to diagnosis into long-term survivorship.
So how are we to rise to these challenges? An obvious place to start is with the measurement of nutritional status to allow the definition of underand over-nutrition with accuracy. In young people with cancer, it was shown more than 30 years ago that weight-for-height, the measure of acute malnutrition recommended by the WHO [20], under-estimated malnutrition at diagnosis, in part because of the contribution of tumour mass to total body weight [21]. This limitation extends to any measure based on weight, including BMI (Body Mass Index). Indeed, BMI is compromised by its inability to distinguish muscle from adipose tissue [22,23]. Consequently, better measures were sought with attention devoted to resolving this limitation. This exercise resulted in more detailed examination of body composition ( Table 2). The use of stable isotopes remains in the realm of research, as is the BOD POD, while CT and MRI (especially the latter) are not widely available in LMICs. BIA offers the advantages of relatively low cost and the ease of portability. DEXA has come to be accepted as a clinical 'gold standard' [24,25] but, although substantially less expensive than CT and MRI, is likewise of restricted availability in LMICs. Nevertheless, this technique ( Figure 1) affords a ready compartmentalization of the body with considerable clinical usefulness (Table 3). Expressing the various compartments as indices e.g. fat mass/height 2 gives added normalization [26], and Z scores for the individual compartments and their indices are provided by current software for densitometers.
The limited availability in LMICs of sophisticated measures for the measurement of nutritional status has resulted in the common use of arm anthropometry, including in children with cancer [27]. Validation of mid-upper arm circumference (MUAC) and triceps skin fold thickness (TSFT) as measures of lean body mass and fat mass respectively has been achieved by comparison with DEXA in children with cancer [28]. More recently, it has been recognized that the relationship of MUAC to nutritional status may vary with ethnicity, as demonstrated in India [29].

More on the dynamic of nutrition and cancer
It is generally accepted that the causes of cancer in children and youth are poorly understood, yet there is a relationship between high birth weight (more than 3.5 kg) and an increased risk of both acute  lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) [30,31]. The strong evidence that ALL can begin antenatally [32] suggests that the role of nutrition may be the promotion of accelerated fetal growth, perhaps mediated by insulin-like growth factors [33] which are known to be involved in normal and malignant hematopoiesis [33].
What then is the corollary; the influence of cancer on nutritional status? At diagnosis, children and adolescents in LMICs are often malnourished, as noted above; a relationship much less common in HICs [34]. Of course this is on a background of notably different rates of malnutrition in the corresponding general populations, but an ongoing study in Guatemala, comparing children and adolescents with ALL at diagnosis to their siblings, points to an adverse impact of cancer on nutritional status [35], additional to the recognized influence of socioeconomic disadvantage [19].

Treatment of cancer and nutritional status
The impact of treatment for cancer on nutritional status in children and adolescents has been studied extensively in HICs, especially following a diagnosis of ALL. Loss of bone mineral has received particular attention, related mainly to the use of corticosteroids and methotrexate [36]. Such osteopenia occurs also in patients with solid tumours [37] and commonly in those with brain tumours in whom it is associated with a negative effect on health-related quality of life (HRQL) [38]. The importance of this loss of bone mineral is best appreciated from the realization that much of the bone mass in adults is accumulated during childhood and adolescence [39]. In children with ALL there is early loss of muscle (sarcopenia) and gain in fat, beginning during remission induction (often under-appreciated from measures of BMI) [40] and persisting into long-term survivorship as sarcopenic obesity with the attendant risks of metabolic and frailty syndromes [41]. Intensive chemotherapy in children with solid tumours often results in marked weight loss with perturbation of body composition [42,43]. This has been reported to occur markedly in children and adolescents with medulloblastoma [44]. However, there remains a paucity of information on the relationship of changes in nutritional status to clinical outcomes in young people with solid tumours [45].
Not surprisingly, much less experience has been reported from LMICs [46]. In India, 40-80% of children with cancer have severe acute malnutrition at diagnosis [47]. This proportion exceeded 85% in a large randomized controlled trial of a nutritional intervention in Mumbai with an additional 14% exhibiting moderate acute malnutrition [48]. Early findings from the study in Guatemala [35], which was limited to patients with ALL, revealed the abnormal body composition at diagnosis with the anticipated gain in fat mass and loss of skeletal muscle mass during remission induction therapy, matching the pattern well described in HICs.

Impact of treatment on clinical outcomes
Malnutrition in children and adolescents with cancer in LMICs is a major contributing factor to early abandonment of therapy, prevalent and severe treatmentrelated toxicities (TRTs), poor clinical outcomes and Table 3. Body composition in a 3 compartment model.  low survival rates [18,40,49,50]. Improving nutritional status can reduce TRTs, such as severe infections and mucositis [50], as well as increasing 5 year overall survival [51]. There is a dearth of experience in long-term follow up in LMICs of survivors of cancer in childhood and adolescence, reflecting a paucity of resources. As a result, there are no substantive data on late morbidity, HRQL and life expectancy in this population.

Strategies for effecting change
An investment in the hiring and training of nutritionists/dieticians is a top priority. Even in HICs there is often a shortfall of these health care practitioners in centres devoted to the care of children and adolescents with cancer [52]. The International Initiative in Pediatrics and Nutrition (IIPAN) has undertaken the education of many hundreds of dieticians in India and has begun a similar programme in Ghana in collaboration with World Child Cancer (EJ Ladas, personal communication, 2022). Complementary exercises with families and other health care professionals are important (Table 4).
Considerable efforts have been made to develop tools for screening of nutritional risk and assessment of nutritional status for use in children and adolescents with cancer in LMICs [53]. In turn, this led to a framework for adapted nutritional therapy [54] and the development of a related algorithm [55], the use of which was shown to lead to better nutritional care [56].
The case for regular monitoring of nutritional status in children with cancer is well established [40]. Scaling up to the national level in LMICs is demanding, but a successful programme has been established in 9 centres representing all 5 geographical regions in Brazil, supported by IIPAN [57]. Such endeavours provide a potential framework for the conduct of clinical trials of nutritional interventions, especially involving local ready-to-use therapeutic foods, as has been reported from a large single centre in India [48].
Many families use complementary and alternative medicines (CAM), usually as supportive care agents, in the treatment of children and adolescents with cancer. This subject has been well reviewed [58], with a particular focus on dietary intervention. SIOP has provided guidelines on the integration of CAM into cancer care, emphasising the importance of non-judgemental decisions with families [59]. Colleagues in the Netherlands have even developed a decision-aid for parents on the use of CAM for control of pain [60].

Investing in progress
Increasing understanding of genetic contributions to the risk of cancer in young people and to protection from the deleterious effects of therapy is well exemplified in the case of Hispanic children. This population has a higher incidence of ALL and poorer treatment outcomes than those of European ancestry [61]; explained in part by the proportion of Native American ancestry in the Hispanic children [62][63][64]. By contrast, this population has less osteotoxicity from treatment of ALL, driven by the proportion of their African ancestry [65] which may reflect the higher bone mineral density in healthy Black children than in those of non-African descent [66].
Much interest is being shown in the gut microbiome and metabolome which influence nutritional status in children [67,68]. A dysbiotic gut may affect the efficacy of chemotherapy, resulting in greater toxicity and poorer clinical outcomes [69]. The prospect of remedying this perturbation is raised by the report from Dr. Jeffrey Gordon and colleagues on the impact of a ready-to-use therapeutic food on 'maturing' the gut microbiome in children with moderate acute malnutrition in Bangladesh [70].
Whatever interventions are invoked, there is an evident requirement to determine its cost-effectiveness from the perspective of the health care system and affordability for families [71]. Indeed, support for families of children and adolescents with cancer in LMICs is a major part of the increasing success of comprehensive care. Local foundations have effected notable reductions in abandonment of therapy [72] while Childhood Cancer International (CCI https:// www.childhoodcancerinternational.org), now partnered with SIOP, has been a highly effective advocate for further progress in pediatric oncology globally. SIOP itself has been instrumental in the successful expansion of the list of essential medicines for children and adolescents with cancer, in partnership with WHO [73].
St. Jude Children's Research Hospital has engaged with WHO in the Global Initiative for Childhood Cancer [74] and announced recently a major investment to establish the Global Platform for Access to Childhood Cancer Medicines to support the availability of quality-assured essential medicines for children and adolescents with cancer in LMICs [75]. Of course there must be a series of metrics by which to evaluate the many interventions designed to improve the outcomes for young people with cancer. These will include selected United Nations Sustainable Development Goals, especially numbers 2 (zero hunger), 10 (reduced inequalities) and 17 (partnerships for the goals). Moreover, a strong case has been made that there can be substantial returns on such investments in pediatric oncology. In the context of nutrition and cancer in children and adolescents in LMICs; this is no better implied than by the related Lancet Oncology Commission: In LMICs, the prevalence of malnutrition in children with cancer, which is associated with higher toxicity rates, reached 50-70% in some regions of the world and is a major cause of decreased survival.
Evidently this calls attention to the importance of nutrition in young people with cancer, especially in under-resourced settings. Heeding that message requires a modest investment with a decidedly high return.

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Funding
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