Full article by Sajad Shanaz
Introduction-Leukaemia is the most common type of paediatric cancer to be diagnosed in children accounting for approximately 30% of all cases.10 With a prevalence of 78%, ALL is the principle subtype of leukaemia to affect children in affluent industrialized countries such as Italy, United States (US), and Switzerland.3, 10 A majority of ALL cases show a sharp peak incidence in children aged between 1 to 4 years (~7 cases per 100000), with a steady decrease in rate to <2 cases per 100000 by age <20 years (Figure 1).3
Methodology-As neonatology encompasses a vast array of interesting topics, the initial search was carried out using ‘Google’ as the primary search engine. Once the topic of childhood ALL was decided, other medically specific search engines such as Scopus, Web of knowledge, PubMed, and DISCOVER, were utilised. Specific key terms such as ‘childhood cancer treatment’, ‘prevalence of obesity’, ‘chemotherapy’, were used to identify suitable articles to be critically appraised.
Discussion-From the four studies that were analysed, study 16 is a case-control study designed to establish a risk association between obesity and ALL therapy. Study 16 used the largest number of participants of the four studies, and focused in depth into the effects of previous treatment on obesity at different age groups with differing treatment combination. The initial results of the study suggest no significant association at developing obesity in patients treated with chemotherapy with/without CRT (10-19Gy), table 1a. However, when the dose of CRT was increased to ≥20Gy and combined with chemotherapy, the prevalence of obesity rose significantly among the female cohorts.. These results are comparative with the study conducted by Sklar et al. who also observed a similar increase in BMI based on final height measurements.22 Among childhood survivors of ALL receiving chemotherapy and high-dose CRT (24Gy) Sklar et al. found 40% of these patients to be overweight by the time they had attained full adult height.22
Conclusion-In conclusion, the review highlights that more prospective studies are required to assess the treatment effects on children based on gender and ethnicity whilst also taking into consideration the genetic profile of the patient. This would enable the tailoring of treatment on an individual basis to optimise outcome whilst lowering side effects. As Campbell LK et al. suggests, more control groups should be utilised for comparison with a similar demography to ALL survivors.31
3.1 Epidemiology of childhood Acute Lymphoblastic Leukaemia (ALL)
Leukaemia is the most common type of paediatric cancer to be diagnosed in children accounting for approximately 30% of all cases.10 With a prevalence of 78%, ALL is the principle subtype of leukaemia to affect children in affluent industrialized countries such as Italy, United States (US), and Switzerland.3,10 A majority of ALL cases show a sharp peak incidence in children aged between 1 to 4 years (~7 cases per 100000), with a steady decrease in rate to <2 cases per 100000 by age <20 years (Figure 1).3
3.2 Pathophysiology of ALL and possible causative agents
The peak age in incidence of childhood ALL and its distribution in affluent nations have led to the development of two infection based theories by the British scientists: Kinlen’s population-mixing hypothesis and Greaves’ delayed-infection hypothesis.1 Kinlen’s theory is based on the studies of clusters of ALL in children who are vulnerable to common non-pathological pathogens from infected ‘carriers’ during normal mixing with local population.1 Greaves’ theory is based on a two hit model of acquiring a random mutation to a haematopoietic stem cell (HSC) during fetal development.1 These are not exposed adequately to common pathogens during early life due to improved living/hygiene standards.1 Therefore, when the child is exposed to common pathogens during later life, the immune system responds in a pathological manner resulting in increased lymphoid proliferation (figure 2).1
3.3Treatment regimen for childhood ALL
The treatment of childhood ALL is generally based on four distinct phases lasting for 2.5 to 3 years: remission induction, intensification, maintenance, and early central nervous system (CNS) prophylaxis (table 1).3, 16, 18 The study by Ishii et al. (2001) was able to demonstrate a significantly high remission rate across all three risk groups during induction and subsequent phases of therapy: 99% of LR and IR and 88% of HR.19
3.4 The consequence of childhood ALL treatment
Survivors of ALL (children, adolescent and young adults) have been shown to develop obesity as a long term complication of treatment.6 Obesity is a very good predictor for the development of hypertension, diabetes mellitus, dyslipidemia, and cardiovascular disease.6 Obesity poses a considerable public health issue, thus targeting high risk groups with aggressive management has been shown to lower the overall obesity related morbidity and mortality.6
There are various factors contributing to weight gain during and after therapy. During therapy the main factors to influence weight gain are cranial radiotherapy (CRT) and steroid exposure.20 Of the range of drugs used in treatment, only glucocorticoids (GCs) have been shown to cause an increase in weight.18 Studies by Marky et al. have shown GC therapy to cause obesity by suppressing growth hormone, whilst Davies et al. have suggested a possible GC induced leptin resistance.21 Therefore, during long treatment phases there is a net positive energy balance; this effect is seen predominantly with dexamethasone compared with prednisolone.20
As neonatology encompasses a vast array of interesting topics, the initial search was carried out using ‘Google’ as the primary search engine. Once the topic of childhood ALL was decided, other medically specific search engines such as Scopus, Web of knowledge, PubMed, and DISCOVER, were utilised. Specific key terms such as ‘childhood cancer treatment’, ‘prevalence of obesity’, ‘chemotherapy’, were used to identify suitable articles to be critically appraised.
*The relevant searches were carried out between the 01/01/14 to 25/05/14.
The following three studies were extracted from the 82 articles filtered by above search strategy using SCOPUS to be reviewed:
1. ‘Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study’ by Oeffinger KC et al.6
2. ‘Obesity and hypertension among children after treatment for acute lymphoblastic leukemia’ by Chow EJ et al.2
3. ‘Obesity in long-term survivors of childhood acute lymphoblastic leukemia’ by Asner S et al.5
Using a similar search strategy as highlighted, one more article was selected to be reviewed:
4. ‘Body Mass Index and Blood Pressure Changes Over the Course of Treatment of Pediatric Acute Lymphoblastic Leukemia’ by Esbenshade AJ et al.4
5. Results of Studies
From the four studies that were analysed, study 16 is a case-control study designed to establish a risk association between obesity and ALL therapy. Study 16 used the largest number of participants of the four studies, and focused in depth into the effects of previous treatment on obesity at different age groups with differing treatment combination. The initial results of the study suggest no significant association at developing obesity in patients treated with chemotherapy with/without CRT (10-19Gy), table 1a. However, when the dose of CRT was increased to ≥20Gy and combined with chemotherapy, the prevalence of obesity rose significantly among the female cohorts.. These results are comparative with the study conducted by Sklar et al. who also observed a similar increase in BMI based on final height measurements.22 Among childhood survivors of ALL receiving chemotherapy and high-dose CRT (24Gy) Sklar et al. found 40% of these patients to be overweight by the time they had attained full adult height.22
Based on the results of study 16, it is clear that females treated at a younger age are more vulnerable to developing obesity than males when given high-dose CRT. The pathogenesis of why females exhibit such a vulnerability to obesity is unclear, however, many authors have suggested the rapid neurocognitive development in females to be a contributing factor in developing obesity.6 Moreover, 97.6% of ALL survivors assessed were treated with prednisone, and thus it is difficult to distinguish the extent to which this may have played a role in causing increased weight gain. Whether high-dose CRT damage makes an individual more susceptible to weight gain by corticosteroid is not measured in this study.
Studies 2 to 4 were all cross sectional studies intending to measure the prevalence of obesity in a single cohort of childhood ALL survivors. Study 22 focused mainly on the use of prednisolone and dexamethasone as chemotherapeutic agents to treat ALL. With only 19.4% of participants treated with CRT, the study identified increased corticosteroid doses to have a significant effect on BMI z-scores. Study 22 failed to elicit the dose dependent effect on obesity between the two types of steroids, this is a form of measurement bias as dexamethasone has been shown to differ in certain aspect to prednisolone.23
Although in study 16 the risk of obesity was primarily seen with higher doses of CRT, in study 22 the effects were more prominent with increasing cumulative steroid doses. As the steroid doses were increased the BMI z-score and obesity odds ratio increased significantly. Likewise, study 22 also shows females to be more likely to have a rise in z-scores than males. This is a profound finding as table 2a shows males to have received a higher median and overall steroid dose compared to females.
Furthermore, study 22 did not find any significant association with CRT to BMI changes among the cohort. This is consist with the findings in study 16 as it also found no significant association with obesity in patients treated with chemotherapy and CRT (10-19Gy). Therefore, the results of study 22 complies with the general outcome of study 16 in regards to females being more vulnerable to obesity from ALL treatment. This is a reflection of the contemporary regimes aimed to reduce overall CRT exposure whilst intensifying the potency of chemotherapy (especially corticosteroids).24 Since the 1970’s, the doses of steroids used have increased by 60% to 80% with additional steroid pulses given during post-induction intensification and maintenance phases.25, 26 The study conducted by Reilly J et al. demonstrates both prednisolone and dexamethasone to cause an increase in energy intake (~20% mean increase in energy intake) during maintenance when given as monthly 5-day pulses.27
In terms of measuring the prevalence of obesity among ALL survivors, Study 35 used the smallest cohort comprising of 54 cases. The study found the prevalence of overweight and obesity in young ALL survivors to be 30% and 18%, respectively. When the authors of study 35 had compared the prevalence of overweight and obesity among their cohort with the standard Swiss children, there was a profound increase in prevalence. A particularly area focused in study 35 looked to establish the critical period of weight gain during treatment and follow up from BMI-SDS values. The results of this analysis suggested most of the weight gaining to occur after the induction/consolidation phases with subsequent returning of BMI to normal towards the end of treatment. These results are consistent with the findings by Razzouk BI et al. who also conducted a similar retrospective study proving BMI at time of diagnosis to be a good predictor of adult obesity among ALL survivors.28
The primary outcome of Study 44 was to assess the effect of maintenance therapy composing of corticosteroid on BMI. The study found an increase in BMI over the first 22 months of maintenance therapy, which was found to be associated with an increased BMI z-score at diagnosis. Interestingly in this study, patients considered high-risk and thus treated with CRT throughout maintenance resulted in having an overall lower BMI z-score compared to patients treated without CRT. When this is compared to the results of study16, there is some contradiction between CRT associated weight gain. This could be explained by the limited number of patients who received CRT (13%) with a median dose of 17.4Gy.4
In study 44 no association between BMI z-score and gender was noted during maintenance therapy, this disassociation is a shared by study 35. Studies by Withycombe JS et al, Garmey EG et al and studies 1&2, both demonstrate a more pronounced association with weight gain in female patients treated especially in the first decade of life.29, 30 Hence, this gender specific change in BMI observed among survivors could be the result of non-therapeutic risk factors associated with prolonged survival.4
Strengths and weaknesses
One of the main strengths to highlight in study 16 is the study design used. The use of a retrospective ‘case-control’ study has been very effective as it enabled the authors to measure an OR to establish an association between obesity and treatment. Moreover, the use of siblings as a ‘control group’ is beneficial as it reduces the variability in environmental factors found amongst individuals which could predispose to obesity.
In terms of the limitations of study 16, the main point to note are the self-reported BMI values obtained directly from the participants. This inherently introduces a certain level of recall bias. In addition, BMI is a calculation which doesn’t differentiate between body fat and lean body mass. Hence the use of a bioelectrical impedance analysis would provide a more accurate measure of mass. Finally, although 97.6% of survivors were treated with steroids (prednisone), many different types of chemotherapeutic agents were used in high quantities. Consequently, it is not possible to relate the effects of obesity to any one of the agents used, as the main difference measured correlated to CRT doses.
Studies 22, 35 and 44 are all cross sectional studies, and so a prevalence of obesity in a single cohort of ALL survivors were calculated. In all three of these studies, the sample sizes are very small in comparison to study 16 and possess the same disproportionate representation of minority ethnic groups; study 35 fails to highlight participant characteristics such as ethnicity, diet, and physical activity.
In conclusion, the review highlights that more prospective studies are required to assess the treatment effects on children based on gender and ethnicity whilst also taking into consideration the genetic profile of the patient. This would enable the tailoring of treatment on an individual basis to optimise outcome whilst lowering side effects. As Campbell LK et al. suggests, more control groups should be utilised for comparison with a similar demography to ALL survivors.31.
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