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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 2  |  Page : 203-206
 

The impact of weight for age on survival in acute lymphoblastic leukemia: Report from a tertiary care center in North India


1 Pediatric Hematology-Oncology Unit, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication5-Feb-2016

Correspondence Address:
A Trehan
Pediatric Hematology-Oncology Unit, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175835

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 » Abstract 

Background: Undernutrition is considered to have a negative impact on survival in children with malignancies. The objective of this retrospective analysis was to evaluate the morbidity pattern and outcome of therapy in undernourished (UN) children with acute lymphoblastic leukemia. Methods: A retrospective analysis of impact of weight for age was performed in children treated for ALL. The IAP & CDC criteria for undernutrition were used in the two different time periods of analysis. Results: There were two cohorts in the study: Between 1995 and 2005, 360 children were evaluated where the weight for age was classified using the Indian Academy of Pediatrics criteria for undernourishment (Group A). Group B of the study included 373 children treated from 2007 to 2011, who were graded as per the Centers for Disease Control criteria for weight for age. In Group A, 35% of the children were malnourished at presentation. The morbidity and supportive care needed in the well-nourished and UN group were similar. The event-free survival and mortality were similar in both groups. Analysis of Group B showed an overall survival of 62.6% with a greater survival in children with a weight of ≥10th centile for age compared to children at the <10th centile, (P = 0.026) with a higher mortality (P = 0.011) in the UN group. Conclusion: Our data have yielded conflicting results. The older cohort did not show a significant difference in survival using malnutrition as a risk factor. However, in the subsequent cohort, a difference in survival was noted. This could be due to the reason that different criteria for classification of undernutrition were applied in the two groups. This analysis lays the foundation for a future prospective analysis to evaluate nutrition as an independent risk factor nutrition as an independent risk factor in the outcome of childhood malignancies.


Keywords: Acute lymphoblastic leukemia, survival, undernutrition


How to cite this article:
Trehan A, Prabhu V, Bansal D. The impact of weight for age on survival in acute lymphoblastic leukemia: Report from a tertiary care center in North India. Indian J Cancer 2015;52:203-6

How to cite this URL:
Trehan A, Prabhu V, Bansal D. The impact of weight for age on survival in acute lymphoblastic leukemia: Report from a tertiary care center in North India. Indian J Cancer [serial online] 2015 [cited 2020 Nov 29];52:203-6. Available from: https://www.indianjcancer.com/text.asp?2015/52/2/203/175835


“We are guilty of many errors and many faults, but our worst crime is abandoning the children, neglecting the foundation of life. Many of the things we need can wait. The child cannot. Right now is the time his bones are being formed, his blood is being made and his senses are being developed.

To him we cannot answer 'Tomorrow.' His name is 'Today.'” Gabriela Mistral, 1948.


 » Introduction Top


The progress made in the outcome of childhood acute lymphoblastic leukemia (ALL) has been remarkable. Current literature from the developed countries reports event-free survival (EFS) of about 75% and overall survival (OS) of about 90%. However, more than 80% of the world's children live in less-advantaged countries, where the cure rate generally does not exceed 35%.[1],[2] There are various factors for this incomparably low cure rate in the developing countries with numerous reasons being cited.[3],[4],[5] Patients with ALL in the developing countries often present with more advanced disease. Co-morbidities such as hepatitis, malaria, and malnourishment are also considered to affect patients' ability to tolerate treatment. Ethnic factors, biology of the malignancy, and altered drug mechanisms have also been considered to play a role in the outcome.[3],[4],[5] Most developing countries face an inadequacy of health care facilities with access to care in cancer centers or pediatric oncology units being limited. Continuation of treatment and follow-up is often difficult because of socioeconomic, cultural, and demographic factors.

Undernutrition is considered to be an adverse prognostic factor in the outcome of treatment in patients with ALL, influencing the course of the disease and the chances of survival.[3],[4],[5],[6] The relationship between malnutrition and poor prognosis of patients with ALL is possibly due to diminished bone marrow reserve in these children resulting in lower than optimal doses of so-called “maintenance” chemotherapy, with subsequent higher relapses.[3],[4],[5],[6],[7] The prevalence of malnutrition in India in children is 45.9% as per the National Family Health Survey (NFHS) of India 3 (2006–2007).[8] As per the World Health Organization (WHO), 1/3rd of the world's malnourished children are from India.[9] The 2011 report on global hunger index has India at a rank of 15. Our study was designed to systematically analyze the prevalence and severity of poor nutrition in children with ALL presenting to our center and to evaluate the morbidity pattern and outcome of therapy in undernourished (UN) children and well-nourished (WN) children.


 » Materials and Methods Top


This retrospective study was carried out in the Hematology-Oncology Unit of the Advanced Pediatric Centre. Data were retrieved from the case records of pediatric oncology clinic files. Children who were started on treatment from January 1, 1995, to December 30, 2011, were the subjects in the study. We have taken weight for age as criteria for nourishment.

All children were treated as per the guidelines of UKALL X (1995–2005) and UKALL 2003 protocol (2007–2011). All children who opted for treatment for ALL were analyzed. Weight and height of the child at diagnosis were recorded in the case record files. This study was done in phases. In the first half of the study, the Indian Academy of Pediatrics (IAP) classification (weight for age: >81st centile: WN; 71–80% expected weight – Grade 1 undernutrition; 61–70% expected weight – Grade II undernutrition; <60% expected weight – Grade III undernutrition) was used for the definition of undernutrition (January 1995 to December 2005).[10] In the analysis, this subgroup is referred to as Group A. In this analysis, details pertaining to episodes of febrile neutropenia, death, need for platelet, and blood transfusions were recorded on a predesigned proforma. From 2007 onward, the weight was compared with the Centers for Disease Control (CDC) normative data for the definition of malnutrition.[11] Analysis was restricted to survival. This cohort was referred to as Group B. Children treated in 2006 were not analyzed due to logistic reasons. For the purpose of analysis, children <10th centile were taken as UN while the rest of the children ≥10th centile were classified as the WN set in Group B.

Statistical analysis

SPSS software version 17 (IBM Statistical Package for Social Sciences Chicago, IL, USA) was used for analysis:

  • The mean and standard deviation (SD) of all quantitative parameters were calculated
  • Percent occurrence rate (frequency) in respect of different morbidities experienced by the sample subjects was calculated. Chi-square test was applied to quantify the extent of intergroup (WN vs. UN) differences
  • Analysis of disease outcome was examined as OS and EFS. OS was measured from the date of initial diagnosis of ALL to the date of death from any cause or the date of last contact using the Kaplan–Meier method. EFS was defined as the time to first induction failure, relapse, or death, whichever was earlier. Treatment-related mortality (TRM) was defined as death unrelated to the primary disease. Association of categorical variables with the presence of complications or mortality was tested by Chi-square test. Odds ratios with 95% confidence interval (CI) were calculated.



 » Results Top


Our analysis is based on the weight for age of the child when diagnosed with leukemia. In cohort named as Group A, 360 children received therapy between January 1995 and December 2005. The mean age at presentation was 5.8 ± 3.1 years (range 0.6–13.5 years). Three hundred and twenty one (89%) children were <10 years of age and 39 (10.8%) were >10 years of age [Table 1]. In this group, as per the IAP classification, 125 (34.7%) were UN. Seventy-three (20.27%) had Grade I malnutrition, 43 (11.9%) had Grade II malnutrition, and 9 (2.5%) had Grade III malnutrition. The mean number of admissions during treatment in the WN group was 3.4 ± 2.196 (range 0–14). The mean number of admissions during treatment in the UN group was 3.18 ± 1.784 (range 0–8) (P = 0.561). The number of episodes of febrile neutropenia, admissions, blood and platelet transfusions is enumerated in [Table 2]. The P value for the morbidities between the two groups was not significant (0.412 for febrile neutropenia, 0.73 for blood transfusion, 0.866 for platelet transfusions, and 0.388 for postponement of therapy). In the analysis, 160 (44.4%) children are survivors, 95 (27.7%) relapsed, 67 (18.6%) died, and 38 (10.6%) defaulted treatment. The survival, relapse, and death which were similar between the WN and the UN children is shown in [Table 3]. The difference in the status between the WN and the UN was not statistically significant (P = 0.63). The estimated disease-free survival in the WN children was 2037.776 ± 114.942 days (CI 1812.489–2263.063 days) and in the UN children it was 2135.918 ± 168.063 days (CI 1806.514–2465.332) with no statistical difference (P = 0.829).
Table 1: Demographics of children with acute lymphoblastic leukemia

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Table 2: Morbidity pattern of the well-nourished and undernourished group (Group A)

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Table 3: Status of children after therapy

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A total of 373 children with ALL treated between January 2007 and December 2011 were analyzed for the effect of a poor nutritional status on outcome. This group is called Group B. The mean age was 5.9 ± 2.9 years (1–13). The male:female ratio was 2.5:1. The CDC criterion was used for classification of weight centiles in this cohort of patients [Table 1]. Fifty-three percent of children had a weight, which was equal to or less than the 5th centile as per CDC criteria. There were only 24 children in the whole cohort whose weight was >75th centile. The ratio of WN verses poorly nourished children did not differ between high risk and standard risk ALL (as per the National Cancer Institute criteria). We compared deaths and events between the children who had a weight of <10th centile with those who had a weight of ≥10th centile. The difference in OS was significant (1579.52 days [95% CI 1419–1740] vs. 1894.6 days [95% CI 1734–2055.2] [P = 0.026]) [Figure 1]. The EFS was also greater in children who had a weight of ≥10th centile (1718.86 days [95% CI 1547–1890] and 1420.34 days [95% CI 1262–1577] [P = 0.022]). TRM was higher in the group with a weight of <10th centile compared to children who had a weight of ≥10th centile (P = 0.011). The relapse rates in both groups were similar (12.7% in the groups with a weight of ≥10th centile and 16.6% in the group with a weight of <10th centile; P = 0.109).
Figure 1: Survival on Group B

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 » Discussion Top


Malnutrition is found in 10–50% of children with cancer in resource-crunched countries.[4],[6] Cancer-associated malnutrition can result from local effects of a tumor, the host response to the tumor, and anticancer therapies. In addition, depletion of lipid stores, alteration in carbohydrate metabolism, and an increased protein turnover are responsible for a poor nutritional status in cancer patients. Undernutrition also adds onto the diminished immunity in patients with malignancy. Drug pharmacokinetics is also considered to be altered based on differences in the body composition in WN compared to UN individuals.[12] In low-income countries, a large proportion of the normal pediatric population is UN and children frequently present late with advanced disease.[13] Undernutrition in young children is a substantial problem in India. Accordingly to NFHS-3, in 2005–2006, 46% of children <3 years of age were underweight, 38% were stunted, and 10% were wasted. The proportion of children who are severely UN is also notable –24% are severely stunted and 16% are severely underweight. The figure is not different in North India with Punjab having a 37% incidence of malnutrition in the <5-year age group.[8]

Many studies show that there exists a relationship between undernutrition and poor prognosis in children being treated for malignancy. However, there are conflicting results as to the outcome in malnourished children with cancer. Lobato-Mendizábal in their review of published literature on 1123 children reported the relative risk of dying to be 1.8 times greater in UN children and have opined that undernutrition may be an independent prognostic factor in the long-term outcome of cancer patients. The correlation between malnutrition and compromised treatment was 0.92.[14] Viana et al. have reported the outcome to be 59% in the WN group in comparison to 27% in the UN group.[7] Sala et al. in their analysis of malnutrition in cancer in a cohort of 2954 children in Central America reported 45% children to be severely depleted as per the criteria of mid-arm circumference. They found poor nutrition to correlate with higher mortality and increased abandonment. In addition, the EFS was 65% in the WN children in comparison to 48% in the UN group.[5] Antillon in 2013 has reported 41.5% patients to have severe nutritional depletion with a 2.4 times greater risk of dying.[15] Rivera-Luna et al. in a multivariate analysis did not find undernutrition to correlate to a poor outcome.[16] A study done in Cuba did not show any difference in outcome related to malnutrition.[17] Closer home, a study published from Lahore failed to demonstrate the effect of malnutrition on the outcome in children with ALL.[18] In the United Kingdom, body mass was seen to have no influence on the outcome of the disease.[19],[20] However, their study was restricted to relapses rather than survival. Pedrosa et al. in their study from Brazil and El Salvador also did not see a demonstrable effect of nutrition on outcome.[21] Studies from India with a limited cohort have shown malnutrition to have an adverse prognosis on morbidity and short-term outcome.[22],[23],[24],[25]

In Group A in our study, undernutrition was not found to have an impact on the outcome of ALL. In addition, the grade of malnutrition also had no effect on the outcome. However, the total number of severely malnourished (Grade III) children was only nine with a mortality of 33%. The small number of severely malnourished children would have probably precluded statistical significance. The mean albumin of the children was 3.638 ± 0.6161 g/dl and did not differ significantly between the WN and the UN children. The normal serum albumin levels in UN children despite their weight for age criteria could explain the comparable levels of outcome in both the nourishment groups. In addition, malnutrition was not seen to be associated with increased episodes of febrile neutropenia, admissions or transfusion requirements in our study. The overall mortality rates in Group A of our study were 18.6% with the mortality rates in the WN and the UN children being almost equal. In the Indian collaborative trial, nutritional status was not seen to be a risk factor influencing outcome and survival.[26] Analysis at a later date on patients between 2007 and 2011 showed a difference in outcome between children <10th centile for age and those above 10th centile as per the CDC criteria, (EFS: 57.1% vs. 69.6%; P = 0.004) [Figure 1], indicating malnutrition to be an independent criteria for the outcome of ALL. TRM was significantly higher in the UN group (P = 0.011). We have conflicting results in relation to the nutritional status at diagnosis in our own data. We would attribute this to the different norms used in the two groups analyzed (IAP and CDC) as the population demographics remain similar. As per the CDC criteria, we found nearly 30% of children to be below the 5th centile and 53% children were at and below the 10th centile. In contrast, in the cohort classified as per the IAP criteria, only 2.5% children had severe malnutrition.

The need for assessment of nutrition in a child with cancer cannot be overemphasized. We have used weight for age as the parameter for assessment. There is no “gold standard” for nutritional assessment. Most studies have been retrospective and have used weight for age as well as SD scores for weight for age, height for age, and weight for height.[6],[14],[18],[20],[24] Studies range from having only ALL in the cohort and a mixed population of tumors. Moreover, all growth charts have fallacies with none being described as “optimal” in a particular setting. WHO charts till recently were for children till 5 years of age and the CDC charts reflect a shorter and heavier sample. Most pediatricians in our country would use the charts recommended by the IAP compiled by Agarwal and Agarwal.[10],[27] Weight for age is reasonably sensitive in assessing children who do not have a solid tumor.

This study is confined being a retrospective analysis with limited available information to further classify nutritional status. Studies across the globe have used varying criteria for assessment. International society of pediatric oncology (SIOP) has recommended weight for height with age-related cut-off and a mid-upper arm circumference for a quantitative assessment of nourishment.[28] A collaborative prospective study using a common algorithm for assessment is needed in India to evaluate the magnitude of the problem and to assess the impact on morbidity and mortality. Moreover, we need to formulate plans for nutritional intervention and prevention of malnutrition during therapy in cancer children to improve the outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Sala A, Rossi E, Antillon F, Molina AL, de Maselli T, Bonilla M, 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;48:243-52.  Back to cited text no. 5
    
6.
Viana MB, Murao M, Ramos G, Oliveira HM, de Carvalho RI, de Bastos M, et al. Malnutrition as a prognostic factor in lymphoblastic leukaemia: A multivariate analysis. Arch Dis Child 1994;71:304-10.  Back to cited text no. 6
    
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Viana MB, Fernandes RA, de Oliveira BM, Murao M, de Andrade Paes C, Duarte AA. Nutritional and socio-economic status in the prognosis of childhood acute lymphoblastic leukemia. Haematologica 2001;86:113-20.  Back to cited text no. 7
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Antillon F, Rossi E, Molina AL, Sala A, Pencharz P, Valsecchi MG, et al. Nutritional status of children during treatment for acute lymphoblastic leukemia in Guatemala. Pediatr Blood Cancer 2013;60:911-5.  Back to cited text no. 15
    
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Rivera-Luna R, Olaya-Vargas A, Velásquez-Aviña M, Frenk S, Cárdenas-Cardós R, Leal-Leal C, et al. Early death in children with acute lymphoblastic leukemia: Does malnutrition play a role? Pediatr Hematol Oncol 2008;25:17-26.  Back to cited text no. 16
    
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González A, Cortina L, González P, González C, García T, de Svarch EG. Longitudinal assessment of nutritional status in children treated for acute lymphoblastic leukaemia in Cuba. Eur J Cancer 2004;40:1031-4.  Back to cited text no. 17
    
18.
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21.
Pedrosa F, Bonilla M, Liu A, Smith K, Davis D, Ribeiro RC, et al. Effect of malnutrition at the time of diagnosis on the survival of children treated for cancer in El Salvador and Northern Brazil. J Pediatr Hematol Oncol 2000;22:502-5.  Back to cited text no. 21
    
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Israels T, Renner L, Hendricks M, Hesseling P, Howard S, Molyneux E; Paediatric Oncology in Developing Countries. SIOP PODC: Recommendations for supportive care of children with cancer in a low-income setting. Pediatr Blood Cancer 2013;60:899-904.  Back to cited text no. 28
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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