Rajesh Kumar, R.K. Marwaha, A.K. Bhalla and M. Gulati*

From the Division of Pediatric Hematology - Oncology, Advanced Pediatric Center and Department of Radiodiagnosis*, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India.

Reprint requests: Dr. R.K. Marawaha, Additional Professor, Division of Pediatric Hematology Oncology, Advanced Pediatric Center, PGIMER, Chandigarh, 160 012, India.

Manuscript received: March 5, 1999; Initial review completed: August 3, 1999; Revision accepted: January 31, 2000.

Objective: To determine the nutritional status and the extent of skeletal muscle wasting in children with acute lymphoblastic leukemia (ALL) at the time of diagnosis and after induction chemotherapy. Design: Prospective observational study. Setting: Tertiary care teaching hospital. Methods: 25 new cases of ALL underwent somatometric measurements and ultrasonographic evaluation of skeletal muscle and subcutaneous fat at initial presentation and after completion of induction therapy. Results: Malnutrition (weight for age <80%) was evident in 13 cases (52%), but cumulative incidence of malnutrition (weight for age <80%, weight for height <90%, height for age <95%, skin fold thickness <5th centile, midarm muscle circumference <5th centile) was 88%. Nine children lost weight during induction (range: 0.2-5.8 kg; means ± SD: 1.9 ± 1.8 kg). All these cases had a complicated course during induction chemotherapy. Fourteen children (56%) had skeletal muscle wasting during induction chemotherapy. All those children who had lost weight also had skeletal muscle wasting. Subcutaneous fat, in contrast increased in 24 cases (96%). Conclusion: Malnutrition exists in a significant proportion of children with ALL. If induction chemotherapy is complicated, children lose significant weight and have significant muscle wasting. Increase in subcutaneous fat occurs in almost all children, which is probably a consequence of therapy with oral steroids.

Key words: Acute lymphoblastic leukemia, Chemotherapy, Malnutrition.

Malnutrition is a common problem among children in developing countries. According to the National Nutrition Monitoring Bureau (NNMB-1989-90) only 10% of Indian children are normal (Gomez classification), while 8.7% are severely malnourished, 68.7% are under weight, 65.1% are stunted and 19.9% are wasted(1). The National Family Health Survey (NFHS) report (1992-93), which covers the whole country, showed an overall pre-valence of underweight as 53.4% with values for Punjab and Haryana being 46% and 37%, respectively(2).

Wasting occurs commonly in any disease state because skeletal muscle is the largest reservoir of protein(3). Malignant neoplasms may also cause and/or aggravate protein - energy malnutration (PEM). Children with cancer are often observed to be malnourished. The degree of malnutrition is likely to influence the pharamacokinetics of chemotherapeutic drugs and the host responses to therapy-related complications, such as infection. Although, some studies on these aspects are available from the developed world, there is scant information from India regarding the nutritional status of children with malignant disorders. Our study was designed to systematically assess nutri-tional status in children with acute lympho-blastic leukemia (ALL) at initial presentation and to determine the changes in body weight and the amount of skeletal muscle wasting after remission induction chemotherapy.

The study was carried out in children diag-nosed to have ALL who were admitted in the Hematology-Oncology Unit of the Advanced Pediatric Center, PGIMER, Chandigarh between January 1996 to April 1997. The study group comprised 25 children (18 males and 7 females), aged between 1 to 12 years. The diagnosis of ALL was established on the basis of standard investigations including blood counts and bone-marrow aspiration. Cases who had received chemotherapy prior to referral were excluded from the study.

Each subject was assessed for the following somatometric measurements using standard techniques and instruments(4). Body weight was measured with minimum undergarments using a platform type beam balance scale with an accuracy of 50 g. Stature (height-vertex) was measured using a Holtain stadiometer with an accuracy of 0.1 cm. Crown-heel length for children 1 to 12 years of age was measured using a Holtain supine length measuring table with an accuracy of 0.1 cm. Mid arm circum-ference was measured using a fiber glass measuring tape with an accuracy of 0.1 cm, as described by Jelliffe(5). Mid thigh circum-ference was measured with a fiber glass measuring tape mid-way between the greater trochanter and the knee joint line. Triceps skin-fold thickness was measured following the techniques given by Tanner and Whitehouse(4) using Holtain skinfold calipers with a dial calibrated to 0.2 mm.

Assessment of muscle mass was made by calculating mid upper arm muscle circum-ference using a formula devised by Jelliffe and Jellife(6) [C2 = C1 – p S, wherein C2 = mid upper arm muscle circumference, C1 = mid upper arm circumference, p = 3.1415 and S = Skin fold measurments (mean of biceps and triceps)].

Upper Arm Muscle Area (AMA) was cal-culated using a formula devised by Jelliffe and Jellife(6):

       (Ca – S)2
M=   –––––––    wherein M = arm muscle area, 
            4pi

Ca = upper arm circumference, p = 3.1415, S = mean of biceps and triceps skin fold thickness.

Quadriceps muscle thickness and mid-thigh subcutaneous fat thickness were measured by ultrasonography using real time scanner equipped with a 7.5 MHz transducer, display-screen, freeze-frame capacity. Electronic calipers were used to measure subcutaneous fat thickness and quadriceps muscle thickness. The thickness was measured at the mid point of the thigh using the technique described by Marie et al.(7).

Muscle index, which gives an estimate of the skeletal muscle protein pool in the body, was computed using the following formula:

                       QM2
Muscle Index = ––––  where QM = Quadriceps muscle thickness and S = Body surface area.
                         S

The body surface area was calculated by using a normogram based on weight and height measurements.

Body mass-index was calculated to assess the adiposity status:

                               Body weight (kg)
Body Mass Index = ––––––––––––––––
                               [(Height (meters)]2

The magnitude of intra/inter-rater error was assessed for every anthropometric measure-ment. It was found to vary between 0-50 g for body weight, 0-2 mm for stature and arm circumference,while it ranged between 0.02 mm for biceps and triceps skinfold thickness. Each of the anthropometric measurements were recorded thrice and the average was regarded as the final baseline data value.

These measurements were taken in children with ALL at the time of diagnosis, before initiating chemotherapy. Repeat measurements were carried out in these subjects after completion of induction chemotherapy which included weekly Vincristine 1.5 mg/m2, oral prednisolone 40 mg/m2 daily, alternate day L-asparaginase 6000 units m2 (´ 9 injections) and intrathecal methotrexate on days 0,14 and 28.

NCHS standards were used for weight and height. Tanner’s standards were taken for triceps skinfold thickness. Mid arm muscle circumference and mid arm muscle area were categorized in accordance with international standards given by Jelliffe(6). Wasting and stunting were defined in accordance with criteria outlined in Waterlow’s classification(8).

Statistical analysis was done using paired Students ‘t’ test for each of the absolute and generated body dimensions. Chi-square test with Yate’s correction was applied to quantify the magnitude of difference recorded in terms of per cent occurrence rates of malnutrition in relation to age groups, sex, disease status and complications during induction chemotherapy.

Of the 25 cases with ALL, 6 were in the age range of 1-4 years, 7 between 4 to 8 years and the remaining between 8-12 years. Six cases (24%) had TLC > 50 ´ 109/L and 11 (44%) cases had hepatosplenomegaly of more than 5 cm below the costal margins. Infection was the most important complication during the first 5 weeks of chemotherapy. Fifteen cases had febrile neutropenia, 2 had candida esophagitis and 7 patients had other complications.

Twenty-two (88%) of the 25 children had one or more abnormal somatometic parameter denoting malnutrition at initial presentation (Table I ). Six (24%) had isolated fat mal-nutrition (triceps skin fold thickness <5th centile). Two (9%) cases had evidence of acute malnutrition, i.e., wasting alone, 6 (27.2%) cases had chronic malnutrition (stunting alone). Eight patients (36.3%) had both wasting and stunting (height 87.5-95% of expected) . In patients with wasting, 7 had mild wasting (weight/height 80 to 90%) and 5 had moderate wasting (weight/height 70 to 80%). The mean duration of symptoms was 1.97 ± 1.52 months in the malnourished group (defined as weight for age <80%) whereas in the well nourished group it was 1.46 ± 0.9 months. (p > 0.05).

Changes in body composition after remission-induction chemotherapy are shown in Table II. Most of the patients (64%) gained weight but 9 children demonstrated a weight loss ranging between 0.2 to 5.8 kg with a mean (± SD) of 1.9 (± 1.8) kg. The latter cases had a complicated course during induction chemo-therapy (febrile neutopenia and/or bleeding manifestations, etc.). Fat, assessed anthro-pometrically and by USG, increased in almost all the cases (triceps skin fold thickness in 24 patients and mid thigh sub-cutaneous fat in 21 children). The mid-arm muscle circumference increased in 11 (44%) case, whilst a decrease was documented in all the patients who had manifest weight loss. Observations recorded by anthropometry and by USG, to document changes in body fat, and in muscle mass, were almost similar.

During induction 5 out of 12 children in the well nourished group and 9 of the 13 mal-nourished children had infection (Table III). This difference was of borderline statistical significance (p = 0.06).

All the children went into remission after induction chemotherapy. The follow-up dura-tion varied from 2.5 years to 3.5 years. Sustained first complete remission was documented in 7 out of 12 children in the well nourised group (defined as weight for age > 80%) and in 5 of the 13 malnourished children. The difference was not statistically significant (Table IV). Two malnourished children died during follow up due to treatment indiscipline (probable relapse) and status epilepticus, respectively. Relapse of disease was docu-mented in 3 malnourished children and in 2 in the well nourished group (bone-marrow : 2, isolated CNS : 2 and lymph nodes : 1) All 3 instances of extramedullary relapse were documented in the malnourished group.

Table I__Indices of Malnutrition at Presentation

Table II__ Changes in Body Composition After Induction Chemotherapy

* Significantly different from pre-chemotherapy (p <0.01).

Table III__Infection during Induction

* Malnutrition defined as weight for age <80%.

Table IV__Outcome in Follow-up

Relapse 3 2

* Malnutrition defined as weight for age <80%.

Malignancies contribute significantly to morbidity and mortality in the pediatric population. Malnutrition is a significant health problem in developing countries like India. This study was designed to find out the prevalence of malnutrition in children with acute leukemia and the effect of inudction chemotherapy on the nutritional status.

The weight for height method of assessing malnutrition can be erroneous in the presence of large intra-abdominal malignant disease. Arm anthropometry has been advocated for detecting malnutrition in childhood cancers(9,10). In our study, when weight for age was taken as criteria for assessing manutrition, only 52% of the patients with ALL had malnutrition. If arm anthropometry was included additionally, the cumulative prevalence of malnutrition rose to 88%. According to weight for age, 9 patients (36%) had mild and 4 (16%) had moderate degree of PEM. No child had severe degree of PEM. The prevalence of malnutrition (52%), in childhood ALL, based on the weight for age criteria was higher than the average prevalence (42%) of malnutrition in children in Punjab and Haryana(2).

Tamminga et al.(11) observed that at the time of diagnosis, weight, height, weight for height and mid-arm circumference were normal in all patients with ALL. A survey from Mexico had, however, shown that there was a high prevalence of malnutrition in acute lympho-blastic leukemia, wherein 21.2% of the patients evaluated had evidence of malnutrition(12). This figure was higher than the malnutrition rates in the population at large. It would be logical to presume that several children in areas where malnutrition is prevalent may have a borderline nutritional status, the balance would be tilted towards the malnutrition range because of the effects of the associated malignant disorder. Delbecque-Boussard et al.(12) showed that there is low intake of energy, carbohydrate, fat and protein in cases with ALL at the time of diagnosis.

There was an overall increase in the weight (mean increase of 0.29 kg) during chemo-therapy, but the increment was not significant (p >0.05). Nine cases had demonstrated an absolute loss of weight (range 0.2 kg to 5.8 kg). All had a complicated course during induction chemotherapy. Other workers(12,13) had also observed that there was no significant change in body weight during initial intensive chemotherapy in cases with ALL.

Cases with ALL receive 40 mg/m2 of oral prednisolone during the first 4 to 6 weeks of chemotherapy. Corticosteroids cause an increase in food intake which is related to the relief of symptoms and euphoric effects of steroids. A complicated course during induction (such as mucositis, gastrointestinal bleed, severe sepsis) can on the other hand, decrease the oral intake significantly and may be the cause of weight loss during induction chemotherapy.

There was a significant increase in triceps skin fold thickness and mid-thigh subcutaneous fat thickness (p <0.01). Koskelo et al.(13) made similar observations in cases with ALL. There was an increse of 33% in adipose tissue after 6 weeks of chemotherapy. But another study documented(12) no change in body composi-tion after 6 weeks of chemotherapy.

Corticosteroid therapy causes alteration in fat metabolism, which has a net effect of increase in body fat and redistribution of body fat causing truncal obesity. In our study also there was significant increase in skinfold thickness. This was inspite of the fact that 14 out of 25 cases (56%) had a complicated course during the first 6-8 weeks of chemotherapy. This increase in body fat is perhaps due to the effect of cortcosteroids.

There was only 0.2% decrease in the mid-arm muscle circumference, 0.01%. decrease in mid-arm muscle area, 0.02%. increase in quardriceps muscle thickness and 0.006% decrease in muscle index. A study(13) during chemotherapy in 14 cases with ALL showed a 27% decrease in muscle index. Another study(12) showed that there was no change in mid arm circumference and in fat free mass after 6 weeks of chemotherapy. We also found no significant change in mid arm circumference and in muscle mass.

Corticosteroids cause negative nitrogen balance in pharmacological doses, but this negative nitrogen balance may be prevented by large amounts of protein in diet. Our study has shown that there was no significant change in muscle mass. This may be due to large amounts of protein in diet in our cases, although we did not analyze the dietary intake of the cases.

The findings of our study highlight that malnutrition exists in a significant proportion of children diagnosed to have ALL. Patients with malnutrition and ALL had tendency for more infection related complications during initial chemotherapy in comparison to those with a normal nurtritional status. Further changes in muscle mass and body fat occur as a result of administration of chemotherapeutic drugs. These observations illustrate the need for evaluating the role of supplemental nutrition and the interplay between pharmacodynamics of chemotherapeutic agents and nutritional status.

Contributors: RK was responsible for data collection and helped in drafting the paper. RKM drafted the paper and was the guide, co-ordinator and main supervisor; he will act as guarantor for the study. AKB contributed in the anthropometric measurements and MG helped in the evaluation of body proportions by ultrasonography.

Funding: None.

Competing Interests: None stated.

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