Sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma: a report from a single institution

Abstract

Background

The incidence and background factors of sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma were not clear in Japan.

Methods

Between August 2018 and September 2019, we recruited adults aged ≥18 years who had childhood leukemia/lymphoma. Blood sampling, body composition measurement by bioelectrical impedance analysis and grip strength test were performed.

Results

Among 81 adult survivors (34 men and 47 women) with a median age of 25.0 years, 9 (11%) had sarcopenia and 10 (12%) had obesity, of whom, 3 had metabolic syndrome. Sarcopenia was observed in 7 (21%) of 33 survivors with hematopoietic stem cell transplantation (HSCT) and 2 (4%) of 48 survivors without hematopoietic stem cell transplantation (P = 0.012). The incidence of obesity was significantly higher in the cranial radiotherapy (P = 0.021) and non-transplanted cases (P = 0.042). Univariate logistic regression analysis revealed that hematopoietic stem cell transplantation for sarcopenia (odds ratio, 6.19; 95% confidence interval, 1.2–32.0; P = 0.03) and cranial radiotherapy for obesity (odds ratio, 5.6; 95% confidence interval, 1.4–22.4; P = 0.015) were significantly associated. Hypertension was more prevalent among the obese survivors, and higher transaminase levels were found more in both the sarcopenia and obese survivors than in others.

Conclusions

Young adult survivors of childhood leukemia/lymphoma could be at risk of developing sarcopenia after hematopoietic stem cell transplantation and obesity after cranial radiotherapy. Further studies are required to assess the body composition of long-term survivors to find detailed risk factors of sarcopenia and metabolic syndrome.

Introduction

The number of adult survivors with childhood cancer has been increasing as a result of treatment improvements (1,2). However, these survivors experience long-term comorbidities such as obesity, endocrine disorders and cardiac dysfunction due to anticancer treatment (3–6). Recently, abnormalities in body mass index (BMI) and body composition, especially decreased lean mass, have been described in survivors who had undergone hematopoietic stem cell transplantation (HSCT) in childhood (7–10).

The word ‘sarcopenia’ is unfamiliar in pediatrics; however, it has been attracting attention recently in aging societies. Sarcopenia is believed to be a phenomenon of aging and is accompanied by muscle mass reduction and muscle power weakness (11,12), which could induce not only glucose metabolism abnormality due to muscle mass reduction but also obesity (sarcopenic obesity) because of physical inactivity, causing metabolic syndrome (MS) as a negative chain (13,14). Secondary sarcopenia can be induced by cancer therapy (14,15). Marriott et al. reported that long-term survivors of acute lymphoblastic leukemia (ALL) often experience sarcopenic obesity, which adversely affects their quality of life, causing excessive adiposity and insufficient muscle mass (16).

Only few reports have described body composition abnormalities in Japanese survivors of childhood cancer (17); hence, this study was conducted to clarify the incidence and background factors of sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma.

Patients and methods

Children aged ≦15 years diagnosed as having leukemia or lymphoma were treated in accordance with the clinical practices of the Kyushu Yamaguchi Childhood Cancer Study Group and the Japanese Pediatric Leukemia Lymphoma Study Group (18–23). We performed HSCT for children with relapsed or refractory hematological malignancies (24,25), who were followed up after the end of the therapy. From this cohort, we registered patients who had completed treatment for childhood acute leukemia/lymphoma, were ≥18 years of age at the time of enrollment and provided written consent to participate in this study. At the regular clinic visit, blood sampling, body composition measurement, grip strength test, nutrition consultation and screen viewing time survey were performed after the routine physical examination.

Measurements of body weight and body composition

Body weight (kg), muscle mass (kg) and body fat percentage (%) were measured using the bioelectrical impedance analysis (BIA) method with a medical body composition analyzer (MC-780A-N, Tanita, Tokyo, Japan), which could measure the fat volume (kg), lean mass (kg), water content (kg) and estimated bone mass (kg). BMI was calculated as body weight (kg)/height (m)². A BMI of ≥25 kg/m² was defined as ‘obesity’, whereas BMI <18.5 and 18.5 ≥ but <25 kg/m² were considered ‘underweight’ and ‘healthy’, respectively, in this study. Lean mass comprised the whole muscle and estimated bone masses. The skeletal muscle masses (kg) of the upper and lower limbs were used as the corrected limb muscle mass, and the result obtained by dividing this by the square of height (m²) was considered the skeletal muscle mass index (SMI). SMIs of 7.0 and 5.7 kg/m² were designated as the cut-off values for sarcopenia in the men and women, respectively (26). The grip strength of both hands was measured twice using a grip strength dynamometer (GRIP-D, T.K.K.5401, Takei, Niigata, Japan), and the mean value was recorded as the grip strength.

Sarcopenia was defined when the grip strength was lower than the age-standardized value and SMI was below the cut-off value mentioned above. Sarcopenic obesity was diagnosed when both the obesity and sarcopenia criteria were simultaneously met (14,15).

Metabolic syndrome

If the waist circumference was ≥85 cm for men and ≥90 cm for women, and the following two or more criteria for MS were met (27), the patient was diagnosed as having MS:

1. triglyceride level ≥150 mg/dl and/or high-density lipoprotein cholesterol level <40 mg/dl;

2. systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg and/or

3. fasting hyperglycemia ≥110 mg/dl.

Clinical items collected from medical records

Data including the date of birth, diagnosis, date of the last chemotherapy and HSCT, chemotherapy protocol, cranial radiotherapy (CRT) and its total dose, surgery, preconditioning regimen for HSCT, acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), history of growth hormone therapy, thyroid hormone replacement therapy, other hormone replacement, body weight and height at diagnosis were collected as the clinical items. The measurement parameters included height, weight, blood pressure, waist circumference, blood biochemistry and blood count at the start of the study.

To compare the measurement results of the ALL survivors, they were divided into four groups according to their treatment patterns such as chemotherapy alone, chemotherapy with CRT and HSCT with total body irradiation (TBI) after chemotherapy with or without CRT. Similarly, in the comparison of the results of the patients with acute myeloid leukemia (AML), the patients were divided into three groups according to their treatment patterns such as chemotherapy, HSCT with TBI and HSCT without TBI after chemotherapy. One patient with ALL and one with AML were excluded from the comparison because their treatment pattern only consisted of HSCT without TBI after chemotherapy with CRT.

Statistical analysis

The patients’ characteristics were summarized using descriptive statistics or contingency tables. The distributions of the three BMI values were compared according to HSCT or chemotherapy by using a Fisher exact test. The background factors were compared between the patients with sarcopenia, obesity and other conditions by using a univariate logistic regression analysis. Each laboratory examination result was compared between the patients with sarcopenia, obesity and other conditions. For the continuous variables, a t-test was used to compare the mean values between the three groups. For the nominal variables, a statistically significant difference was detected using a χ² test. Easy R for medical statistics (EZR; http://www.jichi.ac.jp/saitama-sct) was used as the statistical analysis software (28).

Results

Among the 111 survivors of childhood leukemia or lymphoma who were aged ≥18 years and visited our institution between September 2018 and September 2019, 34 men and 47 women (58%) participated in this study after providing written consent. The characteristics of all the 81 survivors are shown in Table 1. The median and mean ages at the time of the study were 25.0 and 27.3 years (18–19 years, 9%; 20–29 years, 58%; 30–39 years, 26% and 40 years, 7%), respectively. All the patients were of Japanese origin. The most common diagnosis was ALL (51, 63%), followed by acute myeloid leukemia (20, 25%) and lymphoma (10, 12%; one Hodgkin lymphoma and nine non-Hodgkin lymphoma). Twenty-two patients (27%) had a history of CRT, and 33 (41%) underwent HSCT. Of the 81 survivors, 9 (11%) had sarcopenia and 10 (12%) had obesity, of whom, 3 had MS.

The BMI of sarcopenic survivors was underweight (<18.5) in six and healthy (18.5 ≥ but <25) in the remaining three, with no sarcopenic obesity. Table 2 shows the background factors of sarcopenia. Mean age at the study and interval from the therapy completion of survivors with sarcopenia were 31.9 and 22.8 years, which were higher than those without sarcopenia (P = 0.031, 0.048). Sarcopenia was observed in 7 (21%) of 33 patients with HSCT and in 2 (4%) of 48 patients without HSCT (P = 0.012). By performing a univariate logistic regression analysis of the background factors of sarcopenia, we found that HSCT had an odds ratio of 6.19 (95% confidence interval, 1.2–32; P = 0.03) for sarcopenia. Among the 33 patients who underwent HSCT, sarcopenia was diagnosed in 7 (33%) of 21 patients who received preconditioning with TBI, but not in those without TBI (P = 0.032). We found no significant difference in the number of sarcopenia cases according to sex, donor and graft types, aGVHD grade and cGVHD type.

Obesity was significantly more common in the CRT cases (P = 0.021) and non-transplanted cases (P = 0.012; Table 3). In the univariate logistic regression analysis of the background factors of obesity, CRT had an odds ratio of 5.8 (95% confidence interval, 1.4–22.4; P = 0.015) for obesity. A multivariate analysis of the background factors of sarcopenia or obesity could not be performed owing to the small number of participants. We found no significant difference in the number of obese cases according to gender and diagnosis.

Mean z-scores of body weight, height, BMI and muscle mass were significantly lower in the survivors who had undergone HSCT than in those who had had not (P = 0.002, <0.001, 0.005 and < 0.001, respectively; Table 1); however, no significant difference in body fat percentage was found between the patients with and those without HSCT for both men and women.

In the comparison of the measurement results of the survivors of ALL (Table 4), they had a lower BMI z-score, a lower muscle mass, weaker male grip strength and a higher frequency of hypertriglyceridemia in the HSCT with TBI group. The survivors of AML tended to have a lower muscle mass, weaker male grip strength and a higher frequency of high transaminase levels in the HSCT with TBI group (Supplementary Table S1).

The comparison of the selected measurement results among the patients with sarcopenia, obesity and others is shown in Table 5. The incidence of hypertension was higher in the patients with obesity and those of obesity and sarcopenia were higher in the patients with high transaminase levels. Total cholesterol and triglyceride levels were not significantly different among the three categories.

Discussion

The percentages of obese and underweight young adult survivors of pediatric leukemia/lymphoma were 12 and 22%, respectively, in this study. Of the 81 survivors with a median age of 25 years, 9 (11%) had sarcopenia, but none had sarcopenic obesity. HSCT is a background factor of sarcopenia, and CRT is a background factor of obesity; both of these associations have been previously reported (5–10).

In pediatric ALL survivors, another Japanese study that used the same chemotherapy protocols reported an obesity prevalence of 5% (29), while the incidence rates of obesity were reported to range from 34 to 46% from the West (30,31). One of the reasons for the low incidence of obesity after ALL treatment in our cohort might be that the treatment protocol did not include dexamethasone until the early 1990s (18,19,32). CRT was famous as a risk factor of obesity in childhood ALL (30,31), and CRT at a young age could increase the risk of obesity. However, a recent meta-analysis based on 20 studies mostly from Europe and the USA (31) found a high prevalence of obesity in ALL survivors regardless of the survivor’s receipt of CRT, sex or age at diagnosis.

Among AML survivors, the incidence of obesity was 61.8% in the chemotherapy cases in the St. Jude’s Lifetime Cohort study (6). The number of obesity cases was as small as 1 (5%) in 20 patients among the AML survivors in our study, which is partly due to the fact that 15 of the 20 patients had undergone HSCT. However, US data showed that even among patients in the HSCT group, nearly 50% were obese and >30% of their siblings were obese. According to international epidemiological data (33), adult obesity rates are highest in the USA (38.2%) and lowest in Japan (3.7%). Differences in obesity rates according to race and social environment may influence the differences in patient obesity rates in both patients with ALL and those with AML.

The proportion of underweight patients among HSCT survivors, including 76.1% of all hematological malignancies, was reported to be ≥40% in Japan (7). The BMI z-score of the patients who received HSCT in our study was −0.56, and the proportion of those who were underweight was 30%. The incidence of underweight in HSCT survivors might depend on the proportions of the leukemia types and cases with TBI (10). Muscle loss was also observed during chemotherapy for childhood ALL (34,35). Severe infection and prolonged hospitalization can exacerbate muscle loss (34). Reduced growth hormone and gonadal levels due to TBI have been reported as one of the main causes of muscle mass loss (36,37). Although no statistically significant difference was found, the involvement of cGVHD cannot be ruled out (7,8,10), as half of the patients with extensive cGVHD had sarcopenia, and the frequency of hyper-transaminase was high in the survivors with sarcopenia. Combined non-alcoholic fatty liver and sarcopenia has been reported to increase the risk of cardiovascular disease (38). Fatty liver and muscle loss should be evaluated in the follow-up of long-term survivors, especially in those who are underweight.

A multi-frequency segmental body composition analyzer with BIA can be widely used as a tool for evaluating the body composition and muscle mass of not only cancer survivors but also healthy controls (39) owing to its simple measurement operation and almost no risk of radiation exposure. Improving the specifications to be used by small children (40) and developing reference data for children are desirable.

This study has several limitations. First, the number of cases was so small that we could not perform a multivariate analysis to assess the risk factors of sarcopenia and obesity. Second, the study had no healthy control cohort.

In conclusion, young adult survivors with childhood leukemia/lymphoma may have risks of developing sarcopenia, obesity and MS. Further large-scale studies in Japan on the body composition of long-term survivors of childhood cancers are required to provide better understanding of the late effects of cancer and support to cancer survivors.

Acknowledgments

The authors thank all the survivors for participating in this study and the nursing staff of the outpatient follow-up department for their cooperation. We also thank Ms Tomoko Sugimoto for collecting the data. The authors would like to thank Enago (www.enago.jp) for the English language review.

Funding

The authors declare that they received no funding for the study.

Conflict of interest statement

None declared.

Declarations

Ethics approval

This study had been titled, ‘Body weight and body composition among childhood leukemia/lymphoma survivors’, and the ethics committee of Kyushu Cancer Center approved it on 30 July 2018 (Certification no. 2018-36).

Informed consent

We registered patients who provided written consent to participate in the study.

Presentation

N.H. presented the main content of this study in the oral session by the WEB system at the 62nd annual meeting of the Japanese Pediatric Hematology/Oncology, 20 November 2020.

Authors’ contributions

H.N., M.N., R.F., M.S. and J.O. designed the study and recruited the patients. S.T. and her colleagues measured and recorded body weight and body composition. K.Y. and his colleagues made nutritional assessments. M.N. and her colleague nurse recorded the results of and handgrip strength test. H.N. and M.S. performed the data analysis. H.N. wrote the draft of the manuscript. T.U., M.N. and J.O. revised the tables. All authors revised and approved the final version of the manuscript.

References