Abstract
Impaired linear growth is an important morbidity in childhood cancer survivors (CCS); however, chemotherapy-associated factors that affect height outcomes remain elusive. Accordingly, we conducted a single-center, retrospective cohort study that included survivors of childhood-onset acute lymphoblastic leukemia (ALL) diagnosed between 2002 and 2021 who achieved complete remission through chemotherapy alone. Anthropometric parameters and treatment protocols were evaluated based on medical records. Individuals with background disorders or impaired growth were excluded from the study. Associations between anthropometric parameters during chemotherapy and height standard deviation scores (height-SDS) at the current visit were investigated. The results are expressed as the median (interquartile range). Seventy-three individuals (males, N = 44) were included in the study. The median age (years) at diagnosis, end of chemotherapy, and current visit were 4.2 (3.2 to 7.9), 6.3 (5.1 to 10.0), and 15.9 (11.4 to 19.2), respectively. Height-SDS at diagnosis was –0.25 (–0.65 to 0.35), which significantly declined during chemotherapy and recovered thereafter, resulting in a current height-SDS of –0.31 (–0.84 to 0.22). The height-SDS at the investigated time points and its changes during chemotherapy did not differ among the treatment protocols. Multivariate analysis revealed that height-SDS at the current visit was positively associated with changes in body mass index (BMI)-SDS during chemotherapy (β = 0.22, p = 0.01) after adjusting for sex, current age, height-SDS at diagnosis, changes in height-SDS during chemotherapy, and treatment protocols. Since changes in BMI are potentially influenced by nutritional status, our results may underscore the importance of nutritional status during chemotherapy on height outcomes in childhood ALL survivors.
Introduction
Recently, the prognosis of childhood cancer patients has significantly improved, with an estimated 5-year survival rate exceeding 80% in developed countries [1-5]. Nevertheless, many individuals who experienced cancer treatment during childhood, known as childhood cancer survivors (CCS), still face an increased risk of various morbidities, including endocrinological and metabolic disorders, which is attributable to the sequelae of the disorder itself and/or cancer treatments such as chemotherapy (CHT) and radiotherapy [6, 7].
Impaired linear growth is an important complication of CCS, with a frequency ranging from approximately 9% to 40% depending on the underlying disease type [7, 8], and often results in a short adult height. Previous studies have shown that hypothalamic and/or pituitary tumors, surgical procedures involving this area, and craniospinal radiation therapy are associated with short stature in CCS [9]. Additionally, there is evidence to demonstrate that the height standard deviation score (SDS) declines during CHT, indicating that CHT-related factors may have a significant impact on height outcome [10-13]; however, the factors during CHT that influence height outcome are not well clarified.
Emerging evidence underscores the importance of nutritional status during CHT, with suboptimal nutritional status associated with various outcomes, including treatment response, quality of life, and mortality [14-18]. Since there is concrete evidence to show an association between nutritional status and linear growth [19], we speculated that suboptimal nutritional status during CHT is potentially linked to impaired height outcomes in CCS; however, there has been limited evidence on this issue.
To test this hypothesis, we assessed changes in BMI during CHT and its association with height outcome, because anthropometric parameters, including BMI, have long been recommended for assessing nutritional status in childhood cancer patients during treatment [20-22]. However, BMI is also affected by the use of steroids as a chemotherapeutic agent as well as long-term bedridden status, both of which vary among therapeutic protocols for ALL. Therefore, we included the therapeutic protocols as a confounding variable in the statistical analysis. Additionally, we included only childhood ALL survivors treated with CHT alone to minimize the effect of variations in therapeutic strategies, such as radiation, on the findings of the study.
Materials and Methods
Ethical considerations
This study was approved by the Ethical Committee of Osaka Women’s and Children’s Hospital (Approval No. 1621). The opt-out recruitment method was applied with permission from the Ethics Review Board.
Subjects
We conducted a retrospective examination of medical records from Osaka Women’s and Children’s Hospital, focusing on patients with childhood-onset ALL diagnosed between 2002 and 2021. Individuals with T-ALL were not included. To minimize differences in therapeutic regimens, we specifically included patients with ALL diagnosed before the age of 15 years, excluding those treated with hematopoietic stem cell transplantation and/or radiation therapy. Individuals who reached adult height, defined as an annual height increase of <2 cm, at the time of ALL diagnosis were excluded. Individuals diagnosed with ALL before the age of 2 years were also excluded because of the challenges in obtaining standing height data. Accordingly, the study included 73 participants, including 44 males and 29 females, in which no patients had known growth-retarding disorders such as trisomy 21, growth hormone deficiency, or hypogonadism.
All patients were treated according to the JACLS (Japan Association of Childhood Leukemia Study Group) ALL-02 protocol (Table 1) [23]. The protocol adopted repeated intrathecal (IT) therapies instead of prophylactic irradiation, and only patients with initial central nervous system (CNS) involvement were treated with therapeutic irradiation. Therefore, patients with CNS involvement were excluded from the study. The protocol stratified non-T-cell ALL patients into standard-risk (SR), high-risk (HR), and extremely high-risk (ER) groups based on age, initial white blood cell count, and initial response to prednisolone. Although the original protocol adopted two and three administrations of THP-adriamycin (25 mg/m2) during the induction phase in the SR/HR and ER protocols, respectively, the treatment dose was slightly reduced to 20 mg/m2 in June 2005, and THP-adriamycin in induction therapy has been replaced by two administrations of daunorubicin (30 mg/m2) in all three courses of induction therapy since 2009. Based on the results of bone marrow examinations to assess treatment response, individuals who did not achieve hematological complete remission or exhibited residual disease detectable through laboratory tests were reclassified into a higher risk group. One patient was initially treated with the HR protocol, but was switched to the ER protocol due to findings from a bone marrow examination at the end of induction treatment. However, after the confirmation of the disappearance of minimal residual disease in the bone marrow, the patient was switched back to the HR protocol. Consequently, this patient received additional chemotherapy, including etoposide (100 mg/m2/day for 5 days), cytarabine (300 mg/m2/day for 5 days), cyclophosphamide (1,200 mg/m2/day for 1 day), and THP-adriamycin (25 mg/m2/day for 2 days). Since no additional steroids were administered, this patient was classified into the HR group in this study. The doses of chemotherapeutic agents listed in Table 1 were stated based on the current protocol; therefore, it may not necessarily represent the actual dosage used for individual patients.
Table 1 Treatment duration and cumulative dosage of the chemotherapeutic drugs in the JACLS 02 protocol
|
Standard-Risk (N = 22) |
High-Risk (N = 44) |
Extremely High-Risk (N = 7) |
| Duration of CHT, weeks |
102 |
98 |
108 |
| Corticosteroids |
| Predonisolone, treatment duration (dosage) |
195 days (7,625 mg/m2) |
153 days (5,945 mg/m2) |
167 days (6,505 mg/m2) |
| Dexamethasone, treatment duration (dosage) |
12 days (120 mg/m2) |
17 days (170 mg/m2) |
13 days (670 mg/m2) |
| Hydrocortisone (IT), mg/body* |
275 |
350 |
350 |
| Chemotherapeutics |
| Cyclophosphamide, mg/m2 |
1,500 |
7,600 |
8,200 |
| THP-adriamycin, mg/m2 |
50 |
250 |
350 |
| Daunorubicin, mg/m2 |
60 |
60 |
60 |
CHT: chemotherapy, IT: intrathecal injection
*The dosage of hydrocortisone is reduced by 20–40% in patients younger than 3 years old.
The doses of chemotherapeutic agents were stated based on the current protocol.
We measured the height of patients in a standing position using a stadiometer and the weight using a digital scale. BMI was calculated by dividing weight (kg) by height squared (m2). Anthropometric parameters, including weight and height, were recorded at three key time points: diagnosis of ALL, end of CHT, and the current visit. Among the participants, 40 patients (21 males and 19 females) achieved adult height. For those who reached adult height or were older than 17.5 years, we used the sex-matched mean and standard deviation (SD) at 17.5 years old to calculate the SDS for height, weight, and BMI. In contrast, for those who did not reach adult height, the height-SDS, weight-SDS, and BMI-SDS were determined based on the normal growth standards for Japanese children from a national survey in 2000 [24, 25].
Statistical analysis
Values are presented as medians with interquartile ranges (IQR). We used Kruskal-Wallis test for group comparisons. The Wilcoxon signed-rank test was used to compare changes in height and BMI-SDS in each group. Factors influencing the current height-SDS were assessed through correlation analysis using the Spearman’s rank correlation coefficient. Additionally, multiple regression analysis was conducted with adjustment for variables, as specified in the text. Any potential multicollinearity was evaluated using the variance inflation factor (VIF). If none of the VIFs exceed 10, collinearity is not considered problematic. Statistical significance was set at p < 0.05. Statistical analyses were performed using EZR software version 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).
Result
Characteristics of Subjects
The clinical characteristics of the 73 patients are presented in Table 2. The median age at ALL diagnosis was 4.2 years (IQR: 3.2 to 7.9), ranging from 2.0 to 14.7 years. The age at the end of CHT was 6.3 years (IQR: 5.1 to 10.0), with a median CHT duration of 2.0 years (IQR: 2.0 to 2.1). At the current visit, the median age was 15.9 years (IQR: 11.4 to 19.2), and 40 patients reached adult height. The median follow-up period after CHT cessation was 7.6 years (IQR: 2.9 to 12.2).
Table 2 Characteristics of subjects
|
Total |
Non-adult height |
Adult height |
| Number (M/F) |
73 (44/29) |
33 (23/10) |
40 (21/19) |
| At diagnosis |
| Age, year |
4.2 (3.2 to 7.9) |
3.7 (3.1 to 4.8) |
7.2 (3.4 to 9.5) |
| Height-SDS |
–0.25 (–0.65 to 0.35) |
–0.35 (–0.74 to 0.35) |
–0.07 (–0.61 to 0.31) |
| BMI-SDS |
–0.12 (–0.88 to 0.55) |
–0.02 (–0.73 to 0.49) |
–0.20 (–1.11 to 0.57) |
| At the end of CHT |
| Age, year |
6.3 (5.1 to 10.0) |
5.8 (5.1 to 6.9) |
9.2 (5.4 to11.7) |
| Height-SDS |
–0.57 (–0.93 to –0.04)* |
–0.45 (–0.93 to 0.21) |
–0.66 (–0.90 to –0.18)* |
| BMI-SDS |
0.39 (–0.16 to 0.93)† |
0.49 (0.09 to 0.94)†† |
0.24 (–0.20 to 0.84)† |
| ΔHeight during CHT, cm |
11.9 (9.6 to 13.4) |
12.7 (11.6 to 13.6) |
11.0 (8.6 to 12.5) |
| ΔWeight during CHT, kg |
5.6 (4.1 to 8.0) |
5.2 (4.0 to 6.4) |
6.2 (4.2 to 10.1) |
| ΔBMI during CHT, kg/m2 |
1.4 (0.1 to 2.2) |
1.1 (0.2 to 1.8) |
1.8 (0.1 to 3.4) |
| ΔHeight-SDS during CHT |
–0.23 (–0.58 to –0.03) |
–0.12 (–0.23 to 0.17) |
–0.42 (–0.72 to –0.20) |
| ΔWeight-SDS during CHT |
1.35 (0.13 to2.22) |
1.09 (0.15 to 1.82) |
1.76 (0.06 to 3.40) |
| ΔBMI-SDS during CHT |
0.52 (–0.04 to 1.1) |
0.55 (0.14 to 0.97) |
0.50 (–0.09 to 1.1) |
| Duration of CHT, year |
2.0 (2.0 to 2.1) |
2.0 (2.0 to 2.1) |
2.0 (2.0 to 2.2) |
| At the current visit |
| Age, year |
15.9 (11.4 to 19.2) |
10.5 (7.3 to13.5) |
19.1 (17.5 to 22.0) |
| Height-SDS |
–0.31 (–0.84 to 0.22)‡ |
–0.18 (–0.64 to 0.40) |
–0.48 (–0.93 to 0.09) |
| BMI-SDS |
–0.02 (–0.75 to 0.69)§ |
0.24 (–0.20 to 0.72)§§ |
–0.34 (–1.08 to 0.56)§§ |
| Duration after CHT, year |
7.6 (2.9 to 12.2) |
2.9 (0.9 to 6.9) |
11.6 (7.5 to 14.0) |
Data are expressed as the median (interquartile range).
BMI: body mass index, CHT: chemotherapy
*: p < 0.001 vs. height-SDS at diagnosis, by Wilcoxon signed-rank test.
†: p < 0.001, ††: p < 0.01 vs. BMI-SDS at diagnosis, by Wilcoxon signed-rank test.
‡: p < 0.05 vs. height-SDS at the end of CHT, by Wilcoxon signed-rank test.
§: p < 0.001, §§: <0.01 vs. BMI-SDS at the end of CHT, by Wilcoxon signed-rank test.
At diagnosis, the median height-SDS and BMI-SDS were –0.25 and –0.12, respectively. During CHT, height-SDS significantly declined [–0.23 (IQR: –0.58 to –0.03)], whereas it showed a significant increase after CHT (Table 2). This resulted in a difference in height-SDS between diagnosis and the current visit of –0.10 (–0.49 to 0.16) (p = 0.075). In contrast, BMI-SDS showed a significant increase during CHT, followed by significant decline thereafter (Table 2). Two individuals in the HR group had a BMI-SDS over 2.0 at the end of CHT, while another two had a BMI-SDS below –2.0.
The scatter plots assessing the association between changes in BMI (ΔBMI) and those in height (Δheight) or weight (Δweight) during CHT are shown in Fig.1. ΔBMI and ΔBMI-SDS was strongly associated with Δweight and Δweight-SDS, respectively (Fig. 1A). However, their associations with Δheight or Δheight-SDS were weaker than with Δweight or Δweight-SDS, respectively (Fig. 1B), indicating that changes in BMI during CHT are less influenced by height gain impairment than by changes in weight.
Therapeutic regimens are not associated with height outcomes in childhood ALL survivors
We next investigated the association between therapeutic regimens and height outcomes. As shown in Table 1, the duration of prednisolone and dexamethasone treatment was the longest in the SR and HR group, respectively, while the dexamethasone dosage was the highest in the ER group. While the age at diagnosis did not differ among the three groups, the duration of CHT was significantly longer in the ER group than in the HR and SR groups (Table 3). The age at the current visit and the follow-up duration after CHT were not significantly different among the three groups. Height-SDS significantly declined during the CHT in the SR and HR groups. Although the difference was not statistically significant, the same trend was observed in the ER group. Δheight-SDS during CHT did not differ among the three groups. The height-SDS at the end of CHT or at the current visit did not show any significant differences among the three groups.
Table 3 Changes in anthropometric parameters according to therapeutic regimen
|
Standard-Risk (N = 22) |
High-Risk (N = 44) |
Extremely High-Risk (N = 7) |
p-value (among 3 groups ) |
| At diagnosis |
Age, year |
4.9 (3.6 to 7.7) |
3.8 (3.0 to 7.9) |
4.8 (3.7 to 8.6) |
ns |
| Height-SDS |
0.00 (–0.65 to 0.34) |
–0.30 (–0.75 to 0.35) |
–0.12 (–0.50 to 0.16) |
ns |
| BMI-SDS |
0.07 (–0.64 to 0.66) |
–0.16 (–1.06 to 0.55) |
–0.39 (–0.81 to 0.22) |
ns |
| At the end of CHT |
Age, year |
7.0 (5.6 to 9.7) |
5.8 (4.9 to 10.1) |
6.9 (5.9 to 10.7) |
ns |
| Height-SDS |
–0.46 (–0.81 to 0.01)** |
–0.60 (–1.16 to –0.08)* |
–0.65 (–0.68 to 0.07) |
ns |
| BMI-SDS |
0.41 (–0.09 to 1.38)† |
0.26 (–0.21 to 0.75)† |
0.43 (0.31 to 0.89)†† |
ns |
| ΔHeight during CHT, cm |
11.75 (10.20 to 12.55) |
11.90 (9.50 to 13.40) |
13.60 (10.00 to 15.40) |
ns |
| ΔWeight during CHT, kg |
5.55 (4.70 to 7.93) |
5.23 (3.73 to 7.80) |
8.60 (5.30 to 15.13) |
ns |
| ΔBMI during CHT, kg/m2 |
1.55 (–0.03 to 2.46) |
1.14 (0.06 to 1.92) |
1.52 (0.39 to 4.60) |
ns |
| ΔHeight-SDS during CHT |
–0.21 (–0.56 to 0.02) |
–0.23 (–0.49 to –0.09) |
–0.17 (–0.59 to 0.15) |
ns |
| ΔWeight-SDS during CHT |
0.17 (–0.13 to 0.83) |
0.20 (–0.31 to 0.56) |
0.60 (0.23 to 0.90) |
ns |
| ΔBMI-SDS during CHT |
0.49 (0.12 to 0.99) |
0.50 (–0.09 to 1.10) |
0.82 (0.30 to 1.57) |
ns |
| Duration of CHT, year |
2.0 (2.0 to 2.1) |
2.0 (2.0 to 2.1) |
2.1 (2.1 to 2.2) |
<0.05 |
| At the current visit |
Age, year |
16.1 (12.0 to 18.4) |
16.6 (10.3 to 20.6) |
14.7 (13.8 to 18.8) |
ns |
| Height-SDS |
–0.06 (–0.65 to 0.43) |
–0.48 (–0.99 to 0.15) |
–0.24 (–0.40 to 0.10) |
ns |
| BMI-SDS |
0.12 (–0.66 to 0.72)‡ |
–0.19 (–0.85 to 0.59)‡ |
0.38 (–0.11 to 0.54) |
ns |
| Height-SDS deficit from diagnosis |
–0.23 (–0.49 to 0.26) |
–0.10 (–0.51 to 0.15) |
–0.09 (–0.30 to 0.13) |
ns |
| Duration after CHT, year |
8.0 (3.6 to 11.4) |
7.0 (2.1 to 12.9) |
7.6 (6.7 to 8.3) |
ns |
Data are expressed as the median (interquartile range).
Group comparison were performed using Kruskal-Wallis test.
BMI: body mass index, CHT: chemotherapy, ns: not significant
*: p < 0.001, **: p < 0.01 vs. height-SDS at diagnosis, by Wilcoxon signed-rank test.
†: p < 0.01, ††: p < 0.05 vs. BMI-SDS at diagnosis, by Wilcoxon signed-rank test.
‡: p < 0.01 vs. BMI-SDS at the end of CHT, by Wilcoxon signed-rank test.
Next, we explored the association between ΔBMI-SDS during CHT and height outcome. Although the Spearman’s rank correlation coefficient failed to demonstrate a significant association between ΔBMI-SDS during CHT and height-SDS at the current visit (Table 4), multivariate analysis revealed that current height-SDS was associated with ΔBMI-SDS during CHT (β = 0.22, p = 0.01), independent of height-SDS at diagnosis (β = 0.90, p < 0.0001) and Δheight-SDS during CHT (β = 0.27, p < 0.001), after adjustment with sex, current age, and treatment protocol (Table 5). We also assessed associations between Δweight-SDS during CHT and height outcome and found that current height-SDS was positively associated with Δweight-SDS during CHT (β = 0.20, p = 0.01) after adjustments for sex, current age, and the treatment protocol. VIF was less than 2.0 in all models, indicating multicollinearity was not a serious issue.
Table 4 Univariate analysis of associations between current height-SDS and anthropometric parameters (
N = 73)
|
Total (N = 73) |
| rS |
p-value |
| Age |
| At diagnosis |
0.03 |
0.79 |
| At the end of CHT |
0.04 |
0.72 |
| Current Age |
–0.12 |
0.32 |
| Height-SDS |
| At diagnosis |
0.77 |
<0.0001 |
| At the end of CHT |
0.78 |
<0.0001 |
| BMI-SDS |
| At diagnosis |
0.06 |
0.59 |
| At the end of CHT |
0.11 |
0.38 |
| Current Age |
0.19 |
0.10 |
| ΔHeight-SDS during CHT |
0.04 |
0.73 |
| ΔBMI-SDS during CHT |
0.06 |
0.62 |
rS: Spearman’s correlation coefficient
CHT: chemotherapy, BMI: body mass index
Table 5 Multivariate analysis of associations between current height-SDS and anthropometric parameters (
N = 73)
|
STB* |
p-value |
| Age at diagnosis |
0.11 |
0.23 |
| Height-SDS at diagnosis |
0.90 |
<0.0001 |
| BMI-SDS at diagnosis |
–0.07 |
0.42 |
| ΔHeight-SDS during CHT |
0.27 |
<0.001 |
| ΔBMI-SDS during CHT |
0.22 |
0.01 |
*: adjustment for sex, current age, and treatment protocol
STB: standardized β, BMI: body mass index, CHT: chemotherapy
Discussion
Growth impairment and short adult height are common comorbidities in CCS. Demoor-Goldschmidt et al. demonstrated that 9.2% of CCS experienced short adult height, identifying young age, small height at diagnosis, pituitary irradiation, and busulfan use as independent risk factors in a French CCS population [8]. In addition to these factors, there is evidence to show that individuals treated with CHT alone also showed a deficit in adult height. When comparing adult height to the height at ALL diagnosis in individuals treated with CHT alone, a decline in height-SDS was documented in previous publications as follows: –0.59 ± 0.86 [12], –0.49 ± 0.14 [26], and –0.30 ± 0.14 [27], although the decline in height-SDS of –0.10 (IQR: –0.49 to 0.16) between at diagnosis and the current visit did not reach statistical significance in our study (p = 0.075).
The mechanism underlying the reduced height outcome in these populations remains largely unclear, although evidence suggests that height-SDS declines during CHT, followed by suboptimal catch-up growth. For instance, Browne et al. reported partial catch-up growth after a significant decrease in height z-scores during CHT in most cases [28]. Similarly, Touyz et al. documented a substantial decline in height-SDS during treatment, with no recovery observed even seven years after treatment completion [29]. The mechanisms of impaired catch-up growth following the completion of CHT remain elusive. However, given the well-established association of prolonged corticosteroid use and suboptimal nutritional status during childhood with shorter adult height in other conditions [30, 31], the prolonged use of corticosteroids and inadequate nutrition during CHT is unlikely compensated for by the removal of the underlying causes.
To understand the factors that affect impaired height growth during CHT, we first assessed the influence of the therapeutic protocol on height because the dosage of glucocorticoids, which causes growth impairment [32], differs among protocols. Consistent with previous reports [12, 28, 29], our study showed that height-SDS declined during CHT, irrespective of the protocol; however, ∆height-SDS during CHT did not exhibit significant differences among protocols, which indicates that therapeutic regimens are unlikely to be the determining factors for height outcomes in childhood ALL survivors. In line with our results, Browne et al. reported a lack of differences in height-SDS between low-risk and standard/high-risk patients four years after the completion of CHT [28]. However, it is important to note that the corticosteroid dosages used in their study differ significantly from those in our protocols. In their research, the total dosage of prednisolone was 1,120 mg/m2 across all protocols, while the total dosages of dexamethasone were 1,704 mg/m2 for males and 1,464 mg/m2 for females in the low-risk protocol, and 2,436 mg/m2 for males and 2,076 mg/m2 for females in the standard/high-risk protocols [28]. Additional significant differences among the current study protocols include the doses of cyclophosphamide and THP-adriamycin; however, there has been extremely limited evidence showing the deleterious influence of these chemotherapeutics on linear growth, although the use of alkylating agents may have impaired the height outcome [8]. These results suggest that the dose of corticosteroids used even in the low-risk protocol is already sufficient to impair linear growth during CHT, and that the differences in therapeutic protocols may have minimal impact on height outcome in childhood ALL survivors.
Since nutritional status during CHT affects the outcomes of CCS [14-16, 33], we assessed ∆BMI-SDS during CHT and its association with height outcome, because BMI has been used to assess nutritional status in childhood cancer patients during treatment [20-22]. BMI-SDS increased during CHT in the present study and this was consistent with previous studies [13, 34], despite the treatment protocols differing from those in the present study. In a study by Bruzzi et al., the authors reported that, among 162 children with ALL, BMI-SDS increased from a mean of 0.15 to 0.58 [13]. Similarly, Egnell evaluated BMI-SDS in 756 children with ALL and found that BMI-SDS increased by 0.64 during ALL treatment [34]. Multivariate analysis revealed that ∆BMI-SDS during CHT had a significantly positive correlation with height outcome, independent of height-SDS at diagnosis and Δheight-SDS during CHT, potentially highlighting the importance of nutritional status during CHT on height outcome. Nevertheless, the use of BMI as a marker for nutrition may be challenging since BMI can be affected by growth suppressive effect of corticosteroid; therefore, we investigated the association between changes in BMI and weight or height, and found that changes in BMI during CHT are less influenced by height gain impairment than by changes in weight. Additionally, we confirmed in the statistical analysis that multilineality was not an issue in this model. Thus, the current results likely suggest that changes in BMI during CHT are an important determinant of height outcome in childhood ALL survivors. Although additional analyses with the inclusion of markers for nutritional status are required, the current result may underscore the important role of nutritional status during CHT on height outcome in childhood ALL survivors.
The current study has several limitations. First, target height-based analysis was not performed in this study. Since adult height-SDS has been significantly associated with target height, the lack of this information may have caused bias in the interpretation of the results. Second, adult height data were only available for 54.8% of the participants. As adult height is affected by the starting age of puberty, the results of the current study may have been biased since pubertal status was not incorporated in the study design. However, no subjects with gonadal insufficiency were included; hence, we believe that there is minimal influence of the lack of adult height on the conclusions of this study. Third, we used ΔBMI-SDS as a marker of nutritional status. Since changes in BMI do not necessarily reflect nutritional status, the results obtained may have been affected by factors other than nutritional status, such as the use of corticosteroids and immobility; however, due to the retrospective nature of the study, additional assessment of nutritional status, such as nutritional interview and/or mid-upper arm circumference and triceps skinfold thickness, was not conducted.
In conclusion, our study provides evidence that changes in BMI-SDS during CHT are positively associated with height outcomes in childhood ALL survivors treated with CHT alone (Graphical Abstract). Despite the limitations of the current study, particularly the lack of indices that directly assess nutritional status, the current results may shed light on the previously underrecognized association between nutritional status during CHT and height outcome, which can prove valuable in formulating therapeutic strategies to provide optimal nutritional management during CHT to mitigate the risk of developing short adult stature in CCS.
Graphical Abstract
Author Contributions
T.W. and M.K. conceived and designed the study, collected data, and wrote the manuscript. All authors analyzed the data. All authors have read and approved the submission of this manuscript.
Data Availability Statement
The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of research participants, but are available from the corresponding author, M.K., upon reasonable request.
Conflict of Interest Statement
The authors have no conflicts of interest to disclose.
Funding
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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