Pediatric Blood Cancer - 2024 - Nagpal - Ewing Sarcoma Among Children 5 Years of Age or Younger is It a Different
Pediatric Blood Cancer - 2024 - Nagpal - Ewing Sarcoma Among Children 5 Years of Age or Younger is It a Different
Pediatric Blood Cancer - 2024 - Nagpal - Ewing Sarcoma Among Children 5 Years of Age or Younger is It a Different
Correspondence
Sameer Bakhshi, Department of Medical Abstract
Oncology, Dr. B.R.A. Institute Rotary Cancer
Hospital, All India Institute of Medical
Introduction: Children ≤5 years of age with Ewing’s sarcoma (ES) possibly have a
Sciences, New Delhi 110029, India. distinct disease biology, data on which are scarce. We evaluated clinical features,
Email: sambakh@hotmail.com
outcomes, and prognostic factors of ES among children with age ≤5 years.
Shuvadeep Ganguly, Department of Medical
Oncology, Jawaharlal Institute of Post
Methods: Children with ES registered between 2003 and 2019 were included. Baseline
Graduate Medical Education and Research, clinical and treatment details were retrieved from medical records. Prognostic fac-
Puducherry 605006, India.
Email: ganguly.shuvadeep@gmail.com
tors were identified using multivariable Cox regression. Clinical features and outcomes
of children ≤5 years were compared with those greater than 5 years by chi-square
and log-rank tests. Propensity score-matched (PSM) analysis was done to evaluate the
impact of age on survival in the metastatic and localized subgroups.
Results: Out of the 859 patients, 86 (10%) were ≤5 years of age (median age 4 years,
60 males [69.8%]). The most common location was the extremities (37.2%), followed by
thorax (27.9%) and head and neck (H&N) (22.1%); baseline metastases were seen in 25
patients (29.8%). The median event-free-survival (EFS) and overall survival (OS) were
25.6 and 68.7 months, respectively. Metastatic disease predicted inferior OS (hazard
Abbreviations: CI, confidence interval; CT, computed tomography; EFS, event-free survival; EICESS, European Intergroup Cooperative Ewing’s Sarcoma Study; ES, Ewing sarcoma;
EWSR1:NFATC2, Ewings sarcoma RNA binding protein 1–nuclear factor of activated T cells 2; HR, hazard ratio; IQR, interquartile range; OS, overall survival; VAC/IE, vincristine, adriamycin,
cyclophosphamide, ifosfamide, etoposide.
ratio [HR] = 2.54, p = .018) and EFS (HR = 2.47, p = .007], symptom duration ≤3 months
predicted an inferior OS (HR = 2.17, p = .048). Compared to age greater than 5 years,
younger children had more H&N and less pelvic primaries (p < .001) and lesser baseline
metastases (p = .037). PSM analysis did not reveal any significant impact of age on OS
in the metastatic (HR = 1.59, p = .29) or localized cohort (HR = 1.77, p = .09).
Conclusions: Children with ES ≤5 years of age have a distinct favorable clinical pre-
sentation. However, age is not an independent prognostic factor for survival outcomes
when adjusted for confounders.
KEYWORDS
Ewing sarcoma, less than five, pediatric, primitive neuroectodermal tumor, prognostic factors
imaging with computed tomography (CT) or magnetic resonance imag- albumin (<3.5 g/dL) were included as potential prognostic factors
ing (MRI). Metastatic workup included bone marrow aspiration and for survival in patients aged ≤5 years. Their impact on survival was
biopsy, CT scan of the chest with a bone scan, or whole-body 18 F- assessed using univariable Cox regression analysis. Multivariable Cox
fluorodeoxyglucose-positron emission tomography-computed tomog- regression analysis was performed in a forward stepwise manner on
raphy (18 F-FDG-PET/CT) scan in all patients. the factors identified in univariable analysis with p-value ≤.1. Factors
with p-value less than .05 in this model were considered to have a
significant prognostic impact on survival.
2.3 Treatment administered
Standard first-line treatment was given in localized disease. Patients 2.5.2 Survival analysis
with localized disease uniformly received chemotherapy with vin-
cristine, doxorubicin, cyclophosphamide (VAC), alternating with Kaplan–Meier analysis was performed using survival17 and survminer18
ifosfamide-etoposide (IE). Initially it was given at a 3-weekly interval; packages in R. Survival data were reported in the form of median EFS
however, after 2017,15 it was given in a dose-dense 2 weekly interval, or OS with 95% confidence intervals (CI). The survival outcomes of
followed by local control with either surgery or radiotherapy, and then children ≤5 years were compared with those older than 5 years by
adjuvant therapy with the same drugs. Doxorubicin was replaced with Cox regression analyses. Listwise deletion was used for missing vari-
D-actinomycin when its cumulative dose was more than 375 mg/m2 . ables. To account for the imbalance of confounders between the two
In patients with metastatic disease, VAC/IE chemotherapy was age groups (age ≤5 vs. >5 years), a propensity score matched anal-
given in 3 weekly cycles. In these patients, those who had a good ysis was done using matchit package in R.19 A propensity score was
response to neoadjuvant chemotherapy (NACT) at the primary as well estimated for each patient using a logistic regression model with all
as metastatic site(s), they were also administered local therapy in relevant covariates—sex, presence of metastases, tumor site, tumor
the form of surgery or radiation. Adjuvant chemotherapy was con- size, symptom duration, presence of fever, hemoglobin, total leukocyte
tinued following local therapy. The decision regarding the choice of count, and albumin in the metastatic and localized cohort separately
surgery and/or radiation was taken after discussion in multidisciplinary to identify the impact of age on the survival outcomes. Matched pairs
tumor board. After 2017, the chemotherapy in metastatic disease was were developed between the two age groups (≤5 vs. >5 years) in 1:4
changed to a VAC-only regimen without the use of IE.16 ratio by optimal matching without replacement, and the balance of
matched cohort was analyzed using standardized mean difference and
2.4 Outcomes love plot. Finally, the effect of age group in the propensity matched
cohort on EFS and OS was analyzed by multivariable Cox regression
defined as the time from date of diagnosis to the time of disease recur-
rence, progression or death, and overall survival (OS) defined as the
time between date of diagnosis till death due to any cause. The data 3 RESULTS
were censored on December 31, 2022.
3.1 Baseline characteristics
2.5 Statistical analysis During the study period from 2003 to 2019, a total of 1058 patients
with histologically confirmed, treatment-naive ES were registered at
Data analysis was done using Stata (Stata Statistical Software: Release our center. Out of the 856 evaluable patients, 86 (10%) were ≤5 years
15, StataCorp) and R version 4.3.0 (R Project for Statistical Computing). of age (median age 4 years, 60 males [69.8%]) (Figure 1). The baseline
Descriptive statistics were used to describe demographic details and demographic and clinical characteristics of the patients (for both,
baseline clinical features. Categorical data were expressed in the form those with age ≤5 and >5 years) are shown in Table 1. The median
of percentages, and continuous variables as median with interquartile duration of symptoms prior to presentation in patients ≤5 years of
range (IQR). Intergroup comparisons between age more than 5 and age was 3 months (IQR: 2–6 months). Twenty-three children (26.7%)
≤5 years were performed using chi-square tests and unpaired t-test. had extra-osseous primary tumors, and baseline metastases was
observed in 25 patients (29.8%). The most common primary site was
the extremities (37.2%), followed by the thorax (27.9%) and then the
2.5.1 Identification of prognostic features head and neck (22.1%). Compared to age more than 5 years, younger
children had a higher proportion of tumors for which head and neck
Clinical characteristics such as gender, duration of symptoms, sys- was the primary site (22.1% vs. 9.8%) and less pelvic primary tumors
temic symptoms at baseline, tumor diameter, primary tumor site (head (4.6% vs. 18.4%), shorter duration to symptoms prior to presentation
and neck, thorax, abdomen, pelvis, spine, and extremities), low blood (3 vs. 4 months), smaller tumor sizes (7 vs. 9 cm), and lower prevalence
hemoglobin (<10 g/dL), platelet count (<150 × 103 /μL), and serum of metastases at baseline (29.8% vs. 41.5%) (Table 1). There was no
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4 of 9 NAGPAL ET AL .
difference in the types of local therapy received in the form of either (68.7 months [25.8 not reached], 24.5 [12.7 not reached] and 30.3 [13.3
surgery, radiotherapy, or both between the younger cohort ≤5 years not reached], p = .06]. The 3-year OS and EFS in the localized subgroup
and the older one (Table 1). of the patients ≤5 years versus those more than 5 years was 66.7%
(49.9%−79.0%) versus 56.9% (51.6%−61.2%) (p = .20) and 54.8%
(38.8%−68.3%) versus 47.1% (42.0%–52.1%) (p = .40) (Figure 2A,B).
3.2 Prognostic factors for OS and EFS The 3 years OS and EFS in the metastatic subgroup of the patients
≤5 years versus those older than 5 years was 33% (11.7%−56.9%) ver-
On univariable analysis, total leukocyte count greater than sus 23.5% (18.1%−29.4%) (p = .24) and 28.0% (10.6%−48.6%) versus
11,000/mm3 , symptom duration less than 3 months, and metastatic 16.8% (12.2%−22.0%) (p = .18) (Figure 3A,B).
disease at baseline were found to be predictive of inferior OS. Among Propensity score-matched analysis in the metastatic cohort
these, symptom duration less than 3 months (hazard ratio [HR] = 2.17 revealed no difference in the OS between patients who were ≤5 years
[1.01–4.54], p = .048) and metastatic disease at baseline (HR 2.54 compared to the older cohort (HR = 2.15, 95% CI: 0.86–5.35, p = .105),
[1.18–5.49]; p = .018) were independent predictors of OS in mul- as well as in the localized cohort (HR = 1.74, 95% CI: 0.89–3.39,
tivariable analysis (Table 2). Metastases at baseline and symptom p = .100). Similarly, there was no difference in the EFS on propensity
duration less than 3 months were associated with an inferior EFS on score matching in the metastatic (HR = 1.39, 95% CI: 0.62–3.10,
univariable analysis, while only metastatic disease at baseline (HR p = .42) as well as the nonmetastatic cohort (HR = 1.35, 95% CI:
2.47 [1.29–4.76], p = .007) was an independent predictor of EFS on 0.77–2.36, p = .30).
multivariable analysis (Table 3). Patients with lung-only metastasis
had a better survival in the overall cohort (23.9 vs. 15.6 months,
p = .03), but not in the younger cohort (22.1 vs. 26.8 months, p = .95). 4 DISCUSSION
Tumor necrosis data were available in a total of 110 patients in
the overall cohort: the median OS seen in those with necrosis less In this study, we analyzed patients ≤5 years of age with ES treated
than 90% (n = 70) was 37.6 months (18.4 not reached) versus not at our center with a uniform protocol over a period of 16 years. We
reached (27.4 not reached) in those with necrosis ≥90% (p = .04). found that young children with ES had a higher prevalence of head and
In the younger cohort, necrosis data were available in 10 patients, neck and lesser pelvic origin tumors. This cohort tended to present
with 100% necrosis seen in six, 70% in one and no necrosis in three earlier, with smaller tumors at presentation and lower proportion of
patients. patients with baseline metastatic disease than the older cohort. These
findings are congruent with the results of various studies, including
Ioris et al’s cohort of children less than 6 years of age with primary
3.3 Impact of age on survival outcomes bony ES.4–6,13,20 The lower prevalence of metastasis may be attributed
to more head and neck and lesser pelvic primary sites, or to inher-
In the overall cohort, in the age group ≤5 versus 6−10 and more than ent differences in the tumor biology. Unlike head and neck tumors,
10 years, there was no significant difference in EFS (25.6 months [16.4– pelvic origin tumors are more frequently metastatic at presentation
68.7], 19.9 months [17.5–25.0] and 21.6 [19.3–25.9], p = .38) and OS and spread into the visceral space prior to symptom onset.20–22 The
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NAGPAL ET AL . 5 of 9
TA B L E 1 Comparison of baseline demographic, clinical characteristics, and treatment administered to Ewing sarcoma patients based on age
group.
TA B L E 2 Univariable and multivariable analysis of factors predictive of overall survival in patients of age ≤5 years.
high male-to-female ratio observed in our study has also been seen in children, delays due to social factors may be less common on account
previous studies in other childhood tumors from our subcontinent.23 of parental care and attention. The prominent role of biologic drivers in
This highlights the presence of a gender gap in cancer diagnosis in India this age group may, thus, allow for a stronger association between short
that is not explained by tumor biology alone.2,23,24 symptom duration and adverse survival outcomes. However, while the
In our cohort, baseline metastatic disease and shorter duration of difference between symptom duration in the two cohorts was statis-
symptoms (<3 months) were identified as independent predictors of tically significant, the clinical relevance is questionable, as seen from
inferior OS. Ioris et al. also identified metastatic disease as a significant prior studies.28,29
prognostic factor.5 Metastases at presentation is known to be a pow- We found that the younger cohort presented with a favorable
erful predictor of survival, with long-term survival rates dipping down clinical profile in the form of less number of pelvic primaries, and a
from 70% in localized ES to as low as 9%–41% in metastatic ES.2,4,7,10,25 higher proportion of patients presenting with localized disease, both
The prognostic value of symptom duration prior to presentation of which have been associated with a better prognosis in ES.5,20
is controversial, likely due to interaction between social and bio- We however did not identify any difference in survival between the
logic drivers of delayed presentation.26 In non-Hodgkin’s lymphomas, younger and older cohorts in the metastatic and nonmetastatic sub-
quicker presentation to medical care following symptom onset has groups, signifying that age might not be independently predicting
been described as an adverse prognostic factor on account of its asso- outcomes. A further propensity-matched analysis confirmed that there
ciation with more aggressive tumor biology.27 However, in a cohort of was no significant difference between the younger and older cohorts.
bone sarcomas across age groups at our center, time to diagnosis was Therefore, we conclude that age is not an independent prognostic
not seen to have any impact on survival, likely denoting that tumor factor, although the results may be limited by our small sample size.
biology plays the dominant role in determining treatment outcomes, Prior to this study, multiple other groups have also shown mixed
rather than the symptom duration prior to presentation.26 In young results. The Polish sarcoma group,30 European Ewing Tumor Work-
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NAGPAL ET AL . 7 of 9
TA B L E 3 Univariable and multivariable analysis of factors predictive of event-free survival in patients of age ≤5 years.
F I G U R E 2 (A) Kaplan–Meier curves for overall survival in patients without metastatic disease aged ≤5 versus >5 years. (B) Kaplan–Meier
curves for event-free survival in patients without metastatic disease aged ≤5 versus >5 years.
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8 of 9 NAGPAL ET AL .
F I G U R E 3 (A) Kaplan–Meier curves for overall survival in patients with metastatic disease aged ≤5 versus >5 years. (B) Kaplan–Meier curves
for event-free survival in patients with metastatic disease aged ≤5 versus >5 years.
ing Initiative of National Groups 99 (EURO-EWING 99),10 EICESS,3 tent. Sandeep Agarwala; Vishesh Jain; Anjan Dhua; Devender Yadav;
and Children’s Oncology Group (COG)9 have concluded that young Bivas Biswas; Shah Alam Khan; Adarsh Barwad; Asit Ranjan Mirdha;
age is an independent predictor of a better EFS, whereas EW88,7 Ahitagni Biswas; and Deepam Pushpam conceptualized and designed
Wong et al.4 and Rodríguez-Galindo et al.8 have failed to conclude the study; and reviewed it critically for important intellectual con-
the same. tent; and edited the manuscript. Sameer Bakhshi conceptualized and
Our study is a large cohort study that provides data on outcomes designed the study; drafted the manuscript; reviewed it critically for
in children with ES belonging to the age group of ≤5 years. The use important intellectual content; edited the manuscript; and provided
of a uniform protocol allowed for better delineation of disease behav- administrative support. All authors have reviewed and approved the
ior in the absence of confounding factors. However, our study had final version of the manuscript to be published and agree to be account-
a few limitations. Our study did not assess differences in histomor- able for all aspects of the work in ensuring that questions related to
phology and immunohistochemistry in ES such as the presence of the accuracy or integrity of any part of the work are appropriately
Bcl-6 co-repressor (BCOR)-associated, CIC (Capicua)-rearranged and investigated and resolved.
EWSR1:NFATC2 (Ewings sarcoma RNA binding protein 1–nuclear fac-
tor of activated T cells 2) sarcomas in different age groups, which may ACKNOWLEDGMENTS
promote our understanding of the biologic basis of differences in ES The authors acknowledge every member of pediatric oncology team of
across age groups.31 The incorporation of social factors such as familial our center including research staff, nurses, and dietician for their exem-
income and maternal education may have allowed us to better grasp plary clinical services. In particular, the contributions of Ms Mamta
the relevance of biologic factors in the context of prevailing social Kumari who maintains and updates the patient database.
characteristics.
We found that young children with ES have distinct clinical CONFLICT OF INTEREST STATEMENT
presentation with less aggressive presenting characteristics. The authors declare no conflicts of interest.
However, younger age was not associated with better OS or EFS
after matching for all potential confounding baseline characteristics. DATA AVAILABILITY STATEMENT
A separate analysis of younger children with ES from prospective Anonymized patient-level data that support the findings of the study
trials may further enhance our understanding of the disease in this will be available from the corresponding author upon reasonable
age group. Future studies that look at gene expression profiling in request.
younger ES may help us to examine age-wise differences in disease
behavior at a molecular level, and identify potential therapeutic ORCID
targets that may allow us to further improve survival outcomes in Chitrakshi Nagpal https://orcid.org/0000-0002-7352-2446
this cohort. Shuvadeep Ganguly https://orcid.org/0000-0002-7296-6088
Deepam Pushpam https://orcid.org/0000-0001-8222-331X
AUTHOR CONTRIBUTIONS Sandeep Agarwala https://orcid.org/0000-0001-8315-5814
Chitrakshi Nagpal conceptualized the study; acquired; interpreted Vishesh Jain https://orcid.org/0000-0002-9273-097X
and analyzed the data; and drafted the manuscript. Archana Sasi; Anjan Dhua https://orcid.org/0000-0003-2050-7872
Shuvadeep Ganguly; and Vivek Kumar interpreted results; drafted Devender Kumar Yadav https://orcid.org/0000-0003-3158-1322
the work; and reviewed it critically for important intellectual con- Ahitagni Biswas https://orcid.org/0000-0002-3453-5340
15455017, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pbc.31268 by Hacettepe Universitesi, Wiley Online Library on [16/08/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
NAGPAL ET AL . 9 of 9
Sameer Bakhshi https://orcid.org/0000-0001-9367-4407 17. Therneau TM. A package for survival analysis in R. R package ver-
sion 3.7-0. R-Project; 2023. Accessed October 14, 2023. https://cran.
r-project.org/web/packages/survival/index.html
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