Abstract
Background
Survival among children with central nervous system (CNS) tumors has improved markedly. However, long-term cardiac effects of craniospinal irradiation (CSI) remain poorly defined. Emerging data suggest an elevated risk for subclinical systolic dysfunction despite the absence of anthracycline exposure.
Objectives
This study aimed to evaluate longitudinal echocardiographic measures of systolic and diastolic function following CSI and identify predictors of cardiac dysfunction.
Methods
We conducted a retrospective, multi-institutional cohort study of pediatric patients diagnosed with a primary CNS tumor treated with CSI between January 2000 and September 2024. Echocardiographic assessments included M-mode left ventricular ejection fraction (LVEF), LV shortening fraction (LVSF), speckle-tracking global longitudinal strain (GLS), and Doppler-based diastolic indices. Longitudinal changes were modeled using linear mixed-effects models adjusted for demographic, treatment, cardiovascular, and endocrine variables.
Results
Among 129 survivors (median age at diagnosis 8 years [IQR: 5-11]; at evaluation 23 years [IQR: 18-27]; median mean heart radiation dose 1,217 cGy [IQR: 2.340-3.600]), LVEF and LVSF declined progressively (P = 0.006 and P < 0.001). LVEF remained ≥50% in all patients, LVSF was <28% in 14 individuals. Diastolic parameters remained stable. GLS was assessed in 100 patients showing early post-CSI improvement followed by progressive decline (P < 0.001), 5 patients exhibited GLS <16%. Older age at diagnosis was associated with greater decline in LVEF and LVSF, while endocrine comorbidities correlated with lower LVEF as attained age increased. GLS trajectories differed by sex, with lower values in younger females.
Conclusions
Progressive long-term decline in systolic function was observed in CSI-treated CNS tumor survivors despite modest cardiac radiation exposure. Age, sex, and endocrine comorbidities influence cardiac trajectories, supporting longitudinal cardiac surveillance.
Key words: cardiotoxicity, childhood cancer survivors, echocardiography, systolic dysfunction
Central Illustration
Survival rates for pediatric cancer have improved substantially over recent decades, with current 5-year overall survival approaching 80%.1 As survival has increased, cardiovascular disease has emerged as the leading cause of long-term morbidity and premature mortality among childhood cancer survivors (CCS).2, 3, 4 Anthracycline chemotherapy and chest-directed radiation are well-recognized contributors to cardiotoxicity in CCS. Central nervous system (CNS) tumors represent the second most common group of pediatric malignancies after acute leukemia.5,6 Anthracyclines are not routinely used to treat CNS tumors given their poor penetration of the blood-brain barrier. Little is known about the long-term cardiac effects of craniospinal irradiation (CSI), a cornerstone therapy for many pediatric CNS tumors.7,8
Although CSI does not directly target the heart, scatter and exit-dose exposure with photon techniques can deliver approximately 28% to 50% of the prescribed spinal dose to cardiac structures.9 Cardiovascular risk may be further increased by concomitant exposure to alkylating agents, such as cyclophosphamide or ifosfamide.8,10 Endocrine late effects, including growth hormone deficiency, adrenal insufficiency, and the metabolic consequences of glucocorticoid replacement, may exacerbate this risk by promoting obesity, dyslipidemia, insulin resistance, and type 2 diabetes mellitus.11, 12, 13 The North American Childhood Cancer Survivor Study has reported that survivors of CNS tumors experience significantly increased risks of myocardial infarction, congestive heart failure, pericardial disease, and valvular dysfunction.14 Furthermore, echocardiographic assessments have demonstrated subclinical reductions in global longitudinal strain (GLS) measurements, even among survivors with preserved ejection fraction.15
Despite these findings, longitudinal data characterizing cardiac function trajectories after CSI remain limited.16 Current pediatric cardiotoxicity guidelines, which primarily address chest-directed radiation and anthracycline exposure, provide no specific recommendations for survivors treated with CSI.17 Defining the evolution of cardiac function over time in CSI-treated survivors is critical for identifying individuals at increased risk, refining surveillance protocols, and facilitating timely preventive or therapeutic strategies.
To address these gaps, we conducted a retrospective cohort study aimed at evaluating the longitudinal trajectories of cardiac function in CNS tumor survivors treated with CSI. By analyzing serial echocardiograms collected as part of routine care, we sought to identify systolic, diastolic, and GLS echocardiographic parameters affected following CSI and to determine clinical and treatment-related factors associated with declines in cardiac function.
Methods
Study design and setting
This retrospective, multi-institutional cohort study was conducted at The Hospital for Sick Children (Toronto, Canada) and Princess Margaret Cancer Centre, University Health Network (Toronto, Canada). The study received approval from the Research Ethics Boards of both institutions (REB #1000082138 and 23-5325).
Study population
Patients were identified through the Hematology/Oncology Divisional database at The Hospital for Sick Children, with records for individuals who had transitioned to adult care cross-referenced at Princess Margaret Cancer Centre. Eligible participants were children and adolescents aged 0 to 18 years at the time of diagnosis of a primary CNS malignancy who received a CSI-containing regimen or thoracic spinal irradiation between January 2000 and September 2024. Inclusion criteria required at least one post-treatment echocardiogram with digitized images available for centralized review. Patients were excluded if they had preexisting cardiac disease, underlying genetic syndromes associated with cardiovascular abnormalities, or prior exposure to anthracycline chemotherapy. Follow-up extended from completion of CSI to the most recent echocardiographic assessment.
Data sources and collection
Clinical data, including demographics, tumor characteristics, treatment details, and follow-up information, were extracted from institutional electronic health records. Radiation therapy parameters, including modality, prescribed dose, and mean heart dose, were obtained from the radiation planning system. Echocardiographic data were collected from clinical reports and supplemented by centralized review of digitized images by a pediatric cardiologist when necessary. Pre-CSI echocardiograms were rarely available and were therefore excluded. Chamber quantification measurements were performed in accordance with the American Society of Echocardiography pediatric guidelines.18 Left ventricular systolic function was assessed using the short axis M-mode view to calculate left ventricular ejection fraction (LVEF) and LVshortening fraction (LVSF); more contemporary two-dimensional (2D) or three-dimensional (3D) LVEF measurements were not consistently available across the cohort. Diastolic function was evaluated using pulsed Doppler of mitral inflow, with early (E) and late (A) velocities used to compute the E/A ratio, and tissue Doppler imaging of the lateral mitral annulus to derive the mitral E/E’ lateral ratio. GLS was calculated from 3 apical views (apical 4-chamber, apical 2-chamber, and apical 3-chamber views).19 However, GLS data were not routinely acquired in earlier years. Analyses involving GLS were restricted to studies in which GLS data were available (Supplemental Figure 1). Cardiovascular risk factors (dyslipidemia, overweight/obesity, diabetes mellitus, hypertension, chronic kidney disease, history of stroke) and treatment-related endocrinopathies were also abstracted to evaluate their associations with cardiac function.
Statistical analyses
Statistical analyses were performed using R (version 4.0.3), with a 2-sided significance level of P < 0.05. Baseline clinical characteristics were summarized using descriptive statistics. Continuous variables were reported as medians with IQRs, and categorical variables as frequencies and proportions. Group differences were assessed using 2-sample t-tests or Mann-Whitney U tests for continuous variables, as appropriate, and Fisher exact tests for categorical variables.
Longitudinal echocardiographic parameters were analyzed using linear mixed-effects models with random patient-specific intercepts to account for within-subject correlation. All available data were included under a missing-at-random assumption. Time since completion of CSI was evaluated as time scale. To accommodate potential nonlinear patterns, time was modeled using natural cubic splines with 3 degrees of freedom. Model-based estimates were used to generate predicted trajectories with pointwise 95% CIs, and overall time effects were assessed using likelihood ratio tests. Decreasing number of observations at later follow-up is reflected by wider CIs. Individual trajectories for each echocardiographic parameter were visualized using spaghetti plots (Supplemental Figure 2) to display the underlying raw data and illustrate the magnitude and direction of the longitudinal change. To evaluate whether temporal trajectories differed by clinical or treatment-related exposures, time-by-exposure interaction terms were incorporated into multivariable linear mixed-effects models adjusted for age at diagnosis, sex, cumulative cyclophosphamide dose, mean heart dose, prior cardiac events during therapy, cardiovascular, and endocrine comorbidities, For dichotomous exposures, trajectories were visualized separately by group, and for continuous exposures, trajectories were displayed across low, medium, and high values corresponding to the 25th, 50th, and 75th percentiles to account for skewed variable distributions. The significance of interaction effects was assessed using likelihood ratio tests. Cumulative incidence of abnormal echocardiographic parameters was estimated using competing risk models with death as a competing event, and group differences were assessed using Gray’s tests. Administrative censoring was applied at 15 years of follow-up. Abnormal parameters were defined as LVEF <50%, LVSF <28%, and GLS <16%.
Results
Patient, tumor, and treatment characteristics
Among 187 patients treated with CSI for a CNS malignancy over the study period, 129 (69%) had echocardiographic data available and were therefore included in the study (Table 1). This subset differed from the full cohort, with higher-intensity therapy, higher mean heart doses, and greater prevalence of endocrine and cardiovascular comorbidities (Supplemental Table 1). The cohort was 59% male, with a median age of 8 years (IQR: 5-11) at diagnosis, and 23 years (IQR: 18-27) at the last follow-up. Medulloblastoma was the most common diagnosis (80%; n = 103), and 65% (n = 80) had nonmetastatic disease. Nearly all patients received CSI (98%; n = 127), with 2 patients (2%) receiving spine-only irradiation. Photon-based therapy was predominantly used (95%; n = 122). The median CSI dose was 2,360 cGy (IQR: 2,340-3,600), and the median mean heart dose was 1,217 cGy (IQR: 1,086-1,616). Most patients received cisplatin (91%; n = 118) and cyclophosphamide (79%; n = 102), and 50% (n = 64) underwent autologous hematopoietic stem cell transplantation. Cardiac events during therapy occurred in 21 patients (16%), most frequently hypertension (5%; n = 7) and pericardial effusion (5%; n = 6). Endocrine comorbidities were present in 67% (n = 87) of the cohort, while 28% (n = 36) had cardiovascular comorbidities, most commonly dyslipidemia (11%; n = 14) and overweight/obesity (6%, n = 8). Following completion of therapy, 16 patients (12%) experienced disease relapse and 2 patients (2%) developed a second malignant neoplasm. At last follow-up, 112 patients (87%) were alive and in remission, while 16 (12%) had died. All deaths were attributable to disease relapse. Use of cardiac medications was uncommon (2%; n = 3).
Table 1.
Demographic and Clinical Characteristics of CNS Tumor Survivors With Echocardiographic Follow-Up
| Sex, n = 129 | |
| Female | 53 (41%) |
| Male | 76 (59%) |
| Age at diagnosis (y), n = 129 | 8 (5-11) |
| Current age (y), n = 129 | 23 (18-27) |
| Diagnosis, n = 129 | |
| Atypical teratoid/rhabdoid tumor | 2 (2%) |
| Embryonal rhabdomyosarcoma | 1 (1%) |
| Ependymoma | 4 (3%) |
| Germinoma | 1 (1%) |
| Medulloblastoma | 103 (80%) |
| Non-germinomatous germ cell tumor | 4 (3%) |
| Oligodendroglioma (spinal cord) | 1 (1%) |
| Pineoblastoma | 10 (8%) |
| Primitive neuroectodermal tumor | 3 (2%) |
| Disease stage, n =123 | |
| Average risk | 80 (65%) |
| High risk | 43 (35%) |
| CSI as first-line therapy, n = 129 | |
| Yes | 124 (96%) |
| At relapse | 5 (4%) |
| Radiation | |
| Radiotherapy location, n = 129 | |
| Craniospinal | 127 (98%) |
| Thoracic spine | 2 (2%) |
| Radiation modality | |
| Photon | 122 (95%) |
| Proton | 7 (5%) |
| CSI dose (cGy), n = 129 | 2,340 (2,340-3,600) |
| CSI fractions, n = 129 | 13 (13-20) |
| Mean heart dose (cGy), n = 117 | 1,216.9 (1,086.3-1,615.9) |
| Chemotherapy, n = 129 | |
| Any chemotherapy | 124 (96%) |
| Type of chemotherapy, n = 129 | |
| Vinca alkaloids | 118 (91%) |
| Cisplatin | 118 (91%) |
| Cyclophosphamide | 102 (79%) |
| Ifosfamide | 4 (3%) |
| Autologous HSCT | 64 (50%) |
| Cardiac events during treatment, n = 129 | 21 (16%) |
| Type of cardiac event during treatment, n = 21 | |
| Systolic dysfunction | 3 (14%) |
| Hypertension | 7 (33%) |
| Pericardial effusion | 6 (29%) |
| Pulmonary edema | 1 (5%) |
| Shock | 3 (14%) |
| Arrhythmia | 1 (5%) |
| Current patient status, n = 129 | |
| Dead | 16 (12%) |
| Remission | 112 (87%) |
| Relapse | 1 (1%) |
| Comorbidities, n = 129 | |
| Endocrine | 87 (67%) |
| Cardiovascular | 36 (28%) |
| Type of endocrine comorbidities, n = 87 | |
| Growth hormone deficiency | 58 (67%) |
| Hypothyroidism | 9 (10%) |
| Gonadal insufficiency | 4 (5%) |
| Panhypopituitarism | 14 (16%) |
| Other | 2 (2%) |
| Type of cardiovascular comorbidities, n = 36 | |
| Dyslipidemia | 14 (39%) |
| Diabetes mellitus | 6 (17%) |
| Hypertension | 3 (8%) |
| Overweight/obesity | 8 (22%) |
| Stroke | 1 (3%) |
| Chronic kidney disease | 4 (11%) |
| Cardiac medication use, n = 123 | 3 (2%) |
Values are n (%) or median (IQR).
CSI = craniospinal irradiation; CNS = central nervous system; HSCT = hematopoietic stem cell transplantation.
Cardiac function trajectories
Patients contributed a variable number of echocardiographic assessments over follow-up (Supplemental Table 2). The number of patients contributing echocardiographic data decreased at later follow-up intervals (Figure 1). LVEF and LVSF declined significantly over time following radiation therapy (P = 0.006 and P < 0.001, respectively) (Figure 2); LVEF remained ≥50% in all patients, while LVSF fell below 28% in 14 patients (11%). Diastolic parameters remained stable over time. Mitral E/E’ lateral showed no significant change (P = 0.94), and the E/A ratio exhibited mild early increases until age 15 followed by slight late declines (P = 0.015). GLS demonstrated a biphasic pattern following radiation, with an early increase during the first 1 to 3 years followed by gradual decline with extended follow-up (P < 0.001). Five patients (4%) developed GLS <16%. The cumulative incidence of LVSF <28% increased from 3.0% at 2 years to 14.5% at 12 years following radiation therapy, whereas GLS <16% demonstrated a similarly progressive rise over time, reaching 6.5% at 12 years following radiation therapy (Table 2, Figure 3).
Figure 1.
Completeness of Echocardiographic Variables by Time Since Radiation Exposure
Bar graph showing the number of patients with ≥1 echocardiographic measurement by time since radiation exposure. Patients contributed a variable number of assessments over follow-up, with decreasing data availability at later time intervals. E/A ratio = early to late mitral inflow velocity ratio; GLS = global longitudinal strain; LVEF = left ventricular ejection fraction; MV E/E’ = mitral valve E to e’ ratio.
Figure 2.
Trajectories of Echocardiographic Parameters by Time Since Radiation Exposure
Modeled trajectories of LVEF (M-mode), LVSF (M-mode), GLS, MV E/E’ lateral, and E/A ratio by years postradiation. Lines represent model-estimated means; shaded areas denote 95% CIs; P values reflect overall trends. LVEF, LVSF, and GLS declined over time since radiation (LVEF P = 0.006; LVSF and GLS P < 0.001). MV E/E’ lateral remained unchanged across age and time. E/A ratio showed a borderline association with time since radiation (P = 0.056). LVSF = left ventricular shortening fraction; other abbreviations as in Figure 1.
Table 2.
Cumulative Incidence of Abnormal Echocardiographic Parameters by Time Since Radiation Therapy
| Years Since Radiation Completion Parameter | CIF Estimates |
|
|---|---|---|
| GLS <16% | LVSF <28% | |
| 0 | 0.0% (0.0%, 0.0%) | 0.0% (0.0%, 0.0%) |
| 2 | 3.8% (1.5%, 10.1%) | 3.0% (1.0%, 9.2%) |
| 4 | 3.8% (1.5%, 10.1%) | 5.4% (2.3%, 12.7%) |
| 6 | 3.8% (1.5%, 10.1%) | 8.1% (4.0%, 16.6%) |
| 8 | 3.8% (1.5%, 10.1%) | 8.1% (4.0%, 16.6%) |
| 10 | 3.8% (1.5%, 10.1%) | 9.9% (5.0%, 19.5%) |
| 12 | 6.5% (2.5%, 17.1%) | 14.5% (7.8%, 26.7%) |
CIF = cumulative incidence function; GLS = global longitudinal strain; LVSF = left ventricular shortening fraction.
Figure 3.
Cumulative Incidence of Abnormal Echocardiographic Parameters Following Radiation Therapy
Cumulative incidence curves for abnormal echocardiographic parameters following radiation therapy, estimated using competing risk models with death as a competing event and administrative censoring at 12 years, GLS <16% (left) and LVSF <28% (right). Shaded areas represent 95% CIs; numbers at risk are shown below the x-axis. No patients developed LVEF <50% during follow-up; therefore, LVEF is not shown. Abbreviations as in Figures 1 and 2.
In multivariable models adjusted for age at diagnosis, sex, cumulative cyclophosphamide dose, mean heart dose, cardiac events during therapy, cardiovascular and endocrine comorbidities (Figure 4, Tables 3 and 4, Supplemental Table 3), older age at diagnosis was associated with greater declines in LVEF and LVSF over time (P = 0.040 and P < 0.001, respectively). Endocrine comorbidities were linked to progressively lower LVEF as attained age increased (P = 0.037). LVSF trajectories were influenced by cumulative cyclophosphamide exposure, with higher cumulative doses associated with relative stability, while patients who received mid-to-lower doses experienced more pronounced declines after age 15 (P = 0.002). GLS trajectories also differed by sex, with females exhibiting lower absolute GLS values at younger ages compared with males (P = 0.015), although these differences attenuated during adolescence. Cardiovascular comorbidities did not significantly modify GLS patterns. Diastolic parameters were not significantly influenced by treatment exposures or comorbidities, and no associations were observed between mean heart dose and any echocardiographic measures.
Figure 4.
Effect Modification of Echocardiographic Trajectories
Predicted trajectories from adjusted multivariable models demonstrating effect modification of systolic function over time. (A) LVEF (M-mode) by age at diagnosis across months since radiation (interaction P = 0.041). (B) LVSF (M-mode) by age at diagnosis across months since radiation (interaction P < 0.001). (C) GLS by sex across attained age (interaction P = 0.015). (D) LVEF (M-mode) by endocrine comorbidities across attained age (interaction P = 0.037). (E) LVSF (M-mode) by cyclophosphamide cumulative dose across attained age (interaction P = 0.002). Shaded areas represent 95% CIs. Abbreviations as in Figures 1 and 2.
Table 3.
Multivariable Mixed-Effects Analyses of Longitudinal Left Ventricular Ejection Fraction: M-mode
| Model∗ | Cyclophosphamide Cumulative Dose β (95% CI) | P Value | Mean Heart Dose β (95% CI) | P Value | Male β (95% CI) | P Value | Cardiac Event During Treatment β (95% CI) | P Value | Endocrine Comorbidities β (95% CI) | P Value | Cardiovascular Comorbidities β (95% CI) | P Value | Age at Diagnosis β (95% CI) | P Value | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age at diagnosis | T | 0.01 (−0.14, 0.15) | 0.92 | −0.13 (−1.10, 0.83) | 0.78 | −0.15 (−1.76, 1.46) | 0.85 | −0.35 (−2.41, 1.71) | 0.74 | 0.13 (−2.13, 2.38) | 0.91 | −0.07 (−1.93, 1.80) | 0.94 | ||
| A | 0.01 (−0.13, 0.15) | 0.91 | −0.04 (−0.99, 0.92) | 0.94 | −0.45 (−2.03, 1.12) | 0.58 | −0.61 (−2.68, 1.46) | 0.57 | −0.07 (−2.30, 2.17) | 0.95 | −0.03 (−1.89, 1.83) | 0.97 | |||
| Cyclophosphamide cumulative dose | T | −0.17 (−1.14, 0.80) | 0.73 | −0.31 (−1.84, 1.23) | 0.70 | 0.17 (−1.91, 2.24) | 0.88 | −0.02 (−2.23, 2.20) | 0.99 | −0.66 (−2.34, 1.02) | 0.45 | −0.19 (−0.43, 0.05) | 0.130 | ||
| A | 0.03 (−0.98, 1.04) | 0.96 | −0.34 (−1.95, 1.27) | 0.68 | −0.46 (−2.66, 1.73) | 0.68 | −0.12 (−2.41, 2.18) | 0.92 | −0.31 (−2.08, 1.47) | 0.74 | 0.03 (−0.26, 0.33) | 0.83 | |||
| Mean heart dose | T | −0.03 (−0.17, 0.11) | 0.66 | 0.01 (−1.58, 1.59) | 0.99 | 0.26 (−1.77, 2.29) | 0.80 | 0.15 (−2.06, 2.36) | 0.89 | −0.56 (−2.27, 1.15) | 0.52 | −0.24 (−0.49, 0.01) | 0.066 | ||
| A | 0.00 (−0.13, 0.14) | 0.95 | −0.21 (−1.81, 1.38) | 0.79 | −0.29 (−2.33, 1.75) | 0.78 | 0.04 (−2.19, 2.27) | 0.97 | −0.32 (−2.09, 1.44) | 0.72 | 0.03 (−0.26, 0.32) | 0.83 | |||
| Sex | T | −0.01 (−0.14, 0.13) | 0.94 | −0.17 (−1.09, 0.75) | 0.72 | −1.54 (−4.28, 1.20) | 0.27 | −0.13 (−2.10, 1.85) | 0.90 | −0.14 (−2.34, 2.06) | 0.90 | −0.71 (−2.40, 0.99) | 0.42 | −0.23 (−0.47, 0.01) | 0.066 |
| A | −0.01 (−0.14, 0.13) | 0.94 | −0.19 (−1.11, 0.74) | 0.70 | −1.74 (−7.93, 4.45) | 0.58 | −0.32 (−2.35, 1.71) | 0.76 | −0.34 (−2.54, 1.86) | 0.76 | −0.58 (−2.32, 1.16) | 0.52 | 0.02 (−0.28, 0.31) | 0.92 | |
| Cardiac event during treatment | T | −0.02 (−0.15, 0.12) | 0.80 | −0.18 (−1.12, 0.75) | 0.70 | −0.12 (−1.67, 1.44) | 0.88 | −0.64 (−3.93, 2.66) | 0.70 | −0.05 (−2.26, 2.16) | 0.96 | −0.57 (−2.28, 1.13) | 0.51 | −0.23 (−0.48, 0.01) | 0.067 |
| A | −0.01 (−0.14, 0.12) | 0.89 | −0.16 (−1.06, 0.73) | 0.72 | −0.09 (−1.60, 1.42) | 0.91 | −7.15 (−13.48, −0.83) | 0.028 | −0.92 (−3.10, 1.27) | 0.41 | −0.60 (−2.27, 1.07) | 0.48 | −0.03 (−0.31, 0.26) | 0.86 | |
| Endocrine comorbidities | T | −0.01 (−0.14, 0.13) | 0.92 | −0.17 (−1.09, 0.75) | 0.72 | −0.09 (−1.62, 1.45) | 0.91 | 0.04 (−1.92, 2.01) | 0.96 | −0.41 (−3.68, 2.87) | 0.81 | −0.57 (−2.27, 1.13) | 0.51 | −0.24 (−0.48, 0.01) | 0.062 |
| A | −0.00 (−0.14, 0.13) | 0.98 | −0.20 (−1.14, 0.73) | 0.67 | −0.25 (−1.83, 1.32) | 0.75 | −0.09 (−2.20, 2.03) | 0.93 | 6.16 (−2.68, 15.01) | 0.174 | −0.53 (−2.26, 1.20) | 0.55 | −0.04 (−0.35, 0.26) | 0.79 | |
| Cardiovascular comorbidities | T | −0.01 (−0.15, 0.13) | 0.89 | −0.20 (−1.12, 0.72) | 0.67 | −0.16 (−1.70, 1.38) | 0.84 | 0.07 (−1.90, 2.04) | 0.94 | −0.12 (−2.32, 2.08) | 0.92 | −1.27 (−4.36, 1.81) | 0.42 | −0.24 (−0.48, 0.00) | 0.055 |
| A | 0.00 (−0.14, 0.14) | 1.00 | −0.20 (−1.13, 0.72) | 0.67 | −0.26 (−1.84, 1.32) | 0.75 | −0.36 (−2.39, 1.67) | 0.73 | −0.42 (−2.61, 1.77) | 0.71 | 0.55 (−9.48, 10.59) | 0.91 | −0.00 (−0.29, 0.28) | 0.98 |
β coefficients represent adjusted associations from multivariable linear mixed-effects models with patient-level random intercepts. Time was modeled using natural cubic splines. All models account for repeated measures and adjust for the covariates shown in each column. Cyclophosphamide dose and mean heart dose are continuous variables; sex and clinical comorbidities are binary (reference: female and absence of condition, respectively). 95% CIs are shown in brackets; P values are two-sided.
T = time since craniospinal irradiation and A = attained age (years).
Two time scales were used.
Table 4.
Multivariable Mixed-Effects Analyses of Longitudinal Left Ventricular Ejection Fraction: Global Longitudinal Strain
| Model∗ | Cyclophosphamide Cumulative Dose β (95% CI) | P Value | Mean Heart Dose β (95% CI) | P Value | Male β (95% CI) | P Value | Cardiac Event During Treatment β (95% CI) | P Value | Endocrine Comorbidities β (95% CI) | P Value | Cardiovascular Comorbidities β (95% CI) | P Value | Age at Diagnosis β (95% CI) | P Value | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age at diagnosis | T | −0.02 (−0.09, 0.06) | 0.63 | −0.02 (−0.50, 0.45) | 0.92 | 0.48 (−0.35, 1.32) | 0.26 | −0.28 (−1.32, 0.75) | 0.59 | −0.82 (−2.00, 0.35) | 0.174 | −0.29 (−1.24, 0.66) | 0.55 | ||
| A | −0.01 (−0.09, 0.06) | 0.73 | 0.03 (−0.46, 0.52) | 0.90 | 0.49 (−0.37, 1.35) | 0.27 | −0.30 (−1.37, 0.77) | 0.59 | −0.46 (−1.68, 0.77) | 0.47 | −0.21 (−1.19, 0.78) | 0.68 | |||
| Cyclophosphamide cumulative dose | T | −0.03 (−0.57, 0.50) | 0.91 | 0.49 (−0.40, 1.37) | 0.29 | −0.56 (−1.75, 0.62) | 0.36 | −0.63 (−1.85, 0.58) | 0.31 | −0.03 (−0.98, 0.92) | 0.95 | −0.26 (−0.40, −0.12) | <0.001 | ||
| A | 0.07 (−0.48, 0.62) | 0.80 | 0.37 (−0.55, 1.29) | 0.44 | −0.46 (−1.73, 0.80) | 0.47 | −0.09 (−1.40, 1.22) | 0.89 | −0.36 (−1.36, 0.64) | 0.48 | −0.03 (−0.20, 0.14) | 0.71 | |||
| Mean heart dose | T | −0.00 (−0.07, 0.07) | 0.93 | 0.70 (−0.17, 1.56) | 0.120 | −0.14 (−1.18, 0.89) | 0.79 | −0.36 (−1.50, 0.78) | 0.54 | −0.10 (−1.00, 0.80) | 0.83 | −0.21 (−0.34, −0.08) | 0.003 | ||
| A | −0.02 (−0.09, 0.06) | 0.65 | 0.41 (−0.47, 1.29) | 0.37 | −0.03 (−1.11, 1.05) | 0.96 | 0.09 (−1.10, 1.28) | 0.88 | −0.23 (−1.17, 0.71) | 0.64 | −0.02 (−0.18, 0.14) | 0.80 | |||
| Sex | T | 0.01 (−0.06, 0.08) | 0.76 | −0.14 (−0.60, 0.32) | 0.55 | 1.24 (−0.17, 2.65) | 0.086 | −0.30 (−1.30, 0.69) | 0.56 | −0.88 (−1.99, 0.22) | 0.121 | −0.02 (−0.88, 0.85) | 0.97 | −0.27 (−0.40, −0.14) | <0.001 |
| A | −0.02 (−0.09, 0.06) | 0.68 | 0.05 (−0.43, 0.53) | 0.84 | 3.99 (0.54, 7.44) | 0.025 | −0.44 (−1.52, 0.63) | 0.42 | −0.38 (−1.55, 0.79) | 0.53 | −0.18 (−1.12, 0.76) | 0.71 | −0.09 (−0.24, 0.06) | 0.26 | |
| Cardiac event during treatment | T | −0.02 (−0.09, 0.05) | 0.65 | −0.05 (−0.51, 0.42) | 0.84 | 0.46 (−0.37, 1.30) | 0.28 | −1.62 (−3.39, 0.15) | 0.076 | −0.70 (−1.83, 0.43) | 0.23 | −0.01 (−0.92, 0.90) | 0.98 | −0.26 (−0.40, −0.13) | <0.001 |
| A | −0.04 (−0.12, 0.04) | 0.31 | 0.21 (−0.28, 0.71) | 0.40 | 0.37 (−0.52, 1.26) | 0.42 | −0.58 (−3.87, 2.70) | 0.73 | −0.27 (−1.47, 0.94) | 0.67 | −0.29 (−1.25, 0.67) | 0.56 | −0.05 (−0.21, 0.10) | 0.52 | |
| Endocrine comorbidities | T | −0.00 (−0.07, 0.07) | 0.98 | −0.07 (−0.53, 0.40) | 0.78 | 0.42 (−0.41, 1.24) | 0.33 | −0.41 (−1.43, 0.61) | 0.43 | −1.01 (−2.52, 0.50) | 0.191 | −0.09 (−0.99, 0.80) | 0.84 | −0.24 (−0.37, −0.10) | <0.001 |
| A | −0.02 (−0.09, 0.06) | 0.65 | 0.11 (−0.39, 0.61) | 0.67 | 0.28 (−0.60, 1.16) | 0.53 | −0.48 (−1.62, 0.65) | 0.41 | −3.23 (−7.52, 1.05) | 0.142 | −0.13 (−1.09, 0.82) | 0.78 | −0.06 (−0.23, 0.10) | 0.46 | |
| Cardiovascular comorbidities | T | 0.00 (−0.07, 0.07) | 0.96 | −0.06 (−0.53, 0.40) | 0.80 | 0.39 (−0.44, 1.22) | 0.36 | −0.32 (−1.35, 0.71) | 0.54 | −0.80 (−1.94, 0.33) | 0.168 | −0.59 (−2.09, 0.91) | 0.44 | −0.27 (−0.40, −0.13) | <0.001 |
| A | −0.03 (−0.10, 0.04) | 0.43 | 0.17 (−0.32, 0.66) | 0.50 | 0.31 (−0.57, 1.19) | 0.49 | −0.51 (−1.60, 0.59) | 0.37 | −0.37 (−1.56, 0.82) | 0.54 | 0.30 (−4.23, 4.83) | 0.90 | −0.05 (−0.20, 0.11) | 0.56 |
β coefficients represent adjusted associations from multivariable linear mixed-effects models with patient-level random intercepts. Time was modeled using natural cubic splines. All models account for repeated measures and adjust for the covariates shown in each column. Cyclophosphamide dose and mean heart dose are continuous variables; sex and clinical comorbidities are binary (reference: female and absence of condition, respectively). 95% CIs are shown in brackets; P values are 2-sided.
T = time since craniospinal irradiation and A = attained age (years).
Two time scales were used.
Discussion
In this multi-institutional cohort of childhood CNS tumor survivors treated with CSI, we identified longitudinal declines in left ventricular systolic function despite modest mean heart radiation exposure and the absence of anthracycline therapy. Specifically, we observed: 1) progressive declines in LVEF and LVSF over time since CSI. Although these declines were statistically significant, systolic function remained largely preserved with LVEF ≥50% in all patients, while 11% developed LVSF <28%, consistent with subclinical systolic impairment; 2) GLS demonstrated a biphasic trajectory, with early postradiation increases followed by gradual decline over extended follow-up; overt abnormalities were uncommon, with only 4% of patients developing GLS <16%; and 3) modulation of these trajectories by clinical and treatment-related factors, including older age at diagnosis, female sex, cyclophosphamide exposure, and endocrine comorbidities. Collectively, these findings provide novel insights into subclinical myocardial remodeling among CSI-treated survivors and address an important gap in cardio-oncology survivorship research (Central Illustration).
Central Illustration.
Long-Term Cardiac Function After Craniospinal Irradiation in Pediatric Central Nervous System Tumor Survivors
Longitudinal trajectories of left ventricular systolic function (LVEF, LVSF) and GLS show progressive declines over time despite low mean heart radiation doses, whereas diastolic function remains stable. Age at diagnosis, sex, and endocrine comorbidities modify cardiac trajectories. CNS = central nervous system; CSI = craniospinal irradiation; other abbreviations as in Figures 1 and 2.
Prior cardio-oncology studies have focused predominantly on anthracycline-related cardiotoxicity, with limited data on long-term cardiac outcomes following CSI alone.20,21 Dosimetric analyses consistently demonstrate low-to-moderate scatter radiation exposure to the heart, with lower doses observed using contemporary proton therapy.22,23 Accordingly, current survivorship guidelines generally do not recommend routine cardiac imaging for CCS who received <15 Gy mean heart dose in the absence of anthracycline therapy.24,25 Our findings challenge the assumption that such low-dose cardiac radiation is benign. Despite a low median mean heart dose of 1,217 cGy, progressive declines in LVEF and LVSF, alongside evolving abnormalities in myocardial deformation were observed. The absence of a clear dose-response relationship suggests that other patient- and treatment-specific factors may also influence heart function after cancer treatment.
Speckle-tracking echocardiography with assessment of GLS has emerged as a sensitive measure of myocardial function, detecting early changes prior to declines in LVEF.26 In noncancer populations, GLS has demonstrated stronger prognostic value than LVEF for predicting mortality and major adverse cardiac events.27 In CCS, prior studies have shown that a substantial subset exhibits abnormal GLS despite preserved LVEF, reflecting subclinical myocardial dysfunction. For instance, Martinez et al15 reported lower GLS in CSI-treated patients compared with age-matched controls (>12 months post-CSI: −16.2% ± 5.4% vs −21.6% ± 3.7%), while Armstrong et al28 found that 28% of CCS with normal 3D LVEF had abnormal GLS. Our cohort demonstrated a pattern of early postradiation GLS increase followed by gradual decline, though overt GLS abnormalities were uncommon.
The observed age-dependent declines in LVEF and LVSF align with patterns of subclinical ventricular dysfunction previously described in CCS exposed to chest or mediastinal radiotherapy, in which functional deficits may remain clinically silent for years.20,29 This progression reflects the pathophysiological cascade of radiation-induced injury, including microvascular damage, fibrosis, and reduced myocardial reserve.30 Population-level studies have demonstrated that even low-to-moderate radiotherapy doses across cardiac volumes increase the long-term risk of serious cardiac events.21 Additionally, radiation exposure to specific cardiac substructures, including the left ventricle or coronary arteries, has been linked to heightened risk of heart failure, coronary artery disease, and valvular dysfunction.31
Older age at diagnosis was independently associated with greater declines in LVEF and LVSF. Unlike anthracycline cardiotoxicity where younger age often confers increased vulnerability, the impact of age at radiation exposure may differ.21,32, 33, 34 A few plausible explanations warrant consideration. First, physiological data demonstrate that myocardial structure, metabolic programming, and overall cardiovascular geometry continue evolving through childhood and adolescence, suggesting that the developmental stage at the time of exposure may modulate vulnerability to later cardiac injury.35 Second, older children may have received higher cumulative treatment intensity, or be more prone to early metabolic or endocrine impairments, which could synergize with radiation to accelerate myocardial damage.36,37
Endocrine late effects, including pituitary, hypothalamic, and metabolic disorders, are common among CNS tumor survivors treated with CSI.38, 39, 40 In our cohort, these comorbidities were present in approximately two-thirds of patients and independently associated with progressive declines in LVEF with increasing attained age. Endocrine dysfunction has been linked to adverse metabolic and cardiovascular risk profiles, including dyslipidemia, insulin resistance, central adiposity, and hypertension, which may predispose to long-term vascular and myocardial injury.40, 41, 42 However, data directly connecting these disorders to subclinical myocardial remodeling or progressive ventricular dysfunction remain limited.
Sex-specific differences in myocardial function are well-documented in adults, suggesting that biological sex may influence cardiac function.43,44 Data in pediatric populations are limited; in our cohort, females exhibited lower absolute GLS at younger ages compared with males, although these differences attenuated during adolescence. Cyclophosphamide exposure demonstrated an unexpected pattern, with greater LVSF declines observed in patients who received lower cumulative doses, likely reflecting confounding or treatment differences rather than a true dose-response effect.
Study limitations
While this study provides valuable longitudinal insights into cardiac function after CSI, some limitations merit consideration. The retrospective design and absence of baseline pre-CSI echocardiograms limit characterization of early therapy-related cardiac changes. Echocardiographic assessments were collected over 2 decades across 2 centers, introducing potential heterogeneity and reflecting evolving treatment protocols over time. Notably, GLS was not available at all time points and was predominantly measured in more recent studies. No retrospective offline strain analyses were performed on earlier studies. Additionally, LVEF assessments relied primarily on M-mode, a less contemporary method. Simpson’s biplane 2D or 3D LVEF measurements were not consistently available across the cohort. More comprehensive guideline-based echocardiographic parameters for diastolic function assessment were not uniformly available across the study period. Comparisons of longitudinal trajectories between survivors and nonsurvivors were limited, as most patients who died had only a single early echocardiographic assessment. The majority of patients who underwent autologous hematopoietic stem cell transplantation were treated according to the SJMB03 protocol, which was the institutional standard-of-care protocol during part of the study period, though it is no longer widely used. Younger children were underrepresented due to radiation-sparing approaches, which may influence observed age-related associations. Residual confounding from unmeasured variables, such as lifestyle factors, cannot be excluded. Proton therapy was delivered outside of Canada, and detailed proton treatment planning data were unavailable. Finally, the predominance of photon-based CSI may limit generalizability to patients treated with contemporary proton therapy, which may reduce or avoid cardiotoxicity given its ability to treat the neuraxis while sparing the heart completely.45 This is an area that warrants further study in the future to confirm this modality confers lower risk of cardiotoxic late effects. Importantly, this cohort remains relatively young, and whether some individuals will progress to clinically overt cardiac disease with advancing age remains unknown.
Conclusions
Childhood CNS tumor survivors treated with CSI exhibited progressive declines in left ventricular systolic function and GLS over long-term follow-up, despite modest cardiac radiation doses and absence of anthracycline exposure. Age at diagnosis, sex, and endocrine comorbidities influenced the magnitude and trajectory of these changes, whereas diastolic function remained stable. These findings indicate that in patients treated with CSI, subclinical myocardial remodeling may occur, providing novel insights into the cardiac sequelae of CSI in CNS tumor survivors. However, longer follow-up is needed to clarify the clinical implications of these subclinical changes and to determine whether current cardiac surveillance guidelines should be adapted to better identify and manage this at-risk population.
Perspectives.
COMPETENCY IN MEDICAL KNOWLEDGE: Childhood CNS tumor survivors treated with CSI exhibit progressive, subclinical declines in left ventricular systolic function despite low cardiac radiation doses and no anthracycline exposure, challenging current assumptions about cardiotoxic risk. Age at diagnosis, sex, and endocrine comorbidities influence cardiac function trajectories post-CSI.
TRANSLATIONAL OUTLOOK: Future studies should determine optimal surveillance intervals, validate risk-adapted screening strategies, and assess whether early detection of subclinical dysfunction improves long-term cardiovascular outcomes.
Declaration of Generative AI and AI-Assisted Technologies in the Writing Process
AI software (ChatGPT) was used solely for minor language and spelling corrections to assist with English clarity, as English is not the corresponding author’s first language. No content, analysis, or conclusions were generated by AI.
Funding support and author disclosures
Funded, in part, by a Canadian Institutes of Health Research (CIHR) Foundation Grant (PI: Dr Nathan). Drs Tsang and Bennett are consultants with Need (https://www.need.ai), outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgments
The authors acknowledge Stan Lefeber, Medical Student at the Medical Ultrasound Imaging Center, Radboud University Medical Center, Nijmegen, the Netherlands, for his valuable assistance with editing the central illustration graphic.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental tables and figures, please see the online version of this paper.
Appendix
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