A total of 51 patients treated with CSI for CNS malignancies were identified from our database for the years 1986-2018, including 67% (34/51) male and 88% (45/51) white race. The most common diagnosis was medulloblastoma (45/51), with the remaining cases including atypical teratoid, ependymoma, and glioma. Most patients received cisplatin (44/51) and cyclophosphamide (39/51). While almost all patients received craniospinal radiation, 1 received only spinal radiation and 1 received no spinal radiation. The latter patient was excluded from further analysis. Photon therapy was used more often than proton, and more than half of the patients received 30 Gy of spinal radiation (Table 1).
Table 1: Patient and disease characteristics at enrollment. N=50 patients studied.
|
Male
|
Female
|
|
|
|
Sex
|
34
|
17
|
|
|
|
|
White
|
Black
|
Asian
|
Other
|
|
Race
|
45
|
4
|
1
|
1
|
|
|
Medulloblastoma
|
Atypical Teratoid
|
Ependymoma
|
Glioma
|
Other
|
Diagnosis
|
42
|
2
|
1
|
2
|
4
|
|
Brain
|
Spine, cervical
|
Spine, Thoracic
|
Spine, Lumbar
|
Other
|
Cancer Location*
|
51
|
2
|
1
|
4
|
11
|
|
Yes
|
No
|
|
|
|
Chemotherapy Used
|
49
|
2
|
|
|
|
|
Cisplatin
|
Cyclophosphamide
|
Carboplatin
|
Lomustine
|
Ifosfamide
|
Chemotherapy Type
|
44
|
39
|
19
|
19
|
1
|
|
Craniospinal
|
Spinal Only
|
|
|
|
Radiation Location
|
50
|
1
|
|
|
|
|
Photon
|
Proton
|
Unknown
|
|
|
Radiation Type
|
36
|
14
|
1
|
|
|
|
>0 to <30
|
30
|
None#
|
Unknown
|
|
Radiation Dose to the spine, Gy
|
17
|
29
|
1
|
4
|
|
*Other locations included: leptomeningeal (5), positive cerebrospinal fluid (4), sacral (2)
#Patient removed from analysis
Echocardiograms were available in 20 patients at the early time point and 34 patients at the late time point. There were 13 patients with echocardiograms in both groups, however the time points were not compared to each other and considered standalone time points. The oldest echocardiogram included in analysis was performed in 2007. Patients at the late time point were older than those in the early group (21.7±10.4 vs. 13.3 9.6 years, respectively), and time between end of therapy and echocardiogram was greater (13.1±8.8 vs. 0.2±0.3 years, respectively) (Table 2). Standard echocardiographic parameters assessing left ventricular systolic function were normal for all subjects when compared to age-based published normal values. In the late group, two patients were on the combination of lisinopril and carvedilol for a history of mild left ventricular dysfunction, and one was on atenolol for sinus tachycardia and diastolic dysfunction on echocardiogram. Afterload, represented by systolic blood pressure, was normal for both groups. In the early group one patient was on atenolol for hypertension, and in the late group two patients had systolic blood pressure greater than 95%ile but they were not on medication. Parameters known to affect ventricular function such as hemoglobin (anemia) and creatinine (renal dysfunction) were within normal limits for both groups. One patient in the late group was on metformin for diabetes management (Table 2).
Table 2: Demographic and standard echocardiographic measures at early and late timepoints after craniospinal radiation (see text for definition of terms). LV = left ventricular; LVEDD = left ventricular diastolic dimension; LVEF = left ventricular ejection fraction; LVFS = left ventricular fractional shortening; SBP = systolic blood pressure.
|
early
|
late
|
|
|
|
N
|
20*
|
34#
|
Age (years)
|
13.3±9.6
|
21.7±10.4
|
Time since therapy completion (years)
|
0.2±0.3
|
13.1±8.8
|
SBP (mmHg)
|
105.4±10.3
|
115.2±16.1
|
LVEDD (mm)
|
4.0±0.6
|
3.9±0.6
|
LVFS (%)
|
32.6±5.4
|
34.4±3.8
|
LVEF (%)
|
62.3±6.5
|
60.9±4.5
|
Presence of diabetes mellitus^
|
0 (0%)
|
1 (3%)
|
Presence of hypertension+
|
1 (5%)
|
2 (6%)
|
Patient on cardiac medication(s)++
|
1 (5%)
|
3 (9%)
|
Hemoglobin (g/dL)$
|
11.3±1.5
|
13.5±2.3
|
Creatinine (mg/dL) $
|
0.5±0.1
|
0.7±0.3
|
*N available for analysis: LVEDD =19; LVEF = 15; all other = 20.
#N available for analysis: SBP and LVSF = 33; LVEDD and LVEF = 30; hemoglobin = 29; creatinine = 27; all other = 34.
^Patients with a diagnosis of diabetes mellitus documented in the chart or on medication to control diabetes at the time of the echocardiogram.
+Patients with systolic blood pressure >95%ile for age or on antihypertensive medication at the time of the echocardiogram.
++Patients on cardiac medication(s) at time of echocardiogram, including angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta blocker, calcium channel blocker, or mineralocorticoid receptor antagonist.
$Laboratory data collected from the electronic medical record for the value closest in time to the echocardiogram but no greater than ± 8 weeks.
When considering myocardial deformation measured by myocardial strain analysis, at early, CSI vs. control: GLS was -16.8 3.6% vs. -21.3 4.0% (p=0.0002), GCS was -22.5 5.2% vs. -21.3 3.4% (p=0.28), and GRS was 21.8 11.0% vs. 26.9 7.7% (p=0.07). At late, CSI vs. control: GLS was -16.2 5.4% vs. -21.6 3.7% (p<0.0001), GCS was -20.9 6.8% vs. -21.9 3.5% (p=0.42), and GRS was 22.5 10.0% vs. 27.3 8.3% (p=0.03) (Table 3). Because a cut-off of 30 Gy radiation to the heart is a known risk factor for development of cardiotoxicity,6 we assessed the differential effect of low-dose CSI (<30 Gy) and high-dose CSI ( 30 Gy) on strain parameters in the study. In addition, with decreased off-target effects reported for proton vs. photon sources of radiation4 we assessed whether there was a difference in strain values between patients treated with these two modalities. There were no statistically significant differences between either of these treatment conditions at either time point for any of the strain values (Table 3).
Table 3: Global longitudinal strain (GCS), global circumferential strain (GCS), and global radial strain (GRS) in patients vs. age- and sex-matched controls at early and late (see text for definition), photon vs. proton radiation type, and spinal radiation exposure of <30 Gy vs. 30 Gy.
|
early
|
Control
|
p-value
|
|
late
|
Control
|
p-value
|
N
|
19
|
36
|
--
|
|
30
|
48
|
--
|
Male
|
10 (52%)
|
23 (64%)
|
0.56
|
|
21 (70%)
|
31 (65%)
|
0.81
|
Age (year)
|
11.7±8.0
|
11.3±5.0
|
0.36
|
|
21.7±10.1
|
20.3±9.6
|
0.56
|
GLS*
|
-16.8±3.6%
|
-21.3±4.0%
|
0.0002
|
|
-16.2±5.4%
|
-21.6±3.7%
|
<0.0001
|
GCS*
|
-22.5±5.2%
|
-21.1±3.3%
|
0.28
|
|
-20.9±6.8%
|
-21.9±3.5%
|
0.42
|
GRS*
|
21.8±11.0%
|
26.9±7.7%
|
0.07
|
|
22.5±10.0%
|
27.3±8.3%
|
0.03
|
|
early photon
|
early proton
|
p-value
|
|
late photon
|
late proton
|
p-value
|
GLS#
|
-16.4±2.3%
|
-17.6±5.1%
|
0.50
|
|
-15.9±5.3%
|
-16.8±6.3%
|
0.78
|
GCS#
|
-22.0±5.9%
|
-23.4±3.6%
|
0.64
|
|
-20.6±7.4%
|
-21.6±4.6%%
|
0.77
|
GRS#
|
22.5±11.5%
|
20.4±10.9%
|
0.74
|
|
22.1±8.8%
|
24.4±16.0%
|
0.65
|
|
early <30 Gy
|
early 30 Gy
|
p-value
|
|
late <30 Gy
|
late 30 Gy
|
p-value
|
GLS^
|
-17.1±3.9%
|
-17.1±3.6%
|
0.50
|
|
-15.8±4.5%
|
-14.9±4.2%
|
0.72
|
GCS^
|
-24.0±5.2%
|
-20.6±5.9%
|
0.64
|
|
-24.0±8.4%
|
-20.0±7.1%
|
0.31
|
GRS^
|
26.8±10.1%
|
15.7±9.1%
|
0.74
|
|
21.3±12.9%
|
21.2±8.3%
|
0.99
|
*N available for analysis: early = 18 GLS, 15 GCS, and 16 GRS; late = 26 GLS, 29 for GCS and GRS.
#N available for analysis: early photon = 11 GLS and GRS, 10 GCS; early proton = 7 GLS, 5 GCS and GRS; late photon = 23 GLS, 24 GCS and GRS; late proton = 4 GLS, 5 GCS and GRS.
^N available for analysis: early <30 = 8 for all; early >30 = 8 GLS, 5 GCS, and 6 GRS; late <30 = 4 for all; late 30 = 20 GLS, 22 GCS and GRS.