Radiation Treatment and delivery
The clinical pilot study (NCT03748030) was approved by the Western University Human Research Ethics Board (HSREB ID 112991). Of 17 recruited left-sided breast cancer patients, stage T0-T3, one patient was ineligible, and one did not consent. All patients did not have a prior cardiac disease history and one patient was diagnosed with diabetes mellitus. None of the patients received any prior RT to the thorax or breast.
Patients in the study received their RT during 2020–2021. The majority of patients (73%) received standard deep inspiration breath-hold (DIBH) forward planned intensity-modulated radiotherapy (IMRT), 42.5 Gy in 16 fractions and did not receive adjuvant chemotherapy (67%). 7 of the 11 DIBH RT patients received additional boost doses of 10 Gy in 5 fractions. One patient only completed the first five fractions of her radiation treatment and discontinued due to breast swelling, pain and erythema.
Fifteen left-sided breast cancer patients treatment plans were retrospectively reviewed. Treatment planning optimization was performed using the Pinnacle3 treatment planning system (Philips Radiation Oncology Systems, Fitchburg, USA). Contours of the heart, left ventricle (LV), and left anterior descending artery (LAD) were manually delineated on the treatment planning CT performed on the Philips Brilliance Big Bore CT scanner (Philips Medical Systems) using Mim maestro (Mim Software Inc., Cleveland, USA). The mean values for each dose metrics are shown in table 1. Note that this cohort of patients received a low dose in the reported cardiac regions.
Imaging
PET/MR imaging was performed on a 3T-hybrid PET/MRI scanner (Biograph mMR Siemens Medical Systems, Malvern, USA) prior with serial blood work drawn at baseline, within 1-month and within 1-year following the completion of RT. Patients were imaged in the supine position. In this paper, we are reporting the results at 1-month follow-up.
PET imaging (Myocardial inflammation)
The suppression of glycolysis was achieved through fasting (12 hours prior imaging) and a 24-hour diet which was high in fat, low in carbohydrate and low in protein prior to the PET scan. Furthermore, the injection of heparin at 45 minutes (5 µg/kg) and 30 minutes (10 µg/kg) was performed prior to the injection of 18FDG. A 60-minute list-mode scan of 18FDG with a bolus injection at 5 MBq/kg was conducted. All PET data were reconstructed using an iterative three-dimensional ordered subset expectation maximization algorithm (OSEM) [17] with 3 iterations, 21 subsets, 10-minutes intervals, 172 x 172 x 127 matrix size and a 4 mm-Gaussian smoothing filter, yielding a voxel size of 2.08 x 2.08 x 2.03 mm. Attenuation was corrected for all PET scans using a two-point Dixon MR imaging pulse sequence (MRAC), which automatically segments and substitutes discrete attenuation coefficients of the lung, adipose tissue and soft tissue [18]. Myocardial contours were manually delineated on the PET images fused with the MRAC images using Mim maestro, according to the American Heart Association 16-segment model [19].
Myocardial inflammation was assessed using the change from the baseline pre-radiation treatment study in the mean 18FDG/PET standard uptake based on body weight (meanSUVbw) in the myocardial tissue between 40–60 minutes post tracer injection. SUV at 1-month follow-up compared to baseline was calculated where the change was segmented based on each coronary vascular territory: left anterior descending (LAD), left-circumflex (LCX) or right coronary (RC) artery.
Mr Imaging
T2-weighted images of the heart using 3 slice locations (apex, mid and base) were acquired concurrently with PET imaging using TrueFISP 2D sequence with 224.03 ms repetition time, 1.31 ms echo time, flip angle: 60, FOV matrix of 288 x 360 and slice thickness of 6 mm.
The T2-weighted images were followed by a 2D stack of standard non-contrast steady state free precession cine images and T1-weighted images of the whole heart before and during a gadolinium contrast (Gadovist; Bayer Inc, Mississauga, ON) infusion. The cine images were acquired using TrueFISP sequence, flip angle: 50, 43.5 ms repetition time, 1.58 ms echo time, FOV matrix = 253 x 300, and a slice thickness of 6 mm.
The gadolinium contrast was injected as a bolus over 2 minutes (0.1 mmol/kg) and then followed by a constant infusion over 30 minutes 0.002 mmol/kg/min). The T1-weighted post gadolinium constant infusion images were acquired 10 minutes into the constant infusion. Both sets of T1-weighted images were acquired using the MOLLI sequence with 293.92 ms repetition time, 1.22 ms echo time, flip angle: 35, FOV matrix = 255 x 300 and slice thickness 6 mm.
Circle CVI42 v5.11 (Circle Cardiovascular Inc., Calgary, Canada) was used to assess cardiac function, including LV functional parameters (LVEDV, SV and LVEF) and a radiologist (AI) provided clinical assessment of the T2-weighted and T1-weighted post-contrast images. The extracellular volumes (ECV) were calculated using Eq. (1) with the extraction of T1 values of the blood pool and the myocardium between pre- and during- constant infusion, grouped based into three slices locations (apex, mid and basal). The hematocrit ratio was determined from the blood sample.
$$\left(1\right)ECV=\left(1-hematocrit ratio\right)\left(\frac{\frac{1}{Post contrast T1 myocardium}-\frac{1}{native T1 myocardium}}{\frac{1}{Post contrast T1 LV blood pool}-\frac{1}{native T1 LVblood pool}}\right)$$
Bloodwork
Blood for the parameters noted earlier were drawn prior to the baseline pre-radiation scan and measured at 1-month follow-up.
Statistical Analysis
Statistical analyses were performed using SPSS IBM v.23 (IBM SPSS Statistics for Windows, Armonk, NY). Shapiro-Wilk normality test was utilized to check for normality among the values of standard uptake of 18FDG per supplied coronary region, left ventricular functional parameters, blood work and ECV measurements before and 1-month after RT. Based on the Shapiro-Wilk test, all the blood work measurements (hs-TnT, hs-CRP and ESR) were not normally distributed (p < 0.03). Consequently, tests of significance for these parameters were performed using the Wilcoxon signed rank test. A Paired t-test was performed for all other parameters. A bivariate correlation test was performed to compare these changes to relevant dosimetric parameters of the heart and substructures presented in table 1.
Dosimetric parameters of the heart and its substructures were tested for significance between the DIBH and free-breathing-RT group using Mann-Whitney U test. If any of the changes of the 18FDG regional uptake, LV functional parameters, blood work and ECV measurements were significant at follow-up, Mann-Whitney U test was further performed to check for significance between the DIBH and Free-breathing-RT group.