Radiotherapy has led to survival benefits for thoracic cancers, such as breast cancer, Hodgkin's lymphoma (HL), oesophageal cancer and lung cancer. However, because of the longer survival period, the risk of RIHD has increased. A study involving 1474 HL patients reported that the RR in post-radiation patients ranged from 3 to 5, and 66–80% of patients suffered from RIHD induced by mediastinal radiation. Cardiac-induced mortality was the leading cause of non-cancer-induced death in both HL and breast cancer after radiotherapy. Relatively fewer studies have focused on RIHD of oesophageal cancer than on HL and breast cancer because the survival period of oesophageal cancer is obviously shorter. However, the dose to the heart during oesophageal radiotherapy is elevated because of the anatomical location. The mean dose received by the heart in breast cancer is commonly 10–15 Gy, while in distal oesophageal radiotherapy, this dose might reach or exceed 50 Gy. Beukema et al. collected articles published from 1970–2013 related to cardiotoxicity after oesophageal cancer radiotherapy and found that the rate of RHID was approximately 10.8% (5–44%) . Ogino et al. conducted a retrospective study with a median follow-up period of 79 months (range from 48–127 months), and 343 oesophageal cancer patients who received concurrent radiotherapy or radiotherapy alone with long-term survival (more than 4 years) were included. The end point of the study was symptomatic heart disease, with a five-year incidence of 13.8%.
The clinical spectra of heart diseases caused by radiotherapy include pericardial disease, myocarditis, valvular disease, coronary artery disease (CAD) and conduction abnormalities. Pericardium effusion and pericarditis are the most common RIHDs. Pericardium effusion is usually asymptomatic. Acute pericarditis mostly occurs during or after radiotherapy, while delayed chronic pericarditis usually occurs 1 year after treatment. The main mechanism of myocardial damage was fibrosis, which might lead to congestive insufficiency. Most chronic heart failure occurred decades after treatment. CAD is rare in RIHD but is fatal, with a latent period of approximately 10 years. Radiation-induced valvular disease mainly influences the left ventricle. Valvular disease involves valvular contraction and regurgitation. Regurgitation symptoms are more common and usually occur 10 years post-radiation. In a study by Lund et al., the incidence of left ventricular valve regurgitation in patients with HL after radiotherapy was 6–40%, compared with 2% in patients without radiotherapy. The pathological basis of conduction system disorder was also fibrosis induced by irradiation. The manifestation of conduction system disorder is ECG abnormalities, and approximately 70% of patients returned to normal ECG readings without intervention. Other than acute pericarditis, most RIHDs have a relatively long incubation period, and the incidence increases with time.
The two major risk factors of RIHD include irradiation dose and volume. According to a long-term follow-up of 4414 post-radiation breast cancer patients by Honning et al., the rate of RIHD was related to the mean dose to the heart during radiotherapy. Another study of RIHD in breast cancer put forward a specific dosimetric relationship between delivered dose and rate of cardiac mortality, which increased by 3% for every additional 1 Gy of radiation dose. Carmel et al. proved that the rate of pericarditis induced by entire heart irradiation was able to be decreased by blocking the left ventricle and inferior pericardium region. All of this research implies the importance of evaluating the displacement of the heart and its substructures, which would influence the irradiation dose and volume. Apart from these, factors such as fraction dose, radiotherapy techniques, chemotherapeutic agents (mainly anthracyclines and trastuzumab), and patient risk factors such as age have also been proven to be related to RIHD. With the development of radiotherapy technology, the cardiotoxicity of radiotherapy has been significantly reduced. According to Lin SH et al., compared with 3-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiation therapy (IMRT) remarkably reduced cardiac mortality (72.6% vs 52.9%, P < 0.001), but cancer-specific mortality showed no significant difference between methods (P = 0.86). However, the risk of cardiotoxicity has not been eliminated by techniques at present. Anthracyclines are commonly used as chemotherapy schemes in the treatment of breast cancer and HL patients. The most frequent regimen of concurrent radiochemotherapy for oesophageal cancer is 5-FU and cisplatin, which have also been proven to be slightly cardiotoxic[23, 24].
Thus, it is necessary to accurately evaluate the displacement of the heart and its substructures caused by periodic cardiac activity and calculate the compensatory margin that could be applied in clinical practice when creating a radiotherapy plan. Many studies have proven that delineation of the pericardium, heart, LVM, and CA system based on planning CT fails to show the real margin of the substructures mentioned above during the cardiac cycle[9–12], and a compensatory margin for planning CT should be applied. One study based on CBCT recommended compensatory margins of 11 (left), 6 (right), 3 (cranial), 4 (caudal), 7 (anterior), and 5 (posterior) mm for the heart. Kataria et al. measured that radial and cranio-caudal margins of 7 mm and 4 mm, respectively, would cover the range of motions of the CA on CECT . Li et al. found that the maximum compensatory margins in the LR, CC, and AP directions for the CA bifurcations were 6, 6, and 5 mm (left) and 6, 8, and 7 mm (right) on 4D-CT, respectively. Therefore, the volume-dose parameters used to evaluate the dose to the heart might not truly reflect the dose received during oesophageal radiotherapy and could not provide accurate protection for the heart. Studies on heart motion at present mostly focus on the entire heart and CA system based on CT, but the ability to distinguish sophisticated structures has been challenged. Considering that MRI has the advantage of discriminating muscular structures, we aimed to conduct research on the displacement of the pericardium, heart, interatrial septum, interventricular septum, LVM, ALPM and PMPM with 4D-MRI. With the application of the breath-hold technique, the influence of respiratory movement was offset.
Based on our results, the displacement of the whole heart and its substructures caused by cardiac activity was non-negligible, ranging from 4 mm to 26.1 mm. The most significant motion was in the LR direction for the LVM (26.1 mm). The amplitude of pericardium motion was slightly milder than the motion of the LVM, interatrial septum and interventricular septum. Considering that position, volume and morphology changed during the cardiac cycle, we then reconstructed the ITV, which reflected the actual locations based on 20 phases of 4D-MRI. Radiotherapy plans are still mainly designed and evaluated with CT images, so we hoped to provide specific compensatory margins for planning CT to make the recommendations more realistic. Because of the periodic cardiac movement, the ITV that reflected the extent of motion could be larger than the volume contoured on the planning CT for every structure mentioned above theoretically. Consistent with the hypothesis, the ITV boundary of each structure was larger than that contoured on the planning CT, and the compensatory margins ranged from 0.9 mm to 6.6 mm. The volume differences of the pericardium (743.39 ml vs. 726.62 ml) and heart (547.94 ml vs. 546.53 ml) were moderate, while for other structures, the largest difference could as high as an eight-fold difference. The largest differences between the ITV and planning CT volume were for the ALPM and PMPM. This was consistent with the trend that the motion amplitude of the left ventricular papillary muscles was similar to that of other structures (P = 0.423, 0.423, 0.406 respectively in AP, LR, and CC axes), even though these muscles have a much smaller volume. The largest compensatory distance was for the left ventricular papillary muscle. There were no significant differences among the motion amplitudes of the involved substructures, but the compensatory distances were significantly different (P = 0.044). Through further analysis, disparities mainly existed between the heart and ALPM (P = 0.008), heart and PMPM (P = 0.008), LVM and ALPM (P = 0.039), LVM and PMPM (P = 0.038), pericardium and ALPM (P = 0.041) and pericardium and PMPM (P = 0.039). It could be prompted that the left ventricular papillary muscles were more active and that it was more difficult to assess the potential exposure to these muscles with the dose-volume parameters based on planning CT. Part of the reason might be the low resolution of the papillary muscles on CT images, suggesting that the boundary of the papillary muscles contoured on the planning CT might be smaller than the real volume. In conclusion, according to our study, it is necessary to evaluate cardiac radiation exposure by applying compensatory margins on planning CT for a high-risk population who might have symptomatic cardiac damage during thoracic radiation.
Our research had the advantage of applying the breath-hold ECG-gated 4D-MRI technique, as well as focusing on substructures of the heart. However, the research was also limited by the sample size, which led to a relatively large deviation. As a result of a narrow imaging range, the inferior margin of the pericardium and the whole heart were not completely displayed on 4D-MR, which made it impossible to measure the motion amplitude of the pericardium and heart, and their compensatory margins might be smaller than those actually needed. The standard compensatory margins of the heart and its substructures require verification in more clinical trials. This research concentrated on displacement of the heart and its substructures and compensatory margins only, and future research of dose-volume parameters during oesophageal radiotherapy based on 4D-MRI should be conducted.