Introduction
The number of cancer survivors has increased in association with the aging society and the reduction in age-adjusted mortality rates owing to recent advances in cancer therapy [1]. Cardiovascular complications can occur during and after cancer therapy. Generally, based on the concept of onco-cardiology, physicians should maximize the beneficial effects of cancer therapy while avoiding serious, lethal cardiovascular complications [2].
CAD is one of the leading causes of death in patients with esophageal cancer receiving radiation therapy (RT), especially those aged ≥70 years [3,4]. Patients with esophageal cancer are likely to undergo bilateral irradiation of the heart and have multiple cardiovascular risks factors, such as male sex, cigarette smoking, hypertension, dyslipidemia, and diabetes [5]. These factors, including increased irradiation dose to the heart and multiple traditional coronary risk factors, are known to predispose patients to the risk of radiation-induced coronary artery disease (RI-CAD) [6,7]. A significant coronary artery calcification (CAC) is related to increased cardiovascular events in the general population without cancer [8,9]. Recent studies have reported that non-gated computed tomography (CT) imaging is also feasible for evaluating the Agatston score [10–12].
Based on the above mentioned evidence, we conducted a retrospective study on CAC in patients with esophageal cancer receiving RT. This study aimed to investigate the following: (1) CAC at baseline and its progression using non-electrocardiography (ECG)-gated PET-CT (that was performed for the purpose of cancer diagnosis or follow-up), (2) factors associated with CAC, and (3) the clinical impact of CAC on the prognosis.
Methods
Participant eligibility
From May 2007 to August 2019, 517 consecutive patients who underwent RT for esophageal cancer at our institution were retrospectively screened from our institutional cancer treatment database. Patients without baseline ECG or transthoracic echocardiography data and those without baseline or follow-up fluorodeoxyglucose (FDG) PET/CT data were excluded. The procedures followed were in accordance with the ethical standards of the responsible institutional or regional committee on human experimentation.
Data collected at baseline
Data on baseline characteristics including age, sex, comorbidities/previous disease (hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease, history of heart disease), smoking habit (<1 year before initiation of RT), and family history of premature heart disease (age <55 years) were collected. Blood test markers [i.e. C-reactive protein (CRP) levels] were measured. Furthermore, cardiac and coronary vessel investigation results (e.g. ECG and echocardiographic findings) were summarized. Oncological information (e.g. performance status, clinical stage, cancer site, and pathology) and cancer treatment details (e.g. surgery, chemotherapy, and radiation) were also collected.
Image analysis
CAC is commonly assessed by the original Agatston score, which requires ECG-gated CT imaging [7,13]. However, previous studies have demonstrated no significant feasibility issues in evaluating CAC using low-dose and non-ECG-gated CT [10–12,14]. Therefore, FDGPET/CT data before and after RT (performed for cancer diagnosis/follow-up) were used to measure the Agatston score using a calculation software (Institution server: Terarecon Inc., Tokyo, Japan) [15]. Patients fasted for at least 6 h before PET imaging, which was performed using an FDGPET/CT scanner (Biograph 6 or 16; Siemens Healthineers K.K., Osaka, Japan) with a 585-mm field of view. Three-dimensional data acquisition was initiated 60 min after injecting 3.7 MBq/kg of FDG. We acquired data in eight bed positions (2-min acquisition per bed position) according to the range of imaging. Attenuation-corrected transverse images obtained with 18F-FDG were reconstructed using the ordered-subsets expectation-maximization algorithm, based on the point spread function, into 168 × 168 matrices with a 2.00-mm slice thickness. The portion of each slice with a CT value of 130 Hans-field units or more and two pixels or more was considered to exhibit significant calcification [16]. The calcified area of the coronary artery was semi-automatically traced to determine the extent of propagation. The calcified sites of the right coronary artery, left main coronary trunk, left anterior descending artery, and left circumflex artery were manually traced (Fig. 1a–f) by two observers (K.M.: specialist in cardiovascular diagnostic imaging, K.F.: radiologist) with experience in interpreting cardiac CT images. The Agatston scores for each artery (as well as the sum of these values per patient) were calculated. Any discordance regarding the traced area between the two observers was discussed, and re-tracing was performed in collaboration. The same observers (K.M. and K.F.) visually confirmed the progression of CAC on the FDGPET/CT images.
;)
Fig. 1: Actual measurement of the Agatston score. The Agatston score was measured using non-ECG-gated FDGPET/CT. The calcified area of the coronary artery is traced to determine the extent of propagation. The calcified sites of the right coronary artery, left main coronary trunk, left anterior descending artery, and left circumflex artery were manually traced (blue circle), and the Agatston scores for each artery (as well as the sum of these values per patient) were calculated (red part). ECG, electrocardiography; FDGPET/CT, PET-computed tomography.
Radiation treatment protocol
All patients were treated using the three-dimensional conformal RT technique. For treatment planning, 2-mm-thick CT images were used. CT images were also obtained during the expiratory and inspiratory phases to account for respiratory motion of the tumor. The dose was calculated using the superposition method. The gross tumor volume (GTV) was defined as the volume of the visible tumor and lymph node metastasis on CT with reference to FDGPET/CT. The clinical target volume (CTV) was defined as the GTV + a 5–10 mm margin + the prophylactic lymph node area. The planning target volume was defined as the CTV + a 5-mm margin. The total dose of RT was 60 Gy in 30 fractions or 50.4 Gy in 28 fractions for cases in which the irradiation field included the heart. Basically, 40 Gy in 20 fractions (or 39.6 Gy in 22 fractions) was administered from the anterior and posterior directions; thereafter, diagonal beams were used to avoid the spinal cord [17,18]. Per protocol, RT to the middle or lower part of the chest (‘middle-lower chest’) involved cardiac irradiation.
Outcome measures
The primary endpoint was all-cause death, and the secondary endpoint was major adverse cardiovascular events (MACEs; a composite of cardiovascular death, and emergent hospitalization for nonfatal myocardial infarction, unstable angina, or heart failure). The incidence of each endpoint within 3 years of RT was evaluated.
Statistical analyses
Categorical variables are expressed as numbers (proportion; %). Continuous variables are expressed as means ± standard deviations for normally distributed data or medians (first–third quartile) for skewed data. The Agatston scores at baseline were compared with those at 1 year after RT using the Wilcoxon signed-rank test; these comparisons were evaluated in the total population. For subgroup analysis, patients were divided by the location of RT (irradiation to the middle-lower chest or not) and the Agatston score (zero Agatston score at baseline or not), and Kaplan–Meier analysis with the log-rank test was performed to compare all-cause death and MACEs within 3 years. Univariate analysis was performed using a Cox proportional hazard model to assess the association between all-cause death and baseline variables.
All statistical analyses were performed using JMP (SAS Institute, Cary, North Carolina, USA) and GraphPad Prism (GraphPad Software, San Diego, California, USA) when necessary. A P-value <0.05 was considered statistically significant.
Results
Baseline characteristics, cancer characteristics, cancer treatment, and clinical outcomes
Of 516 patients receiving RT for esophageal cancer, those without baseline transthoracic echocardiography or ECG data (n = 134 and 5, respectively) or without baseline or follow-up (>3 months after initiation of RT) FDGPET/CT data (n = 190) were excluded. The remaining 187 patients were examined (Fig. 2). In the 1-year [range: 3–12 months, median: 7 months (first–third quartile: 5–9)] analysis, 18 patients were excluded because of missing FDGPET/CT data during this period; therefore, the images of 169 patients were analyzed. Similarly, at 2 years (range: 13–24 months, median: 20 months [15–22]), the data of 86 patients were analyzed.
Fig. 2: Flowchart showing patient eligibility and schema of analysis. From May 2007 to August 2019, we enrolled all 516 patients who underwent radiation therapy for esophageal cancer at our hospital. Of 516 patients receiving RT for esophageal cancer, those without baseline transthoracic echocardiography or ECG data (n = 134 and n = 5, respectively) and those without baseline or follow-up (>3 months after initiation of RT) FDGPET/CT data (n = 190) were excluded. The remaining 187 patients were examined. CAC scoring and clinical analysis (all-cause death and MACEs) within 2 years were performed for 187 patients. CAC, coronary artery calcification; ECG, electrocardiography; FDGPET/CT, PET-computed tomography; MACEs, major adverse cardiovascular events; RT, radiation therapy.
Most patients were relatively older men (mean age, 73 years) with a current smoking habit, and one-third of the patients had concomitant hypertension (Table 1). All patients independently managed their activities of daily living (performance status: 0, 1, or 2). Regarding the cancer characteristics, most patients had esophageal cancer of the middle-lower chest (75.9%) and squamous cell carcinoma (95.1%). Most patients received concomitant chemotherapy using platinum-based drugs (86.0%). There were 34 (18.1%), 11 (5.8%), and 14 (7.4%) cases of chemoradiotherapy for postoperative recurrence, preoperative adjuvant chemoradiotherapy, and salvage surgery, respectively. There was no difference in the radiation dose between the surgical [2185 (178–3099) Gy] and non-surgical groups [2399 (872–3118) Gy] (P = 0.227). Throughout the observation period (median, 23 months [12–24]; total, 187 person-years), 33 patients died and six developed MACEs (see details below).
Table 1 -
Baseline characteristics, cancer characteristics, cancer treatment, and outcomes
|
All patients (n = 187) |
Hazard ratio (95% CI of ratio) |
P-value for all-cause death |
| Demographics |
| Age, years |
73.0 (68.0–78.0) |
1.017 (0.996–1.040) |
0.471 |
| Men, n (%) |
153 (81.8) |
1.218 (0.813–1.898) |
0.334 |
| Comorbidities and coronary risk factors |
| Hypertension, n (%) |
70 (37.4) |
1.035 (0.745–1.426) |
0.589 |
| Dyslipidemia, n (%) |
23 (12.2) |
0.828 (0.496–1.304) |
0.972 |
| Diabetes mellitus, n (%) |
13 (3.7) |
0.941 (0.480–1.656) |
0.821 |
| Chronic kidney disease, n (%) |
7 (3.7) |
0.769 (0.273–1.686) |
0.468 |
| Previous myocardial infarction, n (%) |
2 (1.0) |
2.057 (0.116–9.371) |
0.294 |
| Previous cardiac surgery/intervention, n (%) |
2 (1.0) |
2.057 (0.116–9.371) |
0.294 |
| Smoking, n (%) |
138 (73.7) |
0.958 (0.678–1.381) |
0.464 |
| Family history (cardiovascular events), n (%) |
5 (2.6) |
0.814 (0.288–1.784) |
0.160 |
| Blood test findings |
| C-reactive protein (mg/dl) |
0.381 (0.081–2.245) |
1.104 (1.033–1.171) |
0.004* |
| Coronary vessel investigation |
| CAC site |
|
|
|
|
Right coronary artery, n (%) |
46 (24.5) |
- |
- |
|
Left main trunk, n (%) |
19 (10.1) |
- |
- |
|
Anterior descending artery, n (%) |
63 (33.6) |
- |
- |
|
Circumflex artery, n (%) |
27 (14.4) |
- |
- |
| Electrocardiographic findings |
|
|
|
| Normal, n (%) |
117 (62.5) |
|
- |
| Atrial fibrillation, n (%) |
9 (4.8) |
- |
- |
| CRBBB, n (%) |
10 (5.3) |
- |
- |
| IRBBB, n (%) |
7 (3.7) |
- |
- |
| Abnormal Q wave, n (%) |
6 (3.2) |
- |
- |
| Left-ventricular hypertrophy, n (%) |
3 (1.6) |
- |
- |
| Complete atrioventricular block, n (%) |
1 (0.5) |
- |
- |
| Echocardiographic findings |
|
- |
- |
| Left-ventricular ejection fraction, % |
71.0 (66.0–77.0) |
0.999 (0.980–1.020) |
0.740 |
| Agatston score |
0 (0–142.0) |
1.000 (0.999–1.000) |
0.309 |
| General cancer conditions |
| Performance status ≤2, n (%) |
185 (98.9) |
0.716 (0.177–2.893) |
0.376 |
| Clinical stage- |
| I, n (%) |
20 (10.6) |
- |
- |
| II, n (%) |
37 (19.7) |
- |
- |
| III, n (%) |
61 (32.6) |
- |
- |
| IV, n (%) |
69 (36.8) |
- |
- |
| Cancer characteristics |
| Middle or lower thoracic location, n (%) |
142 (75.9) |
0.898 (0.633–1.298) |
0.060 |
| Pathology |
| Squamous cell carcinoma, n (%) |
178 (95.1) |
|
- |
| Adenocarcinoma, n (%) |
8 (4.2) |
- |
- |
| Small-cell carcinoma, n (%) |
1 (0.5) |
- |
- |
| Cancer treatment |
| Surgery, n (%) |
59 (31.5) |
1.200 (0.846–1.678) |
0.864 |
| Chemotherapy, n (%) |
162 (86.6) |
- |
- |
| 5FU + CDDP, n (%) |
159 (85.0) |
- |
- |
| DTX, n (%) |
1 (0.5) |
- |
- |
| CDDP + ETP, n (%) |
1 (0.5) |
- |
- |
| TPF, n (%) |
1 (0.5) |
- |
- |
| Platinum, n (%) |
161 (86.0) |
1.258 (0.774–2.196) |
0.017* |
| Outcomes (within 2 years) |
| All-cause death, n (%) |
33 (17.6) |
- |
- |
| MACEs, n (%) |
6 (3.5) |
- |
- |
Categorical variables are expressed as number (proportion: %). Continuous variables are expressed as mean ± SD for normally distributed data or median (first–third quartile) for skewed data. Univariate analysis using a Cox proportional hazard model was performed to assess the association between all-cause death and baseline variables.
CAC, coronary artery calcification; CDDP, cis-diamminedichloroplatinum; CRBBB, complete right bundle branch block; DTX, docetaxel hydrate; ETP, etoposide; FU, 5-fluorouracil; IRBBB, incomplete right bundle branch block; MACE, major adverse cardiac event; TPF, docetaxel hydrate, cisplatin, and fluorouracil.
The comparison of the baseline characteristics between the group with and without irradiation to the middle-lower chest showed significant differences in the CAC site (i.e. left main trunk), pathology (i.e. squamous cell carcinoma and adenocarcinoma), and cancer treatment (i.e. chemotherapy and platinum-based chemotherapy) (Table 2).
Table 2 -
Baseline characteristics and outcomes by irradiation site
|
Irradiation to the middle-lower chest |
P values |
|
+ (n = 142) |
− (n = 45) |
|
| Demographics |
|
|
|
| Age, years |
73.5 (68.0–79.0) |
72.0 (67.5–76.5) |
0.236 |
| Men, n (%) |
118 (83.0) |
40 (88.8) |
0.188 |
| Comorbidities and coronary risk factors |
|
|
|
| Hypertension, n (%) |
57 (40.1) |
13 (28.2) |
0.216 |
| Dyslipidemia, n (%) |
18 (12.6) |
5 (11.1) |
0.805 |
| Diabetes mellitus, n (%) |
9 (6.3) |
4 (8.8) |
0.737 |
| Chronic kidney disease, n (%) |
5 (3.5) |
2 (4.4) |
0.999 |
| Previous myocardial infarction, n (%) |
2 (0.70) |
0 |
0.999 |
| Previous cardiac surgery/intervention, n (%) |
2 (0.70) |
0 |
0.999 |
| Smoking, n (%) |
106 (74.6) |
32 (71.1) |
0.698 |
| Family history (cardiovascular events), n (%) |
5 (3.5) |
0 |
0.339 |
| Blood test findings |
|
|
|
| C-reactive protein (mg/dl) |
0.39 (0.08–1.89) |
0.36 (0.07–3.01) |
0.777 |
| Coronary vessel investigation |
|
|
|
| Coronary artery calcification site |
|
|
|
| Right coronary artery, n (%) |
36 (25.3) |
10 (22.2) |
0.698 |
| Left main trunk, n (%) |
18 (12.6) |
1 (2.2) |
0.047 |
| Anterior descending artery, n (%) |
49 (34.5) |
14 (31.1) |
0.720 |
| Circumflex artery, n (%) |
24 (16.9) |
3 (7.5) |
0.330 |
| Echocardiographic findings |
|
|
|
| Left-ventricular ejection fraction, % |
71.0 (65.0–77.0) |
72.0 (66.0–75.0) |
0.879 |
| Agatston score |
0 (0–152) |
0 (0–114) |
0.399 |
| General cancer conditions |
|
|
|
| Performance status ≤2, n (%) |
140 (98.5) |
45 (100) |
0.999 |
| Clinical stage |
|
|
|
| I, n (%) |
16 (11.2) |
4 (8.8) |
0.786 |
| II, n (%) |
32 (22.5) |
5 (11.1) |
0.131 |
| III, n (%) |
45 (31.6) |
16 (35.5) |
0.715 |
| IV, n (%) |
49 (34.5) |
20 (44.4) |
0.287 |
| Cancer characteristics |
|
|
|
| Pathology |
|
|
|
| Squamous cell carcinoma, n (%) |
138 (97.1) |
40 (88.8) |
0.038 |
| Adenocarcinoma, n (%) |
4 (2.8) |
4 (8.8) |
0.096 |
| Small-cell carcinoma, n (%) |
0 (0) |
1 (2.2) |
0.240 |
| Cancer treatment |
|
|
|
| Surgery, n (%) |
50 (35.2) |
9 (20.0) |
0.066 |
| Chemotherapy, n (%) |
118 (83.0) |
44 (97.7) |
0.010 |
| Platinum, n (%) |
118 (83.0) |
44 (97.7) |
0.010 |
Moreover, the comparison of the baseline characteristics of the groups with and without CAC at baseline revealed significant differences in age, dyslipidemia, diabetes mellitus, and cancer treatment (i.e. surgery, chemotherapy, and platinum) (Table 3).
Table 3 -
Baseline characteristics with and without
coronary artery calcification
|
Baseline Agatston score |
P values |
|
>0 (n = 87) |
=0 (n = 100) |
|
| Demographics |
|
|
|
| Age, years |
75.0 (71.0–78.0) |
70.5 (66.0–78.0) |
0.017 |
| Men, n (%) |
74 (85.0) |
79 (79.0) |
0.343 |
| Comorbidities and coronary risk factors |
|
|
|
| Hypertension, n (%) |
40 (45.9) |
31 (31.0) |
0.216 |
| Dyslipidemia, n (%) |
16 (18.3) |
7 (7.0) |
0.024 |
| Diabetes mellitus, n (%) |
10 (11.4) |
3 (3.0) |
0.040 |
| Chronic kidney disease, n (%) |
2 (2.2) |
5 (5.0) |
0.452 |
| Previous myocardial infarction, n (%) |
2 (2.2) |
0 |
0.210 |
| Previous cardiac surgery/intervention, n (%) |
2 (2.2) |
0 |
0.210 |
| Smoking, n (%) |
63 (72.4) |
75 (75.0) |
0.740 |
| Family history (cardiovascular events), n (%) |
4 (4.5) |
1 (1.0) |
0.185 |
| Blood test findings |
|
|
|
| C-reactive protein (mg/ dl) |
0.33 (0.07–1.68) |
0.44 (0.09–2.77) |
0.399 |
| Coronary vessel investigation |
|
|
|
| Coronary artery calcification site |
|
|
|
| Right coronary artery, n (%) |
46 (52.8) |
0 |
0.001 |
| Left main trunk, n (%) |
19 (21.8) |
0 |
0.001 |
| Anterior descending artery, n (%) |
63 (72.4) |
0 |
0.001 |
| Circumflex artery, n (%) |
27 (31.0) |
0 |
0.001 |
| Echocardiographic findings |
|
|
|
| Left-ventricular ejection fraction, % |
71.0 (66.0–77.0) |
71.5 (64.0–76.7) |
0.561 |
| Agatston score |
176 (50.9–679) |
0 (0–0) |
0.001 |
| General cancer conditions |
|
|
|
| Performance status ≤2, n (%) |
87 (100) |
98 (98.0) |
0.499 |
| Clinical stage |
|
|
|
| I, n (%) |
6 (6.8) |
15 (15.0) |
0.155 |
| II, n (%) |
23 (26.4) |
28 (28.0) |
0.870 |
| III, n (%) |
28 (32.1) |
33 (33.0) |
0.999 |
| IV, n (%) |
30 (34.4) |
39 (39.0) |
0.546 |
| Cancer characteristics |
|
|
|
| Pathology |
|
|
|
| Squamous cell carcinoma, n (%) |
83 (95.4) |
95 (95.0) |
0.999 |
| Adenocarcinoma, n (%) |
4 (4.5) |
4 (4.0) |
0.999 |
| Small-cell carcinoma, n (%) |
0 (0) |
1 (1.0) |
0.999 |
| Cancer treatment |
|
|
|
| Surgery, n (%) |
34 (39.0) |
25 (25.0) |
0.041 |
| Chemotherapy, n (%) |
71 (81.6) |
91 (91.0) |
0.083 |
| Platinum, n (%) |
71 (81.6) |
91 (91.0) |
0.083 |
Progression of CAC before and after RT
The Agatston score significantly increased over the 1-year and 2-year periods (Fig. 3a). A significant increase in the Agatston score over 1 year was also observed when only patients who received RT to the middle-lower chest were analyzed (Fig. 3b). However, there was no increase in the Agatston score for patients who received RT to the upper chest (Fig. 3c). The Agatston score also significantly increased for patients with CAC (i.e. Agatston score >0 points, Fig. 3d) and those without CAC (i.e. Agatston score=0 points, Fig. 3e) at baseline, although the degree of progression was more prominent in the former subgroup.
Fig. 3: Comparison of Agatston scores before and 2 years after radiation therapy using the Wilcoxon signed-rank test. (a) For all radiation-treated patients with esophageal cancer, the Agatston score significantly increased [1 year: 0 (0–133.0) versus 0 (0–223.0), P = 0.001*; 2 years: 0 (0–133.0) versus 0 (0–206.75), P < 0.001*]. (b) A marked increase can be observed for patients who received irradiation of the middle-lower chest [1 year: 0 (0–145.0) versus 0 (0–223.75), P = 0.001*; 2 years: 0 (0–145.0) versus 0 (0–230.0), P < 0.001*]. (c) No obvious change can be observed for patients who did not receive irradiation of the middle-lower chest (1 year: P = 0.528, 2 years: P = 0.070). (d) There is a clear increase for patients with an originally detectable Agatston score [1 year: 188.5 (55.95–700.0) versus 250.0 (73.87–749.5), P = 0.001*; 2 years: 188.5 (55.95–700.0) versus 245.5 (71.55–901.25), P < 0.001*]. (e) A significant increase can also be observed for patients with an originally undetectable Agatston score [1 year: 0 (0–0) versus 0 (0–0), P = 0.015*; 2 years: 0 (0–0) versus 0 (0–0), P = 0.031*].
Kaplan–Meier analysis of all-cause death and MACEs
Among the 33 patients who died during the 2-year study period, 31 died of esophageal cancer, while two died of pneumonia (Fig. 4a). All-cause death tended to occur more frequently in patients who received irradiation to the middle-lower chest than in those who received RT to the upper chest (90.3% versus 73.9%, P = 0.053 by Kaplan–Meier analysis; Fig. 4b). A difference in all-cause death was not observed between patients with CAC (i.e. Agatston score >0 points) and those without CAC at baseline, although there was a tendency toward a more frequent occurrence of all-cause death in patients with CAC at baseline (81.2% versus 71.9%, P = 0.079; Fig. 4c).
Fig. 4: Kaplan–Meier curves for all-cause death and MACEs over 3 years. (a) All-cause death in all patients; 33 of 187 patients died in 3 years. (b) There is a trend for a difference in all-cause death between patients with irradiation of the middle-lower chest and those without irradiation of this area (P = 0.053). (c) Differences in all-cause death can be noted between patients with pre-RT CAC and those without pre-RT CAC (P = 0.079). (d) MACEs in all patients; MACEs occurred in six of 187 patients over 3 years. (e) There is no clear difference in the occurrence of MACEs between patients with irradiation of the middle-lower chest and those without irradiation of this area (P = 0.664). (f) There is no significant difference in the group that presented with CAC before RT (P = 0.473). CAC, coronary artery calcification; MACEs, major adverse cardiovascular events; RT, radiation therapy.
MACEs occurred in six patients (emergent hospitalization for heart failure, n = 3; myocardial infarction, n = 2; unstable angina pectoris, n = 1; Fig. 4d). The occurrence of MACEs was independent of the site of irradiation or the presence of CAC at baseline (Fig. 4e and f). Furthermore, there was no significant difference in the radiation dose to the heart between the MACE (2754 [1829–3192] cGy) and non-MACE groups [2236 (627–3101) cGy] (P = 0.445).
There was no clear significant difference between the all-cause death [0 (0–127)] and other death [0 (0–241)] groups in the change in the Agatston score before and after RT (P = 0.889). There was a significant difference in the Agatston score change before and after RT between the MACE [217 (39–1413)] and non-MACE groups [0 (0–111)] (P = 0.031).
Discussion
Main findings
In aging societies, the progression of atherosclerotic disease in patients with esophageal cancer receiving RT may become a serious concern. In this retrospective study, we efficiently utilized FDG and FDGPET/CT images originally obtained for oncological practice to observe CAC progression. Although previous reports have suggested that FDG accumulation is associated with coronary artery instability [19], in this study, FDG accumulation in the coronary arteries was not observed. We found that CAC progression could occur within 2 years after the initiation of thoracic RT for esophageal cancer. Such progression may be particularly prominent in patients with detectable CAC at baseline and those receiving RT to the middle and lower chest. A total of 17.6% patients died during the 3-year observation period; notably, the cause of death was predominantly cancer rather than a cardiovascular event.
Although previous reports have shown that left main coronary artery lesions and right coronary artery inlet lesions are more common in patients with Hodgkin’s disease and those with breast cancer with a history of RT [20,21], it was interesting to note that the left anterior descending branch of the coronary artery was more common in patients with esophageal cancer in this study.
Effect of cancer RT on CAD
Given the increased recognition of RI-CAD, there has been a shift toward approaches that minimize cardiac exposure to radiation in recent decades [22]. Unlike cardiomyocytes, endothelial cells are sensitive to RT; thus, it is reasonable to expect CAD progression after RT. Radiation exposure may increase the formation of reactive oxygen species, leading to an inflammatory response [22,23]. The morphological features of atherosclerotic disease in patients with RI-CAD are analogous to those without irradiation, including intimal proliferation, lipid-rich macrophage accumulation, inflammation, vascular smooth muscle cell to bone/chondroid cell transformation, and plaque formation [22,24,25].
CAC is a consequence of the aforementioned vascular damage. Importantly, it is known to increase the risk of annual cardiovascular events [26,27]. A previous study reported that, compared to patients without CAC, the adjusted risk of a coronary event increased by a factor of 7.73 for patients with Agatston scores between 101 and 300 points and by a factor of 9.67 for patients with scores >300 points [28]. The factors most frequently associated with death in patients with high Agatston scores are as follows: older age, male sex, high blood pressure, and smoking. In this study, patients with detectable Agatston scores at baseline tended to exhibit higher rates of all-cause death. Given the low occurrence of MACEs and the high frequency of cancer as the cause of death, the clinical impact of CAC progression in these patients may be questionable. However, the role of CAC progression after RT remains to be evaluated in the long term.
Additionally, conventionally-administered platinum as a chemotherapy treatment for esophageal cancer remains in the blood after treatment, and has been reported to be a risk factor for developing late complications of vascular diseases, such as CAC [29]. In this study, 86% of the patients received platinum administration, and we cannot deny the possibility that it had some influence on the progression of CAC within a short period.
Shared risk factors in oncology and cardiology
RT involving the heart in patients who are relatively free of cardiovascular risk factors has been investigated. Patients receiving RT for Hodgkin disease and breast cancer exhibit an increased incidence of CAD compared with those not receiving RT [30,31]. Meanwhile, ‘shared risk factors’ in oncology and cardiology have been receiving increased attention. The risk factors for esophageal cancer partially overlap with those for heart disease; therefore, patients with esophageal cancer may have comorbidities related to risk factors (e.g. smoking-related and obesity-related comorbidities) [32]. In this study, patients with esophageal cancer tended to be older men (mean age, 73 years) with a current smoking habit, and one-third of the patients had concomitant hypertension.
Although RI-CAD is generally considered a late complication, these conventional risk factors have been reported to accelerate radiation-induced vasculopathy [22,33,34]. In the absence of coronary risk factors, the time from radiation exposure to the development of clinically significant CAD is approximately 9 years, and CAD occurs within 20 years of RT in approximately 10% of the patients [35]. In contrast, CAC progressed within 2 years after RT for esophageal cancer in patients in this study, who were mostly complicated by at least one atherosclerotic risk factor. Furthermore, it was reported that the CRP levels and CAC are strong prognostic predictors of coronary artery events [36]. In this study, all-cause death and CRP levels were significantly correlated (P = 0.004); therefore, it is conceivable that the CRP values may have influenced the results of this study.
Proposed management of patients with shared onco-cardiological risk factors receiving RT
As the progression of CAC is considered multifactorial, integrated evaluation of comorbidities and cardiovascular risk factors prior to RT may help optimize cancer therapy, control cardiovascular risk factors, and facilitate follow-up plans. Additionally, utilizing non-ECG-gated FDGPET/CT, primarily used for investigation/follow-up of malignant disease, to evaluate CAC may be an optimal method for utilizing medical resources in such patients.
Limitations
This study has some limitations. First, the Agatston score is usually measured using ECG-gated CT imaging, although we used non-ECG-gated FDGPET/CT in this study. In particular, it was difficult to accurately evaluate lesions at the coronary artery ostia by non-ECG-gated CT. Second, data were analyzed for only 187 patients. Therefore, further studies with larger sample sizes are required. Regardless of whether radiation was applied to the middle-lower chest, the Kaplan–Meier curve in all-cause death revealed many cases of statistical censoring.
Conclusion
Our findings indicate that the progression of CAC can be observed within 2 years after the initiation of RT to the middle or lower chest for esophageal cancer. Such progression may be particularly prominent in those with detectable CAC before the initiation of radiation. Long-term follow-up examination is warranted to investigate the impact of CAC progression on cardiovascular mortality and morbidity.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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