Patients’ characteristics
Of the 204 patients reviewed, 121 patients matched the recruitment criteria while 83 patients were excluded from the analysis with reasons as follows: stage IV (n = 21), radiation dose < 50 Gy (n = 23), post-CCRT follow-up < 3 months (n = 32), histology other than squamous cell carcinoma (n = 5), and use of 3-dimensional conformal radiotherapy (n = 23). Table 1 summarized demographic and clinical characteristics of the 121 patients, including 5 women and 116 men. Six (5.0%) patients had a history of cardiovascular disease (1 coronary artery disease, 3 congestive heart failure, 1 aortic valve infectious endocarditis after valve replacement, and 1 arrhythmia).
Table 1
Demographic and Clinical Characteristics of Patients at Baseline
Characteristic | No. of patients (%) |
Age (years) |
Median (Range) | 56 (34–81) |
≤ 56 : > 56 | 61 (50.4) : 60 (49.6) |
Gender |
Male : Female | 116 (95.9) : 5 (4.1) |
Body mass index (kg/m2) | |
Median (Range) | 21.3 (15.5–30.0) |
≤ 21.3 : > 21.3 | 61 (50.4) : 60 (49.6) |
Body surface area (m2) | |
Median (Range) | 1.65 (1.3–2.1) |
≤ 1.65 : > 1.65 | 63 (52.1) : 58 (47.9) |
Eastern Cooperative Oncology Group performance status |
0 : 1 : 2 : 3 | 11 (9.1) : 95 (78.5) : 14 (11.6) : 1 (0.8) |
Stage |
I : II : III | 2 (1.7) : 8 (6.6) : 111 (91.7) |
Tumor location |
U : M : L | 51 (42.1) : 30 (24.8) : 17 (14.0) |
U + M | 9 (7.4) |
U + M + L | 1 (0.8) |
M + L | 13 (10.7) |
Smoking |
Yes : No | 109 (90.1) : 12 (9.9) |
Alcohol |
Yes : No | 111 (91.7) : 10 (8.3) |
Hypertension |
Yes : No | 24 (19.8) : 97 (80.2) |
Diabetes |
Yes : No | 15 (12.4) : 106 (87.6) |
Cardiovascular disease |
Yes : No | 6 (5.0) : 115 (95.0) |
Heart volume (ml) |
≤ 592 : >592 | 61 (50.4) : 60 (49.6) |
Chemotherapy regimen |
Fluoropyrimidine-based | 113 (93.4) |
Taxane-based | 4 (3.3) |
Others | 4 (3.3) |
Radiation dose (Gy) |
Median (range) | 61.2 (50-66.6) |
≤ 61.2 : > 61.2 | 68 (56.2) : 53 (43.8) |
PTV prescribed to 36 Gy (ml) | |
Median (Range) | 780.4 (97.1-1799.5) |
PTV prescribed to 50 Gy (ml) | |
Median (Range) | 640.0 (26.0-1761.2) |
Abbreviations: L lower thoracic esophagus, M middle thoracic esophagus, PTV planning target volume, U upper thoracic esophagus |
Treatment
The median radiation dose was 61.2 Gy (range, 50-66.6 Gy). Fluoropyrimidine-based chemotherapy regimens were used in 113 (93.4%) patients. Most patients received either cisplatin (25 mg/m2) plus fluorouracil (1000 mg/m2) given intravenously every week or cisplatin (20 mg/m2 daily, on day 1–4) plus fluorouracil (800 mg/m2 daily, on day 1–4) given intravenously every 4 weeks. Other regimens were utilized at the discretion of physicians. Furthermore, during CCRT, enteral nutrition support was given via nasogastric, percutaneous endoscopic gastrostomy, and feeding jejunostomy tubes in eight (6.6%), 11 (9.1%), and 17 (14.0%) patients, respectively. Medications for emesis or pain as well as intravenous hydration were given as clinically indicated.
Clinical characteristics associated with overall survival
The median follow-up was 16.2 months (range, 4.3-109.3). Median OS was 18.4 months (Fig. 1a). Body mass index, body surface area, Eastern Cooperative Oncology Group (ECOG) performance status, stage, chemotherapy regimens, and the volume of PTV were associated with OS in univariate analysis (Table 2). ECOG performance status, stage, chemotherapy regimens, and the volume of PTV were independent prognostic factors of OS by multivariate analysis (Additional file 1–7: Table S1-7). The median OS was longer for patients with ECOG performance status 0–1 (19.0 vs. 6.8 months, p < 0.001; Fig. 1b), stage I-II (not reached vs. 17.7 months, p = 0.022; Fig. 1c), fluoropyrimidine-based chemotherapy (19.0 vs. 11.2 months, p = 0.0016), and smaller volume of PTV prescribed to 50 Gy (27.4 vs. 16.9 months, p = 0.008; Fig. 1d).
Table 2
Univariate Analysis of Clinical Variables Associated with Overall Survival
Variable | Univariate analysis |
HR (95% CI) | P value |
Age (≤ 56 vs. > 56) | 0.986 (0.639–1.522) | 0.951 |
Gender (female vs. male) | 0.710 (0.224–2.254) | 0.561 |
Body mass index (kg/m2) (≤ 21.3 vs. > 21.3) | 1.699 (1.096–2.634) | 0.018 |
Body surface area (m2) (≤ 1.65 vs. > 1.65) | 1.614 (1.042–2.502) | 0.032 |
ECOG performance status (0–1 vs. 2–3) | 0.376 (0.210–0.672) | 0.001 |
Stage (I&II vs. III) | 0.223 (0.055–0.910) | 0.036 |
Tumor location (L&M vs. U) | 1.364 (0.880–2.115) | 0.165 |
Smoking (no vs. yes) | 0.744 (0.358–1.547) | 0.428 |
Alcohol (no vs. yes) | 0.529 (0.214–1.310) | 0.169 |
Hypertension (no vs. yes) | 1.002 (0.587–1.710) | 0.994 |
Diabetes (no vs. yes) | 0.624 (0.335–1.160) | 0.136 |
Cardiovascular disease (no vs. yes) | 0.919 (0.336–2.518) | 0.870 |
Heart volume (ml) (≤ 592 vs > 592) | 1.468 (0.947–2.276) | 0.086 |
Chemotherapy regimen (F vs. NF) | 0.318 (0.150–0.673) | 0.003 |
Radiation dose (Gy) (≤ 61.2 vs. > 61.2) | 1.451 (0.924–2.280) | 0.106 |
PTV prescribed to 36 Gy (ml) (continuous) | 1.001 (1.000-1.001) | 0.055 |
PTV prescribed to 50 Gy (ml) (continuous) | 1.001 (1.000-1.002) | 0.004 |
Abbreviations: ECOG Eastern Cooperative Oncology Group, F fluoropyrimidine-based, L lower thoracic esophagus, M middle thoracic esophagus, NF not fluoropyrimidine-based, PTV planning target volume, U upper thoracic esophagus |
Dose-volume parameters associated with overall survival
Heart V5, V10, and V20 consistently served as independent prognostic factors of OS under consideration of individual pulmonary dose-volume parameters (Table 3 and Additional file 1–7: Table S1-7). The median heart V5, V10, and V20 were 94.3%, 86.4%, and 76.9%, respectively. Longer median OS was observed among patients with heart V5 ≤ 94.3% (24.7 vs. 16.3 months, p = 0.0025; Fig. 2a), heart V10 ≤ 86.4% (24.8 vs. 16.9 months, p = 0.0041; Fig. 2b), and heart V20 ≤ 76.9% (19.0 vs. 17.2 months, p = 0.047; Fig. 2c). In addition, mean lung dose was consistently shown to be a prognostic factor of OS in analytic models including different cardiac dose-volume parameters (Additional file 1–8: Table S1-8). Patients with mean lung dose ≤ 12.63 Gy had a superior median OS (24.8 vs. 17.5 months, p = 0.017; Fig. 2d)
Table 3
Multivariate Analysis for Heart Dose-volume Parameters and Overall Survival under Consideration of Different Lung Parameters
Heart | Mean lung dose | Lung V5 | Lung V10 | Lung V20 | Lung V30 | Lung V40 |
HR (95% CI) P value |
Mean dose | 1.000 (1.000–1.000) 0.052 | 1.000 (1.000–1.000) 0.068 | 1.000 (1.000–1.000) 0.034 | 1.000 (1.000–1.000) 0.035 | 1.000 (1.000–1.000) 0.022 | 1.000 (1.000–1.000) 0.020 |
V5 | 1.011 (1.001–1.020) 0.029 | 1.011 (1.001–1.021) 0.032 | 1.012 (1.002–1.022) 0.016 | 1.012 (1.002–1.021) 0.016 | 1.012 (1.003–1.022) 0.010 | 1.012 (1.003–1.022) 0.009 |
V10 | 1.010 (1.001–1.019) 0.032 | 1.010 (1.001–1.020) 0.039 | 1.011 (1.002–1.020) 0.020 | 1.011 (1.002–1.020) 0.020 | 1.011 (1.003–1.020) 0.012 | 1.012 (1.003–1.021) 0.010 |
V20 | 1.010 (1.001–1.019) 0.029 | 1.010 (1.001–1.020) 0.038 | 1.011 (1.002–1.020) 0.019 | 1.011 (1.002–1.020) 0.020 | 1.011 (1.003–1.020) 0.011 | 1.012 (1.003–1.021) 0.009 |
V30 | 1.010 (1.000-1.020) 0.048 | 1.009 (0.999–1.020) 0.068 | 1.011 (1.001–1.020) 0.035 | 1.010 (1.001–1.020) 0.036 | 1.011 (1.002–1.021) 0.021 | 1.011 (1.002–1.021) 0.016 |
V40 | 1.011 (1.001–1.022) 0.034 | 1.011 (1.000-1.022) 0.053 | 1.012 (1.001–1.023) 0.028 | 1.012 (1.001–1.022) 0.028 | 1.012 (1.002–1.023) 0.019 | 1.013 (1.002–1.023) 0.017 |
V50 | 1.014 (1.000-1.027) 0.046 | 1.012 (0.999–1.026) 0.077 | 1.014 (1.001–1.028) 0.042 | 1.014 (1.001–1.028) 0.038 | 1.014 (1.001–1.028) 0.035 | 1.014 (1.001–1.028) 0.040 |
Dose-volume parameters associated with symptomatic cardiac adverse events
There were 12 symptomatic radiation-induced cardiac adverse events, including ischemic heart disease in one, arrhythmia in three, and pericardial effusion in eight patients. The median interval from the start of IMRT to development of cardiac events was 9.8 months. Lower cumulative incidence of symptomatic cardiac adverse events was found among patients with heart V5 ≤ 94.3% (p = 0.017; Fig. 3a), heart V10 ≤ 86.4% (p = 0.02; Fig. 3b), and heart V20 ≤ 76.9% (p = 0.0057; Fig. 3c). Moreover, patients without symptomatic cardiac adverse events had a higher 3-year OS rate (33.8% vs. 0%, p = 0.03; Fig. 3d). There was a trend toward better survival at 2 years in patients without symptomatic cardiac complications (44.3% vs. 25.0%, p = 0.23).