Cardiac radiation dose predicts survival in esophageal cancer treated by definitive concurrent chemoradiotherapy


 Background

The prognostic significance of cardiac radiation dose in esophageal cancer after definitive concurrent chemoradiotherapy (CCRT) without surgery remains largely unknown. This study aimed to investigate the association between cardiac dose-volume parameters and overall survival (OS) in esophageal cancer after definitive CCRT.
Methods

A total of 121 consecutive esophageal cancer patients undergoing definitive CCRT between 2008 and 2018 were reviewed. Dose-volume parameters of the heart were calculated. Survival of patients and cumulative incidence of adverse events were estimated by the Kaplan–Meier method and compared between groups by the log-rank test. The prognostic significance of cardiac dose-volume parameters was determined with multivariate Cox proportional hazards regression analysis.
Results

Median follow-up was 16.2 months (range, 4.3-109.3). Median OS was 18.4 months. Heart V5, V10, and V20 were independent prognostic factors of OS. The median heart V5, V10, and V20 were 94.3%, 86.4%, and 76.9%, respectively. Median OS was longer for patients with heart V5 ≤ 94.3% (24.7 vs. 16.3 months, p = 0.0025), heart V10 ≤ 86.4% (24.8 vs. 16.9 months, p = 0.0041), and heart V20 ≤ 76.9% (20.0 vs. 17.2 months, p = 0.047). Moreover, lower cumulative incidence of symptomatic cardiac adverse events was observed among patients with heart V5 ≤ 94.3% (p = 0.017), heart V10 ≤ 86.4% (p = 0.02), and heart V20 ≤ 76.9% (p = 0.0057). The patients without symptomatic cardiac adverse events had a higher 3-year OS rate (33.8% vs. 0%, p = 0.03).
Conclusions

Cardiac radiation dose was inversely correlated with survival in esophageal cancer treated by definitive CCRT. Radiation dose to the heart should be minimized.


Introduction
Esophageal cancer is the sixth leading cause of cancer-related death globally [1]. De nitive concurrent chemoradiotherapy (CCRT) without surgery is one of treatment options for locally advanced esophageal cancer [2,3,4,5]. As the outcome of esophageal cancer after de nitive CCRT was unsatisfactory, it is important to nd the prognostic factors and improve the treatment.
Radiation dose to the heart was a prognostic factor of non-small cell lung cancer treated with de nitive CCRT [6,7,8]. Similarly, cardiac radiation dose was shown to correlate with overall survival (OS) in a large group of esophageal cancer patients undergoing CCRT with or without surgery [9]. However, the prognostic signi cance of cardiac radiation dose remains to be elucidated speci cally in esophageal cancer after de nitive CCRT without surgery.
In the present study, we analyzed a single-institution cohort of esophageal squamous cell carcinoma (ESCC) patients receiving de nitive CCRT with intensity modulated radiotherapy (IMRT) technique. The association between cardiac dose-volume parameters and survival was examined.

Patients and study design
This study was approved by the institutional review board of our hospital. Patients with primary ESCC treated by de nitive CCRT at our institution between 2008 and 2018 were retrospectively reviewed. They were recruited on the basis of criteria as follows: newly pathologically con rmed ESCC without distant metastasis, no past history of thoracic radiotherapy, CCRT via IMRT and conventional fractionation with dose ≥ 50 Gy, and follow-up after CCRT ≥ 3 months. The pre-treatment evaluation of esophageal cancer included esophagogastroduodenoscopy, endoscopic ultrasonography, computed tomography (CT) of the chest and abdomen, and bone scan. The clinical stage was classi ed according to the seventh edition of the American Joint Committee on Cancer staging system.

De nitive concurrent chemoradiotherapy
All patients received de nitive CCRT for esophageal cancer with IMRT technique, as previously described [5]. Brie y, the gross tumor volume (GTV) consisted of GTV of the primary (GTVp) and GTV of lymph nodes (GTVn). The clinical target volume (CTV) 1 included GTVp with a 5-cm craniocaudal and 1-cm radial margin along the esophagus, and GTVn with a 1-cm margin. The CTV 2 included GTVp with a 2-cm craniocaudal and 1-cm radial margin along the esophagus, and GTVn with a 1-cm margin. The planning target volume (PTV) was generated by expanding 1 cm around the GTV and CTV in all directions. Elective nodal irradiation was omitted. CTV 1 and CTV 2 with the relevant PTV were sequentially treated to 36 and 50-50.4 Gy, respectively. Thereafter, GTV with the relevant PTV was boosted up to 66.6 Gy if dose constraints of the organs at risk could be met. Normal tissue dose constraints included Dmax < 50 Gy for spinal cord, V50 < 33% for heart, V20 < 33% for lung, Dmax < 55 Gy for stomach, and V35 < 50% for liver.
During radiation treatment, concurrent chemotherapy and supportive therapy were given.

Dosimetric analysis
The organs at risk were delineated on each axial slice of simulation CT scan [10,11]. For heart, the superior aspect began from the level of the inferior border of the pulmonary artery passing the midline and extended inferiorly to the cardiac apex. Dose volume histogram of organs at risk was subsequently generated using the treatment planning system. We calculated the following dose-volume parameters of the heart and lung: mean dose and the percent volumes receiving doses ≥ 5 Gy (V5), ≥ 10 Gy (V10), ≥ 20 Gy (V20), ≥ 30 Gy (V30), ≥ 40 Gy (V40), and ≥ 50 Gy (V50).

Evaluation of symptomatic cardiac adverse events
Follow-up evaluations included clinical examinations, esophagogastroduodenoscopy, and CT scan of the chest at 1 month after CCRT and then every 3-6 months. In addition, electrocardiography, echocardiogram, and other cardiovascular evaluations were arranged as clinically indicated. To identify symptomatic cardiac adverse events, clinical symptoms and signs, CT images, electrocardiograms, echocardiograms, and managements for cardiovascular diseases were reviewed.

Statistical analysis
The data cutoff date was June 26, 2019. OS was calculated from the start of IMRT to the date of death or last follow-up. The time to cardiac adverse events was de ned as the interval from the beginning of IMRT to the identi cation of events. Survival of patients and cumulative incidence of cardiac events were estimated by the Kaplan-Meier method and compared between groups by the log-rank test. The factors associated with OS were checked with univariate analysis. The independent prognostic factors of OS were examined by multivariate Cox proportional hazards regression analyses in 42 models in which clinical variables with a trend in univariate analysis (p < 0.1), one cardiac dose-volume parameter, and one pulmonary parameter were taken into consideration. A p-value < 0.05 was considered statistically signi cant. Statistical analyses were performed with SPSS version 22.0 software and R version 3.5.1 for Windows.

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). uorouracil (800 mg/m 2 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 le 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), uoropyrimidine-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).  Fig. 2c). In addition, mean lung dose was consistently shown to be a prognostic factor of OS in analytic Page 9/19 models including different cardiac dose-volume parameters (Additional le 1-8:  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).

Discussion
The present study analyzed 121 ESCC patients undergoing de nitive CCRT with IMRT technique. We identi ed heart V5, V10, V20, and mean lung dose as independent predictors of prognosis by multivariate analysis. Cardiac radiation dose was correlated with the incidence of symptomatic cardiac adverse events which were inversely associated with survival.
Cardiac dose-volume parameters were found to be independent prognostic factors in a large group of esophageal cancer patients undergoing CCRT [9]. Notably, several key factors differentiated our data from the previously published one. To begin with, the present study speci cally analyzed patients treated with de nitive CCRT without surgery while the previous research included patients receiving CCRT with or without surgery. In addition, patients with adenocarcinoma and ESCC were combined for investigation in the previous report. The current cohort only included patients with ESCC. To the best of authors' knowledge, we were the rst to show the prognostic signi cance of cardiac dose-volume parameters in ESCC after de nitive CCRT without surgery. Finally, we systematically performed the multivariate analyses with models incorporating different lung and heart dose-volume parameters. The prognostic signi cance of the cardiac dose was consistently con rmed under individual consideration of different lung dose-volume parameters in the present study.
In line with the large comprehensive research evaluating the association of cardiac dosimetric factors and the outcomes in esophageal cancer after CCRT with or without surgery [9], heart V20 was shown to in uence the survival of ESCC treated with de nitive CCRT in the present study. However, heart V5 and V10 which acted as independent prognostic factors in the current cohort were not found to independently in uence OS in the previously published report. These discrepant results possibly derived from the difference of cancer histology and treatments between studies as the current cohort only reviewed ESCC patients receiving de nitive CCRT without surgery while the previous research included patients with adenocarcinoma and ESCC treated by CCRT with or without operation. In addition, heart V30, V40, and V50 were not reported as independent predictors of OS in the present study because the statistical signi cance was not achieved in multivariate analytic models in which lung V5 was included. But the existing trend suggested that this negative result might be attributed to the limited sample size. Further investigation with expanded cases is warranted in the future. Moreover, the current study found the inferior survival in patients with large PTV which was a surrogate marker of the tumor burden. This data coincided with the evidence that high tumor burden was associated with poor prognosis in cancers treated with de nitive CCRT [12,13,14].
The previous research did not nd the association between cardiac radiation dose and survival in the subset analysis of esophageal cancer patients undergoing de nitive CCRT [9]. Notably, the present study showed that lower cardiac radiation dose predicted the superior survival in ESCC treated by de nitive CCRT. Our nding is novel and needs external validation in independent cohorts. Moreover, symptomatic radiation-induced cardiac adverse events have been reported in esophageal cancer patients undergoing de nitive CCRT. High cardiac radiation dose was identi ed as a risk factor of cardiac adverse events. [5,15,16,17]. In the current study, the prevalence of symptomatic cardiac adverse events was 9.92% which was comparable to 5.88-18.97% reported in the literature. We further showed that patients with higher radiation dose to the heart had more symptomatic cardiac adverse events which were correlated with worse survival. These results supported the causal relationship between cardiac radiation dose, cardiac adverse events, and poor survival among ESCC patients receiving de nitive CCRT and indicated the importance of sparing the heart from radiation.
Our study was limited by its retrospective research design and all potential inherent biases. In addition, we did dosimetric analyses based on planning CT scan without consideration of cardiac physiological motion. Errors of estimation would exist under such circumstance. Although cardiac synchronized radiotherapy has been developed [18], it is not routinely used in CCRT for esophageal cancer. Better protection of the heart and more precise estimation of cardiac radiation dose would be possible with cardiac synchronized radiotherapy in the future. Moreover, the present study only included ESCC patients undergoing de nitive CCRT without surgery. The results could not be generalized to patients with adenocarcinoma or treated by neoadjuvant CCRT followed by operation. But on the positive side, we provided a speci c information for ESCC patients receiving de nitive CCRT. Further validation with independent cohorts is warranted.

Conclusions
We were the rst to report that the high cardiac radiation dose predicted the inferior outcome of ESCC patients undergoing de nitive concurrent chemotherapy and IMRT. Radiation dose to the heart should be Overall survival A) whole cohort, B) by ECOG performance status, C) by stage, and D) by volume of PTV prescribed to 50 Gy