Outcomes of cardiac surgery after mediastinal radiation therapy: A single‐center experience

Abstract Background Mediastinal radiation therapy (MRT) is a widely used therapy for thoracic malignancies. This therapy has the potential to cause cardiovascular injuries, which may require surgery. The primary aim of this study is to identify the perioperative outcomes of cardiac surgery in patients with a history of MRT. Second, potential predictors of mortality and adverse events were identified. Methods A retrospective study was conducted among 59 patients with prior MRT who underwent cardiac surgery between December 2009 and March 2015. Included surgeries consisted of procedures through median‐ and ministernotomy. Baseline, perioperative, and follow‐up data were obtained and analyzed. Results The majority of patients had a history of breast cancer (n = 43), followed by Hodgkin lymphoma (n = 10) and non‐Hodgkin lymphoma (n = 3). Preoperative estimated mortality with the Euroscore II was 3.4%. Overall 30‐day mortality was 6.8% (n = 4), with a total in‐hospital mortality of 10.2% (n = 6). Postoperatively, nine rethoracotomies (15.3%) had to be performed. During a mean follow‐up of 53 months, an additional 10 patients (16.9%) died, of which 60% (n = 6) as a result of cancer‐related events. Cox proportional modeling showed no differences in mortality between primary malignancies (P  > .05). Conclusion This study shows that cardiac surgery after mediastinal radiotherapy is associated with increased short‐ and long‐term mortality when compared to preoperative mortality risks predicted by the Euroscore II. Surgery‐related events caused all short‐term mortality cases, while malignancy‐related events were the main cause of death during the follow‐up. Mortality was higher in patients with a previous stroke and a lower estimated glomerular filtration rate.


| INTRODUCTION
Mediastinal radiation therapy (MRT) is a widely used treatment method for thoracic malignancies, especially among patients who suffer from breast cancer or thoracic lymphomas. MRT, alongside surgical procedures and chemotherapeutic treatments, has resulted in an increase in survival in these patients. 1,2 In turn, this higher survival rate led to an increase in the number of patients with longterm MRT-induced cardiovascular injuries. 3 The damage caused by MRT might occur decades after the initial treatment and is currently the most common cause of nonmalignant mortality in these patients. 4 The pathogenesis of MRT-induced cardiovascular diseases is initiated by radiation-induced inflammation, which subsequently leads to the development of fibrosis and calcification. [5][6][7] These histological changes can develop in all components of the heart, which could lead to a wide range of cardiovascular diseases, such as valvular stenosis or regurgitation, coronary artery disease (CAD), cardiomyopathy, pericardial disease, and conduction disorders. 4,8 Recent studies have shown a high incidence of long-term MRT-induced cardiovascular side effects. For instance, a study among 6039 patients treated for Hodgkin lymphoma showed that 11.6% developed long-term MRT-induced cardiovascular disease. CAD was the most common complication, occurring in 19% of the cases. 9 Additionally, a recent meta-analysis including 1.2 million participants who underwent MRT as a treatment for breast cancer, indicated an increased risk of developing CAD and cardiac mortality (relative risk 1.30 and 1.38, respectively). 10 Previous studies have already shown worse outcomes of cardiac surgery in patients with a history of MRT compared to patients without a history of MRT. [11][12][13][14][15][16][17] These studies mostly researched a subset of cardiac procedures (mostly valvular surgery). We hypothesize that previous MRT is associated with an increased risk of mortality and complications in the entire spectrum of invasive cardiac procedures. The primary aim of this study is to identify the perioperative outcomes of all invasive cardiac procedures in patients with a history of MRT in a single center in The Netherlands. Furthermore, we aim to identify potential predictors of mortality and adverse events in patients undergoing cardiac surgery after MRT.

| Study parameters
Preoperative patient characteristics, such as comorbidities, data on previous surgeries, laboratory findings (eg, renal and cardiac markers), complications, and echocardiographic findings (eg, left ventricle function and valve function) were obtained. The New York Heart Association classification of each individual was obtained from the health records. Information about the patients' CAD status was obtained from the most recent preoperative coronary angiography.
CAD, renal insufficiency, and myocardial infarction were defined according to the definitions of the Society of Thoracic Surgeons (STS) national cardiac surgery database. Euroscore I and Euroscore II were calculated for each patient. 18 Patients who had not been electively admitted for operation, but did require intervention or surgery on the same admission for medical reasons, were classified as urgent.
Periprocedural characteristics, such as data on the operation (eg, type of surgery, cardiopulmonary bypass duration, and aortic cross clamp duration), complications, adverse events, and admission time were collected for each individual. The majority of the patients was transferred to the referring hospital when they were fit to go; therefore, the hospital admission time as reported in this study is the time between surgery and transfer to the referring hospital.
The follow-up of the included patients was conducted until March 2018. The referring hospitals were contacted to collect information about the postoperative period. In case of incomplete information, the patients' general practitioners were contacted. Readmissions, reoperations, other interventions, related events, and mortality were reported for the follow-up period.

| Statistical analysis
Continuous variables are presented as mean ± standard deviation or as median and interquartile range (IQR), according to the distribution. Continuous variables were analyzed using multivariate regression analysis. Categorical data are presented as frequencies and percentages and were compared with the χ 2 test.   Table 3.
This study did not include any cases of periprocedural mortality (within 24 hours after surgery). A total of six patients (all female) died during their stay in the hospital, of which four within 30 days after surgery. Three out of four of these patients were treated for breast cancer in the past. All short-term mortalities were cardiovascular related. Detailed information about the in-hospital deaths can be found in Table 4.  Of the remaining eight patients, six died because of a malignancy, one because of a cardiac cause, and one due to an unknown cause. The patient who died as a consequence of a cardiac problem suffered from right ventricular failure after a complicated subtotal pericardiectomy, which was planned because of an underlying constrictive pericarditis, 27 months after the primary surgery.

| Mortality
To identify risk factors for mortality, Cox proportional hazard modeling was performed ( showed no significant differences of mortality outcomes. Note: Data are presented as n (%), mean ± SD, or median (interquartile range

| CONCLUSION
This retrospective study showed that short-term mortality is high in patients with a history of MRT. While surgery-related events were the main cause of short-term mortality, malignancy-related events were the main cause of late mortality during the follow-up.
Furthermore, this study indicated that the actual mortality in patients with a history of MRT is higher than predicted by the Euroscore II. This implicates that physicians should be careful when applying mortality risk calculators, since they tend to underestimate the mortality risk of patients with a history of MRT. Finally, a previous stroke and a lower preoperative GFR were identified as a risk factor for all-cause mortality.

CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.

AUTHOR CONTRIBUTIONS
OBD contributed to data gathering, analysis, and manuscript writing; ESF contributed to manuscript co-writing and correction; SMB contributed to echocardiography and manuscript correction; WJPB contributed to data analysis and manuscript correction; and AK contributed to patient selection and manuscript correction.

DATA AVAILABILITY STATEMENT
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request