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J Thorac Cardiovasc Surg 2007;133:404-413
© 2007 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Cardiac surgery after mediastinal radiation: Extent of exposure influences outcome

Albert S.Y. Chang, MDa, Nicholas G. Smedira, MDa,*, Catherine L. Chang, MDb, Monica M. Benavides, BSa, Ulf Myhre, MDa, Jingyuan Feng, MSc, Eugene H. Blackstone, MDa,c, Bruce W. Lytle, MDa

a Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio
b Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio
c Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.

Read at the Thirty-second Annual Meeting of the Western Thoracic Surgical Society, Sun Valley, Idaho, June 21-24, 2006.

Received for publication June 23, 2006; revisions received September 18, 2006; accepted for publication September 29, 2006.

* Address for reprints: Nicholas G. Smedira, MD, Kaufman Center for Heart Failure, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Ave/F24, Cleveland, OH 44195. (Email: smedirn{at}ccf.org).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
OBJECTIVES: Mediastinal radiation for thoracic malignancies uses multiple treatment fields and doses. We investigated whether more extensive radiation exposure is associated with more hospital complications and worse survival after cardiac surgery.

METHODS: From January 2000 to January 2005, 230 patients underwent cardiac surgery after 3 levels of mediastinal radiation: extensive (Hodgkin disease, thymoma, and testicular cancer; n = 70), variable (eg, non-Hodgkin lymphoma and lung cancer; n = 35); and tangential (breast cancer; n = 125). Hospital complications were recorded prospectively, and time-related survival was assessed by patient follow-up (mean follow-up, 2.2 ± 1.4 years).

RESULTS: Patients receiving extensive exposure were youngest (51 vs 64 vs 72 years), with the longest radiation-to-operation interval (25 vs 13 vs 14 years), and had the most diastolic dysfunction, left main stenosis of greater than 70% (21% vs 9% vs 8%), and aortic regurgitation (79% vs 54% vs 50%). Patients receiving extensive and variable exposure had the poorest pulmonary function (percent predicted forced expiratory volume in 1 second, 57% vs 54% vs 67%; percent predicted forced vital capacity, 56% vs 63% vs 66%). All groups received a similar mix of cardiac procedures. Hospital deaths (13% vs 8.6% vs 2.4%) and respiratory complications (24% vs 20% vs 9.6%) were higher after more extensive radiation, and survival was poorer (4-year survival, 64% vs 57% vs 80%) than for patients receiving tangential radiation exposure, and it deviated more from expected matched-population life tables.

CONCLUSIONS: Among patients undergoing cardiac surgery after thoracic radiation, radiation exposure is heterogeneous, and therefore these patients cannot be managed and assessed as a single uniform cohort. Extensively irradiated patients are more likely to develop radiation heart disease, which increases perioperative morbidity and decreases short- and long-term survival.

Abbreviations and Acronyms FEV1 = forced expiratory volume in 1 second; ITA = internal thoracic artery; LV = left ventricular; RV = right ventricular


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 
Thoracic radiation has been an effective treatment for cancers involving the mediastinum and thorax. However, patients so treated might experience subsequent cardiac disease and become candidates for cardiac surgery.1-3Go It has been observed that patients receiving radiation before cardiac surgery, as a group, have poorer short- and long-term outcomes than those not receiving radiation.4-10Go However, postradiation patients are a heterogeneous group in regard to the technique of radiation exposure and possibly in regard to the causation of their heart disease. Past studies combined patients into a single group and did not assess the effect of treatment fields and radiation dosing on outcomes. We hypothesized that patients receiving extensive thoracic radiation exposure have worse outcomes than those receiving less mediastinal exposure. Therefore we (1) contrasted patients, their heart disease, and radiation-related comorbidities according to the extent of radiation treatment; (2) characterized in-hospital complications and their risk factors; and (3) assessed time-related mortality and its risk factors in patients undergoing cardiac surgery after remote radiation therapy.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Limitations
 Conclusions
 References
 
Patients
From January 2000 to January 2005, 15,074 cardiac operations were performed at Cleveland Clinic. Of these, 230 patients had received previous thoracic radiation for treatment of malignancy. Primary data were collected concurrently with patient care as part of the Cardiovascular Information Registry. We reviewed each patient’s medical records to identify type of cancer treatment, including combined chemoradiotherapy and extent and timing of radiation. Expiration summaries and autopsy findings were reviewed to assign a mode of hospital death. Both Cardiovascular Information Registry data and data obtained from medical record review were preapproved for use in research by the institutional review board, such that patient consent was waived.

Radiation Extent
The majority of patients underwent radiation for breast cancer (n = 125, 55%), followed by Hodgkin disease (n = 61, 27%), non-Hodgkin lymphoma (n = 12, 5.2%), lung cancer (n = 15, 6.5%), and other malignancies (testicular cancer, laryngeal cancer, esophageal cancer, thymoma, leukemia, sarcoma, and pulmonary cancer with unknown primary; n = 17, 7.4%). Because exact radiation treatment field and dose were usually unavailable, we grouped patients into 3 categories according to presumed extent of cardiac radiation. During the study period, radiation therapy for Hodgkin disease, thymomas, and testicular cancer typically included extensive mediastinal radiation involving portions of the heart (extensive radiation group). Patients with other thoracic tumors (non-Hodgkin lymphoma; lung, esophageal, and laryngeal cancers; sarcoma; leukemia; and 1 pulmonary cancer with unknown primary) received varying doses of radiation to the mediastinum, heart, and surrounding structures (variable radiation group). Patients with breast cancer typically received peripheral radiation to the breast or chest wall, with less direct exposure of heart structures (tangential radiation group).

Outcomes
Early in-hospital complications assessed included mortality, respiratory insufficiency, renal failure, stroke, myocardial infarction, sepsis, and reoperation for bleeding, as defined for the Society of Thoracic Surgery National Database (Table E1).


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  		TABLE E1. Postoperative complications
 
Time-related survival was assessed by using Institutional Review Board–approved mailed or telephone questionnaires, with the patient’s or a surviving family member’s consent. Circumstances of death were elicited to the extent possible. The common closing date for vital status was July 20, 2004. Active follow-up was amplified when necessary by use of the Social Security Death Index, which was queried on January 20, 2005.11,12Go Mean follow-up was 2.2 ± 1.4 years, with 505 patient-years of information available for analysis.

Data Analysis
Hospital events
Multivariable logistic regression was used to identify risk factors for postoperative events. Radiation extent and tumor type, demographics, symptoms, cardiac rhythm and function, details of the cardiac disease treated, noncardiac comorbidity, hemodynamics, and procedure variables were considered in the analysis (Table E2). Initial screening ensured that at least 5 events were associated with each candidate risk factor. Bootstrap bagging was used for variable selection, with automated analysis of 500 resampled data sets with a P value of .05 or less for variable inclusion, followed by tabulating frequency of occurrence of both single factors and closely related clusters of factors.13,14Go Variables with occurrence higher than 50% were considered reliably identified at a P value of .05 or less.


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  		TABLE E2. Variables used in multivariable analyses
 
Survival
Survival was estimated nonparametrically by using the Kaplan–Meier method and parametrically by using hazard function decomposition.15Go It was compared with expected US population survival matched for age, sex, and race. Multivariable analysis of death was performed in the hazard function domain, using bootstrap bagging for variable selection.15Go

Presentation
Categoric variables are presented as frequencies and percentages. Continuous variables are summarized as means and standard deviations. Asymmetric 68% confidence limits are equivalent to ±1 standard error.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Limitations
 Conclusions
 References
 
Radiation Extent
Patients receiving extensive radiation were the youngest and had the longest interval between radiation treatment and cardiac surgery, the highest preoperative central venous pressures, the greatest diastolic dysfunction, the smallest hearts, and the highest prevalence of pericarditis, left main coronary artery stenosis, and aortic regurgitation (Table 1). 16Go The variable radiation group had the highest prevalence of severe chronic obstructive pulmonary disease, smokers, and renal insufficiency, with the highest preoperative creatinine level. Both groups had higher heart rates and pulmonary artery diastolic pressures and were more likely than the tangential group to have ischemic mitral valve regurgitation. The tangential radiation group was composed entirely of women, who were the oldest patients and had the highest prevalence of degenerative mitral valve disease and highest preoperative predicted forced expiratory volume in 1 second (FEV1).


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  		TABLE 1. Patient characteristics
 
Operations performed were generally similar among the groups (Table 2). Among patients with 50% or greater stenosis of the left anterior descending coronary artery undergoing coronary artery bypass grafting (n = 95), only 44 (46%) received internal thoracic artery (ITA) grafts, and these were similarly distributed among groups (P = .8).


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  		TABLE 2. Operation performed *
 
In-hospital Complications and Their Risk Factors
There were 15 (6.5%) hospital deaths. The most frequent mode of death was multisystem organ failure, often precipitated by respiratory failure (Table 3). Hospital death was higher in the extensive and variable radiation groups than in the tangential group (Table 4); after adjusting for other factors, risk was highest in the extensive radiation group (P = .02, Table E3). These patients were nearly 3.5 times more likely to experience respiratory insufficiency (P = .006, Table E3). Intensive care unit and postoperative lengths of stay were similar among groups (Table 4).


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  		TABLE 3. Modes of hospital death and autopsy findings
 

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  		TABLE 4. Postoperative in-hospital complications
 

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  		TABLE E3. Risk factors for in-hospital complications
 
Time-related Mortality and Its Risk Factors
At 1, 2, and 4 years postoperatively, unadjusted survival for the tangential radiation group (88%, 84%, and 80% at 1, 2, and 4 years, respectively) was higher than that of the extensive (78%, 70%, and 64%) and variable (73%, 64%, and 57%) exposure groups (P = .003) and more nearly matched expected survival for the general population (Figure 1).


Figure 1
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  		Figure 1. Survival after cardiac surgery in patients having prior thoracic radiation exposure. Each symbol represents a death, vertical bars are 68% confidence limits representing ±1 standard error, and numbers in parentheses represent patients alive and being traced. The solid line is the parametric estimate enclosed within dashed confidence limits. The dash-dot-dash line is survival of the age-, race-, and sex-matched US population. A, Extensive radiation group. B, Variable radiation group. C, Tangential radiation group.

 
Both the extensive and variable radiation groups had twice the adjusted risk of death of the tangential radiation group (Table 5), although the smaller number of patients in the variable exposure group resulted in larger uncertainty. In addition, patients with severe pulmonary or renal disease, lower hematocrit values, increased central venous pressure, enlarged left atrium, smaller left ventricular (LV) mass, or longer myocardial ischemic time were at higher risk of mortality (Table 5). Reoperation per se was not identified as a risk factor, nor was use of hypothermic circulatory arrest.


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  		TABLE 5. Incremental risk factors for death
 
Of 39 deaths occurring after hospital discharge, mode of death could not be ascertained in 24. Of the remaining 15, mode of death was cardiac related in 5, pulmonary related in 5, renal failure in 1, multisystem organ failure in 1, and cancer related in 3.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Limitations
 Conclusions
 References
 
Thoracic Radiation Exposure
Published studies examining outcomes of cardiac surgery after thoracic radiation have not differentiated patients by intensity and fields of radiation received.4-10Go This study demonstrates the importance of this distinction.

Radiation groups were created according to generally accepted treatment approaches. In patients with thymoma, seminoma, and Hodgkin disease, radiation fields at that time traditionally encompassed the entire mediastinum (Figure E1). 17-19Go In contrast, breast cancer radiation fields have been tangential to the base of the breast, with minimal exposure to the heart (Figure E2). The remaining cancers in this study were included in the variable radiation group because of inhomogeneity of radiation field design caused by tumor location and evolving historical changes in treatment approach.


Figure 2
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  		Figure E1. Example of fields used for radiation of Hodgkin disease, including the mediastinum, apices of the lung, axillae, and neck. Lung blocks (hatched areas) are used to shield part of the lungs during treatment, but the heart and mediastinum are included in the radiation field.

 
Principal Findings
In essence, patients receiving tangential radiation have cardiac pathology and respond to surgical therapy like nonirradiated patients, and extensively and variably irradiated patients manifest cardiac injury that has been commonly referred to as radiation heart disease. The prominence of pulmonary dysfunction preoperatively and particularly postoperatively has led us to conclude that a more appropriate term is radiation heart and lung (cardiopulmonary) disease.

The well-known microcirculatory injury caused by radiation leads to an assortment of progressive cardiac and pulmonary pathologies, including pericarditis, pericardial effusion, accelerated coronary artery arteriosclerosis (especially ostial lesions), myocardial fibrosis, calcification of the fibrous skeleton of the heart (ie, radiation heart disease), pneumonitis, and lung fibrosis.20-25Go Fewer than 10% of our patients were diagnosed as having pericarditis, and only 6 underwent pericardectomy, suggesting that constrictive pericarditis is an infrequent manifestation of radiation heart and lung disease.

Radiation heart disease produces heart failure symptoms with preserved LV function and is classified as a secondary restrictive cardiomyopathy.26Go Most of our patients had heart failure symptoms in the presence of normal LV function, and more extensively irradiated patients had higher central venous pressures and pulmonary artery pressures, enlarged left atria, worse LV diastolic function, and lower LV end-diastolic volume indices, all of which are consistent with radiation heart disease. Conversely, the tangential group had more typical heart disease with simply a history of previous radiation.

Radiation pulmonary injury results in restrictive lung function, which is found predominantly in extensively irradiated patients, whereas variably irradiated patients were frequently smokers with moderate-to-severe chronic obstructive pulmonary disease, and tangentially exposed women had only mildly reduced FEV1 and forced vital capacity, possibly related to kyphoscoliosis. Although smoking and musculoskeletal changes might play a role, radiation for Hodgkin disease and lung and breast cancers is known to irreversibly impair pulmonary function.27-31Go

In-hospital Complications
Mortality and morbidity were high in irradiated patients. Tangentially irradiated patients fared best. Sternal wound infections were uncommon and occurred equally among the 3 radiation exposure groups, but prevalence was higher than expected among nonirradiated patients and unaffected by use of the ITA.

Respiratory dysfunction, manifesting as pneumonia, intractable pleural effusion, and reintubation for poor ventilatory mechanics, was a frequent precursor to multisystem organ failure among our patients who died. There is likely an important ongoing pulmonary debility that continues well after the cardiac disease has been palliated. This might result from a progressive decrease in chest wall compliance, phrenic nerve and diaphragm dysfunction, intractable pleural effusion, and possibly pulmonary fibrosis.

The exact role of radiation lung injury (found in 1 of 4 patients at autopsy) remains uncertain, but it appears that reduced preoperative pulmonary function (radiation or smoking induced), decreased postoperative pulmonary mechanics, and pulmonary congestion (found in 2 of 4 patients at autopsy) caused by increased left atrial pressures from LV diastolic dysfunction may partially explain early surgical mortality and morbidity.

Time-related Survival
More extensive thoracic radiation exposure was associated with poorer time-related survival that was substantially less than that expected in the general population. The dose effect, risk factors for death, and paucity of cancer-related deaths during follow-up suggest a causal link between both cardiac and pulmonary radiation damage and prognosis.

High resting heart rate and the risk factor of small LV mass together suggest that stroke volume is fixed, both preoperatively and postoperatively, as a result of the restrictive cardiomyopathy. Increased central venous pressure as a risk factor also suggests a component of right ventricular (RV) dysfunction. Few studies, ours included, have focused specifically on radiation effects on RV function. The resulting decrease in RV output leads to decreased LV preload in patients already sensitive to filling conditions. Biventricular dysfunction and diastolic heart failure could explain the worse outcomes.


   Limitations
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Limitations
Conclusions
 References
 
Details of cancer stage, radiation fields, and doses and chemotherapy regimens were not available and might have altered our results. This was a single-institution study, but spanned a short interval during which patient selection criteria and management strategies were rather uniform. We were unable to quantify LV diastolic dysfunction, although in most patients it was graded qualitatively by echocardiographers. We have no information about long-term progression of radiation effects on cardiac and pulmonary dysfunction after surgical intervention. Many times, it was not possible to elicit secure information about mode of late death, and there were few autopsies.

Inferences About Clinical Management
Indications for operation
We use standard indications for surgical intervention in these patients, but believe symptoms must be present before intervening. We could not identify hemodynamic or pulmonary function values below which successful conventional surgery would be precluded, but have recently questioned whether patients with multiple cardiac problems, reduced RV or LV function, restrictive or constrictive hemodynamics, or undergoing reoperation might be better served by heart or heart-lung transplantation. A small series of patients undergoing transplantation sheds little light on this issue.32Go Although at increased lifetime risk of recurrent cancer, the few patients dying from cancer during follow-up suggests that immunosuppression would be safe. However, incisional and bronchial or tracheal anastomotic healing might make this a less-than-ideal solution.

Intraoperative management
Median sternotomy, thought to be less morbid than a thoracotomy, may profoundly impair respiratory mechanics.33,34Go Bauer and colleagues35Go found that 4 days after a ministernotomy or standard sternotomy, both FEV1 and forced vital capacity decreased by 50% from preoperative values and only slowly returned to normal. Thoracotomy is unlikely to be a better alternative. Aggressive preoperative smoking cessation, pulmonary rehabilitation, and draining of pleural effusions might be beneficial. Perhaps a thorough assessment of diaphragmatic function by means of fluoroscopic challenge (sniff test) could be of use to define high-risk patients.

During the study, most hearts were protected with cold, blood-based antegrade and retrograde cardioplegia. This method of myocardial protection, compared with antegrade-only or intermittent aortic clamping, has been associated with a decrease of early diastolic function in normal hearts.36Go Use of hypothermia might also impair diastolic more than systolic function.37Go Although it is impossible to separate the association of longer ischemic time with sicker patients requiring more complex operations, the possibility remains that irradiated hearts are more sensitive to ischemia, mode of myocardial protection, and temperature, leading to increased postoperative diastolic impairment. For patients requiring isolated revascularization, off-pump procedures might be a better alternative.

At a minimum, cardiac operations need to be well planned and executed. This includes use of the ITA and often valve replacement. Infrequent use of the left ITA was unanticipated; the primary authors have routinely used it. Although angiographic assessment of the ITA is used, it is not routine. Chest wall radiation for breast cancer does not preclude use of either the right or left ITA. We acknowledge the advantages of valve repair and lament the difficulties posed by postoperative anticoagulation; however, like Handa and associates,4Go we favor definitive therapy at the initial operation to reduce ischemic times and need for reoperation.

Postoperative management
Because postoperative stroke volume is invariably fixed, maintaining adequate cardiac output requires higher than usual filling pressures and heart rates, with little benefit from inotropic therapy. Medical regimens for diastolic heart failure, including ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockade, diuretics, and aldosterone antagonists, are limited and often ineffective. Use of a selective phosphodiesterase inhibitor III, such as milrinone, might be beneficial because of positive lusitropic and pulmonary vasodilatory properties, bronchodilatory action, and increase of diaphragmatic contractility.


   Conclusions
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Limitations
 Conclusions
References
 
We have demonstrated that extent of exposure among patients who have received thoracic radiation for cancer is variable, and therefore these patients cannot be managed and assessed as a single uniform cohort. Short- and long-term survival is diminished in those who are extensively irradiated, and complications are frequent. Treating these patients remains a great challenge; recent modifications in radiation techniques might reduce future cardiac and pulmonary injury.


   Acknowledgments
 
We thank Songua Lin for statistical programming; Angela York for database construction; Tanya Ashinhurst for registry assistance; Karen Mrazeck for follow-up of patients; Arlene Hann, Stacie Lavin, Lisa Loncaric, and Kevin Pronty for collecting data concurrently with patient care; and Tess Parry for editorial assistance.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Limitations
 Conclusions
 References
 

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J. Rademaker, H. Schoder, N. S. Ariaratnam, H. W. Strauss, J. Yahalom, R. Steingart, and K. C. Oeffinger
Coronary Artery Disease After Radiation Therapy for Hodgkin's Lymphoma: Coronary CT Angiography Findings and Calcium Scores in Nine Asymptomatic Patients
Am. J. Roentgenol., July 1, 2008; 191(1): 32 - 37.
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T. M. Dewey, D. Brown, W. H. Ryan, M. A. Herbert, S. L. Prince, and M. J. Mack
Reliability of risk algorithms in predicting early and late operative outcomes in high-risk patients undergoing aortic valve replacement
J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 180 - 187.
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