Outcomes After Curative Thoracic Radiotherapy in Patients With Coronary Artery Disease and Existing Cardiac Stents.

ORIGINAL ARTICLE

Outcomes After Curative Thoracic Radiotherapy in Patients With Coronary Artery Disease and Existing Cardiac Stents Terence T. Sio, MD, MS,* Jackson J. Liang, DO,w Kenneth Chang, MS,* Paul J. Novotny, MS,z Abhiram Prasad, MD,y and Robert C. Miller, MD, MS*

Objectives: To evaluate outcomes among cancer patients with preexisting coronary artery disease and cardiac stenting who subsequently underwent thoracic radiotherapy (RT). Methods: From 1998 to 2012, 147 patients received percutaneous coronary intervention (PCI) and then curative external beam RT ( > 30 Gy, except for Hodgkin lymphoma patients) involving the heart and the lungs. Heart-specific and lung-specific dosimetric parameters were correlated to overall survival (OS) and cardiac-specific survival by Cox variate methods. Results: The mean interval between PCI and cancer diagnosis was 1.8 years (range, 0.1 to 14.2 y). Hypertension was present in 105 patients (71%), and hyperlipidemia in 82 (56%). At the time of analysis, 69 patients (47%) were alive, 3 (2%) died of cardiac causes, and 53 (36%) died of cancer. In multivariate analyses, OS since PCI was related to cancer type (P = 0.004). Decreased OS since cancer diagnosis was related to older age (P < 0.001) and increased percentage of targeted volume or organ receiving 20 Gy or more for lung (P < 0.001), even after controlling for sex, cancer type, and stage. However, for non– cancer-specific survival and major adverse cardiac event-free survival, older age and underlying cardiopulmonary comorbidities dominated (rather than heart and lung dosimetric parameters) in predicting worse outcome for these patients with preexisting coronary artery disease who later underwent RT. Conclusions: Cancer type, older age, and preexisting cardiopulmonary comorbidities and risk factors most significantly predicted clinical outcome and survival for these patients with existing coronary stents who subsequently received thoracic RT. Dosimetric detrimental effects were not significant in our study. Key Words: coronary artery disease, coronary artery stenting, external beam radiotherapy, percutaneous coronary intervention, survivorship

(Am J Clin Oncol 2014;00:000–000)

From the Departments of *Radiation Oncology; wInternal Medicine; Divisions of zBiomedical Statistics and Informatics; and yCardiovascular Diseases, Mayo Clinic, Rochester, MN. T.T.S. and J.J.L. contributed equally. Portions of this work were presented in abstract form at the 55th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Atlanta, Georgia, September 22 to 25, 2013. Portions of this article have been submitted for consideration for publication in the American Journal of Clinical Oncology: Sio TT, Liang JJ, Chang K, Novotny PJ, Prasad A, Miller RC. Dosimetric Correlate of Cardiac-Specific Survival Among 76 Patients Undergoing Coronary Artery Stenting After Thoracic Radiotherapy for Cancer. The authors declare no conflicts of interest. Reprints: Robert C. Miller, MD, MS, Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: miller. [email protected]. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.amjclinical oncology.com. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000092

American Journal of Clinical Oncology

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ith an aging population and improved treatment of coronary artery disease (CAD), the number of cardiac patients living long enough for cancer to develop is increasing. Radiotherapy (RT) is an integral component of cancer treatment that increases patient survival, with or without other therapeutic modalities including surgery and chemotherapy. However, exposure to radiation predisposes humans to longterm cardiovascular complications, as evidenced by increased rates of adverse cardiac events among Japanese atomic bomb survivors1,2 and cancer patients treated with thoracic RT.3–5 Cardiotoxicity classically manifests as pericardial damage, cardiomyopathy, and accelerated coronary artery atherosclerosis, which may present clinically as heart failure and ischemic heart disease. In addition, pulmonary hypertension may be underrecognized as a potential complication of cardiac and thoracic RT6 and implicated in the pathophysiology of radiation pneumonitis.7 With the advent of improved RT technology and the use of techniques to minimize heart irradiation in patients with Hodgkin lymphoma (ie, 3-dimensional treatment planning, treatment fields, beam weighting, subcarinal blocks, and decreased daily fraction size), the relative risk of fatal myocardial infarction (MI) has decreased significantly since 1940.4 However, the adverse cardiovascular effects of RT based on dose directed to the heart or lungs (or both) (ie, a dosimetric approach) in patients with known CAD have not been well studied previously. These patients may be at particularly increased risk given their underlying cardiopulmonary comorbidities; CAD risk factors, including older age, obesity, hypertension, diabetes mellitus, and smoking, compound this risk.8 Although total RT dose, higher dose per fraction, and heart volume irradiated are known to increase the risk of cardiotoxicity,9 it is unclear whether dosimetric parametric differences exist depending on the amount of irradiation to each specific organ, which may affect overall survival (OS) and cardiac-specific survival. We aimed to examine survivorship among patients with CAD who were subsequently treated with curative thoracic RT to determine the dosimetric correlation of heart and lung RT with noncancer and overall mortality.

METHODS Study Population This retrospective study was approved by the Mayo Clinic Institutional Review Board. The medical records of all patients from May 1998 to October 2012 treated at Mayo Clinic in Rochester, Minnesota, with curative external beam RT involving the heart were searched for International Classification of Diseases, Ninth Revision codes for cancers involving the breast, lung, mediastinum, lymphoid tissue, biliary tree, esophagus, pancreas, gallbladder, and stomach.

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Sio et al



step of saturated models to adjust for potentially significant univariate factors. All tests were 2-sided with 5% type I error rates. P values < 0.05 were considered statistically significant.

The medical record numbers of the patients were then cross matched with the medical record numbers of patients from our institution’s percutaneous coronary intervention (PCI) database who received at least 1 coronary artery stent before their clinical course of external beam RT, resulting in a total of 147 patients. All patients received a curative RT dose of >30 Gy (except for patients with Hodgkin lymphoma), with a portion of the RT beams directed at the heart. Patients were excluded if they received RT for spinal or vertebral tumors, or if they had metastatic disease and received RT that was palliative. In addition, patients were excluded from analysis if they (1) underwent PCI without placement of a stent; (2) died during the index PCI; or (3) were lost to follow-up immediately after discharge.

TABLE 1. Baseline Clinical and Cancer Characteristics of 147 Patients Who First Received a Cardiac Stent and Then External Beam Radiotherapy

Data Collection

Characteristics

Baseline patient demographic and oncologic data were obtained from the electronic medical records. Clinical characteristics at the time of stenting, details of the procedure at the time of stent placement, and subsequent cardiac outcomes were obtained from the PCI database. Radiation-related and oncologic data (RT type, total dose, fractions, volumes, and dosimetric parameters of the heart and lungs), baseline cardiac medications at the time of RT, and anthracycline use (if any) were extracted from the electronic medical records for analysis by 2 physician coauthors (J.J.L. and T.T.S.). For lung cancer cases, multiple fields of radiation beams were used; for breast cancer cases, simple opposing tangents or multiple fields including nodal irradiation were applied. Dosimetric parameters for the lungs included the maximum and mean doses and the percentage of targeted volume or organ receiving 20 Gy or more (V20Gy) or 13 Gy or more (V13Gy). Similarly, dosimetric parameters for the heart included the maximum and mean doses and the percentage of targeted volume or organ receiving 45 Gy or more (V45Gy) or 30 Gy or more (V30Gy). Survival was determined by reviewing electronic medical records and death certificates or autopsy reports, where available. The cause of death for each patient was independently verified by 2 coauthors, an internist (J.J.L.) and a radiation oncologist (T.T.S.), and confirmed with the PCI registry. Death was deemed to have a cardiac cause if a patient died suddenly (within 1 h of having cardiac symptoms), died of MI, or died of another cardiac cause (eg, heart failure, arrhythmia). OS since PCI and RT was calculated up to the patient’s death or to the patient’s last known clinical follow-up. Non–cancer-specific survival included analysis of patient deaths from a cardiac cause, other causes, or unknown cause. Major adverse cardiac event (MACE)-free survival included MI, coronary artery bypass graft surgery, or target vessel revascularization after PCI, and all causes of death in analysis.

Sex (n [%]) Male Female Age (y) At PCIw At cancer diagnosis BMI Cancer type (n [%]) Breast NSCLC Upper GIz Esophageal SCLC Hodgkin lymphoma Cancer stage (n [%]) 0 (DCIS) or I II III or IVA Total RT dose (Gy) RT dose (Gy) (n [%]) > 45 > 30 Received chemotherapy Received anthracycline Comorbidities at PCIw (n [%]) Diabetes mellitus Hypertension Hyperlipidemia Current or former smoker Medication use at RT (n [%]) Aspirin Statin b-blocker ACEI or ARB Thienopyridine Digoxin Cause of death (n [%]) Alive Cancer Cardiac Othery

Statistical Analysis Descriptive statistics were used to summarize distribution of cancer-related and cardiac-related clinical factors and dosimetric parameters. Survival since PCI and cancer diagnosis, non–cancer-specific survival, and MACE-free survival were calculated using the Kaplan-Meier method.10 Log-rank tests were used to determine whether individual variables were associated with survival. Baseline clinical and cancer characteristics used in the variate analyses included sex, age, body mass index (calculated as weight in kilograms divided by height in meters squared), cancer type, comorbidities at the time of PCI, and medication used at the time of RT. Cox proportional hazards models were used to obtain multivariate hazard ratios (HRs) and score P values, with an intermediate

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RESULTS Patient, Clinical, and Treatment Characteristics The analysis included 147 patients (Table 1). They are grouped by cancer type and initial stage in Supplemental

Value* 63 (43) 84 (57) 65.4 (10.1) 67.6 (9.3) 29.3 (5.8) 64 54 11 9 5 4

(44) (37) (8) (6) (3) (3)

63 35 49 53.2

(43) (23) (33) (8.3)

119 144 45 10

(81) (98) (31) (7)

32 105 82 106

(22) (71) (56) (72)

115 112 111 72 22 4

(78) (76) (76) (49) (15) (3)

69 53 3 22

(47) (36) (2) (15)

*Continuous data are presented as mean (SD); categorical data as number of patients and percentage of sample. wAll patients undergoing PCI received 1 or more stents. zUpper GI tumors include gallbladder, biliary, stomach, and pancreatic cancers and cholangiocarcinoma. As a result, part of the patient’s lungs and heart are within the radiation fields. yOther deaths were due to noncardiac and noncancer causes. This category also includes 12 deaths (8%) due to unknown causes. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DCIS, ductal carcinoma in situ; GI, gastrointestinal; NSCLC, non–small cell lung carcinoma; PCI, percutaneous coronary intervention; RT, radiotherapy; SCLC, small cell lung carcinoma.

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Digital Content 1, Table, http://links.lww.com/AJCO/A48. The mean interval between PCI and cancer diagnosis was 1.8 years (range, 0.1 to 14.2 y). Patients with a wide variety of cancers were included, with 136 patients (93%) having a tumor above the diaphragm. The mean clinical tumor size was 3.3 cm (range, 0.2 to 13.6 cm); 52 patients (35%) had a left-sided tumor, 71 (48%) had a right-sided tumor, and 24 (16%) had a tumor that was not lateralized. Forty patients (27%) were active smokers; 66 (45%) were former smokers. All patients received cardiac stenting to at least 1 coronary artery before they underwent external beam RT; consequently, they all had angiographic evidence of occlusive coronary artery atherosclerosis that required stenting intervention (ie, clinically significant CAD). At the time of PCI, 54 patients (37%) had thrombus in a coronary lesion. Twenty patients (14%) had prior, separate percutaneous transluminal coronary angioplasty (PTCA), and 11 (8%) had coronary artery bypass graft surgery. Large portions of patients (range, 49% to 79%) used cardiac medications regularly (except for thienopyridines and digoxin) at the time of receiving RT. Hypertension was present in 105 patients (71%) and hyperlipidemia in 82 (56%); 10 (7%) had previous or current congestive heart failure. All patients received at least 1 course of RT after PCI, and none received RT before PCI. Nine patients (6%) received intensity-modulated RT (for 8 patients with non–small cell lung carcinoma, the total RT dose was 50 to 70 Gy; for 1 patient with Hodgkin lymphoma, RT was planned for 36 Gy); 12 patients (8%) with early non–small cell lung carcinoma were treated with stereotactic body RT. Aside from 2 patients (1%) with Hodgkin lymphoma who received curative RT doses of < 30 Gy, all patients received >30 Gy of RT. The 2 patients treated with < 30 Gy were included in the analysis as their RT dose was appropriate for their disease (24 Gy each for both cases of mediastinal lymphoma).

Dosimetric Parameters Comprehensive dosimetric records and the distribution of bilateral lung and heart doses were retrospectively reviewed (Table 2). The mean (SD) maximum dose to the lungs was 53.3 Gy (14.1 Gy), with an average mean (SD) dose of 6.7 Gy (4.8 Gy). The mean (SD) maximum dose to the heart was TABLE 2. Characteristics of Heart and Lung Dosimetric Parameters for Radiotherapy Plan

Characteristics Lungs Maximum dose point (Gy) Mean dose (Gy) V20Gy (%) V13Gy (%) Heart Maximum dose point (Gy) Mean dose (Gy) V45Gy (%) V40Gy (%) V35Gy (%) V30Gy (%)

Median (Q1-Q3) 54.4 4.9 7.9 10.3

(29.1-63.0) (3.3-9.6) (5.0-15.5) (6.3-23.1)

36.9 2.5 0.0 0.0 0.4 1.1

(7.5-52.0) (0.55-7.0) (0.0-3.0) (0.0-4.5) (0.0-5.9) (0.0-7.5)

Q1 indicates first quartile; Q3, third quartile; V13Gy, percentage of targeted volume or organ receiving 13 Gy or more; V20Gy, percentage of targeted volume or organ receiving 20 Gy or more; V30Gy, percentage of targeted volume or organ receiving 30 Gy or more; V35Gy, percentage of targeted volume or organ receiving 35 Gy or more; V40Gy, percentage of targeted volume or organ receiving 40 Gy or more; V45Gy, percentage of targeted volume or organ receiving 45 Gy or more.

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31.9 Gy (22.8 Gy), with an average mean (SD) dose of 6.2 Gy (9.1 Gy). Breast cancer patients received a lower RT dose to the heart and lungs compared with patients with lung and other cancers. If multifield designs were used, the doses to both organs were increased for locally advanced breast cancer compared with early-stage cases (ie, 2-field opposed tangents). The esophageal carcinoma cases received relatively large lung doses (mean bilateral lung dose, 12.4 Gy; percentage of targeted volume or organ receiving Z20 Gy [V20Gy], 17.8%; percentage of targeted volume or organ receiving Z13 Gy, 38.4%) and the highest heart doses (maximum heart dose, mean 52.8 Gy; mean heart dose, 33.7 Gy). The 4-field conformal design was typically used in esophageal cases. Sixty-four of our patients (44%) were treated for breast cancer (37 left-sided, 27 right-sided). The left-sided breast cancer patients had an average mean heart dose of 3.1 Gy, and the right-sided breast cancer patients had an average mean heart dose of 0.8 Gy (P < 0.001).

Survival Analyses At the time of analysis, 69 patients (47%) were alive (Table 1). The number of cardiac deaths was few (3 of 147 patients; 2%); the most common cause of death was cancer (53 of 147 patients; 36%). Table 3 shows the univariate and multivariate analyses for OS since the first PCI (27 patients [18%] had Z2 PCIs in their lifetime). The median OS was 12.6 years. Younger age at PCI, female sex, breast cancer, stage 0 or I cancer, and fewer cardiac and pulmonary-related comorbidities favored long-term survival in this group of 147 patients. Although OS after PCI was not an RT-related end point, V20Gy for lungs was significant in univariate (but not multivariate) analysis. Cancer type remained the most significant parameter in determining survival outcome since PCI in the final multivariate model (P = 0.004). Table 4 shows the variate analysis for OS since the patient’s cancer diagnosis. The median OS since cancer diagnosis was 6.8 years. Similarly, younger age at cancer diagnosis, female sex, breast cancer, and early stages of cancer were associated with longer survival. For dosimetric parameters, mean dose and V20Gy for the lungs and percentage of targeted volume or organ receiving 45 Gy or more for the heart were statistically significant, with higher radiation dose exposure correlating to poorer survival. Importantly, after controlling for sex, cancer type, and cancer stage, the multivariate analysis showed that age at cancer diagnosis (P < 0.001) and V20Gy for lungs (P < 0.001) remained statistically significant. Among patients with breast cancer as a diagnosis, there was no detected difference between left-sided versus right-sided breast cancer survivors (P = 0.47) for OS since PCI; results were similar for OS since cancer diagnosis (P = 0.54). Tables 5 and 6 show the results of non–cancer-specific survival and MACE-free (cardiac-specific) survival analyses, respectively. Details of the patients who experienced a MACE, categorized by cancer type, are shown in Supplemental Digital Content 2, Table, http://links.lww.com/AJCO/A49. The median MACE-free survival was 6.1 years. These analyses are of particular importance since non–cancer-related factors such as PCI, preexisting comorbidities, and RT-related dosimetric parameters may influence patient survival. Younger age, female sex, and lack of cardiac-adverse clinical factors (number of PCIs, cerebrovascular accident [CVA] or transient ischemic attack, diabetes mellitus, MI, and prior PTCA) are associated with improved non–cancer-specific survival, with 3 of these end points (age, number of PCIs, and CVA or transient ischemic attack) remaining statistically significant in the final multivariate www.amjclinicaloncology.com |

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TABLE 3. Univariate and Multivariate Model Results for OS Since PCI

Variables

Median OS (y)

Age at PCI (y) — BMI — Sex (female vs. 12.4 vs. 9.0 male) Cancer type* Breast vs. lung 14.9 vs. 10.4 Breast vs. other 14.9 vs. 8.8 Stage 0 or 1 vs. 2 14.1 vs. 10.3 0 or 1 vs. 3 or 4 14.1 vs. 10.5 Aspirin (no vs. yes) 11.0 vs. 11.2 b-blocker 11.6 vs. 11.0 (no vs. yes) ACEI or ARB 11.2 vs. 11.0 (no vs. yes) Statin (no vs. yes) 12.4 vs. 11.0 XRT > 45 Gy 12.3 vs. 11.0 (no vs. yes) Diabetes mellitus 11.2 vs. 9.0 (no vs. yes) COPD (no vs. yes) 11.6 vs. 8.6 Multivessel disease 11.6 vs. 10.2 (no vs. yes) Thrombus in lesion 11.0 vs. 11.2 (no vs. yes) Dosimetric parameters for lungs Maximum dose — (Gy) Mean dose (Gy) — V20Gy (%) — V13Gy (%) — Dosimetric — parameters for heart Maximum dose — (Gy) Mean dose (Gy) — V45Gy (%) — V30Gy (%) —

Cox Univariate HR (95% CI)

Cox Univariate Score (P)

1.03 (1.00-1.06) 0.99 (0.95-1.03) 2.20 (1.39-3.48)

0.03 0.49 < 0.001 < 0.001

2.95 (1.70-5.12) 3.15 (1.63-6.09) 0.02 1.88 2.00 1.20 0.94

(1.03-3.43) (1.17-3.43) (0.69-2.09) (0.54-1.61)

0.51 0.81

0.98 (0.62-1.54)

0.93

1.25 (0.73-2.15) 1.50 (0.81-2.79)

0.42 0.20

1.67 (1.00-2.79)

0.047

2.06 (1.23-3.47) 1.77 (1.06-2.94)

0.005 0.03

0.84 (0.53-1.34)

0.46

1.00 (0.99-1.02)

0.70

1.04 (0.99-1.08) 1.03 (1.00-1.05) 1.01 (1.00-1.03)

0.11 0.02 0.17

1.01 (0.99-1.01)

0.83

1.01 (0.99-1.04) 1.02 (0.99-1.05) 1.01 (0.99-1.02)

0.24 0.13 0.15

*Cox multivariate HR, 2.69 (95% CI, 1.35-5.38); P = 0.004. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; OS, overall survival; PCI, percutaneous coronary intervention; V13Gy, percentage of targeted volume or organ receiving 13 Gy or more; V20Gy, percentage of targeted volume or organ receiving 20 Gy or more; V30Gy, percentage of targeted volume or organ receiving 30 Gy or more; V45Gy, percentage of targeted volume or organ receiving 45 Gy or more; XRT, radiotherapy dose.

analysis (Pr0.02 for all values) (Table 5). For MACE-free survival (Table 6), male sex, chronic obstructive pulmonary disease, and cardiac comorbidities (increased number of PCIs, peripheral vascular disease, and multivessel CAD) predicted worse survival, with the presence of multivessel disease remaining a significant negative predictor of survival (P = 0.001) in multivariate analyses. None of the dosimetric parameters was related to non–cancer-specific or MACE-free survival (Tables 5 and 6). The Kaplan-Meier curves for the 4 survival end points listed above are shown in Supplemental Digital Content 3, Figure, http://links.lww.com/AJCO/A50.



TABLE 4. Univariate and Multivariate Model Results for OS Since Cancer Diagnosis

Variables Age at cancer diagnosis (y)* Sex (female vs. male) Cancer type Breast vs. lung Breast vs. other Stage 0 or 1 vs. 2 0 or 1 vs. 3 or 4 XRT > 45 Gy (no vs. yes) Diabetes mellitus (no vs. yes) COPD (no vs. yes) Smoker Current vs. former Current vs. never Thrombus in lesion (no vs. yes) Dosimetric parameters Maximum dose (Gy) Mean dose (Gy) V20Gy (%)w V13Gy (%) Dosimetric parameters Maximum dose (Gy) Mean dose (Gy) V45Gy (%) V30Gy (%)

Median OS (y)



—

1.04 (1.02-1.07)

0.001

9.4 vs. 4.4

2.05 (1.26-3.36)

0.003

9.4 vs. 3.7 9.4 vs. 3.0

2.21 (1.25-3.89) 2.83 (1.45-5.54)

10.4 vs. 5.5 10.4 vs. 4.4 8.0 vs. 6.8

1.72 (0.92-3.22) 2.11 (1.21-3.70) 0.89 (0.48-1.68)

0.73

8.5 vs. 4.6

1.48 (0.87-2.51)

0.14

8.0 vs. 3.7

1.48 (0.85-2.55)

0.16 0.051

4.4 vs. 4.6

0.92 (0.52-1.65)

4.4 vs. 10.4 8.5 vs. 6.0

0.47 (0.24-0.94) 1.22 (0.75-2.00)

0.42

for lungs —

0.99 (0.98-1.01)

0.54

1.06 (1.00-1.12) 1.04 (1.01-1.06) 1.02 (0.99-1.04)

0.04 0.01 0.051

1.01 (1.00-1.02)

0.21

1.02 (1.00-1.04) 1.03 (1.01-1.06) 1.01 (1.00-1.02)

0.08 0.02 0.09

0.003 0.03

— — — for heart — — — —

*Cox multivariate HR, 1.05 (95% CI, 1.02-1.08); P < 0.001. wCox multivariate HR, 1.06 (95% CI, 1.03-1.09); P < 0.001. CI indicates confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; OS, overall survival; V13Gy, percentage of targeted volume or organ receiving 13 Gy or more; V20Gy, percentage of targeted volume or organ receiving 20 Gy or more; V30Gy, percentage of targeted volume or organ receiving 30 Gy or more; V45Gy, percentage of targeted volume or organ receiving 45 Gy or more; XRT, radiotherapy dose.

DISCUSSION Cardiac and pulmonary late effects are well-recognized toxicities of thoracic external beam RT and may be more prominent in patients with underlying cardiopulmonary comorbidities.11 To our knowledge, this is the first and certainly largest study to examine the dosimetric correlations between thoracic RT and cardiac survival and OS among patients with known cardiovascular disease (ie, CAD). Patients with thoracic malignancies treated with RT have higher longterm rates of CAD mortality,4 although the exact amount of contribution from RT to the causality of death is not known. These deleterious effects appear to be dose dependent, as evidenced by the higher rates of subsequent CAD and cardiac mortality in patients with left-sided (vs. right-sided) breast cancers treated with RT.12,13 A recent study of breast cancer patients showed a dose-dependent increase in major cardiac events and ischemic heart disease, with a 7.4% increase per 1 Gy increase in mean RT dose directed at the heart.5 Results from the Danish Breast Cancer Cooperative Group14 have r





TABLE 5. Univariate and Multivariate Model Results for Non– Cancer-specific Survival Since Cancer Diagnosis

Variables


Age at cancer diagnosis (y)* 1.07 BMI 0.95 Sex (female vs. male) 2.85 No. PCIs (1 vs. 2)w 2.78 CVA/TIA (no vs. yes)z 4.17 PVD (no vs. yes) 1.82 Diabetes mellitus 2.83 (no vs. yes) COPD (no vs. yes) 1.55 History of MI ( > 7 d before 2.57 PCI) (no vs. yes) Prior PTCA (no vs. yes) 2.70 Multivessel disease 1.95 (no vs. yes) Thrombus in lesion 0.76 (no vs. yes) Dosimetric parameters for lungs Maximum dose (Gy) 1.01 Mean dose (Gy) 1.01 V20Gy (%) 1.01 V13Gy (%) 1.00 Dosimetric parameters for heart Maximum dose (Gy) 0.99 Mean dose (Gy) 0.95 V45Gy (%) 0.97 V30Gy (%) 0.97

(1.02-1.12) (0.87-1.03) (1.14-7.11) (1.13-6.81) (1.19-14.60) (0.60-5.51) (1.17-6.84) (0.60-4.05) (1.05-6.30)

0.004 0.22 0.019 0.04 0.015 0.28 0.016 0.36 0.032

(1.04-7.04) (0.70-5.43)

0.034 0.19

(0.29-1.99)

0.58

(0.97-1.05) (0.90-1.13) (0.96-1.07) (0.95-1.04)

0.51 0.93 0.64 0.87

(0.97-1.02) (0.87-1.05) (0.91-1.04) (0.92-1.04)

0.64 0.34 0.56 0.36

demonstrated that thoracic RT after mastectomy improves survival in high-risk breast cancer patients and that the survival benefit of RT outweighed the cardiac morbidity and mortality; however, their study excluded patients with known ischemic heart disease before randomization, so the results cannot be extrapolated to patients with CAD. Although 53 patients (36%) in our study died of cancerrelated causes, only 3 (2%) died of cardiac causes after RT despite the presence of underlying CAD in all patients. Even if the 12 patients with deaths due to unknown causes were attributed to a cardiac cause, the 15 presumed cardiac deaths (10%) would still be less than expected in a population of patients who all had been previously treated with coronary artery stenting. This low rate of cardiac mortality may be due in part to the high rates of optimal medical therapy with aspirin, b-blockers, angiotensin-converting enzyme inhibitors, and statins, but it is more likely due to the fact that many patients were dying of their underlying malignancy before cardiac death occurred. Also, as suggested by our data, older age appeared to be related to poorer OS since PCI (HR 1.03 per year, P < 0.03) and to poorer OS since cancer diagnosis (HR 1.04 per year, P < 0.001). This is an important issue to consider, as physicians should account for age and comorbidities in RT or chemoradiotherapy planning.15 In the phase 2 trial by 2014 Lippincott Williams & Wilkins

TABLE 6. Univariate and Multivariate Model Results for Major Adverse Cardiac Event (MACE)-free Survival


*Cox multivariate HR, 1.08 (95% CI, 1.03-1.14); P = 0.002. wCox multivariate HR, 3.73 (95% CI, 1.46-9.50); P = 0.02. zCox multivariate HR, 7.38 (95% CI, 1.93-28.25); P = 0.01. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVA/TIA, history of cerebrovascular accident or transient ischemic attack; HR, hazard ratio; MI, myocardial infarction; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; PVD, peripheral vascular disease; V13Gy, percentage of targeted volume or organ receiving 13 Gy or more; V20Gy, percentage of targeted volume or organ receiving 20 Gy or more; V30Gy, percentage of targeted volume or organ receiving 30 Gy or more; V45Gy, percentage of targeted volume or organ receiving 45 Gy or more.

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Variables

Median Survival (y)

Age at PCI (y) — BMI — Sex (female vs. 8.6 vs. 5.7 male) Cancer type Breast vs. lung 8.2 vs. 5.7 Breast vs. other 8.2 vs. 5.9 Stage 0 or 1 vs. 2 8.2 vs. 6.6 0 or 1 vs. 3 or 4 8.2 vs. 6.7 XRT > 45 Gy 6.0 vs. 7.0 (no vs. yes) No. PCIs 1 vs. 2 7.0 vs. 6.9 1 vs. 3 7.0 vs. 2.0 PVD (no vs. yes) 7.0 vs. 4.1 Diabetes mellitus 7.0 vs. 5.6 (no vs. yes) COPD (no vs. yes) 7.4 vs. 4.6 Smoker Current vs. 6.8 vs. 6.1 former Current vs. never 6.8 vs. 8.6 Multivessel disease 11.2 vs. 5.5 (no vs. yes)* Thrombus in lesion 7.0 vs. 5.7 (no vs. yes) Dosimetric parameters for lungs Maximum dose — (Gy) Mean dose (Gy) — V20Gy (%) — V13Gy (%) — Dosimetric parameters for heart Maximum dose — (Gy) Mean dose (Gy) — V45Gy (%) — V30Gy (%) —



1.02 (0.99-1.04) 1.02 (0.98-1.06) 1.62 (1.05-2.49)

0.23 0.30 0.03 0.01

1.64 (1.01-2.69) 1.67 (0.91-3.08) 0.064 1.30 (0.75-2.25) 1.14 (0.69-1.89) 1.32 (0.74-2.36)

0.34 0.003

0.99 5.03 2.03 1.25

(0.54-1.80) (1.77-14.35) (1.11-3.71) (0.75-2.06)

1.71 (1.04-2.81)

0.02 0.39 0.03 0.23

1.27 (0.77-2.11) 0.79 (0.43-1.45) 2.17 (1.32-3.58)

0.002

0.96 (0.61-1.52)

0.86

1.00 (0.99-1.01)

0.60

1.00 (0.95-1.04) 1.00 (0.98-1.03) 1.00 (0.98-1.02)

0.89 0.72 0.80

1.00 (0.99-1.01)

0.41

1.00 (0.98-1.03) 1.01 (0.98-1.03) 1.00 (0.99-1.01)

0.86 0.61 0.81

*Cox multivariate HR, 2.17 (95% CI, 1.34-3.56); P = 0.001. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; V13Gy, percentage of targeted volume or organ receiving 13 Gy or more; V20Gy, percentage of targeted volume or organ receiving 20 Gy or more; V30Gy, percentage of targeted volume or organ receiving 30 Gy or more; V45Gy, percentage of targeted volume or organ receiving 45 Gy or more; XRT, radiotherapy dose.

Pergolizzi et al,16 curative “involved field” RT (smaller in portal size) to the thorax was thought to be better tolerated for the older patients. A larger study to examine these potential relationships is needed. As expected, OS after cancer diagnosis was highly influenced by cancer type and stage, with early breast cancer survivors living longer than patients with cancers at other sites and cancer stage at time of RT being inversely related to OS. In addition, we found that heart and lung doses may also predict OS. After adjustment for cancer type and other confounding factors, V20Gy was still directly related to worse OS but not MACE-free survival in the final multivariate analyses. This finding suggests the potential importance in www.amjclinicaloncology.com |

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Sio et al

limiting lung doses whenever possible, particularly in older patients (older age is also a significant covariate). Univariate analysis also suggested that an increased amount of irradiation to the heart may be associated with worse OS. Separate physiological interactions of heart and lung RT with normal tissue may contribute to combined cardiopulmonary dysfunction; whereas RT cardiotoxicity manifests as pericardial damage, cardiomyopathy, or vascular damage,3 pulmonary RT complications include radiation pneumonitis and fibrosis17— the pathophysiological connection between the cardiac and thoracic late effects is largely unknown. Recent studies have implicated lung RT to development of pulmonary endothelial cardiopulmonary damage, resulting in pulmonary hypertension and diastolic dysfunction.6,18 In a rat model, RT to the heart alone causes left ventricular perivascular fibrosis and increased left ventricular filling pressures and pulmonary edema. Lung RT alone, however, results in increased pulmonary arterial pressures and left ventricular relaxation time. Simultaneous RT to both the heart and the lungs leads to biventricular diastolic dysfunction, as evidenced by increased left ventricular and right ventricular end-diastolic pressures.19 Pulmonary hypertension and its relationship to RT exposure will continue to be an active area of research and investigation in the future. The analyses examining non–cancer-specific survival after cancer diagnosis as well as MACE-free survival after PCI (both included cardiac mortality) showed no correlation between RTrelated dosimetry directed at the heart or lungs (or both) in the specified outcomes in both univariate and multivariate models. However, worse outcomes were seen for older patients and for those with a more worrisome cardiovascular and pulmonary history (diabetes mellitus, chronic obstructive pulmonary disease, CVA, multivessel CAD, number of PCIs, and prior MI or PTCA). This suggests that worse outcomes were associated predominantly with the presence of cardiopulmonary comorbid conditions as opposed to RT dosage in this population. Nevertheless, the external beam RT dose to the normal tissue of heart and lungs should be minimized whenever possible; one way to accomplish this is to use proton beam RT.20–22 This study was retrospective and thus should be considered exploratory. The high rate of cancer death after RT may have suppressed the development of eventual dose-related adverse cardiac events in our survival analyses. Future studies with larger populations are warranted. Although every effort was made to carefully evaluate the survival outcomes using patient medical records and the PCI database, the mechanism of death in 8% of patients still could not be verified and was attributed to an unknown cause. In addition, as all CAD patients in our cohort had previously undergone coronary artery stenting, it is possible that our results may not be applicable to patients with CAD not treated with coronary stenting.

CONCLUSIONS Multiple factors affect treatment outcomes for patients with CAD who are subsequently treated with thoracic RT for cancer. Although RT may have adverse cardiopulmonary effects, cardiac mortality was low compared with cancerrelated deaths in this group of patients with preexisting CAD. In these patients treated with RT, older age and the presence of underlying cardiopulmonary comorbidities appear to be more predictive of decreased cardiac survival and OS compared with heart and lung RT dosimetry. It is important to note that as few patients died of confirmed cardiac causes in the series, our results are limited by the retrospective nature of this work.



As dosimetric detrimental effects did not appear to be clinically significant with RT, cancer treatment including the clinically indicated use of thoracic RT should take priority to maximize OS. Further research is necessary to determine methods, including image-guided RT and the use of proton beam RT, to further minimize the RT dose to the heart and lungs while adequately treating the underlying malignancy.

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survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. J Clin Oncol. 2013;31:774–781. 19. Ghobadi G, van der Veen S, Bartelds B, et al. Physiological interaction of heart and lung in thoracic irradiation. Int J Radiat Oncol Biol Phys. 2012;84:e639–e646. 20. Armstrong GT, Stovall M, Robison LL. Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the childhood cancer survivor study. Radiat Res. 2010;174:840–850.

r



21. Li J, Dabaja B, Reed V, et al. Rationale for and preliminary results of proton beam therapy for mediastinal lymphoma. Int J Radiat Oncol Biol Phys. 2011;81:167–174. 22. Nichols RC, Huh SN, Henderson RH, et al. Proton radiation therapy offers reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage iii non-small-cell lung cancer: a dosimetric study. Clin Lung Cancer. 2011;12:252–257.

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Coronary artery disease. Drug-eluting stents or CABG?

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Serum lipids and cardiac function correlate with nitrotyrosine and MMP activity in coronary artery disease patients.

Anxiety Level and Cardiac Autonomic Modulations in Coronary Artery Disease and Cardiac Syndrome X Patients.