Abstract
Background
The long-term risk of cardiovascular outcomes from either stereotactic body radiation therapy (SBRT) or three-dimensional conformal radiation therapy (3DCRT) plus intensity-modulated radiation therapy (IMRT) to treat early stage non-small cell lung cancer (NSCLC) is largely unknown. As continued adoption of SBRT accelerates, it is important to delineate unforeseen cardiovascular risks associated with treatment.
Research Question
Does the long-term risk of cardiovascular outcomes for patients with early stage NSCLC treated with either SBRT or 3DCRT plus IMRT differ by tumor laterality?
Study Design and Methods
Data from the Surveillance, Epidemiology, and End Results registry linked to Medicare was analyzed to identify a sample of 3,256 patients (1,506 treated with SBRT and 1,750 treated with 3DCRT plus IMRT) with node-negative stage I or IIA NSCLC. Cardiovascular events were identified using diagnosis codes, and outcomes were compared between left- and right-sided tumors. We assumed that tumor laterality was random and that the radiation field for left-sided tumors likely would result in greater dose to cardiac tissues. Cox regression models were fit to quantify the association of laterality on outcomes.
Results
Patients were followed up for a median of 2 years. Those treated with SBRT showed no difference in hazard of any cardiovascular outcomes by tumor laterality, including the cardiovascular composite (hazard ratio [HR] comparing left- vs right-sided tumors, 0.98; 95% CI, 0.84-1.15). In contrast, patients treated with 3DCRT plus IMRT showed a greater risk of congestive heart failure (HR, 1.23; 95% CI, 1.01-1.48) and percutaneous coronary artery intervention (HR, 2.24; 95% CI, 1.12-4.47).
Interpretation
Patients with left- vs right-sided early stage NSCLC showed similar rates of cardiovascular events when treated with SBRT. However, these patients also showed higher rates of select cardiac events when they were treated with 3DCRT plus IMRT. This study provides evidence that SBRT may provide a safer option over 3DCRT plus IMRT for patients with left-sided early stage NSCLC and underscores the need for long-term follow-up for patients treated with radiation therapy.
Key Words: cardiovascular disease, lung cancer, NSCLC, SBRT
Abbreviations: CPT, Current Procedural Terminology; HR, hazard ratio; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; IMRT, intensity-modulated radiation therapy; NSCLC, non-small cell lung cancer; RT, radiation therapy; SBRT, stereotactic body radiation therapy; SEER, Surveillance, Epidemiology, and End Results; 3DCRT, three-dimensional conformal radiation therapy
Graphical Abstract
Take-home Points.
Study Question: Does having left-sided vs right-sided lung cancer (affecting potential radiation doses to the heart and surrounding vascular structures) impact the risk of adverse cardiovascular outcomes for patients who undergo stereotactic body radiotherapy (SBRT) or conventional three-dimensional radiotherapy (3DCRT) plus intensity-modulated radiation therapy (IMRT)?
Results: Adverse cardiovascular outcomes were not increased in left- vs right-sided tumors among patients with stage I to IIA non-small cell lung cancer treated with SBRT, whereas select adverse outcomes were increased for left- vs right-sided tumors for patients who received 3DCRT plus IMRT.
Interpretation: SBRT was not associated with an increased risk of adverse cardiovascular outcomes when comparing left-sided tumors with right-sided tumors over a 2-year median follow-up.
Lung cancer is the leading cause of cancer death in the United States.1 Historically, most lung cancers have been diagnosed at an advanced stage, but developments in early diagnosis with low-dose CT scan screening are increasing the detection rate of early stage disease.2 Although surgical resection currently is the preferred treatment for early stage node-negative non-small cell lung cancer (NSCLC) and potentially is curative, not all patients can tolerate or choose to undergo surgery. Radiation therapy (RT) using stereotactic body radiation therapy (SBRT) is the primary alternative therapy for these patients with early stage disease. Moderately hypofractionated or dose-intensified three-dimensional conformal RT (3DCRT) plus intensity-modulated RT (IMRT) offers a second, less preferred alternative.3
Medically inoperable patients with node-negative NSCLC traditionally were managed with standard fractionation 3DCRT plus IMRT, although SBRT now often is a preferred approach.4,5 SBRT has been associated with local cancer control rates of 90% to 95% in prospective phase 2 studies, although these studies were limited to tumors of < 50 mm.6 Guidelines express caution regarding use of SBRT for larger tumors because of increased recurrence risk,5 and thus, patients with stage IIA tumors that are too large for treatment with SBRT may be considered candidates for moderately hypofractionated or dose-intensified 3DCRT plus IMRT. 3DCRT plus IMRT also is an alternative to SBRT at centers without an established SBRT program.3
When comparing toxicity profiles, 3DCRT plus IMRT has been associated with short-term complications such as pneumonitis and esophagitis, whereas SBRT has shown comparatively minimal short-term toxicity in prospective studies.6 However, the long-term toxicity risk associated with chest radiotherapy and SBRT for lung cancer is less well understood. Studies of conventionally fractionated RT for breast cancer have demonstrated long-term risk of ischemic heart disease, posing theoretical risks of cardiovascular toxicity for other chest radiotherapy approaches.7 Although nearly half of all patients with lung cancer have concomitant cardiovascular disease, little is known about the long-term cardiovascular complications of chest RT in early stage lung cancer.8 Toxicity profiles of 3DCRT plus IMRT and SBRT may differ. 3DCRT plus IMRT is delivered over more calendar days than SBRT, and although SBRT delivers higher individual doses of radiation to the chest (defined as five or fewer fractions by Medicare), standard care includes measures such as image guidance, tumor tracking, and smaller target margins in an attempt to limit radiation exposure to nontumor structures.5 Some investigations in cardiovascular risk with SBRT in lung cancer have been undertaken, but these studies have been small, including fewer than 200 patients.9,10 Therefore, further clarification of potential long-term risks of these therapies is useful in delineating their harm and benefit profile. Tumor laterality has served as a useful comparison for assessments of cardiovascular radiotherapy toxicity for cancers of the chest, because tumor location is likely to be random, and left-sided tumors are expected potentially to receive a higher dose to the heart and major thoracic vascular structures, thereby allowing for comparison with treatment outcomes for right-sided tumors.7,11 In this study, we used population-based lung cancer data to evaluate the long-term cardiovascular risks in patients with stage I to IIA NSCLC who received SBRT or 3DCRT plus IMRT by comparing these risks by tumor laterality (left vs right).
Study Design and Methods
Our study used data from the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims. From this database, we identified all pathologically confirmed cases of primary stage I to IIA NSCLC diagnosed before autopsy in patients older than 65 years between 1997 and 2014. We limited our study cohort to patients who received SBRT or 3DCRT plus IMRT within 6 months of diagnosis. We excluded patients with right middle-lobe cancers (SBRT, n = 64; 3DCRT plus IMRT, n = 80) because we believe no adequate analog exists to compare right middle-lobe cancers with left-lobe cancers. Our primary analytic sample included 3,256 patients (1,506 patients treated with SBRT, 1,750 patients treated with 3DCRT plus IMRT) with tumors of ≤ 50 mm. A stratified cohort of patients treated with SBRT and 3DCRT plus IMRT also was analyzed based on tumor location to assess if higher radiation doses contributed to long-term cardiovascular risk.
Sociodemographic variables (age, sex, race or ethnicity, and marital status) were obtained from SEER data; patient ages were categorized into four groups (65-69 years, 70-74 years, 75-79 years, and ≥ 80 years). Income quartiles in the zip code of patient residence also were determined based on census data. We obtained tumor characteristics (location, size, and histologic findings) from SEER. Tumor size groupings were based on TNM staging system for stage I and IIA tumors (stage T1a and T1b, ≤ 20 mm; stage T1c, 21-30 mm; stage T2, 31-50 mm). We used the Deyo adaptation of the Charlson index to assess the burden of comorbidities.12, 13, 14 Cardiovascular disease risk factors were identified using diagnostic (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]15) codes present in Medicare data in the 12 months before cancer diagnosis. These risk factors included: obesity (ICD-9-CM codes, 278.0, 278.1, 278.01, 278.00, and V77), smoking (ICD-9-CM codes V15.82, 305.1, and 989.84), type 2 diabetes (ICD-9-CM codes 250.0-250.9), hyperlipidemia (ICD-9-CM codes 272.4, 272.2, and 272.0), hyperthyroidism (ICD-9-CM codes 242.0-242.40 and 242.80-242.90), and arterial hypertension (ICD-9-CM codes 401-405). Finally, patients were categorized as high risk for cardiovascular toxicity if we identified a medical claim indicating acute myocardial infarction (ICD-9-CM codes, 410.01, 410.11, 410.21, 410.31, 410.41, 410.51, 410.61, 410.71, 410.81, and 410.91), coronary artery disease (ICD-9-CM codes 414.0, 414.8, and 414.9), or congestive heart failure (ICD-9-CM codes 398.91, 402.01, 402.11, 402.91, 428.0, 428.1, and 428.9)16 in the year before diagnosis.
We ascertained treatment with RT using SEER data and Medicare claims. A patient’s codes indicated having received RT if SEER data indicated use of external beam radiation or if Medicare inpatient, outpatient, or physician claims were consistent with RT administration (ICD-9-CM codes, 32.24, 92.21, 92.22, 92.23, 92.24, 92.25, 92.26 ,92.29, 92.3, 92.30, 92.31, 92.32, 92.33, and 92.39; Current Procedural Terminology [CPT] codes, 77401, 77402, 77403, 77404, 77406, 77407, 77408, 77409, 77411, 77412, 77413, 77414, 77416, 77417, 77418, 77427, 77431, 77432, 77470, 77499, 77520, 77522, 77523, 77525, 77418, 0073T, 77373, 77435, G0173, G0251, G0339, G0340, 61793, 0082T, and 32998; SBRT CPT code, 77373).17
We identified several cardiovascular events in the treatment cohorts. Specifically, we used a published claims-based definition to find episodes of acute myocardial infarction (ICD-9-CM codes, 410.01, 410.11, 410.21, 410.31, 410.41, 410.51, 410.61, 410.71, 410.81, and 410.91)18 and used previously documented ICD-9-CM criteria to find incident diagnoses of acute pericarditis (ICD-9-CM code, 423.2), coronary artery disease (ICD-9-CM codes, 414.0, 414.8, and 414.9), atrial fibrillation (ICD-9-CM codes, 427.0, 427.2, 427.3, 427.31, and 427.32), congestive heart failure (ICD-9-CM codes, 398.91, 402.01, 402.11, 402.91, 428.0, 428.1, and 428.9), angina (ICD-9-CM codes, 411 and 413), and stroke (ICD-9-CM codes, V1254, 434.91, 430, 433, 434.0, 434.1, 434.9, 435, 435.0, 435.8, 434.9, 437, 437.1, and 438)16 for patients with and without evidence of these conditions before cancer treatment. Concurrently, we used a similar process to ascertain percutaneous coronary interventions (ICD-9-CM codes, 360.1, 360.2, 360.5, 360.6, 360.9; CPT codes, 92980, 92981, 92982, and 92984-92996), and coronary artery bypass graft (ICD-9-CM codes, 361.0-361.4 and 361.9; CPT codes, 33510-33519, 33521-33523, and 33533-33536) procedures.16 In addition, we created a cardiac composite variable to determine grouped cardiovascular outcomes. Cardiac composite specifically included documented diagnoses (myocardial infarction, acute pericarditis, coronary artery disease, atrial fibrillation, congestive heart failure, angina) and procedures performed (percutaneous coronary innervation and coronary artery bypass graft). Finally, we examined cardiovascular death as an outcome by identifying relevant causes of death from SEER data. Time to events were calculated using the date of starting treatment until the date of an adverse cardiovascular event, the date of death, or the end of follow-up for the dataset. Overall cardiac outcome analyses used SEER data, because Medicare does not report cause of death, and were censored on December 31, 2014.
Statistical Analysis
Our comparison of cardiovascular events for left- and right-sided tumors was based on the assumption that the distance of lung cancers from the heart (and therefore tumor laterality) was distributed randomly and that the radiation treatment field for left-sided tumors would be in closer proximity to the cardiovascular structures and would result in greater dose to the normal cardiovascular tissues, including the coronary arteries. Therefore, if cardiovascular events were increased in left-sided tumors, this would indicate excess toxicity resulting from SBRT or 3DCRT plus IMRT exposure. We compared baseline characteristics of patients with right-sided lung cancer vs left-sided lung cancer using the χ 2 test. We plotted Kaplan-Meier curves to compare the primary cardiovascular composite outcome by tumor laterality for patients treated with SBRT and then patients treated with 3DCRT plus IMRT , testing for statistical differences using the log-rank test. We then fit unadjusted Cox regression models to compare time to major events of interest by tumor laterality (left vs right) first in patients who received SBRT and then in those who received 3DCRT plus IMRT. We then used Kaplan-Meier methods to determine the cumulative probability of each adverse event at 3 years. Finally, we performed secondary analyses stratifying by specific location (upper lobes vs lower lobes).
Based on the number of cardiac events expected among patients in the cohort and the size of our comparator group (patients with tumors in the right side of the chest), we calculated that the study had an 80% power to detect a 20% increase in the hazard of cardiac events in patients with left-sided cancers in either treatment cohort (SBRT or 3DCRT plus IMRT) at a P = .05 significance level. All analyses were performed in Stata version 13.1 software (StataCorp). This study was reviewed and deemed exempt by the Mount Sinai Institutional Review Board (Identifier: IRB-19-01516).
Results
We initially identified 13,265 patients 65 years of age or older who received a diagnosis of primary stage I or stage IIA NSCLC. We then excluded patients with tumor sizes of > 50 mm, patients with middle-lobe tumors, and patients who were treated with anything other than SBRT or 3DCRT plus IMRT (Fig 1). The final analytic sample included 3,256 patients (1,506 patients who received SBRT and 1,750 patients who received 3DCRT plus IMRT). Overall, demographic and tumor characteristics for patients treated with either SBRT or 3DCRT plus IMRT (Table 1, Table 2, Table 1, Table 2) were not different when comparing left- vs right-sided tumors (P ≥ .05 for all comparisons). Also no difference was found in the pattern of comorbid illnesses or cardiovascular risk by tumor laterality (all P ≥ .05).
Figure 1.
A, Kaplan-Meier survival curve showing composite cardiovascular event-free survival for patients treated with stereotactic body radiation therapy compared by tumor laterality. No statistically significant difference was found in event-free survival when comparing left-sided with right-sided tumors. B, Kaplan-Meier survival curve showing cardiovascular event-free survival for patients treated with three-dimensional conformal radiation therapy plus intensity-modulated radiation therapy by tumor laterality. Also no significant difference was found in event-free survival when comparing left-sided with right-sided tumors for these patients.
Table 1.
Baseline Characteristics of Patients With Stage I and IIA NSCLC Treated With SBRT or 3DCRT Plus IMRT in Left-Sided Lung Cancer vs Right-Sided Lung Cancer
| Characteristic | SBRT Treatment |
3DCRT Plus IMRT Treatment |
||||
|---|---|---|---|---|---|---|
| Left-Side Lung Cancer (n = 741) | Right-Side Lung Cancer (n = 765) | P Value | Left-Side Lung Cancer (n = 817) | Right-Side Lung Cancer (n = 933) | P Value | |
| Age at diagnosis, y | .48 | .14 | ||||
| 65-69 | 88 (12) | 84 (11) | 122 (15) | 131 (14) | ||
| 70-74 | 149 (20) | 170 (22) | 169 (21) | 234 (25) | ||
| 75-79 | 166 (22) | 186 (24) | 221 (27) | 254 (25) | ||
| ≥ 80 | 338 (46) | 353 (43) | 305 (37) | 314 (34) | ||
| Year of treatment | .55 | .25 | ||||
| 2000-2004 | 11 (1) | < 11a | 278 (34) | 293 (31) | ||
| 2005-2009 | 170 (23) | > 166a | 329 (40) | 412 (44) | ||
| 2010-2014 | 560 (76) | 588 (77) | 210 (26) | 228 (24) | ||
| Female sex | 451 (61) | 476 (62) | .59 | 461 (56) | 524 (56) | .91 |
| Race or ethnicity | .05 | .73 | ||||
| White | 654 (88) | 654 (85) | 700 (86) | 796 (85) | ||
| Black | 33 (4) | 59 (8) | 68 (8) | 89 (10) | ||
| Hispanic | 26 (4) | 21 (3) | 23 (3) | 22 (2) | ||
| Other | 28 (4) | 31 (4) | 26 (3) | 26 (3) | ||
| Married | 331 (45) | 339 (44) | .89 | 363 (44) | 413 (44) | .95 |
| Median income in area of residence | .16 | .89 | ||||
| Lowest quartile | 233 (32) | 240 (32) | 303 (38) | 345 (38) | ||
| Second quartile | 207 (28) | 193 (26) | 227 (29) | 251 (27) | ||
| Third quartile | 155 (21) | 145 (19) | 155 (20) | 187 (20) | ||
| Highest quartile | 135 (18) | 172 (23) | 107 (14) | 131 (14) | ||
| Charlson comorbidity index | .4 | .63 | ||||
| 0-0.99 | 124 (17) | 124 (16) | 160 (20) | 189 (20) | ||
| 1-1.99 | 224 (30) | 265 (33) | 253 (31) | 304 (33) | ||
| ≥ 2 | 393 (53) | 385 (50) | 404 (49) | 440 (47) | ||
| Histologic findings | .46 | .55 | ||||
| Adenocarcinoma | 371 (50) | 399 (52) | 320 (39) | 351 (38) | ||
| Squamous cell carcinoma | 278 (38) | 259 (34) | 321 (39) | 355 (38) | ||
| Large cell carcinoma | < 11a | 11 (1) | 31 (4) | 36 (4) | ||
| Other | > 81a | 96 (13) | . . . | . . . | ||
| Tumor size, mm | .47 | .65 | ||||
| ≤ 20 | 281 (38) | 285 (37) | 193 (24) | 230 (25) | ||
| 21-30 | 284 (38) | 278 (36) | 261 (32) | 309 (33) | ||
| 31-50 | 176 (24) | 202 (26) | 363 (44) | 394 (42) | ||
| Tumor lobe | .63 | .68 | ||||
| Upper | 480 (65) | 484 (63) | 533 (65) | 590 (63) | ||
| Lower | 249 (34) | 264 (34) | 237 (29) | 286 (31) | ||
| Other | 12 (2) | 17 (2) | 47 (6) | 57 (6) | ||
| Cardiovascular risk factors | ||||||
| Obesity | 39 (5) | 42 (5) | .84 | 40 (5) | 34 (4) | .19 |
| Smoking | 274 (37) | 283 (37) | .99 | 226 (28) | 274 (29) | .43 |
| Type 2 diabetes | 225 (30) | 226 (30) | .73 | 236 (29) | 288 (31) | .37 |
| Hyperlipidemia | 523 (71) | 554 (72) | .43 | 480 (59) | 532 (57) | .46 |
| Hypertension | 610 (82) | 637 (83) | .63 | 615 (75) | 715 (77) | .51 |
| Hyperthyroidism | 14 (2) | < 11a | .17 | < 11a | 11 (1) | .69 |
| High cardiovascular risk | 287 (39) | 303 (40) | .73 | 312 (38) | 376 (40) | .37 |
| Follow-up time, mo | 24.9 (14.2-39.0) | 23.1 (14.3-38.5) | .53 | 21.7 (11.7-39.8) | 22.1 (11.4-41.3) | .79 |
Data are presented as No. (%) or median (interquartile range), unless otherwise indicated. 3DCRT = three-dimensional conformal radiation therapy; IMRT = intensity-modulated radiation therapy; NSCLC = non-small cell lung cancer; SBRT = stereotactic body radiation therapy.
Value suppressed or coarsened for confidentiality per National Cancer Institute guidelines.
Table 2.
Cardiovascular Outcomes for Patients With Stage I and IIA NSCLC Treated With SBRT or 3DCRT Plus IMRT Comparing Left-Sided Tumors vs Right-Sided Tumors
| Cardiac Outcome | SBRT Treatment (n = 1,506) |
3DCRT Plus IMRT Treatment (n = 1,750) |
||||
|---|---|---|---|---|---|---|
| No. of Events | 3-Year Probability (%) | HR (95% CI) | No. of Events | 3-Year Probability (%) | HR (95% CI) | |
| Cardiovascular death | 59 | 5.5 | 1.48 (0.88-2.48) | 145 | 10.5 | 1.23 (0.89-1.70) |
| Cardiac composite | 635 | 60.5 | 0.98 (0.84-1.15) | 820 | 62.0 | 0.99 (0.86-1.13) |
| Conditions | ||||||
| Acute myocardial infarction | 64 | 5.5 | 0.73 (0.45-1.20) | 100 | 6.8 | 1.34 (0.91-1.99) |
| Acute pericarditis | < 11a | < 0.7a | 1.71 (0.41-7.17) | 12 | 1.1 | 3.41 (0.92-12.58) |
| Constrictive pericarditis | 0 | 0.0 | N/A | 0 | 0.0 | N/A |
| Coronary artery disease | 471 | 43.4 | 0.90 (0.75-1.07) | 541 | 41.4 | 0.97 (0.82-1.14) |
| Atrial fibrillation | 254 | 25.4 | 1.18 (0.92-1.51) | 372 | 28.6 | 0.94 (0.76-1.15) |
| Congestive heart failure | 317 | 31.8 | 1.08 (0.87-1.34) | 430 | 32.9 | 1.23 (1.01-1.48) |
| Angina | 86 | 8.1 | 1.40 (0.92-2.13) | 138 | 10.5 | 1.19 (0.85-1.66) |
| Stroke | 449 | 35.7 | 1.09 (0.91-1.31) | 488 | 34.1 | 1.07 (0.90-1.28) |
| Procedures | ||||||
| Percutaneous coronary artery intervention | 22 | 1.8 | 1.02 (0.44-2.36) | 36 | 2.4 | 2.24 (1.12-4.47) |
| Coronary artery bypass graft | < 11a | < 0.7a | N/A | < 11a | < 0.6a | N/A |
HR = hazard ratio (for unadjusted time-to-event analysis comparing left-sided tumors vs right-sided tumors); IMRT = intensity-modulated radiation therapy; N/A = low sample size; NSCLC = non-small cell lung cancer; SBRT = stereotactic body radiation therapy; 3DCRT = three-dimensional conformal radiation therapy.
Value suppressed or coarsened for confidentiality per National Cancer Institute guidelines.
Patients were followed up for a median of 2 years, and cardiovascular events were common in both the cohort treated with SBRT and the cohort treated with 3DCRT plus IMRT. The 3-year probability of an event in the SBRT cohort was 60.5% and 62.0% for the 3DCRT plus IMRT cohort. In Cox regression models evaluating cardiovascular events, patients treated with SBRT showed no difference in hazard of any cardiovascular outcomes by tumor laterality. The cardiac composite showed no difference in outcomes by tumor laterality (Fig 1A) (adjusted hazard ratio [HR], 0.98; 95% CI, 0.84-1.15), which included any cardiovascular event. Specific event analysis demonstrated similar results with individual cardiovascular outcomes, including acute myocardial infarction (HR, 0.73; 95% CI, 0.45-1.20), acute pericarditis (HR, 1.71; 95% CI, 0.41-7.17), coronary artery disease (HR, 0.90; 95% CI, 0.75-1.07), atrial fibrillation (HR, 1.18; 95% CI, 0.92-1.51), congestive heart failure (HR, 1.08; 95% CI, 0.87-1.34), angina (HR, 1.40; 95% CI, 0.92-2.13), and stroke (HR, 1.09; 95% CI, 0.91-1.31). Cardiovascular death (HR, 1.48; 95% CI, 0.88-2.48) also was not different between the two groups.
The rate of adverse cardiac composite outcomes was not different for left vs right tumors for patients treated with 3DCRT plus IMRT (Fig 1B). However, patients treated with 3DCRT plus IMRT showed a greater risk of a few individual cardiovascular outcomes, including congestive heart failure (HR, 1.23; 95% CI, 1.01-1.48) (e-Fig 1) and percutaneous coronary artery intervention (HR, 2.24; 95% CI, 1.12-4.47) when comparing left- vs right-sided tumors. The remaining outcomes were not associated with laterality, including acute myocardial infarction (HR, 1.34; 95% CI, 0.91-1.99), acute pericarditis (HR, 3.41; 95% CI, 0.92-12.58), coronary artery disease (HR, 0.97; 95% CI, 0.82-1.14), atrial fibrillation (HR, 0.94; 95% CI, 0.76-1.15), angina (HR, 1.19; 95% CI, 0.85-1.66), stroke (HR, 1.07; 95% CI, 0.90-1.28), and cardiovascular death (HR, 1.23; 95% CI, 0.89-1.70).
We conducted subgroup analyses stratifying the SBRT and primary 3DCRT plus IMRT cohorts by tumor lobar location (e-Tables 1, 2). Patients with upper lobe tumors treated with SBRT showed a greater risk of atrial fibrillation (HR for left- vs right-sided tumors, 1.37; 95% CI, 1.01-1.87). In contrast, patients with upper lobe tumors treated with 3DCRT plus IMRT showed an increased risk of both myocardial infarction (HR, 1.64; 95% CI, 1.01-2.66) and congestive heart failure (HR, 1.29; 95% CI, 1.02-1.64).
Discussion
In this study, we found that treatment of patients with stage I and IIA NSCLC with SBRT was not associated with a statistically significant increase in long-term cardiovascular events when comparing right- vs left-sided tumors. In contrast, patients who received 3DCRT plus IMRT for left-sided tumors showed an increased risk of select adverse cardiovascular outcomes compared with those with right-sided tumors. By comparing these effects by laterality, a presumedly random process, we were able to detect potential causal effects of radiotherapy. Therefore, in patients with left-sided early stage lung cancers, these findings suggest that SBRT may be associated with limited long-term cardiovascular toxicity, whereas 3DCRT plus IMRT approaches may have some long-term cardiovascular risk.
Our findings provide additional support for the increased use of SBRT as well as management considerations for cancer centers that may still use 3DCRT plus IMRT for early stage lung cancers. The increased risk of cardiovascular toxicity resulting from 3DCRT plus IMRT compared with SBRT compounds the growing list of reasons why treatment centers should develop the capacity for SBRT. In addition, if patients must receive 3DCRT plus IMRT, long-term cardiovascular surveillance and medical optimization should be considered.19
The potential for cardiac toxicity resulting from cancer radiotherapy has been well established.20 Cardiac radiosensitivity has been noted in long-term follow-up studies of patients with Hodgkin’s disease treated with radiotherapy.21,22 Further evidence for radiation-induced cardiovascular damage was shown in a prospective cohort study of roughly 300,000 women with breast cancer,23 and population-based registry studies have demonstrated increased cardiovascular toxicity associated with breast tumor laterality.7 A wide range of adverse cardiovascular outcomes have been attributed to thoracic radiotherapy, including dose-dependent exacerbation of atherosclerosis, direct cardiac myocyte damage with cardiomyopathy, pericardial disease, and valve calcification. Radiation administered to left-sided tumors (vs right-sided tumors) is expected to result in higher-dose exposures to these structures, as suggested by both clinical models and outcomes studies.24 Although studies have shown that cardiac doses of 3DCRT plus IMRT are an independent predictor of overall survival in NSCLC, these investigations have examined locally advanced or stage III disease as opposed to our focus on stage I and IIA NSCLC.25,26 Newer focused RT techniques such as SBRT also have been associated with some limited evidence of potential cardiovascular tissue damage in patients with stage I NSCLC, particularly with the treatment of centrally located tumors.27 Despite this, SBRT was not associated with a higher event rate of cardiovascular outcomes in left- vs right-sided early stage lung cancers.
A limited number of previous studies have examined the risk of cardiac toxicity associated with SBRT for lung cancer. Two of these studies examined a relatively small cohort of patients (fewer than 150), but used quantitative metrics to measure cardiac exposure such as dose-volume histograms.9,10 The investigation by Tembhekar et al9 noted that cardiac radiation dose was not a predictor of overall survival after SBRT in early stage (stages I and II) NSCLC. In contrast, a larger study of 803 patients by Stam et al28 showed that maximum dose to the left atrium and a dose to 90% of the superior vena cava were associated significantly with noncancer death, although they did not investigate any association with cardiac events.28 Of note, that study did not control for baseline cardiovascular risk, but did observe that baseline cardiac functioning was prognostic for survival.
In subgroup analyses, we evaluated tumor location to assess if higher radiation doses contributed to long-term cardiovascular risk. Although cardiac dose may be more impacted by axial plane of radiation down the thoracic vertebra levels, rather than tumor lobe location, as evidenced by Teoh et al,29 we noted an increased risk of atrial fibrillation in patients with NSCLC with upper lobe tumors treated with SBRT. This finding was of borderline statistical significance, but has possible physiologic underpinnings because of an increased risk of radiation exposure and damage to conduction fibers surrounding the pulmonary veins.30 Future investigations may need to examine more closely the mechanisms for radiation-induced atrial fibrillation across multiple thoracic cancer types.31,32 In addition, incorporation of specific normal tissue dose constraints in treatment planning for thoracic tumors to prevent atrial fibrillation requires further investigation, specifically in patients with lung cancer.11,31,32
Some strengths and limitations to our study should be acknowledged. First, our study lacks precise information on radiation dosing and exact location of therapy aside from tumor lobe; future studies ideally should include contouring of individual cardiac substructures. Second, our data are limited to individuals older than 65 years and therefore may not be applied to younger individuals. Third, although we noted an increase in coronary interventions for patients with left-sided tumors receiving 3DCRT plus IMRT, the fact that no corresponding increase in angina or myocardial infarction was found highlights a limitation of registry-based research. Nevertheless, our study had several strengths, notably the use of nationally representative data with large numbers of individuals as well as precise estimation and analyses of subgroups that differentiate the statistical power of our study in comparison with previous SBRT analyses. In addition, our results controlled for previous cardiovascular risks and included a wide range of cardiovascular risk variables and outcomes. Finally, in lieu of exact irradiation location, our study capitalized on a presumably random allocation of study groups, comparing left- vs right-sided tumor location to estimate cardiovascular risk.
Interpretation
In summary, this large retrospective cohort investigation suggested that 3DCRT plus IMRT in patients with early stage NSCLC may harbor an increased long-term risk of cardiovascular disease when comparing left- vs right-sided tumors. In contrast, patients treated with SBRT did not show increased cardiovascular risk based on tumor laterality. Therefore, we suggest that SBRT may be a safer option for patients with left-sided early stage lung cancer. This study’s findings suggest that the availability of SBRT may reduce the risk of cardiovascular events in patients with early stage lung cancers who are treated with radiation therapy.
Acknowledgments
Author contributions: B. Y. L. and K. S. were involved in all aspects of the project, including, but not limited to, literature search, figure creation, study design, data collection, data interpretation, and writing. D. M. and S. R. played a large role in figure creation, study design, and data analysis and interpretation. M. S. K., K. E. R., and C. Y. K. was involved in aspects of study design, data interpretation, and writing. J. P. W. was involved in all aspects of the project, including, but not limited to, study design, data interpretation, writing.
Financial/nonfinancial disclosures: None declared.
Role of sponsors: The funding sources had no role in the design, conduct, or analysis of the study or in the decision to submit the manuscript for publication.
Additional information: The e-Figure and e-Tables Supplemental Materialsare available online under “Supplementary Data.”
Footnotes
FUNDING/SUPPORT: This work was supported by the National Cancer Institute [Grant R01CA202956]. D. M.’s contribution to this project was supported in part by the National Cancer Institute, National Institutes of Health [Grant T32 CA225617].
Supplementary Data
References
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