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Annals of Oncology logoLink to Annals of Oncology
. 2010 Mar 8;21(9):1825–1833. doi: 10.1093/annonc/mdq042

Cardiac toxicity in association with chemotherapy and radiation therapy in a large cohort of older patients with non-small-cell lung cancer

D Hardy 1,*, C-C Liu 1, J N Cormier 2, R Xia 1, X L Du 1,3,
PMCID: PMC2980940  PMID: 20211871

Abstract

Background: The study's objective was to investigate the risks of developing cardiac disorders following the administration of chemotherapy and radiation therapy in patients with non-small-cell lung cancer (NSCLC).

Methods: The study consisted of 34 209 patients aged ≥65 years with American Joint Committee on Cancer stages I–IV NSCLC identified from the Surveillance, Epidemiology, and End Result-Medicare linked database (1991–2002) who were free of cardiac disorders at NSCLC diagnosis.

Results: There were significant associations between the use of chemotherapy/radiation and the risks of developing ischemic heart disease, conduction disorders, cardiac dysfunction, and heart failure. The absolute risks for cardiac dysfunction increased with the administration of chemotherapy-only and radiation-only, and incrementally with chemoradiation. Men, blacks, older patients, those with higher comorbidity scores, and advanced disease were at higher risk. The risk for ischemic heart disease increased when radiation/chemoradiation were rendered to the left lung and both lungs and for cardiac dysfunction, radiation administered to the left lung.

Conclusions: There were significant associations especially for cardiac dysfunction with use of chemotherapy/radiation therapy and risks of developing cardiac toxicity in NSCLC patients. The risks of treatment-associated cardiac toxicity, specifically ischemic heart disease and cardiac dysfunction, were greatest among those with left-sided lung tumors.

Keywords: cardiac disorders, chemotherapy, lung cancer, radiation therapy, toxicity

introduction

Lung cancer is a major cause of cancer-related deaths in the United States and is expected to result in 159 390 deaths in 2009 [1]. This number exceeds the total number of cancer deaths from breast, prostate, and colon cancer combined. About one-third of the patients presenting with lung cancer are not candidates for surgical resection because of advanced local disease or distant metastasis. Non-small-cell lung cancer (NSCLC), which accounts for ∼85%–90% of lung cancer cases in the United States, is associated with an overall 5-year survival rate of ∼15% [1].

The National Comprehensive Cancer Network [2] treatment guidelines recommend that patients with early disease (stages I and II) be treated with surgical resection in addition to chemotherapy and/or radiation therapy as potentially curative treatments [3]. For patients with advanced or distant disease (stages III and IV), which comprise the majority of patients with NSCLC at diagnosis, chemotherapy or in combination with radiation therapy are recommended for best supportive care [2].

Chemotherapy [4], radiation therapy [3], and more so combination of chemotherapy and radiation therapy (chemoradiation) [5, 6] have been shown to result in increased survival time for NSCLC patients. However, the toxic effects associated with these treatments may adversely affect the quality associated with the improved outcome [7]. These toxic effects are often correlated with the cumulative dose of the treatment, which can vary among individuals.

Chemotherapy drugs target the growth patterns of specific types of cancer cells; however, healthy cells with similar growth patterns are also often destroyed in the process [8]. Additionally, since radiation therapy is directed to the chest wall in high maximum tolerated doses, underlying structures such as the heart can be included in the treatment field and become compromised [9]. Studies have reported the development of late treatment-associated cardiac toxic effects (>2–3 months) in patients with NSCLC including ischemic heart disease, cardiomyopathy, conduction disorders, cardiac dysfunction, and heart failure or deterioration of these preexisting conditions [10].

There is some evidence that radiation therapy confers an increased risk of cardiac toxicity in reports of patients treated up to 1988 but not in later years (1989–1993) [11, 12], and that chemotherapy may confer more toxicity than radiation therapy [12]. However, more recent clinical trials utilizing chemoradiation show promising results with improved tumor response, increased survival, and decreased toxicity [13]. Moreover, other recent studies have reported an increased risk of developing cardiac toxic effects from all the three treatments rendered [7, 10, 12].

Among recent clinical trials that reported a lower incidence of cardiac toxic effects, specific chemotherapy agents have been identified which have more favorable toxicity profiles. For example, while single-agent gemcitabine [14, 15] has been shown to increase the risk of developing cardiac toxicity in earlier studies, recent studies have shown a more favorable toxicity profiles for these agents [16, 17]. Furthermore, reports in earlier studies have shown that carboplatin as a single/combination agent [18], mitomycin–ifosfamide–cisplatin combination therapy [19], and paclitaxel plus gemcitabine or paclitaxel plus carboplatin combinations [20] may not be associated with increased cardiac toxicity.

Another consideration is toxicity associated with radiation therapy that is administered to tumors of the left lung versus the right lung. Radiation therapy to the left chest has been reported to be associated with more cardiac toxicity and subsequent risk for developing chronic cardiac disorders [2124].

It is not clear whether newer chemotherapy regimens and advances in the field of radiation oncology have resulted in improved treatment toxicity profiles. Additionally, if there is improvement in treatment-associated toxic effects, it is uncertain what the magnitude of change has been over the years. The purpose of this study is to investigate the risks of developing various types of cardiac disorders, including ischemic heart disease, cardiomyopathy, conduction disorders, cardiac dysfunction, and heart failure, in association with administration of chemotherapy, radiation therapy, and chemoradiation, and to see whether the risks of developing such conditions have changed over the past 12 years from 1991 to 2002. An additional aim is to investigate whether administering radiation/chemoradiation to the left lung or both lungs versus the right lung would result in an increased risk for cardiac disorders.

methods

data source

The validity of Medicare claims for examining the use of cancer chemotherapy has been demonstrated [25]. The Surveillance, Epidemiology, and End Results (SEER) Program-Medicare linked data files were used to provide information about incident cancer cases and cancer-directed therapy. The SEER program includes population-based tumor registries in 17 geographic areas. From 1991 to 1999, 12 of 14 SEER registries participated in the SEER-Medicare linkage, which represented ∼14% of the USA population. By the year 2000, four new SEER registries were added, which expanded to 26.2% of the USA population. Atlanta and Rural Georgia were also combined as well as all four registries in California because of too few cases in some registries. Medicare is a federally funded health insurance program primarily for those ≥65 years of age. Medicare eligibility could be identified for 94% of the individuals who appeared in the SEER records [25]. The University of Texas Health Science Center at the Houston Committee for Protection of Human Subjects approved the study protocol.

study population

The final study sample consisted of 34 209 patients aged ≥65 years with American Joint Committee on Cancer (AJCC) stages I–IV NSCLC. Patient files were searched from 1991 to 2002 for disease conditions identified from International Classification of Disease (ICD)-9 procedure codes: ischemic heart disease (410.x–414.x), cardiomyopathy (425.x), conduction disorders (426.x), cardiac dysfunction (427.x), and heart failure (428.x). A patient was considered having a cardiac disorder if there were at least two diagnoses for the condition identified by a physician at least ≥30 days apart after diagnosis of NSCLC. Those who had a history of cardiac disorders identified before the date of NSCLC diagnosis (n = 34 684) were excluded from the study. Alaska natives and Arizona Indians SEER registries were excluded due to small number of cases. In order to ensure completeness of Medicare claims, patients who did not have full coverage of both Medicare Parts A and B or who were members of a Health Maintenance Organization after diagnosis through the date of last follow-up or death were also excluded from the study.

study variables

The outcome variable was time to development (in days) of treatment-related cardiac toxicity, calculated from the date of diagnosis of NSCLC until the development of cardiac toxicity-related conditions, censoring, or date of last follow-up. The following patient and tumor characteristics were considered for adjustment in multivariate analyses: race/ethnicity was designated as whites (non-Hispanic whites), blacks (African-Americans and non-Hispanic blacks from other countries), Asians, Hispanics, other races, and patients from unknown race/ethnic group; year of NSCLC diagnosis (1991–1995, 1996–1999, 2000–2002); age (categorized as 65–69, 70–74, 75–79, or 80+); marital status (married, unmarried: single/widowed/divorced, or unknown); sex; disease stage (AJCC stages I–IV, unstaged); tumor size (cm) (<1, 1–2, 2.1–3, 3.1–4, >4); tumor grade (well differentiated, moderately differentiated, poorly differentiated, and unknown); histology (nonspecific cancer, large cell, squamous cell, adenocarcinoma, bronchioalveolar, adenosquamous cell); positive number of nodes (1, 2–3, 4–5, 6–9, 10–51); surgery within 12 months of NSCLC diagnosis, SEER geographic area (categorized into 12 USA regions); and incident pulmonary fibrosis (490–508, 514.x–518.89, and 515) as (yes/no) identified by a physician for two diagnoses of the condition that were at least ≥30 days apart after diagnosis of NSCLC. The percentage of individuals living below the poverty line at the census tract level was used to define socioeconomic status quartile categories. Comorbidity scores coded as 0, 1, 2, 3, ≥4 were ascertained from Medicare claims by identifying 18 diagnoses (not including cancer) or related procedures recorded between 1 year before and 1 month after the diagnosis of NSCLC. Details on creating a weighted comorbidity score have previously been reported [26].

treatment and exposure variables

The exposure variables, chemotherapy-only, radiation therapy-only, and chemoradiation, were designated according to whether patients received or did not received treatment within 12 months of diagnosis for NSCLC. Information pertaining to the methods of identifying chemotherapy administered from Medicare claims are described elsewhere [25]. In brief, patients who were treated with chemotherapy were identified using the ICD-9 procedure code 9925 for injection or infusion of cancer chemotherapeutic substance, Common Procedure Terminology (CPT) codes (96400–96549, J8510, J8520, J8521, J8530–J8999, J9000–J9999, and Q0083–Q0085) for chemotherapy administration, revenue center codes 0331 for chemotherapy injected, 0332 (chemotherapy oral), 0335 (chemotherapy i.v.), and ICD-9-CM V codes (V58.1, V66.2, or V67.2) for follow-up examination or care after chemotherapy.

Radiation therapy included external beam radiation, radioactive implants, radioisotopes, or other radiation as coded in SEER [27], Medicare claims indicated by ICD-9 procedure codes (9221–9229) for inpatient or outpatient radiation therapy facility claim, CPT codes (77401–77499 or 77750–77799) for physician or outpatient claim for delivery of radiation treatment or brachytherapy, and revenue codes (0330 or 0333) for radiation therapy [28]. Surgical resection was identified using SEER codes (10–70, 90) for local surgical excision, partial wedge/segmental resection, partial lobectomy, and resection of the whole lung, or at least one lobe, but less than the whole lung, or if there were Medicare claims of resection through the ICD-9 procedure codes (32.29–32.99) [29] and CPT codes (32440–32525, 32657, 32663) [30].

statistical analysis

Analyses were carried out using STATA, version 11.0 (StataCorp, College Station, TX). Descriptive statistics comparing treatment groups were carried out using Pearson's chi-square tests of hypothesis for independence with P value of 0.05 as the cut-off point. Cox proportional regression analyses were carried out to assess the risk [hazard ratio (HR)] for developing ischemic heart disease, cardiomyopathy, conduction disorders, cardiac dysfunction, and heart failure for NSCLC patients who received chemotherapy-only, radiation therapy-only, or chemoradiation compared with those who did not receive treatment. The effects of race/ethnicity, age, gender, comorbidity scores, tumor disease stage, and years of diagnosis were assessed over time using multivariate adjustment.

In addition, in Table 3, the risks of developing various cardiac toxic effects were stratified by years of diagnosis (1991–1995, 1996–1999, and 2000–2002). The risk of toxicity was also examined for treatment rendered to the left lung or both lungs compared with the right lung. Interaction terms were constructed for chemotherapy-only, radiation therapy-only, and chemoradiation, with covariates using the likelihood ratio with a P value cut-off point of 0.05. These were included along with single-order covariates in the model. When the proportional hazards assumption was violated, time-dependent variables that interacted with time were created and also included in the multivariate models.

Table 3.

Multivariate analyses of risk factors for developing cardiac conditions by years of diagnosis for patients with non-small-cell lung cancer

Adjusted model Hazard ratio (95% confidence interval)
1991–1995 1996–1999 2000–2002
Ischemic heart disease
    No treatment 1.00 1.00 1.00
    Chemotherapy-only 1.31 (1.02–1.68) 1.22 (0.93–1.60) 1.26 (1.04–1.53)
    Radiation therapy-only 0.89 (0.75–1.06) 0.98 (0.77–1.23) 0.80 (0.65–0.97)
    Chemoradiation 0.98 (0.79–1.21) 1.24 (0.97–1.59) 1.14 (0.93–1.39)
Cardiomyopathy
    No treatment 1.00 1.00 1.00
    Chemotherapy-only 1.19 (0.53–2.69) 1.63 (0.62–4.32) 0.37 (0.15–0.93)
    Radiation therapy-only 0.58 (0.23–1.48) 0.63 (0.17–2.35) 0.29 (0.11–0.79)
    Chemoradiation 0.53 (0.14–2.02) 0.84 (0.15–4.67) 0.29 (0.08–1.09)
Conduction disorders
    No treatment 1.00 1.00 1.00
    Chemotherapy-only 0.67 (0.24–1.84) 1.21 (0.56–2.63) 1.02 (0.54–1.93)
    Radiation therapy-only 1.32 (0.86–2.03) 0.92 (0.51–1.66) 0.80 (0.46–1.38)
    Chemoradiation 0.90 (0.48–1.69) 1.45 (0.80–2.62) 1.59 (0.98–2.58)
Cardiac dysfunction
    No treatment 1.00 1.00 1.00
    Chemotherapy-only 1.54 (1.15–2.05) 1.55 (1.16–2.06) 1.63 (1.30–2.05)
    Radiation therapy-only 1.63 (1.20–2.20) 1.48 (1.05–2.07 1.65 (1.24–2.19)
    Chemoradiation 2.28 (1.56–3.33) 2.36 (1.57–3.57) 2.53 (1.81–3.54)
Heart failure
    No treatment 1.00 1.00 1.00
    Chemotherapy-only 1.44 (1.10–1.89) 1.42 (1.05–1.93) 1.13 (0.89–1.43)
    Radiation therapy-only 1.08 (0.93–1.26) 1.19 (0.96–1.48) 0.97 (0.79–1.18)
    Chemoradiation 1.13 (0.92–1.38) 1.29 (1.02–1.62) 1.17 (0.97–1.42)

See Table 2 for variables adjusted for in the analyses. Statistically significant hazard ratios are in bold.

results

The study population consisted of 34 209 patients who were ≥65 years old, diagnosed with NSCLC from 1 January 1991 to 31 December 31 2002. Table 1 shows the percent distribution of patient characteristics within each treatment group. Of these, 31.2% received no chemotherapy or radiation therapy, 9.4% received chemotherapy-only, 34.4% received radiation therapy-only, and 25.1% received chemoradiation.

Table 1.

Percent distribution of patient characteristics stratified by treatment of 34 209 non-small-cell lung cancer patients diagnosed with cardiac conditions (ischemic heart disease, cardiomyopathy, conduction disorders, cardiac dysfunction, and heart failure) from 1991 to 2002 and follow-up through 2005

Column %
Characteristic No chemotherapy or radiation therapy Chemotherapy-only Radiation therapy-only Chemotherapy plus radiation therapy
(n = 10 666) (n = 3210) (n = 11 761) (n = 8572)
Median age (65–89 years) 74 72 73 71
    65–69 26.3 31.7 27.6 40.7
    70–74 27.6 33.4 29.5 34.1
    75–79 24.9 22.4 24.6 18.6
    80–84 15.1 10.2 13.5 5.7
    ≥85 6.2 2.3 4.8 1.0
Gender
    Male 52.3 53.1 57.4 56.5
    Female 47.7 46.9 42.6 43.5
Race/ethnicity
    White 82.3 83.2 81.7 84.5
    Black 8.4 8.4 9.8 8.2
    Asian 3.5 3.6 2.8 2.8
    Hispanic 1.2 1.3 1.0 0.8
    Other races 3.9 3.0 3.6 3.2
    Unknown 0.7 0.5 1.1 0.5
Socioeconomic status
    Highest quartile 23.2 28.5 23.4 27.6
    Second quartile 24.5 23.3 24.3 25.6
    Third quartile 25.4 26.1 25.5 24.1
    Lowest quartile 25.2 20.6 25.1 21.3
    Unknown 1.7 1.4 1.8 1.5
Marital status
    Married 49.5 57.2 52.0 61.4
    Unmarried 46.3 38.9 44.4 35.1
    Unknown 4.2 3.8 3.6 3.6
Stage
    I 34.7 8.2 12.6 7.1
    II 11.6 4.9 6.7 5.6
    IIIA 6.5 6.8 12.4 16.1
    IIIB 14.0 23.5 18.7 23.6
    IV 22.7 47.2 41.0 40.9
    Unknown 10.6 9.5 8.7 6.8
Comorbid score
    0 44.8 56.1 49.8 57.3
    1 37.5 33.9 34.4 34.5
    2 8.6 7.2 7.7 6.2
    3 2.1 1.8 1.9 1.2
    ≥4 7.1 1.0 6.3 0.8
Histology
    Cancer, nonspecific 17.6 20.8 20.9 21.8
    Large cell 6.3 7.6 9.0 8.8
    Squamous cell 28.7 17.4 35.3 29.7
    Adenocarcinoma 38.4 47.4 32.1 37.0
    Bronchioalveolar 7.3 5.5 1.6 1.4
    Adenosquamous cell 1.8 1.4 1.1 1.4
Tumor grade
    Well differentiated 6.8 3.6 2.9 2.3
    Moderately differentiated 21.0 12.6 14.2 13.4
    Poorly differentiated 32.2 31.0 36.3 37.0
    Undifferentiated 5.2 5.5 6.0 6.6
    Missing/unknown 34.9 47.4 40.6 40.6
Tumor size (cm)
    <1 1.3 1.0 0.8 0.6
    1–1.9 9.8 3.9 3.4 2.8
    2–2.9 16.2 8.4 8.9 8.4
    3–4 13.3 10.4 11.1 10.9
    ≥4 29.0 27.8 39.0 40.2
    Missing 30.5 48.6 36.8 37.1
Positive number of nodes
    None 32.7 7.5 5.4 4.6
    1 3.9 4.6 4.7 6.5
    2–3 1.9 1.8 2.5 3.5
    4–5 0.6 0.7 0.8 0.9
    6–9 0.3 0.3 0.5 0.8
    10–51 1.6 2.7 2.8 4.9
    Missing 59.1 82.6 83.3 79.0
Pulmonary fibrosis
    No 55.1 57.1 60.5 49.0
    Yes 44.9 42.9 39.6 51.0
Surgery
    No 53.7 83.9 86.6 87.5
    Yes 46.3 16.1 13.4 12.5
SEER registry area
    Connecticut 10.6 12.8 13.4 12.8
    Detroit 9.6 11.0 10.3 12.5
    Hawaii 2.3 1.6 2.6 2.3
    Iowa 11.8 9.4 13.9 11.6
    New Mexico 3.8 2.9 4.0 2.8
    Seattle 10.8 8.8 10.1 10.6
    Utah 2.9 2.0 2.8 1.5
    Atlanta/Rural Georgia 5.3 6.6 5.9 5.9
    Kentucky 4.7 5.0 3.7 5.3
    Louisiana 2.5 3.0 2.9 3.9
    New Jersey 4.4 8.5 3.3 6.2
    California 31.2 28.5 27.3 24.6
Year of diagnosis
    1991 7.9 4.6 11.6 6.0
    1992 7.4 5.4 10.2 6.0
    1993 7.5 4.7 10.5 5.3
    1994 7.4 5.2 9.0 5.8
    1995 7.0 5.5 7.6 6.1
    1996 6.4 5.9 7.3 6.0
    1997 6.1 6.0 6.4 6.5
    1998 6.1 6.5 5.5 6.4
    1999 6.0 7.1 4.7 7.2
    2000 11.9 16.3 9.2 14.6
    2001 13.2 15.5 9.5 14.4
    2002 13.0 17.6 8.6 15.6

Total percent in variable groups by treatment categories is subject to rounding error. All P values were <0.001. P values were calculated using Pearson's χ2 tests of hypothesis for independence to assess statistical significance in relationships between patient characteristics and treatments given.

SEER, Surveillance, Epidemiology, and End Result.

Most patients were in the younger-aged elderly groups (65–79 years), of male gender, white race/ethnicity, married, with comorbidity scores of ≤1, tumor disease stage IV, and poorly differentiated tumors ≥4 cm. A higher proportion of patients who were in the chemotherapy-only group had adenocarcinoma, and similarly, for those who were in the radiation therapy-only group and those who took chemoradiation had squamous cell and adenocarcinoma cancers.

The median time to the development of toxicity was longest for cardiomyopathy (510.5 days) and shortest for cardiac dysfunction (78 days) (Table 2). The risks increased with chemotherapy-only treatment of ischemic heart disease [HR = 1.24, 95% confidence interval (CI) 1.09–1.41], cardiac dysfunction (HR = 1.58, 95% CI 1.36–1.83), and heart failure (HR = 1.29, 95% CI 1.10–1.50). Cardiac dysfunction was associated with all three modalities of treatment; however, with chemoradiation, the HR (HR = 2.36, 95% CI 1.91–2.92) was ∼1.5 times the risks for the chemotherapy-only (HR = 1.58, 95% CI 1.36–1.83) and radiation therapy-only (HR = 1.54, 95% CI 1.29–1.83) groups.

Table 2.

Multivariate analyses of risk factors for developing cardiac conditions in patients diagnosed with non-small-cell lung cancer from 1991 to 2002 and follow-up through 2005

Hazard ratio (95% confidence interval)
Ischemic heart disease Cardiomyopathy Conduction disorders Cardiac dysfunction Heart failure
Cardiac events n = 3528 n = 318 n = 415 n = 4509 n = 2606
Median time (days) to development of disease condition 106 510.5 281 78 240
Adjusted model
    Treatment
        No chemotherapy or radiation therapy 1.00 1.00 1.00 1.00 1.00
        Chemotherapy-only 1.24 (1.09–1.41) 0.82 (0.49–1.36) 1.02 (0.66–1.56) 1.58 (1.36–1.83) 1.29 (1.10–1.50)
        Radiation therapy-only 0.85 (0.76–0.95) 0.46 (0.25–0.82) 1.01 (0.76–1.35) 1.54 (1.29–1.83) 1.06 (0.96–1.18)
        Chemoradiation 1.10 (0.971.24) 0.49 (0.22–1.10) 1.37 (1.01–1.87) 2.36 (1.91–2.92) 1.20 (1.06–1.35)
Race/ethnicity
        White 1.00 1.00 1.00 1.00 1.00
        Black 1.06 (0.94–1.19) 2.14 (1.55–2.97) 1.27 (0.90–1.80) 1.26 (1.13–1.41) 1.24 (1.08–1.43)
        Asian 1.13 (0.93–1.37) 0.65 (0.32–1.31) 1.15 (0.72–1.86) 0.93 (0.78–1.10) 0.92 (0.72–1.17)
        Hispanic 1.10 (0.81–1.50) 1.26 (0.47–3.39) 0.86 (0.32–2.32) 1.16 (0.90–1.51) 1.44 (1.04–2.01)
        Other 0.87 (0.69–1.12) 0.81 (0.36–1.83 0.83 (0.43–1.61) 0.99 (0.83–1.19) 0.91 (0.69–1.20)
        Unknown 1.17 (0.72–1.89) 1.06 (0.15–7.63) 0.60 (0.08–4.27) 0.65 (0.38–1.12) 1.44 (0.88–2.37)
    Age
        65–69 1.00 1.00 1.00 1.00 1.00
        70–74 1.03 (0.95–1.12) 0.95 (0.73–1.23) 1.34 (1.03–1.73) 1.17 (1.08–1.27) 1.26 (1.14–1.39)
        75–79 1.08 (0.98–1.18) 0.83 (0.61–1.14) 1.68 (1.28–2.21) 1.32 (1.19–1.47) 1.42 (1.28–1.59)
        80–84 1.25 (1.11–1.41) 1.22 (0.82–1.82) 2.15 (1.53–3.01) 1.54 (1.33–1.77) 1.80 (1.57–2.06)
        ≥85 1.45 (1.19–1.76) 0.58 (0.21–1.57) 3.37 (2.06–5.51) 1.74 (1.40–2.15) 2.29 (1.86–2.81)
    Gender
        Men 1.00 1.00 1.00 1.00 1.00
        Women 0.83 (0.78–0.89) 0.46 (0.33–0.64) 0.78 (0.64–0.95) 0.88 (0.83–0.94) 1.02 (0.94–1.10)
    Comorbidity score
        0 1.00 1.00 1.00 1.00 1.00
        1 0.99 (0.91–1.07) 1.05 (0.82–1.35) 1.01 (0.81–1.25) 1.03 (0.96–1.10) 1.25 (1.15–1.37)
        2 1.32 (1.15–1.52) 1.22 (0.82–1.81) 1.35 (0.97–1.88) 1.00 (0.89–1.12) 1.25 (1.15–1.37)
        3 1.56 (1.23–1.97) 1.04 (0.46–2.39) 2.03 (1.17–3.53) 1.19 (0.96–1.47) 2.24 (1.78–2.82)
        ≥4 0.77 (0.60–0.99) 0.69 (0.31–1.54) 0.67 (0.31–1.45) 0.57 (0.45–0.72) 1.38 (1.08–1.76)
    Disease stage
        Stage IV 1.00 1.00 1.00 1.00 1.00
        Stage IIIB 1.15 (1.01–1.30) 1.26 (0.81–1.93) 1.51 (1.02–2.21) 1.28 (1.15–1.41) 1.24 (1.07–1.43)
        Stage IIIA 1.31 (1.15–1.50) 1.13 (0.71–1.78) 1.44 (0.96–2.16) 1.17 (1.04–1.31) 1.38 (1.19–1.60)
        Stage II 1.40 (1.22–1.61) 1.55 (1.01–2.40) 1.06 (0.68–1.63) 1.19 (1.05–1.34) 1.26 (1.08–1.48)
        Stage I 1.34 (1.19–1.52) 0.94 (0.61–1.44) 1.30 (0.89–1.92) 1.10 (0.98–1.23) 1.20 (1.04–1.37)
        Unstaged 1.38 (1.19–1.60) 1.44 (0.88–2.37) 0.86 (0.50–1.47) 1.28 (1.12–1.46) 1.37 (1.16–1.62)
    Year of diagnosis
        1991–1995 1.00 1.00 1.00 1.00 1.00
        1995–1999 0.99 (0.90–1.08) 0.93 (0.67–1.29) 0.89 (0.69–1.14) 1.14 (1.05–1.23) 0.87 (0.78–0.96)
        2000–2002 0.93 (0.85–1.02) 1.19 (0.86–1.65) 0.89 (0.70–1.12) 1.09 (1.01–1.17) 0.73 (0.66–0.82)
Crude model
    No chemotherapy or radiation 1.00 1.00 1.00 1.00 1.00
    Chemotherapy-only 0.95 (0.84–1.07) 1.14 (0.75–1.74) 0.71 (0.47–1.06) 1.00 (0.89–1.11) 1.05 (0.92–1.21)
    Radiation therapy-only 0.68 (0.62–0.74) 0.88 (0.64–1.20) 0.76 (0.58–0.98) 0.83 (0.77–0.90) 1.03 (0.93–1.13)
    Chemoradiation 0.89 (0.81–0.97) 1.39 (1.05–1.83) 0.92 (0.71–1.18) 1.23 (1.14–1.33) 1.09 (0.98–1.21)

All models adjusted for age, sex, ethnicity/race, socioeconomic status, comorbidity score, tumor size, positive number of nodes, tumor grade, histology, surgery, SEER areas, years of diagnosis, and pulmonary fibrosis, plus interaction terms—for ischemic heart disease model: chemotherapy–radiation therapy–chemoradiation and comorbid score; for cardiomyopathy model: chemotherapy–radiation therapy–chemoradiation and sex; and for cardiac dysfunction: chemotherapy–radiation therapy–chemoradiation and age and chemotherapy–radiation therapy–chemoradiation and surgery, using survival analysis.

SEER, Surveillance, Epidemiology, and End Result. Statistically significant hazard ratios are in bold.

Black patients appeared to be at increased risk for developing cardiomyopathy (HR = 2.24, 95% CI 1.55–2.97), cardiac dysfunction (HR = 1.26, 95% CI 1.13–1.41), and heart failure (HR = 1.24, 95% CI 1.08–1.43), and Hispanic patients were at increased risk for heart failure (HR = 1.44, 95% CI 1.04–2.01). Age was a significant risk factor for ischemic heart disease for those patients ≥80 years and for those who were ≥65 years for conduction disorders, cardiac dysfunction, and heart failure. The risks for conduction disorders, cardiac dysfunction, and heart failure significantly increased over advancing age groups. Women were at lower risk compared with men for developing all conditions, except for heart failure. The risks for ischemic heart disease increased in patients with two to three comorbidities and for heart failure in patients who had ≥1 comorbidity. Patients with earlier disease stage NSCLC were at greater risk for ischemic heart disease, cardiac dysfunction, and heart failure. The risks of cardiac dysfunction appeared to be significantly increased over years of diagnosis from 1991 to 2002. However, these risks attenuated slightly from diagnosis years 1999–1999 (HR = 1.14, 95% CI 1.05–1.23) to 2002–2002 (HR = 1.09, 95% CI 1.01–1.17). When risks for cardiac toxicity conditions were examined for 1991–1995, 1996–1999, and 2000–2002 (Table 3), the risks for cardiac dysfunction increased in succession within stratified years from chemotherapy-only to radiation-only to chemoradiation. The risk for ischemic heart disease was also elevated for the chemotherapy-only group in 2000–2002 (HR = 1.26, 95% CI 1.04–1.53).

We further investigated whether radiation to the left chest was associated with increased cardiac toxicity (Table 4). The risks increased incrementally for ischemic heart disease when treatment was rendered to the left lung compared with the right lung with either radiation-only (HR = 1.18, 95% CI 1.05–1.34) or chemoradiation (HR = 1.29, 95% CI 1.09–1.52) and was highest for chemoradiation rendered to both lungs compared with the right lung (HR = 1.76, 95% CI 1.11–2.78). The risk of cardiac dysfunction increased when radiation-only was administered to the left lung compared with the right lung (HR = 1.10, 95% CI 1.10–1.19).

Table 4.

Multivariate analyses of risk factors for treatment to left lung or both lungs compared with the right lung and risk for developing cardiac conditions in patients diagnosed with non-small-cell lung cancer

Adjusted model Hazard ratio (95% confidence interval)
Ischemic heart disease Cardiomyopathy Conduction disorders Cardiac dysfunction Heart failure
Radiation therapy
    Radiation: R-side 1.00 1.00 1.00 1.00 1.00
    Radiation: L-side 1.18 (1.05–1.34) 0.99 (0.71–1.38) 1.24 (0.84–1.84) 1.10 (1.01–1.19) 0.88 (0.79–0.98)
    Radiation to both sides 1.37 (0.94–1.99) 0.70 (0.17–2.87) 1.17 (0.27–5.00) 0.85 (0.64–1.14) 1.15 (0.81–1.63)
Chemoradiation
    Chemoradiation: R-side 1.00 1.00 1.00 1.00 1.00
    Chemoradiation: L-side 1.29 (1.09–1.52) 1.05 (0.68–1.62) 0.96 (0.64–1.45) 1.11 (1.00–1.24) 1.31 (0.53–3.20)
    Chemoradiation: both sides 1.76 (1.11–2.78) 1.09 (0.26–4.51) 0.46 (0.06–3.36) 1.06 (0.75–1.49) 3.03 (0.31–30.1)

All models adjusted for age, sex, ethnicity/race, socioeconomic status, comorbidity score, tumor size, positive number of nodes, tumor grade, histology, surgery, SEER areas, years of diagnosis, and pulmonary fibrosis using survival analysis, including interaction terms for ischemic heart disease for radiation therapy: radiation therapy and comorbidity score and for chemoradiation: chemoradiation and comorbidity score.

R, right; L, left; SEER, Surveillance, Epidemiology, and End Result. Statistically significant hazard ratios are in bold.

discussion

In this study, all the three modalities of treatment, chemotherapy-only, radiation therapy-only, and chemoradiation were associated with increased risks for developing cardiac dysfunction. In addition, patients who received chemotherapy-only were more likely to develop ischemic heart disease and heart failure while those who received chemoradiation were at increased risk for conduction disorders and heart failure. Men, blacks, older patients, those with higher comorbidity scores, and advanced disease were noted to be at highest risk. The risk of cardiac dysfunction regardless of treatment modality increased over time (years of diagnosis 1991–2002). Patients in the chemotherapy-only group diagnosed from 2000 to 2002 were also at increased risk for ischemic heart disease.

The study also found an increased risk of ischemic heart disease in patients with left-sided tumors treated with radiation-only and with chemoradiation rendered to both lungs. The risk of cardiac dysfunction increased when radiation therapy-only was administered to the left lung compared with the right lung. Of note is that heart failure was less common in patients who received radiation therapy to the left lung compared with the right lung. The explanation for this observation is likely related to lower radiation doses.

Other investigators have reported similar findings with respect to treatment-related cardiac toxicity in NSCLC patients following chemotherapy [10], radiation therapy [10, 12, 24], and chemoradiation [7, 12]. The main findings in this study are the results pertaining to increased risk of cardiac toxicity over time following the administration of chemotherapy-only, radiation therapy-only, and chemoradiation and that the risk for cardiac dysfunction following chemoradiation was above that for chemotherapy-only and radiation therapy-only and over time (1991–2002). An additional finding is that there were increased risks for developing ischemic heart disease and heart failure for those treated with chemotherapy-only and for those receiving chemoradiation for conduction disorders. The risk for ischemic heart disease in the chemotherapy-only group was still elevated over years of diagnosis from 2000 to 2002.

Other studies [2124] reported radiation therapy to be associated with increased risks for cardiac damage when administered to the left side of the chest. In this study, we noted a progressive increase in the risk of developing ischemic heart disease in patients treated with radiation therapy-only and chemoradiation to the left lung or both lungs compared with the right lung and an increased risk of developing cardiac dysfunction when radiation therapy-only was administered to the left lung compared with the right lung.

It is believed that more contemporary techniques for radiation therapy and newer chemotherapeutic regimens may reduce the toxic effects [13]. Most importantly, in this study, chemotherapy-only, radiation therapy-only, and chemoradiation were observed to be associated with a higher risk for developing cardiac dysfunction from 1991 to 2002. Compared with radiation therapy-only, chemotherapy-only was associated with higher risks of ischemic heart disease and heart failure and chemoradiation was associated with increased risks for developing conduction disorders and heart failure.

A strength of this study is the large sample size of 34 209 patients which enables sufficient power to carry out stratified multivariate analyses. In addition, the population is on the basis of 16 SEER areas that accounts for >26% of the USA population, which allows generalizability of our study findings. The limitations of the analyses are that the results may not be applicable to patients <65 years old because our population was limited to Medicare patients. Another limitation is the assumption that the cardiac conditions were due only to chemotherapy/radiation therapy treatment, but this maybe a part of the NSCLC disease process. We were not able to apply cumulative doses or dose intensity of chemotherapy and radiation treatments to determine the risk of developing toxicity. We also did not investigate NSCLC patients with two or more associated toxic effects that may have resulted simultaneously from the treatments rendered.

There may be additional bias involved in selecting patients into the study. The patients in this study were all elderly (≥65 years old), and it is expected that these conditions may occur regardless of cancer treatment. For example, ischemic heart disease takes a long time to develop; however, patients in this study had a median time to development for ischemic heart disease of only 106 days. One explanation may be that ischemic heart disease and other cardiac conditions were not detected but were present at the time of NSCLC diagnosis, and the results of the analysis reflect the progression of a preexisting condition following cancer treatment.

In conclusion, there were increased risks of developing cardiac conditions, especially cardiac dysfunction, following chemotherapy and radiation therapy for patients with NSCLC. There was a progressive increase in the risk for developing ischemic heart disease in patients treated with radiation therapy-only and chemoradiation to the left lung or both lungs compared with the right lung, and an increased risk for developing cardiac dysfunction when radiation therapy-only was administered to the left lung compared with the right lung.

funding

Agency for Healthcare Research and Quality (RO1-HS016743).

Acknowledgments

We acknowledge the creation of this database from the National Cancer Institute, Centers for Medicare and Medicaid Services, Information Management Services, Inc., and SEER tumor registries. The analyses, interpretation, and reporting are the sole responsibilities of the authors.

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