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Doxorubicin, Cardiac Risk Factors, and Cardiac Toxicity in Elderly Patients With Diffuse B-Cell Non-Hodgkin's Lymphoma

Dawn L. Hershman, Russell B. McBride, Andrew Eisenberger, Wei Yann Tsai, Victor R. Grann, Judith S. Jacobson

From the Department of Medicine and the Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, and the Departments of Epidemiology and Biostatistics, Mailman School of Public Health, Columbia University; and New York Presbyterian Hospital, New York, NY

Corresponding author: Dawn L. Hershman, MD, MS, Columbia University Medical Center, 161 Fort Washington Ave, 10-1068, New York, NY 10032; e-mail: dlh23{at}columbia.edu

	ABSTRACT

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Purpose Anthracycline-based chemotherapy, which improves survival for patients with non-Hodgkin's lymphoma, is often withheld from elderly patients because of its cardiotoxicity. We studied the cardiac effects of doxorubicin in a population-based sample of older patients with diffuse large B-cell lymphoma (DLBCL).

Patients and Methods Among patients age 65 years diagnosed with DLBCL from 1991 to 2002 in the Surveillance, Epidemiology, and End Results–Medicare database, we developed logistic regression models of the associations of doxorubicin with demographic, clinical, and cardiac variables. We then developed Cox proportional hazards models of the association between doxorubicin and subsequent congestive heart failure (CHF), taking predictors of CHF into account.

Results Of 9,438 patients with DLBCL, 3,164 (42%) received doxorubicin-based chemotherapy. Any doxorubicin use was associated with a 29% increase in risk of CHF (95% CI, 1.02 to 1.62); CHF risk increased with number of doxorubicin claims, increasing age, prior heart disease, comorbidities, diabetes, and hypertension; hypertension intensified the effect of doxorubicin on risk of CHF (hazard ratio = 1.8; P < .01). In the 8 years after diagnosis, the adjusted CHF-free survival rate was 74% in doxorubicin-treated patients versus 79% in patients not treated with doxorubicin.

Conclusion Among patients receiving chemotherapy for DLBCL, those with prior heart disease were less likely than others to be treated with doxorubicin, and those who received doxorubicin were more likely than others to develop CHF. Various cardiac risk factors increased CHF risk, but only hypertension was synergistic with doxorubicin. Doxorubicin has dramatically improved survival of DLBCL patients; nonetheless, some subgroups may benefit from efforts to reduce doxorubicin-related CHF risk.

	INTRODUCTION

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Anthracycline-based chemotherapy improves survival in patients with non-Hodgkin's lymphoma (NHL).^1-5 However, physicians are often reluctant to give such treatment to elderly patients because it is known to cause short- and long-term cardiac toxicity.⁶ Although even for the elderly, anthracycline-based treatment is superior to other drugs in controlling disease and prolonging survival,^6,7 elderly patients often are treated with other drugs.^8-13

Anthracyclines promote cardiotoxicity because they generate free radicals that can cause myofibril loss and peroxidization of the cardiomyocyte plasma membrane.¹⁴ The most commonly used anthracycline is doxorubicin. The risk of doxorubicin-induced congestive heart failure (CHF) increases with the cumulative dose.¹⁵ Cardiotoxicity is reported in 14% to 49% of patients treated for lymphoma,^16-18 and among patient with NHL, the risk of CHF increases with the patient's age^15,17,18 and history of coronary heart disease, valvular heart disease, hypertension, diabetes, cigarette smoking, or obesity.¹⁹ However, the independent influence of pre-existing cardiac disease or cardiovascular risk factors on the development of doxorubicin-associated CHF has not been investigated.

We studied the long-term effects of doxorubicin on the development of CHF in a population-based sample of elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL). We took duration of treatment, prior history of cardiovascular disease, and cardiac risk factors, such as hypertension and diabetes, into account.

	PATIENTS AND METHODS

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Data Source
We analyzed patient data from the linked Surveillance, Epidemiology, and End Results (SEER)–Medicare database.²⁰ The SEER database contains records of patients diagnosed with cancer in regions representing approximately 26% of the US population. SEER provides information on tumor histology, location, stage of disease, treatment, and survival, along with selected census tract–level demographic information. The Medicare database includes Medicare A and B eligibility status, dates of enrollment onto health maintenance organizations, and billed claims, including inpatient and outpatient services, procedures, and diagnoses.

Sample Selection
We identified all individuals age 65 years who received a pathologically confirmed primary diagnosis of DLBCL (International Classification of Diseases–Ninth Revision [ICD-9] codes: 9593, 9680, 9681, 9682, 9683) from January 1, 1991 to December 31, 2002. We excluded patients who were enrolled onto a health maintenance organization from 12 months before to 12 months after diagnosis and were not covered by Medicare Parts A and B over the same time period. The SEER database includes age, race/ethnicity, sex, marital status, type of hospital, and area of residence. Age at diagnosis was broken down into pentads (5-year discrete numeric intervals) starting at 65 years. Because the sample included few patients who were neither black nor white, we designated race as black, white, or other. For similar reasons, we recoded the SEER marital status variable into married, not married, and unknown.

We generated an aggregate socioeconomic status variable with a 0 to 4 range of values for each patient based on income data from the 2000 census using the median income in the patient's census tract of residence, the zip code median income, the census tract per capita income, and the zip code per capita income. Patients for whom all these values were missing were assigned to the lowest socioeconomic status category based on the method of Krieger et al.²¹

Comorbid Disease
We computed a comorbidity score for each patient using the variables included in the Klabunde adaptation of the Charlson comorbidity index.^22,23 Medicare inpatient and outpatient claims were searched from 365 days before to 30 days after the diagnosis of cancer for all ICD-9-Clinical Modification (CM) diagnostic codes corresponding to each of the following comorbid conditions: peripheral vascular disease; cerebrovascular disease; dementia; chronic pulmonary disease; connective tissue disease; peptic ulcer disease; mild to severe liver disease; hemiplegia; moderate or severe renal disease; and AIDS. Myocardial infarction was removed from the comorbidity index and analyzed as a separate variable. In addition, claims for hypertension and diabetes were obtained from ICD-9-CM codes before diagnosis.

Cardiac Disease
We developed an algorithm using diagnosis and procedure codes in the Medicare files to identify myocardial infarction, ischemia, and atherosclerosis (coronary artery disease [CAD]: 4140, 4148, 4149, 4291, 411, 413, 42290, 42293, 42299, 4290, 420, and 423); CHF and cardiomyopathy (4254, 4259, 42480, 4289, 40291, 40211, and 40201); and other heart disease (HD; 124 to 126, 129, and 138 to 140). The HD variable included ICD-9, Diagnosis-Related Group (DRG), and Current Procedural Terminology codes for myocarditis/pericarditis, arrhythmia, and valvular HD. To avoid misclassification as a result of coding errors, patients were assigned a diagnosis only if they had two or more claims for it. To avoid overestimating the association of treatment with cardiac outcomes, we categorized cardiac diagnoses before or during the 6 months after the DLBCL diagnosis as pretreatment. We counted only those cardiac diagnoses with a first claim more than 6 months after the DLBCL diagnosis as post-treatment. (However, when we analyzed the association without this conservative restriction, the results were similar.) We censored patients who were alive and had not developed CHF by the end of follow-up on December 31, 2004. We also censored patients who initiated a second course of chemotherapy 365 days after diagnosis and had not developed CHF before doing so on the date when they restarted chemotherapy. All myocardial infarctions were detected from hospital discharge codes. Diagnoses of ischemia and atherosclerosis were detected in both hospital discharge and outpatient billing codes.

Treatment Characteristics
We extracted information on chemotherapy from 90 days before to 365 days after the date of diagnosis from the Medicare files by searching Level II Healthcare Common Procedure Coding Systems (HCPCS) codes (J9XXX and Q0083-85), Current Procedural Terminology codes (964XX and 965XX), ICD-9-CM diagnostic codes (V581, V662, and V672) and a procedure code (9925), DRG code (410), and revenue center codes (0331, 0332, and 0335) from national claims history, hospital outpatient claims files (Output), or Medicare Provider Analysis and Review files. We searched for HCPCS codes corresponding to doxorubicin (J9000, J9001, and J9010). We also identified patients who had received other and unspecified chemotherapeutic drugs given during the same period.

The validity of SEER-Medicare claims data for chemotherapy use has been previously described.^24,25 Medicare claims are generated for diagnostic procedures, diagnoses, and treatments for which hospitals and physicians bill, including, for cancer patients, intravenous and injectable chemotherapy. For our analysis, we grouped together patients who received any doxorubicin; we created a separate category for patients treated with chemotherapeutic drugs other than doxorubicin (other chemotherapy). We classified patients as receiving other chemotherapy if their records included a charge for administering chemotherapy with no designation of a particular medication. Some of these charges may represent supervision of oral medication. We did not have direct information on the amount of doxorubicin given per cycle, the number of cycles patients received, or patients’ cumulative doxorubicin dose. As a surrogate for treatment intensity, we grouped doxorubicin-treated patients by the number of claims they accrued within the specified timeframe into those with one to three, four to five, or six or more doxorubicin claims.

We searched for data on radiation therapy in the SEER database and for ICD-9-CM codes (V580, V661, V671, and 9220 to 9229), HCPCS codes (77400 to 77490 and 77500 to 77797), revenue unit codes (280, 289, 330, and 333), DRG code (409), and revenue center codes (0330, 0333, and 0339) within 180 days after diagnosis in the Medicare records.

Statistical Analysis
We used ² tests to compare patients treated with doxorubicin with patients who received other chemotherapy and patients who received no chemotherapy with respect to clinical and demographic factors. We excluded 2,381 patients who received nondoxorubicin chemotherapy from further analysis because they were older and had more comorbidities and pre-existing HD than the doxorubicin group and had significantly worse overall survival than the other two groups (data not shown). Among patients identified as having received chemotherapeutic drugs, we excluded from our analysis of predictors of CHF 1,440 patients who had a claim for CHF before or up to 6 months after the DLBCL diagnosis because the outcome of interest was new-onset disease that might plausibly be treatment related. We used multivariable logistic regression models to analyze the association of doxorubicin-based chemotherapy with clinical, demographic, and cardiac variables.

To estimate the association between treatment and subsequent CHF, while controlling for the other covariates, we used conventional Cox proportional hazards models. In addition, we plotted adjusted survival curves using inverse probability weights.²⁶All analyses were conducted using SAS Version 9.13 (SAS Institute, Cary, NC).

	RESULTS

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We identified 6,388 individuals age 65 years or older in the SEER-Medicare database who met our inclusion criteria and were diagnosed with DLBCL between January 1, 1991 and December 31, 2002. Of these patients, 4,001 (42.4%) received doxorubicin-based chemotherapy, 2,381 (25.2%) received other chemotherapy, and the remaining 3,056 (32.4%) received no chemotherapy (Table 1). The proportion of patients receiving doxorubicin increased significantly over time from 28.6% in 1991 to 49.4% in 2002 (P < .0001). In the sample, cardiac risk factors were common; 31.9% of patients had diabetes claims, 73.1% had hypertension claims, and 53.6% had hypercholesterolemia claims. In addition, 22% of patients had pre-existing CHF claims, and 51% had pre-existing HD claims. Of patients treated with doxorubicin, 34% had one to three claims, 30% had four to five claims, and 36 had six or more claims.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Weighted Kaplan-Meier curve of congestive heart failure (CHF)–free survival in patients treated with doxorubicin compared with patients receiving no chemotherapy (P = .001).

	DISCUSSION

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Patients with hypertension and diabetes had 58% and 27% higher risks of developing CHF, respectively, than patients without those conditions. Other studies in patients with NHL have shown an increased risk of CHF in patients with hypertension,²⁷ but few have evaluated the interaction of pre-existing conditions with treatment. Another study found that male sex, older age, higher dose of doxorubicin, and being overweight were risk factors for the development of cardiomyopathy¹⁷ but did not report on whether these risks modified the effects of doxorubicin. Given the interaction observed in these data, an aggressive effort to reduce hypertension in patients who are to receive doxorubicin may be worth considering.

We found that advanced age was one of the strongest predictors of both withholding doxorubicin and subsequent CHF; patients older than 80 years had more than twice as great a risk of CHF as patients 65 to 70 years old. Given the independent effects of doxorubicin, withholding it from older patients may be rational. However, in our sample, patients who received less than six treatments had no increased risk of CHF. Therefore, rather than withholding it entirely, practitioners may consider fewer cycles of doxorubicin in elderly patients. Small studies suggest that patients treated with doxorubicin for 8 weeks have better response rates and overall survival than patients treated for longer durations.^28,29 Similarly, one population-based study evaluated the effects of early termination of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) in patients with NHL who were intended to receive more than six cycles of therapy. The odds of early termination increased with patient age. Among patients age 60 to 74 years, early termination was associated with worse survival, but among patients older than 74 years, it was not.³⁰

Studies suggest that older patients who undergo chemotherapy for NHL are more likely than younger patients to develop toxicities, such as neutropenia, that can reduce dose-intensity.^2,31,32 In a randomized trial of CHOP versus CHOP plus hematopoietic growth factors in 389 elderly patients, the group treated with growth factors had a higher dose-intensity and response rate than the comparison group but no better overall survival.³³ Hence, among elderly patients, dose-intense or even full treatment may not yield appreciable survival benefits.

In our sample, black patients were 50% less likely to be treated with doxorubicin-based therapy than white patients. Disparities in cancer treatment have been documented in a variety of settings.^34-40 For example, black patients receive less aggressive intravenous chemotherapy,⁴¹ have fewer consultations with medical oncologists,⁴² and have a significantly higher risk of recurrence than whites.⁴³ Black patients, especially men, are also at increased risk for heart disease.^19,44

Using SEER-Medicare data, our group found that the use of doxorubicin in elderly patients with DLBCL was crucial for improving survival outcomes.⁶ This survival effect was substantial and may outweigh the risk of cardiotoxicity.

Anthracycline use has also been found to be associated with late cardiac toxicity in women with breast cancer.^45,46 As in our study, using the SEER-Medicare database, Pinder et al⁴⁶ found a 26% increased risk of CHF in women treated with anthracyclines that persisted over a 10-year period. Others have found that breast cancer survivors have a worse cardiovascular risk factor profile than healthy age-matched controls and are thus at an a priori higher risk of developing cardiotoxicity.⁴⁷ Similar effects have been observed with the use of anthracyclines in sarcoma⁴⁸ and Hodgkin's disease.

One option for patients with cardiac risk factors may be to use agents to protect the heart from cardiac damage. For example, dexrazoxane reduces the risk of doxorubicin-induced cardiomyopathy in women with metastatic breast cancer.⁴⁹ Despite these results, the American Society of Clinical Oncology guidelines cautioned against use of cardioprotective agents such as dexrazoxane in malignancies where doxorubicin has been shown to increase survival, such as NHL, because such agents are thought to reduce the efficacy of therapy.⁵⁰ Another option is to use liposomal doxorubicin, which has been evaluated in elderly patients with aggressive lymphomas. Patients who received the liposomal formulation had less cardiotoxicity and similar complete response rates compared with patients treated with doxorubicin in the standard formulation.^51,52 A third option may be angiotensin II receptor blockers. A recent exploratory study demonstrated that valsartan attenuated measures of acute cardiotoxicity among NHL patients receiving doxorubicin-based therapy.⁵³ Further research is needed on ways of protecting elderly patients from the short- and long-term adverse effects of this life-saving therapy.

Our study included most of the known risk factors for CHF, including male sex, hypertension, diabetes mellitus, CAD, and valvular HD. However, we were unable to capture information on other significant causes of CHF, including obesity and cigarette smoking.^19,54 Another important shortcoming of our data is that we had to rely on billing codes to identify patients with the conditions of interest. In a study of 190 patients with NHL who underwent cardiac evaluation, only one had clinical CHF. However, an additional 39 had subclinical signs of cardiac damage, as measured by left ventricular fractional shortening.¹⁷ Using an approach that others have validated,⁵⁵ we tried to minimize the risk of overdiagnosis bias by including in the CHF category only those patients with two or more CHF claims. Unfortunately, claims data do not include information on cumulative dose, which has been demonstrated to be the strongest predictor of doxorubicin-related cardiotoxicity. We used number of treatment claims as a surrogate for cumulative dose and found that it was indeed predictive of CHF.

To our knowledge, our study is the first to show that hypertension, a known risk factor for CHF, increases the risk of doxorubicin-related cardiotoxicity. We also demonstrated that selection factors may appropriately contribute to the receipt of doxorubicin-based chemotherapy in the elderly. Although late cardiac toxicity is increased with both longer duration of doxorubicin therapy and known predictors of HD, such as advanced age, comorbid conditions, prior heart disease, and diabetes, these other risks did not seem to potentiate the cardiotoxic effects of doxorubicin.

Doxorubicin is an essential agent in the management of DLBCL. As a result, a growing number of long-term survivors are at risk. Further research is needed to identify patients at the greatest risk for adverse effects of treatment and to reduce that risk.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Dawn L. Hershman, Victor R. Grann, Judith S. Jacobson

Financial support: Dawn L. Hershman

Collection and assembly of data: Dawn L. Hershman, Andrew Eisenberger

Data analysis and interpretation: Dawn L. Hershman, Russell B. McBride, Andrew Eisenberger, Wei Yann Tsai, Victor R. Grann, Judith S. Jacobson

Manuscript writing: Dawn L. Hershman, Russell B. McBride, Andrew Eisenberger, Wei Yann Tsai

Final approval of manuscript: Dawn L. Hershman, Russell B. McBride, Andrew Eisenberger, Wei Yann Tsai, Victor R. Grann, Judith S. Jacobson

	ACKNOWLEDGMENTS

 
We acknowledge the efforts of the Applied Research Branch, Division of Cancer Prevention and Population Science, National Cancer Institute; the Office of Information Services and the Office of Strategic Planning, Health Care Financing Administration; Information Management Services, Inc; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database.

	NOTES

 
D.L.H. is the recipient of an American Society of Clinical Oncology Advanced Clinical Research Award. R.B.M. was supported in part by a R25 Award from the National Cancer Institute (CA94061) and a T32 Award (ULI RR024156) from the National Center for Research Resources of the National Institutes of Health.

This study used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted August 22, 2007; accepted January 28, 2008.

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