Cardiac toxicity associated with ... - Wiley Online Library

18 downloads 3410 Views 249KB Size Report
Aug 11, 2009 - was 16% higher in those receiving other agents (HR, 1.16; 95% CI, 0.97-1.39) compared with those .... 425.x), cardiac dysrhythmia (diagnosis code, 427.x), con- ...... able at: http://www.fda.gov/oc/tfrm/Part3.html Accessed.
Original Article

Cardiac Toxicity Associated With Anthracycline-Containing Chemotherapy in Older Women With Breast Cancer Xianglin L. Du, MD, PhD1; Rui Xia, MS1; Chih-Chin Liu, MS1; Janice N. Cormier, MD, MPH2; Yan Xing, PhD2; Dale Hardy, PhD1; Wenyaw Chan, PhD3; and Keith Burau, PhD3

BACKGROUND: The purpose of this study was to determine the risk of chemotherapy-associated cardiac toxicity, including cardiac dysrhythmia, cardiomyopathy, congestive heart failure, ischemic heart disease, and conduction disorders among breast cancer patients with up to 16 years of follow-up. METHODS: The authors studied 19,478 women aged >65 diagnosed with breast cancer in 1991-1997 from 16 regions in the Surveillance, Epidemiology, and End Results program. Incidence density and cumulative incidence of cardiac toxicities were calculated, and the time-to-event (cardiac toxicity) analysis was conducted by using the Cox hazard regression model. RESULTS: The excess cumulative incidence of congestive heart failure in Year 10 among patients receiving anthracycline-containing chemotherapy compared with patients without chemotherapy was 4.7% (31.9% vs 27.2%). After adjusting for patient and tumor characteristics, patients receiving anthracyclines were 25% more likely to have congestive heart failure compared with those without chemotherapy (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46). Those receiving other agents did not have a significantly elevated risk of developing congestive heart failure. The adjusted risk of cardiomyopathy was 2-fold higher in women who received anthracyclines (HR, 1.95; 95% CI, 1.44-2.62) and was 16% higher in those receiving other agents (HR, 1.16; 95% CI, 0.97-1.39) compared with those without chemotherapy. The increased risk for developing congestive heart failure, cardiomyopathy, and cardiac dysrhythmias in association with chemotherapy were similar after adjusting for hypertension and diabetes. The risk of ischemic heart disease and conduction disorders were not significantly different among the 3 groups. CONCLUSIONS: Anthracycline-containing chemotherapy regimens were associated with an increased risk of congestive heart failure, cardiomyopathy, and cardiac dysrhythmias, but not significantly C 2009 associated with ischemic heart disease or conduction disorders. Cancer 2009;115:5296–308. V American Cancer Society. KEY WORDS: breast cancer, chemotherapy, cardiotoxicity, congestive heart failure, Medicare.

The frequency and severity of chemotherapy-associated toxicities are generally the secondary outcome measures of randomized clinical trials, after the primary endpoint on the efficacy of chemotherapy agents. Corresponding author: Xianglin L. Du, MD, PhD, University of Texas School of Public Health, 1200 Herman Pressler, RAS-E631, Houston, TX 77030; Fax: (713)500-9264; [email protected] 1 Division of Epidemiology, University of Texas School of Public Health, Houston, Texas; 2Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 3Division of Biostatistics, University of Texas School of Public Health, Houston, Texas

We acknowledge the efforts of the NCI, CMS, IMS, and the SEER registries in the creation of this database. Received: November 17, 2008; Revised: May 1, 2009; Accepted: May 7, 2009 Published online August 11, 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/cncr.24621, www.interscience.wiley.com

5296

Cancer

November 15, 2009

Cardiac Toxicity and Chemotherapy/Du et al

For example, anthracycline-based combination chemotherapy has been among the most active agents in treating breast cancer and has been beneficial in improving the disease-free and overall survival over the past 2 decades.1 Such trials prospectively collect the most comprehensive and systematic data on adverse events in a monitored setting. In fact, the toxicity profiles of various drugs are often established under such ‘‘ideal world’’ conditions in premarketing clinical trials before approval by the US Food and Drug Administration (FDA).2 This process is particularly true for reporting side effects associated with administration of systemic chemotherapy.3-15 However, clinical trials generally have rigid eligibility criteria, often excluding elderly patients, pregnant women, patients with multiple coexisting diseases, and those taking medications suspected of interacting with the study drug.16,17 Therefore, study participants (motivated volunteers) in clinical trials often represent a much more homogeneous patient population in terms of gender, age, race/ethnicity, and comorbidity, and they are not representative of the population at large, particularly the elderly population who are often substantially underrepresented in clinical trials.16 Furthermore, clinical trials may not have adequate statistical power to detect rare events or have sufficient follow-up to identify long-term toxicities. Hence, the current system of postmarketing surveillance of long-term toxicities requires substantial improvement.17-30 One approach to obtaining more complete information on drug toxicity is to supplement data from premarketing clinical trials with data from postmarketing drug surveillance to produce better estimates. However, there is a paucity of information on cancer chemotherapy-related toxicities from population-based studies.31,32 Several reports have been published on chemotherapy-associated cardiac complications, particularly anthracycline-containing agents that are known to be associated with a range of cardiotoxic syndromes.11-13 Cardiotoxicity may occur either immediately at the time of drug administration or months to years after treatment. Two studies recently examined the incidence of congestive heart failure associated with chemotherapy for breast cancer and found a 14% to 35% increase in risks for those receiving chemotherapy.31,32 The objectives of the current analysis were to extend the scope of these studies: 1) to determine the anthracycline-related risk of a wider range of cardiac disorders, including cardiac dysrhythmia, Cancer

November 15, 2009

cardiomyopathy, congestive heart failure, ischemic heart disease, and conduction disorders; 2) to determine a more accurate estimate of chemotherapy-associated cardiac toxicity by restricting the study cohort to those without preexisting cardiac disease; and 3) to examine patients with long-term follow-up extending up to 16 years to identify late cardiac toxicities.

MATERIALS AND METHODS Data Sources This study used the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database for Medicare beneficiaries diagnosed with breast cancer. The SEER program, supported by the National Cancer Institute, includes population-based tumor registries in selected geographic areas in 1991-1997: San Francisco/Oakland, Detroit, Seattle, Atlanta, Rural Georgia, Los Angeles county, the San Jose–Monterey area; and the states of Connecticut, Iowa, New Mexico, Utah, and Hawaii, covering >14% of the US population.32 The Medicare program provides payments for hospital, physician and outpatient medical services for >97% of persons aged 65. The University of Texas Health Science Center at Houston Committee for the Protection of Human Subjects approved this study.

Study Population The study population comprised 32,004 women diagnosed with American Joint Committee on Cancer (AJCC) stages I-IV breast cancer as the only primary tumor at age 65 years in 1991-1997, who had full coverage of Medicare Parts A and B, and were not enrolled with Health Maintenance Organizations from the year of diagnosis to the last follow-up (December 2005 or date of death). We studied patients from only 1991-1997 to examine the long-term risk of cardiac toxicity associated with anthracycline-based chemotherapy and to minimize the potential impact or confounding of trastuzumab that was a new agent since 1998, which was reported to be associated with an increased risk of cardiac toxicity. For the purpose of this study in determining the relation between chemotherapy and cardiotoxicities, we included patients who were free of cardiovascular diseases at the 5297

Original Article

time of cancer diagnosis, specifically congestive heart failure, cardiomyopathy, cardiac dysrhythmias, conduction disorders, and ischemic heart disease. By doing so, we excluded 11,489 cases with preexisting cardiac diseases, 808 cases who received first chemotherapy after 12 months of diagnosis, and 229 cases with mitoxanthrone, leaving 19,478 subjects for the final analysis. Variables Outcome Variables on Cardiac-Toxicities

Patients were defined to have been diagnosed with cardiac diseases when there were at least 2 claims from the ICD-9-CM diagnosis codes34 with >30 days apart after the date of breast cancer diagnosis: congestive heart failure (diagnosis code, 428.x), cardiomyopathy (diagnosis code, 425.x), cardiac dysrhythmia (diagnosis code, 427.x), conduction disorder (diagnosis code, 426.x), and ischemic heart disease (diagnosis codes, 410.x, 411.x, 412.x, 413.x, or 414.x). The time in days was calculated from the date of diagnosis to the date of the first claim for cardiac condition. Chemotherapy and Other Treatments

Patients were defined as having received chemotherapy if any of the following procedure codes for chemotherapy were present in the inpatient, physician, or outpatient claims within 12 months of breast cancer diagnosis35: the ICD-9-CM procedure code of 9925 and V codes of V58.1, V66.2, or V67.2; the Common Procedure Terminology codes of 96,400-96,549, J8510, J8520, J8521, J8530-J8999, J9000-J9999 and Q0083Q0085; and revenue center codes of 0331, 0332, and 0335. Of these patients, those who received anthracycline-containing regimens were defined when there were claims for doxorubicin (J9000, J9001, or J9010). A small number of 229 subjects with mitoxanthrone (J9293) were not included in the study cohort. Thus, patients were classified into 3 mutually exclusive groups: 1) anthracyclinecontaining chemotherapy (n ¼ 1104); 2) nonanthracycline chemotherapy (n ¼ 3398); or 3) no-chemotherapy (n ¼ 14,986). Breast-conserving surgery, or mastectomy, or radiation therapy36 were defined previously. Socioeconomic Status

The percentage of persons living below the poverty line at the census tract level from the 1990 census for cases 5298

between 1991 and 1997 was used to define the socioeconomic status (SES). These percentages were classified into quartiles: 3.62%, 3.63%-6.62%, 6.63%-11.99%, and 12.00% (poorest SES). Comorbidity Index

Comorbidity was ascertained from Medicare claims by identifying comorbid conditions between 1 year before and 1 month after the diagnosis of breast cancer, including diabetes, liver disease, and dementia, but excluding any malignant tumors. Detailed methods for creating a weighted comorbidity score have been previously reported.37

Analysis Differences in the distribution of baseline characteristics among the 3 chemotherapy groups were tested using the chi-square statistic. Incidence rate (density) was defined as the ratio of the number of new cardiac disorders over the total person-years. Person-years were calculated as the number of patients multiplied by the number of years from diagnosis to the date of the first cardiac toxicity, date of death, or date of last follow-up, whichever occurred first. The cumulative incidence (probability) of cardiotoxicity was calculated using the statistical program by Penman and Johnson.38 The Cox hazard regression model was used to perform the time-to-event (toxicity) analysis by using the PHREG procedure available in SAS (Cary, NC: SAS System).

RESULTS Table 1 presents the distribution of baseline characteristics among the 3 groups of patients stratified by chemotherapy status. Of the 19,478 patients with breast cancer at ages 65-89 years in 1991-1997, 5.7% received anthracyclinebased chemotherapy, 17.4% received other chemotherapy agents (of which 45.6% were flurouracil and 9.6% were taxanes), and 76.9% did not receive chemotherapy. A higher proportion of younger or married women received chemotherapy; 50.5% of patients aged 65-69 years received anthracycline-based chemotherapy, 36.3% received other chemotherapy, and 23.9% received no chemotherapy. A slightly lower percentage of Caucasians received anthracycline-based chemotherapy. There were Cancer

November 15, 2009

Cardiac Toxicity and Chemotherapy/Du et al

Table 1. Comparisons of Characteristics Among Women With Breast Cancer According to the Receipt of Chemotherapy

No. (Column %) of Cases No Chemotherapy (n514,986) No. Median age (range)

%

Other Chemotherapy (n53388) No.

75 (65-89)

%

Anthracycline-Based Chemotherapy (n51104) No.

72 (65-89)

% 70 (65-89)

Age, y 65-69 70-74 75-79 80-84 85-89

3577 3934 3569 2535 1371

23.9 26.3 23.8 16.9 9.2

1229 1062 678 318 101

36.3 31.4 20.0 9.4 3.0

558 338 168 32 8

50.5 30.6 15.2 2.9 0.7

13,261 820 905

88.5 5.5 6.0

3007 192 189

88.7 5.7 5.6

947 89 68

85.8 8.1 6.2

6281 8206 499

41.9 54.8 3.3

1680 1621 87

49.6 47.9 2.6

579 501 24

52.5 45.4 2.2

3781 3824 3839 3317 225

25.2 25.5 25.6 22.2 1.5

882 814 878 769 45

26.0 24.0 25.9 22.7 1.3

309 262 278 233 22

28.0 23.7 25.2 21.0 2.0

8124 3984 690 710 1478

54.2 26.6 4.6 4.7 9.9

1100 1398 337 298 255

32.5 41.3 9.9 8.8 7.5

64 469 290 190 91

5.8 42.5 26.3 17.2 8.2

3040 5352 2648 1068 1466 1412

20.3 35.7 17.7 7.1 9.8 9.4

383 1033 713 380 549 330

11.3 30.5 21.0 11.2 16.2 9.7

39 171 210 137 370 177

3.5 15.5 19.0 12.4 33.5 16.0

8589 883 598 438 262 4216

57.3 5.9 3.9 2.9 1.8 28.1

1436 353 316 310 219 754

42.4 10.4 9.3 9.2 6.5 22.3

126 95 113 189 196 385

11.4 8.6 10.2 17.1 17.7 34.9

2182 4983 3505 4316

14.6 33.3 23.4 28.8

276 1035 1221 856

8.2 30.6 36.0 25.3

41 260 546 257

3.7 23.6 49.5 23.3

9913 1329 3744

69.2 8.9 24.9

2069 684 635

61.1 20.2 18.7

544 310 250

49.3 28.1 22.6

Race/Ethnicity Caucasian African American Other

Marital status Married Unmarried Unknown

Socioeconomic status First quartile (high) Second quartile Third quartile Fourth quartile (low) Missing

Tumor stage I II III IV Unstaged

Tumor size, cm