In 2015, there will be an estimated 11.3 million cancer survivors. With an increasing population of cancer survivors, it is imperative to understand the treatment options available and outcomes for chemotherapy-related cardiomyopathy. Anthracycline-based chemotherapy causes heart failure in approximately 5% of patients. Orthotopic heart transplantation (OHT) is an option for cancer survivors in complete remission who develop end-stage heart failure. We examined retrospective OHT data collected from the United Network of Organ Sharing from 1987 to 2011. The primary aim was to characterize the survival in patients with either the primary diagnosis of “dilated cardiomyopathy: Adriamycin” (DCA) versus “all other” causes of cardiomyopathy. The secondary aim was to define the differences in the primary cause of death and to describe the temporal relationship of DCA OHT. The United Network of Organ Sharing database identified 453 OHTs for the diagnosis of DCA and 51,312 OHTs for all other causes of cardiomyopathy. The DCA group was significantly younger with a greater percentage of women. After adjusting for age, gender, and history of malignancy, the 10-year survival curves showed that patients with DCA have an improved survival compared to those with all other causes of cardiomyopathy (hazard ratio 1.28, p = 0.026). No difference was found in the primary cause of death between the 2 groups. A statistically significant increasing temporal trend was seen in the number of OHTs for the diagnosis DCA. In conclusion, patients who undergo OHT for DCA have favorable 10-year survival, making OHT a good therapeutic option for end-stage heart failure due to anthracyclines. Additionally, no increased risk of cancer-related deaths was found in the DCA group, demonstrating that recurrent malignancy does not affect long-term survival. The temporal trends demonstrated that DCA remains a significant problem for cancer survivors.
As the number of cancer survivors continues to increase, it is critically important to understand the treatment options and outcomes for chemotherapy-related cardiomyopathy. Anthracyclines (ACs) remain a common chemotherapy agent for breast cancer, sarcomas, lymphomas, and leukemias, with an average incidence of heart failure of 5.1% in patients treated with a cumulative dose of 400 mg/m 2 . Adriamycin, the first and most widely used AC, was approved in 1974 and is known to cause progressive cardiomyopathy in a cumulative dose-dependent manner. Orthotopic heart transplantation (OHT) is an option for cancer survivors considered in complete remission who are otherwise eligible for transplantation. We sought to describe the long-term OHT survival outcomes of patients with AC-induced cardiomyopathy, examine the differences in the primary cause of death, and characterize the temporal trends.
Methods
The United Network of Organ Sharing (UNOS) provided de-identified patient data (Standard Transplant Analysis and Research files with follow-up data) from the thoracic organ transplant registry from 1987 to 2011, with follow-up through October 2011. The data included all United States patients undergoing thoracic organ transplantation, who were reported to the Organ Procurement Network during the study period. No center or patient identifiers were included.
We conducted a retrospective review of the UNOS registry and follow-up data from October 1, 1987 through October 31, 2011. The study points were chosen to determine the long-term survival outcomes of OHT patients and to demonstrate the trends in the number of OHTs performed because of AC exposure. From the thoracic registry, we selected only those patients who had undergone OHT for analysis. The UNOS OHT candidate registration forms contain 35 diagnostic classifications for the various causes of cardiomyopathy. We stratified the cohort into 2 groups according to the diagnosis at transplant registration: “dilated cardiomyopathy: Adriamycin” (DCA) versus all other causes of cardiomyopathy. All first-time OHT patients >1 year old were included. A broad age range was included to account for the high prevalence of pediatric cancer survivors.
The baseline demographic and clinical factors were examined. The database included age, gender, race, and various medical conditions at transplantation for DCA and all other cardiomyopathy. Although incomplete, with some missing data, the UNOS database contains information regarding the cancer history at transplantation. The primary end point was the primary cause of death during the study period. We categorized the causes of death as graft failure (acute and chronic), cardiovascular, pulmonary, infection (bacterial, viral, and fungal), renal failure, liver failure, multiorgan failure, central nervous system related, suicide, and malignancy. We used the database to determine whether a difference existed in OHT survival between patients with DCA versus all other causes of cardiomyopathy.
The primary goal of the study was to determine whether any difference was present in the 10-year survival between those with DCA and those with all other causes of cardiomyopathy. The initial hypothesis was that patients with DCA would have decreased long-term survival. All patients with follow-up times >10 years were censored at 10 years. We calculated both the unadjusted and the adjusted hazard ratios for the myopathy group using the Cox proportional hazard model. The other covariates adjusted included age, gender, and history of malignancy. Additionally, we performed a linear model to evaluate the percentage of patients undergoing OCT because of DCA from 1987 to 2011.
Descriptive statistics are presented as the median (interquartile range) or percentages (numbers), as appropriate. Wilson’s score method was used to calculate the 95% confidence intervals for percentages. Comparisons of the baseline characteristics between study groups were performed using the Wilcoxon rank sum test for continuous variables and Pearson’s chi-square test for categorical variables. The Cox proportional hazards regression model was used to assess the difference in 10-year survival between the 2 groups with adjustment for age, gender, and previous malignancy. Age was modeled as a continuous variable, with appropriate transformation using restricted cubic splines with 5 knots to account for a nonlinear relationship. The proportional hazards assumption was assessed using a residual plot and statistical test. All tests were 2-tailed, with a significance level of 5%. Statistical analysis was performed with the statistical software program SPSS Statistics, version 17.0 (SPSS, Chicago, Illinois) and the statistical programming language R, version 2.15.1 (R Development Core Team, Vienna, Austria).
Results
From October 1987 to October 2011 51,765 patients underwent primary OHT. A total of 453 patients underwent OHT because of DCA. The median age of the DCA OHT recipients was significantly younger than that of those with all other cardiomyopathy (median 44 years, interquartile range 23 to 56, vs 52 years, interquartile range 38 to 59, respectively; p <0.001) with a greater percentage of women ( Table 1 ). No difference was found in racial or ethnic diversity between the 2 groups ( Table 1 ).
| Recipient Characteristic | DCA (n = 453) | All Other Cardiomyopathy (n = 51,312) | p Value |
|---|---|---|---|
| Median age (yrs) | 44 ± 18 | 52 ± 19 | <0.001 ∗ |
| Women | 66% | 25% | <0.00l † |
| White race | 74% | 76% | 0.45 † |
| Mean weight (kg) | 64 ± 20 | 72 ± 25 | <0.001 ∗ |
| Previous malignancy type | <0.001 † | ||
| Breast | 24% | 6% | |
| Leukemia | 17% | 7% | |
| Melanoma | 0.3% | 4% | |
| Other skin cancer | 0.3% | 7% | |
| Unknown/other/multiple | 58% | 76% | |
| Diabetes mellitus | 8% | 9% | 0.64 † |
| Cerebrovascular disease | 3% | 3% | 0.78 † |
| Mean serum creatinine (mg/dl) | 1.23 ± 0.81 | 1.31 ± 1.24 | <0.001 ∗ |
| Mean panel reactive antibody (%) | 5.8 ± 16.2 | 6.7 ± 18.2 | 0.79 ∗ |
| Mean ischemic time (hours) | 3.1 ± 1.0 | 3.1 ± 1.1 | 0.34 ∗ |
| Left ventricular assist device | 13% | 16% | 0.059 † |
| Medical condition | 0.012 † | ||
| Hospitalized | 53% | 56% | |
| Intensive care unit | 17% | 14% | |
| Intravenous inotropes | 48% | 39% | <0.00l † |
| Peak oxygen consumption (ml/kg/min) | 11.6 ± 3.7 | 11.7 ± 3.7 | 0.89 ∗ |
| Mean pulmonary artery pressure (mm Hg) | 30.6 ± 8.9 | 30.5 ± 10.7 | 0.42 ∗ |
| Pulmonary capillary wedge pressure (mm Hg) | 20.5 ± 7.9 | 20.9 ± 8.9 | 0.75 ∗ |
| Cardiac output (L/min) | 3.6 ± 1.4 | 4.2 ± 1.4 | <0.001 ∗ |
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