Cost-effectiveness of screening for asymptomatic left ventricular dysfunction in childhood cancer survivors.
It has long been recognized that anthracycline chemotherapy can cause early- and late-onset congestive heart failure (CHF) and cardiomyopathy, which may progress to cardiac-specific death (1). Thus, children treated with anthracycline are monitored during and periodically after therapy. The Children's Oncology Group (COG) developed the Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (COG-LTFU) in 2003 (2). In brief, periodic lifetime screening is recommended, based on age at treatment, cumulative anthracycline dose, and whether the heart was irradiated. These recommendations have been widely adopted. In this issue, 2 groups separately examined these recommendations and report on the cost-effectiveness (CE) of screening to detect asymptomatic left ventricular dysfunction (ALVD) and to reduce CHF risks in childhood cancer survivors who were exposed to anthracycline chemotherapy (3, 4). Cost-effectiveness analysis is a method for evaluating health outcomes and resource costs for health interventions. A base case is established that incorporates data and methods that best represent the interventions and choices under consideration. Its central function is to show the relative value of alternative interventions for improving health. In this case, it represents no screening for ALVD in childhood cancer survivors versus the recommendations of the COG-LTFU guidelines, then varies the screening interval and other variables to determine the CE of different strategies (5). Such analysis should be used as a supplement to other considerations in health care delivery, including equity, benefits many, and community compassion. The perspective used in the CE analysis is of overarching importance because it reflects the type of decisions the analysis is intended to inform. Both studies used a societal perspective, which represents the public interest rather than that of any group or the person. Analyses are intended to inform decisions at the level of broad resource allocation and may provide little guidance about optimal management of persons (5). Reading these studies side by side advances our understanding of this population and illustrates the importance and complexity of an effective screening strategy. It also serves as an example of how 2 experienced groups can apply different assumptions and variables in their respective models and still arrive at broadly similar conclusions: Although application of the COG-LTFU recommendations can reduce the CHF risk, there may be more cost-effective strategies. Wong and colleagues (3) evaluated the 12 risk profiles from the COG-LTFU guidelines, which are used to determine the interval of screening (every 1, 2, or 5 years). Instead, Yeh and colleagues (4) categorized persons as low- or high-risk based on the cumulative anthracycline dose, using a cut point of 250 mg/m2. Both groups used self-reported CHF data from the Childhood Cancer Survivor Study for CHF risk in the target population (6). Wong and colleagues supplemented this with CHF risk estimates from other studies where CHF was determined on the basis of clinical evaluation. Because data on the incidence of CHF beyond 20 to 30 years from diagnosis of childhood cancer is sparse, both groups made their best estimates (which were similar) of CHF incidence during this interval. The sensitivity of echocardiography used for the models was a key difference between the studies. Wong and colleagues used a sensitivity of 75% to 94% based on noncancer population studies comparing ejection fraction (EF) by echocardiography with radionuclide angiography. In contrast, Yeh and colleagues used a sensitivity of 25% based on a single study of adult survivors of childhood cancer comparing echocardiography with cardiac magnetic resonance imaging (cMRI) (7). Several studies have now shown 2-dimensional speckle tracking echocardiography or strain imaging to be more sensitive in detecting left ventricular dysfunction and a stronger predictor of all-cause death than conventional 2-dimensional EF (8, 9). Implementing this method as a screening test in the CE models would likely affect the results. Few data are available on the natural progression from ALVD to CHF in young cancer survivors. Thus, both groups assumed a progression based on extrapolations from patients without cancer who developed CHF secondary to hypertension, coronary disease, and myocardial infarction (10). Of note, the length of time to progress from ALVD to CHF is strongly dependent on the cause and degree of ALVD. The magnitude of ALVD EF reduction was not considered in the prediction of CHF risk in either model. Neither model incorporated clinical information available to the clinician, such as hypertension and vascular disease, which are key determinants in the development of ALVD and progression to CHF. The effectiveness of the treatments that prevent ALVD from progressing to CHF, which is so important in CE modeling, is based on the Studies of Left Ventricular Dysfunction prevention trial, a population with hypertension and coronary disease who had an EF less than 35% (10). Regular cardiac screening in cancer survivors will likely identify ALVD and lead to initiation of cardioprotective treatment earlier and at an EF greater than 35%. It is likely that more survivors would have to be treated longer to demonstrate the effectiveness of therapy. There were other differences between the studies. Wong and colleagues validated their model in additional populations. Yeh and colleagues added 2 twists to their analysis. They assessed the utility of cMRI without echocardiography in the model, assuming a low sensitivity of echocardiography compared with cMRI. They also tested a model where all survivors received lifetime preventive pharmacotherapy for CHF starting 5 years after cancer diagnosis, in lieu of any ALVD screening. This approach was associated with a greater reduction in CHF risk and lower costs but would result in many survivors receiving lifetime drug therapy without any health benefit. When key differences in approach are considered, some differences in their conclusions can be expected. Wong and colleagues found that, based on risk profile, changing from every 1-, 2-, or 5-year screening intervals to 2- to 4-, 5-, and 10-year intervals resulted in maintaining 80% of the health benefit of the COG-LTFU recommended schedule while decreasing the costs by 50%. Yeh and colleagues reported that the preferred strategy for survivors treated with a cumulative anthracycline dose of 250 mg/m2 or greater is screening echocardiography every 2 years or cMRI every 5 years; for low-risk survivors, the preferred strategy was either no echocardiography or cMRI every 10 years. Sensitivity analyses performed in the 2 studies reveal that CE is most influenced by the presumed effectiveness of the drug treatment of ALVD, the duration of the ALVD period before clinically apparent CHF, the absolute excess risk for CHF, the cost and accuracy of echocardiography, and the weight given to the effect of CHF on quality of life. Screening for ALVD had the most utility relatively early after cancer diagnosis where competing causes of illness and death were less common compared with what was seen in the aging patient. In summary, the COG-LTFU guidelines (2) are intended to assist the clinician in caring for an individual patient at the most granular level, and its recommendations are considered in these excellent analyses to be relatively cost-effective from the societal perspective. Yeh and Wong and their colleagues point out the scope of the problem and remind us that screening for cardiomyopathy can be done cost-effectively and is highly likely to improve the quality and quantity of the patient's life. They suggest to the clinician and patient many of the variables that should be explored, along with what tools to use to screen and how often to use them. The clinician and patient should be assured that screening for ALVD is a valuable undertaking and that state-of-the-art CE analyses allow for variation in their choices based on the details of the clinical presentation, patient preference, and local imaging expertise.