Cardiovascular trials in long-term survivors of childhood cancer

Late Cardiotoxicity in Long-Term Survivors of Childhood Cancer The problems of late cardiotoxicity in long-term survivors of childhood cancer are clinically devastating and likely to become more prevalent [1-17]. Premature cardiovascular morbidity and mortality are consistently found across multiple studies [1-17]. Progressive, asymptomatic left ventricular dysfunction, congestive heart failure, cardiac transplantation, and cardiac death from either pump failure or arrhythmias develop much more often in these patients than in children without a history of cancer treatment. Concerns about premature atherosclerosis in this population have also been raised [18-20]. These late cardiovascular effects are typically related to anthracycline use, although radiation to the heart and other oncologic therapies are also associated with late cardiotoxicity [2,5-7,15-17,20-25]. Clearly, we need to both prevent cardiotoxicity in newly diagnosed children with cancer and alter the course of progressive cardiotoxicity in long-term survivors of childhood cancer. Completing a randomized, placebo-controlled, clinical trial in long-term survivors of childhood cancer is an important achievement. The carefully performed longitudinal prospective study by Silber et al [26], the angiotensin converting enzyme inhibitor (ACEI) After Anthracycline (AAA) trial, is one of the first such trials to be completed. The primary purpose of the AAA study was to determine whether enalapril, an ACEI, could lower the rate of decline in cardiac function in survivors of childhood cancer who had been treated with anthracyclines [26,27]. The importance of this question is undisputed. Unfortunately, for the reasons below, the study did not answer this question, creating a dilemma as to whether another larger and potentially more expensive study should be initiated. Interpreting the Results of the AAA Study Although the AAA study did not find that ACEI prevented a decline in ventricular function in patients with anthracycline-associated cardiomyopathy (ACM), the follow-up time in the study was not long enough nor was the study population large enough to conclude that ACEI is not beneficial [26]. The progression of cardiac dysfunction and the appearance of new-onset symptoms is quite slow in ACM [14,28-31], and follow-up in the AAA study ranged from just 2 to 7 years [26]. In addition, the study was not powered to rule out a clinically relevant effect of ACEI, which requires a different study design than proving their clinical effectiveness [26]. Today, the wealth of data supporting the efficacy of ACEI therapy in ischemic, postinfectious, and idiopathic dilated cardiomyopathy (DCM) has led to its first-line use in most patients with symptomatic and asymptomatic left ventricular dysfunction [32,33]. During the AAA study, we also initiated a randomized trial of enalapril in treating long-term survivors of childhood cancer (POG 9480) but terminated the study because of inadequate enrollment. Many of the patients for this trial who met the ventricular dysfunction entrance criteria of the AAA study were either already being treated with an ACEI or had physicians who believed that a placebo-controlled trial of ACEI was unethical, given the clear benefits reported for other DCM populations [8]. The patient pool reviewed for the AAA study included 4,308 subjects, of whom 401 were eligible and 146 agreed to participate [26,27]. The reasons so few patients were eligible and only 36% of these agreed to participate are not stated, but the risk profile for ACEI is generally extremely favorable, so factors other than perceived risk probably account for the low recruitment rate. Substantial evidence about the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 5 MARCH 1 2004