Anthracycline chemotherapy agents are important treatment options in a wide range of pediatric and adult

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1 Pretreatment and Routine Echocardiogram Monitoring During Chemotherapy for Anthracycline-Induced Cardiotoxicity Rarely Identifies Significant Cardiac Dysfunction or Alters Treatment Decisions A 5-Year Review at a Single Pediatric Oncology Center Raymond G. Watts, MD 1 ; McKenzie George 1 ; and Walter H. Johnson, Jr., MD 2 BACKGROUND: The widespread use of anthracycline chemotherapy has contributed to improved outcomes in children with cancer. The most feared complication of the anthracyclines is cardiotoxicity. Routine echocardiographic monitoring typically is used before, during, and after treatment to minimize cardiotoxicity. The ideal use of screening before and during chemotherapy remains uncertain. METHODS: This was a retrospective review of children who were treated at a single cancer treatment center over 5 years. The results of all echocardiograms and related clinical decisions were reviewed. RESULTS: In 356 patients who were identified for review (age range, 3 months to 22 years; mean age, 10 years; median age, 11 years), 991 echocardiograms were reviewed (average, 2.78 echocardiograms per patient; median, 2 echocardiograms per patient; mode, 1; maximum, 11 echocardiograms per patient). Nine abnormal echocardiograms were identified (2.5% of patients and 0.9% of echocardiograms performed). Four echocardiograms were performed during episodes of septic shock, 2 echocardiograms represented false-positive studies after repeat evaluation, and 1 echocardiogram demonstrated mild abnormality of function on the day of surgical resection of a large Wilms tumor. None of the 356 pretreatment echocardiograms altered treatment decisions. In 635 follow-up echocardiograms during treatment, cardiac defects were detected in 2 patients (0.5%). CONCLUSIONS: The routine use of echocardiograms to screen for anthracycline-induced cardiac damage before and during chemotherapy rarely identified significant cardiac damage to impact treatment decisions. Improved screening techniques with better discrimination and predictability are needed. Pediatric Oncology cooperative groups should consider a revision of standard monitoring protocols before and during treatment. Cancer 2012;118: VC 2011 American Cancer Society. KEYWORDS: late effects, chemotherapy protocol, surveillance, cardiotoxicity, treatment decisions, doxorubicin, daunomycin. INTRODUCTION Anthracycline chemotherapy agents are important treatment options in a wide range of pediatric and adult cancers. 1,2 The use of anthracyclines has contributed to the improved outcomes achieved by children with cancer over the last several decades, especially in leukemias, lymphomas, and a variety of solid tumors. 3 The most feared complication of the anthracyclines is cardiotoxicity manifested as myocardial damage and, in extreme cases, congestive heart failure and cardiac death. 4,5 It is now clear that adult survivors of childhood cancer face excessive cardiovascular morbidity and mortality The increased cardiovascular morbidity is correlated with several defined risk factors, including cumulative lifetime anthracycline dose, concomitant radiation therapy, the use of other cardiotoxic medications, genetic predispositions, and other as yet incompletely defined factors Corresponding author: Raymond G. Watts, MD, Division of Pediatric Hematology-Oncology, University of Alabama at Birmingham, 1600 Seventh Avenue South, ACC 512, Birmingham, AL 35233; Fax: (205) ; rwatts@peds.uab.edu 1 Division of Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; 2 Division of Cardiology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama DOI: /cncr.26481, Received: May 20, 2011; Revised: July 5, 2011; Accepted: July 6, 2011, Published online August 31, 2011 in Wiley Online Library (wileyonlinelibrary.com) Cancer April 1,

2 In an effort to minimize cardiotoxicity, routine monitoring of individuals treated with these agents is used before, during, and after treatment. 18 The Children s Oncology Group (COG) standard supportive care recommendations on treatment with anthracycline-containing protocols include pretreatment or baseline electrocardiogram (EKG) and echocardiogram and various interval studies during and at the end of treatment. 19 The COG and other consensus panels recommend routine postchemotherapy echocardiographic follow-up to screen for late cardiotoxicity in childhood cancer survivors The necessity and effectiveness of late cardiac screening is increasingly validated ; however, the importance and cost-effectiveness of routine echocardiographic studies before and during treatment in asymptomatic children who are receiving anthracycline chemotherapy agents remain incompletely defined. To further define the role of routine echocardiograms in children before and during treatment with anthracycline drugs, we conducted a retrospective study of our experience to determine the impact of routine, early monitoring for cardiotoxicity and therapy modification. MATERIALS AND METHODS A retrospective review of all children who received treatment at the Children s Hospital of Alabama over a 5-year period (from January 1, 2003 to December 31, 2007) was conducted using the electronic hospital database. Children who received anthracycline chemotherapy for childhood cancers that were diagnosed during the years studied were eligible for review. To ensure a complete study group, the list of children identified by review of the hospital electronic database was cross-checked against a separate list of all children who underwent echocardiogram studies during the same period. The patient list was compared with the pediatric cardiology database to capture all echocardiograms performed. The results from all echocardiograms and resultant clinical decisions were reviewed. All echocardiograms were performed by an attending pediatric cardiologist or a dedicated pediatric echocardiographic technician, and all echocardiograms were interpreted by an attending pediatric cardiologist. Each echocardiogram included 2-dimensional, m-mode, and color and spectral Doppler evaluation using a series of standard views (typically parasternal, apical, subcostal, and suprasternal,) recorded either digitally or on videotape. Situs, segmental cardiac anatomy, anatomic relations, and the presence or absence of congenital defects were assessed in each patient. M-mode measurement of left atrial (LA) and aortic dimensions, left ventricular (LV) chamber size in diastole and systole, and LV wall thickness in diastole for both septum and posterior wall were obtained. Derived echocardiogram parameters that were calculated at the time of initial interpretation and intended to disclose LV systolic dysfunction included the percentage LV shortening fraction (SF) and the percentage LV ejection fraction (EF). Normal values were defined as 28% for the LV SF and 50% for the LV EF. Regional LV myocardial wall motion was assessed subjectively as either normal or abnormal. Dopplerderived estimates of right heart pressure were made when feasible, depending on the quality of Doppler signals. We also noted the presence or absence of mitral regurgitation, intravascular masses, vegetations, or thrombi as well as pericardial and pleural effusions. The course of central venous catheters, if observed, was noted. Findings like a small patent foramen ovale were considered normal and not clinically significant. A cost analysis was performed using actual charges and payments for echocardiograms in the treatment facility during the study period ( ). A representative charge for echocardiogram for the index years, including 2-dimensional and spectral and color Doppler components, was $450. A representative reimbursement, which was derived from the average reimbursement made by the majority payers (including Medicaid and private insurers), was $238 per echocardiogram. Clinical data on patient age, race, diagnosis, and outcomes were obtained by a review of the hospital electronic medical records system. All studies were conducted after institutional ethics committee review and approval. RESULTS In total, 390 patients were identified by a hospital electronic medical records query. However, after 1 medical record number error was discovered and 3 cases that represented duplicate patients were eliminated, 386 patients remained for detailed review (see Table 1). The patients ranged in age from 3 months to 22 years (mean age, 10 years; median age, 11 years). Echocardiogram studies were available from 356 patients when the hospital-generated list was compared with a pediatric cardiology patient database. These 356 patients are the focus of this report. The diagnoses of the final study group represented a wide range of pediatric cancers, as indicated in 1920 Cancer April 1, 2012

3 Pretreatment & Routine Echocardiograms/Watts et al Table 1. Demographics of the Study Population No. of Patients (%) Characteristic Caucasian African American Hispanic Other Total Males 136 (35) 64 (16) 8 (2) 1 (<1) 209 (54) Females 106 (27) 56 (14) 13 (3) 2 (<1) 177 (46) Total 242 (63) 120 (31) 21 (5) 3 (<1) 386 Table 2. Patient Diagnoses Diagnosis Acute lymphoblastic leukemia 128 (36) Non-Hodgkin lymphoma 42 (12) Hodgkin lymphoma 35 (10) Soft tissue sarcoma 27 (8) Wilms tumor 25 (7) Neuroblastoma 25 (7) Ewing sarcoma/primitive neuroectodermal tumor 25 (7) Acute myelogenous leukemia 24 (7) Osteosarcoma 14 (4) Hepatoblastoma 5 (1) Other a 6 (1) No. of Patients (%) a Other includes angiosarcoma, brain tumor, germ cell tumor, nasopharyngeal carcinoma, acute promyelocytic leukemia, and myofibrolastic tumor. Table 2. Nine hundred ninety-one echocardiograms were available for review. On average, there were 2.78 echocardiograms performed per patient (median, 2 echocardiographs per patient [mode 1]; maximum, 11 echocardiographs per patient). Nine abnormal studies were identified (2.5% of patients and 0.9% of echocardiograms performed) (see Table 3). Four studies were performed during episodes of septic shock (patients 272, 334, 401, and 552), and 1 study represented a false-positive evaluation in an asymptomatic patient (patient 367). One study demonstrated a mild abnormality of function on the day of surgical resection of a large Wilms tumor (patient 534). One patient demonstrated a transient abnormality related to electrolyte abnormalities and tumor lysis syndrome (patient 543). Otherwise, all 356 routine prechemotherapy studies were normal. In no case did the pretreatment study alter treatment decisions. In 635 follow-up studies, cardiac function defects were detected in 2 patients (0.5%). These 2 patients appeared to demonstrate true cardiotoxity (patients 484 and 501) on routine screening during scheduled anthracycline therapy. One child (patient 484) developed symptomatic cardiotoxicity at a cumulative anthracycline dose of 360 mg/m 2 and died of cardiac failure. In a second child (patient 501), an asymptomatic decline in cardiac function resulted in the decision to withhold further anthracycline chemotherapy. Prolonged follow-up failed to demonstrate clinically significant cardiac damage in patient 501. DISCUSSION Routine, risk-based echocardiographic monitoring for cardiovascular toxicity is a key component of late-effects screening for survivors of childhood cancer, primarily for children who receive chest radiation and/or anthracycline chemotherapy The current COG guidelines recommend routine echocardiograms or nuclear medicine-gated heart studies at a frequency of once a year to once every 5 years after completing therapy, depending on patient age, whether concurrent radiation was received, and the cumulative anthracycline dose. 25 Recommendations with regard to cardiac monitoring before and during chemotherapy were published by the Children s Cancer Study Group in In part, the guidelines recommend 1) a baseline cardiac examination with EKG and echocardiogram, 2) follow-up echocardiograms before every other subsequent course of anthracycline chemotherapy at cumulative doses <300 mg/m 2, and 3) an echocardiogram before each course of anthracycline chemotherapy at cumulative doses >300 mg/m 2. Current COG chemotherapy protocols generally follow this recommendation and mandate pretreatment EKG and echocardiogram as protocol entry criteria in all major treatment protocols that use anthracycline chemotherapy agents. Echocardiogram monitoring during ongoing treatment varies in recent and current individual COG treatment protocols. In some cases, only pretreatment and end-of-treatment studies are mandated by the study; whereas, in other protocols, frequent echocardiographic monitoring is required as often as 4 times during the treatment phase. Similar to current North American practice in the COG, there is a wide variation of monitoring recommendations during chemotherapy in European childhood Cancer April 1,

4 Table 3. Summary of Abnormal Studies Patient ID Age, y Sex Race Diagnosis Outcome/Interpretation Female Caucasian AML Abnormal EF (49%) during an episode of septic shock; 6 subsequent studies with normal EF (57%-66%) Female Caucasian AML Abnormal EF (48%) during episode of septic shock (died of sepsis) Male Caucasian ALL A single abnormal EF (35%) in an asymptomatic patient; 4 other studies were normal (EF, 51%-65%) Male Caucasian ALL Abnormal EF (49%) during episode of septic shock Female Caucasian ALL Left ventricular heart failure; cumulative anthracycline dose 360 mg/m 2 ; died of heart failure Female AA Osteosarcoma Routine screening demonstrated an EF of 49% after a cumulative anthracycline dose of 375 mg/m 2 ; 1 course of doxorubicin withheld from chemotherapy protocol Male Caucasian Wilms tumor Single abnormal EF (48%) in study during immediate postoperative period after nephrectomy; repeat studies normal (EF, 73%) and received 120 mg/m 2 doxorubicin without difficulty Male AA ALL Single abnormal EF (45%) during induction chemotherapy for ALL; electrolyte abnormalities and tumor lysis syndrome; subsequent studies normal; EF, 56%-76% Male AA ALL Transferred from outside medical facility with new diagnosis of ALL, shock, and multiorgan failure; EF, 38% Abbreviations: AA, African American; ALL, acute lymphoblastic leukemia AML, acute myelogenous leukemia; EF, ejection fraction; ID, identification. cancer treatment protocols. van Dalen and colleagues reviewed anthracycline monitoring guidelines in a wide array of childhood cancer chemotherapy protocols in Europe from 1996 to Those authors specifically reviewed 12 treatment protocols, and they noted a wide discrepancy between individual protocols with regard to monitoring frequency, monitoring techniques, and treatment modifications in the event of abnormal echocardiographic findings. The authors also noted that the current recommendations for cardiac monitoring before and during treatment are based on limited research data, and they encouraged the standardization of monitoring and further clinical research to define ongoing monitoring recommendations. Clinical research data to address these uncertainties remain limited. A recent report by Avelar and colleagues 26 described a series of 49 children over a 10-year period at a single treatment center. The authors were interested specifically in whether or not the pretreatment echocardiogram altered treatment decisions. Although their study identified a high rate of abnormal echocardiograms (primarily pericardial effusions and trivial or mild aortic insufficiency), in no case did the pretreatment echocardiogram alter the decision to proceed with anthracycline chemotherapy. Porea and coworkers reached a similar conclusion in their review of 128 newly diagnosed patients with acute leukemia. 27 In their review, no alterations in therapy resulted from the initial, pretreatment echocardiogram. Our patient population (356 patients) is considerably larger than the populations described by Avelar et al or Porea et al, but our study reaches the same conclusion. In none of the 356 patients did the pretreatment echocardiogram alter the decision to proceed with protocolrecommended anthracycline chemotherapy. A mild decrease in cardiac EF (48%) was noted in only 1 patient during the immediate postoperative period after nephrectomy for Wilms tumor (patient 534). The abnormal EF value normalized (to 73%) without intervention, and the child proceeded to scheduled anthracycline treatment. In a second case (patient 543), a low EF (48%) was noted during the acute onset of the illness in the setting of electrolyte abnormalities with tumor lysis syndrome. Correction of the electrolyte abnormalities resulted in correction of cardiac function and a decision to proceed with scheduled anthracycline chemotherapy. At most, 2 of the initial 356 echocardiograms (0.5%) identified areas of concern, although neither result altered treatment plans. Clinical research data are even more limited regarding the role of routine echocardiograms during treatment for childhood cancer. Our literature review failed to reveal studies addressing this specific question. How often is therapy modified by echocardiogram screening during treatment? Our patient population contained 635 followup studies in 356 patients. In only 2 patients (0.3% of studies) did follow-up echocardiogram during treatment identify a clinically important finding. One patient 1922 Cancer April 1, 2012

5 Pretreatment & Routine Echocardiograms/Watts et al developed symptomatic cardiotoxicity at a cumulative anthracycline dose of 360 mg/m 2 (T-cell acute lymphoblastic leukemia; patient 484). She was found to have apparent chemotherapy-associated cardiotoxicity and died of that complication. However, even in her case, the decision to perform a follow-up echocardiogram was based on the clinical finding of tachycardia and not based on a routine, protocol-driven echocardiogram interval. In fact, a routine, protocol-driven echocardiogram performed 2 months earlier demonstrated a normal EF of 56%. In patient 501, a routine echocardiogram was used to alter treatment. Near the end of treatment for osteosarcoma, a routine study in this asymptomatic child revealed an EF of 49% (the EF in previous baseline studies ranged from 55% to 57%). On the basis of that result, a single course of doxorubicin therapy was withheld. Ongoing follow-up of patient 501 over 3 years has demonstrated normal heart function, and the most recent echocardiogram revealed an EF of 64%. Table 3 indicates that 7 other patients had abnormal EF percentages on screening echocardiograms; however, in each patient, the abnormality was not related directly to anthracycline chemotherapy and had no impact on treatment decisions. In our current review, only 2 of 991 routine echocardiograms before or during treatment altered treatment decisions. This represents 0.2% of studies (0.5% of patients). It is clear that the patient with overt cardiotoxicity would have been identified without a routine echocardiogram. Our study has several limitations. First, this was a retrospective review. Second, echocardiograms were performed clinically for the purposes of assessing LV systolic function. Echocardiograms were not intended to assess LV diastolic function or other echocardiographically derived parameters of LV function. A single observer (among several attending pediatric cardiology physicians) evaluated each echocardiogram according to standard and widely accepted measurement techniques; however, we did not audit original echocardiogram images or remeasure or attempt to assess interobserver variability. Despite these limitations, our experience mimics the real world of clinical pediatric oncology and cardiology as practiced at pediatric cancer treatment centers in North America. Our study suggests that prechemotherapy echocardiography in children does not change the clinical conduct of their chemotherapy regimen and that intratreatment echocardiogram is likely to change therapy in <1 in 400 patients. Although the 1992 guidelines by Steinherz et al 18 have served children well, it is likely time to re-evaluate these guidelines and recommendations. Several key questions remain. A long-held dogma is that a pretreatment echocardiogram is important if only to gain a pretreatment EF baseline. 18,23 In theory, this baseline would allow the identification of children with a fall in their cardiac EF to values that, although remaining within the normal range, represent a decline from the individual patient s pretreatment value. This within-normal-value decline has been considered a possible clue to impending cardiotoxicity. However, because the most commonly reported measures of cardiac performance are dependent on loading conditions, which, in turn, are greatly affected by factors like anemia, fever, and central vascular volume status (all frequent and changeable conditions in the child with cancer), the true value of a baseline EF to inform an individual strategy for cardiac protection monitoring remains unclear. Another key question is whether or not newer advanced imaging techniques, biomarkers, or cardioprotective interventions can offer better screening and predictive models. 28,29 At the time of this writing, approximately 50 clinical trials involving cardiotoxicity in both child and adult patients were recruiting participants to address these questions. Our data support the concept that what is needed is improved identification of individual patients who are at risk for permanent cardiotoxicity sufficiently early enough during treatment to alter their outcomes. The COG and other cooperative cancer care groups for children in Europe and elsewhere possess the patient numbers and clinical trials infrastructure to define the true effectiveness of routine echocardiograms before and during treatment in children who receive with anthracycline chemotherapy. However, until definitive studies are reported, we agree with the recommendations of Avelar et al 26 and Porea et al 27 that routine pretreatment echocardiograms in children with normal cardiac physical examinations and normal screening EKG should not delay the initiation of specific chemotherapy. In addition, routine echocardiograms during treatment based on a predefined frequency or routine may not provide ideal surveillance. An alternative approach would involve careful clinical monitoring of heart rate, blood pressure, and physical examination, with further EKG and echocardiogram screening based on clinical indications or suspicion. In contrast, routine echocardiographic monitoring as part of a postchemotherapy late effects program is warranted and increasingly has been validated. Only through ongoing research will the evidence needed to improve care and outcomes become available. Cancer April 1,

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