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Noninvasive Evaluation of Late Anthracycline Cardiac Toxicity in Childhood Cancer Survivors

Melissa M. Hudson, Shesh N. Rai, Cesar Nunez, Thomas E. Merchant, Neyssa M. Marina, Nia Zalamea, Cheryl Cox, Sean Phipps, Ronald Pompeu, David Rosenthal

From the Departments of Hematology Oncology, Biostatistics, Radiological Sciences, and Epidemiology and Cancer Control, and the Division of Behavioral Medicine, St Jude Children's Research Hospital, the University of Tennessee, College of Medicine, Memphis, TN; Department of Pediatrics, M.D. Anderson Cancer Center, Houston, TX; Department of Pediatrics and Cardiology, Stanford University Medical Center, Stanford; and Department of Surgical Education, Santa Barbara Cottage Hospital, Santa Barbara, CA

Address reprint requests to Melissa M. Hudson, MD, St Jude Children's Research Hospital, 332 North Lauderdale, Mailstop 735, Memphis, TN 38105; email: melissa.hudson{at}stjude.org

Purpose Childhood cancer survivors treated with anthracyclines and cardiac radiation are at risk for late-onset cardiotoxicity. The purpose of this study was to delineate the relationship between clinical factors and abnormalities of noninvasive cardiac testing (NICT).

Patients and Methods Participants were recruited from a long-term follow-up clinic. Study measures comprised physical examination, laboratory evaluation, echocardiogram, and ECG. Mean fractional shortening (FS) and afterload were compared for survivors who did (at risk [AR]) and did not (no risk [NR]) receive potentially cardiotoxic modalities, and with values expected for comparable age- and sex-matched controls.

Results The 278 study participants (mean age, 18.1 years; median age, 16.8 years; range, 7.5 to 39.7 years) included 223 survivors AR for cardiotoxicity after treatment with anthracyclines (median dose ± standard deviation [SD], 202 ± 109 mg/m²) and/or cardiac radiation. Mean FS (± SD) was lower for AR (0.33 ± 0.06) compared with NR survivors (0.36 ± 0.05; P = .004) and normative controls (0.36 ± 0.04; P < .001). Mean afterload (± SD) was higher for AR (58 ± 21 g/cm²) compared with NR survivors (46 ± 15 g/cm²; P < .001) and normative controls (48 ± 13 g/cm²; P < .001). The distribution of FS and afterload among NR survivors did not differ from that of controls. After adjustment for age group at diagnosis and time since completion of therapy, anthracycline dose predicted decline in distribution of FS (P < .001) and increase in distribution of afterload (P < .001). Treatment with anthracycline doses 100 mg/m² increased the risk of abnormal NICT; survivors who received 270 mg/m² had a 4.5-fold excess risk of abnormal NICT (95% CI, 2.1 to 9.6) compared with controls.

Conclusion Childhood cancer survivors treated with anthracycline doses 270 mg/m² are at greatest risk for abnormalities of FS and afterload.

Supported in part by the Cancer Center Support (CORE) Grant No. CA 21765 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities. Supported by Grant No. R25 CA23944 from the National Cancer Institute (N.Z.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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