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Age Is a Risk Factor for Chemotherapy-Induced Hepatopathy With Vincristine, Dactinomycin, and Cyclophosphamide

From the Mayo Clinic, Rochester, MN; Children's Hospital and Regional Medical Center, Seattle, WA; University of Nebraska Medical Center, Omaha, NE; Duke University Medical Center, Durham, NC; Children's Hospital of Philadelphia, Philadelphia, PA; University of Oklahoma Health Sciences Center, Oklahoma City, OK; and Soft Tissue Sarcoma Committee of the Children's Oncology Group, Arcadia, CA.

Address reprint requests to Carola A.S. Arndt, MD, Department of Pediatric Hematology/Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: carndt{at}mayo.edu

PURPOSE: To evaluate the spectrum of and determine the risk factors for the development of liver toxicity (hepatopathy) after therapy with vincristine, dactinomycin, and cyclophosphamide (VAC) for rhabdomyosarcoma in children and adolescents.

PATIENTS AND METHODS: We prospectively captured all events of hepatopathy occurring on the ongoing Children's Oncology Group intermediate risk protocol, D9803, for children with rhabdomyosarcoma. Patients enrolled onto this trial were randomly assigned to receive either VAC alone or VAC alternating with vincristine, topotecan, and cyclophosphamide. In addition, we reviewed the toxicity database and requested additional information for all patients with elevated bilirubin or transaminase levels. Risk factors were analyzed.

RESULTS: Of 339 patients enrolled through August 2002, 18 developed hepatopathy. All events were captured by mandated toxicity reporting and filing of MedWatch forms, with no additional cases found after the additional search of the database. Four children died after developing this toxicity. All cases occurred after cycles of VAC (n = 16) or vincristine and cyclophosphamide with concomitant abdominal radiotherapy (n = 2). The onset of hepatopathy was 5 to 16 days from the start of a treatment cycle. For the 89 patients under 36 months of age, the risk of hepatopathy was 15%, with two deaths. For the 239 children 3 years of age or older, the risk for hepatopathy was 4%, with two deaths.

CONCLUSION: The greatest risk factor for development of hepatopathy after VAC therapy was age. Dose modifications for younger children receiving VAC therapy are recommended.

Supported by grant Nos. U10 CA098543, U10 CA24507, and CA72989 from the National Cancer Institute, Bethesda, MD.

Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2, 2003.

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

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