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Intensified Platinum Therapy Is an Ineffective Strategy for Improving Outcome in Pediatric Patients With Advanced Hepatoblastoma

Marcio H. Malogolowkin, Howard Katzenstein, Mark D. Krailo, Zhengjia Chen, Laura Bowman, Marleta Reynolds, Milton Finegold, Brian Greffe, Jon Rowland, Kurt Newman, Richard B. Womer, Wendy B. London, Robert P. Castleberry

From the Childrens Hospital Los Angeles; University of Southern California Keck School of Medicine, Los Angeles; Children's Oncology Group Operations Center, Arcadia; Children's Hospital Oakland, Oakland, CA; Children's Healthcare of Atlanta, Emory University, Atlanta, GA; Children's Memorial Medical Center at Chicago, Chicago, IL; Texas Children's Cancer Center at Baylor College of Medicine, Houston, TX; The Children's Hospital, Denver, CO; Children's National Medical Center, Washington, DC; Children's Hospital of Philadelphia, Philadelphia, PA; University of Florida, Gainesville, FL; and the Children's Hospital, University of Alabama, Birmingham, AL

Address reprint requests to Marcio Malogolowkin, MD, Childrens Hospital Los Angeles, Division of Hematology-Oncology, 4650 Sunset Blvd, MS #54, Los Angeles, CA 90027; e-mail: mmalogolowkin{at}chla.usc.edu

PURPOSE: The INT-0098 Intergroup Liver Tumor Study demonstrated no statistically significant differences in event-free and overall survival between patients randomized to treatment with either cisplatin + fluorouracil + vincristine (C5V) or cisplatin + doxorubicin. Results from this and other therapeutic trials suggested that cisplatin was the most active agent against hepatoblastoma. To increase the platinum dose-intensity, a novel regimen was developed alternating carboplatin and cisplatin (CC) every 2 weeks. The P9645 study was designed to compare the risk of treatment failure for patients with stage III/IV hepatoblastoma randomized to either C5V or CC.

METHODS: C5V was given according to INT-0098 and CC consisted of carboplatin at 700 mg/m² on day 0 (560 mg/m² after two cycles) followed by cisplatin 100 mg/m² on day 14. Granulocyte colony-stimulating factor was used after each CC cycle. All patients received four to six cycles of chemotherapy.

RESULTS: From the time the study was opened until the time that random assignment was halted, 56 patients received CC and 53 patients received C5V. The 1-year event-free survival was 37% for patients receiving CC and 57% for those receiving C5V (P = .017). Patients randomly assigned to CC required more blood product support. As a result of a semiannual review by the Children's Oncology Group Data and Safety Monitoring Committee, random assignment was discontinued after 3 years of enrollment because the projected improvement in long-term outcome associated with CC was statistically excluded as a possible outcome of this trial.

CONCLUSION: Intensification of therapy by alternating platinum analogs increased the risk of adverse outcome in children with unresectable or metastatic hepatoblastoma.

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

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