July 15, 2019
3 min read

Reduced chemotherapy safe, effective for certain children with hepatoblastoma

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Children with hepatoblastoma resected at diagnosis demonstrated disease control with a minimal postoperative chemotherapy regimen, according to results from a phase 3 Children’s Oncology Group trial published in The Lancet Oncology.

The regimen consisted of two cycles of cisplatin, fluorouracil and vincristine, instead of the usual four to six cycles, after surgery.

Postoperative chemotherapy has been a routine component of hepatoblastoma therapy, but the optimal number of cycles and cumulative dose needed after resection at diagnosis has not been determined,” Howard M. Katzenstein, MD, director of the division of pediatric hematology/oncology at Nemours Children’s Specialty Care/Wolfson Children’s Hospital in Jacksonville, Florida, and colleagues wrote. “The International Childhood Liver Tumors Strategy Group (SIOPEL) studies of hepatoblastoma have favored the use of preoperative chemotherapy and delayed resection for all patients to minimize surgical morbidity, although this approach usually results in higher cumulative doses of administered chemotherapy. Conversely, the Children’s Oncology Group has advocated for resection at diagnosis, when feasible, to allow for detailed pathologic assessment of untreated tumors, improved tailoring of therapy and reduced cumulative doses of chemotherapy.”

Katzenstein and colleagues evaluated 49 patients aged younger than 21 years (median age at diagnosis, 16 months; range, 0-96; 71% male) with histologically confirmed stage I or stage II hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology. The patients, all of whom were assigned to the low-risk stratum of the phase 3 Children’s Oncology Group trial, had serum alpha-fetoprotein levels higher than 100 ng/mL (median, 14,086 ng/mL) and complete resection at diagnosis; performance status of at least 50% on the Karnofsky scale (patients aged older than 16 years) or the Lansky scale (patients aged 16 years and older); and no prior chemotherapy or other hepatoblastoma-focused treatment.

Patients underwent two 21-day cycles of chemotherapy no more than 42 days after resection. The regimen consisted of:

  • cisplatin 100 mg/m2 per dose or 3.3 mg/kg per dose for children weighing less than 10 kg, via IV over 6 hours on day 1;
  • fluorouracil 600 mg/m2 per dose or 20 mg/kg per dose for children weighing less than 10 kg, via IV push on day 2; and
  • vincristine 1.5 mg/m2 per day, not exceeding 2 mg, or 0.05 mg/kg per day for children weighing less than 10 kg, via IV push on days 2, 9 and 16.

Investigator-evaluated EFS served as the primary outcome. Researchers assessed EFS at 6 years after enrollment based on prespecified protocol.

Median follow-up was 42 months (interquartile range, 36-62).

Results showed 4-year EFS of 92% (95% CI, 79-97) and 5-year EFS of 88% (95% CI, 72-95). Surgical complications, specifically bile leaks, occurred in two (4%) patients.


Grade 3 to grade 4 adverse events included febrile neutropenia (n = 7; 14%), decreased neutrophil count (n = 3; 6%), infections (n =4; 8%) and diarrhea (n =4; 8%). One patient experienced ototoxicity.

Three patients relapsed, including one who died of their disease. After therapy was discontinued, two patients died in clinical remission. No treatment-related deaths occurred.

The researchers cited limitations to their study, including the small number of patients, which precluded a randomized trial. Additionally, further study is needed to compare ototoxicity among intermediate-risk children in the trial treated with higher cumulative doses of cisplatin.

The study included interesting observations, but questions of how to standardize and gauge the value of immediate or delayed surgery, and plan it an objective and comparable fashion, remain unanswered, according to a related editorial by Piotr Czauderna, MD, of the department of surgery and urology for children and adolescents at Medical University of Gdansk in Poland.

Without addressing these issues, it will be difficult to decide which patients benefit the most from immediate surgery and in which cases it should be avoided,” Czauderna wrote. by Jennifer Byrne

Disclosures: Katzenstein reports personal fees from Merck Sharpe & Dohme outside of the submitted work. Please see the study for all other authors’ relevant financial disclosures. Czauderna reports no relevant financial disclosures.