In Hepatoblastoma, Cisplatin Monotherapy Is Just as Good as Combo

Nick Mulcahy

September 18, 2010

October 21, 2009 — In the treatment of the rare childhood disease of hepatoblastoma, a simple monotherapy with cisplatin is not inferior to a combination of cisplatin and doxorubicin in patients with "standard-risk" disease, according to the results of a new randomized trial of 255 children published in the October 22 issue of the New England Journal of Medicine.

The children receiving cisplatin had rates of complete resection and survival similar to those in children receiving the combination adjuvant therapy, according to the international group of authors, led by Giorgio Perilongo, MD, from the University Hospital of Padua in Italy.

"We recommend the use of cisplatin alone for all standard-risk hepatoblastoma," Dr. Perilongo told Medscape Oncology.

The rate of complete resection, which was the trial's primary end point, was 95% in the cisplatin-monotherapy group and 93% in the cisplatin–doxorubicin group.

Three-year event-free survival and overall survival were, respectively, 83% and 95% in the monotherapy group and 85% and 93% in the cisplatin–doxorubicin group. The children were followed for a median of 46 months.

The similar event-free and overall survival rates "bode well for the definitive cure of children with standard-risk hepatoblastoma," write the investigators of the trial, known as International Childhood Liver Tumour Strategy Group 3 (SIOPEL 3).

Predictably, the monotherapy was also less toxic. Acute grade 3 or 4 events, including febrile neutropenia, were much more frequent in the cisplatin–doxorubicin group than in the monotherapy group (74.4% vs 20.6%).

However, Dr. Perilongo and his colleagues noted that strategies consisting of primary surgery and adjuvant multiagent cisplatin-based chemotherapy have resulted in "excellent outcomes" in children with limited extension hepatoblastoma. Differences in risk stratification between these various studies did not allow the investigators from making direct comparisons, they explain.

The current study did not include any children with high-risk disease. These patients are more difficult to treat and are part of the future challenges in hepatoblastoma, said Dr. Perilongo.

"The next steps in hepatoblastoma research are to refine our risk stratification in order to further reduce therapy, improve the cure of children with high-risk hepatoblastoma, and develop a biological drive therapeutic approach based on new agents," he said.

Building on Past Studies

SIOPEL 3 is an outgrowth of the findings of the group's 2 earlier trials. In SIOPEL 1, the investigators administered cisplatin–doxorubicin and identified 2 pretreatment prognostic factors: intrahepatic tumor extension and lung metastases. Based on these findings, they established pretreatment risk groups: standard risk (tumor confined to the liver and not more than 3 hepatic sectors) and high risk (tumors involving the entire liver and beyond).

In SIOPEL 2, which was a pilot study for the current trial, the researchers tried cisplatin monotherapy for the first time, using insight from another trial (J Clin Oncol. 2000;18:2665-2675) that showed a multiagent antracycline-free regimen was just as effective as cisplatin–doxorubicin but with no cardiotoxicity.

In the new study, tumor extension was graded using the pretreatment tumor extension system (PRETEXT). Only standard-risk patients (those with PRETEXT grades I–III) were eligible, and all children had to be younger than 16 years.

Between 1998 and 2006, 126 children were assigned to cisplatin monotherapy (every 14 days) and 129 to cisplatin–doxorubicin (every 21 days). The median number of cycles of preoperative chemotherapy was 4 in both groups. The children were resected on the basis of tumor response and then administered postoperative chemotherapy (both groups had a median of 2 cycles).

The rate of complete resection was chosen as the primary end point for a number of reasons, including the fact that it is the "single most important prognostic factor for long-term survival and event free-survival" in these patients, say the authors.

Not Quite Enough Patients

The authors noted that, in this noninferiority design, they could not statistically prove their conclusion that the 2 regimens were comparable. The reason was the limited number of patients; still, the similar rates of event-free survival and overall survival "provide support" for the noninferiority of cisplatin monotherapy, they argue.

In terms of negative outcomes, 19 patients in the monotherapy group (15%) and 15 in the cisplatin–doxorubicin group (12%) had disease progression or relapse. Seven children in the monotherapy group and 8 in the cisplatin–doxorubicin group died.

Some hearing loss was documented in about a third of all patients tested (53 of 168); however, there was no difference between the 2 groups.

With regard to cardiotoxicity, the investigators said that the small number of affected patients required "longer follow-up" to accurately assess any impairments.

Importantly, during the trial, the protocol was amended and children with alpha-fetoprotein levels of less than 100 ng/mL were excluded because of "mounting evidence of a poor outcome in these patients," write the authors.

The researchers have disclosed no relevant financial relationships.

New Engl J Med. 2009;361:1662-1670.

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