A new approach to the treatment of high-risk hepatoblastoma yielded a dramatic improvement in the survival of these children, according to the results of a new study reported in the August 17 edition of the Lancet.
The prognosis of children with high-risk hepatoblastoma, especially those with metastasis, is poor, with most patients dying within 5 years, say the study authors, led by József Zsiros, MD, of Emma Children's Hospital in Amsterdam, the Netherlands.
The new, single-arm study featured a novel chemotherapy approach in this setting: dose-dense (weekly) preoperative administration of cisplatin, in addition to monthly doxorubicin plus radical surgery.
The 3-year event-free survival was 76% in the 62 patients studied and 77% in the 39 patients with metastasis. The 3-year overall survival was 83%.
"This finding is perhaps the most substantial improvement in survival that has been described for children with solid tumours and metastatic disease in decades," write Muna Qayed, MD, of Emory University in Atlanta, Georgia, and Howard Katzenstein, MD, of Vanderbilt University in Nashville, Tennessee, in an accompanying editorial.
The new findings from the trial, which was conducted by the International Childhood Liver Tumours Strategy Group and is known as SIOPEL-4, compare favorably with results from an earlier effort from the group.
In the previous trial, SIOPEL-3, the 3-year event-free survival was 56%, and the 3-year overall survival was 62% in high-risk patients. This older trial also featured cisplatin, which is the key chemotherapeutic drug in the treatment of hepatoblastoma, but it was used on a standard dosing schedule — not on a weekly, dose-dense schedule as in the new trial.
The survival gain in the new SIOPEL-4 trial seems to hinge on dose intensification — "an old basic tenet of chemotherapy administration that never has been fully evaluated in paediatric malignancies," say the editorialists.
The dose-dense approach came at a cost, however. More than 50% of participants had significant hearing loss.
The editorialists wonder whether this is too high a price, especially in the youngest children. Hepatoblastoma, which is the most common pediatric liver tumor, is typically diagnosed in children younger than 3 years, they point out.
"Since ototoxocity is difficult to measure, notoriously under-reported, and can progress over time, the question remains as to what hearing function these very young patients will have in the long run and whether this loss is an acceptable price to pay for the survival rates observed," the editorialists write.
The trial investigators also report that febrile neutropenia occurred in 71% of patients and that 4 patients had toxic deaths (2 from infection, 1 from surgical bleeding, and 1 with tumor bleeding).
In their essay, Dr. Qayed and Dr. Katzenstein also question one other aspect of the trial: whether dose intensity was really the driver behind the improvement over historical results.
They observe that during the 3 cycles of weekly cisplatin therapy, patients had average cumulative delays of 10 days, which resulted in dose reductions in 9% of the initial chemotherapy cycles. "Interestingly, irrespective of delays in therapy, all patients did well. This outcome somewhat contradicts the study conclusion that dose intensity was the reason for improvement, since the outstanding results were even seen in patients who had delays and reductions in therapy," they write.
However, the editorialists do not offer any explanation as to what else might have been at work in the new trial to improve upon other trials' results in this setting.
Further Trial Details
To be eligible for SIOPEL-4, patients had to be aged 18 years or younger with newly diagnosed hepatoblastoma that was high risk: either metastatic disease, tumor in all liver segments, abdominal extrahepatic disease, major vascular invasion, or tumor rupture.
Treatment consisted of preoperative chemotherapy (cisplatin 80 mg/m2 per day intravenous in 24 hours on day 1; cisplatin 70 mg/m2 per day intravenous in 24 hours on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 per day intravenous in 24 hours on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumor lesions if feasible. Sixteen of the patients received liver transplants.
Patients whose tumor remained unresectable received additional preoperative chemotherapy.
After surgery, postoperative chemotherapy was given and included doxorubicin and carboplatin.
At the end of therapy, 49 of 62 (79%) patients were in complete remission, which was the primary endpoint of the study.
The adverse events included grade 3–4 hematologic toxicity (anemia, neutropenia, or thrombocytopenia), which occurred in 60 patients (97%).
The editorialists believe the new efficacy results are strong enough to justify the SIOPEL-4 regimen's being compared in a randomized trial that further evaluates the toxicities of the treatment scheme.
The study was funded by Cancer Research UK and Cancer Research Switzerland/Oncosuisse. Both the study authors and the editorialists have disclosed no relevant financial relationships.
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