High-dose chemotherapy and autologous stem cell transplantation in children with Ewing’s sarcoma/PNET

Summary

The clinical course of Ewing’s sarcoma/PNET in children is characterized by a rapid increase of tumor mass and early metastases. In this context a substantial part of the affected pediatric population – children with clinically detectable metastatic disease or heavy tumor burden – has a poor prognosis. Although contemporary therapy programs – those that combine systemic chemotherapy with local control measures – achieve  5-year event-free survival (EFS) in 70–80% of children with localized disease, the results in high-risk groups are still to be improved with a 5-year EFS rate of 20–30%. Some research data provides evidence of high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) being a promising option for treatment of these high-risk patients.

Patients and methods

From 2003 to December 2008 a total of 17 pediatric patients with Ewing’s sarcoma/PNET received HDCD with auto-HSCT. There were 11 males and 6 females (male-female ratio of 1.8:1) with a median age at diagnosis of 13.4 yrs (range 3–18 yrs). In all the cases, diagnosis was histologically proved. Of the 17 patients, 13 had metastatic disease and 4 had localized disease. In all the patients with localized disease the initial tumor volume exceeded 200 sm³. In all the cases the therapy program included 6 courses of polychemotherapy (ifosfamide, vincristine, doxorubicin and etoposide), surgical treatment or local irradiation of primary disease sight (48–56 Gy). There were 8 patients who received 8 courses of maintenance chemotherapy (vincristine, dactinomycin, ifosfamide). In 9 cases the maintenance therapy was substituted for HDCT with auto-HSCT. We used the following conditioning regimens: oral busulfan 16 mg/kg and melphalan 140 mg/m² in 7 patients and melphalan 140–200 mg/m² in 2 patients. We used different stem cell sources: bone marrow (BM) in 5 patients, peripheral blood stem cells (PBSC) in 2 patients, and BM and PBSC – due to the poor yield of SC – in 2 patients. A mean dose of CD34+ cells in the graft amounted to 3.26 x 10⁶ (range 1.0–8.9 x 10⁶).

Results

In the maintenance therapy group (n=8) 5 patients had a relapse of metastatic disease and died of tumor progression, 2 patients had a local relapse and received salvage therapy – in one case, HDCT with auto-HSCT – and both are presently disease–free, while 1 patient died of overwhelming sepsis.

In the HDCT group (n=9) 8 of the patients are alive – 1 died of disease progression – 4 patients remain in remission, 2 patients failed to achieve remission and received allogeneic HSCT, and 2 patients relapsed 2–8 months after HDCT with auto-HSCT. All children transplanted in partial remission or disease progression later relapsed. All of the children that are at the moment disease-free were diagnosed stage IV Ewing’s sarcoma– distant metastases at the time of diagnosis – but achieved complete remission (CR) at the end of the induction chemotherapy course. The toxicity of HDCT regimens was moderate: all of the patients had grade II–III mucositis, 6 patients had febrile neutropenia, and 2 patients had toxic hepatitis.

Conclusions

HDCT with auto-HSCT in high-risk group children with Ewing’s sarcoma/PNET has acceptable toxicity and allows improved PFS for patients in CR after standard therapy regimens.

Keywords

Ewing's sarcoma, PNET, autologous hematopoietic stem cell transplantation, maintenance therapy