We performed a pilot study to determine the benefit of high-dose chemotherapy and autologous peripheral blood stem cell transplantation (HDCT/autoPBSCT) for patients with Ewing sarcoma family of tumors.
We retrospectively analyzed the data of patients who received HDCT/autoPBSCT at Korea Cancer Center Hospital. Patients with relapsed, metastatic, or centrally located tumors were eligible for the study.
A total of 9 patients (3 male, 6 female), with a median age at HDCT/autoPBSCT of 13.4 years (range, 7.1 to 28.2 years), were included in this study. Patients underwent conventional chemotherapy and local control either by surgery or radiation therapy, and had achieved complete response (CR, n=7), partial response (n=1), or stable disease (n=1) prior to HDCT/autoPBSCT. There was no transplant-related mortality. However, the median duration of overall survival and event-free survival after HDCT/autoPBSCT were 13.3 months (range, 5.3 to 44.5 months) and 6.2 months (range, 2.1 to 44.5 months), respectively. At present, 4 patients are alive and 5 patients who experienced adverse events (2 metastasis, 2 local recur, and 1 progressive disease) survived for a median time of 2.8 months (range, 0.1 to 10.7 months). The 2-year survival after HDCT/autoPBSCT was 44.4%±16.6% and disease status at the time of HDCT/autoPBSCT tended to influence survival (57.1%±18.7% of cases with CR vs. 0% of cases with non-CR,
Disease status at HDCT/autoPBSCT tended to influence survival. Further studies are necessary to define the role of HDCT/autoPBSCT and to identify subgroup of patients who might benefit from this investigational treatment.
Combination chemotherapy significantly improved the outcome of patients with Ewing sarcoma family of tumors (ESFT)
Few data exist on the efficacy of HDCT in the treatment of Asian patients with ESFT. It has been suggested that incidence and outcome differences of ESFT have a genetic basis
We retrospectively analyzed the data of 9 patients with ESFT who received HDCT/autoPBSCT between January 2007 and December 2010 at the Department of Pediatrics, Korea Cancer Center Hospital. Patients with ESFT were considered eligible for this therapy if they had multiple metastases at the time of diagnosis (n=2), centrally located tumors (n=2), or recurrent disease (n=5). Normal renal, cardiac, and hepatic functions were required. Prior to HDCT/autoPBSCT, patients underwent conventional chemotherapy and local control either by surgery or radiation therapy. Seven patients were treated with tandem HDCT/autoPBSCT. Detailed patient information is presented in
ESFT was diagnosed by immunohistochemical methods, that is, the presence of small round cells, with no cytologic, histologic, or immunohistochemical feature of lymphoma, rhabdomyosarcoma, or neuroblastoma. It is recommended that the diagnosis of ESFT should be based on histologic and cytogenetic analyses, however, due to the retrospective nature of this study, cytogenetic analyses were not feasible. The 2 patients with relapsed ESFT first received surgery and then received radiation therapy and chemotherapy. The remaining 7 patients received neoadjuvant chemotherapy consisting of vincristine+ifosfami de+doxorubicin+etoposide (n=7) or vincristine+doxorubicin+c yclophosphamide alternating with ifosfamide+etoposide (n=1) or gemcitabine+docetaxel (n=1). Eight cases were eligible for response evaluation. The timing of surgery varied, and usually, patients underwent surgery to remove the primary tumor after receiving 4.6 courses of chemotherapy. Histologic response was evaluated in 4 cases and 3 cases showed good response (<10% residual viable tumor). The timing of leukapheresis varied depending on the patient's condition, and patients with pelvic or mandibular tumors underwent leukapheresis before definitive surgery. Four patients underwent 2 rounds of leukapheresis. Granulocyte-colony stimulating factor (G-CSF) (5.10 µg/kg) was subcutaneously administered if the neutrophil count fell below 0.5×109/L after chemotherapy, and G-CSF administration was continued until the completion of stem cell collection. Stem cell collection was started when the white blood cell count exceeded 1.0×109/L with a monocytosis after nadir. We aimed to collect a minimum of 2×106 CD34+ cells/kg, and ideally more than 5×106 CD34+ cells/kg, for rescue during the tandem HDCT with the peripheral blood stem cells (PBSCs) collected during a single leukapheresis round. If the collected number of CD34+ cells was not sufficient, another round of leukapheresis was performed.
Patients underwent HDCT/autoPBSCT after completing conventional chemotherapy and local tumor control with either surgery or radiation therapy. The HDCT regimens used in our patients were; carboplatin+thiotepa+etoposide for the first HDCT, and cyclophosphamide+melphalan for the second HDCT (
Clinical response was evaluated using either computed tomography (CT) or positron emission tomography-CT (PET-CT). Usually, the response of lung metastatic lesions was assessed radiologically by using CT, and response was defined according to the Response Evaluation Criteria In Solid Tumors (RECIST): complete response (CR), disappearance of all target lesions; partial response (PR), ≥30% decrease from baseline; progressive disease (PD), ≥20% increase over smallest sum observed or appearance of new lesions; and stable disease (SD), neither PR nor PD criteria met
Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (ver. 3.0).
Survival analysis was performed using the Kaplan-Meier method, from the date of the first HDCT/autoPBSCT. Events were defined as disease progression or any other cause of death.
There were 6 CR and 3 PR after the mobilization chemotherapy (
There were 7 CR, 1 PR, and 1 SD case at the time of HDCT/autoPBSCT. One patient with PR (patient no. 2) underwent surgery after mobilization chemotherapy, and subsequently achieved CR. For patient no.7, the primary lung tumor and one of the metastatic bone lesions (acetabulum) showed PR and the remaining multiple metastatic bone lesions showed CR at the time of HDCT/autoPBSCT. Patient no.1 developed a metastatic lesion 2.5 months after mobilization chemotherapy. She was treated with chemotherapy and radiotherapy and showed SD at the time of HDCT/autoPBSCT. After HDCT/autoPBSCT, 7 cases showed CR and 2 showed SD.
All patients experienced grade 4 leukopenia, neutropenia, and thrombocytopenia after HDCT/autoPBSCT. Nonhematologic toxicities observed during the 16 courses of HDCT/autoPBSCT were as follows: grade 2/3 stomatitis (n=4), sepsis (n=3; 1 vancomycin-resistant enterococci, 1
A median of 10 days (range, 9 to 14 days) was required to reach a neutrophil count greater than 0.5×109/L, a median of 11 days (range, 9 to 15 days), to reach a neutrophil count greater than 1.0×109/L, and a median of 24 days (range, 13 to 248 days), to reach a platelet count greater than 50×109/L. The median time for hematologic recovery was the same for the first and second course of HDCT/autoPBSCT.
The median follow-up duration was 21.6 months (range, 12.2 to 51.3 months). From the day of the first HDCT/autoPBSCT, the median overall survival (OS) and event-free survival (EFS) were 13.3 months (range, 5.3 to 44.5 months) and 6.2 months (range, 2.1 to 44.5 months), respectively. Four patients were still alive after completion of the study. Five patients experienced disease adverse events (2 metastasis, 2 local recurrences, and 1 PD) at a median time of 4.9 months (range, 2.1 to 5.9 months), and of these, 3 received salvage chemotherapy consisting of vincristin e+topotecan+cyclophosphamide (n=1), gemcitabine+docetaxel (n=1), or cyclophosphamide+topotecan (n=1). However, all of them died after a median time of 2.8 months (range, 0.1 to 10.7 months). The 2-year OS and EFS after HDCT/autoPBSCT were identical (44.4%±16.6%). Disease status at the time of HDCT/autoPBSCT tended to influence survival (
We analyzed the clinicopathologic characteristics and outcome of high-risk ESFT patients who received HDCT/autoPBSCT as a consolidating treatment. High-risk cases were defined as those involving metastatic disease at the time of diagnosis, recurrent disease, or tumors located in the central parts of the body. We observed that disease status at the time of HDCT/autoPBSCT tended to influence survival, although our findings still remain inconclusive regarding the benefit of HDCT/autoPBSCT for this subgroup of patients.
Some limitations of the present study must be considered. The incidence of ESFT is very low in Korea, and accordingly, our study cohort was composed of a very small number of cases. Furthermore, because of its retrospective nature, this study was not prospectively randomized and treatments before HDCT/autoPBSCT were heterogeneous. We also believe that a selection bias may have existed, in that patients who achieved better than a PR and were in durable remission went on to receive HDCT/autoPBSCT.
A variety of cytoreductive regimens have been used, however, it has been difficult to compare their efficacy because of inconsistencies in the definition of high-risk ESFT and limited number of cases. Burdach et al.
The 2-year EFS of 44.4% in our 9 patients is comparable to that of the Euro-American series
The benefit of HDCT for ESFT is still inconclusive. HDCT/autoPBSCT improved the prognosis of recurrent or high-risk solid tumors in children
We believe that survival of certain subgroups of patients may be improved with HDCT. The results of the EURO-EWING 99 trial provided valuable information
Summarizing, we could not observe a clear benefit of HDCT/autoPBSCT for children and adolescents with high-risk ESFT. Disease status at the time of HDCT tended to influence the survival and durable remissions were hardly achieved after HDCT/autoPBSCT, without proper local tumor control. We believe that our study was inconclusive due to its retrospective nature and the small number of cases. Future studies should be conducted in a prospective and randomized design in order to define the role of HDCT as well as to identify a subgroup of patients who might benefit from this investigational treatment.
No potential conflict of interest relevant to this article was reported.
Kaplan-Meier estimate of event-free survival (EFS) in Ewing sarcoma family of tumors patients that underwent high-dose chemotherapy and autologous peripheral blood stem cell transplantation (HDCT/autoPBSCT). Patients who were in complete response (CR) at the time of HDCT/autoPBSCT tended to have better EFS than those who were not in CR (
Summary of the patient characteristics
PBSCT, peripheral blood stem cell transplantation; SD, stable disease; DOD, died of disease; CR, complete remission; NED, no evidence of disease; PR, partial remission; FU, follow-up.
*Time between diagnosis and PBSCT. †Time between PBSCT and death/last follow-up.
High dose chemotherapy regimens