Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults

Abstract

The prognosis of primary disseminated multifocal metastatic Ewing's sarcoma (PDMES) is poor even if a slight improvement has been achieved with high-dose alkylating agent-containing chemotherapy. To enhance treatment efficacy, we assessed the feasibility, safety and efficacy of a tandem high-dose chemotherapy (HDC) regimen. In a single institution, patients with PDMES received six courses of vincristine/ifosfamide/doxorubicin/etoposide induction therapy, followed by high-dose thiotepa, and then melphalan-busulfan, 8 weeks apart. Surgical resection of primary tumour was carried out between the two HDC regimens and 70 days after the last HDC regimen for post-operative radiotherapy or irradiation alone. From October 2002 to 2009, 13 of the 18 consecutive patients with PDMES (72%) received the full treatment programme. The other five patients experienced early progression and died. Among the 13 patients, 11 relapsed after the end of the treatment programme within 6 months (2.2-11.9) from end of therapy. Only two patients are still alive in first complete remission after 9 years. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 and 22%, respectively. The median EFS and OS duration from the diagnosis were 13.4 and 17.3 months, respectively. Neither major complications nor treatment-related death occurred. The tandem-HDC regimen was feasible, with expected side effects, but it did not improve the outcome of patients with PDMES. INTRODUCTIONEwing sarcoma (ES) is the second most common primary malignant bone tumour in children, adolescents and young adults after osteosarcoma. 1 ES is characterised by a specific translocation t(11;22) and transcript EWS-Fli1. 2 Currently, in the field of multimodality therapy, event-free survival (EFS) rates have increased from 10% to 470% in localised disease. 3,4 Isolated pulmonary metastatic disease is associated with an EFS rate of 29-52%. 5 Although a slight improvement has been achieved with single high-dose chemotherapy (HDC) regimen, the outcome of patients with primary disseminated multifocal metastatic Ewing's sarcoma (PDMES) remains dismal. The 3-year EFS rate was 27% with the chemotherapy regimen in the R3 arm of the EuroEWING99 (EE99) trial. 6 This regimen comprised a six-course induction chemotherapy of vincristine/ifosfamide/doxorubicin/ etoposide (VIDE), then one course of vincristine/(d)actinomycin/ ifosfamide (VAI) and a single-HDC regimen by busulfan-melphalan (Bu/Mel), as consolidation therapy, followed by autologus peripheral haematopoietic progenitor (APHP) rescue. Prognostic factors (age, initial tumour volume, number of bone metastases, bone marrow and lung involvement) had allowed clinicians to define a prognostic score in this population. 6,7 The 3-year EFS rate was 50, 25 and 10% for a score of o 3, from 3 to 5 and for a score ⩾ 5, respectively. 6 The benefit of a myeloablative regimen in terms of outcome has been demonstrated in several tumour types with high sensitivity to HDC (for example, high-risk neuroblastomas). 8 In multimeta...

Bone marrow involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow

“…In landmark as well as in recent studies, improvement of local therapy has proven crucial in the treatment of advanced Ewing sarcoma patients [11, 20, 24], whereas the role of high-dose chemotherapy regimen with autologous stem cell transplantation in the treatment of advanced Ewing sarcoma patients remains subject to an ongoing discussion [4, 7, 10, 15–17, 25–35]. The conflicting results of various studies including our previous analyses [6, 20] in contrast to the results of Meyers et al [21] may be due to variation in intensity of local therapy.…”

A novel method to address the association between received dose intensity and survival outcome: benefits of approaching treatment intensification at a more individualised level in a trial of the European Osteosarcoma Intergroup

“…This definition applies to either single cytostatic agents or drug combinations [ 2 ]. The prognostic value of high RDI in cancer survivorship has been discussed in several studies [ 3 – 8 ] and for many cancer types; however, this debate has never reached consensus [ 9 , 10 ].…”

Sinusoidal obstruction syndrome/veno-occlusive disease after high-dose intravenous busulfan/melphalan conditioning therapy in high-risk Ewing Sarcoma

“…To date, the use of intravenous busulfan in high-risk ES was reported for limited cohorts of patients [27,28]. Since 2007, the Rizzoli Orthopaedic Institute, Bologna, has started the transplant activity for high-risk ES patients by using intravenous busulfan in the BU-MEL conditioning regimen before ASCT.…”