In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa)

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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...

Section: Discussionmentioning

confidence: 99%

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

Loschi

Dufour

Oberlin

et al. 2015

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“…Pharmacological studies have demonstrated a correlation between BU exposure and the incidence of HVOD following treatment with the BU-CY combination, 30 as well as with the BU-TTP combination. 31 In a previous study, 29 the incidence of HVOD following BU-TTP was significantly lower than that observed after the BuMel combination, even though the dose of BU was similar in both Bold values indicate significant differences. Risk factors for HVOD after HD BU-TTP in children A Cacchione et al combinations.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated the importance of the doses and type of drugs used in the conditioning regimen as risk factors for HVOD. 8,16,29 Among these drugs, high-dose BU exerts the most significant adverse impact. Pharmacological studies have demonstrated a correlation between BU exposure and the incidence of HVOD following treatment with the BU-CY combination, 30 as well as with the BU-TTP combination.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for hepatic veno-occlusive disease: a retrospective unicentric study in 116 children autografted after a high-dose BU-thiotepa regimen

Cacchione

Lemaître

Couanet

et al. 2008

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At our Institute, during the last decade, the incidence of hepatic veno-occlusive disease (HVOD) appears to be on the increase among pediatric patients treated with BUthiotepa (BU-TTP)-conditioning regimen. We thus performed a retrospective analysis to identify the risk factors for HVOD, which could explain such a change. In total, 116 patients treated at Institut Gustave Roussy, between May 1998 and December 2005 were eligible for this study having received BU-TTP as their first high-dose chemotherapy regimen, followed by autologous hematopoietic SCT (AHSCT). According to McDonald's clinical criteria, HVOD was diagnosed in 31% of these children. Demographic, clinical, biological and therapeutic parameters were evaluated in uni-and multivariate analyses that showed a significant correlation between previous carboplatin therapy and risk of developing post transplant HVOD (P ¼ 0.028). Comparable results were found for etoposide (P ¼ 0.048). In addition, a correlation between HVOD and risk of post transplant death was linked to its association with other types of organ failure (P ¼ 0.029). This study demonstrates that previous VPCARBO administration in conventional chemotherapy significantly increases the risk of HVOD among brain tumor patients later consolidated with BU-TTP followed by AHSCT.

“…It seems that many factors are equally important for VOD development, including underlying disease, pre-existing risk for VOD and particularly other drugs administered concomitantly with BU. 2,18,36 Recently, a higher incidence of acute GVHD (grade X2) was seen in patients with greater BU exposure. 18 In our study group, there were only two such patients; both had GSTM1 null genotype and no correlation was seen with BU exposure (P ¼ 0.9).…”

Section: Discussionmentioning

confidence: 99%

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

Ansari

Lauzon-Joset

et al. 2009

Busulfan (BU) is a key compound in conditioning myeloablative regimens for children undergoing hematopoietic stem cell transplantation (HSCT). There are wide interindividual differences in BU pharmacokinetics, which increase the risk of veno-occlusive disease, graft rejection and disease relapse. As BU is mainly metabolized by glutathione S-transferase (GST), it is hypothesized that functional polymorphisms in GST genes may explain in part the variability in BU pharmacokinetics. We analyzed polymorphisms in GSTA1 (C-69T, A-513G, G-631T, C-1142G), GSTM1 (deletion) and GSTP1 (A1578G, C2293T) genes in 28 children undergoing HSCT. All patients had individualized dosing based on pharmacokinetics after the first dose of intravenous BU. GSTM1-null individuals had higher drug exposure (P(Cmax)=0.008; P(AUC)=0.003; P(Css)=0.02) and lower clearance (P(CL)=0.001). Multivariate regression models showed that, other than the drug dose and age, the GSTM1 genotype was the best predictor of first-dose pharmacokinetic variability. GSTM1-null patients also received lower cumulative BU doses (P=0.02). No association was found between BU exposure and major GSTA1 or GSTP1 gene variants. In children, GSTM1 polymorphism seems to modify BU pharmacokinetics after intravenous drug administration