Impact of High-Dose Busulfan Plus Melphalan As Consolidation in Metastatic Ewing Tumors: A Study by the Société Française des Cancers de l'Enfant

Oberlin, Odile; Rey, Annie; Desfachelles, Anne Sophie; Philip, Thierry; Plantaz, Dominique; Schmitt, Claudine; Plouvier, Emmanuel; Lejars, Odile; Rubie, H; Terrier, Philippe; Michon, Jean

doi:10.1200/jco.2006.05.7059

Cited by 123 publications

(99 citation statements)

References 25 publications

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“…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).…”

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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

Bone Marrow Transplant

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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...

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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

Bone Marrow Transplant

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“…Proteins are considered the hallmark of genetic alterations. Global mRNA expression studies are often performed to follow these changes [29,[30][31][32][33][34]. However, recent comparative studies of mRNA and protein expression in tumor cells revealed only a subset of mRNA correlated with protein abundance [4,12].…”

Section: Discussionmentioning

confidence: 99%

“…Wide excision of tumors in conjunction with multiagent chemotherapy now provides 5-year diseasespecific survivals ranging from 60% to 80% in patients with localized high-grade sarcomas [2,5,27]. Despite this success, the outcomes of patients who have metastatic disease at diagnosis or those with tumors showing a poor response to chemotherapy are still unsatisfactory (5-year disease-specific survival rates, 20%-40%), even with doseintensive or high-dose chemotherapy [9,18,19,33]. For improving the prognosis of patients with these difficult-totreat sarcomas, it is imperative to develop new targeted therapeutic strategies based on an understanding of the biologic mechanisms underlying the metastasis and chemoresistance of these tumors.…”

Section: Introductionmentioning

confidence: 99%

Global Protein-expression Analysis of Bone and Soft Tissue Sarcomas

Kawai¹,

Kondo

Suehara

et al. 2008

Clin Orthop Relat Res

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“…The 5-year EFS for lung-only metastases was 52%, and this compares favorably with the 34% 8-year EFS reported in 32 patients with lung-only metastases reported with chemotherapy. 3 Data regarding the site of metastases are not given in the IBMTR report, and this could be important, as patients with other sites of disease fared much worse in the report by Oberlin et al 4 In conclusion, valid comparisons between chemotherapy and myeloablative therapy can be made only on the basis of a randomized trial. We share the desire with Gardner et al to see the results of the randomized Euro EWING 99 study.…”

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confidence: 99%

“…A prospective study that used etoposide and ifosfamide in induction and consolidation with myeloablative therapy with busulfan and melphalan was reported by Oberlin et al 4 Ninety-seven newly diagnosed patients with metastatic Ewing sarcoma were enrolled and the 5-year EFS was 37%. The 5-year EFS for lung-only metastases was 52%, and this compares favorably with the 34% 8-year EFS reported in 32 patients with lung-only metastases reported with chemotherapy.…”

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Myeloablative chemotherapy with autologous stem cell rescue for Ewing sarcoma

Gilman

Oesterheld

2008

Bone Marrow Transplant

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The report by Gardner et al. 1 analyzes International Blood and Marrow Transplant Registry (IBMTR) data regarding myeloablative therapy with autologous stem cell rescue for Ewing sarcoma. The limitations of this report, which is based on an observational database, are reviewed in the Discussion. Clarifications about some of the comparisons in the Discussion are important because this article will likely influence clinical practice.For example, a comparison of the outcome for patients with localized disease at diagnosis is made. The comparison is between the IBMTR results for megatherapy and the results of a study that incorporated etoposide and ifosfamide. 2 The latter study was not limited to high-risk patients, so it is possible that there was a significant difference in risk factors such as tumor size and location. Because the addition of etoposide and ifosfamide was shown to improve outcome, the induction therapy used is important for this comparison and it is not known for the IBMTR patients.The study of chemotherapy including etoposide and ifosfamide was also reported for patients with metastatic disease. 3 A comparison between the IBMTR data and these data is made in the discussion. The 5-year PFS for the IBMTR data was 34%, and the authors compare this to the 5-year PFS of 29% with chemotherapy. However, the value used by the authors is the overall survival, and the 8-year EFS was only 20%. 3 The follow-up is longer in the chemotherapy study, but the EFS curve did not change much from 5 to 8 years.A prospective study that used etoposide and ifosfamide in induction and consolidation with myeloablative therapy with busulfan and melphalan was reported by Oberlin et al. 4 Ninety-seven newly diagnosed patients with metastatic Ewing sarcoma were enrolled and the 5-year EFS was 37%. The 5-year EFS for lung-only metastases was 52%, and this compares favorably with the 34% 8-year EFS reported in 32 patients with lung-only metastases reported with chemotherapy. 3 Data regarding the site of metastases are not given in the IBMTR report, and this could be important, as patients with other sites of disease fared much worse in the report by Oberlin et al. 4 In conclusion, valid comparisons between chemotherapy and myeloablative therapy can be made only on the basis of a randomized trial. We share the desire with Gardner et al. to see the results of the randomized Euro EWING 99 study. Interestingly, the possible 10-20% advantage in PFS associated with megatherapy suggested above is very similar to that reported for high-risk neuroblastoma. 5 AL Gilman and J Oesterheld

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Impact of High-Dose Busulfan Plus Melphalan As Consolidation in Metastatic Ewing Tumors: A Study by the Société Française des Cancers de l'Enfant

Abstract: Compared with conventional chemotherapy, HDCT may yield benefits for patients with lung-only metastases or bone metastases. These results warrant confirmation in a randomized trial and provide part of the background data for the ongoing Euro-Ewing study.

Cited by 123 publications

References 25 publications

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

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

Global Protein-expression Analysis of Bone and Soft Tissue Sarcomas

Myeloablative chemotherapy with autologous stem cell rescue for Ewing sarcoma

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