Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial

Berthold, Frank; Boos, Joachim; Burdach, Stefan; Erttmann, R.; Henze, Günter; Hermann, J; Klingebiel, Thomas; Kremens, Bernhard; Schilling, Freimut H.; Schrappe, Martin; Simon, Thorsten; Hero, Barbara

doi:10.1016/s1470-2045(05)70291-6

Cited by 353 publications

(260 citation statements)

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“…Matthay et al 2 reported 7% of CEM/TBI-related deaths, and a CEM-related death rate of 3.4% was reported by Berthold et al 3 In the HR-NBL1/SIOPEN study, the severe toxicity rate up to day 100 was o 10% but higher for CEM than Bu-Mel (P = 0.014). The acute toxic death rate was 3% for Bu-Mel and 5% for CEM.…”

Section: Discussionmentioning

confidence: 85%

“…The impact of this strategy has been demonstrated by the results of three pediatric randomized trials. [2][3][4] These trials explored the impact on survival of consolidation regimens consisting of HD CEM and TBI, 2 CEM 3 and HD Mel. 4 They showed a significant improvement of survival in patients with stage 4 HR-NBL.…”

Section: Discussionmentioning

confidence: 99%

“…1 In the HR-NBL population, a correlation between survival and dose intensity has been reported, and three randomized studies showed that HDC followed by autologous stem cell transplantation (ASCT) or autologous bone marrow transplantation (ABMT) improved survival rates. [2][3][4] As NBL is notoriously radiosensitive, hyperfractionated TBI was incorporated into the conditioning regimen and has yielded encouraging results. 5 Alkylating agents were demonstrated to produce a log-linear dose response against tumor cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Pasqualini

Blanchard

et al. 2016

Bone Marrow Transplant

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High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980From to 2009 patients aged 41 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year eventfree survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy. INTRODUCTIONThe improved survival rates of patients with high-risk (HR) neuroblastoma (NBL) observed during the past decades are related to the intensification of induction therapy, high-dose chemotherapy (HDC) and better supportive care. 1 In the HR-NBL population, a correlation between survival and dose intensity has been reported, and three randomized studies showed that HDC followed by autologous stem cell transplantation (ASCT) or autologous bone marrow transplantation (ABMT) improved survival rates. [2][3][4] As NBL is notoriously radiosensitive, hyperfractionated TBI was incorporated into the conditioning regimen and has yielded encouraging results. 5 Alkylating agents were demonstrated to produce a log-linear dose response against tumor cells in vitro. 6 Since the mid-1980s, HDC with alkylating agents and ASCT has been the treatment strategy used at Gustave Roussy. HD busulfan (Bu) was selected because of its specific cytotoxicity against quiescent cells, 7 as an alternative to TBI in HR-NBL patients to avoid its side-effects, 8 especially in this very young population, and to achieve better survival rates.We report here the results of our 30-year experience on patients with HR-NBL treated with HD Bu-containing regimens. Bu was combined with melphalan (Mel) or Mel plus cyclophosphamide, and HDC was followed by stem cell (SC) or bone marrow (BM) transplantation. These results provided the rationale to widely implement the use of HD Bu-Mel, which was then compared with Carboplatin-Etoposide-Mel (CEM) in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized trial. HD Bu-Mel has now become the standard HD regimen in the SIOPEN HR strategy.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Pasqualini

Blanchard

et al. 2016

Bone Marrow Transplant

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“…1 Before the routine use of immunotherapy, 3-5 year progression-free survival (PFS) rates in national studies were 20-40%, [2][3][4][5][6] even with inclusion of patients with what is now known to be intermediate-risk NB. 7 The randomized study of the Children's Oncology Group showed significantly better outcome in patients treated post-ASCT with the anti-G D2 chimeric mAb ch14.18 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin-2.…”

Section: Introductionmentioning

confidence: 99%

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-G_D2immunotherapy and isotretinoin: a prospective Phase II study

et al. 2015

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Relapse of high-risk neuroblastoma (HR-NB) is deemed invariably fatal yet increasing numbers of HR-NB patients achieve a second complete/very good partial remission (CR/VGPR), hence the urgency to find a successful consolidative therapy. Identifying efficacy in patients without assessable disease, however, is problematic. We report the first study providing outcome data for this group of patients with poor prognosis. To prevent another relapse, HR-NB patients in second or later CR/VGPR received the anti-G D2 murine antibody 3F8 plus granulocyte-macrophage colony-stimulating factor plus isotretinoin in a Phase II trial. Upon meeting the target aim for progression-free survival (PFS) in the initial cohort of 33 patients, the trial was amended to allow patients who developed human anti-mouse antibody (HAMA) to receive rituximab to ablate HAMA with or without low-dose maintenance chemotherapy until immunotherapy could resume. For the total of 101 study patients, 5-year PFS and overall survival (OS) rates were 33% § 5% and 48% § 5%, respectively. Among the 33 long-term progression-free survivors, 19 had MYCN amplification, 19 had previously received anti-G D2 immunotherapy plus isotretinoin (as first-line therapy), and 15 never received maintenance chemotherapy. In a multivariate analysis of prognostic factors, only absence of minimal residual disease in bone marrow after 2 cycles of immunotherapy and before initiation of isotretinoin or anti-HAMA therapy was significantly favorable for both PFS and OS. Therefore, long-term PFS is possible for HR-NB patients who achieve at least a second CR/VGPR and receive consolidation that includes anti-G D2 immunotherapy plus isotretinoin, even if the patients received these biological treatments before relapse. Results from this prospective study will aid in the development of future Phase II studies for this growing ultra high-risk patient population.

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“…[5][6][7] A treatment strategy that uses high-dose chemotherapy (HDCT) and auto-SCT has helped to improve the prognosis of recurrent or high-risk solid tumors in children. [8][9][10] Clinical trials using HDCT/auto-SCT for treatment of infants and young children with malignant brain tumors have shown that it is possible to avoid or defer RT until 3 years of age while maintaining or improving survival rates. [11][12][13] Additionally, several recent studies have suggested that dose-escalation using tandem HDCT/auto-SCT might further improve outcomes in the treatment of recurrent or high-risk brain tumors.…”

Section: Introductionmentioning

confidence: 99%

Tandem high-dose chemotherapy and auto-SCT for malignant brain tumors in children under 3 years of age

et al. 2013

Bone Marrow Transplant

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In an effort to improve survival and reduce late adverse effects of radiation therapy (RT), 25 children o3 years of age with malignant brain tumors received tandem high-dose chemotherapy (HDCT) and auto-SCT following six cycles of induction chemotherapy. RT was either not given or deferred until 3 years of age if the patient was in CR after tandem HDCT/auto-SCT. Tumors relapsed or progressed in nine patients (five during induction treatment), and two of these patients survived after receiving salvage treatment, including RT. Two patients died due to toxicities during tandem HDCT/auto-SCT. A total of 16 patients survived to a median follow-up period of 52 months (range 18-96) from the time of diagnosis. Four of these patients did not receive RT, two received local RT (L-RT), three received craniospinal RT (CSRT), and seven received both L-RT and CSRT. The 5-year OS and EFS rates were 67.8 ± 9.4% and 55.5 ± 10.0%, respectively. Neuroendocrine and neurocognitive functions evaluated 3 years after tandem HDCT/auto-SCT were acceptable. Our results indicate that tandem HDCT/auto-SCT may improve survival in young children with malignant brain tumors with an acceptable level of risk of long-term toxicity.

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Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial

Cited by 353 publications

References 25 publications

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-G_D2immunotherapy and isotretinoin: a prospective Phase II study

Tandem high-dose chemotherapy and auto-SCT for malignant brain tumors in children under 3 years of age

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Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial

Cited by 353 publications

References 25 publications

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2immunotherapy and isotretinoin: a prospective Phase II study

Tandem high-dose chemotherapy and auto-SCT for malignant brain tumors in children under 3 years of age

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Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-G_D2immunotherapy and isotretinoin: a prospective Phase II study