Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution

Abstract

Summary:The purpose of this paper is to study prognostic factors in neuroblastoma patients treated with high-dose chemotherapy and hematopoietic stem cell transplantation. Two hundred and eighteen children over 1 year of age and treated for stage 4 neuroblastoma were enrolled in this study. The median age at diagnosis was 39 months, the sex ratio 1.5 and 84% of patients had an abdominal primary tumor. Skeletal disease was detected in 79% of cases and bone marrow involvement in 93%. N-myc oncogene amplification was present in 27% of the patients studied. The probability of eventfree survival at 5 years post-diagnosis was 29% in this series. Three major favorable prognostic factors were significant and independent in the multivariate analysis: age under 2 years at diagnosis (P Ͻ 0.01), absence of bone marrow metastases at diagnosis (P Ͻ 0.04) and the high-dose conditioning regimen containing busulfanmelphalan combination (P ‫؍‬ 0.001). The quality of response to conventional primary chemotherapy was close to significance (P ‫؍‬ 0.053). We conclude that factors related to the patient (age) and extent of disease are predictive of outcome in patients with neuroblastoma treated with conventional chemotherapy followed by surgical excision of the primary and consolidation with high-dose chemotherapy. They should be taken into account in future prospective studies. Moreover, the type of conditioning regimen appears to be the most important prognostic factor. This should encourage new investigations into innovative drug combinations. Keywords: neuroblastoma; SCT; busulfan; melphalan; prognostic factors During the last decade, knowledge concerning the biology of neuroblastoma has expanded considerably. Genetic studies have provided a description of the major genetic events characterizing the different subgroups of the disease. Most of the factors studied were also shown to be of prognostic value. Among them, N-myc amplification and the deletion of 1p are widely used as prognostic factors in localized neuroblastomas. 1-3 Ongoing, prospective studies on localized neuroblastoma are evaluating therapeutic approaches according to these features. 4 The prognostic significance of several other factors such as TRK, CD44 and MDR expression and ploidy are still under investigation. [5][6][7][8][9] However, to date the prognostic value of the above factors proven applicable to neuroblastoma have not been demonstrated to have an impact on patients with the type of disease most frequently observed and which also has the worst outlook, namely stage IV disease in patients over 1 year of age at diagnosis. 3 Similarly, no clear consensus has been reached as to what is the most appropriate therapeutic approach. Several teams are using high-dose therapy with stem cell transplantation (SCT) support for routine treatment of such patients and the value of this strategy is corroborated by the positive results of several historical comparisons and of two randomized studies. [10][11][12] However, other investigators or national groups have not fou...

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

“…27 More recently, a very good outcome has been described in children aged 12-18 months with stage 4 NBL, suggesting that 365 days might not be the best cutoff for risk stratification. [28][29][30] Consequently, the new International Neuroblastoma Risk Group Staging System extended the age group for stage 4s to patients aged o18 months.…”

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

“…10,[12][13][14][15] Identifying the risk factors for HVOD should then enable us to reduce the usual incidence (20-30%) of this disease 5,7,11 and possibly also lower the 5-10% toxicity-related mortality. 11 Several risk factors for HVOD have already been described.…”

“…Among these factors, one of the most clearly correlated with the incidence of HVOD is the use of high doses of BU in the conditioning regimen. 7,8 During the last decade, however, there has been an increase in the incidence of HVOD among patients treated with the BU-thiotepa (BU-TTP) combination, without any modification of the protocol. To identify whether new risk factors for HVOD had appeared during this period, we conducted a retrospective analysis of pediatric patients treated at the Gustave Roussy Institute.…”

The LMCE5 unselected cohort of 25 children consecutively diagnosed with untreated stage 4 neuroblastoma over 1 year at diagnosis

“…The dilemma is thus whether TBI induced sequelae sufficiently severe to justify a clear decrease in survival or can TBI be replaced by something else? The answer may be with busulfan containing regimens (Hartmann et al, 1999) or from tandem therapies as used in some LMCE3 patients (Philip et al, 1993;Grupp et al, 2000). However, high dose busulfan is responsible for acute visceral toxicities, and for delayed endocrinological toxicities (Hartmann et al, 1987).…”