Therapeutic Analysis Of High-dose Chemotherapy With Autologous Stem Cell Rescue In High-risk Neuroblastoma

Objective:Studies have shown that high-dose chemotherapy with autologous hematopoietic stem cell transplantation rescue(HDC/ASCR)can significantly improve the prognosis of patients with high-risk neuroblastoma(NB).The intensified strategy of tandem HDC/ASCR may further improve event-free survival(EFS).Whether patients with high-risk NB can tolerate tandem HDC/ASCR related complications remains controversial.Few publications on HCD/ASCR of patients with NB have been reported and no studies have compared single HDC/ASCR with tandem HDC/ASCR of patients with NB in China.This study aims to investigate therapeutic effects and safety of HDC/ASCR in high-risk NB patients and compare single HDC/ASCR with tandem HDC/ASCR in them for evaluating the prognosis and acute complications of two groups.Methods:From December 2003 to November 2018,seventy-three children with high-risk NB from Tianjin Medical University Cancer Institute and Hospital and Sun Yet-Sun University Cancer Center received multidisciplinary treatment consisting of induction chemotherapy,surgery,single(n=51)or tandem(n=22)HDC/ASCR consolidation therapy,local radiotherapy and 13-cis-retinoic acid maintenance therapy.All patients meet the Children’ Oncology Group(COG)diagnostic criteria for high-risk NB.The statistical software SPSS version 21.0 was utilized to analyze the data.Median and range for continuous variables,as well as percentages and frequencies for categorical variables were tabulated and presented.Continuous variables were analyzed using the T test or Mann-Whitney U test.Categorical variables were analyzed using the χ2 or Fisher’s exact test.Survival curves were estimated using the Kaplan-Meier method with Rothman’s 95% confidence intervals and log-rank tests.P-value < 0.05 was deemed significant.The main endpoints were 3-year event-free survival(EFS),3-year overall survival(OS)and acute complications of the single and tandem HDC/ASCR groups.Results:Among the 73 children with high-risk NB,51 children received single HDC/ASCR and 22 children received tandem HDC/ASCR.At last follow-up,37%(27/73)of cases experienced relapse and 23%(17/73)of cases died of disease progression after relapse.The 3-year EFS and OS rates for all 73 children were 53%(95% CI37%～68%)and 71%(95% CI 56%-85%)respectively.The majority of relapses occurred at metastatic sites such as bone marrow(n=13),intracranial(n=7),skeleton(n=6)and lymph nodes(n=5).All deaths were from progressive disease including one child who died of intracranial relapse within 3 months after single HDC/ASCR.77%(56/73)of cases in this study were still alive.There were no significant benefits in survival between single HDC/ASCR and tandem HDC/ASCR(3-year EFS: 51% vs.57%,P=0.20;3-year OS: 67% vs.78%,P=0.10).There was a significant difference in survival between children who achieved CR and VGPR and those who achieved PR before HDC/ASCR(P<0.01).Time of hemopoietic reconstruction did not differ between single and the second course of HDC/ASCR(P=0.57),the median reconstruction time were 11(9～36days)and 11(8～25days),respectively.The most common acute adverse effect was fever with granulocytopenia(86% and 91% in single and tandem HDC/ASCR,respectively).The incidence of CDI was 14%(7/51)and 27%(6/22)during the single and the second course of tandem HDC/ASCR,respectively(P=0.19).The incidence of VOD was 14%(7/51)and 14%(3/22)during the single and the second course of tandem HDC/ASCR,respectively(P=1.00)and no VOD-related death occurred in neither single or tandem HDC/ASCR.One children assigned to the single HDC/ASCR died of severe pulmonary infection and heart failure within 3 months after transplantation,one developed interstitial pneumonia and one developed pulmonary hypertension.Conclusion:The intensified strategy of single and tandem HDC/ASCR appeared to significantly improve the survival of high-risk NB patients and VGPR or CR should be achieved before transplantation.Compared with single HDC/ASCR,tandem HDC/ASCR did not significantly improve the 3-year EFS,3-year OS.The incidence of fever with granulocytopenia and CDI were higher in the second course of tandem HDC/ASCR.Tandem HDC/ASCR can be tolerated in children with high-risk NB,butmore favorable HDC regimens of single or tandem HDC/ASCR should be explored to further reduce complications and improve the survival of high-risk NB patients.