Written by | Yan Yan editor-in-charge | Zhou Yebin
High-risk neuroblastoma has always been a problem in the clinical treatment of pediatric tumors. Performing an autologous stem cell transplant (ASCR) after high-dose chemotherapy (HDC) improves survival rates for patients. However, long-term survival is low, with more than half of patients relapsing. Immunotherapy further improved the patient's outcome, but its long-term effect remains unclear.
With the application of new treatment strategies such as HDC and immunotherapy, one concern is whether these treatments will have an impact on the recurrence of the situation. Like GD2 (anti-disialoganglioside) antibody treatment, GD2 antibodies can not cross the blood-brain barrier, will this allow tumor cells to obtain a "refuge" in the central nervous system (CNS), resulting in an increase in the proportion of CNS recurrences? At present, various clinical interventions for CNS tumor recurrence are limited, and systematic analysis of CNS recurrence will determine the development direction of clinical treatment of high-risk neuroblastoma in the future.
In February 2021, research groups from the University of Paris and several research institutes published a research paper titled Central nervous system relapse in high-risk stage 4 neuroblastoma: The HR-NBL1/SIOPEN trial experience in the European Journal of Cancer. This paper is a summary of the research of multi-study groups and hospitals since 2002, and a comprehensive analysis of the incidence of high-risk neuroblastoma and THE recurrence of CNS has been made, and the efficacy of different high-risk neuroblastomas and the rationality of the application of immunotherapy are evaluated.
This study is based on the HR-NBL1/SIOPEN clinical trial. The entry criteria were newly diagnosed patients with stage 4 high-risk neuroblastoma between 2002 and 2015 who were older than 12 months or younger than 12 months old but had MYCN amplification. The final study included 1977 patients with stage 4 high-risk neuroblastoma from 170 research centers in 19 countries, 1163 boys, and the median age of all patients was 3 years.
1161 patients (59%) had at least one recurrence before 2016, with a median follow-up time of 5.2 years. 855 had malignant recurrences; 63 had their first recurrence in the CNS. In central imaging, 54 of the 59 patients confirmed a CNS recurrence, and 1 of them had a CNS recurrence but the first recurrence was not in the CNS. Another 5 patients found tumors in the CNS, but it could not be confirmed that the CNS recurrence was due to the deformation of the skull due to cranial cavity dilation, and it was difficult to confirm whether it was parenchymal or leptomeningeal. Therefore, the final analysis cohort was formed by 53 patients who had their first relapse in the CNS in the subsequent analysis. Proportionally, patients with the first recurrence in the CNS accounted for 2.7% of all patients with recurrence and 6.2% of malignant recurrences.
HR-NBL/SIPOPEN CNS recurrence chart
From the perspective of clinical features, the median time from diagnosis to RECURRENCE of CNS is 1 year, which is shorter than the median time of recurrence in other locations of 1.2 years. 90% of CNS recurrences are confirmed by neurologic symptoms, such as elevated cranial pressure and epilepsy, with the vast majority of patients (74%) showing symptoms during treatment. Detailed disease analysis of 40 patients with CNS recurrence found that 18 cases of single CNS recurrence (accounting for 45%) and 22 cases (55% of bone metastases) of combined recurrence (as well as bone metastases) were found. More than half of the CNS injuries were in the supratentorial region, and leptomeningal lesions developed in 7 cases. Due to the extremely rapid progression of the CNS course, it is difficult to obtain high-definition images of the neural axis (neuroaxis). Of the 10 cases with MIBG scans at the time of relapse, 6 of them detected CNS metastases.
From the treatment point of view, 18 of the 53 patients with CNS recurrence did not receive any treatment due to rapid disease progression at the time of recurrence, 27 received chemotherapy, 13 underwent surgery, 18 underwent radiotherapy, and 10 of them underwent intracranial and spinal cord radiotherapy. Prognostic analysis showed one-year and three-year survival rates (OS) of 25% and 7%, respectively, and median survival after recurrence was 4 months. In terms of recurrence time, patients who had a CNS recurrence after the completion of treatment had better short-term survival time than patients who had relapses earlier, with a one-year OS of 45% versus 12%, respectively. But the long-term survival of both groups of patients was poor, with 10% and 6% OS at three years, respectively.
Treatment outcome analysis of 53 cases with first recurrence in the CNS
The one-year survival rate after recurrence, the recurrence of CNS is lower than that of other systems, although the long-term survival rate of recurrence is very low. The prognosis of CNS recurrence alone is better than that of patients with combined CNS recurrence. Three of the patients treated in the study remained alive and were followed up for 4.7, 4.9 and 10.1 years, respectively. It is worth noting that the three patients had only one CNS injury, no metastasis, and all underwent surgical resection and radiation therapy, and one case underwent chemotherapy for Temozolomide.
Comparison of survival rates after CNS recurrence with other post-relapse
What factors are associated with CNS recurrence? In the univariate analysis, CNS recurrence rates were positively correlated with MYCN amplification, liver metastases, and more than one malignant metastasis. The choice of high-dose chemotherapy (HDC) drug does not affect the rate of CNS recurrence. There was no significant difference between the combination of GD2 monob reagents and the use of retinoic acid alone, as well as the use of IL-2, on the effects of CNS recurrence rates. In multivariate analysis, females, MYCN, and liver metastases were all independently significant predisposing factors for CNS recurrence. HDC drug selection is not related to the above factors.
Analysis of patient characteristics and risk of CNS recurrence
In summary, this study is the first large sample to track the CNS recurrence of stage 4 high-risk neuroblastoma for a long time, and the incidence of HR-NBL (2.7%), predisposing factors and outcomes of CNS recurrence have been studied in detail, and it has also been found that chemotherapy drug choice is not affected by CNS recurrence, so the chemotherapy regimen should not be changed halfway. Immunotherapy with GD2 antibodies also does not affect the risk of CNS recurrence. The study also found that patients with a single CNS recurrence can survive for a long time. Because the recurrence rate of CNS is not high, if other methods can be found in the future to find abnormalities in the asymptomatic period, it will have a very positive effect on the prognosis of HR-NBL.
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