Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. OBJECTIVES: To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: The update search did not identify any additional studies. We identified one RCT that included people with high-risk neuroblastoma who received HDCT followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a second random allocation. These 98 participants had no progressive disease after HDCT followed by autologous HSCT. There was no clear evidence of difference between the treatment groups either in overall survival (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.46 to 1.63; one trial; P = 0.66) or in event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59). We calculated the HR values using the complete follow-up period of the trial. The study also reported overall survival estimates at a fixed point in time. At the time point of five years, the survival estimate was reported to be 59% for the retinoic acid group and 41% for the no-further-therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. We could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. We judged the evidence to be of low quality for overall survival and event-free survival, downgraded because of study limitations and imprecision. AUTHORS' CONCLUSIONS: We identified one RCT that evaluated additional retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT versus no further therapy in people with high-risk neuroblastoma. There was no clear evidence of a difference in overall survival and event-free survival between the treatment alternatives. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since when many changes in treatment and risk classification have occurred. Based on the currently available evidence, we are therefore uncertain about the effects of retinoic acid in people with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project.

INTRODUCTION: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the adrenal medullary tissue and an abdominal mass is the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterized by metastasis and other characteristics that increase the risk for an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. OBJECTIVES: To evaluate efficacy and adverse events of retinoic acid after consolidation with high-dose chemotherapy followed by bone marrow transplantation as compared to placebo or no therapy in patients with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). Our outcomes of interest were overall survival and treatment-related mortality as primary outcomes; and progression- and event-free survival, early and late toxicity, and health-related quality of life as secondary outcomes. SEARCH METHODS: We searched the electronic databases CENTRAL (2014, Issue 8) on The Cochrane Library, MEDLINE (1946 to October 2014), and EMBASE (1947 to October 2014). Further searches included trial registries, conference proceedings, and reference lists of recent reviews and relevant articles. We did not apply limits on publication year or languages. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation (HSCT) compared to placebo or no further treatment. DATA COLLECTION AND ANALYSIS: Two review authors performed the study selection, extracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The authors of the included study did not report the results specifically for the treatment groups relevant to this Cochrane Review. Therefore, we deduced the appropriate survival data from the published survival curves and calculated a hazard ratio (HR) based on the deduced data. MAIN RESULTS: We identified one RCT (CCG-3891) that included patients with high-risk neuroblastoma who received high-dose chemotherapy followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a subsequent second random allocation. These patients had no progressive disease after consolidation therapy. There was no clear evidence of difference between the treatment groups in both overall survival (HR 0.87, 95% CI 0.46 to 1.63; one trial; P = 0.66, low quality of evidence) and event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59, low quality of evidence). We calculated these HR values using the complete follow-up period of the trial. The study also reported five-year overall survival rates: 59% for the retinoic acid group and 41% for the no further therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. Also, we could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. AUTHORS' CONCLUSIONS: We identified one RCT that evaluated retinoic acid as a consolidation therapy versus no further therapy after high-dose chemotherapy followed by bone-marrow transplantation in patients with high-risk neuroblastoma. The difference in overall survival and event-free survival between both treatment alternatives was not statistically significantly different. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since then many changes in for example treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of retinoic acid in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Thalamic high-grade gliomas in children: a distinct clinical subset?

Pediatric high-grade gliomas (HGGs) of the thalamic region account for up to 13% of pediatric HGGs and usually result in only anecdotal long-term survival. Because very little is known about these tumors, we aimed to further characterize them. In our series of 99 pediatric thalamic HGGs, there were no significant differences in survival between patients with tumors affecting the thalamus alone (including bithalamic lesions) and patients with tumors affecting the thalamus plus adjacent structures. Tumor resection (event-free survival/overall survival) and an early treatment response to radiotherapy/chemotherapy (event-free survival) had independent prognostic significance, as shown by Kaplan-Meier and multivariate Cox regression analyses. When we compared clinical characteristics and outcomes of pediatric thalamic HGG with those of pediatric (nonthalamic) supratentorial (n = 177) as well as pediatric pontine HGG (including diffuse intrinsic pontine gliomas; n = 234), we found that thalamic HGG shared more similarities with pontine than with supratentorial HGG, but overall, it appeared to represent a clinically distinct subgroup of pediatric HGG. The varying extent of tumor resection in the different tumor localizations may play some role in the observed clinical differences, as shown by multivariate Cox regression analyses, but the tumor site itself was also identified as an independent prognostic parameter. Thus, an additional location-specific effect on survival and/or tumor biology, despite different neurosurgical accessibility, has to be considered. Therefore, future investigations should try to further characterize the obviously site-specific heterogeneity of pediatric HGG on a molecular genetic basis.