High-risk neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the medullary tissue of the endocrine gland located on the top of the kidneys, the adrenal gland. The most common presentation is an abdominal mass. High-risk means one or several clinical symptoms or signs such as metastasis (that is the spread of tumors to other parts of the body distant to the original tumor location) or specific genetic features that are known to increase the risk for an adverse outcome. The assignment to a high-risk group is defined by the International Neuroblastoma Risk Group (INRG) classification system. About 50% of patients have metastatic disease at diagnosis and they have a poor prognosis. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and was considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. We wanted to evaluate the currently available literature to see if addition of a retinoic acid treatment after high-dose chemotherapy followed by bone marrow transplantation may have a survival benefit.
We identified one randomized controlled trial in a literature search that was done in October 2014. We excluded other study designs as they give less reliable results. However, randomized studies are difficult to perform in children with neuroblastoma and other evidence might be available. In the identified randomized study patients with high-risk neuroblastoma were first randomized to receive high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation. Then, patients were randomized to receive either retinoic acid in addition to the previous therapy or no further therapy. Overall survival and event-free survival (that is survival free from any well-defined adverse events) were not different between the two treatment alternatives. Treatment-related mortality, progression-free survival (that is survival with disease present, but stable, so no improvement, but also not worsening), early and late toxicity, and health-related quality of life were not reported. In this study not all biases could be ruled out, mostly because not all needed information was included in the manuscript, and we judged a low quality of evidence. Further high quality studies are needed before definitive conclusions can be made.
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.
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.
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.
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.
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.
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.
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.