Frank Peinemann, Elvira C van Dalen, Heike Enk, Frank Berthold

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. 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). 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. 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. We used standard methodological procedures expected by Cochrane. 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. 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.