Description of the condition
Neuroblastoma is a rare malignant disease and mainly affects infants and very young children (GARD 2011). Tumours develop in the sympathetic nervous system such as adrenal medullary tissue or paraspinal ganglia and may be localised or metastatic at diagnosis (Cole 2012). The median age at diagnosis is 17 months and the incidence rate of neuroblastoma is age dependent with an incidence rate of 64 per million children in the first year of life reducing to 29 per million children in the second year of life (Goodman 2012). The incidence rate in adults is less than 1 per million per year but adults have a considerably worse prognosis (Esiashvili 2007). Cohn 2009 proposed the International Neuroblastoma Risk Group classification system, which is shown in Table 1. Of 8800 patients with neuroblastoma, 36.1% had high-risk neuroblastoma. Patients in the high-risk group had a five-year event-free survival of less than 50%. Time to event was defined as time from diagnosis until time of first occurrence of relapse, progression, secondary malignancy, or death, or until time of last contact if none of these occurred. Matthay 2012 addresses new approaches with targeted therapy that may improve the outcome in patients with high-risk neuroblastoma.
|INRG stage||Age (months)||Histologic category||Grade of tumour differentiation||MYCN||11q aberration||Ploidy||Pretreatment risk group|
|L1/L2||Ganglioneuroma maturing; ganglioneuroblastoma intermixed||A||Very low|
|L1||Any, except ganglioneuroma or ganglioneuroblastoma||Not amplified||B||Very low|
|L2||< 18||Any, except ganglioneuroma or ganglioneuroblastoma||Not amplified||No||D||Low|
|≥ 18||Ganglioneuroblastoma nodular; neuroblastoma||Differentiating||Not amplified||No||E||Low|
|Poorly differentiated or undifferentiated||Not amplified||H||Intermediate|
|M||< 18||Not amplified||Hyperdiploid||F||Low|
|< 12||Not amplified||Diploid||I||Intermediate|
|12 to < 18||Not amplified||Diploid||J||Intermediate|
|MS||< 18||Not amplified||No||C||Very low|
An abdominal mass is the most common presentation of neuroblastoma. In general, neuroblastoma occurs at a single location, usually the medulla of the adrenal gland or along the paravertebral sympathetic chain. As approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis, organ-specific symptoms may be caused by the local presence of metastases, such as eye problems associated with retrobulbar tumours, pancytopenia associated with bone marrow infiltration, abdominal distension and respiratory problems associated with liver enlargement, paralysis and Horner syndrome associated with ganglion involvement (NCI PDQ 2012). Furthermore, there are general signs and symptoms like tiredness, weakness or pain. Some neuroblastoma regress spontaneously without therapy while others progress with a fatal outcome despite therapy. One study of infants younger than 12 months showed nearly half of the study population within three years of follow up had a spontaneous regression at diagnosis (Hero 2008). A tumour mass may be confirmed by ultrasound, X-rays, computed tomography, or magnetic resonance imaging. Guidelines for using imaging methods have been developed in response to the increased importance of image-defined factors in staging and risk assessment (Brisse 2011).
The International Neuroblastoma Staging System provides the current definitions for diagnosis, the stages 1, 2A, 2B, 3, 4 and 4S that are shown in Table 2, and treatment response that is shown in Table 3 (Brodeur 1993). The International Neuroblastoma Risk Group classification system provides the current definitions for the very low, low, intermediate, and high risk group that is shown in Table 1 (Cohn 2009). The authors estimated the event-free survival for each of the four risk groups and tested the clinical importance of 13 potential prognostic factors.
|1||Localised tumour with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumour microscopically (nodes attached to and removed with the primary tumour may be positive).|
|2A||Localised tumour with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumour microscopically.|
|2B||Localised tumour with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumour. Enlarged contralateral lymph nodes must be negative microscopically.|
|3||Unresectable unilateral tumour infiltrating across the midline,(1) with or without regional lymph node involvement; or localised unilateral tumour with contralateral regional lymph node involvement; or midline tumour with bilateral extension by infiltration (unresectable) or by lymph node involvement.|
|4||Any primary tumour with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs (except as defined for stage 4S).|
|4S||Localised primary tumour (as defined for stage 1, 2A or 2B), with dissemination limited to skin, liver, and/or bone marrow(2) (limited to infants less than 1 year of age).|
|Response||Primary tumour||Metastatic sites|
|Complete response||No tumour||No tumour; catecholamines normal.|
|Very good partial response||Decreased by 90% to 99%||No tumour; catecholamines normal; residual 99Tc bone changes allowed.|
|Partial response||Decreased by more than 50%||All measurable sites decreased by greater than 50%. Bones and bone marrow: number of positive bone sites decreased by greater than 50%; no more than 1 positive bone marrow site allowed.|
|Minimal response||No new lesions; more than 50% reduction of any measurable lesion (primary or metastases) with less than 50% reduction in any other; less than 25% increase in any existing lesion.|
|No response||No new lesions; less than 50% reduction but less than 25% increase in any existing lesion.|
|Progressive disease||Any new lesion; increase of any measurable lesion by greater than 25%; previous negative marrow positive for tumour.|
Description of the intervention
Retinoic acid is a derivative of vitamin A (retinol) that includes 13-cis retinoic acid, also known as isotretinoin, among others. Retinoic acid regulates growth and development of epithelial cells. Retinoic acid inhibits growth of human neuroblastoma cells (Sidell 1982). Retinoic acid reduces morphological signs characteristic for several malignant human neuroblastoma cell lines (Sidell 1983). In a phase I clinical trial, 13-cis retinoic acid was used in children with neuroblastoma after autologous hematopoietic stem cell transplantation without signs of myelosuppression (Villablanca 1995). In a phase III clinical trial, 13-cis retinoic acid improved event-free survival for patients with high-risk neuroblastoma (Matthay 1999).
The test intervention of this review is the addition of retinoic acid as part of a therapy that comes after the consolidation therapy. Consolidation therapy that precedes retinoic acid includes either high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation or standard chemotherapy. Matthay 1999 recommended that "retinoic acid should form the basis for the treatment of patients with high-risk neuroblastoma". Yalcin 2010 included three randomised controlled trials (RCTs) in a Cochrane review including Matthay 1999, and showed a significant difference in favour of myeloablative therapy for both overall survival and event-free survival compared to conventional therapy in children with high-risk neuroblastoma.
Retinoic acid has been associated with several adverse events. Grissom 1996 reported hypervitaminosis A in a single patient. Turman 1999 reported two cases with bone marrow transplant nephropathy. Villablanca 1993 observed hypercalcaemia in 12 of 39 patients and a dose-limiting toxicity in three of those. Olson 1983 reported dry skin, dry mucous membranes, conjunctivitis, and hypertriglyceridaemia after vitamin A or retinoids.
How the intervention might work
Retinoic acid induces the differentiation of human neuroblastoma cell lines and stops uncontrolled cell growth in vitro (Reynolds 2003). High dose of retinoic acid might reduce relapse rate after intensive chemotherapy with or without autologous hematopoietic stem cell transplantation in patients with high-risk neuroblastoma.
Why it is important to do this review
Many patients may have an improved survival if retinoic acid is added to the post consolidation therapy. But it is possible that a considerable number of patients may not respond to the addition of retinoic acid. This review is important to evaluate the evidence base for the efficacy and the possible adverse events associated with this treatment.