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Neuroblastoma: The Way Ahead

Future directions for treatment of the childhood cancer Neuroblastoma, and a detailed analysis of current regimens, are included in a Seminar in this week’s edition of The Lancet.

Plans for the development of an International Neuroblastoma Risk Group (INRG) classification system, to develop a consensus to permit comparisons of outcomes of neuroblastoma patients worldwide, are also included in the Seminar, authored by Dr John Maris, Children’s Hospital of Philadelphia, USA, and colleagues. The INRG is currently analysing data obtained from 11,054 patients treated in Europe, Japan, USA, Canada, and Australia between 1974 and 2002 so that this international classification system can be created.

Neuroblastoma is a cancer of the sympathetic nervous system - the nerve network that regulates the “fight or flight” response to the environment. When solid tumours form, which can take the form of a lump or mass, they commonly begin in one of the adrenal glands, though they can also develop in nerve tissues in the neck, chest, abdomen, or pelvis.

It is the most common solid extracranial cancer in childhood, and represents more than 7% of all childhood malignant cancers and 15% of all childhood cancer deaths. It is remarkable for its broad spectrum of clinical behaviour. Likelihood of cure varies widely according to age at diagnosis, extent of disease, and tumour biology.

The authors say: “Although substantial improvement in outcome of certain well-defined subsets of patients has been observed during the past few decades, the outcome for children with a high-risk clinical phenotype has improved only modestly, with long-term survival still less than 40%.”

There are three main sets of presenting signs and symptoms, categorised as localised tumours, metastatic disease, and 4S disease. Around 40% of patients present with localised tumours which can vary in size and occur anywhere in the sympathetic nervous system. In certain locations these tumours can cause compression of the spinal cord and resulting motor weakness in 5-15% of patients. Around half of patients present with metastatic disease, which often involves multiple tumour burdens which can make patients quite ill. This type of tumour can also metastatise bony orbits, and can lead to symptoms such as raccoon eyes (periorbital bruises). 4S disease occurs in only 5% of patients with neuroblastoma – and presents as small localised primary tumours with secondary tumours in liver, skin or bone marrow that almost always spontaneously regress.

The treatment methods used in neuroblastoma management include surgery, chemotherapy, radiotherapy, and biotherapy, as well as observation alone in carefully selected circumstances.

But new approaches to relapsed disease for patients with high-risk neuroblastoma have developed in recent years. These include cytotoxic agents, targeted delivery of radionuclides, immunotherapy, retinoids, angiogenesis inhibitors, and tyrosine kinase inhibitors.

The authors conclude that improvements in understanding of the genomic alterations associated with tumour and behaviour and patient outcome have moved the goal of precise prognosis closer.

They say: “Improved understanding of normal neurodevelopment of the sympathicoadrenal stem will help us identify the key mutational events that initiate neuroblastoma tumorigenesis. Defining these events, as well as those that reliably predict for the acquisition of a high-risk phenotype, might ultimately direct us to the key pathways that can be exploited therapeutically.”

Tony Kirby | alfa
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