Description of the condition
Neuroblastoma (NBL) is the most common extra cranial solid tumour of childhood, derived from the sympathetic nervous system (Gurney 1996). The median age of diagnosis is 18 months. According to the International NBL Staging System (INSS), NBL is classified in four stages, 1 to 4, with a special stage termed 4S. Children with stage 4 NBL present with metastatic disease at diagnosis, mainly involving lymph nodes and bone marrow. The defining characteristics of high-risk NBL include an age of more than one year, metastatic disease, unfavourable Shimada histology and MYCN amplification (Bernstein 1992; Shimada 1995; Shimada 1999). Current high-risk treatment consists of intensive multi-agent chemotherapy induction, extensive surgical resection of the primary tumour, external beam irradiation of residual primary tumour, myelo-ablative chemotherapy (Yalcin 2010) and maintenance with differentiation and immunotherapy. Despite this very intensive treatment, children with advanced-stage high-risk NBL still have a poor prognosis; the long-term survival is less than 40%. This poor outcome necessitates the search for new therapies (Matthay 1999; Simon 2011)
Description of the intervention
The majority of NBL tumours accumulate meta-iodobenzylguanidine (MIBG). When radiolabeled with 123I-, MIBG can be used for imaging and when labelled with 131I- it can be used as a form of targeted radiotherapy (Hattner 1984; Suc 1996). In general, the radiopharmaceutical 131I-MIBG has shown in different studies around the world to have a significant antitumour efficacy against NBL, both in a phase 2, palliative setting and upfront in newly diagnosed patients (Hutchinson 1991; Klingebiel 1991a; Klingebiel 1991b; Lashford 1992; Lumbroso 1991; Matthay 1998; Matthay 2007; Simon 2011; Voute 1991). More than 95% of NBL tumours have an active uptake of 131I-MIBG (Leung 1997). Given the unsatisfactory results of high-intensity induction chemotherapy it is rational to add 131I-MIBG, as 'targeted radiotherapy', to the treatment of high-risk NBL.
Extensive experience exists with 131I-MIBG treatment of children with NBL. Hoefnagel et al reported the value of 131I-MIBG in the detection of NBL (Hoefnagel 1985). In the next years it became clear that there was also a role for therapeutic use of 131I-MIBG. Initially 131I-MIBG therapy was given to patients with recurrent NBL (Matthay 1998; Matthay 2001). After some time, a second group of patients was included, patients with residual disease after chemotherapy and surgery. From these studies it became clear that the most prominent response was obtained in patients with a large tumour burden at the time of 131I-MIBG treatment (Matthay 1998; Matthay 2001). This finding has served as the basis for a study performed in Amsterdam, with the objectives to document response in untreated children with stage IV or non-operable stage III disease, and to further characterise the side-effects of 131I-MIBG treatment. The study was closed in 1999. In summary, 131I-MIBG therapy has a very high response rate at induction of high-risk NBL patients and can be combined with induction chemotherapy followed by mega-therapy and autologous stem cell transplantation. In this study, the chemotherapy was not dose intense and since then we have learned that dose intense chemotherapy results in better outcome (De Kraker 2008). The current Dutch Childhood Oncology group high-risk NBL 2009 treatment protocol combines upfront 131I-MIBG with induction chemotherapy followed by mega-therapy and ASCT. Matthay et al. reported in 2009 the results of a phase I study in refractory or relapsed high-risk NBL patients. It showed that closely spaced infusions of 131I-MIBG can be administered safely using autologous stem cell transplantation without dose-limiting non-haematological toxicity and with rapid and reliable reconstitution of haematopoiesis. Twenty one patients were evaluated in the study, responses included two partial responses, eight mixed responses, three stable disease and seven progressive disease (Matthay 2009).
How the intervention might work
131I-MIBG is a radiopharmaceutical; it is a radio labelled molecule similar to noradrenalin which can be taken up by NBL tissue (Hattner 1984). When NBL has taken up the 131I-MIBG, it releases gamma and beta irradiation (gamma and beta emitting isotope) which can irradiate the neighbouring NBL cells and killing them by causing double strand DNA breaks and damage to lipid bilayer (Hutchinson 1991; Matthay 2007).
Why it is important to do this review
At the moment the prognosis for high-risk NBL patients is still very poor. Relapses remain common, despite the achievement of a complete clinical remission after induction therapy. The place of 131I-MIBG in high-risk treatment is not yet well established.