Paediatric Molecular Radiotherapy at UCLH
by Matthew Aldridge, University College London Hospitals NHS Foundation Trust
I have been working at UCLH for 12 years and have always been involved with the diagnosis and treatment of neuroblastoma, amongst all other aspects of nuclear medicine and radiotherapy.
I was part of the team that treated Jack using Molecular Radiotherapy in 2007, and at this time met Richard and Yvonne Brown. In subsequent years, I learnt about the charity and the link with the Metropolitan Police, and I was fortunate to be given the opportunity from J-A-C-K in 2016, to give full commitment to neuroblastoma research and development. As well as gaining a full understanding of techniques in diagnosis and treatment, I have forged national and international links with colleagues and it is heartening to see the passion and drive that the neuroblastoma community have– both health professionals and parents – that are aiming for cure.
Below is a short summary of the current status and what we have achieved and our goals for the future:
Radiation is the single most effective means of killing a cancer cell. Molecular radiotherapy (MRT) is the delivery of radiation to malignant tissue using a radiopharmaceutical targeted to molecular sites and receptors. More recently, optimisation of treatment has been aided by personalized, dosimetry-based treatment planning and verification of the absorbed dose delivered, especially within clinical trials.
UCLH is currently one of two recognised UK centres offering paediatric molecular radiotherapy, alongside Royal Marsden. It is an inter-disciplinary practice, with key contributions from Clinical and Paediatric Oncology and Nuclear Medicine. We are fortunate to be equipped with 2 age-appropriate therapy rooms (figure 1) with the advantage of adjacent comforter and carer support rooms. Fully trained paediatric nursing and medical ward staff are essential for the treatment of children, as are co-located nuclear medicine facilities for diagnostic and post-therapy imaging.
Neuroblastoma is a neuroendocrine tumour that arises in the developing sympathetic nervous system, which results in tumours in the adrenal glands and/or sympathetic ganglia. Although only about 100 children in the UK are diagnosed each year with neuroblastoma, it is the most common solid tumour in children that occurs outside of the brain. It is 8% of the total number of children’s cancers, yet accounts for 15% of paediatric cancer deaths.
Disease staging is based on metastatic spread and image-defined risk factors. Assignment to low-, intermediate- or high-risk groups is based on stage, age and tumour biology. Patients with low- and intermediate-risk disease have 5-year survival rates > 90%, but more than half of all patients present with high-risk disease. Only around one third of this group become long-term survivors.
Treatment of high-risk disease is complex, consisting of both systemic treatments designed to eradicate metastatic disease: induction and high-dose consolidation chemotherapy and immunotherapy; and local treatments for the primary tumour: surgery and radiotherapy. Not all patients respond well to initial chemotherapy – about 25% are poor responders classed as having refractory disease. These patients have a reduced likelihood of cure. Following apparently successful first line treatment; a significant proportion will relapse. And almost all of these patients will die of their disease despite aggressive further treatment.
For these reasons, neuroblastoma remains one of the major challenges in paediatric oncology, and new and improved treatment strategies need evaluation in clinical trials.
Molecular radiotherapy with 131I-mIBG is established in the treatment of neuroblastoma as a late stage therapy option (figure 2), and whilst response rates are noted, there is recognition of a need to further optimize the treatment pathway. Historically, most reports of mIBG therapy have focused on the administered activity, and full tumour dosimetry has not been undertaken. Future trials will utilize 131I-mIBG as a component of multi-modality treatment schedules. As it is likely that those tumours receiving a higher radiation absorbed dose will respond more favourably, resulting in improved survival, it is essential that future trials include comprehensive dosimetry, to test the hypothesis that there is a dose-response relationship.
The role of clinical trials in childhood cancer is essential, and 60% of children with cancer now participate in clinical trials as part of their treatment, compared with 5% of adults with cancer. There is tremendous potential to improve the effectiveness of molecular radiotherapy treatment through research using dosimetry. This is reflected in two international, multi-centre trials about to commence, with UCLH the lead centre with regard to the molecular radiotherapy aspect of the trials.
MINIVAN. Immunotherapy with anti-GD2 monoclonal antibody treatment is routinely used in the treatment of high-risk neuroblastoma. In addition, anti-PD1 monoclonal antibodies have been used successfully in the adult population for malignant melanoma and renal cell carcinoma amongst other diseases. While these agents have been used successfully as individual treatments, the MINIVAN trial will combine the two for the first time in neuroblastoma. This is a phase I study of 131I-mIBG followed by Nivolumab (an anti-PD1) and Dinutuximab Beta (an anti-GD2) in children with relapsed or refractory neuroblastoma. This is a collaboration between UK sites (Southampton, UCLH), Germany (Greifswald) and the USA (Madison, Wisconsin). The trial will determine the safety and tolerability of this innovative combination of agents.
VERITAS. Another trial will be the first European randomized trial to use 131I-mIBG in one of the treatment arms for refractory neuroblastoma. A key feature of VERITAS (meaning “the truth”) will be the use of 131I-mIBG earlier in the treatment regime (in refractory rather than relapsed patients), with more potential for curative outcomes.
Within UCLH, the neuroblastoma research outlined above will only serve to add to our existing portfolio of novel methodology in the area of paediatric oncology research: LuDO – a Phase II trial of 177Lu-DOTATATE for relapsed and refractory neuroblastoma; 124I-mIBG – a PET CT and PET MRI imaging study including a biokinetic substudy to support the dosimetry of mIBG treatment; and RIT, a trial assessing 90Y labelled anti CD66 radio-immunotherapy as an alternative to total body irradiation for bone marrow transplant conditioning in relapsed leukaemia
Children with neuroblastoma are well represented in social and national media, and recent cases have been particularly prominent. We are grateful for support from parents’ organisations, J-A-C-K and Solving Kids Cancer.