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Targeted radiotherapy of neuroblastoma: Future directions

Mathias Tesson

Radiation Oncology, Institute of Cancer Sciences, University of Glasgow, UK

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Colin Rae

Radiation Oncology, Institute of Cancer Sciences, University of Glasgow, UK

Donna L Nile

Radiation Oncology, Institute of Cancer Sciences, University of Glasgow, UK

Mark N Gaze

University College London Hospitals, UK

Robert J. Mairs

Radiation Oncology, Institute of Cancer Sciences, University of Glasgow, UK

DOI: 10.15761/ICST.1000260

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Neuroblastoma is a malignancy predominantly of infancy. It originates most commonly in the adrenal gland and affects a hundred individuals per year in the UK. Half of neuroblastomas are highly aggressive, disseminated throughout the body of the patient and characterised by unresponsiveness to therapy or early relapse if remission is achieved. High-risk neuroblastoma is responsible for 12% of paediatric cancer fatalities and new treatments are urgently needed [1].

Ninety percent of neuroblastoma tumours express the noradrenaline transporter (NAT). These can be treated with targeted radiotherapy using an iodine-131-radiolabelled drug, meta-iodobenzylguanidine (131I-MIBG), which is structurally similar to noradrenaline. 131I-MIBG has produced long-term remission and palliation in patients with resistant disease [2]. However, some neuroblastoma tumours cease expression of NAT, engendering resistance to 131I-MIBG [2]. This observation prompted the diagnostic and therapeutic application of an alternative radiopharmaceutical - radiolabelled octreotate – which targets somatostatin receptors (SSTRs), expressed on human neuroblastoma cells [3-5].

Octreotate linked to the b-particle-emitting lutetium-177 (177Lu-DOTATATE) binds with high affinity to SSTR2. The safe and successful treatment of children with neuroblastoma using 177Lu-DOTATATE was recently reported [6,7].

The administration of both 131I-MIBG and 177Lu-DOTATATE is expected to enhance therapeutic efficacy. Significantly, as the main unfavourable effect of 131I-MIBG therapy is myelosuppression whereas that of 177Lu-DOTATATE therapy is renal toxicity, the combined treatment with 131I-MIBG and 177Lu-DOTATATE is not expected to intensify adverse effects. In order for a clinical study of the combination of radiopharmaceuticals to proceed, the optimal sequence and timing of administration must be determined. Previous studies indicate that these factors have a profound influence on the efficacy of radionuclide therapy [8].

Following a study of patients with neuroblastoma, non-concordance between 123I-MIBG- and 177Lu-DOTATATE-derived images was reported [6], indicating variation between tumors with respect to capacity for radiopharmaceutical uptake. Significantly, it has been shown that the cellular uptake of both radiopharmaceuticals is enhanced by DNA-damaging agents, including ionizing radiation [9,10]. If such potentiation of receptor expression pertains also in vivo, the sequencing of administration of radiopharmaceuticals and the interval between injections could have a substantial influence on efficacy.

Radionuclide therapy delivers ionizing radiation at very low dose rate (LDR) (≤ 2 cGy/min), which decreases with time. The outcome of fractionated administration of 131I-MIBG and 177Lu-DOTATATE cannot be predicted because it depends on the properties of the radionuclide and of the tumor [8,11-16] (Table 1). Therefore, experimental testing is required to determine the optimal scheduling of delivery of these two radiopharmaceuticals.

Table 1: Factors influencing the response to radionuclide therapy delivered at low dose and low dose rate.

Factors that enhance cell kill

Factors that reduce cell kill

Radiation-induced biological bystander effect

Non-uniformity of tumour uptake of radiopharmaceuticals due to heterogeneity of target expression

Hypersensitivity to low-dose radiation

Increased radioresistance at low radiation dose

Radiation cross-fire

Adaptive response

Redistribution of cells to radiosensitive phases of the cell cycle and reoxygenation

Sustained repair of DNA damage during treatment

Two opposing outcomes of sequential administration of radiopharmaceutical are envisaged: (i) prior exposure of tumour cells to one radiopharmaceutical could enhance the expression of the target of the subsequently applied radiopharmaceutical, engendering a positive therapeutic effect; and (ii) a priming dose of radiopharmaceutical may stimulate radioprotective (adaptive) responses in surviving cells thereby reducing the effectiveness of the subsequently delivered radiopharmaceutical. The establishment of the optimal schedule of delivery of radiopharmaceuticals will minimise the capacity of tumours, which do not succumb to initial radiopharmaceutical treatment, to develop resistance to subsequently administered radiotherapy.

Efforts to improve the therapeutic efficacy of targeted radiotherapy by combination with radiosensitisers are now being implemented. Furthermore, the reduction of resistance to targeted radiotherapy by means of combinations of radiopharmaceuticals which bind to alternative targets is likely to translate into the improvement of the management of patients with high risk neuroblastoma.

Acknowledgements

This work is supported by funding from Children with Cancer UK.

References

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Editorial Information

Editor-in-Chief

Hiroshi Miyamoto
University of Rochester Medical Center

Article Type

Commentary

Publication history

Received date: Oct 06, 2017
Accepted date: Oct 26, 2017
Published date: Oct 29, 2017

Copyright

© 2017 Tesson M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Tesson M, Rae C, Nile DL, Gaze MN, Mairs RJ (2017) Targeted radiotherapy of neuroblastoma: Future directions. Integr Cancer Sci Therap. 4: DOI: 10.15761/ICST.1000260

Corresponding author

Robert Mairs

Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow G61 1BD, Scotland, UK, Tel: +44(0)141 330 4126, Fax: +44(0)141 440 4127

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Table 1: Factors influencing the response to radionuclide therapy delivered at low dose and low dose rate.

Factors that enhance cell kill

Factors that reduce cell kill

Radiation-induced biological bystander effect

Non-uniformity of tumour uptake of radiopharmaceuticals due to heterogeneity of target expression

Hypersensitivity to low-dose radiation

Increased radioresistance at low radiation dose

Radiation cross-fire

Adaptive response

Redistribution of cells to radiosensitive phases of the cell cycle and reoxygenation

Sustained repair of DNA damage during treatment