Radiobiological Modelling of Dose Response and Normal-Tissue Complication for Novel Radiopharmaceutical Therapy Cocktails

In radiopharmaceutical therapy (RPT), cocktails of radionuclides have the potential to target a larger range of metastatic lesion sizes compared to single radionuclides. Given the number of radionuclides becoming clinically available, there has been a renewed interest in the investigation of the use of radionuclide cocktails for RPT.

The aim of this study was to provide a radiobiological framework to investigate the therapeutic efficacy of radionuclide cocktails. Dose response in terms of biological effective dose (BED), tumour control probability (TCP) and normal-tissue complication was modelled for cocktails of radionuclides of recent interest in the field of RPT (⁶⁷Cu, ¹⁶⁶Ho, ¹⁸⁸Re and ²²⁵Ac), in addition to the more conventional cocktail radionuclides ⁹⁰Y and ¹⁷⁷Lu.

Uniform distribution of radionuclide cocktails have been simulated in the Geant4 Monte Carlo toolkit with variable initial activity concentration ratios. The BED was modified to include the absorbed dose-rate effects from the simultaneous administration of 2 radionuclides and TCP values in solid tumours ranging from 100 μm to 2.5 cm were estimated. The equivalent uniform equieffective dose (EUEQDX) to surrounding tissue was assessed up to a distance 3 times the lesion radius for evaluation of normal-tissue complication.

The theoretical benefits of cocktails for treatment of metastatic disease are demonstrated with a greater range of tumour sizes experiencing a higher TCP when exposed to a combination of radionuclides rather than either radionuclide alone. When selecting appropriate radionuclide combinations, the half-life and range of emissions must be considered carefully, with most optimal results seen in this study after combining ¹⁷⁷Lu with ¹⁶⁶Ho or ²²⁵Ac. Care must also be taken with the ratio of administered radionuclide activity concentrations, as the TCP is shown to vary significantly in response to these ratios. In any combination considered in this study the surrounding normal-tissue EUEQD2 equivalent to a 2 Gy external beam radiotherapy (EBRT) regime did not exceed 5.3 Gy.

This modelling study provides a framework for the assessment of dose response and normal-tissue toxicity in the use of novel radionuclide cocktails in RPT. The approach proposed in this work can be used, in the future, to tailor the treatment of metastatic lesions for individual patients by supporting the selection of cocktail of radionuclides of given composition, when appropriate, over single radionuclides.