Targeting Micrometastases: The Effect of Heterogeneous Radionuclide Distribution on Tumor Control Probability

Abstract

The spatial distribution of radiopharmaceuticals that emit short-range high linear-energy-transfer electrons greatly affects the absorbed dose and their biological effectiveness. The purpose of this study was to investigate the effect of heterogeneous radionuclide distribution on tumor control probability (TCP) in a micrometastases model. were generated using an iterative modelling method based on Monte Carlo determined absorbed dose with the PENELOPE code and were compared to SFexp. Radiobiological parameters deduced from experimental results and MC simulations were used to predict the TCP for a 3-D spheroid model. Methods Results:Calculated SFs were in good agreement with experimental data, particularly when an increased value for relative biological effectiveness (RBE) was applied to self-dose deposited by sources located in the nucleus and when radiobiological parameters were adjusted to account for dose protraction. Only in MDA-MB-468 spheroids treated with 111In-EGF was a TCP>0.5 achieved, indicating that for this cell type the radiopeptide would be curative when targeting micrometastases. This is attributed to the relative radiosensitivity of MDA-MB-468 cells, high nuclear uptake of the radiopeptide and uniform distribution of radioactivity throughout the spheroid. Conclusions:It is imperative to include biological endpoints when evaluating the distribution of radionuclides in models emulating micrometastatic disease. The spatial distribution of radioactivity is a clear determinant of biological effect and TCP as demonstrated in this study.

Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression

“…The same fully applies to the delivered radionuclides. 111 In should have the greatest impact in the treatment of hard-to-detect micrometastases and single cancer cells ( Hindie et al, 2016 ; Falzone et al, 2018 ), whereas its effect on large tumors is less pronounced ( Buchegger et al, 2006 ; Bomanji and Papathanasiou, 2012 ). The 111 In-MNT described in this article could be highly in demand for intravesical infusion in the treatment of bladder cancer, which is characterized by a high probability of recurrence ( Sfakianos et al, 2014 ; Kamat et al, 2016 ; Soukup et al, 2017 ).…”

Auger electrons for cancer therapy – a review

“…However, for animal studies, it is possible to perform autoradiography in combination with immunohistochemical staining of excised tissues ex vivo to understand the heterogeneous radioactivity distribution in different regions of tumours and normal organs (Lee et al 2010). In one study, to understand the effect of heterogeneous radioactivity distribution in the tumour on the treatment response, tumour cell spheroids were cultured and incubated with 111 In-DTPA-hEGF or 111 In-DTPA-trastuzumab, then fixed, frozen, and cryo-sectioned (Falzone et al 2018, 2019). One section was used for micro-autoradiography to visualise the radioactivity distribution and the adjacent section was stained for γH2AX to assess DNA damage.…”

Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy

“…This substitution of EBRT for MRT dosimetry cannot adequately account for the distinct and complex cellular localization of ionising radiation with MRT, and the distinctly different dynamic biological response across the timeframe of exposure during MRT. Although in vitro dosimetry methods exist, they require optimization for each cell line, and progressively complicated for each cell line with in vitro 3D spheroid cellular constructs (11). Even despite the best assessments of physical dose by on September 26, 2020.…”