Radiosensitivity of colorectal cancer to 90Y and the radiobiological implications for radioembolisation therapy

Boon Q Lee,James M Thompson,Christiana Kartsonaki,Elliot M Abbott,Nadia Falzone,Katherine A Vallis,Sarah Able,Mark A Hill

doi:10.1088/1361-6560/ab23c4

Abstract

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. 90Y selective internal radiation therapy (SIRT) is an established treatment for metastatic CRC. There is still a fundamental lack of understanding regarding the radiobiology underlying the dose response. This study was designed to determine the radiosensitivity of two CRC cell lines (DLD-1 and HT-29) to 90Y β− radiation exposure, and thus the relative effectiveness of 90Y SIRT in relation to external beam radiotherapy (EBRT).A 90Y-source dish was sandwiched between culture dishes to irradiate DLD-1 or HT-29 cells for a period of 6 d. Cell survival was determined by clonogenic assay. Dose absorbed per 90Y disintegration was calculated using the PENELOPE Monte Carlo code. PENELOPE simulations were benchmarked against relative dose measurements using EBT3 GAFchromic™ film. Statistical regression based on the linear-quadratic model was used to determine the radiosensitivity parameters and using R. These results were compared to radiosensitivity parameters determined for 6 MV clinical x-rays and 137Cs γ-ray exposure. Equivalent dose of EBRT in 2 Gy () and 10 Gy () fractions were derived for 90Y dose.HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and 137Cs γ-ray were equivalent for both cell lines. The ratio for 90Y β−-particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an 90Y SIRT absorbed dose of 60 Gy equates to an of 28.7 and 54.5 Gy and an of 17.6 and 19.3 Gy for DLD-1 and HT-29 cell lines, respectively.We derived radiosensitivity parameters for two CRC cell lines exposed to 90Y β−-particles, 6 MV x-rays, and 137Cs γ-ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of 90Y SIRT relative to other radiation therapy modalities.

Highlights

The success of external beam radiotherapy (EBRT) can partly be attributed to a fundamental understanding of the underlying radiobiology and how this explains the dose response
There is a general acknowledgement that patient-specific dosimetry needs to be performed to optimise treatment, especially since a dose effect has been established for 90Y selective internal radiation therapy (SIRT) (Strigari et al 2010, Cremonesi et al 2014, van den Hoven et al 2016)
This is supported by the fact that free 90Y in 90YCl3 exhibited more extreme nonuniformity in distribution than chelated 90Y in 90Y-DOTATATE and that precipitation was observed visible when cold YCl3 and phosphate buffered saline (PBS) were mixed at high concentration

Summary

Introduction

The success of external beam radiotherapy (EBRT) can partly be attributed to a fundamental understanding of the underlying radiobiology and how this explains the dose response. The evolution of targeted radionuclide therapy (TRT), is marked by a recognised deficiency in dose quantification and sound radiobiological understanding. In the case of 90Y-based selective internal radiation therapy (90Y SIRT), a liver-directed treatment for palliative control of inoperable or chemorefractory tumours (van den Hoven et al 2016), doses are usually prescribed using tables or the Body Surface Area method to determine the amount of activity (MBq) to administer (Vauthey et al 2002). Absorbed doses reported in literature can vary from 50 up to 200 Gy (Strigari et al 2010, Cremonesi et al 2014, van den Hoven et al 2016). There is a general acknowledgement that patient-specific dosimetry needs to be performed to optimise treatment, especially since a dose effect has been established for 90Y SIRT (Strigari et al 2010, Cremonesi et al 2014, van den Hoven et al 2016). Given the recent multicentre phase III trial showing that 90Y SIRT provides better tumour control within the liver when used in conjunction with chemotherapy than chemotherapy alone (Wasan et al 2017), this treatment option could be extended if dosimetric and radiobiological considerations are taken into account in treatment planning

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