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

Abstract

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. 90 Y 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 90 Y β − radiation exposure, and thus the relative effectiveness of 90 Y SIRT in relation to external beam radiotherapy (EBRT). A 90 Y-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 90 Y 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 137 Cs γ -ray exposure. Equivalent dose of EBRT in 2 Gy ( ) and 10 Gy ( ) fractions were derived for 90 Y dose. HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and 137 Cs γ -ray were equivalent for both cell lines. The ratio for 90 Y β − -particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an 90 Y 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 90 Y β − -particles, 6 MV x-rays, and 137 Cs γ -ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of 90 Y SIRT relative to other radiation therapy modalities.

Stereotactic Inverse Dose Planning After Yttrium-90 Selective Internal Radiation Therapy in Hepatocellular Cancer

“…Radiosensitivity characterization of 90 Y SIRT in additional tumor types including HCC, breast, and intrahepatic cholangiocarcinoma would contribute valuable evidence to improve the BED model. 4 , 13 Although the available evidence remains limited, further exploration of the proposed treatment approach, combining the reduced toxicity of 90 Y SIRT with the precision and prospective planning capabilities of SBRT, has merit, as this work demonstrated that combination 90 Y SIRT and SBRT could produce superior dose distributions compared with 90 Y SIRT alone. A larger prospective clinical study to characterize efficacy and toxicity in relation to dose and volume constraints is needed to inform best practice.…”

“…MIM software was used to compare radiation doses from SIRT and EBRT. BED was calculated in terms of 6 MV LINAC photons using the model adapted from equation 2 of Abbott et al 13 The assumed radiobiologic model parameters for HCC informed by the findings from Lee et al 4 and Tai et al 14 are listed in Table 1 .…”

“…In general, modeling to illuminate the radiobiological effects of 90 Y has used the Lea-Catcheside protraction factor (G) applied to the β-term of the linear quadratic model. 4 This assumes that the α-term of the linear quadratic model is equivalent for EBRT and 90 Y SIRT, meaning radiobiologically informed doses were comparable to physical doses from EBRT. However, experimental evidence from 2 in vitro studies has shown that this is not the case.…”

“…In these studies, it was found that a physical dose of 90 Y requires 2 to 3 times the dose of EBRT to achieve the same level of cell-kill. 4 , 5 …”

Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks

“…and rate of efflux from the tumour or normal organs. Several studies have reported the in vitro cancer cell killing effects of low dose rate radiation in comparison with high dose rate exposures [38,39], showing that low dose rate radiation allows repair of sublethal DNA damage during irradiation, such that a higher total absorbed dose is required from MRT to achieve the same proportion of cell kill as EBRT. For example, Gholami et al [38] compared responses to 90 Y and EBRT in colorectal cancer cell lines using a cell viability assay.…”