Optimising radiotherapy of liver tumours: radiobiology of yttrium-90 microsphere treatment

Background: Yttrium-90 selective internal radiotherapy (90Y SIRT) is a treatment aimed at improving tumour control within the liver, from which the disease burden is the most common cause of death. FOXFIRE, SIRFLOX, SARAH and other phase 3 clinical trials of SIRT indicated response in the liver but not increased overall survival. The present work aims to address this phenomenon and hypothesises that optimising treatment around absorbed dose to the liver would result in improved patient outcomes. In addition, the present work hypothesises that treatment planning could be further optimised by considering the factors of radiosensitivity, perfusion, and treatment paradigms to enhance uncomplicated tumour control in the liver and therefore overall survival.
Materials and Methods: Clonogenic assays of cancer cell lines were used to assess radiosensitivity from exposure to 90Y SIRT and EBRT (LINAC and 137Cs). Radiobiological parameters from the survival curves were adapted to a biological effective dose (BED) model useful to compare radiation response between 90Y SIRT and EBRT. In a group of colorectal carcinoma (CRC) patients treated with 90Y SIRT, tumour volumes were contoured and absorbed dose was measured to assess the dose-response relationship. An additional subcohort was analysed based on clinical imaging of perfusion in the liver from dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and perfusion CT (pCT). Perfusion modelling parameter maps in the tumours were used to assess possible associations with dose deposition and response to 90Y SIRT. Additional BED models were applied to a second cohort of ten hepatocellular carcinoma (HCC) patients that received both 90Y SIRT and EBRT to assess tumour volumes, dose, and radiobiological endpoints. Finally, stereotactic ablative radiotherapy (SABR) treatments were planned considering prior 90Y SIRT through radiobiological modelling.
Results: Radiation response from clonogenic assays of CRC cell lines yielded radiobiological fit parameters for 90Y SIRT. These findings suggested greater resistance to 90Y therapy than to either 137Cs or LINAC exposures. A mixed statistical model combining these findings resulted in BED parameters for 90Y SIRT. A dose-response relationship was demonstrated in the CRC patient cohort. Perfusion imaging from the subcohort generally revealed statistically significant relationships between perfusion parameters and dose or response for pCT but not for DCE MRI. In the HCC patient cohort, a methodology was demonstrated to combine doses from different LINAC and 90Y SIRT treatments. Exploratory SABR plans, considering equivalent dose deposition from 90Y SIRT, achieved treatment profiles comparable to those of SABR alone.
Conclusions: The clonogenic assay results extend the BED model and provide a framework for general consideration of 90Y SIRT radiobiology. This work established a framework for such future analyses and identified several hypotheses which could have clinical application for additional radiotherapy in 90Y SIRT patients. Biological response in vitro and in patients suggests there could be clinical utility for radiobiological modelling of 90Y SIRT. Biological response to 90Y SIRT is complex and future clinical trials are necessary to definitively appreciate the clinical response to radiation dose.

Keywords: treatment planning
colorectal cancer
90Y
BED
EBRT
radioembolization
liver cancer
SIRT
radiobiology
dosimetry
combination therapy
Advisor: Vallis, K
Falzone, N