Abstract
Background/AimTargeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI).Methods and MaterialsPatients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data.ResultsResults from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up.ConclusionsThe post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1–8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI.Trial RegistrationEU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304
Highlights
Targeted radiotherapy of liver malignancies has found to be effective in selected patients
Qualitative evidence of focal radiation-induced liver injury (fRILI) by magnetic resonance imaging (MRI) at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group
The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, ursodeoxycholic acid (UDCA) and low molecular weight heparin (LMWH) during weeks 1–8) in the treatment group was comparable to the control group supporting the observation that the agents mitigated fRILI
Summary
Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation leading to either subclinical focal or generalized injury of the liver parenchyma. When the intensity or the extent of radiation-induced liver injury (RILI) exceeds the functional reserve, clinical complications appear in the form of radiation (radioembolization) induced liver disease (RILD or REILD) [4,5,6,7]. Prior exposure or concomitant chemotherapy is thought to increase the risk of RILD (or REILD), and as a consequence is a relatively common complication, for example, after conditioning therapy prior to bone marrow transplantation (BMT) [5,8,9,10]. Liver damage whether associated with whole body irradiation or liver-directed radiotherapy have the same pathology, i.e. venoocclusive disease (VOD) [5,11,12,13]
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