Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation-induced liver toxicity

Abstract

Background/aim: 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. 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 materials: Patients 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.

Results: Results 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.

Conclusions: The 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 registration: EU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304.

Conflict of interest statement

Competing Interests: M. Seidensticker has served as a speaker for Bayer Healthcare and Sirtex medical, and has received research funding from Sirtex medical. R. Seidensticker has served as a speaker for Bayer Healthcare and Sirtex medical, and has received research funding from Sirtex medical. J. Ricke has served as a speaker for Bayer Healthcare and Sirtex medical, and has received research funding from Sirtex medical, Bayer Healthcare and Siemens. M. Pech has served as a speaker for Sirtex medical. B. Sangro has served as a speaker and an advisory board member for Sirtex medical. The authors state herewith that the competing interest as listed above do not alter their adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. T1w-axial THRIVE 20 min after application of Gd-EOB-DTPA (A, C–E and G, H) and BT planning CT with dosimetry (B and F).

A–D, control group. A: pre-treatment MRI displaying a metastasis scheduled for BT treatment (black arrow). B: Planning-CT after introduction of the brachytherapy catheters (black arrows). Clinical target volume (CTV) represented by bold red circle and dosimetry by coloured lines (red: 20 Gy-, blue: 12 Gy-isodose). C: MRI at 6 weeks showing substantial reduction in Gd-EOB-DTPA uptake by liver parenchyma adjacent to treated metastases (i.e. focal radiation-induced liver injury, fRILI). Note: The area of fRILI matches the geometry of the dosimetry (B). Determined threshold dose: 9.75 Gy. D: MRI at 3 months showing shrinkage of the fRILI. Determined threshold dose: 11.9 Gy. E–H, treatment group. E: pre-treatment MRI displaying two metastases (black arrow); two more treated lesions are not displayed in the plane. F: Planning-CT (annotations: see B). G: MRI at 6 weeks showing no fRILI. H: MRI at 3 months after radiotherapy (and 1 month after finishing study treatment) showing a substantial region of fRILI. Determined threshold dose: 15.8 Gy.

Figure 2. CONSORT-diagram.

*Exclusion criterion age was initially disregarded by error in this patient (aged 82). **Exclusion criterion prior radiotherapy was initially disregarded by error in this patient (prior radiotherapy was performed 2 years earlier with location in the contralateral liver lobe).