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

PLoS One. 2014 Nov 13;9(11):e112731. doi: 10.1371/journal.pone.0112731. eCollection 2014.

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Brachytherapy / adverse effects
  • Brachytherapy / methods
  • Colorectal Neoplasms / radiotherapy*
  • Enoxaparin / administration & dosage*
  • Female
  • Humans
  • Liver Neoplasms* / radiotherapy
  • Liver Neoplasms* / secondary
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Pentoxifylline / administration & dosage*
  • Prospective Studies
  • Radiation Injuries / prevention & control*
  • Ursodeoxycholic Acid / administration & dosage*

Substances

  • Enoxaparin
  • Ursodeoxycholic Acid
  • Pentoxifylline

Associated data

  • ClinicalTrials.gov/NCT01149304

Grant support

This study was funded in full by Sirtex medical (http://www.sirtex.com.au/eu/), funding received by university hospital of Magdeburg. The writing of this paper was funded in part by Sirtex medical. Writing support was provided by Rae Hobbs and was funded by Sirtex medical. Apart from that, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.