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


BACKGROUND
EU clinical trials register 2008-002985-70 ClinicalTrials.gov NCT01149304.
Universitätsklinik Magdeburg, Klinik für Radiologie und Nuklearmedizin, Magdeburg, Germany; International School of Image-Guided Interventions, Deutsche Akademie für Mikrotherapie, Magdeburg, Germany.
Max
M
Seidensticker
Universitätsklinik Magdeburg, Klinik für Radiologie und Nuklearmedizin, Magdeburg, Germany; International School of Image-Guided Interventions, Deutsche Akademie für Mikrotherapie, Magdeburg, Germany.
Ricarda
R
Seidensticker
Universitätsklinik Magdeburg, Klinik für Radiologie und Nuklearmedizin, Magdeburg, Germany; International School of Image-Guided Interventions, Deutsche Akademie für Mikrotherapie, Magdeburg, Germany.
Robert
R
Damm
Universitätsklinik Magdeburg, Klinik für Radiologie und Nuklearmedizin, Magdeburg, Germany; International School of Image-Guided Interventions, Deutsche Akademie für Mikrotherapie, Magdeburg, Germany.
Konrad
K
Mohnike
Universitätsklinik Magdeburg, Klinik für Radiologie und Nuklearmedizin, Magdeburg, Germany; International School of Image-Guided Interventions, Deutsche Akademie für Mikrotherapie, Magdeburg, Germany; Medical University of Gdansk, 2nd Department of Radiology, Gdansk, Poland.
Maciej
M
Pech
Clinica Universidad de Navarra, Liver Unit, Department of Internal Medicine, Pamplona, Spain.
Bruno
B
Sangro
Universitätsklinik Magdeburg, Klinik für Strahlentherapie, Magdeburg, Germany.
Peter
P
Hass
Charité Universitätsmedizin Berlin, Klinik für Radioonkologie und Strahlentherapie, Berlin, Germany.
Peter
P
Wust
Universitätsklinik Magdeburg, Institut für Biometrie und Medizinische Informatik, Magdeburg, Germany.
Siegfried
S
Kropf
Universitätsklinik Magdeburg, Klinik für Strahlentherapie, Magdeburg, Germany.
Günther
G
Gademann
Universitätsklinik Magdeburg, Klinik für Radiologie und Nuklearmedizin, Magdeburg, Germany; International School of Image-Guided Interventions, Deutsche Akademie für Mikrotherapie, Magdeburg, Germany.
Jens
J
Ricke
D000368:Aged; D000369:Aged, 80 and over; D001918:Brachytherapy / Q000009:adverse effects / Q000379:methods; D015179:Colorectal Neoplasms / Q000532:radiotherapy*; D017984:Enoxaparin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000532:radiotherapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010431:Pentoxifylline / Q000008:administration & dosage*; D011446:Prospective Studies; D011832:Radiation Injuries / Q000517:prevention & control*; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage*
D017984:Enoxaparin; D014580:Ursodeoxycholic Acid; D010431:Pentoxifylline