Sublethal Irradiation Induces Vascular Endothelial Growth Factor and Promotes Growth of Hepatoma Cells: Implications for Radiotherapy of Hepatocellular Carcinoma

Abstract

Purpose: To investigate the clinical benefit of additional radiotherapy to patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE) and the molecular effects of radiation on gene expression in hepatoma cells. Experimental Design: Between August 1996 and August 2003, 276 and 64 patients with American Joint Committee on Cancer stage T 3 N 0 M 0 hepatocellular carcinoma receiving TACE alone andTACE followed by three-dimensional conformal radiotherapy, respectively, at our institution were studied. Clinical outcome and pattern of failure were analyzed for the association of survival benefit with radiotherapy. The molecular effects of radiotherapy were studied in vitro and in vivo using human hepatoma cells with different p53 mutation and hepatitis B virus infection status. Results: Median follow-up and survival time in theTACE alone and TACE + radiotherapy groups were 39 and 19 months, and 51and 17 months, respectively. Additional radiotherapy toTACE did not improve overall survival (P = 0.65). However, different failure patterns were noted afterTACE and after radiotherapy. Although all irradiated tumors regressed substantially, radiotherapy rapidly enhanced both intrahepatic and extrahepatic tumor progression outside the radiotherapy treatment field in a significant portion of patients, which offset the benefit of radiotherapy on overall survival. In molecular analysis of the radiation effects on human hepatoma cells, radiotherapy rapidly induced p53-independent transcriptional up-regulation of vascular endothelial growth factor (VEGF), increased VEGF secretion in a dose-, time-, and cell type^dependent manner, and promoted hepatoma cell growth in vivo with enhanced intratumor angiogenesis, which correlated well with elevated levels of serumVEGF. Conclusions: Radiotherapy to eradicate a primary hepatocellular carcinoma might result in the outgrowth of previously dormant microtumors not included in the radiotherapy treatment field. Radiotherapy-inducedVEGF could be a paracrine proliferative stimulus.Therapeutic implications of the study justify the combination of three-dimensional conformal radiotherapy with anti-VEGF angiogenic modalities for the treatment of unresectable hepatocellular carcinoma to reduce relapses.

Response of neuroblastoma cells to ionizing radiation: Modulation of in vitro invasiveness and angiogenesis of human microvascular endothelial cells

“…Overexpression of VEGF, an important growth factor controlling angiogenesis, has been associated with tumor progression, metastasis, and reduced survival in neuroblastoma and other tumors (15)(16)(17)(18). The induction of VEGF in tumor cells by irradiation has been previously reported (19)(20)(21). In keeping with these reports, we found an upregulation of the VEGF mRNA transcript and protein after irradiation in neuroblastoma cells analysed.…”

18F‐fluorodeoxyglucose uptake on positron emission tomography as a prognostic predictor in locally advanced hepatocellular carcinoma

“…34,35 Thus, such high-risk patients may benefit from concomitant systemic therapy such as novel agents to block multimolecular pathways. [35][36][37] This study has several limitations. First, quantitative assessments of changes in maximal tumor SUV from baseline after completion of chemoradiotherapy were not performed.…”

Considerations for Radiation Therapy in Hepatocellular Carcinoma: The Radiation Oncologists' Perspective

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