Concurrent versus sequential sorafenib therapy in combination with radiation for hepatocellular carcinoma

• Published in: PloS one 2013-06, Vol.8 (6), p.e65726
• Main Authors: Wild, Aaron T, Gandhi, Nishant, Chettiar, Sivarajan T, Aziz, Khaled, Gajula, Rajendra P, Williams, Russell D, Kumar, Rachit, Taparra, Kekoa, Zeng, Jing, Cades, Jessica A, Velarde, Esteban, Menon, Siddharth, Geschwind, Jean F, Cosgrove, David, Pawlik, Timothy M, Maitra, Anirban, Wong, John, Hales, Russell K, Torbenson, Michael S, Herman, Joseph M, Tran, Phuoc T
• Format: Article
• Language: English
• Subjects: Animals; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Biology; Biotechnology; Brain cancer; Cancer therapies; Carcinoma, Hepatocellular - blood supply; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell adhesion & migration; Cell cycle; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell Line, Tumor; Cell survival; Clinical decision making; Clinical trials; Clinical Trials as Topic; Clothing industry; Combined Modality Therapy - methods; Decision making; Delay; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded - drug effects; DNA Breaks, Double-Stranded - radiation effects; Gamma Rays - therapeutic use; Gene Expression - drug effects; Gene Expression - radiation effects; Growth factors; Health risk assessment; Hepatocellular carcinoma; Hepatoma; Hindlimb - blood supply; Hindlimb - metabolism; Hindlimb - pathology; Histones - genetics; Histones - metabolism; Humans; Immunofluorescence; Inhibitor drugs; Irradiation; Liver cancer; Liver Neoplasms - blood supply; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Medical prognosis; Medicine; Mice; Mice, Nude; Neovascularization, Pathologic - prevention & control; Niacinamide - analogs & derivatives; Niacinamide - therapeutic use; Oncology; Phenylurea Compounds - therapeutic use; Physicians; Post-irradiation; Radiation; Radiation protection; Radiation Tolerance; Radioprotection; Sorafenib; Survival; Targeted cancer therapy; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065726

Sorafenib (SOR) is the only systemic agent known to improve survival for hepatocellular carcinoma (HCC). However, SOR prolongs survival by less than 3 months and does not alter symptomatic progression. To improve outcomes, several phase I-II trials are currently examining SOR with radiation (RT) for HCC utilizing heterogeneous concurrent and sequential treatment regimens. Our study provides preclinical data characterizing the effects of concurrent versus sequential RT-SOR on HCC cells both in vitro and in vivo. Concurrent and sequential RT-SOR regimens were tested for efficacy among 4 HCC cell lines in vitro by assessment of clonogenic survival, apoptosis, cell cycle distribution, and γ-H2AX foci formation. Results were confirmed in vivo by evaluating tumor growth delay and performing immunofluorescence staining in a hind-flank xenograft model. In vitro, concurrent RT-SOR produced radioprotection in 3 of 4 cell lines, whereas sequential RT-SOR produced decreased colony formation among all 4. Sequential RT-SOR increased apoptosis compared to RT alone, while concurrent RT-SOR did not. Sorafenib induced reassortment into less radiosensitive phases of the cell cycle through G1-S delay and cell cycle slowing. More double-strand breaks (DSBs) persisted 24 h post-irradiation for RT alone versus concurrent RT-SOR. In vivo, sequential RT-SOR produced the greatest tumor growth delay, while concurrent RT-SOR was similar to RT alone. More persistent DSBs were observed in xenografts treated with sequential RT-SOR or RT alone versus concurrent RT-SOR. Sequential RT-SOR additionally produced a greater reduction in xenograft tumor vascularity and mitotic index than either concurrent RT-SOR or RT alone. In conclusion, sequential RT-SOR demonstrates greater efficacy against HCC than concurrent RT-SOR both in vitro and in vivo. These results may have implications for clinical decision-making and prospective trial design.