title: Concurrent versus sequential sorafenib therapy in combination with radiation for hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Wild
authors.forename: Nishant
authors.initials: N
authors.lastname: Gandhi
authors.forename: Sivarajan T
authors.initials: ST
authors.lastname: Chettiar
authors.forename: Khaled
authors.initials: K
authors.lastname: Aziz
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Gajula
authors.forename: Russell D
authors.initials: RD
authors.lastname: Williams
authors.forename: Rachit
authors.initials: R
authors.lastname: Kumar
authors.forename: Kekoa
authors.initials: K
authors.lastname: Taparra
authors.forename: Jing
authors.initials: J
authors.lastname: Zeng
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Cades
authors.forename: Esteban
authors.initials: E
authors.lastname: Velarde
authors.forename: Siddharth
authors.initials: S
authors.lastname: Menon
authors.forename: Jean F
authors.initials: JF
authors.lastname: Geschwind
authors.forename: David
authors.initials: D
authors.lastname: Cosgrove
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Pawlik
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.forename: Russell K
authors.initials: RK
authors.lastname: Hales
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herman
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy / Q000379:methods*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011836:Radiation Tolerance; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib