Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma

Aaron T. Wild, Nishant Gandhi, Sivarajan T. Chettiar, Khaled Aziz, Rajendra P. Gajula, Russell D. Williams, Rachit Kumar, Kekoa Taparra, Jing Zeng, Jessica A. Cades, Esteban Velarde, Siddharth Menon, Jean F. Geschwind, David Cosgrove, Timothy M. Pawlik, Anirban Maitra, John Wong, Russell K. Hales, Michael Torbenson, Joseph M. Herman & 1 others Phuoc T. Tran

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere65726
JournalPloS one
Volume8
Issue number6
DOIs
StatePublished - Jun 6 2013
Externally publishedYes

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hepatoma
Hepatocellular Carcinoma
Radiation
therapeutics
cell cycle
neoplasms
apoptosis
cell lines
Therapeutics
fluorescent antibody technique
Cells
decision making
irradiation
sorafenib
Heterografts
Tumors
Cell Cycle
cells
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Wild, A. T., Gandhi, N., Chettiar, S. T., Aziz, K., Gajula, R. P., Williams, R. D., ... Tran, P. T. (2013). Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma. PloS one, 8(6), [e65726]. https://doi.org/10.1371/journal.pone.0065726

Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma. / 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; Herman, Joseph M.; Tran, Phuoc T.

In: PloS one, Vol. 8, No. 6, e65726, 06.06.2013.

Research output: Contribution to journalArticle

Wild, AT, Gandhi, N, Chettiar, ST, Aziz, K, Gajula, RP, Williams, RD, Kumar, R, Taparra, K, Zeng, J, Cades, JA, Velarde, E, Menon, S, Geschwind, JF, Cosgrove, D, Pawlik, TM, Maitra, A, Wong, J, Hales, RK, Torbenson, M, Herman, JM & Tran, PT 2013, 'Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma', PloS one, vol. 8, no. 6, e65726. https://doi.org/10.1371/journal.pone.0065726
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 ; Herman, Joseph M. ; Tran, Phuoc T. / Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma. In: PloS one. 2013 ; Vol. 8, No. 6.
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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.",
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AU - Aziz, Khaled

AU - Gajula, Rajendra P.

AU - Williams, Russell D.

AU - Kumar, Rachit

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AU - Cades, Jessica A.

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AU - Menon, Siddharth

AU - Geschwind, Jean F.

AU - Cosgrove, David

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AU - Maitra, Anirban

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