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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 ?-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.

SUBMITTER: Wild AT

PROVIDER: S-EPMC3675179 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Wild Aaron T AT Gandhi Nishant N Chettiar Sivarajan T ST Aziz Khaled K Gajula Rajendra P RP Williams Russell D RD Kumar Rachit R Taparra Kekoa K Zeng Jing J Cades Jessica A JA Velarde Esteban E Menon Siddharth S Geschwind Jean F JF Cosgrove David D Pawlik Timothy M TM Maitra Anirban A Wong John J Hales Russell K RK Torbenson Michael S MS Herman Joseph M JM Tran Phuoc T PT

PloS one 20130606 6

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 vi ...[more]

PMID: 23762417

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Project description:Purpose:The objective of this study was to evaluate adverse events (AEs) in patients who received both immune checkpoint inhibitors and thoracic radiation therapy (RT). In particular, we compared the rate of toxicities of concurrent versus sequential delivery of thoracic RT and checkpoint inhibitors. Methods and Materials:Patient and treatment characteristics were collected on all patients at our institution who were treated with programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and underwent thoracic RT (n?=?79). Receiving both treatments within 1 month was considered concurrent (n?=?35; 44%), and any treatment up to 6 months apart was considered sequential (n?=?44; 56%). The primary endpoint of this study was the rate of Grade ?2 AEs from combination therapy (immunotherapy and RT), specifically those that are relevant to thoracic RT: Pneumonitis, other pulmonary events, esophagitis, dermatitis, and fatigue. Further univariate analysis was performed to compare AE rates with clinical and therapy-related variables. Results:A total of 79 patients were identified, with lung cancer (n?=?45) and melanoma (n?=?15) being the most common primary histology. Sixty-two (78%) patients were treated with anti-PD-1 or anti-PD-L1 antibodies, 12 (15%) with anti-CTLA-4 antibodies, and 5 (6%) received both anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. The median follow-up for survivors was 5.9 months (range, 2.4-55.6 months). Grade ?2 AEs included pneumonitis (n?=?5; 6%), esophagitis (n?=?6; 8%), and dermatitis (n?=?8; 10%). No statistically significant correlation was found between these AEs when comparing concurrent versus sequential treatment. The only significant variable was a correlation of immunotherapy drug category with Grade ?2 esophagitis (P?=?.04). Conclusions:Overall, Grade ?2 AE rates of thoracic RT and immunotherapy appeared as expected and acceptable. The lack of significant differences in AE rates with concurrent versus sequential treatment suggests that even concurrent immunotherapy and thoracic RT may be safe.

Dataset Information

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

Publications

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

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