Abstract

Transarterial chemoembolization (TACE) is indicated in patients with intermediate-stage, unresectable hepatocellular carcinoma (HCC). Stereotactic body radiation therapy (SBRT) is increasingly being used in HCC. Preclinical studies show that moderate radiation doses (5-10 Gy) induce acute changes in tumor permeability and perfusion. Thus, we hypothesize that SBRT followed by TACE within 24 hours promotes sensitization to TACE. In this prospective phase I trial, we evaluated the feasibility, safety, tolerability, and functional magnetic resonance imaging (MRI) changes associated with single-fraction SBRT followed by TACE within 24 hrs. Patients with HCC, 1-3 lesions, Childs-Pugh A/B liver function, and no major vascular invasion were enrolled. The primary objective was to establish the feasibility of single-dose SBRT (7.5 or 10 Gy) followed by TACE within 24 hrs. Secondary endpoints included safety, tolerability, tumor perfusion changes via dynamic-contrast enhanced (DCE) MRI (at 6 or 24 hrs after SBRT), overall response rate (ORR), clinical benefit rate (CBR), freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS). Tumor response and progression were graded using modified RECIST criteria. The uni-directional exchange rate constants kep (interstitial space to blood plasma) and kpe (blood plasma to interstitial space) were reported as measures of vascular permeability/perfusion. A total of 16 patients were enrolled, and all but one patient received SBRT. Within 24 hours, 13 of these 15 patients successfully underwent TACE. The median age was 64 years (range 48 to 79) and 84.6% of patients were males. Median tumor size was 5.6 cm (range 2.0 to 12.0). Median follow up for living patients is 12.6 months. Crude ORR and CBR are 58% and 75%, respectively. Median OS, PFS, and FFLP are 14.2 months, 6 months, and 5.3 months, respectively. Crude rates of grade 1+ and grade 2+ toxicity are 85% and 38%, respectively. There were no grade 3 or 4 toxicities. One patient died due to TACE-related hemorrhage 4 days after TACE (grade 5). Regarding DCE-MRI metrics, kpe showed a rapid increase within 6 hrs post-SBRT (mean +300.0%, range -6% to +1030%, p=0.01), but a decrease by 24 hrs (mean -34%, range -75% to +17%, p=0.05). A similar trend was also observed for kep, with an increase within 6 hrs post-SBRT (mean +61.3%, range -50% to +218%, p=0.07) and return to near baseline by 24 hrs (mean +21%, range -29% to +155%, p=0.23). Single-fraction SBRT followed by TACE within 24 hrs is a feasible and tolerable strategy for intermediate-stage HCC. DCE-MRI analysis revealed significant acute changes in tumor permeability/perfusion after SBRT. Additional studies are needed to establish the safety and efficacy of this combination, and the effects of SBRT on the HCC microenvironment.

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