Early MRI response monitoring of patients with advanced hepatocellular carcinoma under treatment with the multikinase inhibitor sorafenib

Abstract

Background: New therapeutic principles in clinical oncology require the adjustment of response criteria to govern therapy decisions. For advanced hepatocellular carcinoma (HCC) a new era has recently begun by the approval of the multikinase inhibitor sorafenib. As a unique feature, HCC usually develops in a diseased liver and current imaging technologies employing classical response criteria have not been prospectively evaluated for this new treatment.

Methods: MRI signal patterns were assessed in 21 advanced HCC patients receiving sorafenib. MRI was performed at baseline and in short-term intervals thereafter. Signal changes under therapy on T1WI, T2WI and post-gadolinium images including necrosis volume and its ratio to the entire tumor volume were compared to baseline imaging. To assess the association between the categorical variables, Fisher's exact tests were applied for a statistical analysis. Survey time ranged from 2-65 weeks, and a total of 39 target lesions were evaluated.

Results: Signal abnormalities during sorafenib therapy were disclosed by T1WI and T2WI in 15/21 patients. The predominant tumor signal change was hyperintensity on both T1WI and T2WI. Interestingly, most patients developed MRI signal changes within 4 weeks of therapy; in contrast, two non-responders did not show any signal alteration at follow-up. Under therapy, 16/21 patients presented with new or progressive necrosis, whereas 7 patients achieved temporarily >75% tumor necrosis under sorafenib. Significantly associated MRI variables were increase in T1WI signal and tumor necrosis (p = 0.017) as well as increase of tumor necrosis with an elevated ratio of necrotic to vital tumor areas (p = 0.002). Remarkably, some (3/13) of the patients developing necrotic tumor areas showed a relevant (>20%) increase in tumor volume, which should be considered in the assessment of imaging studies.

Conclusion: As sorafenib induces early intralesional necrosis with profound changes in T1WI/T2WI MRI signal intensities and measurable necrotic tumor areas in most HCC patients, early MRI-based evaluation could pave the way for its rationale and cost-effective application.

Figure 1

A-F. 63-year-old female patient with multicentric HCC (patient #8). Axial nonenhanced T1WI performed at baseline showed a 10 cm large tumor (arrow) in the left liver lobe (Figure 1A). Note a tumor signal (arrow) slightly hypointense to normal liver parenchyma with a small ventral heterogeneous hyperintense area caused by earlier radiofrequency (RFA) ablation. On baseline T2WI, the tumor revealed diffuse mild hyperintensity and a small hypointense area corresponding to the ablation site (Figure 1B). Baseline fat-suppressed post-gadolinium (Gd) imaging demonstrated diffuse tumor enhancement (arrows) with focal necrosis due to the earlier RFA procedure (arrowhead) (Figure 1C). Three weeks after onset of sorafenib, T1WI imaging detected multiple focal hyperintense lesions (arrows) in part with sedimentation levels that have occurred during therapy (Figure 1D). On T2WI at the same time, corresponding hyperintense lesions were seen (arrows) (Figure 1E). Fat-suppressed post-Gd imaging revealed extensive necrosis (arrows) and reduction in tumor perfusion (Figure 1F).

Figure 2

A-F. 71-year-old male patient with multifocal HCC (patient #9). Axial nonenhanced fat-suppressed T1WI imaging of the liver performed at baseline showed multiple mild hypointense HCC lesions (arrow) (Figure 2A). On corresponding coronal HASTE (T2-weighted) images, liver tumors are difficult to distinguish from adjacent liver parenchyma because of signal isointensity (Figure 2B). Fat-suppressed post-Gd SGE imaging showed an almost homogenous signal (arrows) of moderately enhancing liver tumors (Figure 2C). Three weeks after onset of sorafenib therapy, nonenhanced T1WI imaging revealed multiple focal strongly hyperintense lesions (arrows) presumed to represent hemorrhagic necrosis in the known tumors (Figure 2D). Coronal HASTE images performed at the same time demonstrated also hyperintense signals (arrows) of tumors with a good delineation to adjacent liver parenchyma (Figure 2E). Fat-suppressed post-Gd SGE imaging showed central >75% necrosis in most of the HCC lesions following sorafenib therapy (Figure 2F).

Figure 3

A-F. 61-year-old male patient with metastatic HCC (patient #17). Axial nonenhanced T1WI imaging of the liver showed hypointense signal of all HCC lesions (arrows) (Figure 3A). On corresponding T2WI images, HCC lesions demonstrated all a moderate hyperintense signal (arrows) compared to adjacent liver parenchyma (Figure 3B). Fat-suppressed post-Gd SGE imaging revealed a diffuse enhancement throughout all HCC lesions (arrows) with small central areas of necrosis (arrowhead) (Figure 3C). Five weeks after onset of sorafenib therapy, the signal of HCC lesions on T1WI- imaging increased (arrows) becoming iso- to hyperintense to adjacent liver parenchyma (Figure 3D). At this time, there was at best mild increase in tumor signal on fat-suppressed T2WI imaging (arrows) (Figure 3E). However, fat-suppressed post-Gd T1WI demonstrated >75% reduction of enhancing tumor areas due to necrosis (arrows) (Figure 3F).