Figure 2. Perfusion change in hepatocellular carcinoma (HCC) during atezolizumab plus bevacizumab treatment. (a) Representative HCC before (top row) and at 9±2 weeks after starting atezolizumab plus bevacizumab treatment (bottom row), categorized as partial response (left column), stable disease (middle column), and progressive disease (right column) based on mRECIST. HCC perfusion is shown on a color scale, estimated with the tumor-to-liver signal ratio in the arterial phase. (b, c) The change of (b) HCC perfusion (tumor-to-liver signal ratio in the arterial phase) and (c) HCC size for 9±2 weeks of atezolizumab plus bevacizumab treatment in the complete or partial response (CR/PR) group, stable disease (SD) group, and progressive disease (PD) group, when the therapeutic effect was determined using mRECIST at 21±5 weeks after starting treatment.
Three subjects had complete responses (CR), five subjects had partial responses (PR), eight subjects had stable diseases (SD), and three subjects had progressive diseases (PD). The mean baseline tumor long axis was 59±47 mm. Figure 2a shows the representative tumors of the PR, SD, and PD groups in the baseline and the first follow-up scans. The tumor regions are presented in a color scale, while the color represents the tumor-to-liver signal ratio (that is, perfusion). Figure 2b shows the tumor perfusion changes of the favorably responding (CR/PR) group (-26±18%), the SD group (-24±12%), and the PD group (9±13%) for nine weeks of treatment with atezolizumab with or without bevacizumab. There was no difference in perfusion changes between the CR/PR and SD groups (p=0.7368), but a significant difference was found between the CR/PR and PD groups (p=0.0135) or between the SD and PD groups (p=0.0040). Figure 2c shows the tumor-size changes of the CR/PR group (-38±15%), the SD group (-1±11%), and the PD group (17±10%) during the same period of treatment. The tumor-size change in the CR/PR group was significantly different from that in the SD group (p<0.0001) or the PD group (p=0.0003). The tumor-size change in the SD group also was different from that of the PD group (p=0.0285).
Without three atezolizumab monotherapy cases, the tumor perfusion changes for nine weeks in the CR/PR, SD, and PD groups were − 29 ± 17% (n = 7), -23 ± 13% (n = 7), and 3 ± 12% (n = 2), respectively, while the tumor size changes were − 38 ± 16%, -3 ± 11%, and 15 ± 13%, respectively. The perfusion changes in the three tumors treated with atezolizumab alone were − 4% (PR), -28% (SD), and 19% (PD), and the tumor size changes were − 34% (PR), 7% (SD), and 22% (PD).
The tumor perfusion change during nine weeks of treatment using atezolizumab with/without bevacizumab yielded 100% sensitivity and 94% specificity to predict the progressive diseases at 21 weeks after therapy initiation. The tumor size change during the same period also yielded 100% sensitivity, but lower specificity (69%). When the data of atezolizumab monotherapy were excluded, the tumor perfusion change yielded 100% sensitivity and 93% specificity, and the tumor size change yielded 100% sensitivity and 71% specificity.
Figure 3a shows a significant correlation between the tumor perfusion change for nine weeks and the tumor size change for 21 weeks (p = 0.0004, r = 0.81) when the CR group and two outliers in the PR group indicated with the circles are excluded. If the two outliers in the PR group are included, the p and r values are 0.0305 and 0.54, respectively. When the data retrieved only from the CT images were used (n = 9), the tumor perfusion change for nine weeks were significantly correlated with the tumor size change for 21 weeks. However, the correlation was not significant (p = 0.2415, r = 0.51) when the data retrieved only from the MRI images were used (n = 7). Figure 3b shows a significant correlation between the tumor size change for nine weeks and the tumor size change for 21 weeks (p < 0.0001, r = 0.92) when the CR group is excluded.