Baseline characteristics of patients treated with Ultra-FP therapy
One hundred eighteen patients were involved in this study (Fig. 1A and Table 1). The mean age was 72 years. Most of the HCC etiology was non-HBV and/or non-HCV-related HCC (71 patients/118 patients). A treatment history of HCC existed in 71 patients including resection, TACE, RFA/MWA ablation and MTA (Table 1). The numbers of patients based on the stage of the general rules for the clinical and pathological study of primary liver cancer, I/Ⅱ/Ⅲ/ⅣA/ⅣB, were 0/25/45/26/22 patients, respectively. All patients of stage Ⅱ were TACE refractory patients.
The numbers of patients based on the HCC BCLC staging A, B, C and D system were 15/47/56/0 patients, respectively. The presence of portal vein tumor thrombosis (PVTT) was detected in 24 out of 118 patients. The level of the liver reserve was evaluated by the Child-Pugh classification and ALBI grade system. The numbers of patients based on the Child-Pugh classification, A/B/C, were 93/25/0 patients, respectively. The numbers of patients based on ALBI grade system, 1/2a/2b/3 were 34/28/44/12 patients, respectively (Table 1).
Treatment effect of Ultra-FP therapy and adverse events
The treatment effect of Ultra-FP therapy was evaluated by modified RECIST and RECIST ver1.1 after 3 courses of therapy (Table 2 and Fig. 1B). The numbers of HCC patients, CR/PR/SD/PD (modified RECIST), induced by Ultra-FP therapy were 36/52/17/13 patients, respectively. The objective response rate (ORR) of Ultra-FP therapy was 74.6% (88/118 patients) and the disease control rate (DCR) was 89.0% (105/118 patients). Tumor marker reduction (AFP or DCP) was in observed 81.4% (96/118 patients). ORR in the patients with PVTT was 75% (18/24 patients). ORR in the patients with extrahepatic lesion was 64.7% (11/17 patients). Median survival time (MST) of all included HCC patients was 738 days (Fig. 1C).
Grade 1/2 adverse events after initial Ultra-FP therapy were analyzed by using CTCAE ver 5.0. Some patients experienced abdominal pain, fever, malaise, nausea and/or vomiting, anorexia, diarrhea, hypertension creatinine increased, anemia and platelet count decreased (Table 3). Grade 3/4 adverse events induced by tumor lysis (asparate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, GGT increased and hypoalbuminemia) were temporary observed in some patients (Table 3). However, there are no severe adverse events that might have resulted in death.
Subgroup analysis of MST due to the tumor conditions and liver functional reserve
At first, we analyzed the subgroup of HCC patients depending on the various kinds of tumor staging systems. The MST stage based on the general rules for the clinical and pathological study of primary liver cancer, I/Ⅱ/Ⅲ/ⅣA/ⅣB, was NA/1065/764/718/280 days, respectively (Fig. 2A). The MST of UICC staging, IB/Ⅱ/ⅢA/ⅢB/ⅣA/ⅣB was Not reached/1065/384/738/NA/280 days, respectively (Fig. 2B). The MST of BCLC stage A/B/C/D was Not reached/816/585/NA days, respectively (Fig. 2C). The MST of the sub-classification of BCLC (Kinki criteria) stage A/B1/B2/B3/C/D was Not reached/1065/764/596/585/NA days, respectively (Fig. 2D).
Then, we analyzed the subgroup of HCC patients depending on the criteria of the liver functional reserve. The MST of the HCC patients in the Child-Pugh A/B/C were 1065/350/NA days, respectively (Fig. 2E). Moreover, the MST of the HCC patients with ALBI grade 1/2a/2b/3 were NA/1065/476/212 days, respectively (Fig. 2F).
Finally, we analyze the subgroup of HCC patients depending on the existence of PVTT. The treatment response of HCC patients with PVTT by Ultra-FP therapy, CR/PR/SD/PD (modified RECIST), were 2/16/5/1 patients, respectively (Fig. 3A). The response rate of HCC patients with PVTT was 75%. The survival curves of HCC patients with or without PVTT were almost the same (Fig. 3B). The MST of HCC patients with PVTT (-)/PVTT (+) was 816 days/718 days. The treatment response of HCC patients with Vp2, Vp3 and Vp4 by Ultra-FP therapy were shown in Fig. 3C. The treatment response of HCC patients with Vp4 PVTT by Ultra-FP therapy, CR/PR/SD/PD (modified RECIST), were 0/5/1/1 patients, respectively (Fig. 3C). The MST of HCC patients with Vp2/Vp3/Vp4 were 718/Not reached/458 days, respectively (Fig. 3D).
Analysis of liver functional reserve during Ultra-FP therapy
The comparison of ALBI score between before and after 3 course of Ultra-FP therapy was carried out (Fig. 4A). ALBI score was significantly increased during 3 course of Ultra-FP therapy (p = 0.02). However, the change of mean score was 0.1 (pre=-2.23: after=-2.13) (Fig. 4A). The numbers of patients based on ALBI grade system at the pre-treatment, 1/2a/2b/3 were 34/28/44/12 patients, respectively (Fig. 4B). The numbers of patients based on ALBI grade system after 3 course of Ultra-FP therapy, 1/2a/2b/3 were 38/20/42/18 patients, respectively. The proportion of patients based on ALBI grade system was not significantly different between pre and after 3 course Ultra-FP therapy (Fig. 4B).