Efficacy and Safety of Transarterial Chemoembolization with a Three-Stage Mixed Chemoembolic Regimen for Large Unresectable Hepatocellular Carcinoma

Figures & data

Figure 1 Flow chart showing the enrolled patients.

Abbreviation: HCC, hepatocellular carcinoma.

Figure 2 A 31-year-old male underwent M-TACE treatment. (A and B) The t1-weighted unenhanced magnetic resonance imaging (MRI) and t1-weighted enhanced MRI revealed a large enhancing tumor measuring 12.40 cm in the right lobe before M-TACE. (C and D) The hepatic angiography conducted before and after the M-TACE procedure revealed complete devascularization of the tumor’s tumor-feeding arteries. (E and F) Follow up t1-weighted unenhanced MRI and t1-weighted enhanced MRI at 1 month revealed complete response of the tumor.

Figure 3 A 66-year-old female underwent M-TACE treatment. (A) The t1-weighted enhanced magnetic resonance imaging (MRI) revealed a large enhancing tumor measuring 7.07 cm in the right lobe before M-TACE. (B) During M-TACE, an enhanced cone-beam ct (CBCT) scan was performed through a microcatheter to identify the tumor supply artery using the following parameters: contrast flow rate of 1 mL/s, a total volume of 10 mL, and a delay of 4 s. (C) Non-enhanced CBCT was conducted five minutes after lipiodol injection to visualize the distribution of lipiodol.

Table 1 Patient Demographic and Clinical Characteristics

Characteristics (n=82)
Sex
Male	66 (80.5%)
Female	16 (19.5%)
Age (years)
Mean±SD	57.70±12.35
Range	24–82
Etiology
HBV	60 (73.2%)
HCV	3 (3.7%)
Others	19 (23.2%)
BCLC stage
B	20 (24.4%)
C	62 (75.6%)
Child-Pugh class
A	70 (85.4%)
B	12 (14.6%)
Maximum tumor size (cm)	10.71±3.51 (5.3–20.0)
5–10cm	42(51.2%)
>10cm	40(48.8%)
Tumor number
Single	47 (57.3%)
Multiple	35 (42.7%)
AFP (ng/mL)
<200	34 (41.5%)
>200	48 (58.5%)
PIVKA-II (mAU/mL)
<60	11 (13.4%)
>60	71 (86.6%)
PV tumor thrombosis
Yes	38 (46.3%)
No	44 (53.7%)
Extrahepatic metastases
Yes	30 (36.6%)
No	52 (63.4%)
No. of TACE sessions	3.05±1.78 (1–9)
Targeted therapy and/or immunotherapy
Yes	60 (73.2%)
No	22 (26.8%)
Surgical resection
Yes	11(13.4%)
No	71(86.6%)

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; BCLC, Barcelona Clinic Liver Cancer; PV, Portal vein; TACE, transarterial chemoembolization.

Figure 4 Linear regression relationship between the maximum tumor size and the dosage of lipiodol (A) and microspheres (B).

Table 2 Target Lesion Response of the 82 Patients 1 Month Following M-TACE

	Target Lesion Response (%)
mRECIST
CR	19 (23.2%)
PR	42 (51.2%)
SD	15 (18.3%)
PD	6 (7.3%)
ORR (CR+PR)	61 (74.4%)
DCR (CR+PR+SD)	76 (92.7%)

Abbreviations: mRECIST, modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Table 3 Tumor Markers of the 82 Patients 1 Month Following M-TACE

	Before M-TACE	After M-TACE
AFP*	11511.26±20091.65	3983.98±12286.32
PIVKA-II*	22889.43±29932.78	11181.52±21721.54

Notes: *P<0.001.

Abbreviations: AFP, alpha-fetoprotein; PIVKA-II, vitamin K absence or antagonist-II; TACE, transarterial chemoembolization.

Table 4 Subgroup Analysis of 1-Month Overall Response

	CR+PR (N=61)	SD+PD (N=21)	P value
BCLC stage			0.066*
B	18	2
C	43	19
Child-Pugh class			0.067
A	55	15
B	6	6
Maximum tumor size			0.057
5–10cm	26	14
>10cm	35	7
Presence of PV tumor thrombus			0.250
Yes	26	12
No	35	9
Tumor number			0.298
Multiple	24	11
Single	37	10
Extrahepatic metastases			0.868
Yes	22	8
No	39	13
Targeted therapy and/or immunotherapy			0.435
Yes	46	14
No	15	7
AFP (ng/mL)
<400	25	13	0.097
>400	36	8
PIVKA-II (mAU/mL)
<60	7	4	0.460*
>60	54	17

Note: *Fisher’s exact test was used.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; PV, Portal vein; AFP, alpha-fetoprotein; PIVKA-II, vitamin K absence or antagonist-II; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Figure 5 Change in viable target lesion size after M-TACE. ***P<0.001.

Figure 6 Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) following M-TACE.

Table 5 Multivariate Cox Regression Analysis of Prognostic Factors for Overall Survival

	Hazard Ratio	95% CI	P value
AFP (ng/mL)
<400	1.000
>400	1.253	0.443–3.548	0.671
PIVKA-II (mAU/mL)
<60	1.000
>60	1.039	0.261–4.138	0.956
Maximum tumor size
5–10 cm	1.000
>10 cm	0.689	0.274–1.731	0.428
Presence of PV tumor thrombus
No	1.000
Yes	2.184	0.865–5.514	0.098
Tumor number
Single	1.000
Multiple	1.973	0.860–4.527	0.109
Albumin (g/dL)
<35	1.000
≥35	0.899	0.224–3.617	0.881
Tbil (μmol/L)
<20	1.000
>20	1.352	0.497–3.680	0.555
Extrahepatic metastases
No	1.000
Yes	1.080	0.464–2.515	0.859
Targeted therapy and/or immunotherapy
No	1.000
Yes	0.221	0.093–0.528	0.001
Tumor response
SD+PD	1.000
CR+PR	0.281	0.096–0.822	0.020

Abbreviations: AFP, alpha-fetoprotein; PIVKA-II, vitamin K absence or antagonist-II; PV, Portal vein; Tbil, total bilirubin; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CI, confidence interval.

Table 6 Adverse Events and Complications

Severity Grade of ≥2	Number
Fever	23 (28.0%)
Abdominal pain	27 (32.9%)
Nausea and/or vomiting	6 (7.3%)

Figure 7 (A–D) Changes in blood routine indexes before and after M-TACE. (E–H) Changes in liver function indexes before and after M-TACE. *P<0.05; ***P<0.001.

Abbreviations: RBC, red blood cell; WBC, white blood cell; PLT, platelets; HB, hemoglobin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Tbil, total bilirubin; ALB, albumin.

Figure 8 Subgroup analysis of the reduction in (A) albumin (ALB) and (B) platelets (PLT) levels and objective response rates after M-TACE.

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.