Hepatectomy After Conversion Therapy with Hepatic Arterial Infusion Chemotherapy, Tyrosine Kinase Inhibitors and Anti-PD-1 Antibodies for Initially Unresectable Hepatocellular Carcinoma

Figures & data

Table 1 Patient Characteristics

Characteristics	Patients (n = 67)
Sex
Male	61 (91.0)
Female	6 (9.0)
Age, years
Median (range)	52 (26–74)
≤ 50	28 (41.8)
> 50	39 (58.2)
ECOG performance status
0	35 (47.8)
1	32 (52.2)
HBV
Positive	51 (76.1)
Negative	16 (23.9)
HCV
Positive	1 (1.5)
Negative	66 (98.5)
Child-Pugh
5	58 (86.6)
6	6 (9)
7	3 (4.5)
ALBI grade
Grade 1	45 (67.2)
Grade 2	22 (32.8)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV hepatitis C virus.

Table 2 Tumor Characteristics and Treatment Efficacy

Characteristics	Patients (n = 67)
Median treatment session (range)	3 (2–6)
Median interval, months	4.0 (1.4–17.8)
Tumor number
Single	25 (37.3)
Multiple	42 (62.7)
Tumor distribution
Unilobar	41 (61.2)
Bilobar	26 (38.8)
PVTT
Vp0	34 (50.7)
Vp2	4 (6)
Vp3	18 (26.9)
Vp4	11 (16.4)
HVTT
Present	2 (3.0)
Absent	65 (97.0)
Baseline tumor size, cm
Median (range)	11.3 (3.8–23.0)
≤ 10	24 (64.2)
> 10	43 (35.8)
Preoperative tumor size, cm
Median (range)	7 (1.0–15.2)
≤ 10	57 (85.1)
> 10	10 (14.9)
Tumor shrinkage, cm
Median (range)	4.7 (0.9–11.7)
RECIST
PR	51 (76.1)
SD	16 (23.9)
mRECIST
CR	16 (23.9)
PR	51 (76.1)
Baseline AFP, ng/mL
≤ 400	28 (41.8)
> 400	39 (58.2)
Preoperative AFP, ng/mL
≤ 400	53 (79.1)
> 400	14 (20.9)
Change of AFP^#
Elevated-to-elevated	28 (41.8)
Elevated-to-normal	29 (43.3)
Normal-to-normal	10 (14.9)

Notes: ^#Elevated-to-elevated means baseline and preoperative AFP were both elevated; elevated-to-normal means baseline AFP was elevated but preoperative AFP was normal; normal-to-normal means baseline and preoperative AFP were both normal.

Abbreviations: PVTT, portal vein tumor thrombus; HVTT, hepatic vein tumor thrombus RECIST, Response Evaluation Criteria in Solid Tumors; mRECIST, modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; AFP, ⍺-fetoprotein.

Figure 1 Changes in tumor size and AFP levels in patients with HCC after the combination of HAIC with TKIs and anti-PD-1 antibodies. (a) Dot plot of the change in tumor size from baseline assessed based on RECIST. (b) Histogram of the best percentage change in tumor size from baseline assessed based on RECIST. Each bar represents one patient. (c) Dot plot of the change in AFP from baseline to preoperation.

Abbreviations: HCC, hepatocellular carcinoma; HAIC, hepatic arterial infusion chemotherapy; TKI, tyrosine kinase inhibitor; RECIST, Response Evaluation Criteria in Solid Tumors; AFP, ⍺-fetoprotein.

Figure 2 One representative case. (a) Pretreatment CT showing a large tumor with tumor thrombosis in right and main branches of portal vein. (b) Preoperative MRI showing the regression of intrahepatic tumor and tumor thrombosis after treatment. (c) Resected specimen of patients.

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging.

Table 3 Surgical Characteristics

Characteristics	Patients (n = 67)
Resection
Major hepatectomy	35 (52.5)
Minor hepatectomy	32 (47.8)
Portal triad clamping
Present	52 (77.6)
Absent	15 (22.4)
Time of Portal triad clamping, minutes
Median (range)	15 (0–40)
Intraoperative blood loss, mL
Median (range)	300 (50–3000)
Intraoperative blood transfusion
Present	11 (16.4)
Absent	56 (83.6)
Postoperative complication
0	38 (56.7)
I	24 (35.8)
II	3 (4.5)
IV	1 (1.5)
V	1 (1.5)
Post-hepatectomy liver failure
0	32 (47.8)
A	33 (49.3)
B	1 (1.5)
C	1 (1.5)
Postoperative hospital stay, days
Median (range)	6 (4–21)

Table 4 Pathological Characteristics

Characteristics	Patients (n = 67)
Tumor capsule
Present	30 (44.8)
Absent	37 (55.2)
Satellite lesion
Present	13 (19.4)
Absent	54 (80.6)
Microscopic vascular invasion
M0	45 (67.2)
M1/M2	22 (32.8)
Pathological response
pCR	23 (34.3)
Non-pCR	44 (65.7)

Abbreviation: pCR, pathological complete response.

Table 5 Univariate and Multivariate Analyses of Variables Associated with Recurrence-Free Survival

	Univariate	Multivariate	HR (95% CI)
	P value	P value
Sex (Male/Female)	0.991
Age (≤ 50/> 50)	0.243
ECOG performance status (0/1)	0.352
HBV (Positive/Negative)	0.621
Child-Pugh (5/6/7)	0.310
ALBI grade (Grade 1/Grade 2)	0.259
Tumor number (Single/Multiple)	0.300
Tumor distribution (Unilobar/Bilobar)	0.545
PVTT (Present/Absent)	0.430
Baseline tumor size (≤ 10/> 10)	0.061
Preoperative tumor size (≤ 10/> 10)	0.288
RECIST (PR/SD)	0.334
mRECIST (CR/PR)	0.036	NS
Baseline AFP (≤ 400/> 400)	0.130
Preoperative AFP (≤ 400/> 400)	0.249
Change of AFP (elevated-to-elevated / elevated-to-normal / normal-to-normal)^#	0.024
Resection (Major/Minor)	0.930
Portal triad clamping (Present/Absent)	0.447
Intraoperative blood transfusion (Present/Absent)	0.566
Postoperative complication (Present/Absent)	0.072
Post-hepatectomy liver failure (Present/Absent)	0.358
Tumor capsule (Present/Absent)	0.279
Satellite lesion (Present/Absent)	0.375
Macroscopic vascular invasion (Present/Absent)	0.888
Microscopic vascular invasion (M0/M1–2)	0.011	NS
Pathological response (non-pCR/pCR)	0.004	0.041	0.197 (0.041–0.934)

Notes: ^#Elevated-to-elevated means baseline and preoperative AFP were both elevated; elevated-to-normal means baseline AFP was elevated but preoperative AFP was normal; normal-to-normal means baseline and preoperative AFP were both normal.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; PVTT, portal vein tumor thrombus; RECIST, Response Evaluation Criteria in Solid Tumors; mRECIST, modified Response Evaluation Criteria in Solid Tumors; AFP, ⍺-fetoprotein; pCR, pathological complete response; NS, not significant.

Figure 3 Survival analyses of patients with HCC who treated with HAIC combined with TKIs and anti-PD-1 antibodies. DFS (a) and OS (b) of all patients. DFS (c) and OS (d) of patients with different change of AFP. DFS (e) and OS (f) of patients with CR and PR based on mRECIST. DFS (g) and OS (h) of patients with M0 and M1/M2 in MVI. DFS (i) and OS (j) of patients with pCR and non-pCR.

Abbreviations: HCC, hepatocellular carcinoma; HAIC, hepatic arterial infusion chemotherapy; TKI, tyrosine kinases inhibitor; DFS, disease-free survival; OS, overall survival; AFP, ⍺-fetoprotein; CR, complete response; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; MVI, microscopic vascular invasion; pCR, pathological complete response.