A Retrospective Analysis of Conversion Therapy with Lenvatinib, Sintilimab, and Arterially-Directed Therapy in Patients with Initially Unresectable Hepatocellular Carcinoma

Figures & data

Table 1 Clinical Characteristics of the Patients

Variable	PRP, n = 37	NPRP, n = 61	P-value
Age, mean (min, max)	55.54 (31, 79)	59.24 (25, 74)	0.108
Age, years, n (%)			0.061
≤ 65	24 (64.9)	51 (83.6)
> 65	13 (35.1)	10 (16.4)
Sex, n (%)			0.705
Female	8 (21.6)	10 (16.4)
Male	29 (78.4)	51 (83.6)
Hepatitis, n (%)			0.757
No	2 (5.4)	2 (3.3)
HBV	32 (86.5)	53 (86.9)
HCV	1 (2.7)	4 (6.6)
Both HBV and HCV	2 (5.4)	2 (3.3)
Liver cirrhosis, n (%)			1.000
Negative	11 (29.7)	18 (29.5)
Positive	26 (70.3)	43 (70.5)
AFP, mean±SD	14909.75±55,874.88	33,894.46±132,052.33	0.409
AFP group, n (%)			0.710
≤ 400 (ng/mL)	19 (51.4)	35 (57.4)
> 400 (ng/mL)	18 (48.6)	26 (42.6)
Child-Pugh class, n (%)			0.289
A	32 (86.5)	46 (75.4)
B	5 (13.5)	15 (24.6)
BCLC stage, n (%)			0.051
B	21 (56.8)	21 (34.4)
C	16 (43.2)	40 (65.6)
ECOG PS, n (%)			0.220
0	27 (73.0)	34 (55.7)
1	9 (24.3)	23 (37.7)
2	1 (2.7)	4 (6.6)
Metastasis, n (%)			0.003
Absent	34 (91.9)	38 (62.3)
Present	3 (8.1)	23 (37.7)
PVTT, n (%)			0.949
0	25 (67.6)	41 (67.2)
2	1 (2.7)	1 (1.6)
3	5 (13.5)	7 (11.5)
4	6 (16.2)	12 (19.7)
HVTT, n (%)			0.562
Absent	34 (91.9)	59 (96.7)
Present	3 (8.1)	2 (3.3)
Tumor size, cm, n (%)			0.974
≤ 10	27 (73.0)	43 (70.5)
>10	10 (27.0)	18 (29.5)
Tumor number, n (%)			0.159
≤ 3	22 (59.5)	26 (42.6)
> 3	15 (40.5)	35 (57.4)
Size > 10 cm and number > 3, n (%)			0.486
No	32 (86.5)	48 (78.7)
Yes	5 (13.5)	13 (21.3)
History of treatment
no, n (%)	8 (21.6)	30 (49.2)	0.012
Hepatectomy, n (%)	3 (8.1)	14 (23.0)	0.108
Radiofrequency ablation, n (%)	3 (8.1)	8 (13.1)	0.666
Interventional therapy, n (%)	2 (5.4)	13 (21.3)	0.067
Others, n (%)	1 (2.7)	2 (3.3)	1.000

Note: P-values were shown in bold when p<0.05.

Abbreviations: PRP, potentially resectable population; NPRP, Non-potentially resectable population; AFP, α-fetoprotein; SD, standard deviation; HBV, hepatitis B virus; HCV, hepatitis C virus; BCLC, the Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PVTT, portal vein tumor thrombus; HVTT, hepatic vein tumor thrombus.

Figure 1 Patient selection flowchart.

Abbreviations: HCC, hepatocellular carcinoma; BCLC, the Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PRP, Potentially resectable population; NPRP, non-potentially resectable population; CR, complete response; PR, partial response; FLR, future liver remnant.

Figure 2 Comparison of survival between the PRP and the NPRP. A. Kaplan–Meier survival curves showing PFS of the PRP and the NPRP. B. Kaplan–Meier survival curves showing OS of the PRP and the NPRP.

Abbreviations: PRP, Potentially resectable population; NPRP, non-potentially resectable population; PFS, progression-free survival; OS, overall survival.

Table 2 Summary of the Best Responses

Variable	RECIST 1.1			mRECIST
	PRP, n (%) (n = 37)	NPRP, n (%) (n = 61)	P-value	PRP, n (%) (n = 37)	NPRP, n (%) (n = 61)	P-value
CR	0 (0.0)	0 (0.0)	–	3 (8.1)	0 (0.0)	0.098
PR	25 (67.6)	14 (23.0)	0.000	25 (67.6)	19 (31.1)	0.000
SD	7 (18.9)	16 (26.2)	0.408	4 (10.8)	12 (19.7)	0.250
PD	5 (13.5)	31 (50.8)	0.000	5 (13.5)	30 (49.2)	0.000
ORR	25 (67.6)	14 (22.9)	0.000	28 (75.7)	19 (31.1)	0.000
DCR	32 (86.5)	30 (49.2)	0.000	32 (86.5)	31 (50.8)	0.000

Note: P-values were shown in bold when p<0.05.

Abbreviations: RECIST, Response Evaluation Criteria in Solid Tumors; mRECIST, modified Response Evaluation Criteria in Solid Tumors; PRP, potentially resectable population; NPRP, Non-potentially resectable population; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Figure 3 Best percentage changes in the sizes of the intrahepatic target lesions of patients from baseline assessed with RECIST criterion. (A) Waterfall plot of PRP; (B) Waterfall plot of NPRP.

Abbreviations: RECIST, Response Evaluation Criteria in Solid Tumors; PRP, Potentially resectable population; NPRP, non-potentially resectable population; PR, partial response; SD, stable disease; PD, progress diseases.

Figure 4 Best percentage changes in the sizes of the intrahepatic target lesions of patients from baseline assessed with mRECIST criterion. (A) Waterfall plot of PRP; (B) Waterfall plot of NPRP.

Abbreviations: mRECIST, modified Response Evaluation Criteria in Solid Tumors; PRP, Potentially resectable population; NPRP, non-potentially resectable population; CR, complete response; PR, partial response; SD, stable disease; PD, progress diseases.

Figure 5 DCE-MRI and pathology of one HCC patient received conversion surgery. The red arrow points to the site of the tumor (A, B, D and E) or MPVTT (C and F). (A) an irregular mass on T2WI. (B) mass with heterogeneous enhancement at arterial phase. (C) MPVTT at venous phase. (D) the tumor was shrunken, the left lobe of the liver was atrophied on T2WI. (E) mass with absence of significant enhancement at arterial phase. (F) tumor thrombus in the MPV was disappeared at venous phase. (G) extensive necrotic tissue (HE, 100×).

Abbreviations: DCE-MRI, dynamic-contrast enhanced magnetic resonance imaging; HCC, hepatocellular carcinoma; T2WI, T2-weighted imaging; MPVTT, main portal vein tumor thrombi; MPV, main portal vein; HE, hematoxylin-eosin staining.

Figure 6 DCE-MRI and pathology of another HCC patient received conversion surgery. The red arrow points to the site of the tumor (A, B, D and E) or MPVTT (C and F). (A) an irregular mass on T2WI (10.4 x 7.3cm). (B) inhomogeneous enhancement of tumor at arterial phase. (C) MPVTT at venous phase. (D) the tumor was shrank on T2WI (6.6 x 4.7cm). (E) the tumor was shrank at arterial phase. (F) tumor thrombus in the MPV was disappeared at venous phase. (G) extensive necrotic tissue (HE, 100×).

Abbreviations: DCE-MRI, dynamic-contrast enhanced magnetic resonance imaging; HCC, hepatocellular carcinoma; T2WI, T2-weighted imaging; MPVTT, main portal vein tumor thrombi; MPV, main portal vein; HE, hematoxylin-eosin staining.

Table 3 Safety Summary

Variable	PRP (n = 37)		NPRP (n = 61)		P-value
	Any grade n (%)	Grade 3 or 4 n (%)	Any grade n (%)	Grade 3 or 4 n (%)	Any grade	Grade 3 or 4
AEs	99	14	136	23	0.131	0.992
Diarrhea	2 (5.4)	0 (0)	4 (6.5)	0 (0)	1.000	–
Hypertension	10 (27.0)	7 (18.9)	21 (34.4)	11 (18.0)	0.445	0.913
Hand-foot skin reaction	12 (32.4)	0 (0)	7 (11.4)	2 (3.3)	0.011	0.525
Decreased appetite	2 (5.4)	0 (0)	11 (18.0)	0 (0)	0.139	–
Proteinuria	4 (10.8)	0 (0)	5 (8.2)	0 (0)	0.941	–
Vomiting	5 (13.5)	0 (0)	10 (16.4)	0 (0)	0.701	–
Decreased platelet count	17 (45.9)	1 (2.7)	18 (29.5)	4 (6.5)	0.100	0.713
Abnormal liver function	11 (29.7)	3 (8.1)	7 (11.4)	1 (1.6)	0.024	0.297
Dysphonia	2 (5.4)	0 (0)	2 (3.3)	0 (0)	1.000	–
Muscle pain	3 (8.1)	2 (5.4)	1 (1.6)	0 (0)	0.297	0.140
Decreased neutrophil count	10 (27.0)	0 (0)	12 (19.7)	3 (4.9)	0.398	0.444
Bleeding	10 (27.0)	0 (0)	10 (16.4)	1 (1.6)	0.205	1.000
Rash	4 (10.8)	1 (2.7)	10 (16.4)	1 (1.6)	0.444	1.000
Proteinuria	4 (10.8)	0 (0)	5 (8.2)	0 (0)	0.941	–
Fatigue	3 (8.1)	0 (0)	13 (21.3)	0 (0)	0.086	–

Note: P-values were shown in bold when p<0.05.

Abbreviations: PRP, potentially resectable population; NPRP, Non-potentially resectable population; AEs, adverse events.