Adjuvant Lenvatinib Plus PD-1 Antibody for Hepatocellular Carcinoma with High Recurrence Risks After Hepatectomy: A Retrospective Landmark Analysis

Figures & data

Table 1 Baseline Characteristics of Patients (n=137)

Characteristics	The ATG (n=52)	The HG (n=85)	P-value
Age (years)
≤60	39 (75.0)	49 (57.7)	0.061
>60	13 (26.9)	36 (42.4)
Sex
Male	49 (94.2)	66 (77.6)	0.020
Female	3 (5.8)	19 (22.4)
BMI (kg/m^2)
≤23.9	22 (42.3)	42 (49.4)	0.419
>23.9	30 (57.7)	43 (50.6)
Diabetes
No	47 (90.4)	74 (87.1)	0.556
Yes	5 (9.6)	11 (12.9)
Viral hepatitis
No	4 (7.7)	13 (15.3)	0.297
Yes	48 (92.3)	72 (84.7)
HBV-DNA level (IU/mL)
≤2000	36 (69.2)	55 (64.7)	0.586
>2000	16 (30.8)	30 (35.3)
Cirrhosis
No	31 (59.6)	54 (63.5)	0.647
Yes	21 (40.4)	31 (36.5)
Child-Pugh
A	49 (94.2)	81 (95.3)	1.000
B	3 (5.8)	4 (4.7)
AFP (ng/mL)
≤400	33 (63.5)	39 (45.9)	0.068
>400	19 (36.5)	46 (54.1)
BCLC stage
A	39 (75.0)	69 (81.2)	0.520
B	13 (25.0)	16 (18.8)
Number
Solitary	36 (69.2)	69 (81.2)	0.163
Multiple	16 (30.8)	16 (18.8)
Max size (cm)
≤5	12 (23.1)	13 (15.3)	0.252
>5	40 (76.9)	72 (84.7)
MVI
Negative	20 (38.5)	36 (42.4)	0.787
Positive	32 (61.5)	49 (57.6)
Edmonson tumor grade
I–II	31 (59.6)	64 (75.3)	0.082
III–IV	21 (40.4)	21 (24.7)
Satellite nodule
No	33 (63.5)	56 (65.9)	0.917
Yes	19 (36.5)	29 (34.1)
ALT (U/L)	30.0 (21.8, 42.0)	28.0 (20.0, 41.0)	0.922
AST (U/L)	37.0 (32.8, 55.5)	40.0 (29.0, 72.0)	0.799
ALB (g/L)	42.7 (38.8, 46.0)	42.6 (38.5, 46.2)	0.993
γ-GT (U/L)	80.5 (36.3, 126.8)	85.0 (52.0, 146.0)	0.213
ALP (U/L)	111.0 (81.0, 128.0)	97.0 (80.0, 126.0)	0.711
TBIL (µmol/L)	14.1 (9.4, 18.2)	13.1 (10.0, 18.0)	0.981

Notes: Categorical values are shown as n (%). Continuous variables are shown as median (interquartile range).

Abbreviations: ATG, adjuvant therapy group; HG, hepatectomy group; BMI, body mass index; HBV, hepatitis B virus; AFP, alpha-fetal protein; BCLC, Barcelona clinic liver cancer; MVI, microvascular invasion; ALT, alanine transaminase; AST, aspartate aminotransferase; ALB, albumin; γ-GT, γ-glutamyl transferase; ALP, alkaline phosphatase; TBIL, total bilirubin.

Figure 1 Flowchart of patient enrollment. HCC, hepatocellular carcinoma; R0 surgical margin, no residual cancer cells by eyes or microscope; TRAEs, treatment-related adverse events; the HG, the hepatectomy group; the ATG, adjuvant therapy group.

Table 2 Comparison of Recurrence Patterns and Treatments After Recurrence Between Adjuvant Therapy and Hepatectomy Groups

Factors	Total (n = 89)	ATG (n = 21)	HG (n = 68)	P-value
Recurrence site				0.792
Intrahepatic	72(80.9%)	17(81.0%)	55(80.9%)
Extrahepatic	6(6.7%)	2(9.5%)	4(5.9%)
Intrahepatic + extrahepatic	11(12.4%)	2(9.5%)	9(13.2%)
Time to recurrence				0.488
≤12 mouths	74(83.1%)	19(90.5%)	55(80.9%)
>12 mouths	15(16.9%)	2(9.5%)	13(19.1%)
Treatments after recurrence				0.968
Re-hepatectomy	25(28.1%)	5(23.9%)	20(29.4%)
Radiofrequency ablation	14(15.7%)	4(19.0%)	10(14.7%)
TACE	16(18.0%)	4(19.0%)	12(17.6%)
Systemic therapy	11(12.4%)	2(9.5%)	9(13.2%)
Radiofrequency ablation + systemic therapy	12(13.5%)	4(19.0%)	8(11.8%)
TACE + systemic therapy	9(10.1%)	2(9.5%)	7(10.3%)
Best supportive care	2(2.2%)	0(0.0%)	2(3.0%)

Note: Data were presented as n (%).

Abbreviations: ATG, adjuvant therapy group; HG, hepatectomy group; TACE, transcatheter arterial chemoembolization.

Figure 2 Kaplan‒Meier survival curves based on recurrence-free survival (A) and overall survival (B) of the adjuvant therapy group (ATG) and the hepatectomy group (HG).

Figure 3 Landmark analysis based on recurrence-free survival of the adjuvant therapy group (ATG) and the hepatectomy group (HG).

Table 3 Logistic Regression Analysis to Predict Recurrence Within 6 Months in Patients with HCC After Hepatectomy

Variables	Univariable Analysis		Multivariable Analysis
	OR (95% CI)	P-value	OR (95% CI)	P-value
Group		<0.001		<0.001
ATG	1		1
HG	4.725 (2.101–10.627)		6.144 (2.441–15.465)
Age (years)		0.629
≤60	1
>60	1.191 (0.586–2.423)
Sex		0.306
Female	1
Male	0.620 (0.248–1.550)
BMI (kg/m^2)		0.421
≤23.9	1
>23.9	0.755 (0.380–1.498)
Diabetes		0.169
No	1
Yes	2.096 (0.731–6.013)
Viral hepatitis		0.663
No	1
Yes	1.265 (0.439–3.649)
HBV-DNA level (IU/mL)		0.572
≤2000	1
>2000	1.231 (0.599–2.528)
Cirrhosis		0.964
No	1
Yes	1.016 (0.503–2.054)
Child-Pugh		0.105		0.045
A	1		1
B	4.000 (0.747–21.408)		7.447 (1.046–53.002)
AFP (ng/mL)		0.017		0.043
≤400	1		1
>400	2.344 (1.166–4.713)		2.343 (1.029–5.335)
BCLC stage		0.316
A	1
B	1.525 (0.668–3.482)
Number		0.950
Solitary	1
Multiple	1.026 (0.458–2.299)
Max size (cm)		0.333
≤5	1
>5	1.483 (0.668–3.291)
MVI		0.023		0.013
Negative	1		1
Positive	2.321 (1.124–4.795)		2.896 (1.257–6.672)
Edmonson tumor grade		0.419
I–II	1
III–IV	1.354 (0.649–2.825)
Satellite nodule		0.015		0.003
No	1		1
Yes	2.445 (1.190–5.025)		3.791 (1.579–9.102)
ALT (U/L)	1.003 (0.995–1.011)	0.488
AST (U/L)	1.010 (0.999–1.021)	0.078
ALB (g/L)	0.963 (0.906–1.024)	0.226
γ-GT (U/L)	1.003 (0.999–1.007)	0.123
ALP (U/L)	1.004 (0.996–1.024)	0.366
TBIL (µmol/L)	1.015 (0.979–1.052)	0.416

Notes: All variables were included for multivariable logistic regression analysis through the stepwise forward selection method.

Abbreviations: HCC, hepatocellular carcinoma; OR, odds ratio; CI, confidence interval; ATG, adjuvant therapy group; HG, hepatectomy group; BMI, body mass index; HBV, hepatitis B virus; AFP, alpha-fetal protein; BCLC, Barcelona clinic liver cancer; MVI, microvascular invasion; ALT, alanine transaminase; AST, aspartate aminotransferase; ALB, albumin; γ-GT, γ-glutamyl transferase; ALP, alkaline phosphatase; TBIL, total bilirubin.

Figure 4 Subgroup analysis of recurrence-free survival (A) and overall survival (B) stratified by age, AFP level, BCLC stage, number, max size, microvascular invasion (MVI), Edmonson tumor grade, and satellite lesion between adjuvant therapy group and the hepatectomy group.

Table 4 Number of Patients with TRAEs During the Adjuvant Treatment Period

Adverse Events	Any grade	Grade 1	Grade 2	Grade 3
Cardiovascular system
Hypertension	19(36.5%)	13(25.0%)	3(5.8%)	3(5.8%)
Cardiac enzymes increased	1(1.9%)	1(1.9%)	0(0.0%)	0(0.0%)
Liver function
ALP increased	3(5.8%)	2(3.8%)	1(1.9%)	0(0.0%)
γ-GT increased	2(3.8%)	2(3.8%)	0(0.0%)	0(0.0%)
TBIL increased	2(3.8%)	2(3.8%)	0(0.0%)	0(0.0%)
ALT/AST increased	6(11.5%)	4(7.7%)	1(1.9%)	1(1.9%)
Blood system
Leukopenia	2(3.8%)	2(3.8%)	0(0.0%)	0(0.0%)
Thrombocytopenia	5(9.6%)	3(5.8%)	1(1.9%)	1(1.9%)
Neutropenia	2(3.8%)	2(3.8%)	0(0.0%)	0(0.0%)
Anaemia	6(11.5%)	4(7.7%)	2(3.8%)	0(0.0%)
Kidney and urinary system
Proteinuria	5(9.6%)	4(7.7%)	1(1.9%)	0(0.0%)
Scr increased	3(5.8%)	3(5.8%)	0(0.0%)	0(0.0%)
Endocrine System
TSH increased	6(11.5%)	5(9.6%)	1(1.9%)	0(0.0%)
FBG increased	1(1.9%)	1(1.9%)	0(0.0%)	0(0.0%)
Gastrointestinal system
Emesis	5(9.6%)	4(7.7%)	1(1.9%)	0(0.0%)
Diarrhoea	12(23.1%)	8(15.4%)	2(3.8%)	2(3.8%)
Anorexia	7(13.5%)	6(11.5%)	1(1.9%)	0(0.0%)
Others
Fatigue	11(21.2%)	9(17.3%)	2(3.8%)	0(0.0%)
Low-grade fever	9(17.3%)	9(17.3%)	0(0.0%)	0(0.0%)
Rash or itching	15(28.8%)	12(23.1%)	1(1.9%)	2(3.8%)

Note: Data were presented as n (%).

Abbreviations: TRAEs, treatment-related adverse events; ALP, alkaline phosphatase; γ-GT, γ-glutamyl transferase; TBIL, total bilirubin; ALT, alanine transaminase; AST, aspartate aminotransferase; Scr, serum creatinine; TSH, thyroid stimulating hormone; FBG, fasting blood glucose.