Neoadjuvant immunotherapy in resectable hepatocellular carcinoma: A meta-analysis of the current evidence

Table 1 Overview of studies included in the meta-analysis

Ref.	Sample size	Study phase	Study type	Article type	Randomization	NI	Cycles of NI	ICI post-surgery
Bai et al[20], 2022	24	2	Clinical trial	Conference abstract	Randomized	Camrelizumab + apatinib (n = 13)	4	Yes
Chen et al[21], 2022	11	2	Clinical trial	Conference abstract	Non-randomized	Tislelizumab	2	Yes
Cheung et al[30], 2024	20	/	Clinical trial	Full text	/	Nivolumab	3	/
D'Alessio et al[22], 2022	17	1b	Clinical trial	Conference abstract	/	Nivolumab + ipilimumab	2	/
Kaseb et al[23], 2022	30	2	Clinical trial	Full text	Randomized	Nivolumab (n = 13) or nivolumab + ipilimumab (n = 14)	3	Yes
Marron et al[27], 2022	21	2	Clinical trial	Full text	/	Cemiplimab	2	Yes
Ming et al[31], 2024	14	2	Clinical trial	Conference abstract	/	Tislelizumab + lenvatinib	2	Yes
Shi et al[24], 2021	18	1b/2	Clinical trial	Conference abstract	Randomized	Toripalib (n = 10) or toripalib + lenvatinib (n = 8)	1	Yes
Song et al[25], 2023	24	2	Clinical trial	Conference abstract	/	Tislelizumab + lenvatinib	4	Yes
Sun et al[26], 2022	30	2	Clinical trial	Conference abstract	/	Sintilimab + bevacizumab	N/A	/
Wang et al[28], 2022	20	/	Retrospective study	Full text	/	Apatinib + camrelizumab	N/A	/
Xia et al[29], 2022	18	2	Clinical trial	Full text	/	Camrelizumab +apatinib	3	Yes

Summary of study characteristics, including sample size, study type, immunotherapy regimen, number of cycles, and postoperative treatment. NI: Neoadjuvant immunotherapy; ICI: Immune checkpoint inhibitor.

Table 2 Meta-analysis summary

Endpoint	Pooled OR	95%CI lower	95%CI upper	I² (%)	τ²	P value (Q test)
MPR	0.28	0.19	0.41	0.0	0.0	0.8188
ORR	0.54	0.25	1.14	71.4	0.89	0.0004
pCR	0.26	0.11	0.66	76.5	1.57	< 0.0001
Resection rate	5.37	2.70	10.66	62.3	0.87	< 0.0006
Grade 3-4 TRAEs	0.33	0.22	0.50	3.5	0.02	0.4725

Pooled ORs and 95%CIs for each outcome using a random-effects model. Heterogeneity is assessed via I², τ², and Cochran’s Q test. OR: Odds ratio; 95%CI: 95% confidence interval; pCR: Pathological complete response; MPR: Major pathological response; ORR: Overall response rate; TRAE: Treatment-related adverse event.

Table 3 Pooled event rates for clinical endpoints (%)

Endpoint	Pooled %	95%CI	I²	P value
MPR	19	13-25	0.0	0.77
ORR	35	18-52	84.1	< 0.001
pCR	22	10-34	85.5	< 0.001
Resection rate	81	72-91	75.9	< 0.001
Grade 3-4 TRAEs	19	11-26	34.2	0.16

Absolute pooled percentages with 95% confidence intervals for each endpoint (major pathological response, overall response rate, pathological complete response, resection rate, and grade 3-4 treatment-related adverse events), estimated using a random-effects model. 95%CI: 95% confidence interval; pCR: Pathological complete response; MPR: Major pathological response; ORR: Overall response rate; TRAE: Treatment-related adverse event.

Table 4 Assessment of publication bias using funnel plot and Egger’s regression test

Endpoint	No. of studies	Funnel plot	β1 (Egger)	SE (β1)	P value	Interpretation
MPR	10	Symmetrical	-2.36	1.47	0.109	No evidence of small-study effects; the funnel plot does not suggest publication bias
ORR	9	Symmetrical (2 studies lie outside 95%CI limits)	-0.07	1.81	0.969	No indication of small-study effects; the distribution is balanced across effect sizes
pCR	10	Asymmetrical; small studies cluster to the left	-5.00	1.59	0.0016	Significant small-study effects; suggests potential publication bias favoring negative findings
Resection rate	13	Asymmetrical; small studies cluster to the right	+3.68	0.68	< 0.0001	Strong evidence of small-study effects; indicative of possible reporting bias or selective publication of favorable outcomes
Grade 3-4 TRAEs	11	Symmetrical	+0.11	0.79	0.887	No evidence of small-study effects; results appear robust and not influenced by study size

pCR: Pathological complete response; MPR: Major pathological response; ORR: Overall response rate; TRAE: Treatment-related adverse event.

Table 5 Grade 3-4 treatment-related adverse events reported in included studies

Ref.	Neoadjuvant immunotherapy	Cycles of NI	Most common grade 3-4 TRAEs reported
Bai et al[20], 2022	Camrelizumab + apatinib (n = 13)	4	Liver disfunction; thrombocytopenia; and hand-foot syndrome
Chen et al[21], 2022	Tislelizumab	2	No severe events
Cheung et al[30], 2024	Nivolumab	3	No severe events
D'Alessio et al[22], 2022	Nivolumab + ipilimumab	2	ALT/AST elevation
Kaseb et al[23], 2022	Nivolumab (n = 13) or nivolumab + ipilimumab (n = 14)	3	ALT/AST elevation
Marron et al[27], 2022	Cemiplimab	2	ALT/AST elevation; increased blood creatine phosphokinase; and hypoalbuminaemia
Ming et al[31], 2024	Tislelizumab + lenvatinib	2	No severe events
Shi et al[24], 2021	Toripalib (n = 10) or toripalib + lenvatinib (n = 8)	1	Not specified
Song et al[25], 2023	Tislelizumab + lenvatinib	4	No severe events
Sun et al[26], 2022	Sintilimab + bevacizumab	N/A	Not specified
Wang et al[28], 2022	Apatinib + camrelizumab	N/A	Biliary fistula
Xia et al[29], 2022	Camrelizumab +apatinib	3	Rash; hypertension; liver damage; and neutropenia

This table summarizes the most reported grade 3-4 treatment-related adverse events across studies evaluating neoadjuvant immune checkpoint inhibitor regimens in patients with resectable hepatocellular carcinoma. TRAE: Treatment-related adverse event; NI: Neoadjuvant immunotherapy; ICI: Immune checkpoint inhibitor; ALT/AST: Alanine/aspartate aminotransferase; N/A: Not available.