The State of Systematic Therapies in Clinic for Hepatobiliary Cancers

Figures & data

Table 1 Clinical Trial Results of Immunotherapies for Advanced-Stage HCC

Treatments (Trial)	Study Phase	n	ORR	Median PFS	Median OS	Treatment-Related Adverse Event Rates
						Grade ≥ 3	Leading to Discontinuation	Leading to Death
Sintilimab+IBI305 (bevacizumab biosimilar) vs sorafenib (ORIENT-32)	III	571	20.5% vs 4.1%, (P<0.0001)	4.6 vs 2.8 months (P<0.0001)	NE vs 10.4 months (P<0.0001)	33.7% vs 35.7%	13.7% vs 5.9%	2% vs 1%
Atezolizumab (GO30140)	Ib	59	17%	3.4 months	NE	5%	2%	0%
Pembrolizumab + lenvatinib (KEYNOTE-524)	Ib	104	36%	9.3 months	22.0 months	67%	18% (6% for both drugs)	3%
Pembrolizumab (KEYNOTE-224)	II	104	17%	4.9 months	12.9 months	26%	23%	1%
Camrelizumab+ apatinib (RESCUE)	II	120	22.5%	5.5 months	NR	77%	9.2%; requiring corticoids:12%	1%
Durvalumab+ tremelimumab (NCT02519348)	I/II	75	24%	2.2 months	18.7 months	37.8%	10.8%; requiring corticoids: 24.3%	1%
Tremelimumab (NCT01008358)	II	20	17.6%	6.5 months (TTP)	8.2 months	NR	NR	0%
Camrelizumab (NCT02989922)	II	217	14.7%	2.1 months	13.8 months	22%	4%	1%

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, γ-glutamyltransferase; TTP, time to progression; NR, not reported; NE, not estimable.

Table 2 Summary of Clinical Trials on the Applicability of CIK as HCC Treatment Strategies

Cells Used for ACT	Patients (n) Total	Patients (n) Treated with ACT	Overall Survival Rate (ACT vs Control)	Recurrence Rate (ACT vs Control)	Study Reference
Cytokine-induced killer cells	146	72	62.4% vs 18.8% (2 years)	74.7% vs 97.4%	[65]
Cytokine-induced killer cells	83	42	NR	7.14% vs 23.1% (1 year)	[66]
Cytokine-induced killer cells	85	45	100% vs 100% (18 months)	15.6% vs 40.0% (18 months)	[67]
Cytokine-induced killer cells	127	41/43	37.9%/38.1% vs 36.9% (5 years)	73%/72% vs 76% (5 years)	[68]
Cytokine-induced killer cells	132	66	42.4% vs 24.2% (3 years)	72.7% vs 81.8% (3 years)	[69]

Abbreviations: ACT, adoptive cell transfer therapy; NR, not reported.

Table 3 Outcomes of Randomized Controlled Trial Results for Intra-Arterial Treatment of HCC

Randomized Controlled Trial	Region	Experimental Arms	Endpoints	Outcomes	Study Reference
Okusaka et al 2009	Japan	TAI (n = 82) vs cTACE (n = 79)	OS	22.3 months vs 21.2 months; P = 0.383	[73]
Yu et al 2014	China	TEA(n = 49) vs cTACE (n = 49)	OS	24.3 months vs 20.1 months; P = 0.513	[74]
Golfieri et al 2014 (PRECISION ITALIA trial)	Italy	DEB-TACE (n = 89) vs cTACE (n = 88)	OS	56.8% vs 55.4% (2 years); P = 0.949	[75]
Kudo et al 2011 (POST-TACE trial)	Japan, South Korea	cTACE plus sorafenib (n = 229) vs cTACE plus placebo (n = 229)	TTP	5.4 months vs 3.7 months; P = 0.252	[44]
Kudo et al 2014 (BRISK-TA trial)	Global	cTACE/DEB-TACE plus brivanib (n = 249) vs cTACE plus placebo (n = 253)	OS	26.4 months vs 26.1 months; P = 0.53	[78]
Lencioni et al 2016 (SPACE trial)	Global	DEB-TACE plus sorafenib (n = 154) vs DEB-TACE plus placebo (n = 153)	TTP	5.6 months vs 5.5 months; P = 0.072	[79]
Meyer et al 2017 (TACE 2 trial)	UK	DEB-TACE plus sorafenib (n = 157) vs DEB-TACE plus placebo (n = 156)	PFS	7.8 months vs 7.7 months; P = 0.85	[80]
Kudo et al 2018 (ORIENTAL trial)	Japan, South Korea, Taiwan	cTACE plus orantinib (n = 445) vs cTACE plus placebo (n = 444)	OS	31.1 months vs 32.3 months; P = 0.435	[81]
Kudo et al 2019 (TACTICS trial)	Japan	cTACE plus sorafenib (n = 80) vs cTACE (n = 76)	mPFS	25.2 months vs 13.5 months; P = 0.006	[83]

Abbreviations: TAI, transarterial infusion chemotherapy; cTACE, conventional transarterial chemoembolization; TEA, transarterial ethanol ablation; DEB-TACE, drug-eluting bead transarterial chemoembolization; TTP, time to progression; OS, overall survival; mPFS, median progression-free survival.

Table 4 PVTT Classification System of Japanese Liver Cancer Study Group

Grade	Definition
Vp0	Absence of invasion of (or tumor thrombus in) the portal vein
Vp1	Invasion of (or tumor thrombus in) distal to the second-order branches of the portal vein, but not of the second-order branches
Vp2	Invasion of (or tumor thrombus in) second-order branches of the portal vein
Vp3	Invasion of (or tumor thrombus in) first-order branches of the portal vein
Vp4	Invasion of (or tumor thrombus in) the main trunk of the portal vein and/or contra-lateral portal vein branch to the primarily involved lobe

Abbreviation: PVTT, portal vein tumor thrombus.

Kang KJ, Ahn KS. Anatomical resection of hepatocellular carcinoma: a critical review of the procedure and its benefits on survival. World J Gastroenterol. 2017;23(7):1139–1146. doi:10.3748/wjg.v23.i7.1139

 PubMed Web of Science ®Google Scholar

Makuuchi M, Hasegawa H, Yamazaki S. Ultrasonically guided subsegmentectomy. Surg Gynecology Obstetrics. 1985;161:346–350.

 PubMedGoogle Scholar

Shindoh J, Hasegawa K, Inoue Y, et al. Risk factors of post-operative recurrence and adequate surgical approach to improve long-term outcomes of hepatocellular carcinoma. j Int Hepato Pancreato Biliary Assoc. 2013;15(1):31–39. doi:10.1111/j.1477-2574.2012.00552.x

 Google Scholar

Shindoh J, Makuuchi M, Matsuyama Y, et al. Complete removal of the tumor-bearing portal territory decreases local tumor recurrence and improves disease-specific survival of patients with hepatocellular carcinoma. J Hepatol. 2016;64(3):594–600. doi:10.1016/j.jhep.2015.10.015

 PubMed Web of Science ®Google Scholar

Zhang XP, Xu S, Lin ZY, et al. Significance of anatomical resection and resection margin status in patients with HBV-related hepatocellular carcinoma and microvascular invasion: a multicenter propensity score-matched study. Int j Surgery. 2023;109(4):679–688. doi:10.1097/JS9.0000000000000204

 PubMed Web of Science ®Google Scholar

Tanaka K, Shimada H, Matsumoto C, et al. Anatomic versus limited nonanatomic resection for solitary hepatocellular carcinoma. Surgery. 2008;143(5):607–615. doi:10.1016/j.surg.2008.01.006

 PubMed Web of Science ®Google Scholar

Famularo S, Di Sandro S, Giani A. Long-term oncologic results of anatomic vs. parenchyma-sparing resection for hepatocellular carcinoma. A propensity score-matching analysis. Eur j Surgical Oncol. 2018;44(10):1580–1587. doi:10.1016/j.ejso.2018.05.018

 PubMed Web of Science ®Google Scholar

Li SQ, Huang T, Shen SL, et al. Anatomical versus non-anatomical liver resection for hepatocellular carcinoma exceeding Milan criteria. Br J Surg. 2017;104:118–127. doi:10.1002/bjs.10311

 PubMed Web of Science ®Google Scholar

Liu J, O’Donnell JS, Yan J, et al. Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome. Oncoimmunology. 2019;8(5):e1581530. doi:10.1080/2162402X.2019.1581530

 PubMed Web of Science ®Google Scholar

O’Donnell JS. Corrigendum to “EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2019;70(4):817. doi:10.1016/j.jhep.2019.01.020

 PubMed Web of Science ®Google Scholar

Roayaie S, Obeidat K, Sposito C, et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology. 2013;57(4):1426–1435. doi:10.1002/hep.25832

 PubMed Web of Science ®Google Scholar

Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–1236. doi:10.1002/hep.20933

 PubMed Web of Science ®Google Scholar

Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. J Hepatol. 2001;35(3):421–430. doi:10.1016/S0168-8278(01)00130-1

 PubMed Web of Science ®Google Scholar

Imai K, Beppu T, Chikamoto A, et al. Comparison between hepatic resection and radiofrequency ablation as first-line treatment for solitary small-sized hepatocellular carcinoma of 3 cm or less. Hepatol Res. 2013;43(8):853–864. doi:10.1111/hepr.12035

 PubMed Web of Science ®Google Scholar