Table 1.

Studies Design and Characteristics

Study		Abdel-Rahman et al13		Qin et al15		Gish et al14		Yeo et al16		Abou Alfa et al17		Mok et al18
Type of Study		Phase II Randomized Open Label		Phase III Randomized Open Label		Phase III Randomized Open Label		Phase III Randomized Open Label		Phase II Randomized Double-Blind		Phase II Randomized Open Label
Study arms		Sorafenib	Capecitabine	FOLFOX4	Doxorubicin	Nolatrexed	Doxorubicin	Doxorubicin	PIAF	Doxorubicin + sorafenib	Doxorubicin +placebo	Doxorubicin	Nolatrexed
Dosage/frequency		400mg BID daily	1000mg/m2bid d 1–14	Oxa: 85mg/m2 d1 LV200mg/m2 d1and2, FU 400mg/m2 then 600mg/m2 over 22hr every 2 wks	Doxorubicin 50mg/m2 every 3 weeks	800mg/m2 CI over 5 days/3ws	60mg/m2 every 3ws	60mg/m2 every 3 weeks	P: 20 mg/m 2, d1-4 I:5 MU/m2 d 1–4 A: 40mg/m2 D1, F:400 mg/m2 D1-4 every Wk	Doxorubicin 60 mg/m2 every 21 days + sorafenib 400mg BID daily	60 mg/m2 every 21 days	60mg/m2 d1 every 3 weeks	725 mg/m2 over 5 days every 3 weeks
Number in each arm		26	26	184	187	222	223	94	94	47	49	18	36
Main inclusion criteria		No previous therapy Not a candidate for surgery or local treatment		KPS ≥70 Not a candidate for surgery or local treatment Has HBV or HCV with cirrhosis If previous adjuvant CTX should be completed more than 12 ms		KPS ≥ 60% CLIP score≤3 Adequate liver function LVEF ≥50%		Unresectable or metastatic cancer Total bilirubin ≤ 1.75 mg/dl Uncontrolled ascites		No prior chemotherapy LVEF ≥45%		KPS≥ 70 Bilirubin No prior CTX within 4 weeks only
Main exclusion criteria		Renal failure on dialysis CHF NYHA > class II Active CAD Metastatic brain cancer Concurrent Cancer		Previous oxaliplatin or doxorubicin treatment except adjuvant more than 12ms Previous liver transplant CNS metastasis Serious illness		Resectable liver lesion Transplant candidate (included later) Prior doxorubicin or liposomal doxorubicin Severe intercurrent illness		Any history of cancer except NM skin cancer Bone &brain mets Prior CTX Serious illness		Prior TA chemoembolization Psychological or social problem Fibrolamellar or mixed histology		Bilirubin >3 mg/dL, AST or ALT >5.0 ´ upper normal limit or albumin <3 g/d Uncontrolled ascites Another malignancy withi5 years of randomization
Methods of assessment	Baseline	Three-phase CT or MRI		CT or MRI		NS		CT ± US		NS		CT or US
	Follow-up	Repeat imaging every 8w		6w±1 during treatment 2ms ±1w in follow-up		NS		After 3 and 6 cycles of treatment		NS		Repeat imaging with every cycle
Response criteria		RECIST 1.0 for response		RECIST 1.0		WHO criteria for partial and complete response		WHO criteria		RECIST 1.0		WHO criteria for partial and complete response

Abbreviations: CLIP, cancer of the liver Italian program; CI, continuous infusion; FU, 5 fluorouracil; LV, leucovorin; mets, metastases; NS, non-specified; PIAF, cisplatin/interferon α−2b/doxorubicin/fluorouracil; KPS, Karnofesky performance status; RECIST, response evaluation criteria in solid tumors; Oxa, oxaliplatin; TA, transarterial.