Table 6.

Prognostic and predictive value of baseline or changes of alpha-fetoprotein level for patients with hepatocellular carcinoma treated with antiangiogenic therapies alone or combined with systemic therapies

Ref.		Patients (n)	Study design	Treatment	Level values	Clinical impact	Comments
Shim et al[160]	AFP	57	Retrospective	Sorafenib	High level ≥ 400 ng/mL	Shorter TTP	This study suffers from some limits: a retrospective study, a small cohort including only hepatitis B patients, short median follow-up duration, lack of correlation with OS or ORR
Shao et al[69]		72	Prospective	Various AA + CT	AFP response (> 20% decrease from baseline within the first four weeks)	Better DCR	The magnitude of AFP decline (20% or 50%) from baseline was not clearly defined. Similarly, the time point for evaluation of AFP level was not clear also (4 wk? 7 wk?). Limits: a small number of patients with heterogeneous treatment
						Better ORR
						Better PFS
						Better OS
Yau et al[70]		94	Retrospective	Sorafenib	AFP response (> 20% decrease from baseline within the first six weeks)	Clinical benefit rate	The cutoff value to define AFP response was inconsistent between various studies
						Better PFS
						Marginal better OS
Personeni et al[71]		85	Retrospective	Sorafenib	AFP response (> 20% decrease from baseline within the first six weeks)	Better DCR	The authors used the landmark method to limit the potential favorable outcome due to tumor features than to AFP response
						Better TTP
						Better OS
Køstner et al[72]		76	Retrospective	Sorafenib	AFP response (> 20% decrease from baseline within the first four weeks)	Better ORR	No correlation was observed between AFP response and OS probably because of the limited number of patients evaluated and the unusual poor OS seen in all cohort (5.4 mo)
Kuzuya et al[73]		48	Retrospective	Sorafenib	AFP response (decrease from baseline within 2 and 4 wk)	Better DCR	Limits of the study: retrospective design and the small number of patients included
						Better TTP
						Better OS
Nakazawa et al[74]		59	Retrospective	Sorafenib	AFP response (increase from baseline within four weeks)	Progressive disease	Limits of the study: a small number of patients was enrolled in this and retrospective study. No association between AFP level before treatment and tumor response was observed
						Shorter PFS
						Shorter OS
Llovet et al[63]		491	Prospective Phase III trial	Sorafenib vs placebo	High plasma level > 200 ng/mL	Poorer OS	The impact of baseline AFP on survival was observed in both groups of patients treated with placebo or sorafenib
Hsu et al[64]		53	Prospective single-arm Phase II trial	Sorafenib + mT/U	> 400 ng/mL	Poorer OS?	The prognostic value of baseline AFP level was shown only in univariate analysis and only score CLIP ≥ 3 was an independent prognostic factor of poor OS
Baek et al[65]		201	Retrospective	Sorafenib	≥ 400 ng/mL	Shorter FFS	Baseline AFP level, tumor size, PS, albumin and bilirubin levels were the independent factor associated with OS in this study
						Poorer OS
Lin et al[66]		156	Systemic review of the prospective phase II trials	Various systemic therapies	≥ 400 ng/mL	No impact	Limits of the study: heterogeneous population
Shao et al[119]		45	Pooled analysis of single-arm phase II trials	Sorafenib + mT/U and beva + C	> 400 ng/mL	No impact	This study especially focused on the impact of IGF factors on outcome and the small cohort analyzed limits the interpretation of the effect of AFP levels on survival

AA: Antiangiogenic; AFP: Alpha-fetoprotein; Beva: Bevacizumab; C: Capecitabine; CLIP: Cancer of the liver Italian program[161]; CT: Chemotherapy; DCR: Disease control rate; FFS: Failure-free survival; mT/U: Metronomic tegafur/uracil; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; PS: Performance status; TTP: Time to progression.