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part of

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Future Oncol. (2009) 5(6), 889–89910.2217/FON.09.64 © 2009 Future Medicine Ltd

Being the sixth most common cancer in the world, hepatocellular carcinoma (HCC) accounts for 5% of cancer globally, with 626,000 new cases in 2002 [1,2]. The incidence is rising in Western countries, and continues to be high in endemic areas including Southeast Asia and China. HCC is a lethal cancer with high mortal-ity [3,4]. It is a highly heterogeneous disease with median survival in the range of a few months to more than 2 years for patients with unresectable disease [5]. Identification of prognostic factors and development of staging systems is crucial for the risk stratification and assignment of suitable treatment for HCC patients. However, the devel-opment of a prognostication system for HCC is complicated by the comorbidities of viral hepa-titis and cirrhosis. A number of tumor-related features, parameters reflective of liver reserves and other host factors, have been studied exten-sively for their prognostic values in HCC, and, to date, there is no consensus about the most suitable staging system for HCC.

Transarterial therapy and systemic agents remain to be the mainstays of treatment in advanced HCC. Conventionally, the treatment response of HCC to a nonsurgical modality of treatment is assessed by radiologic imaging using conventional criteria, such as WHO criteria or Response Evaluation Criteria in Solid Tumors. However, HCC rarely shrink, despite effective nonsurgical treatment [6,7]. It has constantly been observed that a small subset of HCC patients could derive benefits from treatments despite the absence of radiologic response. There are reports that some candidates could even achieve complete pathological necrosis when there was

minimal tumor shrinkage [8–10]. Thus, the sole use of radiologic criteria has been acknowledged to have underestimated the efficacy of novel bio-logic agents in early clinical trials [11]. Variable attempts have been made to improve the sensi-tivity of radiologic assessment for ablative pro-cedures. For example, the European Association for the Study of the Liver criteria have incor-porated the use of arterial contrast enhance-ment into assessment of response outcome from locoablative procedures [12]. On the other hand, a number of researchers have looked into the use of dynamic magnetic resonance imaging to monitor response to treatment [13–15]. While imaging is being explored, serological markers such as serum a-fetoprotein (AFP) level and circulating vascular endothelial growth factor have been studied [16,17].

a-fetoprotein is a fetal-specific glycoprotein produced primarily by the fetal liver. Its serum concentration falls rapidly after birth, and its synthesis in adult life is repressed. The asso-ciation between AFP and HCC was not made until 1963, when Abelev detected AFP in the blood of mice with transplantable HCCs [18], followed by demonstration of AFP in the serum of patients with HCCs by Tatarinov [19] and Stanislawski-Birenewajg et al. [20]. Apart from HCC, AFP could also be produced by a number of other malignancies, such as testicular, gastric and pancreatobiliary cancers [21,22]. Nowadays, it is known that the glycoprotein is secreted in around 70–80% of HCCs, and the incidence of elevated AFP is higher in endemic areas such as Asia and Africa [23,24]. Since its discovery, the role of serum AFP as a diagnostic and screening

Role of a-fetoprotein in hepatocellular carcinoma: prognostication, treatment monitoring or both?

Stephen L Chan, Anthony TC Chan & Winnie Yeo†

†Author for correspondence: Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China n Tel.: +852 2632 2118 n Fax: +852 2648 7097 n winnieyeo@cuhk.edu.hk

Despite recent breakthroughs in the treatment for both early and advanced hepatocellular carcinoma, the development of markers for prognostication and treatment monitoring remains to be explored. Serum a-fetoprotein has been frequently measured at diagnosis and serially during treatment by clinicians for decades, with an aim for prognostication of disease and monitoring of treatment response. In this review, the evidence regarding the prognostic value of serum a-fetoprotein and the value of serial a-fetoprotein in the monitoring of treatment efficacy will be discussed, with emphasis on recent data.

Keywords

n a-fetoprotein n hepatocellular carcinoma n monitoring treatment n prognostic factor

Revie

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tool has been intensively studied (for review please refer to Johnson et al. [6] and Daniele et al. [25]). The sensitivity and specificity of AFP as a diagnostic marker for HCC depends on the cut-off level chosen, and a cut-off value of 500 ng/ml has been widely used in clinical practice for the diagnosis of HCC [6,26]. On the contrary, the roles of AFP as a factor for prognostication and treatment monitoring have been less explored. Owing to the widespread availability of stan-dardized AFP assays that are inexpensive, and serial blood sampling for AFP being considered an acceptable investigation procedure to most patients, AFP has been routinely measured at diagnosis, and during treatment and follow-up of HCC patients by most clinicians. Despite its widespread clinical usage, there has been no sys-tematic review on the value of AFP as a factor for prognostication and treatment monitoring. In this article, the clinical utility of serum AFP in prognostication, staging and disease monitoring during treatment is reviewed.

Prognostic role of AFPAFP as an individual prognostic factor in HCCThe potential use of AFP as a prognostic fac-tor in HCC was initially suggested early in the 1970s [27]. Despite this, the exact mechanism of how serum AFP could be prognostic in HCC remains unclear. Most clinicians believe that AFP is released as a result of hepatocarcino-genesis, and is hence reflective of the prolifera-tive activity and tumor burden. There has also been preclinical evidence that AFP could exert a modulatory effect on hepatoma cells, suggest-ing that AFP elevation might not only be just an epiphenomenon of malignant transforma-tion, but may also actively participate in tumor proliferation [28–34].

Elevated AFP has been reported by a large number of studies to be a modest (relative risk ranging from >1 to 4) adverse prognostic fac-tor in both early and advanced stages of disease (with recent studies from 1999 summarized in Table 1). In particular, patients with extremely high AFP levels, of more than 10,000 ng/ml, have been described to have much worse out-comes, with a 3-year survival rate of 40%, compared with those with moderately elevated AFP (200–10,000 ng/ml) who have a survival rate close to 70% [35]. Amongst candidates for hepatectomy or liver transplant, an elevated pre-operative level of AFP has been associated with early tumor recurrence, intra-hepatic metasta-sis and worse survival outcome after attempted

curative resection [36–38]. Similar patterns were observed in other early-stage patients receiving radiofrequency ablation or other locoablative procedures [39,40]. It has also been suggested that AFP per tumor volume ratio could be more prognostic than serum AFP value alone in pre-dicting tumor recurrence after hepatectomy [41]. For patients with advanced stage disease, an ele-vated AFP is associated with a hazard ratio (HR) of around 1.5–2 in general, and such prognostic ability seems to not be affected by choices of nonsurgical therapy, namely transarterial ther-apy, internal radiotherapy or best-supportive care. Sex, ethnicity and underlying viral etiol-ogy do not appear to significantly influence the prognostic role of AFP [42].

However, the clinical use of serum AFP as a prognostic factor has been limited by a number of factors. First, the cut-off value is crucial in deter-mining the prognostic ability. It appears that a much higher cut-off value (600–1000 ng/ml) is required for prognostication in HCC, in con-trast to the usual criteria of 400–500 ng/ml used in diagnosis. A large-scale Italian study includ-ing 1158 patients found that although AFP was associated with tumor size, stage, number of lesions and overall survival in the patient cohort, receiver operating characteristic curves demonstrated the best cut-off value should be 600 ng/ml [42]. This finding suggested that the low range of AFP is minimally informative in prognostication of disease. Secondly, part of the prognostic ability of AFP could be accounted for by its strong association with tumor size and unfavorable pathological features (Table 2). At least two studies have simultaneously shown that AFP elevation was uncommon in HCC smaller than 2 cm, while the level would rise progressively to the range of 1000–10,000 ng/ml when tumor size increased to a size beyond 5 cm [40,43]. Higher AFP level has also been found to be associated with more aggressive or poorly dif-ferentiated tumors, bilobar involvement, multi-focal HCC, portal vein thrombosis and higher tumor, node, metastasis (TNM) and Okuda stage, which themselves are known to be adverse prognostic factors in HCC, indicating that AFP level alone is not an independent prognosticator. Furthermore, to support this, several surgical series have not found serum AFP value to be an independent prognostic factor when TNM stage and vascular invasion were included into multivariate analysis [44–46]. Finally, it has to be noted that HCCs are increasingly diagnosed at smaller size and earlier stage of disease as a result of screening. Consequently, the proportion of

Review Chan, Chan & Yeo

www.futuremedicine.com 891future science group

Tab

le 1

. Su

mm

ary

of

stu

die

s (1

999

–20

08

) w

ith

sta

tist

ical

ly s

ign

ifica

nt

resu

lts

on

th

e p

rog

no

stic

val

ue

of

a-f

eto

pro

tein

in h

epat

oce

llula

r ca

rcin

om

a.

Stag

e o

f d

isea

seTr

eatm

ent

mo

dal

ity

Nu

mb

erSt

ud

y d

esig

n &

pat

ien

t ch

arac

teri

stic

sA

FP, c

ut-

off

(n

g/m

l)R

esu

lts

Ref

.

Earl

y H

CC

Surg

ical

tre

atm

ent

90

9 Re

tro

spec

tive

stu

dy

in T

aiw

an

Ove

r 70

% H

BV

200

RR

= 1

.2

[76]

224

Retr

osp

ecti

ve s

tud

y in

Jap

an

Ove

r 6

0%

HC

V

20

RR

= 1

.28

[77]

12,1

18

Cro

ss-s

ecti

onal

stu

dy

in J

apan

67

.3%

HC

V

21–2

00

20

1–10

00

1001

–10,

00

0 O

ver

10,0

00

HR

: 1.

35

1.53

1.

57

1.6

4

[35]

172

Retr

osp

ecti

ve s

tud

y in

Jap

an

All

HC

V

100

0H

R =

2.3

05[78]

Loco

-abl

atio

n41

6Re

tro

spec

tive

stu

dy

in J

apan

O

ver

80

% H

CV

100

HR

= 1

.45

[39]

112

Retr

osp

ecti

ve s

tud

y in

Ital

y

51%

HC

V

31%

alc

oho

lic

20H

R =

2.7

9 [40]

Inte

rmed

iate

/A

dva

nced

HC

CTr

ansa

rter

ial t

hera

py12

1 Re

tro

spec

tive

stu

dy

in J

apan

O

ver

70%

HC

V

100

HR

= 2

.24

[79]

128

Retr

osp

ecti

ve s

tud

y in

Jap

an

80

% H

CV

4

00

HR

= 1

.56

[80]

143

Retr

osp

ecti

ve s

tud

y in

Spa

in

Ove

r 6

0%

HC

V

40

0R

R =

2.8

[81]

182

Retr

osp

ecti

ve s

tud

y in

Ital

y 20

RR

= 1

.71

[82]

320

Retr

osp

ecti

ve s

tud

y in

Hon

g K

ong

M

ainl

y H

BV

100

0 R

R =

4.0

6[83]

Tam

oxife

n ve

rsus

tam

oxife

n pl

us

TAC

E13

8 R

and

omiz

ed P

hase

III t

rial

Ove

r 70

% a

lco

holic

4

00

RR

= 3

.53

[84]

Mis

cella

neo

us

po

pula

tion

Unt

reat

ed10

6 Re

tro

spec

tive

stu

dy

in H

ong

Kon

g

Ove

r 70

% H

BV

100

0H

R =

1.0

0[85]

Mix

ed26

8 Re

tro

spec

tive

stu

dy

in It

aly

A

ppr

oxim

atel

y 70

% H

CV

22

.5

HR

= 2

.25

[86]

176

Retr

osp

ecti

ve s

tud

y in

Ital

y

Ove

r 6

0%

HC

V

32.5

RR

= 1

.56

[87]

82

Retr

osp

ecti

ve s

tud

y in

Am

eric

an A

sian

O

ver

60

% H

BV

100

HR

= 2

.6[88]

157

Retr

osp

ecti

ve s

tud

y in

Jap

an

Chi

ld C

cirr

hosi

s

Ove

r 6

0%

HC

V

40

0 R

R =

1.6

8 [89]

AFP

: a-f

eto

pro

tein

; HBV

: Hep

atit

is B

vir

al c

arri

er, H

CC

: Hep

ato

cellu

lar

carc

ino

ma;

HC

V: H

epat

itis

C v

iral

car

rier

; HR

: Haz

ard

rati

o; O

S: O

vera

ll su

rviv

al; R

R: R

elat

ive

risk

; TA

CE:

Tra

nsar

teri

al c

hem

oem

bo

lizat

ion.

Role of a-fetoprotein in hepatocellular carcinoma Review

Future Oncol. (2009) 5(6)892 future science group

AFP-negative HCC will be increased, and thus could limit the use of AFP in prognostication. Therefore, although many authors consider serum AFP to be potentially prognostic, espe-cially for HCC with massively elevated AFP lev-els of over 10,000 ng/ml, a single value of AFP at diagnosis should not be used alone to determine the prognosis of an individual patient.

Attempts have been made to enhance the spec-ificity and sensitivity of AFP by identification of an AFP isoform specific to HCC. Lens culinaris agglutinin (LCA)-reactive AFP (AFP-L3) is one of the promising isoforms of AFP that has been shown to be more specific for HCC and improve the detection of small HCC in particular [47–52]. Recent data have shown that a high proportion of AFP-L3 out of total AFP (defined as higher than 15%) is at least, if not more, as prognostic as the conventional AFP [39,53]. However, such use in routine clinical practice and further vali-dation in larger-scaled studies have been limited by the cost and the difficulty in standardizing an assay for AFP-L3.

AFP as a prognosticator when incorporated into staging systemsAnother way to enhance the prognostic ability of AFP is to combine it with other prognostic factors in a staging system for HCC. It has been reported that the addition of AFP in non-AFP inclusive staging could enhance its discrimina-tory power [54]. At present, more than ten stag-ing systems have been developed from different patient populations [55,56]. Despite much effort in identifying a universal staging for HCC, it appears that a different staging system is required for each different risk group of patients [57].

a-fetoprotein has been incorporated into a number of staging systems, includ-ing the Cancer of the Liver Italian Program score (CLIP) (Table 3) [58,59] and The Chinese University Prognostic index (CUPI) (Table 4) [60]. CLIP was developed from Caucasian hepatitis C-related HCC and has been externally vali-dated in patient populations from various geo-graphical regions. By taking into consideration a baseline AFP value of higher than 400 ng/ml, tumor morphology, Child–Pugh stage and the presence of portal vein thrombosis, the staging comes up with a total score of 6 with different prognosis. Recent data analyzing the intrascore heterogeneity has suggested that although the prognostic power of AFP may not be as potent as portal vein thrombosis or Child–Pugh stage, addition of AFP at certain scores could have syn-ergism in the prognostic power alongside with Ta

ble

1. S

um

mar

y o

f st

ud

ies

(199

9–2

00

8)

wit

h s

tati

stic

ally

sig

nifi

can

t re

sult

s o

n t

he

pro

gn

ost

ic v

alu

e o

f a

-fet

op

rote

in in

hep

ato

cellu

lar

carc

ino

ma

(co

nt.

).

Stag

e o

f d

isea

seTr

eatm

ent

mo

dal

ity

Nu

mb

erSt

ud

y d

esig

n &

pat

ien

t ch

arac

teri

stic

sA

FP, c

ut-

off

(n

g/m

l)R

esu

lts

Ref

.

Mis

cella

neo

us

po

pula

tion

(co

nt.)

Mix

ed63

81

Retr

osp

ecti

ve s

tud

y in

Tai

wan

O

ver

50

% H

BV

20–4

00

Ove

r 4

00

HR

: 1.

335

1.6

05

[90]

115

8 Re

tro

spec

tive

stu

dy

in It

aly

A

ppr

oxim

atel

y 5

0%

HC

V

Ap

prox

imat

ely

10%

HBV

20

21–4

00

Ove

r 4

00

OS:

12

15

7

mon

ths

[42]

50

6 Re

tro

spec

tive

mul

tice

nter

stu

dy

A

ppr

oxim

atel

y 18

% H

CV

9%

HBV

35

RR

= 1

.7

[62]

40

6 Re

tro

spec

tive

stu

dy

in It

aly

70

% H

CV

4

0 R

R =

1.4

8 [91]

1470

Re

tro

spec

tive

stu

dy

in H

ong

Kon

g

Mai

nly

HBV

4

00

HR

= 1

.59

[92]

926

Retr

osp

ecti

ve s

tud

y in

Hon

g K

ong

M

ainl

y H

BV

50

0H

R =

1.4

1[60]

587

Re

tro

spec

tive

stu

dy

in S

inga

por

e

Ove

r 8

0%

HBV

5

00

–49

99

50

00

–49

99

9 O

ver

50

00

0

RR

: 1.

2

1.8

9 2.

27

[63]

AFP

: a-f

eto

pro

tein

; HBV

: Hep

atit

is B

vir

al c

arri

er, H

CC

: Hep

ato

cellu

lar

carc

ino

ma;

HC

V: H

epat

itis

C v

iral

car

rier

; HR

: Haz

ard

rati

o; O

S: O

vera

ll su

rviv

al; R

R: R

elat

ive

risk

; TA

CE:

Tra

nsar

teri

al c

hem

oem

bo

lizat

ion.

Review Chan, Chan & Yeo

www.futuremedicine.com 893future science group

other factors [61]. For example, the combination of elevated AFP with portal vein thrombosis and Child C stage is associated with significantly poorer prognosis (HR: 9.74) than patients who have similar features in the absence of elevated AFP. The CUPI was derived from an ethnic Chinese group consisting mainly of hepatitis B-related HCC. Based on a summation of statis-tically weighted prognostic factors, the staging could differentiate three different prognostic groups with distinct survival. Apart from the inclusion of AFP, both CLIP and CUPI stag-ing systems share the similarity of derivation from a cohort with more advanced disease. Unpublished data on validation of CUPI in 859 consecutive patients from our center have shown that both AFP-inclusive staging CUPI and CLIP are more discriminatory than other staging, including the Barcelona Clinic Liver Cancer Classification system, Okuda and TNM staging. The strength of CUPI and CLIP is more apparent in stratification of the poor prognostic group (namely CUPI high-risk group and CLIP score 5–6) amongst inoperable HCC. It appears that AFP-inclusive staging plays a more impor-tant role in prognostication amongst patients with advanced HCC. Other AFP-inclusive staging systems, such as the French prognostic index [62] and the Clinical Prognostic Model [63], from the Singaporean group, seem to have similar properties.

AFP in monitoring the treatment of HCCNatural history of AFP trend in untreated HCC The discussion on the function of AFP in moni-toring treatment of HCC cannot be complete without discussing the natural history of the AFP trend in untreated HCC. The trend of serum AFP in HCC has best been described by Macintre et al. in 1972 and 1976 [64,65]. In these two observational studies, the serial AFP values of 40 patients with untreated HCC were followed up. For patients with elevated AFP at baseline, the AFP trend was shown to be static or rising during the course of the disease, except for in one patient who had a transient drop of AFP inbetween multiple blood transfusions. On the other hand, a number of patients with undetectable AFP at baseline were found to have detectable and rising trend of AFP value upon disease progression. Although those two studies may be limited by small sample size and an old-fashioned assay, it concurs with today’s experi-ence that a spontaneous and significant drop of AFP is uncommonly seen in HCC patients in the absence of effective treatment.

Serial AFP as a predictor of treatment responseThe first concept concerning the use of AFP in predicting treatment response could be dated back to 1972, as reported in the same

Table 2. Summary of studies reporting unfavorable pathological features in association with a-fetoprotein.

Tumor size Number of tumors

Portal vein thrombosis/vascular invasion

Tumor grade/differentiation

Others Ref.

+ + + + Okuda and TNM stage [42]

+ N/R + + HBV-related HCC [76]

+ N/R N/R N/R – [43]

+ + + - Bilobed involvement [93]

N/R N/R N/R + – [94]

N/R N/R + N/R – [95]

N/R N/R N/R + – [96] (+): Positive association’; (-): No association. AFP: a-fetoprotein; HBV: Hepatitis B viral carrier, HCC: Hepatocellular carcinoma; N/R: Not reported.

Table 3. The Cancer of the Liver Italian Program (CLIP) scoring system.

Parameter Points

0 1 2

AFP (ng/ml) Under 400 400 or higher

Child–Pugh score A B C

Portal vein thrombosis No Yes

Tumor morphology Uninodular & extension of 50% or less

Multinodular & extension of 50% or less

Massive or extension of 50% or more

Score: 0, 1, 2, 3, 4, 5–6. AFP: a-fetoprotein.

Role of a-fetoprotein in hepatocellular carcinoma Review

Future Oncol. (2009) 5(6)894 future science group

observational study [65]. AFP levels were mea-sured in 90 subjects with histologically con-firmed HCC. Amongst the 70 subjects with elevated AFP, the serial AFP levels of 41 subjects were followed up before and after treatment. Depending on efficacy of different modalities of therapy, two AFP patterns were observed: for all of the patients who underwent partial hepatectomy, the AFP level reduced rapidly and remarkably after removal of tumors, but this rose back at the time of recurrence, while for patients who received minimally effective systemic chemo therapy, despite a small and transient drop (<1 logarithm), the pattern of the serial AFP val-ues resembles those of untreated patients. The same group has published an updated result in 1976 based on a similar cohort of a larger sample size. A similar AFP trend was observed in patients who received surgery and systemic chemotherapy. The authors additionally demon-strated that a dropping trend in AFP was noted in five out of eight patients receiving transarterial chemotherapy. More importantly, while it was observed that such a drop of AFP was not associ-ated with radiologic regression, the decrease was also associated with doubling of survival time compared with the untreated subjects. These findings suggested that AFP response could be potentially useful in predicting survival and the efficacy of nonsurgical treatment.

Since the two reports in the 1970s, there have been case reports or series reporting the drop-ping trend of AFP in association with response to nonsurgical treatments; there have also been occasional trials incorporating the use of AFP response as an end point. In 1980, Johnson et al. demonstrated that the falls in serum AFP level

were associated with decrease in tumor mass after chemo therapy [66]. In 1999, Leung et al. reported that amongst patients who achieved complete pathological necrosis or minimally residual dis-ease after intensive chemotherapy, AFP has fre-quently fallen to zero or close to reference range [8]. Similar patterns have also been observed in selective internal radiation therapy using yttrium-90 microspheres [67]. In several clinical trials on transarterial chemo embolization, a drop of AFP of 50% after treatment has been employed to define serological responses [68–70].

However, there has been a lack of prospec-tive data with systematic evaluation on the use of AFP trend in HCC before 2005. Although the use of serial AFP monitoring has been com-monly practiced by physicians, three pivotal questions remain to be addressed for clinical use. First, a clinically meaningful drop of AFP has not been well defined. Do the patients need a significant fall of AFP to be qualified as AFP responders? Reported studies have empirically defined a 50% drop as an AFP response, while this has not been validated critically in prospec-tive series. Secondly, what is the association of AFP response with radiologic response? Could the change of AFP level identify ‘responder’ amongst patients with radiologic static disease? The last and probably the most important ques-tion is: do patients with post-treatment drop of AFP have better survival?

Recent data of AFP response for monitoring of treatmentIn 2005, a Taiwan group attempted to address part of these questions by correlating the AFP response with radiologic response and survival in

Table 4. The Chinese University Prognostic Index (CUPI) staging system.

Parameter Finding Score

TNM stage Stage I or stage II -3

Stage III -1

Stage IV 0

Disease symptom on presentation None Yes

-4 0

Ascites Yes No

3 0

AFP (ng/ml) 500 or more Less than 500

2 0

Serum total bilirubin (µmol/l) Less than 34 34–51 52 or more

0 3 4

Alkaline phosphatase (200 IU/l) 200 or more Less than 200

3 0

Score: ≤1 (low risk), 2–7 (medium risk), ≥8 (high risk).AFP: a-fetoprotein.

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a 45-patient cohort of HCC treated with thalido-mide [71]. AFP response was arbitrarily defined as 50% decrease in level after 4 weeks of treatment. It was found that the achievement of an AFP response was associated with more than 60% improvement in both disease-free and overall survival. More interestingly, they also reported an observation that the fall of AFP could be noticed as early as 4 weeks after treatment, and the radiologic response rate within the AFP responder group was only 30%. Such features have strongly suggested AFP to be more sensitive than conventional radiologic imaging in picking up responders early on in the treatment.

In the same year, our group published a Phase III randomized controlled trial compar-ing the efficacy and tolerability of two palliative chemotherapeutic regimens [72]. In the study, the superiority in radiologic response rate with the combination chemotherapy regimen of cisplatin, interferon a-2b, doxorubicin and fluoro uracil did not translate into a survival advantage. During the conduct of the study, serial serum AFP was measured prospectively in a scheduled manner (baseline, day 1 and 10 of each 3-week cycle of chemotherapy). The change of AFP in relation to radiologic response and survival was subsequently evaluated. Out of 188 trial sub-jects, 117 patients had elevation of baseline AFP before chemotherapy (defined as >20 ng/ml). We have attempted to quantitate AFP response by defining various degrees (10–50%) of the drop of AFP after treatment, and found that a drop of 20% or more just after 2–3 cycles of chemotherapy was associated with more than doubling of overall survival (13.5 vs 5.6 months; p < 0.0001) [73]. In multivariate analysis, the achievement of AFP response appeared to be the stringent prognostic factor (HR: 0.413; p < 0.001) [73]. AFP response was strongly cor-related with radiologic response. In addition to the predicted AFP response amongst radiologic responders, those who had radiologic static dis-ease but an AFP response tended to have better survival than those AFP nonresponders [73]. The results of this study further consolidate the clini-cal use of AFP response as a tool for monitoring treatment response. This suggests that clinicians could continue systemic treatment for advanced HCC as long as there is an AFP response, even when there is lack of impressive shrinkage of tumors. On the other hand, patients with ele-vation of AFP or a minor drop of AFP of less than 20% after chemotherapy have poor out-come, and should be considered for alternative treatment accordingly.

Limitation of AFP in monitoring of treatment response AFP response would be of limited use in AFP-negative HCC. Our data have shown that AFP level may falsely drop in a small proportion of patients who have a relatively low range of AFP (20–100 ng/ml) [73]. This is most likely due to the low specificity of AFP for HCC at this relatively low level. On the other hand, a small number of patients may have persistently elevated AFP due to uncontrolled viral hepatitis despite radiologic responses. Clinicians should be cautious in making use of the AFP trend in concluding response when baseline AFP level is lower than 100 ng/ml, or when there is clini-cal evidence of uncontrolled hepatitis. The use of AFP response in patients undergoing trans-arterial chemoembolization or embolization has not been studied systematically, but it is antici-pated that AFP response could reflect the treat-ment response in these clinical scenarios, as in the case of systemic chemotherapy as described above. Furthermore, the clinical value of AFP monitoring in predicting the response of the tar-geted therapy sorafenib is unclear, and future trials should assess this end point in view of the exceedingly low radiologic responses reported in Phase III clinical trials [74,75].

Conclusion & future perspectivea-fetoprotein is a useful and inexpensive, albeit old, tool in daily clinical management of HCC. Apart from its role in screening and diagnosis, AFP has a potential role in both prognostication and treatment monitoring. It appears that the prognostic ability of a single value of serum AFP at diagnosis is limited. AFP should best be evalu-ated together with other known prognostic fac-tors in the context of clinical staging for HCC. For most of the AFP-positive HCCs, the trend of AFP is useful in assisting physicians in moni-toring the treatment outcome in non surgical treatment, and this has been proven in the set-ting of cytotoxic chemotherapy. The use of the serological end point of AFP response, which is defined as a 20% drop of AFP 6–9 weeks after chemotherapy, could supplement the deficiency of radiologic assessment.

There are still missing gaps regarding the role of AFP in prognostication and monitoring of treat-ment in HCC. For prognostication, testing the use of the isoform AFP-L3 in a larger patient cohort, and direct comparison with AFP at different cut-off values, will be important. Further research in combining AFP with other novel markers, such as protein induced by vitamin K absence or

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antagonist-II (PIVK A-II) and Glypican-3, are warranted. On the other hand, the construction of a mathematical model by incorporating the change in AFP kinetics could be helpful to cli-nicians in monitoring and predicting treatment response. Until novel markers are developed and validated, AFP remains an important tumor marker and should be measured serially alongside imaging assessment in future clinical trials on the use of novel targeted therapy.

Executive summary

Background nPrognostication for hepatocellular carcinoma (HCC) is complicated by tumorous processes and co-morbidities of cirrhosis and hepatitis.

There is no consensus about a universal staging system for HCC. nRadiologic assessment with conventional radiologic criteria is not sensitive in the evaluation of response to nonsurgical treatment, and

would lead to underestimation of treatment efficacy. nSerum a-fetoprotein (AFP) is routinely measured in clinical practice for diagnosis or screening of HCC, but its role in prognostication

and monitoring of treatment is also important.

Prognostic role of AFP: AFP as an individual prognostic factor in HCCnSerum AFP at baseline is a modest adverse prognostic factor for both early and advanced HCC.nThe prognostic value of AFP is limited by its high cut-off value, its association with worse tumor pathology and its lack of sensitivity in

small tumors. nAn AFP isoform, AFP-L3, appears to improve the prognostic power, but its use is limited by the lack of standardized assays.

Prognostic role of AFP: AFP as a prognosticator when incorporated into staging systemsnAFP has been included into a number of staging systems to improve the prognostication ability. nBoth AFP-inclusive staging Cancer of the Liver Italian Program score (CLIP) and The Chinese University Prognostic index (CUPI) appear

to be more discriminatory than non-AFP-inclusive staging in advanced HCC.

AFP in monitoring treatment of HCC: natural history of AFP trend in untreated HCC nIn untreated patients with elevated AFP, the AFP value shows a static or rising trend during disease progression. nPatients with unelevated AFP at diagnosis could have a detectable and rising AFP level during disease progression nSpontaneous drop of AFP is rarely observed without effective treatment.

AFP in monitoring treatment of HCC: serial AFP as a predictor of treatment responsenMultiple case series have suggested that the AFP trend could be used in monitoring the treatment response in both surgical and

nonsurgical candidates. nSeveral clinical trials on transarterial therapy have arbitrarily made use of a 50% drop of AFP in defining AFP response.

AFP in monitoring treatment of HCC: recent data of AFP response for monitoring of treatmentnFrom the prospective clinical trial data, AFP with a drop of more than 20% (AFP response) after 6–9 weeks of cytotoxic chemotherapy

is associated with significant improvement in overall survival in HCC. nThe presence of an AFP response is associated with radiologic responses. nIn addition to the predicted AFP response in radiologic responders, AFP responders tended to have better overall survival than AFP

nonresponders amongst patients with radiologic static disease. .

AFP in monitoring treatment of HCC: limitation of AFP in monitoring of treatment response nThe use of AFP response may be less reliable in patients with a low range of baseline AFP (<100 ng/ml), or amongst patients with active

hepatitis or hepatitis B reactivation. nData regarding the use of AFP response in transarterial therapy and sorafenib treatment is lacking.

Conclusion & future perspective nSerum AFP should be interpreted in the context of clinical staging systems, rather than be used alone for assessment of prognosis.nAmongst AFP-positive HCC, the serial trend of AFP is of clinical value in identifying patients responding to chemotherapy despite

absence of radiologic responding disease. nFurther studies regarding the use of AFP response in transarterial therapy and targeted therapy are warranted.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the sub-ject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Affiliationsn Stephen L Chan

Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China

n Anthony TC Chan Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China

n Winnie Yeo Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China Tel.: +852 2632 2118 Fax: +852 2648 7097 winnieyeo@cuhk.edu.hk

Role of a-fetoprotein in hepatocellular carcinoma Review