International Hepatology

The resurrection of alphafetoprotein

Morris Sherman*

Department of Medicine, University of Toronto and University Health Network, Toronto, Canada

COMMENTARY ON: Theoretically, alphafetoprotein (AFP) measurements may be

Alphafetoprotein response after locoregional therapy for

hepatocellular carcinoma: oncologic marker of radiologicresponse, progression, and survival.

Riaz A, Ryu RK, Kulik LM, Mulcahy MF, Lewandowski RJ,Minocha J, Ibrahim SM, Sato KT, Baker T, Miller FH, NewmanS, Omary R, Abecassis M, Benson 3rd AB, Salem R. J Clin Oncol2009;27(34): 5734–42. Epub 2009 Oct 5. Copyright (2009).

Reprinted with permission from the American Society of Clin-ical Oncology in the format Journal via the Copyright ClearanceCenter.Abstract: Purpose: Alphafetoprotein (AFP) is considered to be anindicator of tumour activity in hepatocellular carcinoma (HCC). Wepresent a novel correlation of AFP response to radiologic response,time-to-progression (TTP), progression-free survival (PFS), and over-all survival (OS) in patients treated with locoregional therapies.Patients and methods: Four hundred sixty-three patients with HCCwere treated with chemoembolization or radioembolization at ourinstitution. One hundred twenty-five patients with baseline AFPhigher than 200 ng/mL were studied for this analysis. AFP responsewas defined as more than 50% decrease from baseline. One hundrednineteen patients with follow-up imaging were studied for the AFPimaging correlation analysis. AFP response was correlated to radiologicresponse, TTP, PFS, and OS. Multivariate analyses were performed.Results: Eighty-one patients (65%) showed AFP response. AFPresponse was seen in 26 (55%) of 47 and 55 (70%) of 78 of patientstreated with chemoembolization and radioembolization, respectively(P = .12). WHO response was seen in 41 (53%) of 77 and 10 (24%) of42 of AFP responders and nonresponders, respectively (P = .002). Thehazard ratio (HR) for TTP in AFP nonresponders compared withresponders was 2.8 (95% CI, 1.5–5.1). The HR for PFS was 4.2 (95%CI, 2.4–7.2) in AFP nonresponders compared with responders. TheHR for OS in AFP nonresponders compared with responders was5.5 (95% CI, 3.1–9.9) and 2.7 (95% CI, 1.6– 4.6) on univariate andmultivariate analyses, respectively.Conclusion: The data presented support the use of AFP response seenafter locoregional therapy as an ancillary method of assessingtumour response and survival, as well as an early objective screeningtool for progression by imaging.� 2010 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.

Journal of Hepatology 20

Keywords: Alphafetoprotein; Hepatocellular carcinoma.* Address: Toronto General Hospital, Room # NCS 11C 1252, 585 UniversityAvenue, Toronto, ON, Canada M5G 2N2. Tel.: +1 416 340 476; fax: +1 416 5912107.E-mail address: morris.sherman@uhn.on.ca.

informative for the clinician managing patients at risk for or suf-fering from hepatocellular carcinoma (HCC) under several differ-ent circumstances. These include risk stratification, surveillance,prognosis, and monitoring of response to therapy. However, stud-ies have suggested that for most of these circumstances the valueof measuring AFP is limited.

AFP testing might be used for hepatocellular carcinoma riskstratification, because the risk of future HCC is higher in thosewith chronically elevated AFP than those with persistently nor-mal AFP [1,2]. Although chronically elevated AFP indicates anincreased risk of developing HCC, this is usually in patientsalready known to be at risk for HCC, and who are likely alreadyunder surveillance for other reasons, such as the presence of cir-rhosis or chronic hepatitis B. Thus, measuring AFP does not helpdetermine who should or should not undergo surveillance and istherefore not really useful for risk stratification.

Historically, AFP was used as a diagnostic test to confirm thepresence of HCC in a patient presenting with liver failure and/or a mass in the liver. This was before the availability of ultra-sound or computerized tomography when a diagnosis of HCCcould only be made by angiography or by percutaneous biopsyof an obvious liver mass. However, with the advent of ultrasonog-raphy, computerized tomography, and magnetic resonance imag-ing the importance of AFP as a diagnostic test has declined.

Very high AFP concentrations in serum are diagnostic of HCC(in the absence of a testicular tumour), but anywhere between20% and 80% of patients with HCC do not have elevated AFP,depending on tumour size at diagnosis [3–5]. However, sinceradiology is so highly specific, and is always required to confirmthe diagnosis of HCC and to plan therapy, AFP testing seemssuperfluous. Patients in whom HCC is not initially suspected, suchas those presenting with non-specific abdominal complaints, arelikely to have imaging such as an ultrasound, which will identifyif a mass is present. This would need to be confirmed as HCC byadditional radiology. An occasional patient will have a diffuselyinfiltrating HCC that is not detectable by imaging and under thosecircumstances the AFP value might help confirm the diagnosis.

In patients diagnosed with HCC an elevated AFP is an adverseprognostic sign [6,7]. However, this is sufficiently variable that itis of little clinical use. This test has not been used to excludepatients from any particular form of therapy that might be indi-cated for their lesion. For example, even though an elevated AFPindicates a higher risk for HCC recurrence post liver transplant [8]it is not used to exclude patients from receiving a new liver.

In 2001, I wrote an ‘‘obituary” for the use of alphafetoprotein(AFP) as a surveillance test for hepatocellular carcinoma (HCC)

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International Hepatology

[9]. Nonetheless, AFP measurement remains in common use forsurveillance in patients at risk for HCC, despite ample evidencethat it is not a good surveillance test [10–12]. AFP measurementclearly has not died as a surveillance test, although hopefully itis in its death throes. However, measurement of AFP seems to havebeen resurrected as a component of post-treatment follow-up.

AFP has long been used to monitor the response to HCC ther-apy, a fall in AFP concentration being thought to indicate a goodresponse to treatment. However, this has seldom been correlatedwith outcomes such as survival or any of the other commonlyused endpoints in oncology, such as time-to-progression or pro-gression-free survival.

Recently there have been three studies that have correlated adecline in AFP concentration after treatment with such endpoints.Chan et al. [13] evaluated AFP response in patients undergoingsystemic chemotherapy. Riaz et al. [14] correlated AFP responsewith tumour response by WHO and EASL criteria, as well as withoverall survival, time-to-progression, and progression-free sur-vival in patients undergoing treatment with either chemoemboli-zation or radioembolization. Finally, Chen et al. [15] evaluated AFPresponse in patients undergoing treatment with thalidomide.

All three studies showed some degree of correlation betweenthe decline in AFP concentration after treatment and outcomes.This led the authors in all three studies to recommend that AFPmonitoring should be included as part of clinical trials of HCCtherapy, particularly since treatment with molecular-targetedagents might show survival advantage without showing majorchanges in tumour size. Riaz et al. [14] make the point that it isstandard to perform radiology 3 months after treatment and atthree monthly intervals thereafter, while an AFP can be measuredeasily and more frequently, and might predict response to treat-ment sooner than radiology. Perhaps this is so, but radiologyremains the gold standard to assess response, and at least in theirpaper, the AFP response was sufficiently heterogeneous that itcannot be used to replace radiological assessment of response.Of course, in HCC it is uncertain whether even radiologicalresponse correlates well with survival. Only a few studies haveevaluated this. Given the severity of underlying liver disease inmany patients, death from liver failure is a confounding factorin assessing outcome that has nothing to do with tumourresponse. Riaz et al. [14] did not compare AFP as a predictor ofoutcome vs. radiological response. Only if AFP is a better predic-tor of outcome than radiology will it be a useful test.

Riaz et al. [14] also comment that the converse of their findingsalso needs further study, namely whether increasing AFP post-treatment correlates with a worse outcome. However, even if thiswere true measuring AFP would once again only be useful if thecorrelation between AFP and poor prognosis was better than thecorrelation between radiological progression and poor prognosis.

AFP concentration in serum is a function of tumour burden.The decline in AFP concentration seen after therapy is likely areflection of decline in tumour burden, and the improvement inoutcome also likely related to a decline in tumour burden. How-ever, shrinkage of the tumour might not be a good indicator ofoutcome with new agents that inhibit tumour metabolic path-ways, such as sorafenib. In the registration studies for this agentthe response rate, in terms of tumour shrinkage was only about3%, but nonetheless, survival was enhanced [16,17]. There is asyet no information on how AFP behaves under these circum-stances. It may be that there is little correlation between AFPand outcome, particularly since the tumour burden does notseem to change greatly.

940 Journal of Hepatology 201

AFP measurement has been around for a long time, but inmodern times has not found a niche that everyone agrees is use-ful. It may be that it will be a useful measure of treatment effi-cacy, but I am not holding my breath. I suspect that the resultswill be too heterogeneous to be useful. At present I remainunconvinced that it contributes much to the management ofpatients at risk for or with HCC.

Conflicts of interest

The Authors who have taken part in this study declared that theydo not have anything to disclose regarding funding or conflict ofinterest with respect to this manuscript.

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