Elsevier

Journal of Hepatology

Volume 56, Issue 5, May 2012, Pages 1112-1120
Journal of Hepatology

Research Article
Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis

https://doi.org/10.1016/j.jhep.2011.11.020Get rights and content

Background & Aims

Alpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: (a) correlation between AFP response and imaging response, and (b) ability of AFP, EASL, and WHO response to predict survival outcomes in patients with solitary HCC.

Methods

Six hundred and twenty-nine HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP ⩾200 ng/ml, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as >50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel–Byar methodologies. None of the patients received sorafenib.

Results

Three months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3%, and 93.3%, respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL, and AFP responders survived longer than non-responders (p = 0.006, 0.0001, and <0.0001, respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel–Byar methodologies (p <0.05).

Conclusions

Response by AFP and EASL are predictors of survival outcome in patients with solitary HCC. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies (LRTs).

Introduction

The incidence of HCC is increasing [1]; it has tripled between 1975 and 2005 [2]. Most patients present at an advanced stage beyond curative therapies, with sorafenib prolonging survival in advanced HCC [3], [4]. LRTs play a palliative role by inducing tumor necrosis, delaying progression, and improving survival [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. Following HCC treatment, it is the clinical standard of care to follow patients with triphasic contrast-enhanced computerized tomography (CT) and magnetic resonance (MR) imaging. The utility of tumor markers to assess response, such as AFP, remains controversial.

AFP is the only universally recognized tumor marker for hepatocellular carcinoma. It has been investigated as a potential screening, diagnostic, and prognostic tool [15], [16], [17]. Several studies have reported the capability of AFP response in prognosticating response to therapy and survival outcomes. Riaz et al. demonstrated that AFP response to LRTs can be used for assessing tumor response, time-to-progression, and overall survival [18]. Such studies have also been reported with resection, chemotherapy, and radiofrequency ablation [19], [20], [21].

The observation of response to any treatment by imaging or AFP is time-dependent [22]. Since treatment algorithms for HCC using LRTs are based on staged sessions separated by weeks/months, it is of interest to correlate these variables in a time-dependent fashion. Does AFP response correlate with imaging response, or is it better able to predict survival than imaging response [10], [23]? Establishing a correlation between AFP and imaging response has the potential to help assess response in clinical scenarios where standard cross-sectional imaging findings are equivocal.

Recently, three novel statistical methods were used to demonstrate the importance of imaging response in HCC; the study concluded that tumor response was a potentially significant surrogate of survival [22]. Given the well-known difficulties in assessing treatment response in HCC (inter-observer subjectivity, scan thickness, variable enhancement, regenerative/dysplastic nodules, perfusional abnormalities), we hypothesized that AFP response (objective, no inter-observer variability) may provide a simple, reproducible and potentially less subjective method of response assessment [10], [23]. We performed a comprehensive study addressing whether: (a) AFP correlates with imaging response by WHO and EASL methodologies, and (b) if AFP response can predict improved survival.

Section snippets

Materials and methods

This study was compliant with the Health Insurance Portability and Accountability Act and approved by the Northwestern University Institutional Review Board. Between 2000 and 2010, 629 HCC patients were treated with LRTs (90Y: N = 406; TACE: N = 223); this constitutes the source population. Patients were eligible for LRTs if they exhibited unresectable HCC and bilirubin <3.0 mg/dl (discussed at weekly multidisciplinary HCC conference). To create the study population for this specific analysis, we

Baseline characteristics

Table 1 describes the baseline characteristics. 28 (55%) were ⩾65, 30 (59%) were male, and 48 (94%) were treatment naive. Eighteen patients were diagnosed by biopsy. Tumor grade information was only available for 9 patients (well-differentiated: N = 3, moderately differentiated: N = 2, poorly-differentiated: N = 4). Baseline imaging, laboratory characteristics and cancer stages are also summarized.

AFP-imaging response correlation

Table 2 summarizes the correlation between AFP and imaging response by WHO and EASL guidelines at 3 and 6

Discussion

HCC patients usually present beyond potentially curative options [42]. In this scenario, systemic agents and LRTs have an established palliative role [3], [4], [7], [8], [12], [26]. Consequently, response assessment following LRTs has also been extensively studied in order to develop appropriate guidelines for accurate response monitoring [10], [26], [33]. AFP may play a potential role in this scenario, where, combined with imaging, it may improve the ability to assess treatment response and

Conclusions

This study investigates AFP response in a time-dependent fashion. AFP response assessment is simple, reproducible, operator-independent and is highly sensitive for detecting radiologic response. Response by AFP and EASL predicts improved survival. Consideration should be made to develop HCC treatments that not only prolong TTP, but also elicit AFP and tumor response [22]. Future research should focus on incorporating AFP in response assessment methodologies.

Financial support

There was no funding provided for this study. R.S. and R.A.O. are supported in part by NIH Grant CA126809.

Conflict of interest

The underlying research reported in this study was funded by the NIH Institutes of Health.

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