Prognostic value of α-fetoprotein and des-γ-carboxy prothrombin responses in patients with hepatocellular carcinoma treated with transarterial chemoembolization

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death globally [1]. Unless HCC is diagnosed at an early stage when liver transplantation, hepatic resection, and radiofrequency ablation are feasible, a poor prognosis is expected due to the limited treatment options [2]. Although several treatment modalities have been applied to advanced HCC, [3, 4] only trans-arterial chemoembolization (TACE) [5‐10] and Sorafenib [11] exhibit survival benefit. Accordingly, TACE and Sorafenib are recommended for HCC in the intermediate and advanced Barcelona Clinic of Liver Cancer (BCLC) stages, respectively [12, 13].

Alpha-fetoprotein (AFP) was first described about 40 years ago and is proposed as a screening and diagnostic tool for HCC [14‐19]. Recently, the national comprehensive cancer network guidelines also proposed AFP as a alternative tool for diagnosing HCC [20]. Though there is no definitive evidence to support an absolute value of AFP cut-offs [21, 22]. Moreover, several studies have reported that changes in AFP levels may predict treatment outcome [23‐25]. A recent study showed a correlation between AFP response and radiologic response, time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) in patients treated with loco-regional therapies [26, 27]. In contrast, controversies regarding the diagnostic role of des gamma carboxy prothrombin (DCP) remain. However, the clinical significance of DCP is emphasized in Asia [28]. Recently, its clinical usefulness was emphasized in a different ethnic group [17, 29, 30].

The primary aim of this study was to determine the clinical utility of AFP and DCP as predictors of treatment outcome in patients with HCC undergoing TACE.

Tumor response evaluation using CT or MRI after systemic chemotherapy or loco-regional treatment is widely used to decide whether to treat further or change treatment strategies. However, high cost, radiation hazard, and associated cancer risks are drawbacks to these response evaluation modalities, [34] whereas tumor marker evaluation after anti-cancer treatment is rapid, easier to estimate, and less expensive. Thus, the clinical implications of tumor response evaluation using tumor markers have been continuously investigated [35‐38].

This study also showed that AFP response can be an independent predictor of OS in patients undergoing TACE as the first treatment modality, whereas radiologic response was not significant in predicting PFS and OS. Several previous studies have also proposed the clinical usefulness of AFP response. Riaz et al. [27] proposed AFP response after loco-regional therapy as an ancillary method of assessing tumor response and survival, as well as an early objective screening tool for progression by imaging. Furthermore, the supplementary role of AFP response for tumor response evaluation and prediction of better survival and extrahepatic metastasis in patients undergoing hepatic arterial infusional chemotherapy, localized concurrent chemoradiation therapy, and anti-angiogenic treatment such as Sorafenib and Bevacizumab has been proposed [26, 36, 37]. However, to our disappointment, AFP response didn’t show its novel value of prediction in PFS of HCC patients. It might be caused by that all subjects did not have the same follow-up period and timing of assessment scan, furthermore definition of PFS might be subject to bias. So it could be a limitation of our study.

The baseline AFP level in our study also showed statistical significance for predicting PFS in a multivariate analysis (P = 0.035). Similarly, the significance of the prognostic role of baseline AFP level has been accepted in previous studies and several staging systems [39, 40]. In contrast, baseline DCP level was significantly associated with OS in our study. Several other studies investigated the usefulness of baseline DCP level, and demonstrated that higher baseline DCP level was significantly correlated with poor prognosis in HBV-related HCC and with a higher risk of recurrence after curative treatment [35, 41]. Although the reasons why HCC with a higher baseline DCP level is related to poor prognosis remain uncertain, it may in part be due to the fact that the higher baseline DCP level is significantly associated with the presence of vascular invasion, intra-hepatic metastasis, tumor size, Tumor-Node-Metastasis (TNM) stage, and a high frequency of tumor recurrence [42].

When we consider that only viable HCC can produce AFP and that the mRECIST criteria were developed to evaluate the amount of viable HCC, it is not surprising that AFP response showed a significant correlation to tumor response evaluated by mRECIST criteria. Although DCP is also produced by viable HCC, DCP response was not correlated with mRECIST response. This may be because, in contrast to AFP, DCP can be produced in surrounding non-cancer tissues after being stimulated by HCC [42], which might have attenuated the correlation between DCP response and radiologic tumor response by the mRECIST criteria. This also supports our result that DCP response was not significant for predicting PFS or OS after TACE. Because the WHO criteria do not consider specific situations (such as necrosis and the viable portion of HCC) neither the AFP nor DCP responses were correlated with radiologic response evaluation by the WHO criteria.

We further analyzed patients showing discordant outcomes assessed by cTM response and radiologic response, because in this situation physicians must decide whether to maintain the current treatment modality or change it. Although baseline albumin level was identified as a predictor of discordance between cTM response and radiologic response, there was no statistical difference in OS between cTM responders with radiologic non-response and those with cTM non-response but radiologic response (33.8 vs. 7.5 months; P = 0.354). Because a longer OS was noted in patients with cTM response and radiologic non-response in spite of the lack of statistical significance and because the clinical significance of the cTM response might have been attenuated due to the small discordant sub-population, a larger study is needed to reveal the role of cTM response in these cases. In the same context, if the role of cTM response in discordant cases can be demonstrated, cTM non-responders who experience radiologic response may need to have their disease progression monitored closely.

Interestingly, baseline GGT level was identified as an independent prognostic factor of PFS, similar to a recent study that proposed that GGT level is an important prognostic factor in patients with BCLC-intermediate HCC treated with TACE [43]. Considering that GGT level is associated with oxidative stress and resistance to platinum drugs [44, 45], the prognostic value of GGT levels for discriminating subgroups with different risks of disease progression or mortality should be determined.

This study has limitations. First, this was a retrospective study with a relatively small sample size. Also, some study subjects were included in article published recently and analyzed about prognostic value of AFP and DCP by the same institute [46]. However, the aim of this study is clearly different from previous one focusing on the prognostic value of baseline AFP and DCP in all patients with treatment-naïve HCC. In the present study, we focused on the prognostic value of the responses of AFP and DCP by TACE. Second, we excluded patients with low baseline AFP or DCP levels before TACE. Our results might not apply to patients with low baseline AFP or DCP levels. However, because we simply investigated the prognostic values of AFP and DCP response simultaneously, we inevitably selected only patients with elevated AFP and DCP in spite of a potential selection bias. Third, because AFP can be confounded by hepatic necroinflammation, the predictability of the AFP response might have been influenced. AFP response could be poor in patients with persistently elevated ALT after TACE. Furthermore, patients with persistently elevated ALT are reportedly associated with poor OS due to more rapid impairment of the liver function. Physicians should be cautious in applying baseline AFP or AFP response to patients suffering from active hepatitis or to those without elevated baseline AFP and DCP levels. Finally, considering that TACE was introduced as a palliative treatment for intermediate-stage HCC, many HCC patients with BCLC stage A in our study who were indicated for curative treatment underwent TACE. For several reasons, these patients decide to take TACE. Some of them refused surgical resection and others are unable to surgical resection because of their medical condition such as old age(>70 yrs) and poor general conditions (ECOG PS ≥ 2 and/or cachexia). Furthermore, sub-segmental TACE using iodized oil and a gelatin sponge remains an important therapeutic option for patients with HCC in Japan [47]. This is not surprising, because sub-segmental TACE as a curative treatment modality has become widely accepted in Korea as well as in Japan.

The present study demonstrated the clinical importance of AFP response and baseline DCP level for predicting OS in treatment-naïve patients with HCC undergoing TACE as an initial treatment modality. In the future, a treatment algorithm incorporating tumor marker response and radiologic response, which compensate for each other’s drawbacks, should be established to more accurately predict treatment outcomes after TACE.