SCORES FOR RETREATMENT WITH TACE

The first score to highlight the importance of retreatment strategies with TACE was the Assessment for Retreatment with TACE (ART) score, Table 8. It was proposed by Sieghart et al in a cohort of 107 patients with BCLC stage A and B who had received at least two TACE cycles within 90 days. The score included the increase in pre-TACE 2 Child-Pugh score +1 or ≥2 points (+1.5 or +3 points, respectively), AST increase >25% (+4 points) and the absence of radiological tumor response (+1 point). They defined two groups (0–1.5 and >2.5 points) with survival significantly higher in the first group (23.5 vs 6.6 months; P<0.001).32

One of the strong points of this score is the consideration of the dynamic change in liver function status and the radiologic response of the tumor. Unfortunately, the liver function assessment was still performed with Child-Pugh score, which raises a lot of concerns, as discussed earlier. One of the pitfalls of the ART score is the presence of significant difference for different TACE techniques (p=0.002).42,43

Indeed, it became clear that intermediate stage HCC patients receiving TACE need a proper prognostic score that offers valid clinical prediction and supports proper decision-making. Hucke et al, proposed the STATE score and START strategy where they made use of the predictive power of ART score for treatment response and supported it with more parameters to identify patients unfit for TACE as a treatment modality from the start. The STATE score included serum albumin level (g/L) as a set of points, which is further subtracted by 12 points each, if the tumor volume is beyond the up-to-7 criteria and/or CRP levels are ≥1 mg/dL.31


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The STATE score identified two groups (<18, ≥18 points) with prognosis of 5.3 vs 19.5 months respectively, P<0.001. Maehringer-Kunz et al validated the STATE score and START strategy and they concluded that the STATE score was an unreliable tool to determine the suitability for first TACE, but the START strategy offered a slight increase in the prognostic ability of ART score. However, other studies concluded the limited ability of the single use of either of them.44

In 2015, Adhoute et al proposed ABCR score (Table 9) based on baseline BCLC stage (A =0, B =+2 and C =+3 points) and AFP level (>200 ng/mL =+1 point) in addition to pre-second TACE Child-Pugh score (≥2-point increase =+2 points) and radiologic tumor response (if yes =−3 points). They concluded that patients with ABCR score ≥4 prior to the second TACE will not benefit from the intervention.45 Unfortunately, Kloeckner et al reported the poor prognostic ability of ART and ABCR scores in a validation study which included 176 patients, they also reported that these scores were not sufficient to rely on for valid clinical decision-making regarding stopping TACE sessions.43

Consequently, Pinato et al validated and compared both ART and HAP scores in a cohort of 660 patients. They showed that HAP score had better prognostic power while ART score had better prediction of TACE failure. This conclusion is consistent with the factors on which both scores are based, as ART score considers the radiologic response which is an important indicator of treatment failure with TACE.46,47

RETREATMENT OF REFRACTORY CASES WITH TACE

The key point in retreatment of patients with TACE after declaring failure is considering the potential risk and benefits as survival outcomes. This should be guided using prognostic scores, especially those considered for retreatment such as ART or ABCR score. Patients with >2.5 points in ART score were found to have shorter survival and more adverse events after second TACE. Likewise, patients with ABCR score of ≥4 were found to be at higher risk, with no benefit of retreatment. However, the predictive power of those scores has been questioned and it is doubtful whether they led to accurate decision-making in many studies. Noteworthy, in a large validation study of 627 Japanese patients, ART score was also found to be non-predictive of outcomes after the second TACE.42 In another study, ABCR and ART scores were validated and both of them were found to be of no aid in clinical decision-making regarding further TACE sessions. In this context, it has been agreed that this poor performance of ART and ABCR scores is due to the lack of response to TAE as a parameter in both scores.43,48,49

To guide decision-making regarding retreatment, we should take into consideration that TACE also has an impact on liver functions. It has been found that time to decompensation was shorter in those patients who had retreatment with TACE than those who switched to sorafenib.50 Also, it has been reported that overall survival was better in patients who received <2 unsuccessful TACE procedures than those who had three or more successive TACE procedures before sorafenib administration.2 This was also evidenced in another study that showed the association of progressive increase in CP score and retreatment with TACE. With the emergence of regorafenib and the better outcomes achieved, it is a must to reconsider the benefits and risk of retreatment with TACE.51

TREATMENT MODALITIES BEYOND CONVENTIONAL TACE FOR INTERMEDIATE STAGE HCC

Drug-eluting bead (DEB)-TACE and transarterial radioembolization (TARE) vs conventional TACE

TACE has been the standard of care for intermediate stage HCC for many years. However, other treatment modalities have been debated for a long time. In Table 10, we summarized different studies which comparted different treatment options in terms of objective response and patient’s survival. Noteworthy, DEBs provided a great option to overcome the drawbacks of conventional TACE and increased the intensity and duration of ischemia in the target lesion in addition to improving drug delivery to the tumor without significant systemic action.52 Despite the previously mentioned positive effects, in a meta-analysis by Facciorusso et al in 2016 which included eight studies and 1,449 patients with intermediate stage HCC, they reported that DEB-TACE showed no superiority over conventional TACE in terms of survival.53 One of the limitations of DEBs is that it needs proper size selection so that small particles can reach the tumor, and it requires a super-selective approach which is not feasible in all centers.52 The only positive result that was noted in several randomized controlled trials in favor of DEB-TACE, was the better safety profile with significant decrease in serious liver-related adverse events and systemic side effects, particularly alopecia, in comparison to conventional TACE.54 Recently, DEBs are beyond loading with conventional anti-neoplastic drugs. Recent studies reported using tyrosine kinase inhibitors, bevacizumab and new compounds such as SW43-DOX.55,56

(To view a larger version of Table 10, click here.)