Publication bias

The funnel plots were evaluated and seemed symmetrical. No publication bias was observed and Egger’s tests for asymmetry were not significant (P-value=0.851 for OS, P=0.806 for RFS and P=0.573).


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Sensitivity analysis

Sensitivity analyses were performed in order to examine the stability of the results (data not shown). The pooled HRs suggest that results were statistically reliable because they were not changed substantially omitting 1 study at a time.

Discussion

In this meta-analysis of >10,000 individuals, we evaluated what factors are capable of predicting OS and RFS in HCC patients treated with RFA. As most studies and meta-analyses considered RFA vs surgery, this is the first meta-analysis to have evaluated only clinical or laboratory parameters in this subset of patients without comparing with surgery.

Our study showed that Child–Pugh B was a significant predictor of poor OS (HR =2.32) and RFS (HR =1.24). Our data showed that other liver function parameters are also highly predictive of poor OS (bilirubin, presence of portosystemic circles, prothrombin, and albumin), whereas only Child–Pugh B vs Child–Pugh A was predictive of poor RFS. The severity of the underlying liver disease may also be a risk factor for the development and recurrence of HCC, suggesting the importance of the role of the liver function in these patients. A recent study by Wei-Yu Kao et al12 evaluated ALBI grade and platelet-albumin-bilirubin grade as prognostic and predictive indexes in patients treated with RFA. The data highlighted a significant difference in OS between Child–Pugh A and ALBI grade 1 vs Child–Pugh A and ALBI grade 1 and 2. This study showed for the first time that ALBI grade can better stratify these patients. Their results have also been confirmed by Oh Is et al41 and CH Lo et al.42 Also, our meta-analysis confirms that ALBI grade is currently one of the best indexes for predicting survival in this patient subset. As shown by other works at different disease stages,43–45 ALBI grade is better predictive index than Child–Pugh, as the latter is composed of 5 arbitrary parameters, whereas the former is formed by only 2 non-arbitrary parameters (albumin and bilirubin). Interestingly, this meta-analysis showed that the presence of the portosystemic collateral is a predictive factor of OS. As for liver resection, the presence of portal hypertension is a well-known predictor for survival, regardless of the Child–Pugh class.46,47

Another factor evaluated in this meta-analysis was the pre RFA tumor size. The size of the nodules, taken as a continuous variable, was not predictive of either OS or RFS, because many studies included in the meta-analysis considered only small nodules. Conversely, when we evaluated the size of the nodule as a cutoff value, we observed that the maximum benefit of RFA was reached when nodules were <2 cm, confirming the literature data48 and supporting the choice of RFA as the first treatment option. For tumors >2 cm, other factors must also be considered. As for the number of nodules, our meta-analysis showed that the presence of multiple nodules is a negative prognostic index both in terms of OS (HR =1.59) and RFS (HR =1.62): therefore, in most nodular patients, especially if operable, RFA is not recommended.

In regard to etiology, our results showed that HBV-positive patients have better OS and worse RFS (HR =1.16) when treated with RFA. These data, however, are difficult to explain, particularly for the contrasting data between OS and RFS. In all considered studies, etiology was regarded as presence or absence of HBV or HCV infection. Only in 1 study,31 the different etiologies were directly compared, highlighting our data as a benefit in terms of OS in HBV-positive patients compared with HCV-positive patients with a 56% reduction in death risk.

Concerning the predictive role of alpha fetoprotein, our meta-analysis revealed that only a cutoff of 20 ng/mL can predict OS and RFS outcomes in these patients.

Although NLR might play a role in predicting OS and RFS, data are currently limited and cannot be employed in normal clinical practice.

Limitations

Among the limitations of our meta-analysis are the low number of published studies considered for some subgroup analyses by prognostic factor, and the consideration of studies only reporting HR and 95% CI, thus potentially introducing further bias. Another limitation is that in this is a meta-analysis of aggregate patient data and not of individual patient data.

CONCLUSION

Our meta-analysis highlighted that the maximum benefit of RFA in terms of OS and RFS is reached when all the following features are present: Child–Pugh A, ALBI score 1, single-nodule tumor sized <2 cm, and alpha-fetoprotein <20 ng/mL. The role of the different etiologies still remains to be clarified. These clinical/laboratory data should also be used to better stratify patients in future RFA randomized trials.

Acknowledgments

The authors would like to thank Veronica Zanoni and Cristiano Verna for editorial assistance.

The abstract for this paper was presented at the 27th Annual Conference of The Asian Pacific Association for the Study of the Liver (APASL), March 14–18, 2018, New Delhi, India and was published in Hepatology International Volume 12, Supplement 2, 2018.

Disclosure

The authors report no conflicts of interest in this work.


Andrea Casadei Gardini,1 Giorgia Marisi,2 Matteo Canale,2 Francesco Giuseppe Foschi,3 Gabriele Donati,4 Giorgio Ercolani,5,6 Martina Valgiusti,1 Alessandro Passardi,1 Giovanni Luca Frassineti,1Emanuela Scarpi7

1Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 2Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 3Department of Internal Medicine, Degli Infermi Hospital, Faenza, Italy; 4Internal Medicine, Infermi Hospital, AUSL Romagna, Rimini, Italy;5Department of General Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy; 6Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 7Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 


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Source: OncoTargets and Therapy.
Originally published October 5, 2018.