06635607

March 09, 2024, 11:47

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Dear Authors, We would like to congratulate with you for the publication of the article “Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus.” on World Journal of Gastroenterology. We really much appreciated your work as it reinforces the modern concept that multimodal treatment of advance HCC is of utmost importance to achieve good survival outcomes in a setting featured with dismal prognosis. Still, we believe that some comments are in order. As far as methodology of the study is concerned, it is needless to say that the quality of the evidence that can be drawn from a retrospective study is dismal. Hence, we would recommend not to state that a superiority of the triple regimen TACE, PD-1 inhibitor, Lenvatinib has been proven. In fact, as you mentioned in the section dedicated to the limits of the article, the small dimension of the study population, its heterogeneity, the retrospective nature of the study along with the selection bias jeopardize the possibility to apply your conclusion to a specific population of HCC patients. In particular, we would suggest, for future research, to select a more specific population of advanced HCC. Although you showed a statistical homogeneity between the two study groups, it must be highlighted that the rate of patients with extra-hepatic disease in the two groups tends to statistical significance and it could be supposed that, with a higher numerosity, the difference could have reached it. This would have meant that one of the possible reasons for the inferiority of the dual regiment in terms of oncological outcomes could be attributed to the greater biological aggressiveness or advanced stage of HCC rather than to the true inferiority of the treatment. Moreover, it could be objectionable the reason why TACE was performed in patients with HCC with very advanced neoplastic portal vein thrombosis and distant metastasis. We would suggest to apply more stringent selection criteria such as exclusion of metastatic HCC and PVTT type III and IV. This would help identify a specific population of HCC patient that could benefit from the advantages you advocate a triple regimen seems to provide them with. Another suggestion to improve the applicability of the study would be to limit the use of immune-check point inhibitors to a single specific drug rather than to a wide group of different molecules and to specify the criteria that prompt the use of a specific molecule over another. Finally, it has to be noted that the vast majority of the population was affected by HBV-related liver cirrhosis. We know about the trend in changing prevalence of the etiology of liver cirrhosis in Western countries, with increasing rate of dysmetabolic and alcoholic etiologies over the viral ones, mainly due to the efficacy and wide distribution of the treatment of HCV with DAA. One could postulate that HCC harbored on HBV-related cirrhosis could be differently aggressive compared to other etiologies making it difficult to draw similar conclusion in a Western setting, where other etiologies are more prevalent and related HCC can possibly have different biological profile. From a mere linguistic point of view, we would suggest the following correction: - Line 3 of the introduction, change “concerning” with “accounting for”. - Inclusion criteria n° 9: we would express this concept saying that the presence of extra-hepatic disease would not represent an exclusion criterion. - In Table 1, the unit for bilirubin is clearly expressed in mmol/l rather than mg/dl. - There is no agreement between the Figure 2C (p = 0.029) and what expressed in table 3 (p = 0.009). - In the last line of first paragraph on page 852, we would rephrase as following “such association was not investigated”. - Line 5 and 6 on the same paragraph, we would rephrase as following: “It means that patients with TACE-induced sever liver injury may have limited efficacy as liver function deterioration can hinder the administration of systemic drugs”.

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