Response to letter entitled Re: Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients

Dear Editor, We would like to thank Professor Zhu and colleagues for their great interest in our work and for sharing their interesting thoughts on it with us. As underlined in their comments, ours is a retrospective work and, therefore, characterised by biases and gaps in the data collection and the balancing of the subgroups that could certainly have influenced the results obtained from our analyses. These important limitations have been widely reported in the discussion of our work, so much so that we have preferred to define it as a proof-of-concept study due to its not extremely robust statistical basis [[1]Persano M. Rimini M. Tada T. et al.Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients.Eur J Cancer. 2023; 189112933Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. As rightly hypothesised in their suggestions, the subgroup of patients who performed transarterial chemo-embolization (TACE) second line had favourable baseline characteristics that could have influenced the better survival outcomes obtained compared to patients treated with sorafenib second line. In fact, patients treated with TACE more frequently presented intermediate-stage disease (p < 0.01), in the absence of extrahepatic involvement (p < 0.01), and with a history of previous locoregional treatments received even before the first-line systemic therapy (p < 0.01). On the other hand, the subgroup treated with sorafenib included more patients of Eastern ethnicity (p < 0.01), and with preserved liver function, both in terms of Child–Pugh score (p = 0.02) and in terms of Albumin–Bilirubin grade (p < 0.01). Unfortunately, the gaps in the data regarding baseline characteristics before the second-line therapy prevented us from using more robust statistical techniques, such as inverse probability of treatment weighting and propensity score matching, to balance subgroups and thus obtain more reliable results as we have done in other retrospective studies performed by our research group [2Casadei-Gardini A. Rimini M. Tada T. et al.Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population.Eur J Cancer. 2023; 180: 9-20Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 3Rimini M. Rimassa L. Ueshima K. et al.Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.ESMO Open. 2022; 7100591Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. In conclusion, our study, although including a large patient population, is to be considered a proof-of-concept and, as such, represents only the starting point in the context of the search for the most effective and safest therapeutic strategies for hepatocellular carcinoma patients. As wisely suggested in the letter comments, it is necessary to perform retrospective analyses using more robust statistical techniques and, even better, prospective studies clarifying the best treatment paradigms in a field currently in constant evolution thanks to the introduction of new therapies and combinations [[4]Reig M. Forner A. Rimola J. et al.BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.J Hepatol. 2022; 76: 681-693Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar]. With this aim, international cooperation is needed for the creation of large databases that allow us to provide valuable answers to guide our daily clinical practice. This work did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.