Repeated Previous Transarterial Treatments Negatively Affect Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors of the manuscript intend to evaluate the overall survival of patients with HCC subjected to treatment with sorafenib after several sessions of interventional treatment (TARE or TACE).
The manuscript is well presented and collects almost 700 patients from different Italian centers.  However, it is necessary to make some clarifications:

- clarify why it is correct to talk about retrospective work if the data were collected prospectively and only analyzed retrospectively

- clarify why it is helpful to perform univariate and multivariate analyses before propensity score matching

- perform, where possible, a subgroup analysis among patients with > or > 2 TACE procedures and between patients with > or > 2 TARE procedures

Comments on the Quality of English Language

The English language is correct and fluent. It is only necessary to correct some spelling errors.

Author Response

POINT-TO-POINT RESPONSE TO REVIEWER 1

 

• Clarify why it is correct to talk about retrospective work if the data were collected prospectively and only analyzed retrospectively

Response: Thanks for this observation. We added the following specification (2.1 Study design): “We consider the data analysis to be retrospective in nature because we analyzed the number of transarterial procedures that the patients received before starting sorafenib, while the observation of each patient began with the first administration of sorafenib.

• clarify why it is helpful to perform univariate and multivariate analyses before propensity score matching.

Response: Univariable and multivariable analysisi before propensity score matching allowed us to evaluate the initial differences between treatment groups and better assess the role of potential confounders. We added the following specification (2.7 Statistical analyses): “Univariable and multivariable analyses were perfomed before and after performing a propensity score matching, to evaluate the initial differences between treatment groups and better assess the role of potential confounders”.

• perform, where possible, a subgroup analysis among patients with > or > 2 TACE procedures and between patients with > or > 2 TARE procedures

Response: We agree with the reviewer that this analysis would bring interesting information, as it is likely that TARE (which are usually used to treat large nodules) impacted more on liver function compared to TACE. Unfortunaely, we did not possess enough data for this kind of analysis as no patients had received more than 2 TARE procedures and only 4 patients had received more than 1 TARE procedure (Table 1).

Reviewer 2 Report

Comments and Suggestions for Authors

In this retrospective study, Stefanini and colleagues, investigated the prognostic impact of repeated transarterial chemoembolization in the outcome of HCC patients who received sorafenib as first-line treatment. Overall, they studied 696 patients, including 139 patients having received >2 transarterial procedures before sorafenib initiation. The propensity score matching analysis identified 139 pairs of patients. They found that having received >2 locoregional treatments was independently associated with a shorter survival. This pattern was confirmed amongst responders to sorafenib, but not in progressors. A trend toward a higher rate of permanent discontinuation of sorafenib due to liver failure and a lower rate of eligibility to second-line treatments was observed in patients who had received > 2 transarterial procedures.
The study raises an important clinical issue. However, to establish a real prognostic impact of higher number of TACE treatments, additional informations should be provided. 1) TACE procedure: the authors should describe the transarterial technical procedure/methods: selective vs superselectvive, number of HCC nodules (maximum number of treated nodules per session). This information may influence the efficacy and safety of the treatment (doi: 10.1007/s00270-019-02221-w.); 2) discontinuation of sorafenib due to liver failure: it would be of prognostic relevance to describe whether there were patients experiencing after the first TACE a reversible liver function deterioration suggesting a more fragile liver functional reserve ( doi: 10.1016/j.jhep.2021.11.013.); 3) the authors should investigate in the Cox regression the prognostic impact of eligibility to second-line systemic therapy after first-line sorafenib since the treatment sequences of sorafenib followed by second (-third) line therapy(ies) may traslate in different OS.

Comments on the Quality of English Language

Minor editing of language style is required.

Author Response

POINT-TO-POINT RESPONSE TO REVIEWER 2

• TACE procedure: the authors should describe the transarterial technical procedure/methods: selective vs superselectvive, number of HCC nodules (maximum number of treated nodules per session). This information may influence the efficacy and safety of the treatment (doi: 10.1007/s00270-019-02221-w.);

 

Response: We agree with this consideration.  We added the following information (2.3 Number of previous trans-arterial procedures): Generally speaking, patients with more than 6 nodules or with nodules >6 cm were not considered candidates for TACE. At the same time, no more than 3 nodules were treated during each procedure. All TACE procedures were performed using superselective techniques.

 

• discontinuation of sorafenib due to liver failure: it would be of prognostic relevance to describe whether there were patients experiencing after the first TACE a reversible liver function deterioration suggesting a more fragile liver functional reserve ( doi: 10.1016/j.jhep.2021.11.013.)

 

Response: We agree with the reviewer that this analysis would bring interesting information. Unfortunately, the ARPES database does not contain this variable. We added this consideration in the limitations section with the pertinent reference (Discussion): “At the same time, we were unable to assess whether patients had experienced a reversible liver function deterioration after the first TACE, an event with a potential prognostic relevance as it suggests a more fragile liver functional reserve”.  

 

• the authors should investigate in the Cox regression the prognostic impact of eligibility to second-line systemic therapy after first-line sorafenib since the treatment sequences of sorafenib followed by second (-third) line therapy(ies) may translate in different OS.

 

Response: We fully agree with the reviewer. We hypothesized that fewer TACE procedures might translate into a more preserved liver function and a higher eligibility rate for further treatments upon progression to sorafenib, leading to improved survival. Therefore, we think adding the requested analysis might strengthen the relevance of our findings. From a statistical point of view, it would not be correct to integrate the variable “eligibility to the second line” into the existing Cox regression models for two different reasons. First, the value of this variable can not be known at the baseline, and therefore, an immortal time bias could ensue. Second, this analysis should include only patients who permanently discontinued sorafenib (while the existing Cox regression models include the whole population). Therefore, we performed the requested analysis a separate log-rank test.  We added the following text (3.2 Propensity score analysis): Patients eligible to second-line treatments upon sorafenib failure experienced a longer OS compared to patients who had received sorafenib as the only drug [17.1 (13.5-20.7) vs 8.9 (7.5-10.3) months, p<0.001].