Real-World, Observational, Retrospective Study to Evaluate the Effectiveness and Safety of Treatment with Sorafenib in Patients with Advanced Hepatocellular Carcinoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

There are some comments. 

 1. It would be better to explain the method for assessing radiological and symptomatic/clinical progression in more detail. 

2. It would be better to indicate which toxicities were most responsible for treatment discontinuation. 

3. It would be better to have extended follow-up periods for a more comprehensive assessment of sorafenib's long-term effectiveness and safety.

4. It would be better to explain other etiology (n=16) in Table 1 footnote.

Comments on the Quality of English Language

Please check English grammar and spelling.

Author Response

Comment 1: It would be better to explain the method for assessing radiological and symptomatic/clinical progression in more detail. 

Response 1:

Thanks for your suggestion. Since this is a real-world study evaluating clinical practice, the medical assessment described in the medical record regarding radiological and symptomatic/clinical progression was considered. Thus, the attending physician evaluated the imaging exams and the signs and symptoms of progression and included this assessment in the patient's record. Generally, physicians consider radiological progression per RECIST 1.1 criteria and symptomatic progression as a worsening of performance status to 3-4 according to ECOG scale, or the onset of severe organ disfunction.  This information was considered for the evaluation of progression for this project. The manuscript has been revised to enhance clarity regarding this information.

 

Comment 2: It would be better to indicate which toxicities were most responsible for treatment discontinuation. 

Response 2:

We recognize that this is valuable information. However, for the scope of this retrospective project, we evaluated the reason for treatment discontinuation (radiological progression, symptomatic/clinical progression, or toxicity) and also assessed whether the treatment was well tolerated by the patients, with both evaluations conducted based on the medical assessments present in the records. Due to the retrospective nature and the risk of underreporting data, we did not collect the type of toxicity. 

 

Comment 3: It would be better to have extended follow-up periods for a more comprehensive assessment of sorafenib's long-term effectiveness and safety.

Response 3:

This study was designed as a real-world, observational, and retrospective analysis. Therefore, a prospective follow-up assessment of patients treated with sorafenib was not considered. Additionally, at the time of data collection, 88.58% of the study participants had already deceased. Thus, for the majority of patients, the collected data took into account the entire period from the start of treatment with sorafenib until the date of death.

 

Comment 4: It would be better to explain other etiology (n=16) in Table 1 footnote.

Response 4:

The etiologies that were classified as 'others' (n=16) were:  hemochromatosis (n=8), schistosomiasis (n=6), alpha-1 antitrypsin deficiency (n=1), and autoimmune disease (n=1). This information has been added in the footnote of Table 1.

 

Comment 5: Please check English grammar and spelling.

Response 5:

The entire manuscript has been reviewed for spelling and grammar for the new version.

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors present a fair work about sorafenib and HCC, with local population evaluation. This kind of study is always interesting and useful, however it need some extra data ir to increase its atractiveness

M&M can be improved. I cannot be sure if the patients were or were not subjected to surgery. If they were, surgical details should be present as well as histological details: TNM classification, HCC morphology, subtype, vascular invasion, etc

If not, how were selected the ", 78 of which 126 because they had other diagnosis than HCC" - biopsy? and the HCC? were biopsed? this has to be clarified.

If there are histological data it should be analysed regarding sorafenib efficiency

Follow-up protocol should be detailed

Was any patient submited to histological evaluation of the relapse? if so describe

A radiologic picture would provide some value to the paper

Language is ok, withou issues. Bibliograpgy is correct

Author Response

Comment 1: M&M can be improved. I cannot be sure if the patients were or were not subjected to surgery. If they were, surgical details should be present as well as histological details: TNM classification, HCC morphology, subtype, vascular invasion, etc

Response 1:

Thank you for pointing this out. The Materials and Methods section has been revised to evaluate possible improvements, including the description of inclusion and exclusion criteria, aiming to provide greater clarity regarding the population selected for the assessment of their retrospective data. The fact that patients may or may not have undergone prior surgery was not part of the eligibility criteria or the primary scope of this project. However, this information was collected, and 12.22% of the included participants had undergone surgery prior to treatment with sorafenib. This was the case of patients previously diagnosed with resectable disease, and presented unresectable recurrence during the follow-up. The histological details of this sample were not collected for the scope of this project.

 

Comment 2: If not, how were selected the ", 78 of which 126 because they had other diagnosis than HCC" - biopsy? and the HCC? were biopsed? this has to be clarified.

Response 2:

The study is a retrospective evaluation of real-world data, through the collection of patient records of those directed to treatment with sorafenib between 2009 and 2020 at the institution. A total of 494 patients who had received a prescription for sorafenib were screened; however, 78 of them were prescribed the medication for other oncological indications that were not hepatocellular carcinoma (HCC), mainly thyroid and renal carcinoma, as well as off-label use for other types of cancer. Since the scope of the study refers only to HCC, the other patients were not analyzed.

Regarding biopsy, in the institution's practice, it is not performed on all patients with suspected HCC, only on those for whom imaging tests are insufficient for diagnosis. The exact number of patients in the sample who required biopsy was not collected, as this information was not part of the project's scope, provided that there was a diagnosis of HCC.

 

 

Comment 3: If there are histological data it should be analysed regarding sorafenib efficiency

Response 3:

Histological data were not collected for this project, as they were not part of its scope.

 

Comment 4: Follow-up protocol should be detailed

Response 4:

As this is a real-world, observational, monocentric study with retrospective data collection to evaluate the effectiveness and safety of sorafenib treatment in patients with advanced HCC, the aim of the study was to assess patients based on past data, up until the time of data collection. Information was obtained from the electronic medical records in Tasy (Philips Tasy - Health Management Solution) at the Cancer Institute of the State of Sao Paulo (ICESP). Data were collected from patients whose sorafenib treatment began between 2009 and 2020. This period was defined starting in 2009, as it was the year the drug began to be prescribed at the institution, and ending in 2020, as it was the last complete year before the start of this study, which was approved in 2021.

Participants of both sexes aged 18 years or older with a diagnosis of advanced HCC who received first-line treatment for advanced HCC with sorafenib at the institution were considered eligible for the study, provided that the necessary data for the research were available in the institution's electronic medical records. The pre-defined exclusion criteria were: participants diagnosed with other invasive neoplasms in the five years prior to the diagnosis of HCC, patients who started sorafenib treatment at other institutions and were referred to ICESP for treatment continuation, and patients who received experimental drugs for the treatment of HCC and/or its complications.

During the period evaluated by this study, sorafenib was the first-line treatment available for candidates for systemic therapy at the institution. Sorafenib was administered orally at an initial dose of 400 mg twice daily, which could be adjusted based on the type and severity of adverse events. Clinical and laboratory assessments were typically performed at the beginning of treatment and monthly, while radiological evaluations were generally conducted bi-monthly. Treatment typically continued until symptomatic progression, radiological progression, treatment intolerance, or death.

Data collection was carried out only after the project was approved by the Research Ethics Committee (CEP), in accordance with opinion number 4,681,412 dated April 29, 2021. The data were collected in the second half of 2021.

After collection, the data were included in the study database for organization and tabulation. Clinical and epidemiological characteristics were analyzed using descriptive statistics. Continuous variables were expressed as means, medians, standard deviations, and minimum and maximum values; categorical variables were expressed as absolute and relative frequencies. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. The Cox regression method was used to estimate the hazard ratio (HR) and 95% confidence intervals, thus evaluating the interaction between potential prognostic factors and survival. A significance level of 5% was adopted for all hypothesis tests. The analyses were conducted using SPSS for Windows v.25.

The methodology section has been more thoroughly detailed in the new version of the manuscript.

 

Comment 5: Was any patient submited to histological evaluation of the relapse? if so describe

Response 5:

Histological data were not collected for this project, as they were not part of its scope.

 

Comment 6: A radiologic picture would provide some value to the paper

Response 6:

We recognize that this is valuable information. However, radiological imaging data were not collected for this project, as it was not part of its scope and objectives. The physician´s interpretation of radiological reports was used to define radiological progression or response. Thus, the medical evaluations included in the records related to the imaging exams were analyzed.

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript was well revised.

There are minor comments.

It would be better to confirm whether the Tables and Figures are clearer and more readable.

 

Comments on the Quality of English Language

Please check English grammar.

For example,

The analyses was  ->  The analyses were 

3.4. Overall survival ->3.4. Overall Survival

Median (IC95%) -> Median (95% IC)

HR (IC95%) -> HR (95% CI)

Author Response

Comments 1: It would be better to confirm whether the Tables and Figures are clearer and more readable.

Response 1: Thank you for the suggestion. The tables and figures have been revised to make them more readable and easier to understand.

 

Comments 2: Please check English grammar. For example,

The analyses was  ->  The analyses were 

3.4. Overall survival ->3.4. Overall Survival

Median (IC95%) -> Median (95% IC)

HR (IC95%) -> HR (95% CI)

Response 2: All examples cited have been corrected in the new version. Additionally, the entire text of the article has been revised regarding English grammar, with the necessary corrections made.

Author Response File: Author Response.pdf