The Objective Response and Disease Control Rates in Patients with Liver Metastastic Breast Cancer Receiving Transarterial Radioembolization: A Meta-Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review:  the Objective Response and Disease Control Rates in Patients with Breast Cancer receiving TARE: a Meta-analysis

General Comment:  This is a review paper analyzing the current technological advances for using TARE (transarterial radioembolization) to treat and treat liver metastases in patients with advanced.  The authors use ORR a nd DCR to evaluate the overall tumor response and its impact on overall patient survival.  The paper is well-written, however, there are inconsistencies in among the various papers analyzed which do not support the “significant improvements in the outcome of patients with metastatic BC…” statement in the introduction of the manuscript.

Specific  Comments:

Line 49:  “wiy”” should be “with”?

Lines 71-73:  The references used to make the statement, “TARE efficiently controls tumor development and minimize symptoms, improving quality of life while prolonging longeveity…” are not used in the study as indicated by the authors listed in Tables 1 and 2.  Only one of the studies reported a median OS of 35.4 months while the median OS averages only 10.5 months (Table 2).  I am not convinced that 10.5 months is “significantly” better than other treatment modalities in terms of longeveity. 

Figure 1 summarizes the “relevant bias” in the studies analyzed.  It is unclear in the Methods section how bias was evaluated/measured to create this graph.

Lines 167 – 168.  This sentence is awkward and should be reworded.

Paragraph starting on line 130:  ORR = (CR+PR)/total patients  and  DCR = (CR+PR+SD)/total patients  How is PR quantified?  A partial response can be 2%, 30%. 80%, etc. reduction in tumor volume, essentially anything.   This could artificially mean that the ORR and DCR numbers could be relatively high indicators of good positive outcomes, but in truth, do not indicate much better OS compared to other  treatment modalities.

Paragraph starting on 209:  SIRT is mentioned in comparison to TARE.  Since both are very similar, for a more general audience, perhaps the authors should consider briefly describing how the two differ and why TARE is more beneficial over SIRT.

Paragraph starting on 238:  SBRT is a specialized EBRT procedure.  In radiation oncology, EBRT is generally referred to 3D conformal or IMRT/VMAT radiation therapy modalities.  Please verify for the reader if this is consistent with the authors definition.  In SBRT, the radiation is delivered to small volumes at higher doses, lower fractionation with steep dose fall-off at the target margins to minimize dose to the organs at risk.  The last statement of the paragraph is true if this is the definition of EBRT, but not SBRT which is a form of EBRT.

Line 281:  I agree with the statement “it is difficult to draw valid conclusions about the efficacy of TARE in disease control…” but this is not the overall theme presented in the introduction to this paper.

Comments on the Quality of English Language

English is generally good although some errors were found.  See comments above.

Author Response

General Comment:  This is a review paper analyzing the current technological  advances for using TARE (transarterial radioembolization) to treat and treat liver metastases in patients with advanced.  The authors use ORR and DCR to evaluate the overall tumor response and its impact on overall patient survival.  The paper is well-written, however, there are inconsistencies in among the various papers analyzed which do not support the “significant improvements in the outcome of patients with metastatic BC…” statement in the introduction of the manuscript.

Lines 71-73:  The references used to make the statement, “TARE efficiently controls tumor development and minimize symptoms, improving quality of life while prolonging longevity…” are not used in the study as indicated by the authors listed in Tables 1 and 2.  Only one of the studies reported a median OS of 35.4 months while the median OS averages only 10.5 months (Table 2).  I am not convinced that 10.5 months is “significantly” better than other treatment modalities in terms of longevity. 

Response: We thank the Reviewer for the thoroughly evaluation and the insightful comments. We have modified the assertive tone of the sentence as follows: “TARE has the potential to help manage tumor development and alleviate symptoms, which may contribute to an improved quality of life and potentially extend longevity by enhancing ORR and DCR.“ In addition we have replaced the references with the paper by Chang showing a benefit in terms of overall survival in the group treated with TARE compared to that submitted to TACE. 

Figure 1 summarizes the “relevant bias” in the studies analyzed.  It is unclear in the Methods section how bias was evaluated/measured to create this graph.

Response: Following the Reviewer’s suggestions, the 'Materials and Methods' section has been expanded, and additional details about the QUADAS-2 tool have been included to clarify the text. The following paragraph has been added: 'The QUADAS-2 tool is designed to evaluate the risk of bias and applicability in diagnostic accuracy studies across four domains: patient selection, index test, reference standard, and flow and timing. Each domain includes signaling questions to guide judgments on risk of bias, while the first three domains also assess concerns regarding applicability.”

Lines 167 – 168.  This sentence is awkward and should be reworded.

Response: According to Reviewer’s suggestions, the sentence has been changed as follows: “Notably, the three studies that used PERCIST criteria reported some of the highest DCRs (100%, 100%, and 96.67%) among all the selected papers (Table 2). Overall, the risk of bias was low across all studies (Figure 2).”

Paragraph starting on line 130:  ORR = (CR+PR)/total patients  and  DCR = (CR+PR+SD)/total patients  How is PR quantified?  A partial response can be 2%, 30%. 80%, etc. reduction in tumor volume, essentially anything.   This could artificially mean that the ORR and DCR numbers could be relatively high indicators of good positive outcomes, but in truth, do not indicate much better OS compared to other  treatment modalities.

Response: We thank the Reviewers for the comments. We have added the following sentence in the materials and methods: “… partial response (PR), stable disease (SD) and progressive disease (PD) was extracted, as defined according to Response evaluation criteria in solid tumors (RECIST version 1.1) or PET PET response criteria in solid tumors (PERCIST )”. In addition, this paragraph has been added to the Discussion: “In addition, it should be emphasized that a limitation of our study is the method of assessing treatment response, which was performed in three cases according to PERCIST criteria and in the remaining cases according to RECIST. Furthermore, the category 'partial response' inherently includes variability in the depth and degree of response. Finally, it should be noted that, although our meta-analysis shows the potential of TARE to achieve satisfying disease control in mBC, higher ORR and BCR do not automatically translate into benefits in terms of OS or PFS. These topics should be the subject of future investigations.”

Paragraph starting on 209:  SIRT is mentioned in comparison to TARE.  Since both are very similar, for a more general audience, perhaps the authors should consider briefly describing how the two differ and why TARE is more beneficial over SIRT.

Response: “Although the method based on the administration of microspheres was initially referred to as SIRT to highlight its therapeutic component based on radionuclide emission, it is now more commonly identified by the acronym TARE. The two terms are, in fact, used interchangeably. In any case, to minimize any possible confusion in the text, the term SIRT has been replaced with TARE wherever it appears.”

Paragraph starting on 238:  SBRT is a specialized EBRT procedure.  In radiation oncology, EBRT is generally referred to 3D conformal or IMRT/VMAT radiation therapy modalities.  Please verify for the reader if this is consistent with the authors definition.  In SBRT, the radiation is delivered to small volumes at higher doses, lower fractionation with steep dose fall-off at the target margins to minimize dose to the organs at risk.  The last statement of the paragraph is true if this is the definition of EBRT, but not SBRT which is a form of EBRT.

Response: We understand Reviewer’s point of view. Therefore, we have changed the test accordingly: “In this context, EBRT, including SBRT as a specialized approach, has several limitations in the treatment of liver metastases compared to TARE, including respiratory motion, the requirement for fiducial markers, increased radiation exposure to healthy liver tissue, and the need for repeated therapeutic sessions.”

Line 281:  I agree with the statement “it is difficult to draw valid conclusions about the efficacy of TARE in disease control…” but this is not the overall theme presented in the introduction to this paper. 

Response: The sentence has been modified as follows: “Further studies, ideally prospective and involving larger cohorts, are needed to better define the efficacy and safety of TARE in the clinical setting of hepatic metastases from breast cancer. These studies should also consider the differences between the various types of microspheres and the varying intervals of post-TARE radiological surveillance.”

English is generally good although some errors were found.  See comments above.

English has been revised by a native English-speaker. 

Reviewer 2 Report

Comments and Suggestions for Authors

Name of Journal: Current Oncology (ISSN 1718-7729)

Manuscript NO:curroncol-3224264-peer-

Manuscript Title:The Objective Response and Disease Control Rates in Patients with Breast Cancer receiving TARE: a Meta-analysis

Comments

The author of this paper meta-analyzed the utility of radioembolization in patients with liver-dominant metastatic breast cancer (BC), based on the objective response rate (ORR) and disease control rate (DCR).. The subject of this manuscript is of value, but there are a few of defects need to be modified.

1. The description of research content is unclear: meta-analyzed the utility of radioembolization in patients with liver-dominant metastatic breast cancer (BC); or meta-analyzed the utility of radioembolization in patients with Breast Cancer. Please check and revise. Please check the full text, including the title. Very important.

2. Is the author evaluating the treatment response of liver lesions or breast lesions, or both.Please describe clearly.Very important.

3. Why the following search terms were not used to retrieve literature: liver metastasis, or hepatic metastases......Please explain.

4. Abstract section: the DCR is the ratio between patients with CR, PR or stable disease (SD) over the total number of patients treated with radioembolization. DCR is the ratio of the sum of PR, CR, and SD to the total number of cases. Please check if the English is correct (Please check “or”).

5. In addition, the calculation formulas for ORR and DCR are not described in the methods section in the text, the author should consider whether to add or not.

6. Should the author consider replacing radioembolization with TARE.

7. Materials and Methods section: English-language articles were not included. Is there any description error or opposite meaning.What language articles are included and excluded should be described clearly. Please check and revise.

Author Response

Comment: The author of this paper meta-analyzed the utility of radioembolization in patients with liver-dominant metastatic breast cancer (BC), based on the objective response rate (ORR) and disease control rate (DCR). The subject of this manuscript is of value, but there are a few of defects need to be modified.

1. The description of research content is unclear: meta-analyzed the utility of radioembolization in patients with liver-dominant metastatic breast cancer (BC); or meta-analyzed the utility of radioembolization in patients with Breast Cancer. Please check and revise. Please check the full text, including the title. Very important.

A: we appreciated the valuable comment. We modified the title of the manuscript and the text uniformly. We prefer to refer to liver metastatic BC. Most of the study treated patients with liver-dominant disease. All but  2 studies included subgroups of patietns with extrahepatic metastases. One out of the two studies did not report information about subcohort of patients with extrahepatic metastastice disease, the other study included only BC patients with liver-only metastastic disease.

1. Is the author evaluating the treatment response of liver lesions or breast lesions, or both. Please describe clearly. Very important.

A: the authors and all the studies included in the systematic review are estimating the treatment response of liver lesions. We make it more clear, adding in the abstract “The ORR is the ratio between patients with liver lesions showing complete response (CR) or partial response. Also in the methods, in the statistical analysis, we pointed out that the treatment response of liver metastatic lesions was determined based on the response criteria adopted in each article.  

1. Why the following search terms were not used to retrieve literature: liver metastasis, or hepatic metastases......Please explain.

A: Dear reviewe the search query used in Pubmed/MEDLINE was ("Breast Neoplasms"[MeSH] OR breast[tiab] OR mamma*[tiab]) AND ("Infusions, Intra-Arterial"[MeSH] OR intra-arterial infusion*[tiab] OR radioemboliz*[tiab] OR yttrium[tiab]) NOT (Review[pt] OR "Case Reports"[pt]) since we tried to be more general and include all the possible articles. Furthermore, we have made an additional check and the inclusion of the two additional terms did not add further relevant articles to the literature search.

4. Abstract section: the DCR is the ratio between patients with CR, PR or stable disease (SD) over the total number of patients treated with radioembolization. DCR is the ratio of the sum of PR, CR, and SD to the total number of cases. Please check if the English is correct (Please check “or”). 

A: dear reviewer we confirm the correctness of “or”..

5. In addition, the calculation formulas for ORR and DCR are not described in the methods section in the text, the author should consider whether to add or not.

A: dear reviewer, since ORR and DCR are two commonly used terms in clinical trials, we believe that the description in the abstract and in the methods is sufficient for the audience of the journal.

6. Should the author consider replacing radioembolization with TARE.

A: We replaced radioembolization with TARE throughout the text.

7. Materials and Methods section: English-language articles were not included. Is there any description error or opposite meaning.What language articles are included and excluded should be described clearly. Please check and revise.

A: Thank you for spotting this error we meant that non-English-language articles were not included. We revised the text accordingly.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I am satisfied by the authors revisions to the paper to address my comments in the original manuscript.  I have no further comments.  I would recommend this manuscript be approved for publication.

Author Response

Comment 1: I am satisfied by the authors revisions to the paper to address my comments in the original manuscript.  I have no further comments.  I would recommend this manuscript be approved for publication.

Response: Thank you very much for your appreciation.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have revised the manuscript in accordance with the peer-review report. I have found two minor issues.Please check. Besides, I don't have any more comments.

1,Introduction section: Line 75.breast cancer (BC), should be changed to:BC.

2,Materials and Methods 2.3. Data extraction section: or PET PET response criteria in solid tumors (PERCIST). There are two “PET”,please check and revise it (deleted one?).

Author Response

The authors have revised the manuscript in accordance with the peer-review report. I have found two minor issues.Please check. Besides, I don't have any more comments.

Comment 1,Introduction section: Line 75.breast cancer (BC), should be changed to:BC. 

Response: We change "breast cancer (BC)" in "BC".

Comment 2,Materials and Methods 2.3. Data extraction section: or PET PET response criteria in solid tumors (PERCIST). There are two “PET”,please check and revise it (deleted one?).

Response: We deleted one "PET".