The Impact of Neoadjuvant versus Adjuvant Chemotherapy on Survival Outcomes in Locally Advanced Breast Cancer
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsComments:
Main manuscript:
- Did authors used the PRISMA checklist for reporting?
- Did their protocol was registered?
Table 2: is it true that authors entered "clinical N" and Nstage would be "pathological N"?
Table 3: Could the result be reported with a forrect plot? More visual.
Local cohort: how many pts progressed during treatment and could never be operated?
Discussion, line 218: "emerging data"-are not that emerging now!
The important missing part in the manuscript is the discussion about the time the trials were conducted and the chemotherapy regimens used. These are old trials with chemotherapy regimens not used nowadays in LABC. Therefore, a detailed discussion about the implication could add to the paper.
Table section:
Supplementary Table 2:
-Suggest to add the year of publication (or the year if possible th trial was conducted)
- what is MMM and MM?
- suprised, 3 trials with no information on the chemotherapy administered?
- Gazet et al, a typo for the % of adjuvant (entered 15% instead of 50%)
Supplementary table 3: GAzet, is there something missing in the first sentence?
Instead of description of the trial, could it be in a table e.g. year of conduct, regimen used, OS, PFS etc?
Supplementary table 4: Suggest to change herceptin of trastuzumab
Author Response
Comment: - Did authors used the PRISMA checklist for reporting? - Did their protocol was registered?
Response: Reviewer #1 emphasizes an important point regarding the utilization of the term meta-analysis in our paper and our lack of standardized registered protocol in identifying trials in our analysis. Although initially a systematic search was conducted by our centre’s librarian in search of applicable trials, the time gap between the search, the ability of different trial groups to make individual patient data available for our analysis has created deficits PRISMA-based reporting. Recognizing the importance of appropriate terminology use, we changed the use of “meta-analysis” in this manuscript to “combined statistical analysis of individual patient data” to prevent confusion for the readers. We have further noted the different chemotherapeutic regimens and lack of targeted therapy in the included trials within the 6th paragraph of discussion to emphasize this point. That said, we still believe that the lack of differences in the clinical outcomes in the included 779 patients with locally-advanced breast cancer is an important and relevant finding that adds to the available literature.
Comment: Table 2: is it true that authors entered "clinical N" and Nstage would be "pathological N"?
Response: We thank reviewer #2 for pointing out the possible confusion by the table titles, and have added the word “pathological” prior to N-stage in the second column of the table to clarify this point.
Comment: Table 3: Could the result be reported with a forrect plot? More visual.
Response: We removed this table from the main manuscript as we wanted to highlight the main finding of the comparison of outcomes between the combined LABC from the 6 RCTs. Noting the comment of reviewer #1, we moved this table which depicts the p value associated with the cox analysis in each cohort to the supplementary data section in case the readers are interested in knowing the statistical significance of the HR associated with neoadjuvant vs. adjuvant chemotherapy in each trial.
Comment: Local cohort: how many pts progressed during treatment and could never be operated?
Response: We thank the reviewer for pointing out the concern regarding progressive disease that is not amenable to surgical intervention while on neoadjuvant chemotherapy. Our local prospective dataset includes patients undergoing surgical intervention, and as such, the data regarding patients unable to undergo surgery was not captured. That said, a study by Caudle et al. (Breast Oncology 2011) on 1928 patients with stage I-III breast cancers undergoing neoadjuvant chemotherapy, noted that 7 patients (0.36%) could not undergo surgical treatment due to disease progression. We have added this limitation of our local cohort to the discussion section, and reported on the findings of Caudle et al.
Comment: Discussion, line 218: "emerging data"-are not that emerging now!
Response: We note the reviewers’ comment about neoadjuvant chemotherapy being well-established, and as such, we have removed this phrase from the discussion.
Comment: The important missing part in the manuscript is the discussion about the time the trials were conducted and the chemotherapy regimens used. These are old trials with chemotherapy regimens not used nowadays in LABC. Therefore, a detailed discussion about the implication could add to the paper.
Response: We have responded to this important comment in the paragraph #6 of discussion, detailing this limitation in terms of generalizability to current patient care standards.
Comment: Table section:
Supplementary Table 2:
-Suggest to add the year of publication (or the year if possible the trial was conducted)
Response: As per recommendation of the reviewer, the year of publication of each trial was added to the supplementary table.
Comment: - what is MMM and MM?
Response: These chemotherapy regimens were clarified in the Supplementary Table 3.
Comment: - suprised, 3 trials with no information on the chemotherapy administered?
Response: This information was left out by error in the submitted table, and has been updated in the supplementary information.
Comment: - Gazet et al, a typo for the % of adjuvant (entered 15% instead of 50%)
Response: We thank reviewer#1 for noting this mistake in the table, which has been corrected.
Comment: Supplementary table 3: GAzet, is there something missing in the first sentence?
Instead of description of the trial, could it be in a table e.g. year of conduct, regimen used, OS, PFS etc?
Response: We note that this table was excessive, and as such, details such as dates and regimens were added to supplementary table 2, and supplementary table 3 was removed.
Comment: Supplementary table 4: Suggest to change herceptin of trastuzumab
Response: We have changed the label from Herceptin to Trastuzumab as recommended by Reviewer #1.
Reviewer 2 Report
Comments and Suggestions for Authors
Neoadjuvant chemotherapy is the standard of care for both inoperable and operable LABCs, intending to facilitate breast‐conserving surgery (BCS) as well. This study focuses on the survival benefit for LABC patients receiving neoadjuvant chemotherapy through a meta-analysis of individual patient data from randomized controlled trials. They confirmed neoadjuvant chemotherapy has similar survival outcomes in the LABC cohort as those receiving adjuvant systemic treatment. Moreover, they also noticed that the main cause of the delay between neoadjuvant chemotherapy and surgery was not chemotherapy-related complications. However, several obscure descriptions in this manuscript concern me before acceptance.
1. In lines 24-25, did those unexpected delay causes make an outcome difference in your study? Please comment on the clinical significance of your key findings.
2. In line 27, I have not found any data analysis for the subsets with residual disease.
3. In line 138, is there any information for HER2 status, target therapy, and radiation therapy in Table 1?
4. The criteria for the selection of all the RCTs were not very precisely described.
5. In lines 217-230, as I said before, no results have been presented for the subsets with residual disease the discussions were meaningless. Maybe you could consider shortening this paragraph.
6. There are no limitations in the discussion section that should be presented.
7. The percentages in Table 5 were incorrect. Please check.
8. In the introduction, please add more detailed information about the clinical question for the interval between the completion of neoadjuvant chemotherapy and surgery. Also, please provide the reason for you to choose delay of >8 weeks for the study endpoint.
Author Response
Reviewer #2 –
Neoadjuvant chemotherapy is the standard of care for both inoperable and operable LABCs, intending to facilitate breast‐conserving surgery (BCS) as well. This study focuses on the survival benefit for LABC patients receiving neoadjuvant chemotherapy through a meta-analysis of individual patient data from randomized controlled trials. They confirmed neoadjuvant chemotherapy has similar survival outcomes in the LABC cohort as those receiving adjuvant systemic treatment. Moreover, they also noticed that the main cause of the delay between neoadjuvant chemotherapy and surgery was not chemotherapy-related complications. However, several obscure descriptions in this manuscript concern me before acceptance.
Comment: In lines 24-25, did those unexpected delay causes make an outcome difference in your study? Please comment on the clinical significance of your key findings.
Response: Reviewer #2 presents an important comment about the outcome differences associated with delays to surgery. Based on previously reported hazard ratios of outcomes related to delay of >8 weeks by Sanford et al. (Breast Oncology 2015), our clinical dataset did not have the appropriate number of mortality or disease-progression events to have adequate power in reporting a difference in terms of outcomes. As such, we referenced previous publications regarding differences in clinical outcomes, and focused on reporting the frequency of events in this article.
Comment: In line 27, I have not found any data analysis for the subsets with residual disease.
Response: We note reviewer #2’s concern about the potential confusion caused by this comment in the abstract as we did not focus on outcomes related to residual disease in our local cohort analysis, and as such, removed this phrasing from the abstract as recommended.
Comment: In line 138, is there any information for HER2 status, target therapy, and radiation therapy in Table 1?
Response: As the included trials were done in the late 1990s and early 2000s, the information regarding HER2 status and targeted therapy is not provided. We have included this limitation of these trials, along with the importance of different chemotherapy regimens used in these trials compared to current first-line treatments in paragraph #6 of the discussion as a limitation of this study.
Comment: The criteria for the selection of all the RCTs were not very precisely described.
Response: A systematic search was carried out by our local librarian in identification of RCTs applicable to our study. Due to the time gap between identification of studies, retrieval of individual patient data from each author and our statistical analysis, reporting as per PRISMA guidelines was no longer possible. Understanding the potential confusion in use of the terminology “meta-analysis” in our report, we decided to take the reviewer #1 and reviewer #2 comments into account and clarify our analysis for readers by removing this terminology and refer to our analysis as a combined individual patient data analysis of 6 RCTs instead of “meta-analysis”.
Comment: In lines 217-230, as I said before, no results have been presented for the subsets with residual disease the discussions were meaningless. Maybe you could consider shortening this paragraph.
Response: This paragraph was shortened as per reviewer #2 comment.
Comment: There are no limitations in the discussion section that should be presented.
Response: We note this deficit and added several important limitations of our study and the included data in the added paragraphs #5 and 6 of discussion. Namely, we have now noted that cohort only captured patients who underwent surgical intervention and patients that may have had disease-progression and not able to undergo surgery were not captured. We discuss that based on other reported data, such outcome is a rare event. We also note the limitations in the provided information regarding HER2 status of tumours in the included trials in this paragraph, and the different chemotherapy regimens used in these trials compared to current first-line regimens.
Comment: The percentages in Table 5 were incorrect. Please check.
Response: We thank reviewer #2 for pointing out the error. The percentage “6.5%” was rounded down to “6%” to be compatible with the number of significant digits reported in the rest of the rows in the table.
Comment: In the introduction, please add more detailed information about the clinical question for the interval between the completion of neoadjuvant chemotherapy and surgery. Also, please provide the reason for you to choose delay of >8 weeks for the study endpoint.
Response: We have added information on the rationale behind the choice of >8 weeks in the introduction section of the manuscript.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThank you for your efforts on your work.
