The Impact of Real-World Alternative Dosing Strategies of Palbociclib on Progression-Free Survival in Patients with Metastatic Breast Cancer

Round 1

Reviewer 1 Report

The revised paper is now suitable for publication.  I have no further edit requests.

Reviewer 2 Report

The paper has already been reviewd. it is in my opinion eligible to be published.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The main objective of the study was to evaluate alternative dosing strategies of palbociclib prescribed by oncologists in a real-world setting.  The primary clinical endpoint was PFS.  The paper is interesting but requires revision and data reanalysis before it is suitable for publication. I present several points that the authors need to address.

 

1. The data source was a retrospective chart review. It is very difficult to objectively measure PFS in a retrospective chart review for a variety of reasons such as the timing and reading of individual scans.  A more accurate surrogate measure of PFS is time to next active treatment, which is feasible in the current analysis because the majority of patients CDK 4/6 inhibitors in the first line setting.
2. The authors described PFS “the time to discontinuation of treatment due to documented progression of disease”.  This is not consistent with the FDA definition, which is a 30% reduction is the largest assessable lesion or death. What they present here is not PFS, but closer to TTP.  So the TTP measured here cannot be compared to the PFS reported in the registration trials. This is a major limitation that needs to be addressed before this paper gets accepted for publication.
3. Progression-free survival was reported at 6-months, 12-months, and 18-months. I would strongly recommend that Kaplan Meier Curves also be generated from this data.  This would provide a median time to PFS and an indication of what is happening at the tail end of the curve.
4. The final sample size is 73 patients. This would be enough for formally evaluate the various dosing strategies via Cox Multivariable analysis.  The regression should also evaluate some of the baseline variables presented in table 1. This would provide you with a p value and a hazard ratio.  For 3 and 4 above, I would recommend the authors engage a biostatistician.
5. How do you know that other factors such as performance status and site of metastases contributed to the finding that the 3 weeks on, 2 weeks off patients did better?
6. The primary recommendation of the study was that palbociclib should be prescribed 3 weeks on, 2 weeks off. However, this was based only on 8 patients. Can you really make such a recommendation from 8 patients?  As best, the findings of this study are hypothesis generating.  Hence, the conclusions need to be revised to reflect his.

 

To summarize the revisions, the authors need to modify their primary endpoint to what they actually measured or use “time to next treatment or death” as a surrogate to PFS.  They also need to apply more comprehensive statistical analysis (e.g. Kaplan Meier Curves and Cox multivariable regression analysis) to better evaluate their data.  Lastly, they need to revise their conclusions based on their limited sample size.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

An interesting original study showing a modification of palbociclib dosing strategies in patients in combination with either letrozole or fulvestrant. Reducing the dose decreased the risk of neutropenia associated with the drug; only minor revisions:

In the conclusions, the possibility of proposing alternative dosages for palbociclib also in other patients/treatments should be expanded.

Page 2 line 56 you should add: various side effects have been associated with Cdk 4 inhibitors, from neutropenia to cutaneous adverse reactions such as alopecia, bullous skin rash, and  Stevens-Johnson syndrome" and cite an article such as : doi: 10.1007/s40264-021-01071-1. 

Author Response

Please see the attachment.

Author Response File: Author Response.docx