Our Experience and Literature Update Regarding Concomitant Radiotherapy with CDK4/6 Inhibitors and Hormonal Therapy in Metastatic Breast Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This article describes the treatment of HER2-negative hormone-dependent breast cancer. A total of 20 patients were recruited. Currently, the most accepted and common type of therapy is the following: in combination with hormonal therapy, patients with hormone-dependent breast cancer (HER2-negative hormone-dependent tumors) may be prescribed the following drugs: CDK 4/6 inhibitors, alpelisib (in the presence of PIK3CA mutation), everolimus.
The most effective and widely used drugs from the group of CDK4/6 inhibitors. They include: ribociclib, palbociclib, abemaciclib.
These drugs can be used in combination with both aromatase inhibitors (letrozole, anastrozole) and fulvestrant. Taking hormone therapy and these drugs together can significantly improve treatment results. All of these drugs are available in tablet form, but the schedule of administration depends on the specific drug: ribociclib and palbociclib are administered at weekly intervals (21 days of tablets alternating with a 7-day break), while abemaciclib is taken continuously. This paper describes this entire treatment methodology in detail and is therefore very important for practicing physicians and specialist pharmacologists and chemotherapists.  The only comment on this paper is the lack of genetic status of the patients. If it is possible for the authors of the paper, these data should be added. The paper deserves to be published after a minor revision.

Author Response

Dear Reviewer 1,

Thank you very much for appreciating our study.

We have added the genetics status of the patients, as follows: the BRCA testing was made for patients under 50 years old; in our lot was only two patients under 50 years old, for which the BRCA1 tests was negative.

Reviewer 2 Report

Comments and Suggestions for Authors

This study explored the application of CDK4/6 inhibitors combined with radiotherapy and hormonal therapy in advanced metastatic breast cancer. The study has certain novelty. However, the authors only included 20 patients, which is a too small sample size. Moreover, the treatment regimens (such as the types of CDK4/6 inhibitors, radiotherapy techniques, and dose fractionation) are highly diverse, resulting in high heterogeneity. The small sample size leads to insufficient statistical power, making it difficult to accurately assess the incidence of toxic reactions and the universality of treatment effects. Major revision is recommended.

 

1. The authors need to explain that without setting up control groups for simple CDK4/6 inhibitors combined with hormonal therapy or radiotherapy alone, it is impossible to clarify the additional benefits or toxic risks of the combined treatment.
2. The authors only reported acute toxicities (such as radiation dermatitis and enteritis), but did not mention long - term toxicities (such as fibrosis and the risk of secondary tumors). The grading criteria for hematological toxicities (such as the version of CTCAE) were not clearly stated, and the correlation between toxicities and dose - volume parameters (such as V35 of the intestine) was not analyzed. It is recommended to supplement this information.
3. 80% of the patients received 3DCRT technology, while the proportion of modern precision radiotherapy techniques (such as IMRT/VMAT) was insufficient. The differences in the protection of normal tissues by different techniques may affect the toxicity results. It is recommended to conduct subgroup analyses on this.
4. It is recommended that the authors report efficacy endpoint data such as local control rate, progression - free survival (PFS), and overall survival (OS).
5. The patients included in the study are mainly those with bone metastases (85%), and the histological types are relatively homogeneous (95% are invasive ductal carcinomas). It is recommended to adjust the title and relevant conclusions.

Author Response

Response to Reviewer 2

This study explored the application of CDK4/6 inhibitors combined with radiotherapy and hormonal therapy in advanced metastatic breast cancer. The study has certain novelty. However, the authors only included 20 patients, which is a too small sample size. Moreover, the treatment regimens (such as the types of CDK4/6 inhibitors, radiotherapy techniques, and dose fractionation) are highly diverse, resulting in high heterogeneity. The small sample size leads to insufficient statistical power, making it difficult to accurately assess the incidence of toxic reactions and the universality of treatment effects. Major revision is recommended.

 

Dear Reviewer 2,

Thank you very much for appreciating our study.  Your advice was important, thank you!

We completed the work as follows:

 

1. The authors need to explain that without setting up control groups for simple CDK4/6 inhibitors combined with hormonal therapy or radiotherapy alone, it is impossible to clarify the additional benefits or toxic risks of the combined treatment.

The purpose of this study was not making the comparations between combined treatment and radiotherapy alone, that’s why we didn’t have a control group; never the less, all patients had indications for radiotherapy for symptom’s control (brain metastases and pain from bone metastasis) and for tumor control in progressive disease (liver metastases.

2. The authors only reported acute toxicities (such as radiation dermatitis and enteritis), but did not mention long - term toxicities (such as fibrosis and the risk of secondary tumors). The grading criteria for hematological toxicities (such as the version of CTCAE) were not clearly stated, and the correlation between toxicities and dose - volume parameters (such as V35 of the intestine) was not analyzed. It is recommended to supplement this information.

The aim of this study was to analyze the acute hematological and non-hematological toxicities in patients with indication for radiotherapy, during the treatment with CDK4/6 inhibitors, all cases being metastatic patients. Taking into consideration PALOMA study which interrupted the palbociclib administration one day before radiotherapy beginning and repeat it after one week from radiotherapy ending, there are no information regarding the combined therapy, CDK4/6 inhibitors with radiotherapy and our concerns was about the safety of this combinations. Also, in Monarch study the patients performing radiotherapy were not included in study.

Long - term toxicities are:  fibrosis and the risk of secondary tumors but we did not follow them for long time. We want, in future, to make a study analyzing the long-term toxicities.

The criteria for hematological toxicities was CTCAE criteria, version 5.

We checked the dose constraints in the intestine, and we identified the preservation of the limits of QUANTEC V35Gy<35% and V45Gy<195 cubic centimeters (c.c.); in our case, after the EQD2 dose conversion (the conversion dose from hypofractioned regimes into 2Gy/fr.) the V35 becomes V29, and the value was: V29=10.63%; V45 become V37.5 and this value was V37.5Gy=117.8 c.c. V35Gy represents the percentage volume of the structure (bowel bag) receiving 35Gy and Being the only one patient manifesting this type of toxicity, there was no correlation to be obtain between V35Gy or V45 at bowel bag and grade 3 enteritis.

 

3. 80% of the patients received 3DCRT technology, while the proportion of modern precision radiotherapy techniques (such as IMRT/VMAT) was insufficient. The differences in the protection of normal tissues by different techniques may affect the toxicity results. It is recommended to conduct subgroup analyses on this.

In 2020 – the starting point of this study, in our radiotherapy clinic, the 3DCRT was the only one available, this is the reason of high percentage of patients (80%) was treated with this technique. Since 2022 we perform, also IMRT/VMAT radiotherapy (for 15% of the patients included in this study). More than this, we had patients with 2 or more sites treated in our clinic (re-irradiation or repeat irradiation) with different radiotherapy technique (e.g. first irradiation with 3DCRT and second one with IMRT/VMAT)

This is the reason of difficulty of subgroup analysis, existing the risk of bias data.   

 

4. It is recommended that the authors report efficacy endpoint data such as local control rate, progression - free survival (PFS), and overall survival (OS).

PFS is difficult to performed given the heterogeneity of lot; there are patients with stage IV of disease from the begging of study and, also, there are patients which became metastatic during the treatment of CDK4/6 inhibitors (after first or second course). Radiotherapy was started after 1 or 2 therapy line of CDK4/6 inhibitors.   

OS and PFS are different function of disease stage, the moment of metastases occurrence, if the patient was oligometastatic or with multiple metastases. Never the less we have to take into account the heterogeneity of radiotherapy techniques, having patients with 2 or more sites treated in our clinic (re-irradiation or repeat irradiation) with different radiotherapy technique (e.g. first irradiation with 3DCRT and second one with IMRT/VMAT).

 

We also, analyzed overall survival (OS) for 19 patients; one of them was lost from follow-up and excluded from OS analyzed. Kaplan – Mayer survival curve indicated a 75% OS for our patients.

 

 

 

5. The patients included in the study are mainly those with bone metastases (85%), and the histological types are relatively homogeneous (95% are invasive ductal carcinomas). It is recommended to adjust the title and relevant conclusions.

We have adjusted the title and conclusions as follows:

Title: Our Experience and Literature Update Regarding Concomitant Radiotherapy with CDK4/6 Inhibitors and Hormonal Therapy in Metastatic Breast Cancer

Conclusions:

… The further studies will bring data about the safety of the administration of combined treatment and the evaluation of late toxicities. We are recommending IMRT/VMAT or SBRT radiotherapy techniques, but if are not available and when we are using the 3DCRT technique, the CDK4/6 inhibitors treatment to be interrupt and repeated after 7 days from end of radiotherapy. Also, the CDK4/6 inhibitors must be interruptd if the patient presents neutropenia, grade 2 or 3.

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This retrospective study investigates clinical outcomes and toxicities in 20 patients with metastatic breast cancer treated with a combination of CDK4/6 inhibitors, hormonal therapy, and radiotherapy. Given the limited data in this area, the study offers valuable clinical insight. However, the manuscript requires significant revision in terms of structure, clarity, and analytical depth.

While the study presents important clinical data, the description of treatment-related toxicities and outcomes lacks sufficient clarity and organization. To improve readability and clinical applicability, the authors should include a summary table that outlines the specific toxicities observed, their severity (graded, ideally using CTCAE criteria), timing relative to radiotherapy, management approaches, and clinical outcomes (e.g., symptom relief, local control, treatment discontinuation).

A structured breakdown of side effects by type and patient characteristics would allow readers better to assess the safety profile of the combined therapy. Additionally, outcome measures should be more clearly defined and consistently reported across cases.

In the discussion section, more emphasis should be placed on contextualizing the authors’ findings within the current literature and critically comparing the study’s observations with published clinical data. The discussion should evaluate whether the observed toxicity patterns align with, contradict, or add to prior studies, especially in terms of rare or unexpected adverse events. Furthermore, the conclusion requires revision as it is a repetition of content from the discussion. It would benefit from being more concise and clearly outlining key takeaways and clinical implications.

Finally, the manuscript requires thorough language editing. Numerous grammatical errors and phrasings (e.g., “grade 1 associated with CDK4 inhibitors, occurring anterior radiotherapy beginning…”) should be corrected. The integration of tables and references to cases also needs improvement, and Table 3 requires proper labeling and formatting.

 

Author Response

Dear Reviewer 3,

Thank you very much for appreciating our study. Taking into account your advice, we have added at the paper as follows:

This retrospective study investigates clinical outcomes and toxicities in 20 patients with metastatic breast cancer treated with a combination of CDK4/6 inhibitors, hormonal therapy, and radiotherapy. Given the limited data in this area, the study offers valuable clinical insight. However, the manuscript requires significant revision in terms of structure, clarity, and analytical depth.

While the study presents important clinical data, the description of treatment-related toxicities and outcomes lacks sufficient clarity and organization. To improve readability and clinical applicability, the authors should include a summary table that outlines the specific toxicities observed, their severity (graded, ideally using CTCAE criteria), timing relative to radiotherapy, management approaches, and clinical outcomes (e.g., symptom relief, local control, treatment discontinuation).

We added the table 3.  Distribution of toxicities

Toxicities	Grade 1	Grade 2	Grade 3	Grade 4
Hematological
thrombocytopenia	4	2	-
anemia	4	1	-
Skin
Radiodermatitis	1	3	1
Digestive
enteritis	-	-	1
Others
Esophagitis	-	1	-
Hepatic cytolysis	-	1	1

 

A structured breakdown of side effects by type and patient characteristics would allow readers better to assess the safety profile of the combined therapy. Additionally, outcome measures should be more clearly defined and consistently reported across cases.

The outcome measures regarding the side effects by type and patient characteristics were: for leucopenia, we administrated cortico-therapy, for enteritis - antispastic, sulphalazine drugs and diet. For hepatic cytolysis we administrated hepatoprotectors medicines. Knowing that the hematological toxicity is the most important factor involved in CDK4/6 inhibitors dose’s reducing, in patients with toxicities we continued CDK4/6 treatment but with reduced doses; for all patients with grade 3 toxicities the dose of inhibitors was reduced.

 

In the discussion section, more emphasis should be placed on contextualizing the authors’ findings within the current literature and critically comparing the study’s observations with published clinical data. The discussion should evaluate whether the observed toxicity patterns align with, contradict, or add to prior studies, especially in terms of rare or unexpected adverse events. Furthermore, the conclusion requires revision as it is a repetition of content from the discussion. It would benefit from being more concise and clearly outlining key takeaways and clinical implications.

The study’s observations compared with published clinical data:

 Neutropenia in our patients is similar to the literature.

No correlations were found between V35 parameters and grade 3 enteritis, nor between the average dose at the esophageal level and the presence of radicular esophagitis.

The observed toxicity patterns are aligned with to prior studies, especially in terms of rare or unexpected adverse events.

The rare or unexpected adverse event was: grade 3 enteritis.

Conclusions:

The further studies will bring data about the safety of the administration of com-bined treatment and the evaluation of late toxicities. We are recommending IMRT/VMAT or SBRT radiotherapy technique, but if are not available and when we are using the 3DCRT technique, the CDK4/6 inhibitors treatment must be interrupt and repeated after 7 days from end of radiotherapy. Also, the CDK4/6 inhibitors must be interrupted if the pa-tient presents neutropenia, grade 2 or 3.

 

Finally, the manuscript requires thorough language editing. Numerous grammatical errors and phrasings (e.g., “grade 1 associated with CDK4 inhibitors, occurring anterior radiotherapy beginning…”) should be corrected. The integration of tables and references to cases also needs improvement, and Table 3 requires proper labeling and formatting

We will make the request to MDPI to make the language editing.

We corrected :(e.g., “grade 1 toxicities associated with CDK4 inhibitors, occurring anterior radiotherapy beginning…”)

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors explained why they did not set up a control group; candidly disclosed technical limitations (only 3DCRT technology was available in 2020); clearly specified using CTCAE version 5 for toxicity assessment and provided detailed intestinal dose constraint data; added overall survival analysis showing a 75% survival rate; modified the title to more accurately reflect the study population (primarily patients with bone metastases); proposed specific clinical recommendations in the conclusion, including recommending IMRT/VMAT or SBRT techniques, as well as management protocols for CDK4/6 inhibitors after using 3DCRT; and frankly acknowledged limitations regarding small sample size and heterogeneity of treatment regimens. These improvements, within the existing research framework, provide some novel information for this field and to some extent enhance the scientific rigor and clinical application value of the study.

Author Response

Response to Reviewer 2 Round 2

Authors explained why they did not set up a control group; candidly disclosed technical limitations (only 3DCRT technology was available in 2020); clearly specified using CTCAE version 5 for toxicity assessment and provided detailed intestinal dose constraint data; added overall survival analysis showing a 75% survival rate; modified the title to more accurately reflect the study population (primarily patients with bone metastases); proposed specific clinical recommendations in the conclusion, including recommending IMRT/VMAT or SBRT techniques, as well as management protocols for CDK4/6 inhibitors after using 3DCRT; and frankly acknowledged limitations regarding small sample size and heterogeneity of treatment regimens. These improvements, within the existing research framework, provide some novel information for this field and to some extent enhance the scientific rigor and clinical application value of the study

Dear Reviewer 2

Thank you so much for  taking the time to review our manuscript!

Your recommendations were valuable to us and contributed to increasing the quality and clarity of the manuscript.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

I appreciate the authors’ efforts in addressing my previous comments. However, further improvements could enhance the clarity and impact of the manuscript.

In particular, the Discussion section, though enriched with additional content, would benefit from rewriting for better flow and cohesion, especially the added fragments. Presenting the literature in a more narrative and thematically grouped manner—such as organizing findings by toxicity type or clinical implication—would greatly improve readability and help highlight how the authors’ findings align with or differ from existing data.

The added toxicity table is a valuable improvement.  However, it could be further strengthened by including more detailed information, specifically, indicating which treatment combinations (e.g., CDK4/6 inhibitor, radiotherapy site, technique) led to which toxicities. This would allow readers to interpret any patterns or correlations between treatment variables and observed adverse events more effectively.

Author Response

Response to Reviewer 3 Round 2

 

I appreciate the authors’ efforts in addressing my previous comments. However, further improvements could enhance the clarity and impact of the manuscript.

 

In particular, the Discussion section, though enriched with additional content, would benefit from rewriting for better flow and cohesion, especially the added fragments. Presenting the literature in a more narrative and thematically grouped manner—such as organizing findings by toxicity type or clinical implication—would greatly improve readability and help highlight how the authors’ findings align with or differ from existing data.

 

The added toxicity table is a valuable improvement.  However, it could be further strengthened by including more detailed information, specifically, indicating which treatment combinations (e.g., CDK4/6 inhibitor, radiotherapy site, technique) led to which toxicities. This would allow readers to interpret any patterns or correlations between treatment variables and observed adverse events more effectively

Dear Reviewer 3

Thank you so much for  taking the time to review our manuscript!

Your recommendations were valuable to us and contributed to increasing the quality and clarity of the manuscript.

We rearranged the discussions to make them more coherent.

We added the following discussions to the manuscript (bold-green colour):

Response 1

In our study, grade 3 toxicities were recorded in 4 patients:

- regarding the radiotherapy technique: 2 patients underwent 3D conformational radiotherapy, and 2 patients underwent radiotherapy using the IMRT technique.

- regarding  the CDK4/6 Inhibitor administered, 3 patients received Palbociclib and 1 patient received Ribociclib

Response 2

We were unable to establish statistically significant correlations between the type of CDK4/6 inhibitors and the radiotherapy technique administered; however, we noted the development of enteritis in only one case, who underwent radiotherapy with the 3D technique at the iliac site.

The grade 3 hepatic cytolysis reported in the patient with Palbociclib, Fulvestrant and IMRT radiotherapy was not due to the association between the CDK4/6 inhibitor and radiotherapy, the radiotherapy being performed at the T6 vertebra level.

 

Author Response File: Author Response.pdf