Vascular and Cardiac Prognostic Determinants in Patients with Gynecological Cancers: A Six-Year Follow-up Study

Round 1

Reviewer 1 Report

This is a very interesting, well-designed, well-written study and adds new and important information about the cardio toxicity of chemotherapeutics agents when they are applied for the treatment of gynaecological malignancies. My only concern is that the samples size is quite small. Could the authors anyhow increase their samples size?

Author Response

Reviewer #1

We thank this Reviewer for the constructive comments and suggestions. Furthermore, we would like to really thank him/her for his/her appreciation about our research. This is our point to point reply.

1. This is a very interesting, well-designed, well-written study and adds new and important information about the cardio toxicity of chemotherapeutics agents when they are applied for the treatment of gynaecological malignancies. My only concern is that the samples size is quite small. Could the authors anyhow increase their samples size?

We would like to really thank the reviewer for his/her appreciation of our work. We are really honoured about his/her comment. According to the small sample size, the study was prospectively designed 6 years ago and involved only the included patients. Indeed, after preliminary results obtained about 3 years ago, we decided to manage further studies which will include wider sample size in order to improve and confirm the results.

Reviewer 2 Report

Thank you for submitting this gut written paper and for giving me the Chance to review it.

From the gynecological Point of view, the subject of this work is very interesting, but I still have some comments:

1- Please provide the approval number of local ethic committee for this study.

2- In Table 1, the patients, who underwent surgery could statistically significant better survive than patients who receive chemotherapy. I think this is an interesting result to be mentioned and discussed.

3- In discussion, lines 230-232: why did you exclude surgery as a treatment modality from this statement?

4- LVEF and TAPSE were independent prognostic factors for mortality, but what is about morbidity? Was it possible to prove the deterioration of these values with times and after cancer-therapies in survivors?

5- It is good to be able even to provide information about the impact of endothelial function and morbidity, as you have followed the patients for a long time.

6- One of shortcomings of this study is the heterogeneity of included gynecological tumor entities. There are any data from ovarian cancer patients only (as the biggest subgroup with more harmonic therapy options).

Author Response

Reviewer #2

We thank this Reviewer for her/his useful suggestions. We sincerely appreciate his/her comments on our work. This is our point-to-point reply:

1. Please provide the approval number of local ethic committee for this study

The approval number of the local ethic committee is 964/07-07-2009.

1. In Table 1, the patients, who underwent surgery could statistically significant better survive than patients who receive chemotherapy. I think this is an interesting result to be mentioned and discussed.

Thank you very much for your comment. We do agree with the reviewer that surgery seemed to improve survival, while no influence was from chemotherapy. Indeed, surgery did not confirm to act as independent predictor of mortality at multivariate regression analysis (table 3). For this reason we do not concentrate the attention on this point. Furthermore, we think that the improvement in the sample size in future studies will try to give a chance to surgery for possible role in the overall survival of patients with gynaecological cancers.

1. In discussion, lines 230-232: why did you exclude surgery as a treatment modality from this statement?

The reviewer is right. We updated the sentence by including surgery.

1. LVEF and TAPSE were independent prognostic factors for mortality, but what is about morbidity? Was it possible to prove the deterioration of these values with times and after cancer-therapies in survivors?

Once more thank you very much for this important comment. This is a really good point to be addressed. We tried to evaluate the impact of comorbidities at the univariate and multivariate Cox regression analysis. Only age and peripheral artery diseases demonstrated to be predictor of mortality at univariate regression analysis. Nevertheless, they failed to act as independent predictors at multivariate regression analysis. All the comorbidities of the patients as outlined in table 1 failed to be predictors at univariate regression analysis.

1. It is good to be able even to provide information about the impact of endothelial function and morbidity, as you have followed the patients for a long time.

We really thank the reviewer for this insight. The endothelial function early revealed to distinguish survivors from non-survivors. As outlined from table 2, FMD effectively impact on the long-term prognosis of the patients with gynaecological cancers. This was the most important novelty of this paper. No previous researches have focused on the role of FMD on the survival of cancer patients, thus no substantial importance has been given to the role of endothelial function in cancer. Furthermore, we demonstrated that FMD confirmed to be an independent predictor of mortality even after multivariate regression analysis. Therefore, comorbidities did not influence the role of FMD values as predictors of mortality. It would be great if FMD values would have been evaluated after 6 years follow-up but we have not such data as we concentrated on the mortality rate of the patients. Indeed, this is a good point to be addressed in further analyses.

1. One of shortcomings of this study is the heterogeneity of included gynecological tumor entities. There are any data from ovarian cancer patients only (as the biggest subgroup with more harmonic therapy options).

Thank you very much for this interesting insight. We performed a further analysis on the subgroup of patients with ovarian cancer.

Table 1. Baseline characteristics of the study population with ovarian cancer, survival, and non-survival patients.

Number are expressed as mean±standard deviation or number and percentages.

Abbreviations: CVD: cardiovascular diseases; Hb: haemoglobin; HCT: haematocrit; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol; MCH: Mean Corpuscolar Haemoglobin; MCHC: mean corpuscular hemoglobin concentration; MCV: Mean Corpuscular Volume; PLT: platelets; RBC: red blood cells; TG: triglycerides; TIA: transient ischemic attack; WBC: white blood cells.

Table 2. Echocardiographic and vascular parameters: comparisons between survivors and non-survivors patients.

Number are expressed as mean±standard deviation.

Abbreviations: AoR: aortic root diameter; APAO: antero-posterior diameter of the infrarenal abdominal aorta; FMD: flow-mediated vasodilatation; ET: ejection time; IVCT: isovolumic contraction time; IVRT: isovolumic relaxation time; IVS: interventricular septum; LA-APD: left atrial – antero-posterior diameter; LVEDD: left ventricle end-diastolic diameter; LVEF: left ventricle ejection fraction; LVESD: left ventricle end-systolic diameter; mean C-IMT: mean common carotid intima-media thickness; TAPSE: tricuspid annular plane systolic excursion.

At ROC analysis, LVEF was significantly associated with mortality, while FMD did not reach statically significant results.

Table 3. Echocardiographic and vascular predictors of all-cause mortality.

Abbreviations: APAO: antero-posterior diameter of the infrarenal abdominal aorta; AUC: area under the curve; FMD: flow-mediated vasodilatation; LVEF: left ventricle ejection fraction; mean C-IMT: mean common carotid intima-media thickness; TAPSE: tricuspid annular plane systolic excursion.

At multivariare Cox regression analysis only LVEF confirmed to be an independent predictor of mortality in these patients

Indeed, we think that a greater sample size will allow better predictions in such a subgroup of patients.