Ultra- and Moderately Hypofractionated Radiotherapy for Inoperable Cholangiocarcinoma: A Single-Institution Retrospective Analysis
, Zhihui Amy Liu 1,2, Michael Yan 1,2, Laura Ann Dawson 1,2, Ali Hosni Abdalaty 1,2, Jelena Lukovic 1,2, Rebecca Wong 1,2, Aisling Barry 1,2, John Kim 1,2, Jennifer J. Knox 3, Chaya Shwaartz 4,5 and Aruz Mesci 1,2,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe title of the manuscript: „Ultra- and Moderately Hypofractionated Radiotherapy for Inoperable Cholangiocarcinoma: A Single Institution Retrospective Analysis.”
This is a well-written paper, with interesting data for the clinicians as well. The topic of the manuscript is the one-center experience with definitive dose radiation treatment of localized biliary tract cancers, based on a nearly 2-decade retrospective database. Although there are a great number of papers found in this topic in the medical literature, the relatively high number of patients, the well-processed data, and the specific observations and messages make the present material worthy of publication in the referee's opinion. The reviewer has only a few comments, which are as follows:
1, The median diameter of the treated tumors was rather large, as the authors indicate in the discussion, compared with similar data from other clinical publications. The tumor marker values ​​examined can also be considered extremely high. Based on all this, it can be stated that this is a locoregional advanced disease cohort, with a presumably high potential of dissemination. I think this fact should be emphasized in any part of the publication. Moreover, perhaps this fact can also explain the not clear RT dose dependence considering the survival and local control data.
2, Perhaps those patients who could not complete the RT, or even did not reach half of the planned dose, should not have been excluded from the data processing?
3, Results section: pp. 196-197.: Theauthors describe that the survival results were numerically slightly worse in case of SBRT treatment compared to moderately hypo-fractionated radiotherapy. However, when looking at the survival curves (Figure 2.), this cannot be observed, and it seems that the median OS is higher for SBRT (see the survival surves). It is recommended to control this data, and perhaps briefly review the other clinical/statistical data.
Author Response
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Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThere are some comments.
A pretreatment biopsy was performed; however, it would be preferable to include additional histopathological information, such as histological type, grade, tumor size, and pathological stage.
The types of biliary complications should be clarified in more detail (e.g., cholangitis, biliary obstruction, stent occlusion, or other procedure-related events).
The tables could be improved for better readability—for example, by ensuring a clear separation between variables, categories, and values in Table 1.
Please check referernces.
For example, Ref. 15. J Clin Orthod. -> J Clin Oncol.
Comments on the Quality of English LanguagePlease check English grammar and spelling.
For example, Page 3, line 92. Data was ... -> Data were
Author Response
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Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors present the outcomes from a retrospective single center study aiming to evaluate the overall & progression-free survival, recurrence patterns, and the association between biliary complications and OS in patients with inoperable, localized CCA treated with RT. This is an interesting study, it is well written and structured.
A number of issues to be addressed by the authors:
- IRB number if available should be provided
- Avoid starting sentences with a written number
- Provide range for all median values ie L152
- Do the authors feel that extrahepatic CCA and perihilar should be grouped together?
- Since the authors highlight that biliary complications impact OS, which makes sense, it coule be useful to run an analysis for risk factors for biliary obstruction. This would produce a powerful clinical message.
- A limitations section is not clear. For instance, this is a historic series regardless of the utility of RT, and immunotherapy which is now the standard of care was used in a tiny proportion of patients. These limitations need to be acknowledged and further explanded.
Author Response
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Reviewer 4 Report
Comments and Suggestions for AuthorsSummary
The study's objectives were to assess overall survival (OS), progression-free survival (PFS), recurrence patterns, and the relationship between biliary complications and OS in patients with inoperable, localized cholangiocarcinoma treated solely with radiation therapy (RT).
Though the incidence rate of this cancer type is not as high as for other cancers, I applaud the authors for doing such an excellent job to raise awareness.
My comments:
Line 62: Delete "in"
When you say "metastatic disease," what does that mean? Are you referring to cancer or any disease that can spread?
Did authors observe patients who were below 30 years?
I'm confused. Was systematic therapy a prerequisite or not for the studies?
What informed the average age?
What type of RT was used for the treatment? I missed the radiation source.
Will the liver, gallbladder, and small intestine be compromised during treatment?
Table 1 is quite difficult to understand. What is the percentage in parentheses?
I did not see carcinoembryonic antigen in the baseline table. This is a biomarker too.
Authors could have considered other biomarkers.
Although several studies have recently been carried out to try to find and verify CCA biomarkers, the identification and validation of novel biomarkers useful for risk stratification, diagnosis, prognosis, and prediction of therapy response remains an unmet need for patients with CCA. I believe authors will consider this path in the future.
Author Response
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Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe manuscript has been well revised.
It would be better to include histological subtypes (e.g., adenocarcinoma) of intrahepatic and distal cholangiocarcinoma and hepatocellular carcinoma.
Please add spaces between numbers and units:
For example, 55Gy → 55 Gy
0.5cc → 0.5 cc
Please check English grammar.
For example, Absent of Satellite Nodules -> Absence of Satellite Nodules
Author Response
Comment 1: It would be better to include histological subtypes (e.g., adenocarcinoma) of intrahepatic and distal cholangiocarcinoma and hepatocellular carcinoma.
Answer: All the patients included in the study were those with a biopsy-proven adenocarcinoma. HCC and mixed histology were not included to avoid confounding the results.
Comment 2: Please add spaces between numbers and units.
Answer: The typographic errors have been corrected.
Comment 3: Please check English grammar.
Answer: The typographic errors have been corrected. Thank you for your thoughtful and constructive review of our manuscript. We sincerely appreciate the time and expertise you dedicated to it.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors have adequatelly addressed my remarks.
Author Response
We are grateful for your careful review and insightful feedback. Your suggestions were extremely helpful in refining the manuscript, and we appreciate the effort you invested in guiding its improvement.
