An “Older Old” Woman with Large Squamous Cell Carcinoma of the Nasal Pyramid: Excellent Response to Ultra-Hypofractionated Radiation Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors described a case study, where they threat a "old Woman" with a squamous cell carcinoma of the 2 nasal pyramid in a very short schema

 

In the actual format, the article is ready to be published.

 

They authors put emphasis on the age of the patient and on her problem. They found an elegant way, how they can treat her. They report in the proper way the follow up and the results are promising.

I hope that they can have the possibility to use the same schema for other patient, to prove that this schema can be used in this particular situation.

Author Response

Reviewer 1

The authors described a case study, where they threat a "old Woman" with a squamous cell carcinoma of the 2 nasal pyramid in a very short schema

In the actual format, the article is ready to be published.

They authors put emphasis on the age of the patient and on her problem. They found an elegant way, how they can treat her. They report in the proper way the follow up and the results are promising.

I hope that they can have the possibility to use the same schema for other patient, to prove that this schema can be used in this particular situation.

Answer: We are gratified by the favorable comments of the reviewer and are particularly encouraged by the prospect of utilizing this approach in analogous cases.

Reviewer 2 Report

Comments and Suggestions for Authors

Sir, 

I have recently reviewed the manuscript "Older old” woman with large squamous cell carcinoma of the nasal pyramid: excellent response to ultra-hypofractionated radiation therapy" submitted by Carla Pisani and co-workers. 

I believe that this manuscript is an interesting case report (it is not overly ambitious and acknowledges exactly the right type of publication). 

It is a simple case of squamous cell carcinoma with a less frequently seen extent of exophytic growth. The authors provide a reasonable (and rather educative!) discussion on the advantages of hypofractionation of radiotherapy. This is a less frequently mentioned topic/approach with clinical significance on elderly and physically disabled populations. 

I believe that the manuscript should be improved in: 

a) please, reconsider the evident ethical dilemma: Lines 87-88 "Patient provided written informed consent." (Once again, line 247).  It contrasts with line 151-152 "Considering the patient's deteriorating neurocognitive status,..." Please reconsider the wording of these statements. Better wording would certainly prevent any implications regarding patient´s ability to provide any valid consent. It was a well-intended and efficient treatment, and you must just exclude any confusion (e.g. presence and participation of legal representatives, family emmbers or custodians of any type would be rather reassuring). 

b) the authors use numerous abbreviations without listing them (or explaining them in the test upon first mentioning them). 

c) In the discussion, the authors completely omitted recently available pharmacological treatments for locally advanced squamous cell carcinomas (meaning e.g. cemiplimab). I would NOT advocate cemiplimab as a better treatment in such a case, but this is academic communication, and it should be at least briefly mentioned. Using the cost/effect analysis - I believe that the authors can easily find highly favourable reasoning for RT. 

d) the authors should acknowledge that the clinical response observed for only 124 days is a rather short follow-up. 

To conclude, I believe that the submitted case report is interesting, educative and worthy of attention.  The authors can easily cope with the above-mentioned issues. I am keen to see the final version soon. 

Comments on the Quality of English Language

No serious objections.

Author Response

Reviewer 2

Sir, 

I have recently reviewed the manuscript "Older old” woman with large squamous cell carcinoma of the nasal pyramid: excellent response to ultra-hypofractionated radiation therapy" submitted by Carla Pisani and co-workers. 

I believe that this manuscript is an interesting case report (it is not overly ambitious and acknowledges exactly the right type of publication). 

It is a simple case of squamous cell carcinoma with a less frequently seen extent of exophytic growth. The authors provide a reasonable (and rather educative!) discussion on the advantages of hypofractionation of radiotherapy. This is a less frequently mentioned topic/approach with clinical significance on elderly and physically disabled populations. 

Answer: We are gratified by the favorable comments of the reviewer.

I believe that the manuscript should be improved in: 

1. a) please, reconsider the evident ethical dilemma: Lines 87-88 "Patient provided written informed consent." (Once again, line 247).  It contrasts with line 151-152 "Considering the patient's deteriorating neurocognitive status,..." Please reconsider the wording of these statements. Better wording would certainly prevent any implications regarding patient´s ability to provide any valid consent. It was a well-intended and efficient treatment, and you must just exclude any confusion (e.g. presence and participation of legal representatives, family members or custodians of any type would be rather reassuring). 

Answer: We are grateful for the identification of this potential source of confusion. The patient is, and has been, capable of understanding and expressing an opinion. However, she does experience occasional episodes of space-time confusion, yet there are no medical or legal limitations to her capacity. Furthermore, we have highlighted that the patient underwent an onco-geriatric assessment, which did not reveal any evidence of significant neurological impairment.  In the discussion chapter, modifications were made to reflect this concern and to underscore the potential for neurocognitive impairment, which was not initially a significant issue. We modified lines: 55-56, 89-92, 184-187

1. b) the authors use numerous abbreviations without listing them (or explaining them in the test upon first mentioning them). 

Answer: It was noted that numerous abbreviations were in use, and it was deemed appropriate to provide a list of these at the end of the document (lines: 312-327). We are grateful to the reviewer for highlighting this point.

1. c) In the discussion, the authors completely omitted recently available pharmacological treatments for locally advanced squamous cell carcinomas (meaning e.g. cemiplimab). I would NOT advocate cemiplimab as a better treatment in such a case, but this is academic communication, and it should be at least briefly mentioned. Using the cost/effect analysis - I believe that the authors can easily find highly favourable reasoning for RT. 

Answer: The viewpoint put forth by the reviewer is readily recognizable and comprehensible. It was not our intention to omit any information when the paper was first drafted. However, it has been recognized that the absence of any mention of new therapies may limit the value of the discussion. Accordingly, we have incorporated the pertinent bibliographical references and expanded the discussion section (lines 93-95 and 163-186).  Furthermore, the cost-benefit analysis conducted by the multidisciplinary forum has been made explicit (lines: 304-306).

1. d) the authors should acknowledge that the clinical response observed for only 124 days is a rather short follow-up.

Answer: We are grateful for your recommendation to highlight this limitation in our case report. We

added some sentences in this regard (lines: 278-284).

To conclude, I believe that the submitted case report is interesting, educative and worthy of attention.  The authors can easily cope with the above-mentioned issues. I am keen to see the final version soon. 

Reviewer 3 Report

Comments and Suggestions for Authors

The case report highlights the challenges the author encountered in the treatment of a patient with locally advanced squamous cell carcinoma of the nasal cavity, involving a 98-year-old female patient. Given the patient’s advanced age and condition, surgery was deemed inappropriate, leading to the employment of a specialized radiotherapy approach. Post-treatment, the patient exhibited significant clinical improvement.

Major Comments

Lack of Detail in the Treatment Decision-Making Process: The report lacks a thorough comparison of alternative treatment modalities that were considered before selecting hypofractionated hyperdense radiation therapy. For instance, while it is generally accepted that cytotoxic chemotherapy is not advisable, immune checkpoint inhibitors and molecular targeted therapies might be appropriate in certain contexts. Additionally, the consideration of proton beam therapy, heavy particle therapy, or boron neutron capture therapy should be discussed. The report should clarify whether issues of cost-effectiveness, particularly in light of the patient’s age and financial status, were taken into account. It is crucial to explicitly state whether these discussions occurred, and if not, provide a rationale.

Minor Comments

Pain Management and Quality of Life: There is a need for more detailed information on pain management strategies and their effects during and after treatment. Specifically, it should address how pain was managed in this very elderly patient with cognitive decline. While there is a mention of quality of life (QOL) improvement (lines 108-109), there is a lack of concrete evidence demonstrating how the patient's QOL was enhanced.

Comparison and Positioning with Other Literature: The report lacks comparisons with other studies on similar cases. Currently, it only follows the treatment outcomes of other elderly patients. It should be emphasized that this report is significant because it details the treatment of a nearly 100-year-old patient with very poor performance status (PS) using a simple, low-risk method that yielded results comparable to complete remission (CR).

Discussion of the Risks and Benefits of Radiotherapy: A more comprehensive discussion of the risks and benefits of radiotherapy is necessary. Particularly, the report should detail specific side effects and the tolerability of the treatment in elderly patients.

Conclusion

Overall, this article holds clinical value as it demonstrates the effectiveness of radiotherapy in elderly patients. However, enhancing the paper by addressing the aforementioned points would significantly improve its quality. This would hopefully contribute to the development of treatment guidelines for similar cases and their application in clinical practice.

Author Response

Reviewer 3

The case report highlights the challenges the author encountered in the treatment of a patient with locally advanced squamous cell carcinoma of the nasal cavity, involving a 98-year-old female patient. Given the patient’s advanced age and condition, surgery was deemed inappropriate, leading to the employment of a specialized radiotherapy approach. Post-treatment, the patient exhibited significant clinical improvement.

Answer: We would like to express our gratitude to the Reviewer for their time and attention. We hope that we have been able to implement the suggested improvements to our work.

Major Comments

Lack of Detail in the Treatment Decision-Making Process: The report lacks a thorough comparison of alternative treatment modalities that were considered before selecting hypofractionated hyperdense radiation therapy. For instance, while it is generally accepted that cytotoxic chemotherapy is not advisable, immune checkpoint inhibitors and molecular targeted therapies might be appropriate in certain contexts. Additionally, the consideration of proton beam therapy, heavy particle therapy, or boron neutron capture therapy should be discussed. The report should clarify whether issues of cost-effectiveness, particularly in light of the patient’s age and financial status, were taken into account. It is crucial to explicitly state whether these discussions occurred, and if not, provide a rationale.

Answer: The viewpoint put forth by the reviewer is readily recognizable and comprehensible. It was not our intention to omit any information when the paper was first drafted. However, it has been recognized that the absence of any mention of alternative therapies may limit the value of the discussion. Accordingly, we have incorporated the pertinent bibliographical references and expanded the discussion section (lines: 93-95; 174-179; lines: 264-277). Moreover, the cost-benefit analysis conducted by the multidisciplinary forum has been made explicit.

Minor Comments

Pain Management and Quality of Life: There is a need for more detailed information on pain management strategies and their effects during and after treatment. Specifically, it should address how pain was managed in this very elderly patient with cognitive decline. While there is a mention of quality of life (QOL) improvement (lines 108-109), there is a lack of concrete evidence demonstrating how the patient's QOL was enhanced.

Answer: We extend our gratitude to you for your meticulous examination and analysis. The article includes a description of the onco-geriatric evaluation that the patient underwent. 
The patient's quality of life was evaluated using the CASP-12 scale, which has been demonstrated to be an effective assessment system for elderly patients. We have included the references and the improvement in the perception of quality of life in the text. Similarly, the NRS scale was employed to evaluate and contrast the intensity of the pain experienced. We also added some sentences about pharmacological therapy (see “Presentation of the case”). Lines: 62-67, 89-92, 124-129.

Comparison and Positioning with Other Literature: The report lacks comparisons with other studies on similar cases. Currently, it only follows the treatment outcomes of other elderly patients. It should be emphasized that this report is significant because it details the treatment of a nearly 100-year-old patient with very poor performance status (PS) using a simple, low-risk method that yielded results comparable to complete remission (CR).

Answer: We are grateful to the reviewer for this accurate observation, which cannot be refuted. To the best of our knowledge, this is the only published work on an almost centenarian patient with a low performance status. It would be beneficial to initiate multicenter comparisons for the treatment of similar patients. We add some sentences, lines: 213-216, 260-263, 289-294.

Discussion of the Risks and Benefits of Radiotherapy: A more comprehensive discussion of the risks and benefits of radiotherapy is necessary. Particularly, the report should detail specific side effects and the tolerability of the treatment in elderly patients.

Answer: Some additional paragraphs on the role of hypofractionation and age-related toxicities have been added (lines: 203-208, 213-216).

Conclusion

Overall, this article holds clinical value as it demonstrates the effectiveness of radiotherapy in elderly patients. However, enhancing the paper by addressing the aforementioned points would significantly improve its quality. This would hopefully contribute to the development of treatment guidelines for similar cases and their application in clinical practice.

Reviewer 4 Report

Comments and Suggestions for Authors

A nice case report, with at least some (but missing others) references of small series doing the same. Although nicely reported, a single case report does not add sufficiently to the already accepted practice in dealing with non-melanoma cutaneous carcinoma in patients who are not candidates for resection. 

Comments on the Quality of English Language

Minor issues, such as wrong pronoun (he).

Author Response

Reviewer 4

A nice case report, with at least some (but missing others) references of small series doing the same. Although nicely reported, a single case report does not add sufficiently to the already accepted practice in dealing with non-melanoma cutaneous carcinoma in patients who are not candidates for resection. 

Answer: We would like to express our gratitude to the reviewer for taking the time to read our case report. It is not our intention to suggest that this case will result in a change to clinical practice. However, we believe that it is of value to share with the scientific community a positive outcome in a patient who was not only elderly but also presented with several additional problems that made even conventional radiotherapy treatment challenging.

English language, Minor issues, such as wrong pronoun (he).

Answer: We are most grateful to you for pointing out these oversights. The modification has been implemented in the text, as indicated by the yellow highlighting (line 26).

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Editor,

I have reviewed the second version of the manuscript radiation-3122012 (Case Report Title:  “Older old” woman with large squamous cell carcinoma of the nasal pyramid: excellent response to ultra-hypofractionated radiation therapy") submitted by Carla Pisani and co-workers.  

I have studied the rebuttal letter and point-by-point responses provided by the authors.  The authors honestly dealt with all the criticism listed in my previous report. I believe they collectively made substantial improvements to the manuscript, and I do not see any outstanding issues in this case.  I can very easily support this case report as it is now for publication and for the general benefit of interested scientists and physicians and also affected patients.   

Author Response

I have reviewed the second version of the manuscript radiation-3122012 (Case Report Title:  “Older old” woman with large squamous cell carcinoma of the nasal pyramid: excellent response to ultra-hypofractionated radiation therapy") submitted by Carla Pisani and co-workers.  

I have studied the rebuttal letter and point-by-point responses provided by the authors.  The authors honestly dealt with all the criticism listed in my previous report. I believe they collectively made substantial improvements to the manuscript, and I do not see any outstanding issues in this case.  I can very easily support this case report as it is now for publication and for the general benefit of interested scientists and physicians and also affected patients.   

We are grateful to the Reviewer for this valuable feedback. The first feedback has enabled us to enhance the work and, we believe, make it more useful to future patients.

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you for submitting your revised version. We appreciate the time and effort spent in responding to the reviewers' comments and making the necessary revisions.

Author Response

Thank you for submitting your revised version. We appreciate the time and effort spent in responding to the reviewers' comments and making the necessary revisions.

Thank you very much

Reviewer 4 Report

Comments and Suggestions for Authors

The additional materials do not enhance the paper. In fact a case report that should be highly targeted has been made lengthier. Large areas should be removed if you think am even a very concise case report that discusses only irradiation options is warranted at all. If you want a concise case report regarding solely on the successful palliative irradiation they did then a much much shorter focused report might be considered. 

  Comments on the Quality of English Language

The additional materials do not enhance the paper. In fact a case report that should be highly targeted has been made lengthier. Large areas should be removed if you think am even a very concise case report that discusses only irradiation options is warranted at all. If you want a concise case report regarding solely on the successful palliative irradiation they did then a much much shorter focused report might be considered. 

Author Response

The additional materials do not enhance the paper. In fact a case report that should be highly targeted has been made lengthier. Large areas should be removed if you think am even a very concise case report that discusses only irradiation options is warranted at all. If you want a concise case report regarding solely on the successful palliative irradiation they did then a much much shorter focused report might be considered. 

We are grateful to the Reviewer for this further analysis of our case report.

The additional material included in the initial draft was prompted by the recommendations of two other Reviewers, who encouraged us to enhance the paper by exploring potential non-radiotherapy alternatives (such as drug therapy) or different radiotherapy modalities (such as proton therapy).

Furthermore, the Editor recommended that we expand the scope of the case report by conducting a more comprehensive review. We apologize if this has negatively impacted the quality of the paper; however, removing the additional materials would be contrary to the constructive feedback we have received from other Reviewers.

In accordance with the Reviewer’s request, we have incorporated two supplementary case reports (in addition to those already included in the bibliography). De Felice (2021) and Roberson (2021). Both cases concentrated on alternative hypofractionation techniques in the context of elderly patients. It should be noted that our work is not a systematic review and therefore we do not claim to have cited all relevant cases in the literature. Nevertheless, to the best of our knowledge, we have included all cases published in the last ten years.