Oral Toxicities in Cancer Patients, Who Receive Immunotherapy: A Case Series of 24 Patients

Round 1

Reviewer 1 Report

Nicolatou-Galitis et al. presents in the paper "Oral toxicities in cancer patients, who receive immunotherapy. A case series of 24 patients." treatment realted toxicity for 24 cases of cancer patients who benefited from immunotherapy. The study group includes different tumor anatomical sites and histological types and also a heterogeneity in the association of systemic treatments (chemotherapy, antiangiogenic agents, bone target therapy) or locoregional (radiotherapy) concurrent or sequential. The authors mention and illustrate with images each case of toxicity, identifying irAEs as the predominant adverse effect. Pre-existing pathologies of the oral cavity that could be exacerbated by the treatment are also mentioned, as well as the involvement of possible synergistic effects between immunotherapy and the other multimodal treatments. I would take into account and propose the introduction of a paragraph to briefly present the registration trials and implications in prognostic for the most used ICIs (Nivolumab, Pembrolizumab, Atezolizumab, Ipilimumab, Durvalumab) considering that the subject may be of interest to other MD specialists unfamiliar with the " immunotherapy revolution". For the English language, I would recommend the evaluation of the manuscript by a English native speaker. Being a less explored and definitely undervalued subject of irAEs of the oral cavity, this article would add value to this subject in reporting and improving the management of irAEs for the oral cavity, but also to identify possible synergistic risks and pre-existing aggravating factors.

Author Response

Reviewer #1
	Comment	Author response
1.	Would propose the introduction of a short paragraph to briefly present the registration trials and implications in prognosis for the most used ICIs (Nivolumab, Pembrolizumab, Atezolizumab, Ipilimumab, Durvalumab), considering the subject may be of interest to other MD specialists unfamiliar with the “immunotherapy revolution”	Thank you very much for your excellent point and the interest of the MD doctor’s community. We have included 11 references on the role of several immunotherapy drugs in cancer. A recent one, 2023, on durvalumab in head and neck cancer treatment, led by the 2nd co-author of this manuscript, was also added in the references, and was briefly mentioned in the Introduction. Furthermore, it was also the opinion of the medical oncology co-authors (16 doctors), that a short review on immunotherapy clinical trials in cancer is rather the scope of a next review manuscript.
2	Would recommend the evaluation of the manuscript by an English native speaker.	The manuscript was re-read by some of our Medical Oncologists co-authors, with more than 10 years’ work in USA Hospitals. If you feel that we need more advanced English language editing, we can ask for a professional office.
3	This article would add value to this subject in reporting and improving the management of irAEs for the oral cavity, but also to identify possible synergistic risks and pre-existing aggravating factors.	We thank very much the reviewer for the kind words.

 

Reviewer 2 Report

I thank the Authors for this excellent paper, illustrating side effects not adequately studied of immunotherapy in cancer patients and the complexity of cancer treatments in recent years.

Few minor notes.

Abstract:

line 41 : 6 (26.92%) infections , should be 25%

line 43 : the 8 patients, with BTA : without comma?

line 43 : the 8 patients, with BTA : BTA appears for the first time (at line 36 without abbreviation : 8 received bone targeting agents, alone or in combinations)

line 46-47 : Maybe better if “various oral complications might be related to interplay ….” ?

Introduction

Line 76 : oral mucosal iroral AEs ; oral mucosal irAEs ? mucosal ir-oral AEs?

 Table 1 needs to be reformatted. In latest lines (MRONJ) : Concurrent zoledronic; please add acid

Figure 3 : pembro-lizumab to be corrected

 

Discussion

Line 173 : either prior or consequential or concurrently with immunotherapy. “Consequential” is not clear. Please reformulate the sentence.  

Line 175 : Recently, few cases of osteonecrosis of the jaw in  patients who received immunotherapy either alone or combined with other therapies. It lacks the verb. “...have been published”?

Please check the references according to Journal style

Author Response

Reviewer #2
1	I thank the reviewers for this excellent paper, illustrating side effects not adequately studied of immunotherapy in cancer patients and the complexity of cancer treatments in recent years.	We thank the reviewer for the kindest words
2	Few minor notes: Abstract: line 41, should be 25%   Line 43, not comma   Line 43, BTA not with abbreviation   Line 46-47: various oral complications might be related to interplay…	Done, thank you!   Comma was deleted.   Done, corrected: Bone Targeting Agents   Yes, the sentence was changed to that wording.
3	Few minor notes: Introduction: Line 76: oral mucosal iroral irAEs	The wording was changed to oral mucosal irAEs
4	Few minor notes: Table 1: needs to be reformatted; concurrent zoledronic   Figure 3: pembro-lizumab	It was edited to zoledronic acid.     Done: pembrolizumab
5	Discussion: Line 173: reformulate the sentence:       Line 175: Recently few cases of … therapies: verd is lacking.    Check the references to Journal style	Line 173 was reformulated: either prior or concurrently with…   the verb was added: “have been published”.     References style was checked

Reviewer 3 Report

 

The manuscript “Oral toxicities in cancer patients, who receive immunotherapy. A case series of 24 patients” is a case-control study whose aim is “to report the oral problems/toxicity of 24 cancer patients”.

The paper falls within the scope of the journal.

Moderate English changes are required.

In my opinion, the paper possesses some flaws, in detail:

·      introduction, the authors often used the prefix “ir-“. In order to help the reader, it is better to describe the acronym in the text (page 2, line 85);

·      M&M, the place of enrollment of patients should be described. Additionally, it could added also the ethics committee approval number;

·      Results; please add the standard deviation to the mean age. Furthermore, there is one patient whose “reason of referral” is “Referred by oncologist”. Probably, it could be better to describe it as “dental extraction follow-up” (or something similar).

However, overall, the paper is very interesting.

Author Response

Reviewer #3
	Comment	Author response
1.	Methods description could be improved.	We improved the description of the Methods.
2	Moderate English changes are required.	Moderate English changes were looked for.
3	Introduction: “ir-“	Ir- corrected. page 2, line 85. Please let me know if I understood well the comment. Thank you.
4	MM The place of enrolment of patients was described.               Ethics committee approval number	All patients had been referred from Public and private Hospital to the private Clinic of Professor Oral Oncologist ONG. Smear for Candida species was received when needed. Panoramic radiographs and/or Cone Beam Computed Tomography were performed, when needed, by Drs EG and DG, who work with Professor ONG. This report was undertaken as a preliminary case series report, within the scope to planning a multicentre research study of oral toxicities of immunotherapy. Ethics committee approval number was considered not applicable at this report.
5	Add the standard deviation of the mean age.	Standard deviation of the mean age was 9.20 (mean age was 65.88).
6	Referred by oncologist to change	Corrected: Dental extraction follow-up
7.	Overall, the paper is very interesting	We thank very much the reviewer for the kind words

Round 2

Reviewer 1 Report

A topic of such interest for medical oncologists, radiation oncologists and head and neck surgeons regarding a topic of maximum topicality and interest - the toxicity of immunotherapy

Reviewer 2 Report

I thank the Authors for the work.

Reviewer 3 Report

The Authors defined all the issues and improved the manuscript