Current Advances in Radioactive Iodine-Refractory Differentiated Thyroid Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors, Thank you for a very comprehensive discussion on Radioactive Iodine Refractory Differentiated Thyroid Cancer.  I have a few comments and suggestions.

From reading the paper, it does not seem like English is the first language of the authors - so I suggest that you have a native English speaker to proofread and change the grammar as needed.  One example, in the introduction....Radioactive iodine..... it became useless when cancer cells develop refractoriness  - this needs to be rephrase

Also in the introduction, there are several abbreviations used that have not been defined - FA-Pi, PSMA, SSTR

Last 2 paragraphs in section 2 limnes 94 - 110 may be beyond the scope of your article - could be omitted

Section 6 seems a bit too long - especially the first page from lines 179 - 250 could be shortened by 50% and still convey the same information?

Please also check the following comments:

1. Introduction – You may want to add a statement to inform the reader which patients have a higher risk of developing RAIR thyroid ca - ?age ?tumor size ?any specific histologic subtypes

2. Defining RAIR Diff Thyroid Ca – Suggest that the last 2 paragraphs could be abbreviated since the focus of the manuscript is on clinical aspects of RAIR.

3. Identifying RAI-R  Please add a comment on the role of serum thyroglobulin (Tg) in the identification of RAI-R - ?absolute levels of Tg  ?doubling time of Tg 

4. Current molecular imaging and care options  - In this section, you may wish to discuss the role of molecular markers in the choice of treatment options – Which mutations are detected in RAI-R thyroid ca?  and how often.   It is also suggested that current standard option of Lenvatinib should be emphasized in this section.  It would be helpful to discuss Reference 89 in this section.  As it currently stands, the reader of this section may have some confusion when to use the various drugs. What is the mechanism of action of Cabozantinib?  This should be included

5. Future diagnostic and therapeutic perspectives – This section seems a bit long and thus may be cause some confusion for the reader as to which approach is recommended.  Therefore, it may improve this section by separating the diagnostic vs. therapeutic approaches.  So for future diagnostic, one could discuss Ga-DOTA, 18F choline; FAPi while under future therapeutic, one could discuss 177-Lu labelled tracers and re-differentiation protocols

6. A case of re-differentiation – no comments

7. Conclusions – You may want to add any information on current clinical trials for RAI-R thyroid cancer.

Comments on the Quality of English Language

Moderate changes needed, please have an English speaker proofread and make changes as required. 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The article deals with a still relevant issue in thyoid oncology, the radioactive iodine refractory thyoid carcinoma.  After years where this therapy was standard of care, it is now restricted only to a defined category of carcinoma. This is shown by a decrease in radioiodine therapies (Gordeon et al 2022, https://doi.org/10.1001/jamaoto.2022.3360). The recommendations of ATA guideline regarding RAI therapy are classified as weak with low evidence in low and intermediate risk patients, strong an moderate in high risk.

So I feel you should discuss the value of RAI therapy, the evidence base and the indications much more clearly. I think it would be helpful to separate the diagnostic implications of RAI-R from the therapeutic (separate table?). In line 45/46 you state, that RAI ablation is successful in low risk situations or thyroid remnants. This is not covered by the ATA guideline as an indication.

Line 112: please explain the difference between PT-WBS and D-WBS.

Several protocols have been used for re-differentiation. Please include them to your review and discuss, e.g. retinoic acid shows re-stimulation rates up to 50 % (e.g. Pak et al 2018 https://doi.org/10.1159/000484206; Groener et al 2019 10.1055/a-0765-9078 ; Coelho 2015 doi: 10.2174/1381612054367490 and many others) or Selumetinib (e.g. Ho et al 2013 NEJM doi: 10.1056/NEJMoa1209288, Ho et al 2022 JCO and many others). How successful is re-stimulation for diagnostic radioiodine scan related to therapeutic success of RAI-therapy?

·          The knowledge on RAIR mechanisms is increasing, recent data suggest a correlation with MAP-kinase pathways, especially BRAF mutations. So one should consider RAIR a sign of tumor mutation, indicating the need for targeted therapies. Please discuss the therapeutic options in this setting (recent review of agents tested in this setting: Anamaterou et al Thyroid Res 2023 10.1186/s13044-023-00147-7, Boucai et al JAMA 2024 doi:10.1001/jama.2023.26348)

 

 

 

Please explain „CDT“ (lines 50, 58, 59)

Line 194/195: „was“ missing

Line 274: DX-WBS or D-WBS?

Line 297 ff: was there a therapeutic effect of trametinib and dabrafenib on the tumor manifestations?

Please streamline the article, some messages are redundant. 

Comments on the Quality of English Language

fine with minor issues

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors, thanks for your revisions.  We will proceed with the usual checks prior to publication.

Reviewer 2 Report

Comments and Suggestions for Authors

fine work