Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery

Round 1

Reviewer 1 Report

The submitted review is nicely written, clear and concise. It surely can be published after several minor corrections, listed below.

Lines 39 and 109, NSAIDs stands for “non-steroidal anti-inflammatory drugs”

Line 64, it should be „related”

Line 109, it should be “NSAIDs”

Table 2, what does “nr” stands for?

Table 2, exactly what opioid?

Author Response

1. The submitted review is nicely written, clear and concise. It surely can be published after several minor corrections, listed below.

We thank this reviewer for these positive comments.

2. Lines 39 and 109, NSAIDs stands for “non-steroidal anti-inflammatory drugs”

Thank you for this careful reading: although this was correct in the text it was not in the figure legend, and we have corrected this. On the second use, on line 109, we have simply retained the acronym as it has been previously defined.

3. Line 64, it should be „related”

We have corrected this typo.

4. Line 109, it should be “NSAIDs”

Thank you; as above this is corrected.

5. Table 2, what does “nr” stands for?

This is already made clear in the table legend: nr = not reported. We have made no change.

6. Table 2, exactly what opioid?

The purpose of this table comparison summary is to assess whether or not opioids were used – it does not matter for purposes of this study which opioid. Hence we have altered the table legend to state “any opioid” to make this point clearer.

Reviewer 2 Report

First, the manuscript submitted not fall within the journal scope.  Drugs and Drug Candidates journal covering all critical steps involved in the story of a marketed or potential therapeutic agent.

 

The manuscript entitled “Do certain anaesthetic drugs affect postoperative cancer recurrence rates? Implications for drug discovery” is well observed retrospective analysis on the application of better anaesthetic process in the cancer surgical treatment. The manuscript needs to be edited before acceptable for publication.

Overall, the structure of the manuscript not in a good shape. The sections described were not related to the study of the focus and rationale of the research design.

The abstract – some statements need to be revised. Line #2 and 4 better to written as continuation.

Delete several (repeated) word from Line 15.

Write the level of significance observed in Line 18.

Write a note on why only two combinations results reported in the manuscript?

Cite the references in para 1 of the introduction.

Why propofol only discussed in Fig.1? Improve quality of the Fig.1 for better clarity. The drawing colors are no longer in out of the boxes. Please rewrite the fig.

 

Author Response

1. First, the manuscript submitted not fall within the journal scope.  Drugs and Drug Candidates journal covering all critical steps involved in the story of a marketed or potential therapeutic agent.

We respectfully disagree. This article was submitted at the specific request of the Editor-in-Chief. We appreciate the reviewer’s point that there are many critical steps in drug discovery but it is difficult or impossible for a single article to encompass all these steps: each article can focus on just one or two steps in the process. 

2. The manuscript entitled “Do certain anaesthetic drugs affect postoperative cancer recurrence rates? Implications for drug discovery” is well observed retrospective analysis on the application of better anaesthetic process in the cancer surgical treatment. The manuscript needs to be edited before acceptable for publication.

We understand and accept the need for editing all articles that are submitted to a journal. Unfortunately the points made above do not direct us to do that in any specific way. We further add that the publisher/editor has mis-interpreted these comments to indicate the paper needs an English language review. We remind the reviewer and editorial team that we are native English-born citizens, and speak no other language other than English. While style may need improving clearly language does not.

3. Overall, the structure of the manuscript not in a good shape.

The reviewer has not suggested a better ‘shape’ for this manuscript so it is difficult for us to respond in any specific way.

4. The sections described were not related to the study of the focus and rationale of the research design.

We think that later subediting of this manuscript by the publisher before it was sent out for review has caused confusion in relation to subheadings. In our original submission these were clearly in bold, and sub-subheadings in italics, but the bold and italic type has been removed by publisher. Consequently, the logic and order created by the subheadings has been destroyed. We have re-inserted the bold and hope this restores the clarity the reviewer is seeking.

5. The abstract – some statements need to be revised. Line #2 and 4 better to written as continuation.

If we joined lines 2-4 this would make for a very long sentence indeed, with many subclauses. Instead we have addressed the reviewer’s point by using italics to contrast the words ‘enhance’ and ‘diminish’ in these sentences, and also add the word ‘other’. We hope this makes better sense.

6. Delete several (repeated) word from Line 15.

We have corrected this typo.

7. Write the level of significance observed in Line 18.

We have added this p-value.

8. Write a note on why only two combinations results reported in the manuscript?

We think by ‘two combinations’ the reviewer means ‘general anaesthetics’ and ‘analgesics’? This is difficult to answer because this is primarily the hypothesis of others, which we are seeking to address and understand. Also, these are really only the two elements of anaesthesia (paralysis and amnesia apart). Of course, within each there are more combinations: thus general anaesthesia encompasses volatile and intravenous; while analgesics encompasses local anaesthesia, NSAIDs, opioids, etc. So there is arguably more than one combination, as we discuss.

9. Cite the references in para 1 of the introduction.

We have added some references.

10. Why propofol only discussed in Fig.1? Improve quality of the Fig.1 for better clarity. The drawing colors are no longer in out of the boxes. Please rewrite the fig.

We have greatly improved Figure 1. We are however confused by the comment “why propofol only discussed in Fig. 1?” – propofol is not discussed.

Reviewer 3 Report

Thank you for permitting me to review this manuscript 

the authors have  FAIRLY cited all RCT in which no  role has been found for the anesthetic /analgesic technique  in influencing the cancer outcome and  I congratulate them for their sincerity 

this should be highlighted , the fact that so far nothing has been found should not automatically result in the statement = larger  RCT are necessary but it should also discuss , may be research in this area should be stopped and ressources oriented in other studies to promote anesthesia or analgesia  technique which they are experts , and may be cancer research should be coordinated totally with oncologist who are expert in onclogy. fondamental resarch on rodents  should not always be extrapolated to humans  

here are my suggestion 

Abstract The lancet article is now 3 years old , there is no need to specifically  mention it in the abstract, another phraze must replace it 

line 31 please provide reference  PPR

line 299 , please describe with reference , why other cancer types may respond popsitively , if there is no reference available , then use a more cautious phraze 

 line 331 ,  I would avoid speaking anti oncogenic and pro immune effect of propofol use more moderate adjective please rephrase

At the end I would also add the fact the real mechanism of general anesthesia is not really understood , therefore it would be difficult to detect and explain their  putative direct role in the outcome of cancers.

Author Response

1. Thank you for permitting me to review this manuscript. The authors have  FAIRLY cited all RCT in which no  role has been found for the anesthetic /analgesic technique  in influencing the cancer outcome and  I congratulate them for their sincerity.

We thank the reviewer for these positive comments.

2. this should be highlighted , the fact that so far nothing has been found should not automatically result in the statement = larger  RCT are necessary but it should also discuss , may be research in this area should be stopped and ressources oriented in other studies to promote anesthesia or analgesia  technique which they are experts , and may be cancer research should be coordinated totally with oncologist who are expert in onclogy. fondamental resarch on rodents  should not always be extrapolated to humans  

The reviewer makes an interesting point and we have added this sentiment in part in the conclusion: “However, an argument could also be made that if even these RCTs fail to demonstrate any positive results, then a time may come when research efforts and expense should be di-rected elsewhere rather than seeking marginal gains in this field of enquiry.”

3. here are my suggestion. Abstract The lancet article is now 3 years old , there is no need to specifically  mention it in the abstract, another phraze must replace it 

We understand that the reviewer wishes us not to focus on one paper. The strength of mentioning it at least in part is the word ‘however’ we use in the abstract – note that we do not specifically mention the paper by name. Therefore we have retained the sentence – but we have removed the word ‘recently’.

4. line 31 please provide reference  PPR

We have now added references to this paragraph, as also suggested by another reviewer.

5. line 299 , please describe with reference , why other cancer types may respond popsitively , if there is no reference available , then use a more cautious phraze 

We have done as advised, and used more cautious wording.

6. line 331 ,  I would avoid speaking anti oncogenic and pro immune effect of propofol use more moderate adjective please rephrase

We have changed the phrasing to avoid these words.

7. At the end I would also add the fact the real mechanism of general anesthesia is not really understood , therefore it would be difficult to detect and explain their  putative direct role in the outcome of cancers.

This is a good point and we have added these words: “If their primary mechanism of action with respect to hypnosis is poorly understood, then it would seem more difficult to ascertain their mechanisms with respect to ‘secondary’ actions such as on cancer recurrence”.

Round 2

Reviewer 1 Report

This corrected version can be accepted for publication "as it is".

Reviewer 2 Report

No further comments.

Reviewer 3 Report

The authors had adequately responded to my queries