Comparison of Perioperative Chemotherapy versus Postoperative Chemoradiotherapy for Operable Stomach Cancer: A Western Canadian Province Experience

Round 1

Reviewer 1 Report

This is a retrospective study  of 88 patients with gastric and  gastroesophgeal junction cancer  who received postoperative radiochemotherapy ( n=67) or  perioperative chemotherapy, mostly ECF ( n=21). The medial overall survival,  relapse free survival and toxicities  were similar.  The study is important  and the patients' characteristics in the  two groups are comparable. 

There are some  observations :

1. Please describe  in the material and method the RCT and PC ( only preoperative or pre and postoperative?)
2.  Is it possible to have a separate analysis for GE junction tumors alone ?
3. Please explain how  the follow-up was done and how did you obtain the survival data. 
4. It is not clear the difference between the clinical stage and pathological stage ( table I). Please clarify.

Author Response

Reviewer 1

1. Please describe in the material and method the RCT and PC (only preoperative or pre and postoperative?)

 

We have specified detail of peri-operative chemotherapy and post-operative chemo-radiation in the method section of the revised manuscript……. lines 104-114  

1. Is it possible to have a separate analysis for GE junction tumors alone?

 

During the study period majority of patients with GE junction cancer were treated with CROSS protocol with neoadjuvant chemoradiation therapy who were excluded as per figure 1. Since we only have a very small number patients with GE junction cancer a meaningful analysis was not feasible.

1. Please explain how the follow-up was done and how did you obtain the survival data. 

Follow up and survival data was recorded from patient individual medical record and the registry. It has been specified in the method section of the revised manuscript…..lines 118-123.

1. It is not clear the difference between the clinical stage and pathological stage (table I). Please clarify.

 

Clinical staging was based on pre-treatment scan. It is specified in line 99.  

Author Response File: Author Response.doc

Reviewer 2 Report

This is a worthwhile undertaking. I have some suggestions.

1. In your Introduction, you state that "Surgery is the only curative therapy".  However, you then cite much literature proving that chemotherapy prolongs survival, including to some extent long-term survival.  Would you not agree that in some cases chemotherapy can also be curative in the setting of surgery?
2. At the end of the Intro section, you should be more explicit that this was not a randomized study, and why patients were treated one way or another.  Having read the paper, it still isn't clear why patients received PC or PCR therapy.  Was it to do with the era of treatment? Was it arbitrary?  Was it by institution? Or because of referral to one specialist and not another? Obviously this could influence the comparability of the groups (which is the chief concern in analysis like this, not withstanding the broad comparability depicted in Table1).
3. I may have missed it but there was not much discussion/mention of what secondary treatments these pts received when they did relapse, which obviously might be different between the groups (or not, as the case may be) and which could influence survival albeit not PFS.
4. I suggest you put the details of the regimens used up front and not only in the discussion section. 
5. In the Discussion, you state "PC has also evolved and improved over time with better results than that seen with the FLOT..."     Do the words 'than that' belong in this sentence? I think you mean "..better results such as that seen with the FLOT..."??
6. In Table 4, the incidence of anemia in the 'Adjuvant Chemoradiotherapy Group is listed at 50% but I think it's a typo and should be 5%. 
7. Also the hospitalization rates are very different and listed in the toxicity table; this sure sounds like the toxicities were not in fact "comparable" as you state above the Table.  I think you need to give us some more insight into these hospitalization differences, because most of the tox differences in the table trend the other way.
8. With the FLOT OS at 50 months do you really think there is a place for PCR?  If so, who in particular should get it? I also think you should make some statement to the effect that FLOT is looking like a new standard in fit patients, but if there are are pts who should have RT in addition to chemo, we have to be very careful how to administer RT near to FLOT and not do it together, and preferably only on a trial, or similar cautionary language.   
9. Also you should make a quick statement to the effect we are now moving into an era where immune checkpoint inhibitors will likely play a role in selected pts.  

Author Response

Reviewer 2

This is a worthwhile undertaking. I have some suggestions.

1. In your Introduction, you state that "Surgery is the only curative therapy".  However, you then cite much literature proving that chemotherapy prolongs survival, including to some extent long-term survival.  Would you not agree that in some cases chemotherapy can also be curative in the setting of surgery?

 

We agree that perioperative and adjuvant therapy improve patients’ outcomes and improves cure rate. The text has been modified…. line 38.

 

1. At the end of the Intro section, you should be more explicit that this was not a randomized study, and why patients were treated one way or another.  Having read the paper, it still isn't clear why patients received PC or PCR therapy.  Was it to do with the era of treatment? Was it arbitrary?  Was it by institution? Or because of referral to one specialist and not another? Obviously this could influence the comparability of the groups (which is the chief concern in analysis like this, not withstanding the broad comparability depicted in Table1).

 

We appreciate reviewer comments and have specified in the methods section in lines 116-118 that patients received treatment based on various patients and tumor related factors at the discretion of treating physicians. During the study period, tumor boards were better established and more and more patients were discussed in it before proceeding with any treatment.

To mitigate patient selection a Cox proportional multivariate analysis was performed and after adjustment for other variable including age, performance status and comorbid illnesses treatment independently was not associated with better outcome. 

 

1. I may have missed it but there was not much discussion/mention of what secondary treatments these pts received when they did relapse, which obviously might be different between the groups (or not, as the case may be) and which could influence survival albeit not PFS.

 

We agree that palliative therapy following the recurrent disease could influence the overall survival. However, data for secondary treatments was not collected. It has been specified in discussion, lines 238-239.

 

1. I suggest you put the details of the regimens used up front and not only in the discussion section. 

 

We have specified detail of peri-operative chemotherapy and post-operative chemo-radiation in the method section of the revised manuscript……. lines 104-114 

1. In the Discussion, you state "PC has also evolved and improved over time with better results than that seen with the FLOT..."     Do the words 'than that' belong in this sentence? I think you mean "..better results such as that seen with the FLOT..."??

 

        Thanks for the correction. We have modified it , lines 222-23.

 

1. In Table 4, the incidence of anemia in the 'Adjuvant Chemoradiotherapy Group is listed at 50% but I think it's a typo and should be 5%. 

 

         Thank you for pointing it, correction has been made.

 

1. Also the hospitalization rates are very different and listed in the toxicity table; this sure sounds like the toxicities were not in fact "comparable" as you state above the Table.  I think you need to give us some more insight into these hospitalization differences, because most of the tox differences in the table trend the other way.

 

The reasons for hospitalization were quite different and do not appear to follow any trend.  It is possible that given the small numbers in the perioperative chemotherapy group, few extra hospitalizations are making substantial difference to the overall percentage. We have highlighted difference of hospital admission rates in the discussion 244-45.

 

1. With the FLOT OS at 50 months do you really think there is a place for PCR?  If so, who in particular should get it? I also think you should make some statement to the effect that FLOT is looking like a new standard in fit patients, but if there are are pts who should have RT in addition to chemo, we have to be very careful how to administer RT near to FLOT and not do it together, and preferably only on a trial, or similar cautionary language.   

 

We have modified the text to reflect author comments, lines 261-266.

 

1. Also you should make a quick statement to the effect we are now moving into an era where immune checkpoint inhibitors will likely play a role in selected pts.  

 

We have modified the text to reflect author comments, lines 266-268.

 

Author Response File: Author Response.doc