Multimodal Approaches to Patient Selection for Pancreas Cancer Surgery

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is interesting narrative review to investigate risk factors for the early recurrence of pancreatic carcinoma after curative-intent resection identified with thorough preoperative staging, thus enabling proper patient selection for surgical resection. This review supports evidence for multidisciplinary and multimodality staging, comprehensive neoadjuvant treatment strategies, and optimal patient selection for curative intent surgical resections.

A standardized approach at the Mayo Clinic and extrapolate to inform potential future investigations are interesting.

My MAJOR comments are:

1)      Authors wrote: Of historical interest, a landmark randomized trial showed a higher risk of complications and increased hospitalization frequency with preoperative biliary stent decompression compared to those who had surgery within one week of diagnosis with  presenting bilirubin levels <14.6mg/dL.27 Consequently, in rare cases without plans for neoadjuvant chemotherapy, patients with resectable PDAC may proceed directly to surgery if bilirubin levels are <14.6 mg/dL.

Could you please specify numbers (percentages) of those patients who had proceed directly to surgery?

2)      Authors wrote: While these evolving data suggest that long term survival may be possible even in setting of R1 resections, at present, R0 resection should be the goal and most available evidence suggests that if a margin positive resection is likely, that consolidative chemo/XRT does less patient harm.

No data are provided form the Mayo Clinic on the comparison of the R1 and R0 survival comparison.

3)      Authors wrote: At the Mayo clinic, independent of vascular involvement, neoadjuvant therapy is typically recommended for all patients. Our studies have shown a remarkable 3-year overall survival of 59% and a median overall survival of 51.1 months for patients with borderline resectable and locally advanced PDAC who received neoadjuvant therapy. In contrast, reported overall survival with use of neoadjuvant therapy from other institutions show a median overall survival of 31.5 months.

This is result of RESECTABILITY DUE TO VASCULAR INVOLVEMENT definition at every institution. This means high variability in that issue, that may be the cause of substantial differences in overall survival. The issue clearly deserves comment and clarification.

4)      Authors derives conclusions on “Reconstructability and Recoverability”, that are not supported (in the manuscript) by literature evidence, nor institutional evidence.

Author Response

This is interesting narrative review to investigate risk factors for the early recurrence of pancreatic carcinoma after curative-intent resection identified with thorough preoperative staging, thus enabling proper patient selection for surgical resection. This review supports evidence for multidisciplinary and multimodality staging, comprehensive neoadjuvant treatment strategies, and optimal patient selection for curative intent surgical resections. A standardized approach at the Mayo Clinic and extrapolate to inform potential future investigations are interesting.

My MAJOR comments are:

• Authors wrote: Of historical interest, a landmark randomized trial showed a higher risk of complications and increased hospitalization frequency with preoperative biliary stent decompression compared to those who had surgery within one week of diagnosis with  presenting bilirubin levels <14.6mg/dL.27 Consequently, in rare cases without plans for neoadjuvant chemotherapy, patients with resectable PDAC may proceed directly to surgery if bilirubin levels are <14.6 mg/dL. Could you please specify numbers (percentages) of those patients who had proceed directly to surgery?

Thank you for your insight and for bringing this to our attention. The paragraph was intended to bring focus to our current practice at the Mayo Clinic. We rephrased this to reflect the intended meaning on page 2, lines 60-65.

• Authors wrote: While these evolving data suggest that long term survival may be possible even in setting of R1 resections, at present, R0 resection should be the goal and most available evidence suggests that if a margin positive resection is likely, that consolidative chemo/XRT does less patient harm. No data are provided form the Mayo Clinic on the comparison of the R1 and R0 survival comparison.

Apologies for the oversight on our end. We added a citation in support of this statement on page 10, line 311.

• Authors wrote: At the Mayo clinic, independent of vascular involvement, neoadjuvant therapy is typically recommended for all patients. Our studies have shown a remarkable 3-year overall survival of 59% and a median overall survival of 51.1 months for patients with borderline resectable and locally advanced PDAC who received neoadjuvant therapy. In contrast, reported overall survival with use of neoadjuvant therapy from other institutions show a median overall survival of 31.5 months. This is result of RESECTABILITY DUE TO VASCULAR INVOLVEMENT definition at every institution. This means high variability in that issue, that may be the cause of substantial differences in overall survival. The issue clearly deserves comment and clarification.

We appreciate your insight. Adjustments were made to this paragraph on page 10 & 11, lines 344-347.

• Authors derives conclusions on “Reconstructability and Recoverability”, that are not supported (in the manuscript) by literature evidence, nor institutional evidence.

This was previously described in detail by Dr. Truty in his prestigious publication “En Bloc Celiac Axis Resection for Pancreatic Cancer: Classification of Anatomical Variants Based on Tumor Extent”. We agree with your comment and feedback. Therefore, we rephrased parts of the section to acknowledge this and we added the appropriate citation to reflect the previous work (page 11, lines 358, 360-361 and 382-387). This conclusion provides an accurate and important summary of the guiding principles utilized at our center to guide our treatment strategy.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you to the authors for this important review on risk stratification and subsequent treatment approach for patients with PDAC. Highlighting the authors' institution will be of interest to Current Oncology readers. A few comments: 

1. Several studies have indicated that imaging (i.e. CT and MRI ) after neoadjuvant therapy for PDAC have low specificity for predicting pathologic response and thus resectability. The authors have expertly discussed the rationale and evidence for serial FDG-PET, in addition to acknowledging this may not be feasible at all institutions. 

2. Can the authors define how they determine "maximum response" as listed in the Figure 2 legend?

3. Routine use of diagnostic laparoscopy of PDAC has yet to be established as standard of care. However, the authors provide clear rationale in favor of diagnostic laparoscopy for PDAC patients. Given it has yet to be adopted as standard of care, perhaps addition of other studies to support the author's rationale here would be beneficial (ex. Sell et al ASO 2018, Allen et al Cochrane Database Review 2016 etc), as well as acknowledgement that other studies have indicated that selective use may be more favorable (ex. Pisters et al BJS 2001)

4. While the authors highlight recoverability as a guiding principle in the review's conclusion when determining whether patients would benefit from intervention, this area does not seem to be highlighted elsewhere in the review. Undoubtedly, the recoverability measures such as nutritional status, comorbidities, overall fitness etc are important aspects when determining the course of treatment for individual PDAC patients. 

Author Response

Thank you to the authors for this important review on risk stratification and subsequent treatment approach for patients with PDAC. Highlighting the authors' institution will be of interest to Current Oncology readers. A few comments: 

• Several studies have indicated that imaging (i.e. CT and MRI) after neoadjuvant therapy for PDAC have low specificity for predicting pathologic response and thus resectability. The authors have expertly discussed the rationale and evidence for serial FDG-PET, in addition to acknowledging this may not be feasible at all institutions. 

Thank you for your feedback.

• Can the authors define how they determine "maximum response" as listed in the Figure 2 legend?

Thank you for your feedback. We made the changes to the figure legend on page 4, lines 107-108.

• Routine use of diagnostic laparoscopy of PDAC has yet to be established as standard of care. However, the authors provide clear rationale in favor of diagnostic laparoscopy for PDAC patients. Given it has yet to be adopted as standard of care, perhaps addition of other studies to support the author's rationale here would be beneficial (ex. Sell et al ASO 2018, Allen et al Cochrane Database Review 2016 etc), as well as acknowledgement that other studies have indicated that selective use may be more favorable (ex. Pisters et al BJS 2001)

We appreciate this insight and we added the latest citations on this topic as per your suggestion on page 6, line 207.

• While the authors highlight recoverability as a guiding principle in the review's conclusion when determining whether patients would benefit from intervention, this area does not seem to be highlighted elsewhere in the review. Undoubtedly, the recoverability measures such as nutritional status, comorbidities, overall fitness etc are important aspects when determining the course of treatment for individual PDAC patients. 

We agree with your feedback. Therefore, we rephrased parts of the section to acknowledge this and we added the appropriate citation to reflect the previous work (page 11, lines 358, 360-361 and 382-387). This conclusion provides an accurate and important summary of the guiding principles utilized at our center to guide our treatment strategy.

Reviewer 3 Report

Comments and Suggestions for Authors

This is an interesting contribution to a subject which is under debate nowadays:

when to operate PDAC patients.

It is well written and easy to understand.

However, there are some minor issues that should be improved.

1) Figure 1 should mention the references on which the figure is based.

2) The non-specialized reader does not know what R0, R1, and R2 mean, unless the full word is written the first time these abbreviations are used. I suggest to include a Table regarding the criteria for each R.

3) Abraxane is a trade mark, please replace it for the chemical name such as nab-paclitaxel.

4) Typo:  dissemation Line 49

5) mFOLFOX give the composition. Not all the readers know what it stands for.

6) Figure 2: XRT , please change it for radiotherapy. Readers may not know what you are meaning by XRT. Besides this is not the usual abbreviation used in other papers.

7) Figure 2: please replace peritoneal disease for peritoneal metastasis.

8)  In addition, some augment their protocol by providing negative oral contrast (e.g., water) to enhance duodenal wall examination.

Who is some. Please modify this sentence and give a reference about who some is supposed to be.

9) You say that:  CA 19-9 demonstrates sensitivity and specificity for PDAC ranging between 70-90% and can be highly correlated with resectability and survival rates.

I have serious doubts about this sentence. I do not think that CA19-9 permits any important decision making. Please elaborate further on the issue.

10) FDG-PET: please write the whole name when first used: 18Fluor 2-deoxyglucose.

11) You say: When given prior to resection, up to 80% of patients will receive  all or most of their prescribed chemotherapy, whereas when administered post-operatively only 50% of patients will even receive 1-2 chemotherapy doses/

Please explain why.

12) RCTs please full name. You abuse unclarified abbreviations. 

Author Response

This is an interesting contribution to a subject which is under debate nowadays:

when to operate PDAC patients. It is well written and easy to understand. However, there are some minor issues that should be improved.

• Figure 1 should mention the references on which the figure is based.

Thank you, we added the appropriate citations on page 1, line 26.

• The non-specialized reader does not know what R0, R1, and R2 mean, unless the full word is written the first time these abbreviations are used. I suggest to include a Table regarding the criteria for each R.

Thank you for the suggestion. We added the definitions of R0, R1, and R2 to the manuscript on page 2, lines 27-29

• Abraxane is a trade mark, please replace it for the chemical name such as nab-paclitaxel.

Certainly agree. This modification was made throughout the manuscript on pages 5 lines 102-103, page 8 line 261 and figure 2.

• Typo:  dissemation Line 49

Thank you. This was corrected on page 2, line 50.

• mFOLFOX give the composition. Not all the readers know what it stands for.

The composite was added to page 2, lines 68-71.

• Figure 2: XRT, please change it for radiotherapy. Readers may not know what you are meaning by XRT. Besides this is not the usual abbreviation used in other papers.

Thank you for bringing this to our attention. We made the change to the figure.

• Figure 2: please replace peritoneal disease for peritoneal metastasis.

This was replaced as per your suggestion.

• In addition, some augment their protocol by providing negative oral contrast (e.g., water) to enhance duodenal wall examination. Who is some. Please modify this sentence and give a reference about who some is supposed to be.

Apologies for omitting the reference. We clarified the sentence and added the intended citations on page 5, lines 126-128.

• You say that:  CA 19-9 demonstrates sensitivity and specificity for PDAC ranging between 70-90% and can be highly correlated with resectability and survival rates. I have serious doubts about this sentence. I do not think that CA19-9 permits any important decision making. Please elaborate further on the issue.

Thank you for this feedback. We rephrased this to reflect the intended meaning on page 5&6, lines 147-152.

• FDG-PET: please write the whole name when first used: 18Fluor 2-deoxyglucose.

We added the whole name on page 6, line 171.

• You say: When given prior to resection, up to 80% of patients will receive all or most of their prescribed chemotherapy, whereas when administered post-operatively only 50% of patients will even receive 1-2 chemotherapy doses. Please explain why.

Thank you for bringing this to our attention. We rephrased this to reflect our intended meaning on page 7, lines 214-215.

• RCTs please full name. You abuse unclarified abbreviations. 

Apologies for the oversight. This was changed to full name on page 10, line 304.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I am satisfied with the changes introduced by the authors. The manuscript has been improved.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you to the authors for addressing and clarifying! I have no additional comments. 

Reviewer 3 Report

Comments and Suggestions for Authors

No further comments