Duodenal Adenocarcinoma: The Relationship between Type of Surgery and Site of Recurrence in a Spanish Cohort

Round 1

Reviewer 1 Report

The manuscript by Blanco-Fernandez presents the retrospective analysis of patients undergoing surgery for duodenal tumors from 3 university hospitals In Spain. The study is not novel, but represents confirmation of findings on survival after partial versus radical resection for duodenal adenocarcinoma. The included patient number is small, and the sample size limits the impact of findings, as most of the findings are trends. Nevertheless, research design and interpretation of findings are scientifically sound. I would recommend the publication, as the real world data from different geographical regions is needed, especially on tumors with low incidence. Nevertheless, I suggest the change of the title to reflect the limitations: e.g. adding "in the Spanish cohort", or "real world data", or "pilot study".

Author Response

Dear Reviwer,

Thank you very much for the opportunity to make changes to the manuscript. We appreciate the time and effort you and each of the reviewers have dedicated in providing insightful feedback on ways to strengthen our paper. We have revised the manuscript in accordance with your suggestions. Our changes have been highlighted in the revised manuscript.

Our point-by-point responses to your comments and the revisions made are summarized below. The comments helped us considerably in improving our manuscript.

The manuscript by Blanco-Fernandez presents the retrospective analysis of patients undergoing surgery for duodenal tumors from 3 university hospitals In Spain. The study is not novel, but represents confirmation of findings on survival after partial versus radical resection for duodenal adenocarcinoma. The included patient number is small, and the sample size limits the impact of findings, as most of the findings are trends. Nevertheless, research design and interpretation of findings are scientifically sound. I would recommend the publication, as the real world data from different geographical regions is needed, especially on tumors with low incidence. Nevertheless, I suggest the change of the title to reflect the limitations: e.g. adding "in the Spanish cohort", or "real world data", or "pilot study".

Thank you for taking the time to review our work and for your kind comments.

The title has been changed according to your suggestions: “Duodenal adenocarcinoma: the relationship between type of surgery and site of recurrence in a Spanish cohort”.

Reviewer 2 Report

The article provides valuable insights into the surgical management of duodenal adenocarcinoma, advocating for both pancreaticoduodenectomy and limited resection as viable options depending on specific patient and tumor characteristics, focusing on the relationship between the type of surgery and site of recurrence. Duodenal adenocarcinoma is a relatively rare cancer, and studies like this can significantly contribute to understanding and managing this disease more effectively. The research is a multicenter retrospective study, which adds diversity to the patient pool and may improve the generalizability of the findings. The study suggests both pancreaticoduodenectomy and limited resection are valid surgical options, with pancreaticoduodenectomy showing lower rates of loco-regional recurrence. This finding could have practical implications in surgical decision-making. However, it has some limitations, including a small sample size and the lack of control group.

1. One of the limitations mentioned in the article is the relatively small sample size, which may limit the generalizability of the findings. Larger sample sizes would provide more robust results. With only 32 patients included in the study, the power to detect significant differences between groups or to perform comprehensive multivariate analyses may be limited.
2. The absence of a non-surgical control group or comparison with alternative treatments limits understanding of the relative efficacy of the surgical interventions studied.

3.      (line 43) I wonder the incidence of duodenal adenocarcinoma and how fetal (mortality) it is among other malignancies in Spain? What is the difference of incidence of duodenal adenocarcinoma from Asian population?

4.      (line 48) You mentioned just the rarity of relationship between type of surgery and site of recurrence in duodenal adenocarcinoma. I think the introduction length is too short to understand why you authors start to investigate this study. I mean, it is not by the rarity. Please explain any background or trend or pros or cons of the surgical technique of duodenal adenocarcinoma.

5.      (line 232) how worse is the prognosis of this tumor? Please explain more, compared to other intestinal or you mentioned, intestinal-type adenocarcinoma of ampulla of Vater.

6.      (Discussion) In you results, there were no statistical significances of adjuvant therapy. However, please describe the comparisons of your results to other studies, for example the exploration of adjuvant therapies and their role in improving patient outcomes?

Author Response

Dear Reviewer,

Thank you very much for the opportunity to make changes to the manuscript. We appreciate the time and effort you and each of the reviewers have dedicated in providing insightful feedback on ways to strengthen our paper. We have revised the manuscript in accordance with your suggestions. Our changes have been highlighted in the revised manuscript.

Our point-by-point responses to your comments and the revisions made are summarized below. The comments helped us considerably in improving our manuscript.

The article provides valuable insights into the surgical management of duodenal adenocarcinoma, advocating for both pancreaticoduodenectomy and limited resection as viable options depending on specific patient and tumor characteristics, focusing on the relationship between the type of surgery and site of recurrence. Duodenal adenocarcinoma is a relatively rare cancer, and studies like this can significantly contribute to understanding and managing this disease more effectively. The research is a multicenter retrospective study, which adds diversity to the patient pool and may improve the generalizability of the findings. The study suggests both pancreaticoduodenectomy and limited resection are valid surgical options, with pancreaticoduodenectomy showing lower rates of loco-regional recurrence. This finding could have practical implications in surgical decision-making. However, it has some limitations, including a small sample size and the lack of control group.

Thank you for taking the time to review our work and for your kind comments.

1. One of the limitations mentioned in the article is the relatively small sample size, which may limit the generalizability of the findings. Larger sample sizes would provide more robust results. With only 32 patients included in the study, the power to detect significant differences between groups or to perform comprehensive multivariate analyses may be limited.

We fully agree with your comment. We have emphasized these limitations in the discussion, line 319:

“Larger sample sizes would provide more robust results. With only 32 patients included in the study, the power to detect significant differences between groups or to perform comprehensive multivariate analyses may be limited”.

1. The absence of a non-surgical control group or comparison with alternative treatments limits understanding of the relative efficacy of the surgical interventions studied.

We fully agree with your comment. We have added this aspect to the limitations of the study, line 324:

“Furthermore, the absence of a non-surgical control group or comparison with alternative treatments limits understanding of the relative efficacy of the surgical interventions studied”.

3. (line 43) I wonder the incidence of duodenal adenocarcinomaand how fetal (mortality) it is among other malignancies in Spain? What is the difference of incidence of duodenal adenocarcinoma from Asian population?

We do not have specific data for Spain, but there are data on the incidence in other European countries. We have added the following paragraph in the Introduction, line 43:

“Duodenal cancer presents an increasing incidence. The number of cases of duodenal cancer diagnosed in North America is 3.0-3.7 per million population and in Europe 2.9-4.3 per million population [4–8]. In contrast, the incidence in Eastern countries is higher. According to data from the National Cancer Registry of Japan, in 2016 there was an ex-tremely high incidence of 23.7 per million population [9]”.

4. (line 48) You mentioned just the rarity of relationship between type of surgery and site of recurrence in duodenal adenocarcinoma. I think the introduction length is too short to understand why you authors start to investigate this study. I mean, it is not by the rarity. Please explain any background or trend or pros or cons of the surgical technique of duodenal adenocarcinoma.

Thank you for highlighting this interesting topic. We have added the following paragraph in the Introduction, line 54:

“The potential advantage of performing duodenal resection with pancreatic preservation is to avoid the complications of pancreaticoduodenectomy, however the theoretical risk of this type of procedure is a higher rate of incomplete resections and a lower number of nodes removed. This could translate into a higher rate of local recurrence”.

5. (line 232) how worse is the prognosis of this tumor? Please explain more, compared to other intestinal or you mentioned, intestinal-type adenocarcinoma of ampulla of Vater.

Thank you for your comment. We have added the following paragraph in the Discussion, line 250:

“However, it should be noted that, duodenal adenocarcinoma has classically been studied alongside the rest of small bowel carcinoma. However, it is a separate malignant neoplasm that can be subdivided according to immunohistochemical reactivity into intestinal phenotype, which is morphologically similar to colorectal adenocarcinoma and follows an adenoma-carcinoma sequence, and non-intestinal phenotype, mainly represented by the gastric phenotype and the pancreaticobiliary phenotype [12,13]. According to some authors, cases of intestinal-type duodenal adenocarcinoma, which originate most frequently in the supraampullary duodenum, have better postoperative results and longer survival [14]”.

6. (Discussion) In your results, there were no statistical significances of adjuvant therapy. However, please describe the comparisons of your results to other studies, for example the exploration of adjuvant therapies and their role in improving patient outcomes?

In a systematic review the authors have investigated the role of adjuvant and neoadjuvant therapy. In most of the studies analyzed no benefit has been found in overall survival, either with chemoradiotherapy or chemotherapy alone. In this study, adjuvant chemo(radiation) therapy did not result in a proven survival benefit, even after correction for nodal metastases. In two studies included in the review, adjuvant therapy resulted in similar survival rates compared with no adjuvant therapy, despite a higher prevalence of lymph node involvement in the adjuvant therapy group. The authors conclude that could be a selection bias of patients for adjuvant therapy and might suggest a benefit for administration of adjuvant therapy in patients with worse prognosis (reference 32). It has been included in the Discussion, line 305:

“The benefit of adjuvant treatment is controversial. In a systematic review the authors have investigated the role of adjuvant and neoadjuvant therapy. In most of the studies analyzed no benefit has been found on overall survival, either with chemoradiotherapy or chemotherapy alone. However, the authors conclude that could be a selection bias of patients for adjuvant therapy and might suggest a benefit for administration of adjuvant therapy in patients with worse prognosis [32]”.

Reviewer 3 Report

In this article, the authors retrospectively analyzed the prognosis of patients who underwent surgical resection for their duodenal adenocarcinoma. The analysis of 32 patients showed that conservative surgery correlated with local site recurrence, although it did not affect overall survival.

This article is potentially interesting as duodenal cancer is a rare disease, and there are only a few reports regarding the prognostic factors or adequate treatment. However, there are several points that the authors should reconsider.

1) They should describe whether the diagnosis of duodenal cancer is correctly performed. The diagnosis of periampullary cancer is sometimes difficult. They included 14 patients within 32 patients whose tumor was located in the descending part of the duodenum. They should describe how they distinguished from ampullary cancer or pancreatic cancer.

2) Within 32 patients, seven patients showed Clavien-Dindo V complication, resulting in a mortality rate of more than 20%. This number was extremely high. The mortality rate of patients who underwent pancreaticoduodenectomy is usually reported under 10%. They should describe the details of these C-D V complications.

Minor points

1) Table 1: The font size differed from other cases in cases 30, 31, and 32. 

2) Table 2: “Dindo Iva” should be “Dindo IVa”

They were well written. 

Author Response

Dear Reviewer,

Thank you very much for the opportunity to make changes to the manuscript. We appreciate the time and effort you and each of the reviewers have dedicated in providing insightful feedback on ways to strengthen our paper. We have revised the manuscript in accordance with your suggestions. Our changes have been highlighted in the revised manuscript.

Our point-by-point responses to your comments and the revisions made are summarized below. The comments helped us considerably in improving our manuscript.

In this article, the authors retrospectively analyzed the prognosis of patients who underwent surgical resection for their duodenal adenocarcinoma. The analysis of 32 patients showed that conservative surgery correlated with local site recurrence, although it did not affect overall survival.

This article is potentially interesting as duodenal cancer is a rare disease, and there are only a few reports regarding the prognostic factors or adequate treatment. However, there are several points that the authors should reconsider.

Thank you for taking the time to review our work and for your kind comments.

1) They should describe whether the diagnosis of duodenal cancer is correctly performed. The diagnosis of periampullary cancer is sometimes difficult. They included 14 patients within 32 patients whose tumor was located in the descending part of the duodenum. They should describe how they distinguished from ampullary cancer or pancreatic cancer.

Thank you for your suggestion that helps us improve the description of the methods.

To ensure that we are not dealing with an ampullary cancer, during the endoscopy it was verified that the ampulla of Vater was free of tumor. Likewise, we performed an abdominal CT scan of the abdomen to ensure that it was not a pancreatic tumor.

We have added this paragraph in Methods, line 82:

“To ensure that we are not dealing with an ampullary cancer, during the endoscopy it was verified that the ampulla of Vater was free of tumor. Likewise, patients underwent an abdominal CT scan of the abdomen to ensure that it was not a pancreatic tumor as well as rule out any infiltration of adjacent structures”.

2) Within 32 patients, seven patients showed Clavien-Dindo V complication, resulting in a mortality rate of more than 20%. This number was extremely high. The mortality rate of patients who underwent pancreaticoduodenectomy is usually reported under 10%. They should describe the details of these C-D V complications.

I totally agree that the C-D V rate is surprisingly high.

We think that since this is a series with a small number of cases in each surgery group, when cases of death occur, the rate is penalized. We have added this aspect in the discussion (line 274) and have detailed the cause of each case of death in Results as follow, line 199:

“Seven patients died in the postoperative period -four patients in the PD group and three patients in the conservative surgery group. Of the four patients in the PD group, the cause of death was pancreatic fistula in three of them, and in the other case, there was respiratory failure in an asthmatic patient. In the conservative surgery group, death was caused by duodenal suture dehiscence in two cases and the other by cardiac arrest”.

Minor points

1) Table 1: The font size differed from other cases in cases 30, 31, and 32.

Thanks for highlighting this mistake. We have corrected it.

2) Table 2: “Dindo Iva” should be “Dindo IVa”

Thanks for highlighting this mistake. We have corrected it.

Round 2

Reviewer 3 Report

The authors promptly responded my review comments.