Iterative Cytoreductive Surgery and HIPEC for Peritoneal Metastases from Primary Appendiceal and Colorectal Cancers: An Observational Study^†

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 Iterative Cytoreductive Surgery and HIPEC for Peritoneal Metastases from Primary Appendiceal and Colorectal Cancers: An Observational Study

Abstract : 

• Twenty-seven pAC patients (27/67, 40%) and 13/36 pCRC patients (36%) developed disease recurrence.
• Nine of the 27 relapsed pAC patients and 5 of the 13 relapsed pCRC patients underwent repeat CRS/HIPEC.
• Conclusion: Repeat CRS/HIPEC for isolated peritoneal recurrence is safe and offers the potential for long-term survival. Patient selection is key to ensure optimal cytoreduction.

Based in 14 patients; no clear how many had HIPEC

 

Methods and Materials

• The current analysis represents a retrospective cohort study examining patients undergoing cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CRS +/- HIPEC) for appendiceal (pAC) and colorectal (pCRC) peritoneal metastases.

The iterative CRS HIPEC  with or without HIPEC?

• Patients with a diagnosis of pAC or pCRC were identified within the electronic medical record from 2011 to 2022. A diagnosis of pAC or pCRC was confirmed by individual review of pathological reports. Patients

There is not pathologic diagnostic, all cases are pAC or pCRC

There is analysis of treatment of primary tumor pAC + pCRC: 103 p  in 11 years 

• CRS +/- HIPEC. All patients with pCRC received 90-minute HIPEC with 98 Mitomycin-C.

It is not known how many patients had HIPEC. Neither the cytotoxic drug in pAC

 

Results

• Thus, one hundred and three patients undergoing CRS +/- HIPEC for pAC or pCRC were identified n=67 pAC, n=36 pCRC

No identification how many HIPEC performed

No identification of pathology

• Of these 27 patients with relapsed pAC, 9/27 underwent repeat CRS +/- HIPEC (33.3%) and 18/27 did not (66.7%).

No defined criteria for surgery or other treatment.

Neither for HIPEC or not

• 9/9 patients undergoing repeat CRS +/- HIPEC for pAC had low grade disease (100.0%), and 1/9 had signet ring histology (11.1%).

100% low grade disease (not known if mucinous or enteroid). Not specify type of primary and  PMP

SRC in a low grade??

• Of 18 patients with relapsed pAC who did not undergo repeat CRS +/- HIPEC, 8/18 had low grade disease (44.4%), 8/18 had high grade disease (44.4%), and 2/18 had unknown disease grade (11.1%). Six of these patients (6/18) had signet ring histology (33.3%), and 12/18 had non-signet ring histology (66.6%).

Confused way to describe appendicular tumor pathology

• Among 36 patients undergoing CRS +/- HIPEC for pCRC, 23/36 experienced disease relapse (63.9%), and 13/36 had NED at follow up (36.1%). Of these 23 patients with relapsed 130 pCRC, 5/23 underwent repeat CRS +/- HIPEC (21.7%) and 18/23 did not (78.2%).

Figures of recurrent are different to the Abstract. No criteria for type of treatment

• Table 1: it is not possible to analyze together colorectal cancer with appendicular tumors related with PCI, neoadjuvant and adjuvant chemo, time of surgery, … .

Repeat CRS +/- HIPEC

• Among 50 patients who experienced disease relapse, 14/50 underwent repeat CRS +/- HIPEC, and 36 did not (Table 2).

There are no criteria of selection for CRS or not

 

Author Response

Reviewer #1:

Abstract : 

• Twenty-seven pAC patients (27/67, 40%) and 13/36 pCRC patients (36%) developed disease recurrence.
• Nine of the 27 relapsed pAC patients and 5 of the 13 relapsed pCRC patients underwent repeat CRS/HIPEC.
• Conclusion: Repeat CRS/HIPEC for isolated peritoneal recurrence is safe and offers the potential for long-term survival. Patient selection is key to ensure optimal cytoreduction.

Based in 14 patients; no clear how many had HIPEC

ANSWER:  All 14 patients underwent repeat CRS/HIPEC after initial CRS/HIPEC.

Methods and Materials

• The current analysis represents a retrospective cohort study examining patients undergoing cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (CRS +/- HIPEC) for appendiceal (pAC) and colorectal (pCRC) peritoneal metastases.

The iterative CRS HIPEC  with or without HIPEC?

ANSWER: The iterative CRS/HIPEC was performed with HIPEC using mitomycin C.

• Patients with a diagnosis of pAC or pCRC were identified within the electronic medical record from 2011 to 2022. A diagnosis of pAC or pCRC was confirmed by individual review of pathological reports. Patients

There is not pathologic diagnostic, all cases are pAC or pCRC.

ANSWER: Correct, all cases included in this analysis were pAC or pCRC.  All other pathologies were excluded.

The Methods section includes the following sentence (highlighted in yellow):

“Patients were excluded if they were treated for other histologies (desmoplastic small round cell tumor, gastric adenocarcinoma, hepatocellular carcinoma, ovarian carcinoma, primary peritoneal mesothelioma, fallopian carcinoma, and small bowel adenocarcinoma), or had not completed treatment at the time of analysis.”

There is analysis of treatment of primary tumor pAC + pCRC: 103 p  in 11 years 

• CRS +/- HIPEC. All patients with pCRC received 90-minute HIPEC with 98 Mitomycin-C.

It is not known how many patients had HIPEC. Neither the cytotoxic drug in pAC

ANSWER:  All patients underwent initial CRS/HIPEC and subsequently underwent iterative CRS/HIPEC.  The verbiage “+/-“ was removed from the Methods section and throughout the manuscript.

The following sentence was modified in the methods section (highlighted in yellow): “All patients received 90-minute HIPEC with mitomycin C.”

Results

• Thus, one hundred and three patients undergoing CRS +/- HIPEC for pAC or pCRC were identified n=67 pAC, n=36 pCRC

No identification how many HIPEC performed.

ANSWER:  HIPEC was performed for all 103 pAC and pCRC patients.  The verbiage “+/-“ HIPEC was modified to “CRS/HIPEC.”

No identification of pathology.

ANSWER: All patients in this study were pAC or pCRC pathologies. All other pathologies were excluded

• Of these 27 patients with relapsed pAC, 9/27 underwent repeat CRS +/- HIPEC (33.3%) and 18/27 did not (66.7%).

No defined criteria for surgery or other treatment.

ANSWER:  The following sentence is highlighted in the Methods section (highlighted in yellow):

Patients with disease relapse were then stratified further by receipt of repeat CRS/HIPEC to identify factors associated with receipt of iterative surgical intervention. 

• 9/9 patients undergoing repeat CRS +/- HIPEC for pAC had low grade disease (100.0%), and 1/9 had signet ring histology (11.1%).

100% low grade disease (not known if mucinous or enteroid). Not specify type of primary and  PMP

ANSWER: Low grade disease represented low grade appendiceal mucinous neoplasm.  The primary tumor type was appendiceal.

The following was added to the Methods section (highlighted in yellow):

Patient characteristics (age in years, race, biological sex, American Society of Anesthesiologists (ASA) physical status classification, history of prior laparotomy, history of previous treatment with systemic chemotherapy), disease characteristics (primary site, PCI), “pAC tumor grade (low-grade: low grade appendiceal mucinous neoplasm (LAMN), high-grade: signet ring cell histology)”…

SRC in a low grade??

ANSWER: The single patient with SRC had both low-grade and high-grade histology’s present within the specimen.

• Of 18 patients with relapsed pAC who did not undergo repeat CRS +/- HIPEC, 8/18 had low grade disease (44.4%), 8/18 had high grade disease (44.4%), and 2/18 had unknown disease grade (11.1%). Six of these patients (6/18) had signet ring histology (33.3%), and 12/18 had non-signet ring histology (66.6%).

Confused way to describe appendicular tumor pathology.

ANSWER:  There was no easy way to describe the various histology’s represented other than as described above.

• Among 36 patients undergoing CRS +/- HIPEC for pCRC, 23/36 experienced disease relapse (63.9%), and 13/36 had NED at follow up (36.1%). Of these 23 patients with relapsed pCRC, 5/23 underwent repeat CRS +/- HIPEC (21.7%) and 18/23 did not (78.2%).

Figures of recurrent are different to the Abstract. No criteria for type of treatment.

ANSWER:  Thank you for this correction.  The abstract has been corrected (highlighted in yellow).  Only patients who underwent repeat CRS/HIPEC were further examined.

• Table 1: it is not possible to analyze together colorectal cancer with appendicular tumors related with PCI, neoadjuvant and adjuvant chemo, time of surgery, … .

 

ANSWER:  Table 1 is meant to stratify based purely on relapse after CRS/HIPEC, irrespective of histology. 

Repeat CRS +/- HIPEC

• Among 50 patients who experienced disease relapse, 14/50 underwent repeat CRS +/- HIPEC, and 36 did not (Table 2).

There are no criteria of selection for CRS or not.

ANSWER:  Patients who underwent Repeat CRS/HIPEC were compared to those who did not undergo repeat CRS/HIPEC.  The receipt of CRS/HIPEC was the selection criteria.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Andrew M. Fleming et al submitted a manuscript titled, “Iterative Cytoreductive Surgery and HIPEC for Peritoneal Metastases from Primary Appendiceal and Colorectal Cancers: An Observational Study”. The aim of this manuscript is to conduct a retrospective study to analyze the outcome for appendiceal and colorectal cancer patients who underwent repeat CRS/HIPEC after isolated peritoneal recurrence. Also, authors aimed to study the overall survival of the repeat CRS/HIPEC cohort for non-repetitive CRS/HIPEC. The materials and methods sections encompassed search criteria and related aspects. The study was conducted according to the guidelines of STROBE. The results were discussed clearly, and the corresponding data were presented in the form of tables and figures. The univariate analysis of patients undergoing HIPEC for metastatic appendiceal or colorectal cancers stratified by disease relapse and mentioned in the table. Data of repeat CRS +/- HIPEC, for relapsed pAC, and pCRC have been analyzed by the authors, and the obtained p-values indicated a good statistical significance. The authors discussed extensively the obtained results and included the limitations of the study. Authors finally concluded that repeat CRS/HIPEC for isolated peritoneal recurrence is safe and can provide the potential for long-term survival. This is one of the scholarly research deserves publication. The data and analysis of this retrospective study yielded a good result and were observed as a novel study. As mentioned by the authors, the patient selection and including a large number of patients can further improve the therapeutic outcomes. The manuscript can be accepted in its present form.

Author Response

Andrew M. Fleming et al submitted a manuscript titled, “Iterative Cytoreductive Surgery and HIPEC for Peritoneal Metastases from Primary Appendiceal and Colorectal Cancers: An Observational Study”. The aim of this manuscript is to conduct a retrospective study to analyze the outcome for appendiceal and colorectal cancer patients who underwent repeat CRS/HIPEC after isolated peritoneal recurrence. Also, authors aimed to study the overall survival of the repeat CRS/HIPEC cohort for non-repetitive CRS/HIPEC. The materials and methods sections encompassed search criteria and related aspects. The study was conducted according to the guidelines of STROBE. The results were discussed clearly, and the corresponding data were presented in the form of tables and figures. The univariate analysis of patients undergoing HIPEC for metastatic appendiceal or colorectal cancers stratified by disease relapse and mentioned in the table. Data of repeat CRS +/- HIPEC, for relapsed pAC, and pCRC have been analyzed by the authors, and the obtained p-values indicated a good statistical significance. The authors discussed extensively the obtained results and included the limitations of the study. Authors finally concluded that repeat CRS/HIPEC for isolated peritoneal recurrence is safe and can provide the potential for long-term survival. This is one of the scholarly research deserves publication. The data and analysis of this retrospective study yielded a good result and were observed as a novel study. As mentioned by the authors, the patient selection and including a large number of patients can further improve the therapeutic outcomes. The manuscript can be accepted in its present form.

ANSWER: The Authors thank the Reviewer for the thorough summary and insightful commentary.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors present their institutional experience with repeat CRS/HIPEC. While this is not a novel concept and there are published reports with larger patient experiences, this manuscript originates from a "newer peritoneal surface malignancy program" and is well written and methodical.

I have the following questions/comments:

1. Have the authors identified factors that prohibited surgical management in patient with relapse who did not undergo repeat CRS/HIPEC?
2. I am not clear from the Tables on follow-up in months: In the 50 patients with relapse, follow-up was 21.5 mo (11-42). Yet, in the repeat vs no repeat CRS?HIPEC, it was 51 mo (23-92) and 16 mo (10-29), respectively. Please clarify the apparent range discrepancy.

Author Response

Reviewer #3:

The authors present their institutional experience with repeat CRS/HIPEC. While this is not a novel concept and there are published reports with larger patient experiences, this manuscript originates from a "newer peritoneal surface malignancy program" and is well written and methodical.

I have the following questions/comments:

1. Have the authors identified factors that prohibited surgical management in patient with relapse who did not undergo repeat CRS/HIPEC?

 

ANSWER:  Patient selection was a key determinant to who was offered repeat CRS/HIPEC and those who were observed or offered systemic chemotherapy alone.  Factors such as time to recurrence (disease free interval), pattern of recurrence (obstruction versus radiologic finding), etc.  The following sentence was added to the Limitations section of the Discussion (Highlighted in yellow):

Patients were screened and selected for surgery based on a variety of factors, anecdotally with disease free interval, disease biology and anticipated complete removal of recurrent peritoneal disease the primary determinant factors.  It is important to recognize, however, that when considering surgery, time to recurrence, previous chemotherapy exposure, tumor grade, disease burden, performance status and potential for postoperative morbidity must all be considered in the decision-making process. 

 

 

1. I am not clear from the Tables on follow-up in months: In the 50 patients with relapse, follow-up was 21.5 mo (11-42). Yet, in the repeat vs no repeat CRS?HIPEC, it was 51 mo (23-92) and 16 mo (10-29), respectively. Please clarify the apparent range discrepancy.

 

ANSWER:  The difference in follow up range was based on stratification: relapse (Yes vs No) or repeat CRS/HIPEC (Yes vs No).

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors

 Retrospective review describes and concludes that Repeat CRS/HIPEC for isolated peritoneal recurrence is safe and offers the potential for long-term survival.

Corrections are required –

1) A single institution database to assess perioperative outcomes after repeat CRS/HIPEC for appendiceal (pAC) and colorectal (pCRC) cancers – Please mention institution name clearly.

2) Studies are conducted without IRB approval – Authors must explain clearly.

3) Please add up-to-date references in the introduction and discussion section.

Author Response

Reviewer #4:

Dear Authors

 Retrospective review describes and concludes that Repeat CRS/HIPEC for isolated peritoneal recurrence is safe and offers the potential for long-term survival.

Corrections are required –

• A single institution database to assess perioperative outcomes after repeat CRS/HIPEC for appendiceal (pAC) and colorectal (pCRC) cancers – Please mention institution name clearly.

ANSWER: The institution was added to the Methods section (Highlighted in yellow).

This analysis was institutional review board-approved and was performed in accordance with federal law and the University of Tennessee Health Science Center (UTHSC IRB 17-05211-XP).

• Studies are conducted without IRB approval – Authors must explain clearly.

ANSWER:  IRB Approval was obtained.  Please see the sentence above including the IRB reference number from the University of Tennessee Health Science Center.

• Please add up-to-date references in the introduction and discussion section.

ANSWER:  Given the limited number of references to repeat CRS/HIPEC, current references are limited. Nonetheless, references have been updated with multiple references ranging from 2014-2024.

Author Response File: Author Response.pdf

Round 2

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors, Revised manuscript explains well.