A Modified Intraperitoneal Chemotherapy Regimen for Ovarian Cancer: Technique and Treatment Outcomes

Round 1

Reviewer 1 Report

Comments,

The manuscript by Lim et al describes modifications to procedural techniques in addition to a modified IP chemotherapy procedure and showed a better completion rate when applying IP chemotherapy with promising survival outcomes. Overall the manuscript is written well and fits the scope of Cancers and, interesting topic for the readers in this area. Thus, the manuscript is acceptable for publication. 

Author Response

We are sincerely grateful for your precious time in reviewing our paper and consideration of our study.  

Reviewer 2 Report

A modified intraperitoneal chemotherapy regimen for ovarian cancer: Technique and treatment outcomes

 

Major comment :

 

The aim of the study is not easy to understand for me.

Authors claimed that ip chemotherapy had some limitations and propose to change part of the treatment protocol. In that type of study this a feasibility study and the construction of the study is different.

 

The completion rate for planned IP chemotherapy before change had to be give as a benchmark situation for the same Korean single team. Without that analysis it is impossible to consider the study.

Change had to be done in a consecutive group of patient and the rate of improving had to be proposed to decide the number of cases that had to be included in the study to detect a change.

 

 

Minor comment :

 

Some construction of the sentence are difficult to understand : by example line 29

« Moreover, intraperitoneal chemotherapy could be started safely without delaying

the schedule while avoiding an intraperitoneal infusion of cisplatin at the first cycle. »

If the intraperitoneal cisplatin is not delivered the ip did not start ? So no change in fact?

 

References are not correctly reported : please control

 

“Subcutaneous tissue below the IP port chamber was removed” That could induce skin necrosis – I’m not convince. I did not recommend that.

 

Dextrose fluid injection can increase the risk of postoperative fistula in case of digestive anastomosis – the number of cases reported (n=12) is very small and that risk is not evaluated by the authors. By example if the risk of fistula is at 4% and if dextrose double the risk at 8% the number of cases necessary to detect that change is more than 100 cases in each group.  

 

 

Author Response

Response to Reviewer 2 Comments

 

[Major Comment]

 

Point 1: The aim of the study is not easy to understand for me.

Authors claimed that IP chemotherapy had some limitations and propose to change part of the treatment protocol. In that type of study this a feasibility study and the construction of the study is different.

 

Response 1: Thank you for your comments. The study aimed to present an evidence-based assessment of three modifications of IP chemotherapy that improved completion rates of chemotherapy cycles and provided the feasibility of IP chemotherapy in patients who underwent low anterior resection.

 

To clarify the aim of the study, we corrected some sentences mentioned with the purpose of the study. (Lines 43-46)

“Three institutional modifications to IP chemotherapy increased the completion rate for planned IP chemotherapy even after left colonic surgery. Further studies involving a larger study cohort are required to confirm survival outcomes using these modifications.”

 

 

(Continued to next page)

Point 2: The completion rate for planned IP chemotherapy before change had to be give as a benchmark situation for the same Korean single team. Without that analysis it is impossible to consider the study. Change had to be done in a consecutive group of patients and the rate of improving had to be proposed to decide the number of cases that had to be included in the study to detect a change.

 

Response 2: Thank you for your comments. After 3 randomized controlled study about IP chemotherapy was published, our institution-initiated IP chemotherapy with GOG 172 regimen without any modification of procedures. However, consecutive 8 cases of IP chemotherapy were all failed to complete 6 planned cycles and converted to intravenous chemotherapy. We present additional table for the data of earlier cases without any modifications as below.

 

[table]

 

Table 1. Patient and Baseline disease characteristics of earlier case without modifications
Characteristics	Earlier case (N=8)
Age (yr)
Mean ± SD (years)	68.4 ± 5.9
Median(min-max) (years)	68.5 (59.0 - 77.0)
FIGO surgical stage (FIGO stage 2014)
IIB	1 (12.5%)
IIIC	7 (87.5%)
Histology (No.)
High grade serous	5 (62.5%)
Endometrioid	1 (12.5%)
Clear cell carcinoma	1 (12.5%)
others	1 (12.5%)
Histologic grade
Grade 1	0 (0.0%)
Grade 2	1 (12.5%)
Grade 3	7 (87.5%)
Primary disease site (No.)
Ovary	7 (87.5%)
Peritoneum	0 (0.0%)
Fallopian tube	1 (12.5%)
Previous surgery
Primary
Primary cytoreductive surgery	6 (75.0%)
Interval debulking surgery	1 (12.5%)
Secondary	1 (12.5%)
Left colonic or Rectosigmoidal surgery
Yes	3 (37.5%)
No	5 (62.5%)
FIGO , International Federation of Gynecology and Obstetrics

 

 

Table 2. Characteristics and Results of earlier case without modifications
	Earlier case (N=8)
Modified regimen
Warmed dextrose IP infusion	8
IV cisplatin day 2 when Left colonic surgery	5
Cycle Completion
cycle ≤ 2 (number, %)	6 (75.0%)
2 < cycle < 6 (number, %)	2 (25.0%)
cycle 6 (number, %)	0 (0.0%)
GOG, Gynecologic Oncology Group;

 

Table 3. Rate of grade 3-4 Adverse Effects during any course of chemotherapy in earlier case without modifications
Adverse event	Earlier case (N=8)
Anemia	0 (0.0%)
Neutropenia	1 (12.5%)
Thrombocytopenia	0 (0.0%)
Fever	1 (12.5%)
Gastrointestinal	6 (75.0%)
Hemoglobin	1 (12.5%)
Infection	2 (25%)
Renal	0 (0.0%)
Metabolic	2 (25.0%)
Neurologic	0 (0.0%)
IP port related
IP port obstruction	2 (25.0%)
IP port infection	1 (12.5%)
Others	1 (12.5%)
AE, adverse events; AST, aspartate aminotransferase; ALT, alanine aminotransferase
CTCAE 5.0

 

Median progression free survival (PFS) for earlier cases was 7.50 months (95% CI, 2.47 - Not Reached).   

 

[Minor Comment]

 

Point 3: Some constructions of the sentence are difficult to understand: by example line 29

« Moreover, intraperitoneal chemotherapy could be started safely without delaying

the schedule while avoiding an intraperitoneal infusion of cisplatin at the first cycle. »

If the intraperitoneal cisplatin is not delivered the ip did not start? So no change in fact?

 

Response 3: Thank you for your comments. We corrected several sentences for better understanding without exceeding word limit. We hope the changed part has been improved accordingly. 

" Among patients who underwent left colonic surgery, including low anterior resection, 27 were investigated to identify the rate of completion of six planned cycles and feasibility of IP chemo-therapy. With modifications in IP chemotherapy, the completion rate improved even after pa-tients underwent left colonic surgery during cytoreduction with enhanced feasibility." (Line 26-29)

Point 4: References are not correctly reported: please control 

Response 4: Thank you for your comments. We erased the invalid reference and looked over again. We did our best to correct these mistakes.

 

Point 5: “Subcutaneous tissue below the IP port chamber was removed” That could induce skin necrosis – I’m not convince. I did not recommend that.

 

Response 5: Thank you for your comments. We agree with the reviewer that full thickness tissue loss might induce skin necrosis. In our case, the port (Celsite®, Inc. B. Braun, Germany) that we used was small as 26 x 20 x 9.7 mm, and the subcutaneous tissue was removed as much as the size of the port not the full thickness. The former sentence could confuse the reader to understand the tissue might be fully removed, so we modified the sentence as shown below and the Figure.1 as well. 

 

(B) Subcutaneous tissue below the IP port chamber was partially removed for easy insertion of the needle into the IP port. (Line 111)

 

At Figure 3. After modification of the IP port insertion, the subcutaneous tissue on the IP port was surgically reduced for easy palpation of the port and efficient needling of the IP port. (Line 226,230)

 

 

Point 6: Dextrose fluid injection can increase the risk of postoperative fistula in case of digestive anastomosis – the number of cases reported (n=12) is very small and that risk is not evaluated by the authors. By example if the risk of fistula is at 4% and if dextrose double the risk at 8% the number of cases necessary to detect that change is more than 100 cases in each group.

 

Response 6: Thank you for your comments. We agree with your opinion that necessitate case-control study with larger group. We admit that we did not fully evaluate postoperative adhesion prevention and its effectiveness with postoperative irrigation. We mentioned about our limitations

 

“Bowel function recovery according to intraperitoneal irrigation and hydration via the IP port needs to be investigated in future studies. “ (Line 238-240)

Author Response File: Author Response.docx

Reviewer 3 Report

Overall, a well prepared manuscript on new surgical technique of port placement for intraperitoneal  chemotherapy application in a specific subgroup of patients. However, the title, abstract, and the corresponding introduction and conclusions sections of the manuscript should reflect that the main focus of the paper is the modified port placement techniques, how that is relevant to the treatment implementation (i.e., number of chemotherapy cycles, blockage of the port, infection, etc.) and to patient care outcomes (i.e., survival, quality if life, etc.).

Author Response

Response to Reviewer 3 Comments

 

Point 1: Overall, a well-prepared manuscript on new surgical technique of port placement for intraperitoneal chemotherapy application in a specific subgroup of patients. However, the title, abstract, and the corresponding introduction and conclusions sections of the manuscript should reflect that the main focus of the paper is the modified port placement techniques, how that is relevant to the treatment implementation (i.e., number of chemotherapy cycles, blockage of the port, infection, etc.) and to patient care outcomes (i.e., survival, quality of life, etc.).

Response 1: Thank you for your comments. We have gone through your comments carefully and tried our best to focus on main subject (modified port placement techniques). We hope the manuscript has been improved accordingly.

 

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Simple Summary and abstract were corrected to clarify the main purpose of the study.

Simple Summary

“Twenty-seven patients were investigated to identify the completion rate of six planned cycles and feasibility of IP chemotherapy in patients who underwent left colonic surgery including low anterior resection. With modifications of IP chemotherapy, the completion rate was improved even after patients underwent left colonic surgery during cytoreduction with enhanced feasibility.” (Lines 26-30)

 

Abstract

“All patients underwent three institutional modifications to IP chemotherapy, and for the chemotherapy regimen, modified Gynecologic Oncology Group 172 regimen was used.” (Lines 33-35) 

“Of 17 primary and 10 patients with recurrent ovarian cancer, 55.6% (15/27) underwent left colonic surgery including low anterior resection.” (Lines 36-37)

 

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Introduction

In line 79, purpose of the study is mentioned.

"Port-related complications and IP chemotherapy-related toxicities continue to be obstacles to completing six planned cycles, and further improvement is required." (Line 79-81)

In line 85, the sentence was corrected simple. 

" Therefore, this study aimed to investigate treatment outcomes in terms of: the completion rate of the six planned cycles, complications related to IP chemotherapy, and survival after institutional modifications to IP chemotherapy." (Line 85-88)

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Materials and methods

Figure.1-C is updated to depict guidewire penetration with more details

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Discussion

In the discussion, we wanted to emphasize that three modifications of IP chemotherapy improved the completion rate of IP chemotherapy in a cohort that underwent left colon surgery, including low anterior resection.

In line 190-192,259-261, and 271-273, the sentences were corrected.

 

“In this study, the completion rates of patients who underwent left colonic surgery in the IP chemotherapy with institutional modification were improved compared to previous publications.” (Lines 190-192)

 

“Additionally, according to our institutional data for 8 earlier cases without modifications, while 3 (37.5%) patients underwent left colonic surgery, they all failed to complete IP chemotherapy with cisplatin injected via the IP route in the first cycle” (Lines 259-261)

 

“In conclusion, modifications to procedural techniques, in addition to a modified IP chemotherapy regimen showed a better completion rate with propitious survival out-comes.” (Lines 271-273)

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Changes have ben donne 

OK for publication for me