Target region resection in patients undergoing cytoreductive surgery for peritoneal metastases-is it necessary in absence of visible disease?

Target region resection in patients undergoing cytoreductive surgery for peritoneal metastases-is it necessary in absence of visible disease?

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Journal Pre-proof Target region resection in patients undergoing cytoreductive surgery for peritoneal metastases-is it necessary in absence of visible disease? Aditi Bhatt, Yutaka Yonemura, Sanket Mehta, Nazim Benzerdjeb, Praveen Kammar, Loma Parikh, Mita Y. Shah, Sakina Shaikh BHMS, Aruna Prabhu, Suniti Mishra, Snita Sinukumar, Vahan Kepenekian, Naoual Bakrin, Guillaume Passot, Olivier Glehen PII:

S0748-7983(19)31441-6

DOI:

https://doi.org/10.1016/j.ejso.2019.11.495

Reference:

YEJSO 5546

To appear in:

European Journal of Surgical Oncology

Received Date: 25 September 2019 Revised Date:

4 November 2019

Accepted Date: 10 November 2019

Please cite this article as: Bhatt A, Yonemura Y, Mehta S, Benzerdjeb N, Kammar P, Parikh L, Shah MY, Shaikh BHMS S, Prabhu A, Mishra S, Sinukumar S, Kepenekian V, Bakrin N, Passot G, Glehen O, Target region resection in patients undergoing cytoreductive surgery for peritoneal metastases-is it necessary in absence of visible disease?, European Journal of Surgical Oncology (2019), doi: https:// doi.org/10.1016/j.ejso.2019.11.495. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

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Target region resection in patients undergoing cytoreductive surgery for

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peritoneal metastases- is it necessary in absence of visible disease?

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Aditi Bhatt MS MCh. 1, Yutaka Yonemura MD, PhD.2, Sanket Mehta DNB3, Nazim

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Benzerdjeb MD PhD.4, Praveen Kammar MS, MCh.3, Loma Parikh MD5, Mita Y Shah MD6,

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Sakina Shaikh BHMS1, Aruna Prabhu MS, MCh.7, Suniti Mishra MD8, Snita Sinukumar9,

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Vahan Kepenekian MD10, Naoual Bakrin MD, PhD10, Guillaume Passot MD, PhD10, Olivier

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Glehen MD, PhD10

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1

Dept. of Surgical Oncology, Zydus hospital, Ahmedabad, India

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2

Peritoneal Metastases Center, Kishiwada Tokushukai Hospital, Osaka, Japan,

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3

Dept. of Surgical Oncology, Saifee hospital, Mumbai, India

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4

Dept. of Pathology, Centre Hospitalier Lyon-sud, Lyon, France

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Dept. of Pathology, Zydus hospital, Ahmedabad, India,

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Dept. of Pathology, Saifee hospital, Mumbai, India

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Dept. of Surgical Oncology, Thangam Cancer Centre, Nammakkal, India

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Dept. of Pathology, Fortis Hospital, Bangalore, India

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Dept. of Surgical Oncology, Jehangir hospital, Pune, India

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Dept. of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France

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Corresponding author- Prof. Olivier Glehen, MD, PhD.,

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Address- Centre Hospitalier Lyon Sud,

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Hospices Civils de Lyon,

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69495 Pierre Bénite, France

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Phone- (33) 478 86 23 71 E-mail- [email protected]

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Words-2999

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Pages-17

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Tables- 6

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Figures-0

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The authors have no disclosures or conflict of interests

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The authors received no funding for this study

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Abstract

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Background

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The aim was to study the patterns of target region (greater omentum, lesser omentum,

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falciform and umbilical round ligament) involvement in patients undergoing cytoreductive

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surgery (CRS) from various primary tumors, factors affecting involvement and implications

18

on surgical practice.

19

Methods

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All patients undergoing CRS from July 2018 to December 2018 were included in this

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prospective study. The incidence of target region involvement in presence and absence of

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visible disease and the impact of primary tumor site, PCI and other variables on target region

23

involvement was evaluated.

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Results

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In 191 patients, greater omentum was involved in over 15% of patients irrespective of the

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primary tumor type and in 15.7 % in absence of visible disease. 75% of these had PCI <20.

2

1

The involvement of the other three target regions was higher than 20% in ovarian cancer,

2

appendiceal tumors and peritoneal mesothelioma. Involvement of these 3 regions was

3

associated with a higher PCI (p<0.001 for all) and omental involvement (p<0.001for all).

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2.1% of colorectal cancer patients had umbilical round ligament involvement, 4.2% had

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falciform ligament involvement and none had lesser omentum involvement.

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Conclusions

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Target region involvement varies according to primary tumour site and disease extent.

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Resection of the greater omentum should be performed during CRS for PM arising from all

9

primary sites. Resection of other target organs may be performed for selected patients with

10

ovarian cancer, peritoneal mesothelioma and mucinous appendiceal tumours in absence of

11

visible disease. For other patients, it should be done only in presence of visible disease.

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Key words- Omental resection, lesser omentum, falciform ligament, ligamentum teres,

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cytoreductive surgery, target region resection

14 15

Introduction

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Cytoreductive surgery with or without HIPEC is used as a potentially curative treatment for

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patients selected patients with peritoneal metastases and comprises of resection of tumor

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bearing regions of the peritoneum along with the adjacent viscera when involved. [1] The

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greater omentum, falciform and umbilical round ligaments are often resected in patients

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undergoing cytoreductive surgery (CRS) for peritoneal metastases (PM) arising from various

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primary tumors in absence of visible disease. These sites are most likely to harbor occult

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metastases as the concentration of lymphatic stomata and milky spots is comparatively high

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in these regions. [2, 3] Such a rationale, however, is borrowed from the principles of

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treatment of ovarian cancer and appendiceal tumors with peritoneal dissemination. In ovarian

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cancer, normal peritoneal regions are resected/biopsied in patients undergoing surgery for all

3

1

stages of the disease. [4] The incidence of upstaging is 18% for all stages of epithelial ovarian

2

cancer. [5] The principles of CRS developed by Paul Sugarbaker come largely from those

3

used to treat mucinous appendiceal tumors. [6, 7] The mechanisms of peritoneal

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dissemination are different for other primary tumors as are the disease distribution and

5

morphology. [8] In some tumors like epithelial ovarian cancer, peritoneal mesothelioma and

6

mucinous appendiceal tumors, there is a higher incidence of occult disease in normal looking

7

peritoneum as compared to others like colorectal and gastric cancer. [9] It may be presumed

8

that ‘target regions’ like the greater omentum, umbilical round ligament and falciform

9

ligament have a greater propensity for harboring occult disease in these patients as compared

10

to others.

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It is not known in what percentage of patients these structures are involved by disease in

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patients undergoing CRS. The involvement in relation to the disease extent within the

13

peritoneal cavity is also not known. Similarly, the incidence of lesser omental involvement

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and factors predicting its involvement are not known.

15

Our goal was to study the patterns of omental, lesser omental, falciform and round ligament

16

involvement in patients undergoing CRS from various primary tumors, factors affecting their

17

involvement and the implications on surgical practice. Secondly, we wanted to look at the

18

necessity of resecting these regions in absence of visible disease on intraoperative inspection.

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Methods

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This prospective study was carried out at four peritoneal surface malignancy centers.

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Institutional permission was obtained. All patients undergoing cytoreductive surgery from

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various primary tumors were included in the study. The use of intraperitoneal chemotherapy

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had no bearing on inclusion in the study.

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Surgical procedures

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1

The goal of surgery was to obtain a complete cytoreduction (CC-0/1 resection; CC-1

2

resection is acceptable for low grade mucinous carcinoma peritonei and peritoneal

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mesotheliomia). [10] Intraoperative estimation of peritoneal cancer index was performed for

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all patients and termed as the surgical PCI (sPCI). [10]

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Patients taken up for surgery with the intent of complete cytoreduction were included even if

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an incomplete cytoreduction was performed. Patients undergoing prophylactic and second

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look surgeries were included in the study. This is because we wanted to study the patterns of

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involvement in patients with occult disease or no disease. Standard peritonectomy procedures

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and visceral resections were performed as described previously (Supplement 1). [11] The

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resection of regions like the greater omentum, lesser omentum, falciform and round ligament

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in absence of visible disease was at the discretion of the surgeon. The umbilical round

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ligament (URL) may be covered by varying thickness of the liver parenchyma termed as the

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‘hepatic bridge’ or ‘pont hepatique’. [12] The URL with its surrounding peritoneum was

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resected completely as described by Sugarbaker. [12] All surgeons perform a supracolic

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omentectomy irrespective of the extent of peritoneal disease and presence or absence of

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greater omental disease. The policy to preserve or sacrifice the Arc of Barkov in presence and

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absence of disease was different at different centers. Lesser omentectomy was performed

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preserving the right and left gastric vessels as far as possible.

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Pathological assessment

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Each of the 5 peritoneal regions and their sub-regions included in the 5 peritonectomies

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described by Sugarbaker were marked out by the surgeon and the maximum tumor size in

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each region mentioned separately. [11]

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A protocol for pathological evaluation was laid down based on the practices at each

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institution and has been described elsewhere. [9] It involved assessment of the tumor in each

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sub-region of the peritoneum, calculation of the pathological PCI (pPCI), evaluation of nodes

5

1

in relation to the primary tumor and peritoneal disease, evaluation of the pathological

2

response to chemotherapy and evaluation of normal regions of the peritoneum in proximity to

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and at a distance from the tumor nodules. [9] Structures in each region were defined using the

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PROMISE internet application. [13]

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The presence of disease on histopathology was considered to be disease in that region. The

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greater omentum, lesser omentum, umbilical round ligament (URL) and falciform ligament

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were grouped as ‘target regions’ and the impact of primary tumor site, surgical and

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pathological PCI, and other variables on target region involvement was evaluated. We looked

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at correlation between target region involvement and the pathological and surgical PCI both.

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Our preliminary findings showed a marked difference in the surgical and pathological PCI

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but intraoperative decision making depends on the surgeons’ evaluation and hence we have

12

considered both. [9]

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Regions 5, 6, 7 were included in the ‘lower region’, 1,4,8 in the ‘middle region’ and 1,2,3 in

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the ‘upper region’.

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Histological sub-types

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All tumors of appendiceal origin including low and high grade mucinous carcinoma

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peritonei, mucinous and non-mucinous adenocarcinomas were classified as appendiceal

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primary tumors. Mucinous peritoneal deposits from other primary tumors (except colorectal

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cancer) were included in ‘rare primary tumors’.

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Only patients with stage III-C and above of epithelial ovarian cancer were included in

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ovarian cancers in this study. Non-epithelial ovarian tumors and mucinous ovarian tumors

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were included in rare-primary tumors.

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Statistical analysis

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Categorical data were described as number (%). Abnormally distributed continuous data were

6

1

2 expressed as the median and range. Categorical data were compared with the x test. When

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multiple variables were being compared, post-hoc analysis was performed and Bonferroni

3

correction applied to determine the impact of each variable separately. For comparison of

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median values, non-parametric independent sample t test and for means, independent sample

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t test was used, where in Levene’s test for equality of variance was applied.

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A p-value of <0.05 was considered statistically significant.

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Results

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From July 2018 to Dec 2018, 191 patients were included in the study. The primary tumor site

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was appendix in 49 (25.6%), colorectal (CRC) in 47 (24.6%), ovary in 44 (23.0%%),

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stomach in 18 (9.4%), mesothelioma in 15 (7.8%) and rare primary (or unusual indications

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for CRS; supplementary material 2) in 18 (9.4%). The median sPCI was 11 [range 0-39] and

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a CC-0/1 resection was obtained in 171 (89.4%). Neoadjuvant chemotherapy was

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administered to 132 (69.1%) of the patients. The median pathological PCI was 6 [range 0-

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39]. Lymph nodes were positive in 32.4%. The surgical intervention for PM was the first in

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143 (74.8%) patients, the second in 43 (22.5%) and the third or more in 7 (3.6%) patients.

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Histological subtypes of various primary tumors

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In patients with epithelial ovarian cancer, 88.6% had high grade serous tumors. 15.9% of the

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patients were undergoing a primary CRS, 43.1% interval CRS, 13.6% had a second look

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surgery for an incomplete first cytoreduction and 27.2% had salvage surgery for recurrent

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disease.

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Of the appendiceal tumors, 44.8% had low grade mucinous carcinoma peritonei, 38.7 % had

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high grade mucinous carcinoma peritonei, 2% had high grade mucinous carcinoma peritonei

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with signet ring cells and 14.2% had non-mucinous adenocarcinoma.

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1

Greater omentum

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The greater omentum was resected in 155 (81.1 %) patients and was involved by tumor in 89

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(46.5%) (Table 1). In the remaining it had already been removed during a prior surgical

4

intervention. The greater omentum was consistently involved in over 15% of the patients

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with PM from different primary tumors. It was involved in 80% of the patients with

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mesothelioma and only 19.1% with colorectal cancer (Table 2). In 14 (15.7%) patients, it

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was seen in absence of visible disease. In 6 (12.7%) patients with colorectal cancer,

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involvement of the greater omentum was seen in absence of visible disease. Patients with

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greater omentum involvement had disease in the lower region in 85.3% as opposed to

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patients without involvement in 43.9% (p<0.001). In patients whom the lower region was not

11

involved were those who had undergone a prior CRS or incomplete cytoreduction and the

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lower region had not been evaluated. 34.8% of patients with omental involvement had a

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pPCI <10 and 73.0% of them had a pPCI <20. There was a significantly higher incidence of

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URL, falciform and lesser omentum involvement in patients who had disease in the greater

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omentum as opposed to those that did not (p<0.001 for all, Table 1).

16 17

Umbilical round ligament

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The umbilical round ligament (URL) was resected in 88 (46.0%) patients. It was positive for

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malignancy in 36 (18.8%) and negative in 52 (27.2%) (Table 3). The median surgical

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(p=0.001) and pathological PCI (p<0.001) were both significantly higher in patients with

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URL involvement. The proportion of patients with a sPCI>20 (p<0.001) and pPCI>20

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(p<0.001) was also significantly higher in this group. In 22.2% of the patients with URL

23

involvement, pPCI was less than10 and more than 50% had a pPCI<20. In 13.8% it was seen

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in absence of visible disease.

8

1

Disease in the upper and lower regions was present in all patients with URL involvement and

2

the greater omentum was involved in 88.8% of these patients. Disease in the URL was

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present in >25% of the patients with ovarian cancer, peritoneal mesothelioma and

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appendiceal cancer and only in 2.1% with colorectal cancer and none of the patients with

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gastric cancer. Twenty-three patients with colorectal cancer had resection of the URL of

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which only one had disease on pathological examination and 8 patients with gastric cancer

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had resection of which none had disease on pathological examination.

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Lesser omentum

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The lesser omentum was resected in 74 (38.7%) patients and positive in 35 (18.3%) (Table

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4). There were 17.1% in whom involvement was seen in absence of visible disease. Patients

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with involvement of the lesser omentum had a higher median surgical and pathological PCI

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compared to those without involvement (p<0.001 for both). There were more patients in this

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group with a sPCI>20 and pPCI >10 (p<0.001 for both). Only 2 patients (5.4%) with lesser

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omentum involvement had a pPCI<10 whereas 51.4% had a pPCI<20.

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Lesser omentum was involved in 46.6% of the patients with peritoneal mesothelioma, 30.6%

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with appendiceal tumors and 20.4% with ovarian cancer. Only patients with ovarian (9.0%)

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and appendiceal (4.0 %) tumors had involvement in absence of visible disease. None of the

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patients with colorectal and only one patient (5.6%) with gastric cancer had lesser omental

19

involvement. All patients with involvement of the lesser omentum had disease in all three

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regions of the peritoneal cavity.

21

Falciform ligament

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The falciform ligament was resected in 70 (36.6%) patients and was positive for disease in 22

23

(11.5%) (Table 5). In 13.6%, it was seen in absence of visible disease. Patients with

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falciform involvement had a significantly higher median surgical and pathological PCI as

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compared to those that did not (p=<0.001 for sPCI and 0.003 for pPCI). Majority of the

9

1

patients had involvement of the upper, lower and middle regions in these patients and 68.1%

2

of the patients with falciform ligament involvement had a pPCI of more than 10. Falciform

3

involvement was seen in more than 20% of the patients with appendiceal tumors and

4

peritoneal mesothelioma and under 15% in all other tumors (p=0.013).

5

The post-hoc analysis with Bonferroni correction for the above results is provided in

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supplementary material 3-7.

7 8

Discussion

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Our results show that involvement of target regions is different in peritoneal metastases

10

arising from different primary tumors and different surgical strategies should be employed

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for each of these. The clinical implications of these findings are discussed here.

12

Greater Omentum

13

The greater omentum was involved in over 15% of the patients with PM from different

14

primary sites and in 15.7% in absence of visible disease. Hence, it may be inferred that

15

resection of the omentum in all PM from epithelial tumors. Omental involvement in known to

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occur in absence of visible disease in peritoneal mesothelioma, ovarian cancer and PM from

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mucinous appendiceal tumors. [9, 14, 15] Our results concur with the findings of a recent

18

study which showed the presence of microscopic disease in the omentum in absence of gross

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disease in around 15% of the patients with colorectal PM. [16] Thus, the results support

20

performing a greater omentectomy in all patients undergoing CRS for colorectal PM.

21

It was a surgical policy at all institutions to perform a supracolic omentectomy. The patients

22

included in this study all had advanced or recurrent ovarian cancer and none of the surgeons

23

performed an infracolic omentectomy for such patients. However, we cannot derive

24

conclusions on whether to resect the gastroepiploic arch or not in different patients. [17] An

10

1

analysis of the patterns of recurrence would be needed as well as the incidence and pattern of

2

omental lymph node involvement as most of these nodes are along the arc of Barkov.

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Greater omentectomy may be performed for practical reasons, when HIPEC is given (i.e. to

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ensure better perfusate circulation throughout the peritoneal cavity.)

5 6

Umbilical Round ligament

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The URL is a remnant of the fetal umbilical vein that is contained in the inferior border of the

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falciform ligament and divided the liver into the right and left lobes. [18] The falciform

9

ligament itself is a fold of the peritoneum that connects the anterior part of the liver to the

10

anterior abdominal wall. [19]

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These regions communicate with the subperitoneal lymphatics and are presumed to harbour

12

occult disease which if not addressed leads to recurrence. [20] There is only one study that

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describes the round ligament as the sole site of recurrence and this study is for appendiceal

14

tumours. [21] This study largely focuses on dividing the hepatic bridge when it is present to

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completely resect the URL and its surrounding peritoneum. Our results show a high

16

incidence of URL involvement in patients with ovarian cancer and appendiceal tumours and a

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low incidence in gastric cancer and colorectal cancer. In both patients with extensive disease

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and limited disease, involvement of the round ligament was not seen in colorectal cancer

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(Tables 2 and 3). Hence, resection of this structure in absence of visible disease may not be

20

required in these patients. The same can be concluded for gastric cancer. Another study has

21

shown that it could be involved in absence of gross disease, however, this study included

22

patients from different primary sites and does not look at the impact of primary tumour site

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on its involvement. [22] Based on these results, the URL should be resected in all patients

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undergoing CRS for advanced ovarian cancer, peritoneal mesothelioma and PM from

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mucinous appendiceal tumours. For all others, it may be resected when disease is present. For

11

1

colorectal cancer, second look and prophylactic procedures are performed at some centres,

2

largely as part of clinical trials and some of them include resection of such target regions.

3

[23] Our findings do not support performing such resections. It may be argued that resection

4

of such structures causes little morbidity but some areas can be technically challenging like

5

division of the hepatic bridge. Moreover, there is the risk of tumour implantation in

6

uninvolved regions by disruption of normal tissue planes which should be avoided when

7

there is a miniscule possibility of finding disease in those regions. [24]

8

Lesser omentum

9

Lesser omentum involvement was seen in over 20% of the patients with ovarian cancer,

10

peritoneal mesothelioma and mucinous appendiceal neoplasms and was associated with

11

increased extent of peritoneal disease. The lesser omentum may be resected in patients with

12

PM from these primaries especially when there is disease in the upper and middle regions.

13

For other primary sites, it should be resected only when there is visible disease. But, it may

14

also be discussed to resect it systematically to facilitate the perfusion of omental bursa and of

15

the retro-gastric space when cytoreductive surgery is combined with intraperitoneal

16

chemotherapy.

17

Falciform ligament

18

The recommendations for resection of the lesser omentum can be applied to resection of the

19

falciform ligament as well except for ovarian cancer in which falciform ligament was less

20

commonly involved. It may be argued that the URL and falciform ligament should be

21

considered as one entity however, we noticed a difference in the pattern of involvement in

22

some cancers which could be explained by a differential concentration of lymphatics in some

23

areas of the falciform and the peritoneal fold containing the round ligament.

24

This study is limited by the small numbers and ideally a sample size should have been

25

calculated for the study to have adequate power to predict the probability of involvement of

12

1

each structure in different risk groups. But there is no scientific literature reporting the overall

2

incidence of each target region involvement and incidence according to the disease extent of

3

any of these regions. And because of this, current surgical practices vary from one surgeon or

4

institution to another. The main strength of this study is that it was prospective with a fixed

5

protocol for pathological evaluation. We have provided a set of recommendations in Table 6

6

based on our findings that can be adopted till more evidence is available. Though these

7

findings should be further confirmed in larger series, there are some negative findings which

8

cannot be ignored and may be considered sufficient to derive practice changing conclusions.

9

For e.g. a very low incidence (<5%) of involvement of the target regions (except the greater

10

omentum) in colorectal and gastric cancer indicating that resection of these regions is not

11

required in absence of visible disease. Secondly, greater omental involvement occurred in

12

more than 15% of the patients irrespective of the primary tumour type. Nearly two thirds of

13

the patients had a PCI <20 which is the case with most of the patients undergoing CRS.

14

Hence we recommend extrapolating these findings to all patients and perform resection of the

15

greater omentum even in the absence of visible disease, irrespective of the PCI.

16

It is also important as intraoperative decisions are based on visual inspection that is

17

inaccurate in predicting the presence of absence of disease. [25] There are three ways of

18

determining whether to resect a structure or not- presence of visible disease, high probability

19

of involvement in absence of visible disease and thirdly, impact on survival. We have

20

considered the first two methods in this manuscript to base our recommendations on. It is not

21

possible to determine the impact of resection of a particular peritoneal region on survival

22

since multiple variables are involved in these patients. We also recommend that the impact

23

of neoadjuvant chemotherapy should be studied in future studies.

24

This study can be considered a pilot study to carry out further research in this direction and to

25

the best of our knowledge, this issue has not been address prospectively and in this manner

13

1

before.

2

Conclusions

3

Target region involvement varies according to the primary tumour site and disease extent.

4

Resection of the greater omentum should be performed during CRS for PM arising from all

5

primary sites. Resection of other target organs like umbilical round ligament, falciform

6

ligament and lesser omentum may be performed for selected patients with ovarian cancer,

7

peritoneal mesothelioma and mucinous appendiceal tumours in absence of visible disease.

8

For other patients, it should be done only in presence of visible disease.

9 10 11 12

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2. Yonemura Y. Canbay E, Liu Y, et al. Trans-lymphatic metastasis in peritoneal

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Tables Table 1 Clinical and pathological findings in patients with or without resection of the greater omentum Characteristic

Primary tumor site

All patients N=191(%) Appendix Colorectal Ovary Mesothelioma Stomach Rare primary

Surgical PCI (sPCI)

0-9 10-19 20-29 30-39 Pathological PCI (pPCI) 0-9 10-19 20-29 30-39 Median surgical PCI (sPCI) [range]

49 (25.6) 47 (24.6) 44 (23.0) 15 (7.8) 18 (9.4) 18 (9.4)

Greater omentum not resected N=36 (%) 10 (27.7) 11 (30.5) 6 (16.6) 2 (5.5) 3 (8.3) 4 (11.1)

Greater omentum resected Positive for Negative for disease disease N=89 (%) N=66 (%) 29 (32.5) 10 (15.1) 9 (10.1) 27 (40.9) 28 (31.4)) 10 (15.1) 12 (13.4) 1 (1.5) 5 (5.6) 10 (15.1) 6 (6.7) 8 (12.1)

p-value

0.001

88 (46.0) 44 (23.0) 41 (21.4) 18 (9.4) 115 (60.2) 46 (24.0) 28 (14.6) 2 (1.0) 11 [0-39]

29 (80.5) 10 (27.7) 4 (11.1) 3 (8.3) 24 (66.6) 6 (16.6) 5 (13.8) 1 (2.7) 9 [0-39]

20 (22.4) 22 (24.7) 33 (37.0) 14 (15.7) 31 (34.8) 34 (38.2) 23 (25.8) 1 (1.1) 21[0-39]

47 (71.2) 12 (18.1) 4 (6.0) 1 (1.5) 60 (90.9) 6 (9.0) 0 (0.0) 0 (0.0) 5 [0-35]

<0.001

6 [0-39]

5 [0-35]

13 [0-39]

2 [0-15]

<0.001

126 (65.9) 45 (23.5) 20 (10.4) 95 (49.7)

25 (69.4) 6 (16.6) 5 (13.8) 15 (41.6)

45 (50.5) 32 (35.9) 12 (13.4) 66 (74.1)

56 (84.8) 7 (10.6) 3 (4.5) 14 (21.1)

<0.001

Upper region disease

CC-0 CC-1 CC-2/3 Present

Lower region disease

Present

129 (47.5)

25 (69.4)

76 (85.3)

28 (42.2)

<0.001

Middle region disease

Present

119 (62.3)

12(33.3)

89 (100.0)

18 (25.7)

<0.001

Disease in the URL

36 (18.8)

2 (5.5%)

32 (35.9)

2 (3.0)

<0.001

Disease in the falciform ligament

22 (11.5)

1 (2.7)

19 (21.3)

2 (3.0)

<0.001

Disease in the lesser omentum

35 (18.3)

1 (2.7)

33 (37.0)

1 (1.5)

<0.001

Median pathological PCI (pPCI) [range] CC-score

<0.001

<0.001

<0.001

Abbreviations: PCI- peritoneal cancer index; CC-score- completeness of cytoreduction score; URL- Umbilical round ligament

Table 2 Disease distribution and target region involvement according to primary tumor site All patients N=191 (%)

Median sPCI [Range] Median pPCI [Range] CC-score CC-0 CC-1 CC-2/3

Ovarian cancer N=44 19 (43.1) 15 (34.0) 10 (22.7) 0 (0.0) 27 (61.3) 14 (31.8) 3 (6.8) 0 (0.0) 10 [0-31] 6 [0-26] 32 (72.7) 10 (22.7) 2 (4.5)

Appendiceal cancer N=49 12 (24.4) 10 (20.4) 16 (32.6) 11 (22.4) 20 (40.8) 12 (24.4) 16 (32.6) 1 (2.0) 21.5 [0-39] 13.5 [0-39] 24 (48.9) 16 (32.6) 9 (18.3)

Mesothelioma N=15

88 (46.0) 44 (23.0) 41 (21.4) 18 (9.4) 115 (60.2) 46 (24.0) 28 (14.6) 2 (1.0) 11 [0-39] 6 [0-39] 126 (65.9) 45 (23.5) 20 (10.4)

Colorectal cancer N=47 32 (68.0) 8 (17.0) 5 (10.6) 2 (4.2) 37 (78.7) 6 (12.7) 4 (8.5) 0 (0.0) 6 [0-35] 2 [0-23] 41 (87.2) 3 (6.3) 3 (6.3)

Greater omentum resection

Performed Not performed Present Absent Performed Not performed Present Absent Performed Not performed Present Absent

155 (81.1) 36 (28.9)

36 (76.5) 11 (23.5)

38 (86.3) 6 (13.7)

89 (46.5) 66 (34.5) 88 (46.0) 103 (53.9)

9 (19.1)) 27 (57.4) 23 (48.9) 24 (51.1)

36 (18.8) 52 (27.2) 74 (38.7) 117 (61.2)

Surgical PCI (sPCI)

Pathological PCI

(pPCI)

Disease in greater omentum URL resection

Disease in URL Lesser omentum resection Disease in lesser omentum Falciform resected

Disease in falciform

Upper region disease Lower region disease Middle region disease

1 (6.6) 4 (26.6) 7 (46.6) 3 (20.0) 2 (13.3) 9 (60.0) 3 (20.0) 1 (6.6) 26 [0-39] 16.5 [4-35] 4 (26.6) 7 (46.6) 4 (26.6)

Gastric cancer N=18 13 (72.2) 3 (16.6) 2 (11.1) 0 (0.0) 15 (83.3) 3 (16.7) 0 (0.0) 0 (0.0) 3.5 [0-26] 2 [0-15] 15 (83.3) 1 (5.6) 2 (11.1)

Rare primaries N=18 11 (61.1) 4 (22.2) 1 (5.6) 2 (11.1) 14 (77.7) 2 (11.1) 2 (11.1) 0 (0.0) 11 0-33] 8 [0-26] 10 (55.5) 7 (38.8) 1 (5.6)

39 (79.5) 10 (20.5)

13 (86.6) 2 (13.3)

15 (83.3) 3 (16.7)

14 (77.8) 4 (22.2)

0.929

28 (63.6) 10 (22.7) 24 (54.5) 20 (45.5)

29 (59.1) 10 (20.5) 22 (44.8) 27 (55.1)

12 (80.0) 1 (6.6) 7 (46.6) 8 (53.4)

5 (27.7) 10 (55.5) 8 (44.4) 10 (55.5)

6 (33.3) 8 (44.4) 4 (22.2) 14(77.7)

<0.001

1 (2.1) 22 (46.8) 13 (27.6) 34 (72.4)

16 (36.3) 8 (18.1) 20 (45.5) 24 (54.5)

12 (24.4) 10 (20.5) 21 (42.8) 28 (57.1)

6 (40.9) 1 (6.6) 9 (60.0) 6 (40.0)

0 (0.0) 8 (44.4) 2 (11.1) 16 (88.9)

1 (5.6) 3 (16.7) 9 (50.0) 9 (50.0)

<0.001

35 (18.3) 39 (20.4)

0(0.0) 12 (25.5)

15 (30.6) 7 (14.2)

7 (46.6) 2 (13.3)

1 (5.6) 1 (5.6)

3 (16.7) 6 (33.3)

0.010

Performed Not performed Present Absent

70 (36.6) 121 (63.3)

10 (21.2) 37 (78.7)

9 (20.4) 11 (25..0) 24 (54.5) 20 (45.5)

18 (36.7) 31 (63.3)

7 (46.6) 8 (53.4)

4 (22.2) 14 (77.8)

7 (38.8) 11 (61.2)

0.022

22 (11.5) 48 (25.1)

2 (4.2) 45 (95.8)

2 (4.5) 42 (95.5)

11 (22.4) 38 (77.6)

4 (26.6) 11 (73.4)

1 (5.6) 17 (94.4)

2 (11.1) 16 (88.9)

0.013

Present Present Present

95 (49.7) 129 (47.5) 119 (62.3)

13 (27.6) 23 (48.9) 21 (44.6)

28 (63.6) 32 (72.7) 29 (55.7)

32 (65.3) 38 (77.5) 38 (77.5)

10 (66.6) 14 (93.3) 12 (80.0)

3 (16.7) 7 (38.8) 8 (44.4)

9 (50.0) 15 (83.3) 11 (61.1)

<0.001 <0.001 0.004

0-9 10-19 20-29 30-39 0-9 10-19 20-29 30-39

Abbreviations: PCI- peritoneal cancer index; CC-score- completeness of cytoreduction score; URL- Umbilical round ligament

pvalue <0.001

<0.001

<0.001 <0.001 <0.001

0.970

0.037

Table 3 Clinical and pathological findings in patients with and without resection of the umbilical round ligament

Characteristic

Primary tumor site

All patients n=191(%) 49 (25.6) 47 (24.6) 44 (23.0) 15 (7.8) 18 (9.4) 18 (9.4)

URL resected Positive Negative for for disease disease N=36 N=52

p-value

Omental disease

CC-0 CC-1 CC-2/3 Present

12 (33.3) 1 (2.7) 16 (44.4) 6 (16.6) 0 (0.0) 1 (2.7) 8 (22.2) 10 (27.7) 16 (48.4) 2 (5.5) 8 (22.2) 14 (38.8) 13 (36.1) 1 (2.7) 21 [0-39] 17 [2-26] 17 (47.2) 19 (52.7) 0 (0.0) 32 (88.8)

10 (19.2) 22 (42.3) 9 (17.3) 1 (1.9) 7 (13.4) 3 (5.7) 30 (57.6) 13 (25.0) 9 (17.3) 0 (0.0) 37 (71.1) 9 (17.3) 6 (11.5) 0 (0.0) 8 [0-28] 4 [0-35] 47 (90.3) 5 (9.6) 0 (0.0) 17 (32.6)

<0.001

88 (46.0) 44 (23.0) 41 (21.4) 18 (9.4) 115 (60.2) 46 (24.0) 28 (14.6) 2 (1.0) 11 [0-39] 6 [0-39] 126 (65.9) 45 (23.5) 20 (10.4) 89 (46.5)

27 (26.2) 24 (23.3) 19 (18.4) 8 (7.7) 11 (10.6) 14 (13.5) 50 (48.5) 21 (20.3) 16 (15.5) 16 (15.5) 70 (67.9) 23 (22.3) 8 (7.7) 1 (0.9) 10 [0-39] 4.5 [0-39] 62 (60.1) 21 (20.3) 20 (19.4) 40 (38.8)

Upper region disease

Present

95 (49.7)

41 (39.8)

36 (100.0)

18 (34.6)

<0.001

Lower region disease

Present

129 (47.5)

67 (65.0)

36 (100.0)

26 (50.0)

<0.001

Middle region disease

Present

119 (62.3)

59 (57.2)

34 (94.4)

26 (50.0)

<0.001

Surgical PCI (sPCI)

Pathological PCI (pPCI)

Appendix Colorectal Ovary Mesothelioma Stomach Rare primary 0-9 10-19 20-29 30-39 0-9 10-19 20-29 30-39

URL not resected N=103

Median sPCI [Range] Median pPCI [Range]

CC-score

<0.001

<0.001

0.001 <0.001 <0.001

<0.001

Abbreviations: PCI- peritoneal cancer index; CC-score- completeness of cytoreduction score; URL- Umbilical round ligament

Table 4 Clinical and pathological findings in patients with and without resection of the lesser omentum Characteristic

All patients n=191(%)

Primary tumor site

49 (25.6) 47 (24.6) 44 (23.0) 15 (7.8) 18 (9.4) 18 (9.4) 88 (46.0) 44 (23.0) 41 (21.4) 18 (9.4) 115 (60.2) 46 (24.0) 28 (14.6) 2 (1.0) 11 [0-39]

Lesser omentum not resected N=117 28 (23.9) 34 (29.0) 24 (20.5) 6 (5.1) 16 (13.6) 9 (7.6) 68 (56.4) 26 (22.2) 14 (12.8) 10 (8.5) 85 (72.6) 18 (15.3) 13 (11.1) 1 (0.8) 8 [0-39]

6 [0-39]

4 [0-39]

19 [6-35]

4.5 [0-14]

<0.001

CC-0 CC-1 CC-2/3 Present

126 (65.9) 45 (23.5) 20 (10.4) 89 (46.5)

89 (76.0) 18 (15.3) 10 (8.5) 36 (30.7)

12 (34.2) 19 (54.2) 4 (11.4) 33 (94.2)

25 (64.1) 8 (20.5) 6 (15.3) 20 (51.2)

<0.001

<0.001

Present

95 (49.7)

47 (40.1)

35 (100.0)

15 (38.4)

<0.001

Present

129 (47.5)

70 (59.8)

35 (100.0)

26 (66.6)

<0.001

Present

119 (62.3)

60 (51.2)

35 (100.0)

26 (66.6)

<0.001

Appendix Colorectal Ovary Mesothelioma Stomach Rare primary Surgical PCI 0-9 (sPCI) 10-19 20-29 30-39 Pathological PCI 0-9 (pPCI) 10-19 20-29 30-39 Median sPCI [Range] Median pPCI [Range] CC-score

Omental disease Upper region disease Lower region disease Middle region disease

Lesser omentum resected Positive for Negative disease for disease N=35 N=39 15 (42.8) 6 (15.3) 0 (0.0) 13 (33.3) 9 (25.7) 11(28.2) 7 (20.0) 2 (5.1) 1 (2.8) 1 (2.5) 3 (8.5) 6 (15.3) 2 (5.7) 18 (48.7) 10 (28.5) 8 (20.5) 18 (51.4) 9 (23.0) 5 (14.2) 3 (7.6) 2 (5.7) 28 (71.7) 18 (51.4) 10 (25.6) 14 (40.0) 1 (2.5) 1 (2.8) 0 (0.0) 23 [0-39] 11.5 [0-35]

p-value

0.001

<0.001

<0.001

<0.001

Abbreviations: PCI- peritoneal cancer index; CC-score- completeness of cytoreduction score;

Table 5 Clinical and pathological findings in patients with and without resection of the falciform ligament

Characteristic

Primary tumor site

Surgical PCI (sPCI)

Appendix Colorectal Ovary Mesothelioma Stomach Rare primary 0-9 10-19 20-29 30-39 0-9 10-19 20-29 30-39

All patients n=191(%)

Falciform not resected N=121 (%)

49 (25.6) 47 (24.6) 44 (23.0) 15 (7.8) 18 (9.4) 18 (9.4)

31(25.6) 37 (30.5) 20 (16.5) 8 (6.6) 14 (11.5) 11(9.0) 67 (55.3) 27 (22.3) 21(17.3) 6 (4.95) 75 (61.9) 25(20.6) 19(15.7) 2 (1.6) 9 [0-39]

Falciform resected Positive for Negative disease for disease N=22 N=48 11(50.0) 7 (14.5) 2 (9.0) 8 (16.6) 2 (9.0) 22 (45.8) 4 (18.1) 3 (6.2) 1 (4.5) 3 (6.2) 2 (9.0) 5 (10.4) 1(4.5) 20 (41.6) 4 (18.1) 13(27.0) 8 (36.3) 12 (25.0) 9 (40.9) 3 (6.2) 7 (31.2) 33(68.7) 9 (40.9) 12(25.0) 6 (27.2) 3 (6.2) 0 (0.0) 0 (0.0) 28 [8-39] 11.5[0-39]

p-value

<0.001

Median sPCI

[Range]

88 (46.0) 44 (23.0) 41 (21.4) 18 (9.4) 115 (60.2) 46 (24.0) 28 (14.6) 2 (1.0) 11 [0-39]

Median pPCI

[Range]

6 [0-39]

5.5 [0-39]

15 [2-29]

6 [0-27]

0.003

CC-0 CC-1 CC-2/3 Present

126 (65.9) 45 (23.5) 20 (10.4) 89 (46.5)

94(77.6) 21(17.3) 6 (4.9) 44 (36.3)

4 (18.1) 9 (40.9) 9 (40.9) 19 (86.3)

28 (58.3) 14(29.1) 6 (12.5) 26 (54.1)

<0.001

<0.001

Present Present Present

95 (49.7) 129 (47.5) 119 (62.3)

54(44.6) 74(61.1) 69(57.0)

19 (86.3) 20 (90.9) 21(95.4)

22(45.8) 35(72.9) 29(60.4)

0.001 0.041 0.002

Pathological PCI (pPCI)

CC-score

Greater omentum disease Upper region disease Lower region disease Middle region disease

<0.001

0.063

<0.001

Abbreviations: PCI- peritoneal cancer index; CC-score- completeness of cytoreduction score; URL- Umbilical round ligament

Table 6 Recommendations for target region resection in different clinical situations in absence of visible disease* Primary site

Clinical situations

Greater omentum

Colorectal cancer (nonmucinous)

No visible disease Disease in upper region Disease in lower region alone

No visible disease Disease in upper region Disease in lower region alone Appendiceal No visible disease adenocarcinoma (nonDisease in upper region mucinous)* Disease in lower region alone Gastric cancer No visible disease Disease in upper region Disease in lower region alone Epithelial ovarian No visible disease cancer (non-mucinous) Disease in upper region Disease in lower region alone Epithelial ovarian No visible disease cancer (mucinous) Disease in upper region Disease in lower region alone Peritoneal mesothelioma No visible disease Disease in upper region Disease in lower region alone

Appendiceal mucinous tumors

*Are treated like colorectal adenocarcinomas

Yes Yes Yes

Lesser Umbilical omentum round ligament No No No No No No

No No No

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes Yes Uncertain No No No No Uncertain No Yes Yes Uncertain Yes Yes Uncertain Yes Yes Yes

Yes Yes Yes No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes Yes Yes No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes

Falciform ligament